Copper nanoparticles and immunotherapy rapidly eliminate cancer cells – Pilot Study

Copper nanoparticles and immunotherapy rapidly eliminate cancer cells – Pilot Study

The combination of the nanoparticles and immunotherapy made the tumours disappear entirely and, as a result, works as a vaccine for lung and colon cancer – the two types that were investigated in the study. To confirm their finding, the researchers injected tumour cells back into the mice. These cells were immediately eliminated by the immune system, which was on the lookout for any new, similar, cells invading the body.

#copper #cancer #immunotherapy

Hendrik Naatz, Bella B. Manshian, Carla Rios Luci, Vasiliki Tsikourkitoudi, Yiannis Deligiannakis, Johannes Birkenstock, Suman Pokhrel, Lutz Mädler, Stefaan J. Soenen. Model-Based Nanoengineered Pharmacokinetics of Iron-Doped Copper Oxide for Nanomedical Applications. Angewandte Chemie International Edition, 2020; DOI: 10.1002/anie.201912312

https://onlinelibrary.wiley.com/doi/full/10.1002/anie.201912312

100% Cure Rate Pancreatic Cancer Experimental Study Animal Model

100% Cure Rate Pancreatic Cancer Experimental Study Animal Model

100% Cure Rate Pancreatic Cancer Experimental Study Animal Model

A research team reports that combining a type of radiation therapy with immunotherapy not only cures pancreatic cancer in mice, but appears to reprogram the immune system to create an ‘immune memory’ in the same way that a vaccine keeps the flu away. The result is that the combination treatment also destroyed pancreatic cells that had spread to the liver, a common site for metastatic disease.

#il-12 #sbrt #pancraticcancercure

Bradley N. Mills, Kelli A. Connolly, Jian Ye, Joseph D. Murphy, Taylor P. Uccello, Booyeon J. Han, Tony Zhao, Michael G. Drage, Aditi Murthy, Haoming Qiu, Ankit Patel, Nathania M. Figueroa, Carl J. Johnston, Peter A. Prieto, Nejat K. Egilmez, Brian A. Belt, Edith M. Lord, David C. Linehan, Scott A. Gerber. Stereotactic Body Radiation and Interleukin-12 Combination Therapy Eradicates Pancreatic Tumors by Repolarizing the Immune Microenvironment. Cell Reports, 2019; 29 (2): 406 DOI: 10.1016/j.celrep.2019.08.095

https://www.cell.com/cell-reports/fulltext/S2211-1247(19)31157-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS221112471931157X%3Fshowall%3Dtrue

Pancreatic cancer, il-12, sbrt, stereotactic body radiotherapy, pancreas, cancer, aggressive, advanced, study, CD8, treatment, immune system, vaccine, cancer vaccine, liver cancer, metastatic

Influenza A vaccination associated with 6.3 times more aerosol shedding than non vaccinated

Editors Note (Ralph Turchiano: I encourage you to review the full study as I shall link it below. I am only highlighting the two outcomes that require urgent further investigation due to the rapid mutagenicity of H3N2 .

Study Quote # 1  “In adjusted models, we observed 6.3 (95% CI 1.9–21.5) times more aerosol shedding among cases with vaccination in the current and previous season compared with having no vaccination in those two seasons.”

Study Quote #2 “ The association of current and prior year vaccination with increased shedding of influenza A might lead one to speculate that certain types of prior immunity promote lung inflammation, airway closure, and aerosol generation. This first observation of the phenomenon needs confirmation. If confirmed, this observation, together with recent literature suggesting reduced protection with annual vaccination, would have implications for influenza vaccination recommendations and policies.

 

Full Text Link: http://www.pnas.org/content/early/2018/01/17/1716561115.full

mmm

VACC1

vac2

Dramatic FLU virus mutations may be due to antiquated vaccine manufacturing

Dramatic FLU virus mutations may be due to antiquated vaccine manufacturing

Dramatic FLU virus mutations may be due to antiquated vaccine manufacturing

Researchers discovered that by manufacturing the vaccine through the use of chicken eggs it had the unintentional consequence of causing dramatic mutations in the H3N2 Virus. These mutations the researchers speculate resulted in a equally dramatic decline in vaccine effectiveness

Prediction of influenza vaccine effectiveness for the influenza season 2017/18 in the US [version 1; referees: 1 approved]. F1000Research 2017, 6:2067 (doi: 10.12688/f1000research.13198.1)

A structural explanation for the low effectiveness of the seasonal influenza H3N2 vaccine  (doi: /10.1371/journal.ppat.1006682)

Can Vaccines change how you feel?

Can Vaccines change how you feel?

A quick review of three separate clinical studies, that used vaccines to induce behavior changes in healthy subjects. The original intent was to use vaccines to mimic disease like conditions in individuals. Since the hypothesis was that disease itself would alter the mood of healthy individuals. Regardless of the intent, the vaccines themselves were shown to alter behavior. Often the studies ended prior to the effected subjects behavior ever returning back to normal.

These studies reflect more on cytokine induced behavior changes, and do not look at microbiome or other biological alterations.

This segment is just to answer whether vaccine can alter mood, and not an argument for or against vaccines.

The BIG Question

If certain vaccines can cause behavior disorders in susceptible populations. Should Depression, Anxiety, PTSD, or other similar medical conditions be listed as a medical exemption for certain vaccinations?

Cited Material:
Illness, cytokines, and depression *Psychoneuroendocrinology. 1998 May;23(4):337-51.
Cytokines, “depression due to a general medical condition,” and antidepressant drugs. Adv Exp Med Biol. 1999;461:283-316.
Change in human social behavior in response to a common vaccine. Ann Epidemiol. 2010 Oct;20(10):729-33. doi: 10.1016/j.annepidem.2010.06.014
Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity Biol Psychiatry. 2009 Sep 1;66(5):407-14. doi: 10.1016/j.biopsych.2009.03.015. Epub 2009 May 7.

Case against Merck allegedly providing false data on vaccine efficacy allowed to advance

Antitrust, FCA Claims On Merck Mumps Vaccine To Advance
By Dan Packel

Law360, Philadelphia (September 05, 2014, 6:12 PM ET) — Two lawsuits accusing Merck & Co. Inc. of lying about the efficacy of its mumps inoculation in order to keep competitors from bringing their own versions of the vaccine to market will move forward, after a Pennsylvania federal judge ruled in favor of whistleblowers and direct purchasers Thursday.
U.S. District Judge C. Darnell Jones II ruled that the whistleblowers had sufficiently pled that Merck might have provided false statements to the government and that the direct purchasers had shown enough evidence to establish that these falsehoods could have helped the company gain a monopoly. The judge did ax breach of contract and unjust enrichment claims against the pharmaceutical giant.

“We are pleased that the court has upheld our federal antitrust claim in this important case. While Merck has enjoyed an exclusive monopoly on the sale of mumps vaccine in the United States, mumps outbreaks continue to occur because, as we allege in our lawsuit, Merck has misled the public about the vaccine’s efficacy,” Kellie Lerner of Robins Kaplan Miller & Ciresi LLP, representing the direct purchasers, said in a statement. “This decision brings us one step closer to shining a light on Merck’s deceptive business practices so that new and more effective vaccines will ultimately be developed in the future.”

Since 1967, Merck has been the sole pharmaceutical company in the U.S. licensed to produce mumps vaccine, and the company has long represented that the vaccine is 95 percent effective in preventing the disease.
The whistleblowers, two individuals who worked as virologists in a Merck lab performing efficacy tests, claimed that after the company’s tests showed the vaccines slipping below the 95 percent threshold, it changed its methodology and falsified results but kept reporting to the Food and Drug Administration that the drug was 95 percent effective.

They claimed in their lawsuit, unsealed in June 2012, that Merck violated the False Claims Act by billing the Centers for Disease Control and Prevention for the vaccine while they were aware of its diminished efficacy and by falsifying and manipulating data that should have been shared with the government. They claimed that, as a result, the government had spent hundreds of millions of dollars on ineffective medicine. Continue reading “Case against Merck allegedly providing false data on vaccine efficacy allowed to advance”

Aluminum in Vaccines, a Bad Mix


Aluminum in Vaccines, a Bad Mix

– A study of whooping cough vaccinations in Gothenburg a few years ago showed that almost one per cent of the children developed pruritic nodules in the area of the vaccination. Three out of four of the children who had a reaction with nodules also developed an allergy to aluminium.
“This was completely unexpected. Aluminium has been used as an adjuvant, intensifier, in vaccines for over 70 years with only a small number of reports of pruritic nodules and allergic contact dermatitis

Lund University. “Allergy treatments containing aluminum may cause new allergy, study suggests.” ScienceDaily, 15 December 2010.

Primary Citations:

Eur J Pediatr. 2014 Oct;173(10):1297-307. doi: 10.1007/s00431-014-2318-2. Epub 2014 Apr 22.
How common are long-lasting, intensely itching vaccination granulomas and contact allergy to aluminium induced by currently used pediatric vaccines? A prospective cohort study.

Vaccine. 2003 Dec 8;22(1):64-9.
Unexpectedly high incidence of persistent itching nodules and delayed hypersensitivity to aluminium in children after the use of adsorbed vaccines from a single manufacturer.

JAMA Pediatr. 2013 Sep;167(9):870-2. doi: 10.1001/jamapediatrics.2013.108.
Effect of routine vaccination on aluminum and essential element levels in preterm infants. Continue reading “Aluminum in Vaccines, a Bad Mix”

74 percent of parents would remove their kids from daycare if others are unvaccinated

41 percent of parents say under-vaccinated kids should be excluded from daycare, according to U-M’s National Poll on Children’s Health

ANN ARBOR, Mich. – Most parents agree that all children in daycare centers should be vaccinated, and that daycare providers should be checking vaccine records every year, according to the University of Michigan C.S. Mott Children’s Hospital National Poll on Children’s Health.

All states require vaccines for children who attend daycare, but those requirements may not include every vaccine from birth to age 5 years. As a result, some children still don’t receive all recommended vaccines–leaving daycare providers and parents to decide how to handle the situation of a child who is not up-to-date on vaccines.

In this national sample of parents of child 0-5 years, most indicate that daycare providers should review children’s immunization status every year to ensure they are up-to-date (52 percent strongly agree, 22 percent agree).

“Results of this poll indicate that most parents want strong policies around making sure children in daycare are up-to-date on vaccines,” says Sarah J. Clark, M.P.H. , associate director of the National Poll on Children’s Health and associate research scientist in the University of Michigan Department of Pediatrics. “Checking vaccination records every year is beyond the scope of many state requirements, and may represent a significant change in practice at many daycares.”

The poll gave parents a scenario where 1 in 4 children in their daycare center were not up-to-date on vaccines. In response to this scenario, 74 percent of parents would consider removing their own child from the daycare.

“This scenario mirrors the national statistics that show approximately 25 percent of preschool children in the United States are not fully vaccinated,” says Clark. “Parents may not realize that so many children are not up-to-date; in some daycares, this scenario is a reality.” Continue reading “74 percent of parents would remove their kids from daycare if others are unvaccinated”

Vaccines in the short-term may accelerate the transition from subclinical MS to overt autoimmunity in patients with existing disease

Vaccines and the Risk of Multiple Sclerosis and Other Central Nervous System Demyelinating Diseases

JAMA Neurol. Published online October 20, 2014. doi:10.1001/jamaneurol.2014.2633

Importance  Because vaccinations are common, even a small increased risk of multiple sclerosis (MS) or other acquired central nervous system demyelinating syndromes (CNS ADS) could have a significant effect on public health.

Objective  To determine whether vaccines, particularly those for hepatitis B (HepB) and human papillomavirus (HPV), increase the risk of MS or other CNS ADS.

Design, Setting, and Participants  A nested case-control study was conducted using data obtained from the complete electronic health records of Kaiser Permanente Southern California (KPSC) members. Cases were identified through the KPSC CNS ADS cohort between 2008 and 2011, which included extensive review of medical records by an MS specialist. Five controls per case were matched on age, sex, and zip code.

Exposures  Vaccination of any type (particularly HepB and HPV) identified through the electronic vaccination records system.

Main Outcomes and Measures  All forms of CNS ADS were analyzed using conditional logistic regression adjusted for race/ethnicity, health care utilization, comorbid diseases, and infectious illnesses before symptom onset.

Results  We identified 780 incident cases of CNS ADS and 3885 controls; 92 cases and 459 controls were females aged 9 to 26 years, which is the indicated age range for HPV vaccination. There were no associations between HepB vaccination (odds ratio [OR], 1.12; 95% CI, 0.72-1.73), HPV vaccination (OR, 1.05; 95% CI, 0.62-1.78), or any vaccination (OR, 1.03; 95% CI, 0.86-1.22) and the risk of CNS ADS up to 3 years later. Vaccination of any type was associated with an increased risk of CNS ADS onset within the first 30 days after vaccination only in younger (<50 years) individuals (OR, 2.32; 95% CI, 1.18-4.57).

Conclusions and Relevance  We found no longer-term association of vaccines with MS or any other CNS ADS, which argues against a causal association. The short-term increase in risk suggests that vaccines may accelerate the transition from subclinical to overt autoimmunity in patients with existing disease. Our findings support clinical anecdotes of CNS ADS symptom onset shortly after vaccination but do not suggest a need for a change in vaccine policy.

Continue reading “Vaccines in the short-term may accelerate the transition from subclinical MS to overt autoimmunity in patients with existing disease”

Dozens of children die in Syria after tainted vaccines

Despite rumors of sabotage, health experts believe that it was a bad batch of vaccines.
By Aileen Graef | Sept. 17, 2014 at 9:48 AM

ALEPPO, Syria, Sept. 17 (UPI) — At least 36 children are dead after receiving tainted measles vaccines at U.N. clinics Monday night in the rebel-held region of Syria.The children were injected with the vaccines before quickly falling ill and dying in what was described as an “excruciating” manner. The program has been shut down since rumors of sabotage spread throughout the country to prevent the worsening of the civil war’s death toll from the outbreak of measles.

“It’s very bad. The figures of dead we are getting go into the 30s. Children are dying very quickly,” Daher Zidan, the coordinator of the medical charity Uossm, told The Telegraph. “We think it will get worse.”

Health experts say it was likely a contaminated batch of vaccines and a major setback to an effort praised by the World Health Organization (WHO) to vaccinate 1.6 million children.

Local governments are investigating the incident to find out how the two batches were tainted.

Continue reading “Dozens of children die in Syria after tainted vaccines”

Dosing schedule of pneumococcal vaccine linked with increased risk of getting multiresistant strain

Public release date: 7-Sep-2010 – EEV: Requested Re-Post from the HRR site.

Infants who received heptavalent pneumococcal conjugate vaccination (PCV-7) at 2, 4, and 11 months were more likely than unvaccinated controls to have nasopharyngeal acquisition of pneumococcal serotype 19A

– the increase in serotype 19A disease was associated in time with the widespread implementation of PCV-7 in routine infant immunization programs

– A rapid increase in the presence of pneumococcal serotype 19A strains that are often multiresistant to antibiotics has been observed over the last decade

– serotype 19A is now the leading causative pneumococcal serotype of invasive and respiratory pneumococcal disease

Question mark in Esbjerg
Question mark in Esbjerg (Photo credit: alexanderdrachmann)

Infants who received heptavalent pneumococcal conjugate vaccination (PCV-7) at 2, 4, and 11 months were more likely than unvaccinated controls to have nasopharyngeal (in the nasal passages and upper part of the throat behind the nose) acquisition of pneumococcal serotype 19A, a leading cause of respiratory pneumococcal disease, according to a study in the September 8 issue of JAMA. Continue reading “Dosing schedule of pneumococcal vaccine linked with increased risk of getting multiresistant strain”

Vaccination campaign doubles HBV mutations

Contact: Garth Hogan ghogan@asmusa.org 202-942-9389 American Society for Microbiology

WASHINGTON, DC – October 7, 2013 – A universal infant vaccination campaign in China has led the Hepatitis B virus (HBV) to more than double its rate of “breakout” mutations. These mutations may enable the virus to elude the vaccine, necessitating new vaccination strategies. Researchers at the Chinese Centers for Disease Control and Prevention and University of North Carolina, Chapel Hill, report their findings in an article published ahead of print in the Journal of Virology.

Until a universal vaccination program for infants was implemented in 1992, nearly ten percent of Chinese—children included—were infected with HBV. The vaccination campaign has protected an estimated 80 million children, dramatically reducing the percentage of children under 5 who are infected, from nearly 10 percent in 1992 to less than one percent in 2005. But these gains are in danger of being eroded as the virus develops surface mutations.

Taking advantage of 1992 and 2005 survey, investigators found that the prevalence of HBV escape mutants in children rose from 6.5 percent in 1992, before the start of the universal vaccination program, to nearly 15 percent in 2005. Among the control group of adults unaffected by the universal vaccination campaign, the rate of break-out mutants was virtually unchanged.

Hepatitis B is an infectious illness of the liver which can cause vomiting, inflammation, jaundice, and, rarely, death. About a third of the world’s population has been infected at some point in their lives. Transmission of hepatitis B virus results from exposure to infectious blood or bodily fluids containing blood. The infection is preventable by vaccination, which has been routinely used since the 1980s.

Researcher Tao Bian of Chapel Hill says that the vaccine remains quite effective, but that because escape mutants are likely to increase, public health officials need to track the rise of escape mutants, in order to know when it becomes time to consider new vaccination strategies. Measures that might be taken include boosting doses, adjusting the timing of vaccinations, or improving the vaccine. A next generation HBV vaccine has been invented, containing a second antigen in addition to the virus’ surface antigen. That means that both antigens would have to develop breakout mutations in order to elude the vaccine.

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A copy of the manuscript can be found online at http://bit.ly/asmtip0913e.  Formal publication is scheduled for the November 2013 issue of the Journal of Virology.

The Journal of Virology is a publication of the American Society for Microbiology (ASM). The ASM is the largest single life science society, composed of over 39,000 scientists and health professionals. ASM’s mission is to advance the microbiological sciences as a vehicle for understanding life processes and to apply and communicate this knowledge for the improvement of health and environmental and economic well-being worldwide.

Expert questions US public health agency advice on influenza vaccines: “All influenza is “flu,” but only one in six “flus” might be influenza”

Contact: Emma Dickinson edickinson@bmj.com 44-020-738-36529 BMJ-British Medical Journal

Marketing influenza vaccines involves marketing influenza as a threat of great proportions, argues Johns Hopkins fellow

Promotion of influenza vaccines is one of the most visible and aggressive public health policies today, writes Doshi. Today around 135 million doses of influenza vaccine annually enter the US market, with vaccinations administered in drug stores, supermarkets – even some drive-throughs.

This enormous growth has not been fuelled by popular demand but instead by a public health campaign that delivers a straightforward message: influenza is a serious disease, we are all at risk of complications from influenza, the flu shot is virtually risk free, and vaccination saves lives.

Yet, Doshi argues that the vaccine might be less beneficial and less safe than has been claimed, and the threat of influenza appears overstated.

To support its case, the CDC cites two studies of influenza vaccines, published in high-impact, peer-reviewed journals and carried out by academic and government researchers with non-commercial funding. Both found a large (up to 48%) relative reduction in the risk of death.

“If true, these statistics indicate that influenza vaccines can save more lives than any other single licensed medicine on the planet,” says Doshi. But he argues that these studies are “simply implausible” and likely the product of the ‘healthy-user effect’ (in this case, a propensity for healthier people to be more likely to get vaccinated than less healthy people).

In addition, he says, there is virtually no evidence that influenza vaccines reduce elderly deaths – the very reason the policy was originally created.

He points out that the agency itself acknowledges the evidence may be undermined by bias. Yet, he says “for most people, and possibly most doctors, officials need only claim that vaccines save lives, and it is assumed there must be solid research behind it.”

He also questions the CDC’s recommendation that beyond those for whom the vaccine is contraindicated, influenza vaccine can only do good, pointing to serious reactions to influenza vaccines in Australia (febrile convulsions in young children) and Sweden and Finland (a spike in cases of narcolepsy among adolescents).

Doshi suggests that influenza is yet one more case of “disease mongering” – medicalising ordinary life to expand markets for new products. But, he warns that unlike most stories of selling sickness, “here the salesmen are public health officials, worried little about which brand of vaccine you get so long as they can convince you to take influenza seriously.”

But perhaps the cleverest aspect of the influenza marketing strategy surrounds the claim that “flu” and “influenza” are the same, he concludes. “All influenza is “flu,” but only one in six “flus” might be influenza. It’s no wonder so many people feel that “flu shots” don’t work: for most flus, they can’t.”

Earlier this year, the BMJ launched a ‘Too Much Medicine’ campaign to help tackle the threat to health and the waste of money caused by unnecessary care. The journal will also partner at an international conference Preventing Overdiagnosis to be held in September in the USA

Large HIV study stopped after safety review found more study participants who received the vaccine later became infected

HIV vaccine study halted by US government over unsuccessful shots

Associated Press in Washington

guardian.co.uk,  Thursday 25 April 2013 17.52 EDT

A pharmaceutical machine loaded with ARV medicine at the Themba Lethu HIV/Aids clinic, Johannesburg

A 2009 study in Thailand is the only HIV/Aids study ever to show a modest success. Photograph: Denis Farrell/AP

The US government halted a large HIV vaccine study on Thursday, saying the experimental shots were not successful in preventing infection.

Nor did the shots reduce the amount of the Aids virus in the blood when people who had been vaccinated later became infected, the National Institutes of Health said.

“It’s disappointing,” said Dr Anthony Fauci, head of NIH’s National Institute of Allergy and Infectious Diseases. But he said there was “important information” gained from the study that will help determine what to try next.

The study had enrolled 2,504 volunteers, mostly gay men, in 19 cities since 2009. Half received dummy shots, and half received a two-part experimental vaccine developed by the NIH. All were provided free condoms and given extensive counseling about the risks of HIV.

It’s a strategy known as “prime-boost”. A DNA-based vaccine made with genetically engineered HIV material is given to prime the immune system to attack the Aids virus. Then a different vaccine, encasing the same material inside a shell made of a disabled cold virus, acts as a booster shot to strengthen that response. Neither vaccine could cause HIV.

The idea was to train immune cells known as T cells to spot and attack the very earliest HIV-infected cells in someone’s body. The hope was that the vaccine could either prevent HIV infection, or help those infected anyway to fight it.

A safety review this week found that slightly more study participants who had received the vaccine later became infected with HIV. It’s not clear why. But the difference wasn’t statistically significant, meaning it may be due to chance. Overall, there were 41 HIV infections in the vaccinated group and 30 among placebo recipients. When researchers examined only participants diagnosed after being in the study for at least 28 weeks – long enough for the shots to have done their job – there were 27 HIV infections among the vaccinated and 21 among the placebo recipients.

The NIH said Thursday that it is stopping vaccinations in the study, known as HVTN 505, but that researchers will continue to study the volunteers’ health.

Josh Robbins, 30, of Nashville, Tennessee, was one of the participants who became infected with HIV. He said he was glad he had taken part because its close monitoring meant he was diagnosed and treated much sooner than most people.

“We’ve got to keep moving forward,” Robbins said. The study “certainly can lead us down a new direction to hopefully find something that might work.”

Multiple attempts at creating an Aids vaccine have failed over the years. A 2009 study in Thailand is the only one ever to show a modest success, using a somewhat different prime-boost approach. Newer research suggests another approach – to try creating powerful antibodies that could work a step earlier than the T-cell attack, before HIV gets inside the first cell.

Both approaches need continued research funding, said Mitchell Warren of the international Aids Vaccine Advocacy Coalition.  “Clearly an Aids vaccine remains critical,” he said.

http://www.guardian.co.uk/society/2013/apr/25/hiv-aids-vaccine-study-us-government

 

Scientists described small genetic changes that enable the H5N1 bird flu virus to replicate more easily in the noses of mammals

 

Bird flu mutation study offers vaccine clue

by  Sam Wong   08 April 2013                   

main image

 

shadow Scientists have described small genetic changes that enable the H5N1 bird flu virus to replicate more easily in the noses of mammals.

So far there have only been isolated cases of bird flu in humans, and no widespread transmission as the H5N1 virus can’t replicate efficiently in the nose. The new study, using weakened viruses in the lab, supports the conclusions of controversial research published in 2012 which demonstrated that just a few genetic mutations could enable bird flu to spread between ferrets, which are used to model flu infection in humans.

Researchers say the new findings could help to develop more effective vaccines against new strains of bird flu that can spread between humans.

“Knowing why bird flu struggles to replicate in the nose and understanding the genetic mutations that would enable it to happen are vital for monitoring viruses circulating in birds and preparing for an outbreak in humans,” said Professor Wendy Barclay, from the Department of Medicine at Imperial College London, who led the study.

“The studies published last year pointed to a mechanism that restricts replication of H5N1 viruses in the nose. We’ve engineered a different mutation with the same effect into one of the virus proteins and achieved a similar outcome. This suggests that there is a common mechanism by which bird flu could evolve to spread between humans, but that a number of different specific mutations might mediate that.”

Bird flu only rarely infects humans because the human nose has different receptors to those of birds and is also more acidic. The Imperial team studied mutations in the gene for haemagglutinin, a protein on the surface of the virus that enables it to get into host cells. They carried out their experiments in a laboratory strain of flu with the same proteins on its surface as bird flu, but engineered so that it cannot cause serious illness.

The more we understand about the kinds of mutations that will enable them to transmit between humans, the better we can prepare for a possible pandemic.– Professor Wendy Barclay

Department of Medicine

The research found that mutations in the H5 haemagglutinin enabled the protein to tolerate higher levels of acidity. Viruses with these mutations and others that enabled them to bind to different receptors were able to replicate more efficiently in ferrets and spread from one animal to another.

The results have important implications for designing vaccines against potential pandemic strains of bird flu. Live attenuated flu vaccines (LAIV) might be used in a pandemic situation because it is possible to manufacture many more doses of this type of vaccine than of the killed virus vaccines used to protect against seasonal flu. LAIV are based on weakened viruses that don’t cause illness, but they still have to replicate in order to elicit a strong immune response. Viruses with modified haemagglutinin proteins induced strong antibody responses in ferrets in this study, suggesting that vaccines with similar modifications might prove more effective than those tested previously.

“We can’t predict how bird flu viruses will evolve in the wild, but the more we understand about the kinds of mutations that will enable them to transmit between humans, the better we can prepare for a possible pandemic,” said Professor Barclay.

The research was funded by the Medical Research Council and the Wellcome Trust and published in the Journal of General Virology.

Reference

H Shelton et al. ‘Mutations in hemagglutinin that affect receptor binding and pH stability increase replication of a PR8 influenza virus with H5 HA in the upper respiratory tract of ferrets and may contribute to transmissibility.’ Journal of General Virology (2013) doi:10.1099/vir.0.050526-0

http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/newssummary/news_8-4-2013-12-47-4

 

Sweden confirms swine flu vaccine and narcolepsy

Saturday, 30 March 2013

The swine flu vaccine Pandemrix has a direct link to causing narcolepsy, especially among the younger people who were vaccinated, a new Swedish study revealed on Tuesday.

The Swedish Medical Products Agency (Läkemedelsverket) ordered the massive study to determine if the vaccine had any connection to narcolepsy after dozens of reported cases of young people coming down with the affliction after receiving a swine flu jab.

The study, which took place between October 2009 and the December 2011, compared 3.3 million vaccinated Swedes with 2.5 million who were not vaccinated.

“We can see that over the whole study period we have 126 cases of those vaccinated getting narcolepsy,” Ingemar Person, professor behind the study, said in a statement on Tuesday.

“There were 20 cases among those not vaccinated. We’re talking about a threefold increase in risk.”

The risk was found to be highest among the youngest people who took the vaccines. For those under the age of 21, the risk of contracting narcolepsy was three times higher for those who were vaccinated with Pandemrix, whereas those aged between 21 and 30 had double the risk.

Those vaccinated over the age of 40 had the same risk as those who didn’t, according to the study.

Person added that it was “very difficult” to determine whether there was any connection with other sicknesses or diseases from taking the vaccine.

http://macedoniaonline.eu/content/view/23020/54/

Increased risk of sleep disorder in children who received swine flu vaccine : Up to 16-fold increased risk

Contact: Emma Dickinson edickinson@bmjgroup.com 44-020-738-36529 BMJ-British Medical Journal

Results consistent with findings from Finland and Sweden, but may still be overestimated

The results are consistent with previous studies from Finland and Sweden and indicate that the association is not confined to Scandinavian populations. However, the authors stress that the risk may still be overestimated, and they call for longer term monitoring of the cohort of children and adolescents exposed to Pandemrix to evaluate the exact level of risk.

In 2009, pandemic influenza A (H1N1) virus spread rapidly, resulting in millions of cases and over 18,000 deaths in over 200 countries. In England the vaccine Pandemrix was introduced in October 2009. By March 2010, around one in four (24%) of healthy children aged under 5 and just over a third (37%) aged 2-15 in a risk group had been vaccinated.

In August 2010 concerns were raised in Finland and Sweden about a possible association between narcolepsy and Pandemrix. And in 2012 a study from Finland reported a 13-fold increased risk in children and young people aged 4-19.

But a lack of reported cases in other countries led to speculation that any possible association might be restricted to these Scandinavian populations.

Narcolepsy is a chronic disorder of excessive daytime sleepiness, often accompanied by sudden muscle weakness triggered by strong emotion (known as cataplexy). To evaluate the risk after vaccination in England, a team of researchers reviewed case notes for 245 children and young people aged 4-18 from sleep centres and child neurology centres across England.

Of these, 75 had narcolepsy (56 with cataplexy) with onset after 1 January 2008. Eleven had been vaccinated before onset of symptoms; seven within six months.

After adjusting for clinical conditions, vaccination at any time was associated with a 14-fold increased risk of narcolepsy, whereas vaccination within six months before onset was associated with a 16-fold increased risk.

In absolute numbers, this means that one in 52,000 to 57,500 doses are associated with narcolepsy, say the authors.

They write: “The increased risk of narcolepsy after vaccination with ASO3 adjuvanted pandemic A/H1N1 2009 vaccine indicates a causal association, consistent with findings from Finland. Because of variable delay in diagnosis, however, the risk might be overestimated by more rapid referral of vaccinated children.”

While further use of this vaccine for prevention of seasonal flu seems unlikely, they say their findings “have implications for the future licensure and use of AS03 adjuvanted pandemic vaccines containing different subtypes such H5 or H9.”

And they conclude: “Further studies to assess the risk, if any, associated with the other A/H1N1 2009 vaccines used in the pandemic, including those with and without adjuvants, are also needed to inform the use of such vaccines in the event of a future pandemic.”

Insight: Evidence grows for narcolepsy link to GSK swine flu shot : Doctors are fearful of having their reputations ruined by reporting possible links

By Kate Kelland, Health and Science Correspondent | Reuters – 8 mins ago

STOCKHOLM (Reuters) – Emelie is plagued by hallucinations and nightmares. When she wakes up, she’s often paralyzed, unable to breathe properly or call for help. During the day she can barely stay awake, and often misses school or having fun with friends. She is only 14, but at times she has wondered if her life is worth living.

Emelie is one of around 800 children in Sweden and elsewhere in Europe who developed narcolepsy, an incurable sleep disorder, after being immunized with the Pandemrix H1N1 swine flu vaccine made by British drugmaker GlaxoSmithKline in 2009.

Finland, Norway, Ireland and France have seen spikes in narcolepsy cases, too, and people familiar with the results of a soon-to-be-published study in Britain have told Reuters it will show a similar pattern in children there.

Their fate, coping with an illness that all but destroys normal life, is developing into what the health official who coordinated Sweden’s vaccination campaign calls a “medical tragedy” that will demand rising scientific and medical attention.

Europe’s drugs regulator has ruled Pandemrix should no longer be used in people aged under 20. The chief medical officer at GSK’s vaccines division, Norman Begg, says his firm views the issue extremely seriously and is “absolutely committed to getting to the bottom of this”, but adds there is not yet enough data or evidence to suggest a causal link.

Others – including Emmanuel Mignot, one of the world’s leading experts on narcolepsy, who is being funded by GSK to investigate further – agree more research is needed but say the evidence is already clearly pointing in one direction.

“There’s no doubt in my mind whatsoever that Pandemrix increased the occurrence of narcolepsy onset in children in some countries – and probably in most countries,” says Mignot, a specialist in the sleep disorder at Stanford University in the United States.

30 MILLION RECEIVED PANDEMRIX

In total, the GSK shot was given to more than 30 million people in 47 countries during the 2009-2010 H1N1 swine flu pandemic. Because it contains an adjuvant, or booster, it was not used in the United States because drug regulators there are wary of adjuvanted vaccines.

GSK says 795 people across Europe have reported developing narcolepsy since the vaccine’s use began in 2009.

Questions about how the narcolepsy cases are linked to Pandemrix, what the triggers and biological mechanisms might have been, and whether there might be a genetic susceptibility are currently the subject of deep scientific investigation.

But experts on all sides are wary. Rare adverse reactions can swiftly develop into “vaccine scares” that spiral out of proportion and cast what one of Europe’s top flu experts calls a “long shadow” over public confidence in vaccines that control potential killers like measles and polio.

“No-one wants to be the next Wakefield,” said Mignot, referring to the now discredited British doctor Andrew Wakefield who sparked a decades-long backlash against the measles, mumps and rubella (MMR) shot with false claims of links to autism.

With the narcolepsy studies, there is no suggestion that the findings are the work of one rogue doctor.

Independent teams of scientists have published peer-reviewed studies from Sweden, Finland and Ireland showing the risk of developing narcolepsy after the 2009-2010 immunization campaign was between seven and 13 times higher for children who had Pandemrix than for their unvaccinated peers.

“We really do want to get to the bottom of this. It’s not in anyone’s interests if there is a safety issue that needs to be addressed,” said GSK’s Begg.

LIFE CHANGED

Emelie’s parents, Charles and Marie Olsson, say she was a top student who loved playing the piano, taking tennis lessons, creating art and having fun with friends. But her life started to change in early 2010, a few months after she had Pandemrix. In the spring of 2010, they noticed she was often tired, needing to sleep when she came home from school.

But it wasn’t until May, when she began collapsing at school, that it became clear something serious was happening.

As well as the life-limiting bouts of daytime sleepiness, narcolepsy brings nightmares, hallucinations, sleep paralysis and episodes of cataplexy – when strong emotions trigger a sudden and dramatic loss of muscle strength.

In Emelie’s case, having fun is the emotional trigger. “I can’t laugh or joke about with my friends anymore, because when I do I get cataplexies and collapse,” she said in an interview at her home in the Swedish capital.

Narcolepsy is estimated to affect between 200 and 500 people per million and is a lifelong condition. It has no known cure and scientists don’t really know what causes it. But they do know patients have a deficit of a brain neurotransmitter called orexin, also known as hypocretin, which regulates wakefulness.

Research has found that some people are born with a variant in a gene known as HLA that means they have low hypocretin, making them more susceptible to narcolepsy. Around 25 percent of Europeans are thought to have this genetic vulnerability.

When results of Emelie’s hypocretin test came back in November last year, it showed she had 15 percent of the normal amount, typical of heavy narcolepsy with cataplexy.

The seriousness of her strange new illness has forced her to contemplate life far more than many other young teens: “In the beginning I didn’t really want to live any more, but now I have learned to handle things better,” she said.

TRIGGERS?

Scientists investigating these cases are looking in detail at Pandemrix’s adjuvant, called AS03, for clues.

Some suggest AS03, or maybe its boosting effect, or even the H1N1 flu itself, may have triggered the onset of narcolepsy in those who have the susceptible HLA gene variant.

Angus Nicoll, a flu expert at the European Centre for Disease Prevention and Control (ECDC), says genes may well play a part, but don’t tell the whole story.

“Yes, there’s a genetic predisposition to this condition, but that alone cannot explain these cases,” he said. “There was also something to do with receiving this specific vaccination. Whether it was the vaccine plus the genetic disposition alone or a third factor as well – like another infection – we simply do not know yet.”

GSK is funding a study in Canada, where its adjuvanted vaccine Arepanrix, similar to Pandemrix, was used during the 2009-2010 pandemic. The study won’t be completed until 2014, and some experts fear it may not shed much light since the vaccines were similar but not precisely the same.

It all leaves this investigation with far more questions than answers, and a lot more research ahead.

WAS IT WORTH IT?

In his glass-topped office building overlooking the Maria Magdalena church in Stockholm, Goran Stiernstedt, a doctor turned public health official, has spent many difficult hours going over what happened in his country during the swine flu pandemic, wondering if things should have been different.

“The big question is was it worth it? And retrospectively I have to say it was not,” he told Reuters in an interview.

Being a wealthy country, Sweden was at the front of the queue for pandemic vaccines. It got Pandemrix from GSK almost as soon as it was available, and a nationwide campaign got uptake of the vaccine to 59 percent, meaning around 5 million people got the shot.

Stiernstedt, director for health and social care at the Swedish Association of Local Authorities and Regions, helped coordinate the vaccination campaign across Sweden’s 21 regions.

The World Health Organization (WHO) says the 2009-2010 pandemic killed 18,500 people, although a study last year said that total might be up to 15 times higher.

While estimates vary, Stiernstedt says Sweden’s mass vaccination saved between 30 and 60 people from swine flu death. Yet since the pandemic ended, more than 200 cases of narcolepsy have been reported in Sweden.

With hindsight, this risk-benefit balance is unacceptable. “This is a medical tragedy,” he said. “Hundreds of young people have had their lives almost destroyed.”

PANDEMICS ARE EMERGENCIES

Yet the problem with risk-benefit analyses is that they often look radically different when the world is facing a pandemic with the potential to wipe out millions than they do when it has emerged relatively unscathed from one, like H1N1, which turned out to be much milder than first feared.

David Salisbury, the British government’s director of immunization, says “therein lies the risk, and the difficulty, of working in public health” when a viral emergency hits.

“In the event of a severe pandemic, the risk of death is far higher than the risk of narcolepsy,” he told Reuters. “If we spent longer developing and testing the vaccine on very large numbers of people and waited to see whether any of them developed narcolepsy, much of the population might be dead.”

Pandemrix was authorized by European drug regulators using a so-called “mock-up procedure” that allows a vaccine to be authorized ahead of a possible pandemic using another flu strain. In Pandemrix’s case, the substitute was H5N1 bird flu.

When the WHO declared a pandemic, GSK replaced the mock-up’s strain with the pandemic-causing H1N1 strain to form Pandemrix.

GSK says the final H1N1 version was tested in trials involving around 3,600 patients, including children, adolescents, adults and the elderly, before it was rolled out.

The ECDC’s Nicoll says early warning systems that give a more accurate analysis of a flu strain’s threat are the best way to minimize risks of this kind of tragedy happening in future.

Salisbury agrees, and says progress towards a universal flu vaccine – one that wouldn’t need last-minute changes made when a new strain emerged – would cuts risks further.

“Ideally, we would have a better vaccine that would work against all strains of influenza and we wouldn’t need to worry about this ever again,” he said. “But that’s a long way off.”

With scientists facing years of investigation and research, Emelie just wants to make the best of her life.

She reluctantly accepts that to do so, she needs a cocktail of drugs to try to control the narcolepsy symptoms. The stimulant Ritalin and the sleeping pill Sobril are prescribed for Emelie’s daytime sleepiness and night terrors. Then there’s Prozac to try to stabilize her and limit her cataplexies.

“That’s one of the things that makes me feel most uncomfortable,” she explains. “Before I got this condition I didn’t take any pills, and now I have to take lots – maybe for the rest of my life. It’s not good to take so many medicines, especially when you know they have side effects.”

(Reporting by Kate Kelland; Editing by Will Waterman)

http://news.yahoo.com/insight-evidence-grows-narcolepsy-gsk-swine-flu-shot-070212916–finance.html

 

Designer bacteria may lead to better vaccines: Contaminated vaccines work better!!!

Contact: Daniel Oppenheimer daniel.oppenheimer@utexas.edu 512-745-3353 University of Texas at Austin

Designer bacteria may lead to better vaccines

61 new strains of genetically engineered bacteria may improve the efficacy of vaccines for diseases such as flu, pertussis, cholera and HPV

AUSTIN, Texas — Researchers at The University of Texas at Austin have developed a menu of 61 new strains of genetically engineered bacteria that may improve the efficacy of vaccines for diseases such as flu, pertussis, cholera and HPV.

The strains of E. coli, which were described in a paper published this month in the journal PNAS, are part of a new class of biological “adjuvants” that is poised to transform vaccine design. Adjuvants are substances added to vaccines to boost the human immune response.

“For 70 years the only adjuvants being used were aluminum salts,” said Stephen Trent, associate professor of biology in the College of Natural Sciences. “They worked, but we didn’t fully understand why, and there were limitations. Then four years ago the first biological adjuvant was approved by the Food and Drug Administration. I think what we’re doing is a step forward from that. It’s going to allow us to design vaccines in a much more intentional way.”

Adjuvants were discovered in the early years of commercial vaccine production, when it was noticed that batches of vaccine that were accidentally contaminated often seemed to be more effective than those that were pure.

“They’re called the ‘dirty little secret’ of immunology,” said Trent. “If the vials were dirty, they elicited a better immune response.”

What researchers eventually realized was that they could produce a one-two punch by intentionally adding their own dirt (adjuvant) to the mix. The main ingredient of the vaccine, which was a killed or inactivated version of the bacteria or virus that the vaccine was meant to protect against, did what it was supposed to do. It “taught” the body’s immune system to recognize it and produce antibodies in response to it.

The adjuvant amplifies that response by triggering a more general alarm, which puts more agents of the immune system in circulation in the bloodstream, where they can then learn to recognize the key antigen. The result is an immune system more heavily armed to fight the virus or bacteria when it encounters it in the future.

For about 70 years the adjuvant of choice, in nearly every vaccine worldwide, was an aluminum salt. Then in 2009, the FDA approved a new vaccine for human papillomavirus (HPV). It included a new kind of adjuvant that’s a modified version of an endotoxin molecule.

These molecules, which can be dangerous, appear on the cell surface of a wide range of bacteria. As a result, humans have evolved over millions of years to detect and respond to them quickly. They trigger an immediate red alert.

“In some of its forms an endotoxin can kill you,” said Trent. “But the adjuvant, which is called MPL, is a very small, carefully modified piece of it, so it’s able to trigger the immune response without overdoing it.”

What Trent and his colleagues have done is expand on that basic premise. Rather than just work with an inert piece of endotoxin, they’ve engineered E. coli bacteria to express the endotoxin in many configurations on the cell surface.

“These 61 E. coli strains each have a different profile on their surface,” said Brittany Needham, a doctoral student in Trent’s lab and the first author on the paper. “In every case the surface structure of the endotoxin is safe, but it will interact with the immune system in a range of ways. Suddenly we have a huge potential menu of adjuvants to test out with different kinds of vaccines.”

One form might work better with cholera vaccine, another with pertussis (whooping cough) and another with a future HIV vaccine. Trent, Needham and their colleagues should be able to fine-tune the adjuvants with increasing precision as more E. coli strains are engineered and tested, and as their understanding of how they interact with the immune system deepens.

“I think we’re at the dawn of a new age of vaccine design,” said Trent. “For a long time vaccinology was really a trial-and-error field. It was a black box. We knew certain things worked. We knew certain vaccines had certain side effects. But we didn’t entirely know why. Now that’s changing.”

Trent said that an additional advantage of their system is that the E. coli can be engineered to express key viral and bacterial antigens along with the endotoxin. A single cell could deliver both parts of the one-two punch, or even a one-two-three punch, if antigens from multiple diseases were expressed in a single E. coli.

“It makes possible a vaccine that provides protection from multiple pathogens at the same time,” said Trent.

Trent and his colleagues are working on a second round of designer E. coli. They have also filed a provisional patent on their system and are working with the university to find a corporate partner to pay for clinical trials.

“This is ready to go,” said Trent. “I can’t predict whether it will actually make it to the market. But it’s very similar to the adjuvant that has already been approved, and my instinct is that if a company will undertake to do the trials, it will get approved. A company could call us tomorrow, we could send them a strain, and they could start working.”

Paradox of Vaccination: Is Vaccination Really Effective against Avian Flu Epidemics?

Abstract

Background

Although vaccination can be a useful tool for control of avian influenza epidemics, it might engender emergence of a vaccine-resistant strain. Field and experimental studies show that some avian influenza strains acquire resistance ability against vaccination. We investigated, in the context of the emergence of a vaccine-resistant strain, whether a vaccination program can prevent the spread of infectious disease. We also investigated how losses from immunization by vaccination imposed by the resistant strain affect the spread of the disease.

Methods and Findings

We designed and analyzed a deterministic compartment model illustrating transmission of vaccine-sensitive and vaccine-resistant strains during a vaccination program. We investigated how the loss of protection effectiveness impacts the program. Results show that a vaccination to prevent the spread of disease can instead spread the disease when the resistant strain is less virulent than the sensitive strain. If the loss is high, the program does not prevent the spread of the resistant strain despite a large prevalence rate of the program. The epidemic’s final size can be larger than that before the vaccination program. We propose how to use poor vaccines, which have a large loss, to maximize program effects and describe various program risks, which can be estimated using available epidemiological data.

Conclusions

We presented clear and simple concepts to elucidate vaccination program guidelines to avoid negative program effects. Using our theory, monitoring the virulence of the resistant strain and investigating the loss caused by the resistant strain better development of vaccination strategies is possible.

Citation: Iwami S, Suzuki T, Takeuchi Y (2009) Paradox of Vaccination: Is Vaccination Really Effective against Avian Flu Epidemics? PLoS ONE 4(3):          e4915.            doi:10.1371/journal.pone.0004915

Editor: Carl Kingsford, University of Maryland, United States of America

Received: November 12, 2008; Accepted: November 26, 2008; Published: March 18, 2009

Copyright: © 2009 Iwami et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

* E-mail: takeuchi@sys.eng.shizuoka.ac.jp

Introduction

Highly pathogenic H5N1 influenza A viruses have spread relentlessly across the globe since 2003. They are associated with widespread death of poultry, substantial economic loss to farmers, and reported infections of more than 300 people with a mortality rate of 60% [1]. Influenza prevention and containment strategies can be considered under the broad categories of antiviral, vaccine, and non-pharmaceutical measures [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13]. A major public health concern is the next influenza pandemic; yet it remains unclear how to control such a crisis.

Vaccination of domestic poultry against the H5N1 subtype of avian influenza has been used in several countries such as Pakistan, Hong Kong, Indonesia, China, and Vietnam [14], [15], [16]. Using vaccination to reduce the transmission rate might provide an alternative to mass culling, by reducing both the susceptibility of healthy birds and the infectiousness of infected birds [14], [17], [18]. However, incomplete protection at the bird level can cause the silent spread of the virus within and among birds [11]. Furthermore, vaccines might provide immunological pressure on the circulating strains, which might engender the emergence of drifted or shifted variants with enhanced potential for pathogenicity in humans [1]. Therefore, although vaccination programs have been recommended recently, some field evidence indicates that vaccination alone will not achieve eradication. Moreover, if not used appropriately, vaccination might result in the infection becoming endemic [11], [17].

An important issue related to influenza epidemics is the potential for the emergence of vaccine-resistant influenza viruses. The vaccine-resistant strain, in general, causes a loss of the protection effectiveness of vaccination [19], [20], [21], [22] (there is experimental evidence of the loss of the protection effectiveness for antiviral-resistant strains [23]). Consequently, a vaccination program that engenders the emergence of the resistant strain might promote the spread of the resistant strain and undermine the control of the infectious disease, even if the vaccination protects against the transmission of a vaccine-sensitive strain [20], [21], [22].

For example, in China, despite a compulsory program for the vaccination of all poultry commencing in September 2005, the H5N1 influenza virus has caused outbreaks in poultry in 12 provinces from October 2005 to August 2006 [14], [15], [22]. Genetic analysis revealed that an H5N1 influenza variant (Fujian-like, FJ like), which is a previously uncharacterized H5N1 virus sublineage, had emerged and subsequently became the prevalent variant in each of the provinces, replacing those previously established multiple sublineages in different regions of southern China. Some data suggest that the poultry vaccine currently used in China might only generate very low neutralizing antibodies to FJ-like viruses (seroconversion rates remain low and vaccinated birds are poorly immunized against FJ-like viruses) in comparison to other previously cocirculating H5N1 sublineages [20], [22]. That evidence implies the possibility that the emergence and replacement of FJ-like virus was preceded by and facilitated by the vaccination program, although the mechanism remains unknown epidemiologically and virologically (some researchers consider that the emergence and replacement of FJ-like virus are questionable [24], [25]).

Furthermore, the H5N2 vaccines have been used in Mexico since 1995 [17], [19], [21]. Phylogenetic analysis suggests the presence of (previously uncharacterized) multiple sublineages of Mexican lineage isolates which emerged after the introduction of the vaccine. Vaccine protection studies further confirmed in vitro serologic results indicating that commercial vaccine was not able to prevent virus shedding when chickens were challenged with the multiple sublineage isolates [19], [21]. Therefore, the vaccine protective efficacy would be impaired and the use of this specific vaccine would eventually become obsolete. That fact also implies that the vaccine promotes the selection of mutation in the circulating virus.

The emergence of a vaccine-resistant strain presents the risk of generating a new pandemic virus that is dangerous for humans through an avian-human link because of the spread of vaccine-resistant strain. The dynamics of competition between vaccine-sensitive and vaccine-resistant strains is, in general, complex [8], [9]. Actually, outcomes of the dynamics might be influenced by several factors, including a loss of protection effectiveness, a competitive advantage of vaccine-resistant strain, and a prevalence rate of vaccination. Understanding the dynamics of a spread of vaccine-resistant is therefore crucial for implementation of effective mitigation strategies.

Several theoretical studies have investigated the impact of an emergence of a resistant strain of antiviral drug such as M2 inhibitors and NA inhibitors during an influenza pandemic among humans [2], [3], [8], [9], [10], [12], [26]. However, to our knowledge, no study has used a mathematical model to investigate the application of vaccination program among poultry in the context of an emergence of a vaccine-resistant strain. It remains unclear whether a vaccination program can prevent the spread of infectious disease when the vaccine-resistant strain emerges and how a loss of immunization by vaccination within birds infected with the vaccine-resistant strain affects the spread of infectious disease among birds. Nobody can give a simple and clear explanation to capture the problems described above in a theoretical framework (using numerical simulations, many qualitative and quantitative but sometimes very complex studies have investigated effects of antiviral drugs [3], [8], [9], [10], [12], [26]). Furthermore, we remain skeptical that a vaccination program can reduce the number of total infectious individuals even if the vaccination protects against transmission of a vaccine-sensitive strain. We developed a simple mathematical model to evaluate the effectiveness, as a strategy to control influenza epidemic, of a vaccination program among poultry which can engender the emergence of a vaccine-resistant strain.

Methods

Herein, we describe a homogeneous population model of infectious disease and its control using a vaccination program in the presence of a vaccine-resistant strain (Fig. 1).

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Figure 1. Model structure for the emergence of vaccine-resistant strain during a vaccination program: Susceptible birds (X) become infected with vaccine-sensitive (Y) and vaccine-resistant (Z) strains at rates in direct relation to the number of respective infectious birds.

We assume that vaccinated birds (V) can be protected completely from the vaccine-sensitive strain, but are partially protected from vaccine-resistant strains with a loss of protection effectiveness of the vaccination (σ). See the Mathematical model section for corresponding equations.

doi:10.1371/journal.pone.0004915.g001

All birds in the effective population are divided into several compartments, respectively including susceptible birds (X), vaccinated birds (V), birds infected with vaccine-sensitive strain (Y), and birds infected with vaccine-resistant strain (Z). We assume that susceptible birds are born or restocked at a rate of c per day and that all birds are naturally dead or removed from the effective population at a rate of b per day.

In the absence of vaccination, transmission occurs at a rate that is directly related to the number of infectious birds, with respective transmission rate constants ω and φ from infected birds with the vaccine-sensitive strain and with the vaccine-resistant strain. The infectiousness of vaccine-sensitive and vaccine-resistant strain are assumed to be exponentially distributed, respectively, with mean durations of 1/(b+my) and 1/(b+mz) days. Actually, my and mz respectively signify virulence of vaccine-sensitive and vaccine-resistant strains.

At the beginning of the vaccination program, X moves directly to V by the vaccination. However, after some period after the initial vaccination, the direct movement might vanish because almost all birds are vaccinated. Therefore, we can assume that vaccination is only administered to the newly hatched birds. The newly hatched birds are vaccinated at the rate 0≤p≤1 (more appropriately, p is proportional). Actually, p represents the prevalence rate of the vaccination program.

To simplify the theoretical treatment, as described in [11], we assume that the vaccinated birds can be protected completely from the vaccine-sensitive strain (note that the assumption is not necessary for our results: see Supplementary Information: Text S1, Fig. S10, S11). Actually, in laboratory experience, many avian influenza vaccines confer a very high level of protection against clinical signs and mortality (90–100% protected birds) [21]. However, many factors determine whether a vaccinated bird becomes infected, including age, species, challenge dose, health, antibody titre, infections of immunosuppressive diseases, and cross-reactivity of other avian influenza serotypes [11], [27], [28], [29]. On the other hand, we assume that the vaccinated birds are partially protected from the vaccine-resistant strain at the rate (proportion) 0≤1−σ≤1 because of cross-reactivity of immune systems [19], [20], [22], [23], [29] (e.g., σ = 0 represents complete cross immunity against vaccine-resistant strains). Actually, σ represents a loss of protection effectiveness of the vaccination caused by a vaccine-resistant strain.

Mathematical model

We extended the standard susceptible–infective model [30] including the effect of a vaccination program that can engender the emergence of a vaccine-resistant strain. Our mathematical model is given by the following equations: (1) Model (1) is a simplified one that is used in [31]. We considered a mechanism for the emergence and replacement of the FJ-like virus over a large geographical region in China using a more complex patch-structured model in the heterogeneous area [31]. Here we investigate the impact of the vaccination program in a homogeneous area and specifically examine the role of epidemiological parameters such as the prevalence rate of the vaccination program (p) and the loss of protection effectiveness of the vaccination (σ) in the spread of the disease.

Estimation of epidemiological parameters

Baseline values of model parameters and their respective ranges used for simulations are presented in Table 1 and 2. These parameters are based on avian influenza epidemics among poultry in The Netherlands in 2003 [32], [33], [34].

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Table 1. Description of physical characteristics, transmission, infectious, and vaccination parameters of the model with their baseline values and ranges used for simulations.

doi:10.1371/journal.pone.0004915.t001

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Table 2. Basic reproductive numbers and invasion reproductive numbers before the vaccination program.

doi:10.1371/journal.pone.0004915.t002

The initial population size was c/b = 984 birds at the 2003 epidemic [34]. Usually, the mean lifespan of poultry is about 2 years. However, we assume that the mean duration of a bird being in effective population is about 1/b = 100 days because of migration and marketing. Therefore, the birth or restocking rate of birds is c = 9.84 birds per day. Estimated infectious period and transmission parameters are 1/(b+my) = 13.8 days and ω = 4.78×10−4 day−1 individual−1, respectively, [34]. These physical characteristics, in addition to infectious and transmission parameters, are used in our model as parameters of the vaccine-sensitive strain.

The epidemiological and biological feature of antiviral drug-resistance is well reported in [23]. The transmissibility and virulence of drug-resistant strains are usually lower than those of the wild strain because of its mutation cost [8], [10], [23], [35]. Actually, antiviral drugs are also used for prophylaxis drug intervention as vaccination [8], [10], [12]. Herein, we use some reduced value of transmissibility (φ/ω = 0.58) and the increased value of infectious period of the vaccine-sensitive strain ((b+my)/(b+mz) = 1.32) for parameters of vaccine-resistant strain (sensitivity analyses are given in Supplementary Information: Text S1, Fig. S6, S7, S8, S9).

Reproductive numbers

A measure of transmissibility and of the stringency of control policies necessary to stop an epidemic is the basic reproductive number, which is the number of secondary cases produced by each primary case [30]. We obtain basic reproductive quantities of vaccine-sensitive strain and vaccine-resistant strain before vaccination program (superscript n means no vaccination). In fact, during the vaccination program, the basic reproductive numbers depend on the rate of prevalence of the vaccination program. We derived these basic reproductive numbers depending on the prevalence rate in Supplementary Information: Text S1. With the estimated parameters in Table 1 the basic reproductive number of vaccine-sensitive and vaccine-resistant strain are and , respectively (note that corresponds to an estimated value in [34]).

Furthermore, to clarify the concept of competition among strains simply, we introduce the invasion reproductive number for the vaccine-resistant strain before the vaccination program , which signifies an expected number of new infectious cases with the vaccine-resistant strain after a spread of a vaccine-sensitive strain among birds. The invasion reproductive number is considered as a competitive condition (relative fitness), which represents some advantage measure of the vaccine-resistant strain against the vaccine-sensitive strain. The estimated invasion reproductive number of the vaccine-resistant strain is . During the vaccination program, the invasion reproductive number also depends on the prevalence rate of the vaccination program (see Supplementary Information: Text S1).

Results

We consider a scenario in which a vaccine-resistant strain can emerge (i.e., be eventually selected) during a vaccination program designed to be effective against the spread of a vaccine-sensitive strain. This implies that : otherwise the vaccine-resistant strain can not emerge at all (see Supplementary Information: Text S1, Fig. S1, S2, S3). Acquisition of resistance ability usually engenders a strain which, in the absence of a pharmaceutical intervention, is less fit than the sensitive strain [8], [9], [12], [35]. Therefore, . We generally assume the following conditions for reproductive numbers before the vaccination program (our baseline parameter values are satisfied with these assumptions):

The assumption precludes the possibility that a pre-existing vaccine-resistant strain beats the vaccine-sensitive strain before the vaccination program because .

Evaluation of the effect of a vaccination program

Although vaccination is an important tool to control epidemics, the use of vaccination might engender a spread of a vaccine-resistant strain. To demonstrate the interplay between these opposing effects, we simulated our model to determine the final size of an epidemic (total infected individuals Y+Z at equilibrium level) over vaccination prevalence (0≤p≤1) in Fig. 2 (we use our baseline parameter values except for mz). We assume that the loss of the protection effectiveness is 35% (σ = 0.35: this value can be chosen arbitrarily with little effect on the meaning of the results). The estimated infectious period of the vaccine-sensitive strain is 13.8 days [34] (see Table 1). Therefore, the virulence of vaccine-sensitive strain is my = 0.062 day−1. Results show that the patterns of the final size can be divided into two cases, which depend strongly on the virulence of the vaccine-resistant strain. If the virulence of the vaccine-resistant strain is lower than that of vaccine-sensitive strain (e.g., we choose mz = 0.045), then increasing the prevalence rate of vaccination from 13.5% to 30.3% can increase the final size (green line at top figure in Fig. 2). On the other hand, if the virulence is higher (mz = 0.065), increasing the prevalence always decreases the final size (bottom figure in Fig. 2). These two patterns are qualitatively preserved for different virulence of the vaccine-resistant strain.

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Figure 2. Final size of epidemics related with the prevalence rate of the vaccination: The top figure represents that the vaccination is not always effective in the case of lower virulence of vaccine-resistant strain.

The bottom figure represents that the vaccination is always effective in the case of higher virulence of the vaccine-resistant strain. We assume that σ = 0.35, mz = 0.045 (top) and mz = 0.065 (bottom). These values of σ and mz are not so influential on the result. The blue, green, and red lines respectively signify situations in which only the vaccine-sensitive strain exists, both the vaccine-sensitive and the vaccine-resistant strains exist, and only the vaccine-resistant strain exists.

doi:10.1371/journal.pone.0004915.g002

In [8], [9], although they consider the emergence of an antiviral drug-resistant virus, a similar tendency (increasing the treatment level increases the final size of the epidemic) was obtained through complex models that are difficult to treat mathematically. The mathematical model presented herein demonstrates that the patterns of final size over vaccination prevalence only depend on the virulence of the vaccine-resistant strain as follows (see Supplementary Information: Text S1). Increasing the prevalence rate increases the final size when only both strains co-exist if the virulence of vaccine-resistant strain is lower than that of vaccine-sensitive strain (my>mz). That is to say, the vaccination is effective when either a vaccine-sensitive or a vaccine-resistant strain exists. On the other hand, if the virulence of vaccine-resistant strain is higher than that of vaccine-sensitive strain (my<mz), the final size always decreases as the prevalence rate increases. The other parameters can not change these patterns. In fact, many studies have ignored the impact of the virulence of the vaccine-resistant strain. In [7], we also found that the virulence of mutant strain determines a choice of the optimal prevention policy for avian influenza epidemic. Therefore, we suggest that, to monitor and investigate the virulence evolution between the vaccine-sensitive and vaccine-resistant strain is important to develop avian flu epidemic plans. In fact, if the vaccine-resistant strain has higher virulence than the vaccine-sensitive strain, the vaccination program is always effective, even though the program engenders the emergence of a vaccine-resistant strain. On the other hand, if the vaccine-resistant strain has lower virulence, we must carefully manage vaccination to prevent the spread of a vaccine-resistant strain.

Impact of loss of protection effectiveness of vaccination

To ensure an effective vaccination program, the vaccine must protect vaccinated animals against clinical signs of the disease and prevent mortality [21]. However, the vaccine-resistant strain causes a loss of the protection effectiveness of the vaccination [19], [20], [21], [22], [37]. We investigate an impact of the loss of the protection on change of final size of the epidemic over the vaccination prevalence. Assume, hereafter, that the virulence of vaccine-resistant strain is lower than that of vaccine-sensitive strain (my>mz): otherwise, the vaccination is always effective (our baseline parameter values are satisfied with my>mz). Actually, a resistant strain seems to have reduced virulence in general [8], [10], [23], [35].

We conduct a simulation using our model to elucidate the change of the final size with the loss of the protection effectiveness 5%, 15%, and 80% over vaccination prevalence in Fig. 3. Results showed that the patterns of the change are divisible into three cases. In theory, we can estimate the threshold values of the loss of the protection which determines the patterns (see Supplementary Information: Text S1, Fig. S4):

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Figure 3. Impact of the loss of the protection effectiveness of the vaccination on the change of the final size of the epidemic: The losses of the protection in the top, middle, and bottom figure are σ = 0.05, 0.15, and 0.8, respectively.

The top (0≤σσ*) and middle () figures portray the possibility of eradication of the infectious disease through the vaccination program. However, in the bottom figure (), the vaccination engenders a failure to prevent the spread of the disease. The patterns of the change are divisible into these three cases, depending on the loss of the protection. The blue, green, and red lines respectively correspond to the situation in which only the vaccine-sensitive strain exists, both the vaccine-sensitive and the vaccine-resistant strains exist, and only the vaccine-resistant strain exists.

doi:10.1371/journal.pone.0004915.g003

In fact, σ* = 0.056 and in our simulation from Table 1. When the loss of the protection is between 0% and σ* = 5.6% (5%: the top figure in Fig. 3), the vaccination can control the epidemic with the prevalence rate of 84.7% without the emergence of a resistant strain (a vaccine-resistant strain never emerges in the population). Therefore, increasing the prevalence rate of vaccination always decreases the final size of the epidemic. For the loss of the protection is between σ* = 5.6% and (15%: the middle figure in Fig. 3), the vaccination eventually prevents the spread of the disease with 94.1% of vaccination prevalence in spite of the emergence of the resistant strain. Increasing the prevalence rate from 31.5% to 44.1% increases the final size. Therefore, the vaccination is not always effective. However, when the loss of the protection is between and 100% (80%: the bottom figure in Fig. 3), the vaccination no longer controls the disease (even if the prevalence rate is 100%) and the vaccine-resistant strain spreads widely through the population instead of the vaccine-sensitive strain. In this case, the vaccination only slightly provides beneficial effects for preventing the spread of the disease. Therefore, the loss of the protection effectiveness of vaccination plays an important role in preventing the spread of the disease.

Vaccination can facilitate spread of disease

Sometimes a considerable spread of the resistant strain partially compromises the benefits of a vaccination program [19], [20], [22], [37]. For example, even if we can completely execute the vaccination program (p = 1), the final size of the epidemic can become larger than that before the vaccination program (p = 0) by the emergence of vaccine-resistant strain (bottom figure in Fig. 3). This implies that the vaccination, which is expected to prevent the spread of the disease, can instead help the spread of the disease. If the loss of the protection effectiveness of vaccination is high (σ*σ≤1), the vaccination might increase the final size over vaccination prevalence compared with that before the vaccination program (vaccination always decreases the final size if 0≤σσ* (top figure in Fig. 3)). Here we can also calculate such a risk of help, which depends on the loss of the protection (see Supplementary Information: Text S1). Let

Actually, σc = 0.236 in our simulation is from Table 1. When the loss of the protection is between 23.6% and 100%, we found that the vaccination program is attended by the risk that the final size becomes larger than that before the vaccination program (see Supplementary Information: Text S1).

Difficulty of prediction of a prevalent strain

Vaccination is well known to engender “silent carriers or excretors” if the vaccine can not completely protect the vaccinated animals against clinical signs of the disease [16], [21]. The existence of silent carriers or excretors is dangerous because they become a virus reservoir and shed the virus into their environment, causing potential outbreaks among their own and other species. Furthermore, even if a vaccination is effective in a bird (individual level), an incomplete vaccination program for all birds (population level) can engender the “silent spread” of an infectious disease [1], [11]. Additionally, we found that it is difficult for us to predict a prevalent strain even if we can completely estimate the basic reproductive number of vaccine-sensitive and vaccine-resistant strains during the vaccination program (although estimations, usually, are almost impossible). Even when the basic reproductive number of the vaccine-resistant strain is less than that of the vaccine-sensitive strain (), the vaccine-resistant strain can beat the vaccine-sensitive strain and spread widely through the population (see Supplementary Information: Text S1, Fig. S5). Therefore, a non-ideal vaccination program might make a prediction of prevalent strain difficult.

Optimal prevalence rate of vaccination program

In the absence of a vaccine-resistant strain, a goal of vaccination program is to reduce the basic reproductive number of vaccine-sensitive strain to be less than 1. We assume that . Therefore, the vaccination can eradicate the vaccine-sensitive strain if at least 84.7% of the birds in poultry are vaccinated effectively based on the fraction of [30]. However, in the presence of the resistant strain, the simple theory is inapplicable to an optimal prevalence rate of vaccination program. Here we define the optimal prevalence rate of a vaccination program which minimizes both the final size of the epidemic and the prevalence rate (see Supplementary Information: Text S1).

We calculate the optimal prevalence rate, which depends on the loss of the protection effectiveness of the vaccination in Fig. 4 (sensitivity analyses are given in Supplementary Information: Text S1, Fig. S6). At the point where the loss of the protection effectiveness is greater than some threshold value σo, the optimal prevalence rate changes catastrophically from high prevalence rate to a low prevalence rate. Here

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Figure 4. Optimal prevalence rate of vaccination program: Increasing of the loss of the protection effectiveness engenders a catastrophic change in the optimal prevalence rate.

The optimal rate increases as the loss increases if the loss of the protection effectiveness is small (0≤σσo). This implies that a small loss of the protection effectiveness can be compensated by a high optimal prevalence rate of the vaccination program. On the other hand, if the loss is large (σoσ≤1), the optimal rate decreases as the loss of the protection effectiveness increases. This eventuality implies that a large loss of the protection effectiveness is no longer compensated by the high optimal prevalence rate of the vaccination program. Therefore, a low prevalence rate, which does not engender the emergence of a vaccine-resistant strain becomes optimal because the poor vaccine engenders the increase of final size of the epidemic because of the spread of the resistant strain.

doi:10.1371/journal.pone.0004915.g004

Actually, σo = 0.461 in our simulation from Table 1. The optimal prevalence rate is 84.6% when the loss of the protection effectiveness is between 0% and 5.6%. In addition, if the loss rate is between 5.6% and 20.1%, then the optimal prevalence rate increases from 84.6% to 100%. Furthermore, if the loss rate is between 20.1% and 46.1%, then the optimal prevalence rate must always be 100%. Consequently, as long as the loss of the protection effectiveness is small (0%–46.1%), the loss can be compensated by a high optimal prevalence rate of the vaccination program. However, if the loss rate is greater than 46.1%, the loss is no longer compensated by the high prevalence rate of the vaccination program. The optimal prevalence rate changes catastrophically from 100% to 10.2%. Afterward, as the loss rate increases from 46.1% to 100%, the optimal prevalence rate decreases from 10.2% to 4.72% (the low prevalence rate becomes optimal). This is true because the poor vaccine (with a large loss of the protection) engenders the emergence of the vaccine-resistant strain for the high prevalence rate; in addition, the spread of the resistant strain increases the final size of the epidemic. Therefore, the loss of the protection effectiveness strongly impacts also on the optimal prevalence rate.

Variation of final size of epidemic according to the vaccination program

In countries where poultry are mainly backyard scavengers, optimum vaccination coverage might be difficult to achieve [21]. The final size of the epidemic might be increased and the program might fail if the optimal prevalence rate of the vaccination program can not be achieved. However, if we can achieve optimum vaccination coverage, the final size is greatly reduced. The final size of the epidemics can be variable depending on the prevalence rate. Here we calculate the optimal (smallest) and worst (largest) final size of the epidemic over the vaccination prevalence (see Supplementary Information: Text S1) in Fig. 5 (black and yellow bars respectively represent the optimal and worst final size). The variation of the final size is between black and yellow bars shown in Fig. 5 (sensitivity analyses are given in Supplementary Information: Text S1, Fig. S7).

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Figure 5. Variation of the final size of the epidemic over the vaccination prevalence: The black bar represents the optimal (smallest) final size of the epidemic.

The yellow bar represents the worst (largest) final size of the epidemic over the vaccination prevalence. The variation of the final size depending on the prevalence rate is between black and yellow bars. If the loss of protection effectiveness is small, then the variation is very large. On the other hand, if the loss becomes large, then the variation decreases. Therefore, the final size of the epidemic is strongly affected by the vaccination coverage and the loss of protection effectiveness: a bad vaccination program (far from the optimal prevalence rate) increases the final size and prevents eradication of the disease.

doi:10.1371/journal.pone.0004915.g005

If the loss of protection effectiveness is small, then the variation is very large. The vaccination program can eradicate the disease or reduce the final size of the epidemic to a very small size if we can execute the vaccination program near the optimal prevalence rate. The variation is sensitive for the prevalence rate. Therefore, we must carefully manage the vaccination program to control the disease when the loss is small. However, as the loss of protection effectiveness increases, the variation decreases. In particular, when the loss is medium, the reduction of the variation is remarkable. In addition, the reduction of the variation remains almost unchanged when the loss is large. This implies that the variation becomes insensitive if the loss is high. In this case, even if we can execute the vaccination program near the optimal prevalence rate, the effect of the program is not large. Therefore, although the final size is strongly affected by the vaccination coverage and a non-optimal vaccination program (far from the optimal prevalence rate) increases the final size, in general, good vaccine treatment with small loss of protection effectiveness has a great possibility for disease control. Demonstrably, poor vaccine application has little or no benefit.

Effects of non-pharmaceutical intervention

Avian influenza vaccination need not be used alone to eradicate the disease: additional non-pharmaceutical intervention is beneficial. Additional interventions must include culling infected animals, strict quarantine, movement controls and increased biosecurity, extensive surveillance [11], [16], [21], [34], [37]. We investigate the effects of some additional non-pharmaceutical intervention measures on the vaccination program. The effects are considered by changing model parameters (1).

In the European Union (EU), regulations for the control of avian influenza strains are imposed by EU council directive 92/40/EEC [34]. Virus output is reduced by the killing and removal of infected poultry flocks (culling). During the H7N7 epidemic in The Netherlands in 2003, this and other approaches were executed. To investigate the effectiveness of the control measures, A. Stegeman et al. quantified the transmission characteristics of the H7N7 strain before and after detection of the first outbreak of avian influenza in The Netherlands in 2003 [34]. In Table 1, we present the chosen epidemiological parameters, which are estimated on the H7N7 epidemic before notification of the circulation of the avian influenza (these parameters are not affected by the additional control measures). Here we choose other epidemiological parameters for vaccine-sensitive strain which are estimated by the H7N7 epidemic after the notification in [34] (these parameters are affected by the additional control measures) to evaluate an effect of the non-pharmaceutical intervention on the vaccination program. The estimate of the transmission parameter ω decreases considerably from 4.78×10−4 day−1 individual−1 to 1.70×10−4 day−1 individual−1 by the control measures. Furthermore, the estimate of the infectious period 1/(b+my) is also reduced from 13.8 days to 7.3 days. Therefore, control measures can reduce the basic reproductive number from 6.53 to 1.22 [34]. In addition, we assume, for example, that the relative transmissibility of vaccine-resistant strains is φ/ω = 0.7 and that the relative infectious period of vaccine-resistant strain is (b+my)/(b+mz) = 1.32 (these values are not strongly influential on our results).

We calculated the threshold values of the loss of protection effectiveness of the vaccination and present them in Table 3 when the vaccination program accompanies non-pharmaceutical intervention. Results show that the non-pharmaceutical intervention markedly reduces the risk of the emergence of the vaccine-resistant strain because σ* changes from 5.6% to 37.2%. In addition, the possibility that the vaccination program eventually eradicates the spread of the disease increases because changes from 20.1% to 88.6%. Furthermore, because σc changes from 23.6% to 100%, the vaccination program always decreases the final size of the epidemic compared with that before the vaccination program, even if the size increases when both strains co-exist. When the vaccination program accompanies non-pharmaceutical intervention, even if the loss of protection effectiveness is increased considerably by the vaccine-resistant strain, the loss can almost be compensated by the high optimal prevalence rate of the vaccination program: σo changes from 46.1% to 96.8%.

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Table 3. Threshold values of the loss of protection effectiveness of the vaccination.

doi:10.1371/journal.pone.0004915.t003

Figure 6 portrays the optimal prevalence rate of a vaccination program (top figure) and the optimal final size of the epidemic (bottom figure) with (pink curve and bar) or without (black curve and bar) the non-pharmaceutical intervention. The non-pharmaceutical intervention makes it easy to achieve an optimal prevalence rate and to prevent the spread of the disease. Moreover, catastrophic change does not occur until the loss of protection effectiveness becomes very high (top figure in Fig. 6). Furthermore, the optimal final size is also dramatically reduced by the additional intervention (bottom figure in Fig. 6). Even if vaccination without the additional intervention can not prevent the spread of the disease, the vaccination with the intervention can eradicate the disease (for example σ = 60%). Therefore, non-pharmaceutical intervention improves weak points of vaccination programs such as the difficult control of optimal vaccination coverage, the small applicability of the program with respect to the loss of protection effectiveness caused by the vaccine-resistant strain, and so on.

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Figure 6. Effects of non-pharmaceutical intervention: The top figure shows the optimal prevalence rate of the vaccination program with (pink curve) or without (black curve) non-pharmaceutical intervention.

The non-pharmaceutical intervention readily achieves the optimal prevalence rate and hinders the catastrophic change. The bottom figure shows the optimal final size of the epidemic with (pink bar) or without (black bar) the non-pharmaceutical intervention. The intervention also dramatically reduces the final size of the epidemic.

doi:10.1371/journal.pone.0004915.g006

Time-course of the spread of the disease

Finally, we investigate the time-course of spread of the disease according to vaccination and non-pharmaceutical interventions for 500 days in the presence of a vaccine-resistant strain. The results are presented in Fig. 7. We consider that the vaccination program and non-pharmaceutical interventions are executed after the vaccine-sensitive strain spreads and becomes endemic (around 200 days). Furthermore, the vaccine-resistant strain is assumed to occur in a few individuals after the start of the vaccination program (around 260 days). We assume that the prevalence rate of the vaccination program is p = 50%, the loss of protection effectiveness is σ = 80%; the other parameters are the same as those used in the descriptions above. These values of p and σ are not influential on our results (sensitivity analyses are shown in Supplementary Information: Text S1, Fig. S8, S9).

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Figure 7. Time-course of the spread of the disease with vaccination and non-pharmaceutical interventions: We calculate epidemic curves with a vaccination program for 500 days.

The vaccination program and non-pharmaceutical intervention are started after the vaccine-sensitive strain becomes endemic (around 200 days). We assume that the vaccine-resistant strain occurs after the start of vaccination (around 260 days). The top, middle, and bottom figures respectively depict time courses of infection without the vaccination program, with only the vaccination program, and with both the vaccination program and the non-pharmaceutical intervention. The blue and red curves respectively represent the number of infected individuals with vaccine-sensitive and vaccine-resistant strains. We assume that the prevalence rate of vaccination program is p = 0.5, the loss of protection effectiveness is σ = 0.8.

doi:10.1371/journal.pone.0004915.g007

The top figure in Fig. 7 depicts the epidemic curve without the vaccination program. It is apparent that the vaccine-sensitive strain (the blue curve) becomes endemic at around 200 days after a pandemic phase of the disease if we execute no intervention policy. The middle figure portrays the time-course of spread of the disease, assuming the vaccination program alone. A vaccine-resistant strain (the red curve) emerges and spreads widely through the population by replacing the vaccine-sensitive strain. It becomes endemic at around 450 days. This result shows the possibility that the emergence and replacement of the resistant strain can be facilitated by the vaccination program, as in some vaccination programs [19], [21], [22]. We can observe that it takes about several months for the resistant strain to beat the sensitive strain (see the middle figure in Fig. 7). Actually, the replacement time of the resistant strain was reported as several months in the China and Mexico epidemics [19], [21], [22]. The final size of the simulated epidemic is larger than that before (without) the vaccination program because the loss of protection effectiveness σ = 80% is greater than (see Fig. 3). In this case, the vaccination program negatively affects the control of infectious disease. The bottom figure presents the time-course of the spread of the disease with both the vaccination program and non-pharmaceutical interventions. The vaccine-sensitive strain is dramatically reduced and the vaccine-resistant strain hardly spreads in the population; therefore, both strains are eventually controlled at a low level by the interventions. Thus, non-pharmaceutical interventions can help the vaccination program and control the resistant strain to spread in the population.

Discussion

A serious problem of vaccination strategy is the emergence of vaccine-resistant strains [19], [20], [21], [22]. Even if a resistant strain emerges, a vaccination program must be managed to control the spread of the disease. In the absence of the resistant strain, our mathematical model certainly shows that a large prevalence of the vaccination program might markedly reduce an epidemic curve and the final size of the epidemic. Therefore, we can control infectious diseases as in previous models [30]. However, in the presence of the emergence of a vaccine-resistant strain, the vaccination program can not simply control the spread of the disease. The control of the infectious disease through vaccination becomes more difficult.

The paradoxical result obtained here is that if the virulence of vaccine-resistant strain is less than that of vaccine-sensitive strain, the final size of the epidemic might increase as the prevalence rate of the vaccination program increases (see Fig. 2). A vaccination that is expected to prevent the spread of the disease can instead foster the spread of the disease. Although qualitatively similar results were obtained through more complex models [8], [9], which can be treated analytically only to a slight degree, one of our important results is the clear and simple concept illustrating the value and pitfalls of vaccination programs; the concept can help farmers and administrators to avoid negative effects from paradoxical phenomena.

We investigated how the loss of protection effectiveness impacts a vaccination program’s results in the lower virulence case. If the loss of protection effectiveness is between 0 and , the vaccination program can eventually eradicate the disease, even if a vaccine-resistant strain emerges (see Fig. 3). In particular, if the loss is between 0 and σ*, the program prevents even the emergence of the resistant strain. However, when the loss is greater than , the program no longer prevents the wide spread of the resistant strain in spite of the large prevalence rate of the program. Furthermore, if the loss is between σc and 1, the program presents the risk that the final size will become larger than that without the vaccination program. Therefore, in the context of the emergence of the resistant strain, we must carefully execute the program to exercise a positive effect of the vaccine effectively. Additionally, we investigated the optimal prevalence rate of the vaccination program, its final size, and the worst-case final size (see Fig. 4, 5 and Supplementary Information: Text S1). The catastrophic change of the optimal prevalence rate and the variation of the final size depending on the loss of protection effectiveness were confirmed.

From our theoretical analysis, we propose that monitoring the virulence of the resistant strain and investigating the loss resulting from a resistant strain can have important consequences for developing a vaccination strategy. In particular, all thresholds derived herein are only constructed using basic reproductive numbers and transmissibilities that prevail before the vaccination program, which can be estimated using epidemiological data (it is usually almost impossible to estimate basic and invasion reproductive numbers during vaccination programs). Therefore, using our theory, we were able to calculate various risks in the vaccination program using the available data (Table 3) and propose how we might use a poor vaccine, which has a large loss of protection effectiveness, against the resistant strain to maximize the effects of the program (Fig. 4, 5, and 6). For the results reported here, we assumed that the vaccinated birds can perfectly protect the infection from the vaccine-sensitive strain. Although that assumption is not unreasonable [21], in Supplementary Information: Text S1, Fig. S10, S11, we present an investigation of the effect of the loss of protection effectiveness against the vaccine-sensitive strain. Qualitatively similar results were obtained using numerical simulations.

Vaccination is now being used extensively to aid the prevention of emergence or to control the spread of avian influenza [14]. However, if the vaccinations are not used appropriately, prevention and control will be negatively affected by the vaccination program [1], [11], [19], [21], [22]. Actually, when the vaccine-resistant strain emerges, our model predicts various risks in the program. Therefore, to eradicate the infectious disease effectively by vaccination, early detection of the resistant strain, monitoring of its virulence and loss of protection effectiveness of vaccination caused by the resistant strain, and attendance of non-pharmaceutical interventions, in addition to collaboration among farmers, industry, public health authorities, and the government are all required.

Supporting Information

Figure S1.

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Figure S2.

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Figure S5.

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Figure S7.

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Figure S8.

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Figure S9.

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Figure S10.

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Figure S11.

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Text S1.

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Author Contributions

Analyzed the data: SI TS YT. Contributed reagents/materials/analysis tools: SI TS YT. Wrote the paper: SI.

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Poultry disease vaccine brings short-term results but long-term problems: live vaccines that protect poultry against Newcastle Disease may be altering the genetic makeup of the wild virus strains

2010 study posted for filing

Contact: Amitabh Avasthi axa47@psu.edu 814-865-9481 Penn State

Attenuated live vaccines that protect poultry against Newcastle Disease may be altering the genetic makeup of the wild virus strains, which could make future outbreaks unpredictable and difficult to tackle, according to biologists.

Newcastle Disease is an economically devastating poultry disease that costs the industry millions of dollars.

“Many vaccines in the animal industry are developed by modifying a virulent live virus,” said Mary Poss, professor of biology and veterinary and biomedical sciences, Penn State. “These vaccines elicit a strong protection against disease.”

However, vaccinated birds can shed the vaccine virus to infect other birds, and live virus vaccines do not always protect birds from infection from other viral strains of Newcastle disease.

Poss and her Penn State colleagues Yee Ling Chong, graduate student in biology; Abinash Padhi, post-doctoral fellow and Peter J. Hudson, Willaman professor of biology, found that one vaccine strain recombined — exchanged genetic material — with at least three wild strains, creating new viruses. These viruses are found in both domestic and wild birds. The team’s findings appear today (Apr. 22) in PLoS Pathogens.

“Our findings indicate that birds can be simultaneously infected with the live virus vaccine and several other strains of this avian virus,” said Poss. “This raises concerns that modified live virus vaccines, though effective, may combine with circulating viruses to create unpredictable new strains.”

A modified live virus vaccine is essentially a weakened virus that does not cause disease but mimics a natural infection that in turn evokes a strong immune response from the infected host. But Poss argues that vaccination may be unwittingly increasing the diversity of Newcastle Disease viruses that are circulating in wild birds.

For instance, many poultry farmers typically vaccinate the flock by mixing the vaccine in the birds’ drinking water or by aerosol, which means wild birds and pigeons can also become infected with the vaccine virus.

This sets up the opportunity for viral recombination. A bird is infected with two different viruses at the same time, one from the weakened vaccine and one naturally, and both viruses then infect the same cell.

In addition to the possibility of creating new viruses, different strains of the virus that causes Newcastle disease may be evolving in different environments. Recombination among these strains could bring together genes that have multiple means to evade immunity in a host.

Poss added that vaccine developers need to be aware of the potential for driving virus evolution using modified live viruses and should instead consider using killed or inactivated viruses. Scientists are already using that approach against Newcastle Disease in some areas but not globally.

“We need to step up the surveillance and monitoring of viral diseases in poultry and wild birds,” said Poss. “We need to be aware that management practices including the use of live virus vaccines can change viral diversity and the consequences of such changes will not be evident for several generations.”

While many virus strains undergo a boom and bust cycle — they are present for a period of time and then die out — Poss notes that the use of live virus vaccines creates a persistent level of the vaccine strains in the global bird population.

Poultry farmers around the world vaccinate birds with vaccine made from one of two live strains of an avian virus that causes Newcastle Disease. While vaccines from the first strain are used mainly in Asia, the second strain is used in vaccines worldwide. Since the 1950s, vaccines derived from the two strains have helped poultry farmers avoid devastating economic losses.

To determine the impact of vaccination on the evolution of wild viruses, researchers analyzed the evolutionary history of 54 samples of full-length genome sequences of the avian paramyxovirus — the virus that causes Newcastle Disease — isolated from infected birds.

If all six genes that make up the paramyxovirus shared the same ancestor, Poss reasoned, the family trees of each gene would look the same. However, genes that are derived from a different strain would have family trees distinct from the other genes of that virus, a strong signature of recombination.

Statistical analysis of the gene sequences indicates that recombination occurred in at least five of the sampled genomes. Four of these five genomes contained gene sequences from one of the two vaccine strains.

Researchers next reconstructed the population history of the different viral strains. The strain from which the vaccine was derived showed a higher and more constant population size compared to other circulating strains.

“When viruses don’t change, it is typically a good thing,” Poss explained. “But as soon as they start to change, like the flu, we don’t know what the transmission and disease potential are going to be like from one year to another. So driving up viral diversity is not a good thing.”

New DNA vaccine technology poised to deliver safe and cost-effective disease protection

 

Contact: Richard Harth
richard.harth@asu.edu
Arizona State University

New and increasingly sophisticated vaccines are taking aim at a broad range of disease-causing pathogens, targeting them with greater effectiveness at lower cost and with improved measures to ensure safety.

To advance this quest, a research team led by Roy Curtiss, director of the Center for Infectious Diseases and Vaccinology, and Wei Kong, a research assistant professor, at Arizona State University’s Biodesign Institute have taken a dramatic step forward, revealing the design of a universal platform for delivering highly potent DNA vaccines, by employing a cleverly re-engineered bacterium to speed delivery to host cells in the vaccine recipient.

“The technology that we’re describing in this paper can be used to develop a vaccine against any virus, any parasite, any fungus, whereas this was never possible before the development of recombinant attenuated bacterial strains like those produced in our lab,” Curtiss says.

The experimental vaccine described in the new research demonstrated complete protection from influenza in mice, but Wei Kong, the leading author of the new study stresses that the innovative technique could be applied to the rapid manufacture of effective vaccines against virtually any infectious invader at dramatically reduced cost and without risk to either those vaccinated or the wider public.

“By delivering the DNA vaccine using a recombinant attenuated bacterium, we can get 10,000-100,000 doses per liter of culture,” Kong says, an improvement of 3-4 orders of magnitude over use of the naked plasmid DNA, which must be painstakingly isolated from bacteria before injection.

The group’s research results appear in the online Early Edition (EE) of the Proceedings of the National Academy of Sciences, the week of November 5, 2012.

 

Designing a vaccine that is both safe and effective presents a kind of Catch-22 for researchers. Live pathogenic strains typically generate a robust immune response, mimicking natural infection, but many challenges exist in terms of ensuring such strains do not cause illness or escape into the environment, where they have the potential to remain viable. Killed pathogen strains or vaccines produced from pathogen subunits sacrifice some of their immunogenic effectiveness for enhanced safety, and may require subsequent booster doses to ensure continued effectiveness.

The Curtiss team has worked to combine safety and effectiveness in orally administered vaccines that can be produced at a fraction of the cost of traditional methods. To do this, they have pioneered techniques using Salmonella—the notorious agent associated with food-borne illness—as a cargo vessel to deliver a suite of disease antigens to the recipient. The result has been the development and ongoing refinement of so-called RASVs (for recombinant attenuated Salmonella vaccines), capable of provoking an intense, system-wide immune response and conferring effective immunity.

One of the key innovations developed earlier by Wei Kong and other members of the Curtiss group, is a specialized Salmonella strain that can be timed to self-destruct in the body once it has carried out its immunization duties. To create this strain, the researchers modified the bacterium in such a way that it can only survive on a non-naturally occurring form of sugar. Once the Salmonella cells exhaust their store of specialized sugar, supplied to them as part of the vaccine, they are unable to maintain the integrity of their cell walls and they essentially implode. “This crucial safety feature ensures that Salmonella are unable to persist as living organisms to survive if excreted into the environment,” says Kong.

This self-destruct feature can be fine-tuned so that the bacteria fully colonize host cells, provoking a strong response from both humoral and cell-mediated arms of the immune system. Inside host tissues, recombinant Salmonella are able to synthesize protective antigens, releasing their contents when they become unstable and lyse into the intracellular fluid or cytosol.

The group demonstrated the effectiveness of this delayed-lysis bacteria in vaccine experiments with a variety of pathogens, including influenza and mycobacteria (causative agent of tuberculosis) and an RASV vaccine developed in the Curtiss lab against infant pneumonia is currently in FDA Phase I clinical trials. This earlier work focused on producing protective protein antigens in a bacterium, which would subsequently release a bolus of these antigens when the bacterial cell lysed within host cells and tissues.

In the latest research, the group sought to turn a delayed-lysis Salmonella strain into a universal DNA vaccine delivery vehicle. DNA vaccines stimulate cellular and humoral immune responses to protein antigens through the direct introduction of genetic material, prompting host cells to manufacture specific gene products. This is a crucial advance as it allows for the production of antigens that undergo host cell modification through the addition carbohydrates—a process known as glycosylation. Such modified antigens, which occur in a broad range of pathogenic viruses, fungi and parasites require synthesis by host cells, rather than by the attenuated bacteria.

“Here, we were able to deliver a vaccine whose DNA sequence induces the immunized individual to make the protective glycoprotein the way you would during a viral infection,” Curtiss says. Previous efforts to achieve this advance for delivery of DNA vacines by bacteria date to 1995, but only now has such work come to fruition.

A number of key modifications to the delayed-lysis RASV were required for this feat, and the Kong and Curtiss team has worked intensively over the past 5 years to achieve them. A hyperinvasive form of Salmonella was constructed through recombinant DNA methods in order to maximize the vaccine vector’s ability to invade host cells and become internalized.

Following host cell uptake, Salmonella are encased in a membrane-bound endosome known as the Salmonella Containing Vacuole. The RASV was further modified to permit escape from the endosome so that the mature bacterium could spew its immunogenic contents into the host cell’s cytosol.

Finally, further revisions to the Salmonella strain were applied to diminish the pathogen’s ability to cause host cell death, which would prevent the DNA vaccine from migrating to the host cell nucleus to induce the synthesis of protective antigens necessary for the immune response.

The authors note that their orally-administered RASV is markedly superior to earlier efforts which introduced DNA vaccines by means of intramuscular injection or gene gun. These methods fail to deliver the vaccine to both mucosal tissues and certain internal lymphoid tissues, vital to a sustained, protective immunity. “We can protect mice to doses of influenza that would be lethal were they not effectively immunized,” Curtiss says, adding that “RASV safety has been established in mice just two hours old as well as in pregnant and immunodeficient mice”.

Influenza spreads around the world in seasonal epidemics, resulting in about three to five million yearly cases of severe illness and about 250,000 to 500,000 yearly deaths, rising to millions in some pandemic years. Current manufacture of influenza vaccines requires use of chick embryos or cell culture methods. Global capacity is limited, making sufficient vaccine to immunize everyone impossible. Adding to concerns about managing future naturally occurring influenza epidemics is the potential for bioterrorists to produce weaponized influenza strains created using plasmid-based reverse genetics systems. “Increasing the speed of producing a matching vaccine is key in the context of response to an influenza epidemic,” Kong says.

The ability to rapidly engineer and scale up effective vaccines for influenza and other potentially lethal pathogens will require innovative approaches to vaccine design, manufacture and application. The universal DNA vaccine platform outlined in the new study represents an important advance.

“The vast majority of viruses including influenza, measles, mumps and HIV all have glycosylated proteins. You could never deliver protective immunity using a bacterium to produce those protein antigens,” Curtiss says. “But now we have the opportunity to produce vaccines against such pathogens,” Kong says. Further, the technique permits large quantities of DNA vaccine to be produced rapidly at low cost, freeze-dried and stockpiled to be used when needed.

###

Dr Roy Curtiss is also a professor in the College of Liberal Arts and Sciences, School of Life Sciences

Written by: Richard Harth
Science Writer: The Biodesign Institute
richard.harth@asu.edu

Sources:
Roy Curtiss, (480) 727-0445
Wei Kong, (480) 727-9591

Aspirin, Tylenol May Decrease Effectiveness of Vaccines: “if you block COX-1, you might be decreasing the amount of antibodies your body is producing”

2009 study posted for filing

Contact: Kelsey Jackson JacksonKN@missouri.edu 573-882-8353 University of Missouri-Columbia

Aspirin, tylenol may decrease effectiveness of vaccines

Mizzou scientists discover aspirin and Tylenol block enzymes that could inhibit vaccines

COLUMBIA, Mo. – With flu season in full swing and the threat of H1N1 looming, demand for vaccines is at an all-time high. Although those vaccines are expected to be effective, University of Missouri researchers have found further evidence that some over-the-counter drugs, such as aspirin and Tylenol, that inhibit certain enzymes could impact the effectiveness of vaccines.

“If you’re taking aspirin regularly, which many people do for cardiovascular treatment, or acetaminophen (Tylenol) for pain and fever and get a flu shot, there is a good chance that you won’t have a good antibody response,” said Charles Brown, associate professor of veterinary pathobiology in the MU College of Veterinary Medicine. “These drugs block the enzyme COX-1, which works in tissues throughout the body. We have found that if you block COX-1, you might be decreasing the amount of antibodies your body is producing, and you need high amounts of antibodies to be protected.”

COX enzymes play important roles in the regulation of the immune system. The role of these enzymes is not yet understood completely, and medications that inhibit them may have adverse side effects. Recent research has discovered that drugs that inhibit COX enzymes, such as COX-2, have an impact on the effectiveness of vaccines. Brown’s research indicates that inhibiting COX-1, which is present in tissues throughout the body, such as the brain or kidneys, could also impact vaccines’ effectiveness.

These MU researchers also are studying the regulation of inflammation and how that leads to the development or prevention of disease. Many diseases, such as arthritis, cardiovascular disease and diabetes, are all chronic inflammatory diseases. Contrary to previous beliefs, inflammation is generally a good thing that helps protect individuals from infection. Many of the non-steroidal drugs that treat inflammatory conditions reduce antibody responses, which are necessary for treating infections.

“So far, we’ve tested this on an animal model and have found that these non-steroidal drugs do inhibit vaccines, but the next step is to test it on humans,” Brown said. “If our results show that COX-1 inhibitors affect vaccines, the takeaway might be to not take drugs, such as aspirin, Tylenol and ibuprofen, for a couple weeks before and after you get a vaccine.”

###

Brown’s research, “Cycloozygenase-1 Orchestrates Germinal Center Formation and Antibody Class-Switch via Regulation of IL-17,” has been published in The Journal of Immunology.

Health Canada suspends dispersal of Novartis flu shots after discovery of virus particle clumps

By Helen Branswell, The Canadian  PressOctober 27, 2012

TORONTO – Canada is following the lead of several European countries and  suspending distribution of flu vaccine made by the pharmaceutical firm  Novartis.

The decision relates to the discovery by the company of tiny clumps of virus  particles in some batches of flu vaccines made at the Novartis production  facility in Italy.

Health Canada, which announced the move, said Novartis has agreed to suspend  distribution of its vaccines — sold in Canada as Fluad and Agriflu — while the  department investigates the situation. All the Novartis vaccine Canada purchases  is made at the Italian plant.

The department is also telling doctors and others who administer flu shots to  hold off using Novartis product for the time being.

“We think it’s prudent, given the response of certain European countries to .  . . request of Novartis — and they will be complying — to stop distributing and  then to recommend to practitioners to refrain from using the (Novartis) vaccine  just until this review is completed,” Dr. Paul Gully, senior medical advisory  for Health Canada, said Friday.

Italy, Germany and Switzerland have suspended distribution of some Novartis  flu vaccine, and in the case of Germany recalled some lots of vaccine, after the  clumping issue came to light.

In a statement issued Friday night, the company said more than one million  doses of its flu vaccines have been administered in Europe so far this season  and no unexpected adverse events have been reported.

As well, it said that it has already delivered about 70 per cent of its  Canadian order (roughly 1.5 million doses), again without hearing of problems in  people who have received Novartis flu shots. The company said people who have  received Novartis flu shots are not at risk.

Novartis said finding minute clumps of virus protein in vaccines is not  unusual. They said their vaccines passed quality inspections and they are  confident the products are safe.

“The aggregate proteins are predominantly influenza virus-derived (mainly  hemagglutinin), all normal and necessary components of influenza vaccines,” the  company said. “Aggregation of these proteins is not unusual in vaccines  manufacturing.”

Hemagglutinin is the protein on the outside of flu viruses that locks onto  cells in the human respiratory tract to start the process of infection. Flu  vaccines are designed to provoke the immune system to produce antibodies to  hemagglutinin to protect against infection.

In fact, this isn’t the first time protein clumping has disrupted Canada’s  flu vaccine supply.

During the 2009 pandemic, there was a delay in delivery of unadjuvanted  vaccine for pregnant women when GlaxoSmithKline, Canada’s pandemic vaccine  supplier, found visible protein aggregation in some of the vaccine.

Adjuvants are compounds that boost the response a vaccine generates. Canada  used adjuvanted vaccine during the pandemic, but bought some unboosted product  for pregnant women as a precaution.

Novartis makes only about 20 per cent of Canada’s annual flu vaccine  purchase. GlaxoSmithKline makes the bulk of Canada’s seasonal flu vaccine,  though a variety of other suppliers have a share of the Canadian market.

Still, because of the way vaccine orders are placed, the hold on Novartis  vaccine could put some provinces and territories in a position where they face a  temporary vaccine shortfall, just at the time when flu shot programs are getting  underway, Gully admitted.

He said Health Canada hopes there is a rapid resolution of the situation. But  if provinces or territories have a problem with supply, efforts will be made to  share across jurisdictions, he said.

Both Fluad and Agriflu are sold in single-dose formulations, pre-loaded into  a syringe.

Fluad contains an adjuvant and is licensed for use in people 65 and older.  Older adults do not mount a good response to flu vaccine and the inclusion of an  adjuvant is an effort to improve the protection they get from flu  shots.

© Copyright (c

Read more: http://www.ottawacitizen.com/health/Canada+suspends+dispersal+Novartis+shots+after+discovery+virus/7458536/story.html#ixzz2AZeegZfY

Spain regulator halts sale of some Novartis flu vaccines

Update #2 : France, Germany, Spain, Italy, and Switzerland now imposing partial ban on the Novartis Flu Vaccine

Italy has banned them..Switzerland is now considering

Thu, 25 Oct 2012 16:57 GMT

Source: reuters

MADRID, Oct 25 (Reuters) – Spain joined other European countries in halting the sale of anti-influenza vaccines made by Swiss group Novartis, after small particles were found in some of the injections.

Spain will halt the sale of all the Chiromas and Chiroflu vaccines, produced by Novartis in Italy, the Spanish Medicines and Health Products Agency (AEMPS) said in a statement on Thursday.

Spain follows Italy, where the sale and use of four anti-flu vaccines produced by Novartis was banned on Wednesday pending tests for possible side effects after white floating material was discovered in some vaccines.

“Some of the affected batches have already been sold in Spain and other European countries, without any recorded increase in adverse reactions,” the AEMPS said in a statement.

“Nevertheless, as a precautionary measure and until there is a full report detailing the origin and extent of the problem, we have decided to halt all specimens of both vaccines.”

Switzerland has also taken precautionary measures, while Germany’s vaccination agency said on Thursday some Novartis vaccines should not be used and that the Swiss drugmaker had agreed to recall them.

Novartis Chief Executive Joseph Jimenez said on Thursday he was confident the vaccines are safe and added he did not expect other countries to take action.  (Reporting by Clare Kane; Editing by David Holmes)

http://www.trust.org/alertnet/news/spain-regulator-halts-sale-of-some-novartis-flu-vaccines/

Italy bans Novartis flu vaccines pending tests. Switzerland to also take precautionary steps.

Wed, 24 Oct 2012 17:14 GMT

Source: reuters

ROME/ZURICH, Oct 24 (Reuters) – Italy banned the sale and use of anti-influenza vaccines produced by Novartis on Wednesday pending tests for possible side effects, prompting authorities in Switzerland to also take precautionary steps.

The Italian Health Ministry advised citizens not to buy or use the drugs Agrippal, Fluad, subunit Influpozzi and adjunvated Influpozzi until further notice.

It said 487,738 vaccine doses were affected, and the move came after the Italian Pharmaceutical Agency decided further tests on the products may be necessary following indications of possible side effects.

Switzerland’s drug watchdog then also raised a precautionary red flag for flu vaccines Agrippal and Fluad, saying that at most 160,000 doses were affected.

“Given the current unclear situation Swissmedic has issued a halt to deliveries for the cited vaccines and recommends not using them until further notice,” it said.

Preliminary investigations had shown Italy’s ban came after the discovery of white particles in the injections, which could suggest some of the components of the vaccine had clumped together, Swissmedic said.

Novartis said it was cooperating with Italian health authorities to understand the reasons behind the decision, and it had already provided authorities with an assessment in support of the quality, efficacy and safety of the vaccines.

Last week, Italy’s Health Ministry said Netherlands-based vaccine maker Crucell, a unit of U.S. drugmaker Johnson & Johnson, had suspended a delivery of 2.36 million seasonal flu vaccine doses to Italy after finding problems with two lots of it.

The ministry said last week it would make up the shortfall by purchasing more doses from other manufacturers.

Italy uses between 10 million and 12 million doses of flu vaccines every year, according to the ministry.

http://www.trust.org/alertnet/news/italy-bans-novartis-flu-vaccines-pending-tests/

700,000 travellers ‘at risk of typhoid due to dud jab’

More than 700,000 people who thought they were protected against typhoid may be vulnerable to the disease, because of a dud batches of a vaccine.

16 batches of the Typhim Vi vaccine for typhoid have been found to contain doses that have 'reduced potency' to fight the bacterial infection.

16 batches of the Typhim Vi vaccine for typhoid have been found to contain doses that have ‘reduced potency’ to fight the bacterial infection. Photo: ALAMY

<!– remove the whitespace added by escenic before end of tag –>

Stephen Adams

By , Medical Correspondent

5:46PM BST 08 Oct 2012

Manufacturer Sanofi Pasteur MSD has recalled 16 batches of its Typhim Vi vaccine – some 88 per cent of its stock – after tests found some of it was too weak.

The “reduced potency” shots could have been given to anyone immunised since January 2011.

The firm last night emphasised that defective doses of the vaccine itself were not dangerous.

However, the Medicines and Healthcare products Regulatory Agency (MHRA), which regulates drugs, said it could mean up to 729,606 had received weak vaccine.

This would mean they were more exposed to the bacterial infection that causes typhoid, than they thought.

An MHRA spokesman said: “This recall is due to concerns about the effectiveness of the vaccine in some syringes distributed from 7 January 2011 following filling problems in the manufacturing process.

“Therefore some patients who have been vaccinated with Typhim Vi may not be fully protected against the disease.

“If you received this vaccine and have recently returned from abroad, and are unwell, you should contact your doctor.”

Typhoid is a bacterial infection spread through contaminated food and water. It is rare in Britain but common throughout the tropics and sub-tropics.

Infections can cause intestinal bleeding, heart problems, pneumonia, seizures and swelling of the brain. If not treated with antibiotics, it can be fatal.

The vaccine is available free on the NHS for those travelling to high risk areas, or can be purchased through private clinics.

A spokesman for Sanofi Pasteur said the company decided to recall the batches after discovering that too many had reduced potency.

He said the cause of the problem had been identified, “but there will be a shortage” in coming months.

“We are hoping to get supplies back to normal by early 2013,” he said.

“We understand the difficulties this recall may cause for our customers and people relying upon our vaccines. We would like to offer our most sincere apologies for the inconveniences incurred.”

A Department of Health spokesman said: “Typhoid is rare in this country and is usually associated with travel to countries where sanitation is inadequate.

“The vaccine is still available and we are working with manufacturers to help ensure that current supply problems are resolved as soon as possible.

“People who have recently been immunised should seek medical advice about precautions to take whilst abroad to minimise the risk of infection, in case the vaccine has not provided full protection.”

A spokesman for the Health Protection Agency said: “Provisional data from 2011 to September 2012 do not suggest that there has been a spike in cases of Typhoid since January 2011 when the problem with the vaccine dates back to.

“Normal typhoid vaccine is 50-80 per cent effective travellers are advised to practise strict food, water and personal hygiene precautions even if vaccinated.”

 

Children with MS were 1.74 times more likely to have received a certain type of hepatitis B vaccine, called Engerix B®. Those children with MS developed symptoms three or more years after the vaccine.

Public release date: 25-Sep-2008 Re-Posted for Filing

Contact: Rachel Seroka
rseroka@aan.com
651-695-2738
American Academy of Neurology

Majority of children vaccinated against hepatitis B not at increased risk of MS

ST. PAUL, Minn. – The majority of children vaccinated against hepatitis B are not at an increased risk of developing multiple sclerosis (MS), according to a study to be published in the October 8, 2008, online issue of Neurology®, the medical journal of the American Academy of Neurology.

The study based in France involved 349 children with MS and 2,941 children without the disease. The children were all under the age of 16. A total of 24.4 percent of the children with MS were vaccinated for hepatitis B in the three years before the study, compared to 27.3 percent for the children without MS.

Although the study found that hepatitis B vaccination does not generally increase the risk of multiple sclerosis, the children with MS were 1.74 times more likely to have received a certain type of hepatitis B vaccine, called Engerix B®. Those children with MS developed symptoms three or more years after the vaccine. The risk was only found for this specific type of hepatitis B vaccine and not found for all vaccines against hepatitis B.

This association cannot be taken as confirmation that the vaccine caused MS. Further studies are needed to determine whether this is a causal relationship.

 

###

The American Academy of Neurology, an association of more than 21,000 neurologists and neuroscience professionals, is dedicated to improving patient care through education and research. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as stroke, Alzheimer’s disease, epilepsy, Parkinson’s disease, and multiple sclerosis.

For more information about the American Academy of Neurology, visit www.aan.com.

Autism May Be Caused By An Immune System Response To Measles: Only Autistic Children Had Brain Autoantibodies

Re-Posted at Request 1998 Study..I hope this helps

Contact: Nancy Ross-Flanigan rossflan@umich.edu 734-647-1853 University of Michigan

Autism May Be Caused By An Immune System Response To A Virus

ANN ARBOR—Antibodies found in the blood of autistic children suggest that at least some cases of autism are caused by a misguided immune response, triggered by exposure to a virus, researchers in the University of Michigan’s College of Pharmacy report.

The researchers found that autistic children who had been exposed to certain viruses in the past showed unusually high levels of antibodies to brain proteins, suggesting an autoimmune response.  Their findings appear in the October issue of the peer-reviewed journal, Clinical Immunology and Immunopathology.

Autism is a developmental disorder that affects brain function, interfering with reasoning ability, imagination, communication, and social interaction.  Children with autism start talking later than other children, and when they do speak, their communication skills are extremely limited.  They often avoid looking at other people and don’t learn to read others’ faces for signs of emotion or other cues.  These children typically are unable to play creatively, and some engage in repetitive, sometimes self-destructive, behavior, such as rocking, hand flapping or head-banging.

No single cause of autism has been found, and researchers believe that genes and environmental factors (such as viruses or chemicals) both may contribute.  The kinds of brain abnormalities found in people with autism suggest that the disorder arises when something disrupts normal brain development.

One possibility is that early exposure to a virus prods the body into mounting an immune response that somehow goes awry.  In addition to producing antibodies against the virus, the body makes antibodies against itself, resulting in damage to tissues and organs.

This “autoimmune” response is what happens in autoimmune diseases such as lupus, and some researchers think a similar response may account for the brain abnormalities found in people with autism.

It was this possibility that U-M researchers Vijendra Singh and Victor Yang and undergraduate student assistant Sheren Lin investigated.  In their study of 48 autistic children and 34 normal children and adults, the researchers measured levels of antibodies to two viruses—measles virus and human herpesvirus-6—in the subjects’ blood.  These antibodies were chosen because they are often used in research on known autoimmune diseases, says Singh, the principal investigator of the project and an assistant research scientist in the College of Pharmacy.

The researchers also measured levels of two brain autoantibodies (antibodies to brain tissue).  One, anti-MBP, is an antibody to myelin basic protein, a protein found in the protective sheaths around nerve fibers in the brain.  The other, anti-NAFP, is an antibody to neuron-axon filament protein, a protein that makes up the nerve fibers themselves.

Virus antibody levels were essentially the same in autistic and non-autistic subjects, as the researchers expected.  But the majority of autistic children who had virus antibodies also had brain autoantibodies.  The higher the level of virus antibodies, the more likely an autistic child was to have brain autoantibodies.  None of the non-autistic subjects had brain autoantibodies.

The strongest link found in the autistic children was between measles virus antibodies and anti-MBP, suggesting that exposure to the measles virus may trigger an autoimmune response that interferes with the development of myelin, says Singh.  If myelin in the brain doesn’t develop properly, nerve fibers won’t work as they should.  This could be one way that the brain abnormalities associated with autism arise.

The question of how exposure to measles virus occurs raises a controversial issue.  Parents of children with autism often report that the children started showing signs of the disorder shortly after being immunized with measles-mumps-rubella (MMR) or diphtheria-pertussis-tetanus (DPT) vaccine, but no scientific studies have shown a link between vaccines and autism.  In the U-M study, almost all the subjects had had MMR immunizations, and none had ever had a case of measles.  It is possible, however, that some might have been infected with measles virus but never developed symptoms of measles, says Singh.

###Contact:  Nancy Ross-Flanigan University of Michigan 412 Maynard St. Ann Arbor, MI 48109-1399 Phone:  (734) 647-1853 rossflan@umich.edu

Scientists develop fungus-fighting vaccine

Contact: Nickey Henry henryn@rockefeller.edu 212-327-8366 Journal of Experimental Medicine

A group of scientists in Italy have developed a vaccine with the potential to protect against fungal pathogens that commonly infect humans, according to a study by Torosantucci and colleagues in the September 5 issue of The Journal of Experimental Medicine.  Although these fungi pose little threat to people with healthy immune systems, they can cause fatal infections in those whose immune systems have been weakened by cancer treatments or post-transplant immunosuppressive therapies.  No anti-fungal vaccines are currently available.

The new vaccine was made of a sugar-like molecule called beta-glucan that is found on the cell wall of the fungus and that the fungus needs to grow and survive.  To induce a robust immune response to the vaccine, the group attached the relatively innocuous beta-glucan to a protein called diptheria toxin that is known to stimulate the immune system and has been used in other human vaccines.

The vaccine protected rodents from fatal fungal infections by triggering the production of anti-beta-glucan antibodies.  These antibodies stuck to the invading fungal cell wall and prevented the fungus from growing.  The authors now plan to test the vaccine in humans and hope the results are equally promising.

Reposted for Filing 2005

Rogue strain of MMR vaccine ’caused deafness’

A rogue strain of the vaccine for measles, mumps and rubella has been found to have caused deafness in at least two children, it has been claimed.

A rogue strain of the vaccine for measles, mumps and rubella has been found to have caused deafness in at least two children, it has been claimed.

Photo: PA

7:00AM BST 05 Sep 2012

Katie Stephen, who lost the use of her left ear days after being inoculated as a child, is reportedly the first known victim to prove her case to the Vaccine Damage Payments Unit.

But the 21-year-old has been refused the £120,000 payout for vaccine injury because it is only given to people with 60% disablement.

The measure used by the Department of Work and Pensions (DWP) to decide payouts defines single-sided deafness as 20% disablement.

It comes after a second victim, who lost hearing in both ears, received compensation in a previous case, the paper said.

Miss Stephen’s mother Wendy said: “She wasn’t born this way. This was done to her by the Department of Health. They distributed pamphlets arguing that this was the right thing to do for your child and not just that but the right thing to do for herd immunity in the UK against these three illnesses.”

Paul Breckell, chief executive of Action on Hearing Loss, said: “We are disappointed that the formula used by the Vaccine Damage Payments Unit does not fully recognise the impact for Katie in completely losing the hearing in her left ear.”

Miss Stephen, from Stonehaven, in Aberdeenshire, was 15 months old when she was given the inoculation in 1991.

A health visitor recorded hearing problems at 18 months old, although previous tests had been normal, and in 1996 she was diagnosed with deafness.

According to The Times newspaper, her medical records show that she was deafened by an MMR jab using the rogue Urabe strain of mumps, which was given to 5.4 million British children between 1988 and 1992.

In total, 10 cases of deafness after the jab were formally recorded at the time, the paper said.

An academic study found that the cause of deafness in six of those cases was unknown but MMR was a possibility, it added. Four of the suspect cases had single-sided deafness.

Asked why the industrial injuries measure was being used on vaccine-damaged children, a SWP spokeswoman said: “This is not in regulations – it was considered at the inception of the scheme that disablement should be assessed as a percentage similar to the system as applied in the War Pensions and Industrial Injuries Schemes.”

She added: “The payments were set at the same level as the Industrial Injuries Benefit and does provide financial support to those eligible.

“Those who are eligible for this help may also be eligible for other support from the benefits system.”

The Department of Health (DoH) stressed the importance of the MMR vaccine and said it had saved many lives.

Director of Immunisation Professor David Salisbury said: “It is important that parents get their child vaccinated against measles, mumps and rubella – all of which are highly infectious.

“Uptake rates for the MMR vaccine are at their highest level for 10 years and it is the best way to protect children against all three infections.”

FDA ties pneumonia deaths to infant vaccine

Repost from 2008

 

WASHINGTON – GlaxoSmithKline Plc’s rotavirus vaccine is associated with increased pneumonia-related deaths and other adverse reactions, U.S. regulatory staff said in documents posted on Friday.

The review comes ahead of a Food and Drug Administration advisory meeting next Wednesday to consider approval of the oral vaccine to prevent the most common cause of severe diarrhea and dehydration among infants and young children in the world.

FDA staff said its analysis of 11 studies revealed that in the largest trial, there was a statistically significant increase in deaths related to pneumonia compared with placebo, documents posted on the FDA’s Web site said.

That study, which enrolled about 63,000 children, also found an increase in convulsions in children given the drug, named Rotarix. Another study found an increased rate of bronchitis, compared with placebo.

 

In a conclusion section, the FDA documents noted the pneumonia-related deaths and convulsions, but did not appear to make a recommendation to the advisory panel.

That expert panel will weigh the staff review, but makes its own recommendation, which is typically followed by the FDA

Compound discovered that boosts effect of vaccines against HIV and flu: polyethyleneimine (PEI) 100% Letahl Flu Protection

Contact: University of Oxford press.office@admin.ox.ac.uk 44-018-652-80530 University of Oxford

Novel vaccine additive to enhance the body’s immune response shows promise in mice

Oxford University scientists have discovered a compound that greatly boosts the effect of vaccines against viruses like flu, HIV and herpes in mice.

An ‘adjuvant’ is a substance added to a vaccine to enhance the immune response and offer better protection against infection.

The Oxford University team, along with Swedish and US colleagues, have shown that a type of polymer called polyethyleneimine (PEI) is a potent adjuvant for test vaccines against HIV, flu and herpes when given in mice.

The researchers were part-funded by the UK Medical Research Council and report their findings in the journal Nature Biotechnology.

Mice given a single dose of a flu vaccine including PEI via a nasal droplet were completely protected against a lethal dose of flu. This was a marked improvement over mice given the flu vaccine without an adjuvant or in formulations with other adjuvants.

The Oxford researchers now intend to test the PEI adjuvant in ferrets, a better animal model for studying flu. They also want to understand how long the protection lasts for. It is likely to be a couple of years before a flu vaccine using the adjuvant could be tested in clinical trials in humans, the researchers say.

‘Gaining complete protection against flu from just one immunisation is pretty unheard of, even in a study in mice,’ says Professor Quentin Sattentau of the Dunn School of Pathology at Oxford University, who led the work. ‘This gives us confidence that PEI has the potential to be a potent adjuvant for vaccines against viruses like flu or HIV, though there are many steps ahead if it is ever to be used in humans.’

HIV, flu and herpes are some of the most difficult targets to develop vaccines against. HIV and flu viruses are able to change and evolve to escape immune responses stimulated by vaccines. There aren’t any effective vaccines against HIV and herpes as yet, and the flu vaccine needs reformulating each year and doesn’t offer complete protection to everyone who receives it. Finding better adjuvants could help in developing more effective vaccines against these diseases.

Most vaccines include an adjuvant. The main ingredient of the vaccine – whether it is a dead or disabled pathogen, or just a part of the virus or bacteria causing the disease – primes the body’s immune system so it knows what to attack in case of infection. But the adjuvant is needed as well to stimulate this process.

While the need for adjuvants in vaccines has been recognised for nearly 100 years, the way adjuvants work has only recently been understood. The result has been that only a small set of adjuvants is used in current vaccines, often for historical reasons.

The most common adjuvant by far is alum, an aluminium-containing compound that has been given in many different vaccines worldwide for decades. However, alum is not the most potent adjuvant for many vaccine designs.

‘There is a need to develop new adjuvants to get the most appropriate immune response from vaccines,’ says Professor Sattentau, who is also a James Martin Senior Fellow at the Oxford Martin School, University of Oxford.

The Oxford University team found that PEI, a standard polymer often used in genetic and cell biology, has strong adjuvant activity.

When included in a vaccine with a protein from HIV, flu or herpes virus, mice subsequently mounted a strong immune response against that virus. The immune response was stronger than with other adjuvants that are currently being investigated.

The team also showed that PEI is a potent adjuvant in rabbits, showing the effect is not just specific to mice and could be general.

Another potential advantage of PEI is that it works well as an adjuvant for ‘mucosal vaccines’. These vaccines are taken up the nose or in the mouth and absorbed through the mucus-lined tissues there, getting rid of any pain and anxiety from a needle. Mucosal vaccines may also be better in some ways as mucosal tissues are the sites of infection for these diseases (airways for respiratory diseases, genital mucosa for HIV and herpes).

Professor Sattentau suggests that: ‘In the best of all possible worlds, you could imagine people would have one dose of flu vaccine that they’d just sniff up their nose or put under their tongue. And that would be it: no injections and they’d be protected from flu for a number of years.

‘It’s just a vision for the future at the moment, but this promising adjuvant suggests it is a vision that is at least possible.’

###

Notes to Editors

* The body’s immune system is made up of two arms: the innate immune system and the adaptive immune system. The adaptive immune system consists of the antibodies and immune cells (T and B cells) the body develops specifically to combat a particular foreign agent.

The innate immune system had been thought of as playing a more primitive, non-specific role in protecting against invaders like viruses and parasites. However, it is now realised that the innate immune system is essential in kicking off any immune response. It needs to be activated first to generate an adaptive immune response.

But the innate immune system doesn’t just press the start button. It tailors the body’s adaptive immune response, deciding on what particular mix of antibodies and T cells is needed and teaching them what to attack.

It is the adjuvants in vaccines that stimulate the innate immune system. So having the right adjuvant can help the body produce the most appropriate immune response to protect against future infection.

* The paper ‘Polyethyleneimine is a potent mucosal adjuvant for glycoproteins with innate and adaptive immune activating properties’ is to be published in the journal Nature Biotechnology with an embargo of 18:00 UK time / 13:00 US Eastern time on Sunday 26 August 2012.

* The study was funded by the UK Medical Research Council, European Commission, the International AIDS Vaccine Initiative (IAVI), the Bill and Melinda Gates Foundation and Dormeur Investment Service Ltd.

* Professor Sattentau is an investigator in the Jenner Institute at Oxford University and a James Martin Senior Fellow at the Oxford Martin School, Oxford University.

* For almost 100 years the Medical Research Council has improved the health of people in the UK and around the world by supporting the highest quality science. The MRC invests in world-class scientists. It has produced 29 Nobel Prize winners and sustains a flourishing environment for internationally recognised research. The MRC focuses on making an impact and provides the financial muscle and scientific expertise behind medical breakthroughs, including one of the first antibiotics penicillin, the structure of DNA and the lethal link between smoking and cancer. Today MRC funded scientists tackle research into the major health challenges of the 21st century. www.mrc.ac.uk

* The Oxford Martin School

is a unique interdisciplinary community within the University of Oxford. The School fosters innovative thinking, deep scholarship and collaborative activity to address the most pressing risks and realise new opportunities of the 21st century. It was founded in 2005 through the vision and generosity of James Martin, and currently comprises over 35 interdisciplinary research programmes on global future challenges. The Oxford Martin School’s Director is Ian Goldin, Professor at the University of Oxford. http://www.oxfordmartin.ox.ac.uk

* Oxford University’s Medical Sciences Division is one of the largest biomedical research centres in Europe, with over 2,500 people involved in research and more than 2,800 students. The University is rated the best in the world for medicine, and it is home to the UK’s top-ranked medical school.

From the genetic and molecular basis of disease to the latest advances in neuroscience, Oxford is at the forefront of medical research. It has one of the largest clinical trial portfolios in the UK and great expertise in taking discoveries from the lab into the clinic. Partnerships with the local NHS Trusts enable patients to benefit from close links between medical research and healthcare delivery.

A great strength of Oxford medicine is its long-standing network of clinical research units in Asia and Africa, enabling world-leading research on the most pressing global health challenges such as malaria, TB, HIV/AIDS and flu. Oxford is also renowned for its large-scale studies which examine the role of factors such as smoking, alcohol and diet on cancer, heart disease and other

OHSU research suggests America may over-vaccinate

 

 

PORTLAND, Ore. –A new study published in the New England Journal of Medicine this week by Oregon Health & Science University researchers suggests that timelines for vaccinating and revaccinating Americans against disease should possibly be reevaluated and adjusted. The study shows that in many cases, the established duration of protective immunity for many vaccines is greatly underestimated. This means that people are getting booster shots when their immunity levels most likely do not require it. The results are published in the November 8 edition of the journal

 

“The goal of this study was to determine how long immunity could be maintained after infection or vaccination. We expected to see long-lived immunity following a viral infection and relatively short-lived immunity after vaccination, especially since this is the reasoning for requiring booster vaccinations. Surprisingly, we found that immunity following vaccination with tetanus and diphtheria was much more long-lived than anyone realized and that antibody responses following viral infections were essentially maintained for life,” explained Mark Slifka, Ph.D. Slifka serves as an associate scientist at the Vaccine and Gene Therapy Institute with joint appointments at the Oregon National Primate Research Center and the department of molecular microbiology and immunology in the OHSU School of Medicine.

 

The research also reconfirmed a previous finding by Slifka and his colleagues: that the duration of immunity after smallpox vaccination is much longer than previously thought. In that earlier study published in the journal Nature Medicine in 2003, these OHSU researchers observed surprisingly long-lived antiviral antibody responses but they were unable to measure the slow rate of decline. In this current study, they demonstrate that this type of immunity is maintained with a calculated half-life of 92 years – a number that is substantially longer than the estimate of only 3 to 5 years of immunity following vaccination that was previously proposed by experts at the Centers for Disease Control and Prevention.

 

“Another example is the tetanus vaccine,” said Slifka. “Doctors are told that vaccination is effective for a period of 10 years – but after that, people should be revaccinated. Based on our studies and the work of others, once a person has received their primary series of vaccinations they are likely to be protected for at least three decades. Indeed, other countries such as Sweden have changed their vaccination policies and doctors are advised to offer tetanus revaccination only once every 30 years.” Importantly, this has not resulted in any increase in the number of tetanus cases in Sweden and demonstrates first-hand that switching from the 10-year to 30-year policy is safe and effective. Taking this small step in vaccination scheduling could save hundreds of millions of dollars on health care here in the US.”

* Requested Repost

 

New salmonella-based ‘clean vaccines’ aid the fight against infectious disease:To accomplish this, a recombinant strain of Salmonella was constructed using genes from another pathogen, Francisella tularensis

* They are using genes from tularensis ” inhaling as few as 10 bacteria could be potentially deadly ” I feel uncomfortable with the Gates foundation funding support utilizing a Bioweapon strain of  Rabbit Fever?

 

New salmonella-based ‘clean vaccines’ aid the fight against infectious disease

A powerful new class of therapeutics, known as recombinant attenuated Salmonella vaccines (RASV), holds great potential in the fight against fatal diseases including hepatitis B, tuberculosis, cholera, typhoid fever, AIDS and pneumonia.

Now, Qingke Kong and his colleagues at the Biodesign Institute at Arizona State University, have developed a technique to make such vaccines safer and more effective. The group, under the direction of Dr. Roy Curtiss, chief scientist at Biodesign’s Center for Infectious Diseases and Vaccinology, demonstrated that a modified strain of Salmonella showed a five-fold reduction in virulence in mice, while preserving strong immunogenic properties.

Their findings appear in the cover story of the current issue of the Journal of Immunology.

Streptococcus pneumoniae, an aerobic bacterium, is the causative agent of diseases including community-acquired pneumonia, otitis media, meningitis, and bacteremia. It remains a leading killer—childhood pneumonia alone causing some 3 million fatalities annually, mostly in poorer countries.

Existing vaccines are inadequate for protecting vulnerable populations for several reasons. Heat stabilization and needle injection are required, which are often impractical for mass inoculation efforts in the developing world. Repeated doses are also needed to induce full immunity. Finally, the prohibitively high costs of existing vaccines often deprive those who need them most.  The problem is exacerbated by the recent emergence of antibiotic-resistant strains of pneumococcus causing the disease, highlighting the urgency of developing safe, effective, and lower-cost antipneumococcal vaccines.

One of the most promising strategies for new vaccine development is to use a given pathogen as a cargo ship to deliver key antigens from the pathogen researchers wish to vaccinate against. Salmonella, the bacterium responsible for food poisoning, has proven particularly attractive for this purpose, as Curtiss explains: “Orally-administered RASVs stimulate all three branches of the immune system stimulating mucosal, humoral, and cellular immunity that will be protective, in this case, against a majority of pneumococcal strains causing disease.”

Recombinant Salmonella is a highly versatile vector—capable of delivering disease-causing antigens originating from viruses, bacteria and parasites.  An attenuated Salmonella vaccine against pneumonia, developed in the Curtiss lab, is currently in FDA phase 1 clinical trials.

In the current research, the team describe a method aimed at retaining the immunogenicity of an anti-pneumonia RASV while reducing or eliminating unwanted side effects sometimes associated with such vaccines, including  fever and intestinal distress. “Many of the symptoms associated with reactogenic Salmonella vaccines are consistent with known reactions to lipid A, the endotoxin component of the Salmonella lipopolysaccharide (LPS),” the the major surface membrane component , Kong explained.   “In this paper, we describe a method for detoxifying the lipid A component of LPS in living cells without compromising the ability of the vaccine to stimulate a desirable immune response.”

To achieve detoxification, Salmonella was induced to produce dephosphoylated lipid A, rendering the vaccine safer, while leaving its ability to generate a profound, system-wide immune response, intact.

To accomplish this, a recombinant strain of Salmonella was constructed using genes from another pathogen, Francisella tularensis, a bacterium associated with tularemia or rabbit fever. Salmonella expressing lipid A 1-phosphatase from tularensis (lpxE) showed less virulence in mice, yet acted to inoculate the mice against subsequent infection by wild-type Salmonella.

In further experiments, the group showed that Salmonella strains could also be constructed to additionally synthesize pneumococcal surface protein A (PspA)—a key antigen responsible for generating antibodies to pneumonia. Again, the candidate RASV displayed nearly complete dephosphorylation of lipid A, thereby reducing toxicity.

Following inoculation with the new Salmonella strain, mice produced a strong antibody response to PspA and showed greatly improved immunity to wild-type Streptococcus pneumoniae, compared with those inoculated with Salmonella lacking  the PspA antigen. Tissue culture studies showing reduction of inflammatory cytokines following application of modified lipid A further buttressed the results.

Francisella LpxE was shown to effectively strip the 1-phosphate group from Salmonella‘s lipid A, without loss of the bacterium’s capacity for colonization. The research holds promise for constructing modified live attenuated Salmonella vaccine strains for humans, with dephosphoylated lipid A providing additional safety benefits.

###

 

The research was supported by grants from the Bill and Melinda Gates Foundation and the National Institute of Health

* Reposted on Request

Vaccine tied to ‘superbug’ ear infection – Old Prevnar 2007 Historical Only

*Requested Repost From 2007 – Info is Historical

 

A vaccine that has dramatically curbed pneumonia and other serious illnesses in children is also having an unfortunate effect: promoting new superbugs that cause ear infections

On Monday, doctors reported discovering the first such germ that is resistant to all drugs approved to treat childhood ear infections. Nine toddlers in Rochester, N.Y., have had the bug and researchers say it may be turning up elsewhere, too.

Wyeth anticipated this and is testing a second-generation vaccine. But it is at least two years from reaching the market, and the new strains could become a public health problem in the meantime if they spread hard-to-treat infections through day care centers and schools.

It is a strain of strep bacteria not included in the pneumococcal vaccine, Wyeth’s Prevnar, which came on the market in 2000. It is recommended for children under age 2.

Prevnar, however, is losing its punch because strains not covered by the vaccine are filling the biological niche that the vaccine strains used to occupy, and they are causing disease.

One strain in particular, called 19A, is big trouble. A new subtype of it caused ear infections in the nine Rochester children, ages 6 months to 18 months, that were resistant to all pediatric medications, said Dr. Michael Pichichero, a microbiologist at the University of Rochester Medical Center.

The children had been unsuccessfully treated with two or more antibiotics, including high-dose amoxicillin and multiple shots of another drug. Many needed surgery to place ear tubes to drain the infection, and some recovered only after treatment with a newer, powerful antibiotic whose safety in children has not been established.

–Scientists from a drug company and two labs analyzed more than 21,000 bacterial samples from around the nation and found 19A increasing. Among children 2 and under, the portion of samples that were this strain rose to 15 percent in 2005-2006, from 4 percent in the previous three years.

–A British lab tracking respiratory infections in U.S. kids found that the 19A strain accounted for 40 percent of drug-resistant cases.

–University of Iowa researchers found 19A accounted for 35 percent of penicillin-resistant infections in 2004-05, compared with less than 2 percent the year before the new vaccine came out.

‘MMR vaccine causes autism’ claim banned – Followed by 15 studies that link Strong Correlation, it May

By

8:34AM BST 08 Aug 2012

Babyjabs.co.uk said the vaccine “could be causing autism in up to 10% of   autistic children in the UK”. It also said: “Most experts now agree that the   large rise (in autism) has been caused partly by increased diagnosis, but   also by a real increase in the number of children with autism.”

A further claim said the vaccine-strain measles virus has been found in the   gut and brain of some autistic children, which supports many parents’ belief   that the MMR vaccine caused autism in their children.

One person complained that the claims are misleading and unsubstantiated.

Defending the claims, Babyjabs referred to one study in particular from 2002,   which it considered to be one of the strongest pieces of evidence that the   MMR vaccine does not cause autism but which it claimed includes the lead   author’s conclusion: “We cannot rule out the existence of a susceptible   subgroup with an increased risk of autism if vaccinated.”

It also said The Truth About Vaccines, a book written by Babyjabs medical   director Dr Richard Halvorsen, stated: “If one in 800 MMR vaccinations   triggered an autistic disorder, this would result in around 1,200 children a   year in the UK being made autistic by the bundling of the vaccines. This is   probably the worst case scenario.”

Dr Halvorsen added that “research, including large population studies, has   since shown that the MMR is not causing the large majority of autism, but   has been unable to exclude the possibility that it is causing autism in a   small number of susceptible children”.

Upholding the complaint, the Advertising Standards Authority (ASA) noted that   the website makes clear that the original allegations of a link between the   MMR vaccine and autism by Andrew Wakefield was “strongly rejected” by   government and the medical establishment”.

But it said consumers are likely to infer from the website’s claims that the   vaccine might have played a role in the “increase” in the number of children   with autism.

The ASA said: “We understood that the position held by the World Health   Organisation and the Department of Health was that no evidence existed of a   causal association between the MMR vaccine and autism or autistic disorders,   and that the Cochrane review, looking at the general evidence available,   could find no significant association between MMR immunisation and autism.

“We noted that the evidence provided by the advertiser included studies and an   article which looked at the increased prevalence of autism, but did not   include evidence that any increase was due to the MMR vaccine.”

It ruled that the claims must not appear again in their current form

 

Now for the Correlating studies in Support of Neurlogical Damage: With thanks to Gaia Health and The refusers…This is the counter argumant

 

Viral/Immune studies:

Abnormal measles-mumps-rubella antibodies and CNS autoimmunity in children with autism.

Autoimmunity to the central nervous system (CNS), especially to myelin basic protein (MBP), may play a causal role in  autism, a neurodevelopmental disorder. Because many autistic children harbor elevated levels of measles antibodies, we conducted a serological study of measles-mumps-rubella (MMR) and MBP autoantibodies.

….over 90% of MMR antibody-positive autistic sera were also positive for MBP autoantibodies, suggesting a strong association between MMR and CNS autoimmunity in autism. Stemming from this evidence, we suggest that an inappropriate antibody response to MMR, specifically the measles component thereof, might be related to pathogenesis of autism.

Serological association of measles virus and human herpes virus-6 with brain auto-antibodies in autism.

This study is the first to report an association between virus serology and brain autoantibody in autism; it supports the  hypothesis that a virus-induced autoimmune response may play a causal role in autism.

Hypothesis: conjugate vaccines may predispose children to autism spectrum disorders.

Conjugate vaccines fundamentally change the manner in which the immune systems of infants and young children function by deviating their immune responses to the targeted carbohydrate antigens from a state of hypo-responsiveness to a robust B2 B cell mediated response.

This period of hypo-responsiveness to carbohydrate antigens coincides with the intense myelination process in infants and young children, and conjugate vaccines may have disrupted evolutionary forces that favored early brain development over the need to protect infants and young children from capsular bacteria.

Effects of diphtheria-tetanus-pertussis or tetanus vaccination on allergies and allergy-related respiratory symptoms among children and adolescents in the United States.

The odds of having a history of asthma was twice as great among vaccinated subjects than among unvaccinated subjects The odds of having had any allergy-related respiratory symptom in the past 12 months was 63% greater among vaccinated subjects than unvaccinated subjects The associations between vaccination and subsequent allergies and symptoms were greatest among children aged 5 through 10 years.

Neurological Complications of Pertussis Immunization

Review is made of 107 cases of neurological complications of pertussis inoculation reported in the literature. The early onset of neurological symptoms was characteristic, with changes of consciousness and convulsions as the most striking features. The question of aetiology is considered and contraindications are discussed….as is the grave danger of further inoculations when a previous one has produced any suggestion of a neurological reaction.

Hepatitis B vaccination of male neonates and autism diagnosis, NHIS 1997-2002.

Findings suggest that U.S. male neonates vaccinated with the hepatitis B vaccine prior to 1999 (from vaccination record) had a threefold higher risk for parental report of autism diagnosis compared to boys not vaccinated as neonates during that same time period. Nonwhite boys bore a greater risk.

Aluminum Studies:

Do aluminum vaccine adjuvants contribute to the rising prevalence of autism?

Our results show that: (i) children from countries with the highest ASD prevalence appear to have the highest exposure to Al from vaccines; (ii) the increase in exposure to Al adjuvants significantly correlates with the increase in ASD prevalence in the United States observed over the last two decades;

and (iii) a significant correlation exists between the amounts of Al administered to preschool children and the current prevalence of ASD in seven Western countries, particularly at 3-4 months of age.

Aluminum hydroxide injections lead to motor deficits and motor neuron degeneration.

…A second series of experiments was conducted on mice injected with six doses of aluminum hydroxide. Behavioural analyses in these mice revealed significant impairments in a number of motor functions as well as diminished spatial memory capacity.

Aluminum Vaccine Adjuvants: Are they Safe?

Experimental research, clearly shows that aluminum adjuvants have a potential to induce serious immunological disorders in humans. In particular, aluminum in adjuvant form carries a risk for autoimmunity, long-term brain inflammation and associated neurological complications and may thus have profound and widespread adverse health consequences. click for entire study

Thimerosal studies:

Integrating experimental (in vitro and in vivo) neurotoxicity studies of low-dose thimerosal relevant to vaccines.

There is a need to interpret neurotoxic studies to help deal with uncertainties surrounding pregnant mothers, newborns and young children who must receive repeated doses of Thimerosal-containing vaccines (TCVs).

Information extracted from studies indicates that: (a) activity of low doses of Thimerosal against isolated human and animal brain cells was found in all studies and is consistent with Hg neurotoxicity; (b) the neurotoxic effect of ethylmercury has not been studied with co-occurring adjuvant-Al in TCVs; (c) animal studies have shown that exposure to Thimerosal-Hg can lead to accumulation of inorganic Hg in brain, and that (d) doses relevant to TCV exposure possess the potential to affect human neuro-development.

Neurodevelopmental disorders following thimerosal-containing childhood immunizations: a follow-up analysis.

“The present study provides additional epidemiological evidence supporting previous epidemiological, clinical and experimental evidence that administration of thimerosal-containing vaccines in the United States resulted in a significant number of children developing NDs.”

Neonatal administration of thimerosal causes persistent changes in mu opioid receptors in the rat brain

“These data document that exposure to thimerosal during early postnatal life produces lasting alterations in the densities of brain opioid receptors along with other neuropathological changes, which may disturb brain development.”

Persistent behavioral impairments and alterations of brain dopamine system after early postnatal administration of thimerosal in rats.

“These data document that early postnatal THIM administration causes lasting neurobehavioral impairments and neurochemical alterations in the brain, dependent on dose and sex. If similar changes occur in THIM/mercurial-exposed children, they could contribute do neurodevelopmental disorders.”

Maternal Thimerosal Exposure Results in Aberrant Cerebellar Oxidative Stress, Thyroid Hormone Metabolism, and Motor Behavior in Rat Pups; Sex- and Strain-Dependent Effects.

Thimerisol exposure also resulted in a significant increase in cerebellar levels of the oxidative stress marker 3-nitrotyrosine…. This coincided with an increased (47.0%) expression of a gene negatively regulated by T3,… Our data  thus demonstrate a negative neurodevelopmental impact of perinatal thimerisol exposure.

Administration of thimerosal to infant rats increases overflow of glutamate and aspartate in the prefrontal cortex: protective role of dehydroepiandrosterone sulfate.

Thimerosal, a mercury-containing vaccine preservative, is a suspected factor in the etiology of neurodevelopmental disorders. We previously showed that its administration to infant rats causes behavioral, neurochemical and neuropathological abnormalities similar to those present in autism.

#16, Extra Credit:

Influenza Vaccination during Pregnancy

The ACIP’s recommendation of influenza vaccination during pregnancy is not supported by citations in its own policy paper or in current medical literature. Considering the potential risks of maternal and fetal mercury exposure, the administration of thimerosal during pregnancy is both unjustified and unwise.

Also, take note of the 71 references at the end of this study

Why Do Pertussis Vaccines Fail? It Suggest Corrupted Science

Original Abstract:
Why Do Pertussis Vaccines Fail?
James D. Cherry, MD, MSc
Pediatric Infectious Diseases, Mattel Children’s Hospital University of California Los Angeles, and the Department of Pediatrics, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California
KEY WORDSpertussis
DTP
DTaP
adolescent- and adult-formulated tetanus and diphtheria toxoids and acellular pertussis vaccine
•Abbreviations: DTaP — pediatric diphtheria and tetanus toxoids and acellular pertussis vaccineDTP — pediatric diphtheria and tetanus toxoids and whole-cell pertussis vaccineFHA — filamentous hemagglutininFIM — fimbriaePCR — polymerase chain reactionPRN — pertactinPT — pertussis toxinWHO — World Health Organization

Possible Reasons Why DTP, DTaP, and Adolescent- and Adult-Formulated Tetanus and Diphtheria Toxoids and Acellular Pertussis Vaccines Fail

The first reason, and perhaps the most important one, is that our estimates of vaccine efficacy have been inflated because of case definition.3–11 At the time of the pediatric diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine efficacy trials in the early 1990s, it was hoped that a universal case definition could be developed so that the results of the various trials could be compared. To this end, the World Health Organization (WHO) case definition was developed.3 The primary case definition required laboratory confirmation and ≥21 days of paroxysmal cough. I was a member of the WHO committee and disagreed with the primary case definition because it was clear at that time that this definition would eliminate a substantial number of cases and therefore inflate reported efficacy values.4–11 Nevertheless, the Center for Biologics Evaluation and Research of the Food and Drug Administration accepted this definition, and package inserts of the US-licensed DTaP vaccines reflect this. For example, Infanrix (containing 25 μg pertussis toxin [PT], 25 μg filamentous hemagglutinin [FHA], and 8 μg pertactin [PRN]) and Daptacel (containing 10 μg PT, 5 μg FHA, 5 μg fimbriae [FIM]-2/3, and 3 μg

Adjuvanted flu vaccine associated with child narcolepsy in Finland

A sudden increase in narcolepsy in Finnish children at the beginning of 2010 was likely related to the Pandemrix vaccine used in response to the H1N1 2009 flu pandemic, according to two reports published Mar. 28 in the open access journal PLoS ONE.

The authors of the studies, led by Markku Partinen of the Helsinki Sleep Clinic and Hanna Nohynek of the National Institute for Health and Welfare in Finland, found that the average annual incidence of narcolepsy between 2002 and 2009 among children younger than 17 was 0.31 per 100,000, and in 2010, this incidence was about 17 times higher, at 5.3 cases per 100,000. In contrast, the incidence rate for adults over 20 was essentially unchanged over that same time period.

To further evaluate the potential connection between the vaccine and narcolepsy, the researchers collected vaccination and childhood narcolepsy data for children born between January 1991 and December 2005.

They found that the narcolepsy incidence for vaccinated individuals within this age group was 9.0 per 100,000 people, as compared to just 0.7 per 100,000 for unvaccinated individuals – almost 13 times lower.

Together, these results provide compelling evidence that the Pandemrix vaccine, used in 2009 and 2010 in association with the H1N1 flu pandemic, contributed to narcolepsy in patients between the age of 4 and 19 in Finland, the authors conclude.

Gene-swapping vaccines spawn lethal poultry virus – experts

Three vaccines used to prevent respiratory disease in chickens have swapped genes, producing two lethal new strains that have killed tens of thousands of fowl across two states in Australia, scientists reported on Friday.

The creation of the deadly new variant was only possible because the vaccines contained live viruses, even though they were weakened forms, said Joanne Devlin, lead author of the paper published in the journal Science.

Devlin and her team discovered how closely related the two new strains were with viruses in the vaccines after analysing their genes.

“What we found was the field viruses … were actually a mixture of the genomes from different vaccine viruses,” said Devlin, a lecturer at the University of Melbourne’s School of Veterinary Science. “They actually combined, mixed together.”

The viruses emerged in 2008, a year after Australia started using a European vaccine along with two very similar Australian vaccines to fight acute respiratory disease in poultry. The illness causes coughing, sneezing and breathing difficulties in birds, normally killing 5 percent of them.

The two new strains, however, were far more harmful, and since they were created have killed up to 17 percent of chicken flocks across Victoria and New South Wales, the two main chicken rearing states in Australia.

“What could have happened was one chicken was vaccinated with one vaccine and later was exposed to the other vaccine somehow, from nearby chickens,” Devlin said.

Agricultural authorities in Australia have been informed of the results of the study, and are considering how to prevent similar cross-overs happening again.

“Use of only one vaccine in a population of birds will prevent different viruses from combining,” Devlin said.

“Authorities are reviewing labels on vaccine to change the way vaccines are used and prevent different vaccines being used in one population.”