Pregnant nurse, 29, is FIRED after she refuses to have flu shot to protect her unborn child

  • Dreonna Breton from Pennsylvania, became alarmed after the packaging for a number of major brands of the flu vaccine warned it ‘should be given to a pregnant woman only if clearly needed
  • She showed no symptoms of having the flu and has suffered two miscarriages in four pregnancies so rejected the vaccine
  • But because the shot is compulsory for all staff at her workplace, Horizon Healthcare Services, was told to leave
  • It’s common for hospitals to enforce mandatory flu shots in an effort to prevent  staff spreading the bug to patients but they often allow exemptions for religious or medical reasons

By Helen Pow

PUBLISHED:    19:20 EST, 22 December 2013

 

A pregnant nurse in Pennsylvania has been fired after she refused a mandatory flu shot to protect her unborn baby.

Dreonna Breton, 29, learned she was pregnant with her second child in October, a month before all staff at her Lancaster employer, Horizon Healthcare Services, were required to have had a compulsory flu shot.

But she became alarmed after the packaging for a number of major brands of the vaccine warned it ‘should be given to a pregnant woman only if clearly needed,’ and other notifications highlighted that it’s unclear whether the shot can harm an unborn child.

She showed no symptoms of having the flu and having suffered two miscarriages since her son, Westen, was born 18 months ago, she didn’t want to take the chance so rejected the vaccine. But she was subsequently told to leave.

Fired: Dreonna Breton, pictured with her son Westen, was fired after she refused a mandatory flu shot to protect her unborn baby 

Fired: Dreonna Breton, pictured with her son Westen, was fired after she refused a mandatory flu shot to protect her unborn baby Continue reading “Pregnant nurse, 29, is FIRED after she refuses to have flu shot to protect her unborn child”

Vaccine’s, the Lucky Rabbits Foot, and Shhh No questions allowed ( Part 1 )

Vaccines are just a form of medicine like everything else. Some of them good, and some of them not so good. In any case you have a right to know.

Just remember Scientific Method – Observation, Hypothesis, and Theory as well as Risk to Benefit Ratio ..> But don’t get me started on Epigenetics

We should all have the freedom to inoculate ourselves based upon fact… The first one However, I threw in for fun ; )

There are many more as this is just part 1 …. Just sticking with RECENT Peer Review. But let the first Salvo fly

Change in human social behavior in response to a common vaccine and Funvax Using Vaccines to Alter Human Behavior VMAT2 Gene 

Pneumococcal vaccination in adults does not appear to work

Live Vaccination against ( German Measles ) Rubella caused Signifigant Depression up to 10 weeks – Vaccines/ Bacteria Can Alter Mood and Behavior

No significant influenza (FLU) vaccine effectiveness could  be demonstrated for any season, age or setting after adjusting for county, sex, insurance, chronic conditions recommended for influenza vaccination and timing of influenza vaccination

The Hidden Threat That Could Prevent Polio’s Global Eradication – Vaccinated Children that Become  “chronic excreters”

U.S. Court Confrims M.M.R. Vaccine Caused Autism or Cumulative  (Verified through Multiple Sources) From DEC 2012 Judgment

Pig Virus DNA Found in Rotavirus Vaccine : Millions of children worldwide, including 1 million in the U.S. exposed

Seasonal flu vaccination increase the risk of infection with pandemic H1N1 flu by 68%

Flu vaccine may not protect seniors well / Vaccine was totally ineffective

OHSU research suggests America may over-vaccinate

Some children vaccinated against hepatitis B may have an increased risk of MS

Flu shot does not cut risk of death in elderly / no decrease in hospital admissions or all-cause mortality

Measles, Mumps, Rubella vaccine linked with 2-fold risk of seizures

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

Influenza Vaccine Failure among Highly Vaccinated Military Personal, No protection against Pandemic Strains.

Live virus used in polio vaccine can evolve and infect, warns TAU researcher

India: Paralysis cases soar after oral polio vaccine introduced

Flu Vaccine offers no Protection in seniors

Common cold virus can cause polio in mice when injected into muscles

Flu shot does not reduce risk of death

Swine flu vaccine linked to child narcolepsy: EU Confirmation

WHO and the pandemic flu “conspiracies” – FULL report from the BMJ and The Bureau of Investigative Journalism  2010

A vaccine-derived strain of poliovirus that has spread in recent years is serious but it can be tackled with an existing vaccine

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

Expert questions US public health agency advice on influenza vaccines

Whooping Cough Vaccine is obsolete ” Bulk of the cases were in fully vaccinated children ” few cases among unvaccinated children

Flu vaccine backfires in pigs / vaccinated against H1N2 influenza were more vulnerable to the rarer H1N1 strain

Higher anaphylaxis rates after HPV vaccination: CMAJ study / significantly higher – 5 to 20 fold – than that identified in comparable school-based vaccination programs

Allergic to Gummy Bears? Be Cautious Getting the Flu Shot

Vaccination campaign doubles HBV mutations

Allergic to Gummy Bears? Be Cautious Getting the Flu Shot

Those with gelatin allergy can have reaction from flu vaccinations

BALTIMORE, MD. (November 8, 2013) – Do marshmallows make your tongue swell? Gummy bears make you itchy? If you’ve answered yes and are allergic to gelatin, you will want to take some precautions when getting the flu shot. While the vaccine is recommended for those six months of age and older, a case report being presented at the American College of Allergy, Asthma and Immunology (ACAAI) Annual Scientific Meeting notes that individuals with a gelatin allergy can have a mild to severe reaction from the shot.

“Gelatin is used in the flu shot, as well as other vaccines, as a stabilizer,” said Stephanie Albin, MD, an allergist and ACAAI member. “Because it is found in the vaccine, those with a known allergy to gelatin can experience allergic reactions, such as hives, sneezing and difficulty breathing.”

There is a misconception about allergies and the flu shot, with many believing those with an egg allergy should not receive the vaccination. But last month, ACAAI published an update that found even those with a severe egg allergy can receive the vaccine without special precautions.

“Gelatin reactions can cause hives, swelling, itchiness, shortness of breath and a severe life-threatening reaction known as anaphylaxis,” explained Dr. Albin. “Because of this, precautions should be taken, such as having a board-certified allergist administer the vaccine in a person with known gelatin allergy in case a reaction occurs.”

Gelatin can contain proteins derived from cow, pig or fish. Gelatin can be found in a variety of foods and pharmaceuticals, including gummy vitamins, marshmallows and candy.

“Gelatin allergy is very rare,” said allergist Richard Weber, M.D., ACAAI president. “Many food intolerances can be mistaken as allergies. Those who believe they might have an allergy should be tested and diagnosed by an allergist before taking extreme avoidance measures or skipping vaccinations. The flu shot is an important vaccine and can even be life-saving for individuals that are at an increased risk for severe side effects associated with the flu.”

The Centers for Disease Control and Prevention (CDC) recommends receiving an annual flu shot, especially for high risk age groups as children and the elderly. The vaccination can be given either as a shot or a nasal spray, both of which can contain gelatin.

For more information about allergies and to locate an allergist in your area, visit AllergyandAsthmaRelief.org. The ACAAI Annual Meeting is being held Nov. 7-11 at the Baltimore Convention Center in Baltimore. For more news and research being presented at the meeting, follow the conversation on Twitter #ACAAI.

About ACAAI

The ACAAI is a professional medical organization of more than 5,700 allergists-immunologists and allied health professionals, headquartered in Arlington Heights, Ill. The College fosters a culture of collaboration and congeniality in which its members work together and with others toward the common goals of patient care, education, advocacy and research. ACAAI allergists are board-certified physicians trained to diagnose allergies and asthma, administer immunotherapy, and provide patients with the best treatment outcomes. For more information and to find relief, visit AllergyandAsthmaRelief.org. Join us on Facebook, Pinterest and Twitter.

Video – Health Research Reports 9 SEP 2013

Topics:
Arginine performs as well as established drugs for Diabetes
* American Scientific journal Enocrinology Sep 2013
Nutritional Supplements reduce hospital stays by 21%
* American Journal of Managed Care Sep 2013
Sirtuin in the brain delays the process of aging
* Cell Metabolism Sep 2013
H1N2 influenza vaccine disables the bodies defense against H1N1 Swine flu
* Science Translational Medicine Aug 2013

Flu vaccine backfires in pigs / vaccinated against H1N2 influenza were more vulnerable to the rarer H1N1 strain

Antibodies against one strain increase risk of infection with another.

28 August 2013
Pigs vaccinated against H1N2 influenza were more vulnerable to the rarer H1N1 strain.

Andy Rouse/Photoshot

Preventing seasonal sniffles may be more complicated than researchers suspected. A vaccine that protects piglets from one common influenza virus also makes them more vulnerable to a rarer flu strain, researchers report today in Science Translational Medicine1.

The team gave piglets a vaccine against H1N2 influenza. The animals responded by making antibodies that blocked that virus — but aided infection with the swine flu H1N1, which caused a pandemic among humans in 2009. In the study, H1N1 infected more cells and caused more severe pneumonia in vaccinated piglets than unvaccinated ones.

The root of the different immune responses lies with the mushroom-shaped haemagglutinin protein found on the outside of influenza-virus particles, which helps them to attach onto cells in the airways. The protein occurs in all types of flu, but the make-up of its cap and stem vary between strains.

In the study, a vaccine for H1N2 spurred pigs to produce antibodies that bound the cap and the stem of that virus’s haemagglutinin. But some of those antibodies also targeted the stem of H1N1’s haemagglutinin protein, helping that virus fuse to cell membranes. That made H1N1 more efficient at infecting pigs and causing disease.

Stem vaccines

The finding may give some vaccine developers pause. Much of the work to develop a universal flu vaccine has targeted the stems of haemagglutinin proteins, because they are relatively consistent across many types of influenza viruses.

The new study suggests that such vaccines could also produce antibodies that enhance the ability of some viruses to infect new hosts, says James Crowe, an immunologist at Vanderbilt University in Nashville, Tennessee. But that does not mean that researchers should stop developing novel flu vaccines, including those that target haemagglutinin stems, he adds. “We should be very careful.”

Gary Nabel, a flu-vaccine researcher and chief scientific officer at the biotechnology firm Sanofi in Cambridge, Massachusetts, agrees. “It raises a warning flag, but at the same time it provides a tool to manage that risk,” he says of the new study’s results and methods.

Still, researchers have not yet tested whether human influenza vaccines can produce the same effect. And differences between pigs and humans make it difficult to interpret how relevant the findings are to the development of human vaccines, says Sarah Gilbert, a vaccine researcher at the University of Oxford, UK.

Lead author Hana Golding, a microbiologist at the US Food and Drug Administration in Bethesda, Maryland, agrees — and stresses that seasonal vaccines are still safe and effective. “This has no relevance to the regular vaccinations,” she says. “We think that people should definitely take them.”

Journal name:
Nature
DOI:
doi:10.1038/nature.2013.13621

References

  1. Khurana, S. et al. Sci. Transl. Med. 5, 200ra114 (2013).

 

http://www.nature.com/news/flu-vaccine-backfires-in-pigs-1.13621

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

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/

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 S3.

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Figure S4.

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Figure S5.

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Figure S6.

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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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  37. Webster RG, Kawaoka Y, Bean WJ, Beard CW, Brugh M (1985) Chemotherapy and vaccination: a possible strategy for the control of highly virulent influenza virus. J Virol  55: 173–176.                        Find this article online

US Nurses fired for refusing Flu vaccine: “the flu vaccine not just it doesn’t protect people from the flu, but it has complicated the health of thousands of people who took it”

Friday, 04 January 2013
An Indiana hospital has fired eight employees, including at least three veteran nurses, after they refused mandatory flu shots, stirring up controversy over which should come first: employee rights or patient safety. The hospital imposed mandatory vaccines, responding to rising concerns about the spread of influenza..
Ethel Hoover wore all black on her last day of work as a nurse in the critical care unit at Indiana University Health Goshen Hospital. She said she was in “mourning” because she would have been at the hospital 22 years in February, and she’s only called out of work four or five times in her whole career , she said.

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“This is my body. I have a right to refuse the flu vaccine,” Hoover, 61, told ABCNews.com. “For 21 years, I have religiously not taken the flu vaccine, and now you’re telling me that I believe in it.”

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More than 15,100 flu cases have been reported to the Centers for Disease Control and Prevention since Sept. 30, including 16 pediatric deaths. Indiana’s flu activity level is considered high, according to the CDC, which last month announced that the flu season came a month earlier than usual.

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When Hoover first heard about the mandate, she said she didn’t realize officials would take it so seriously. She said she filed two medical exemptions, a religious exemption and two appeals, but they were all denied. The Dec. 15 flu shot deadline came and went. Hoover’s last day of employment was Dec. 21.

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Fellow nurse Kacy Davis said she and her colleagues were “horrified” over Hoover’s firing, calling her their “go-to” nurse and a “preceptor.”
“It was a good place to work,” Hoover said. “We’ve worked together all these years. We’re like a family.”

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The hospital said in a statement that it implemented the mandate to promote patient safety based on recommendations from the American Medical Association, the American Nurses Association, and the Centers for Disease Control and Prevention. It announced the mandate in September. Of the hospital’s 26,000 employees statewide, 95 percent complied. That means 1,300 employees did not comply, but only eight were fired.

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As irony would have it, the flu vaccine not just it doesn’t protect people from the flu, but it has complicated the health of thousands of people who took it.

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https://engineeringevil.wordpress.com/wp-admin/post-new.php

Scientists urge ministers: tell truth on ‘over-hyped’ flu vaccine

 

Jeremy Laurance

Wednesday, 21 November 2012

The flu vaccine given to millions of people each year in Britain is “over-promoted” and “over-hyped” and the protection it offers against the seasonal illness has been exaggerated, scientists claim.

Flu causes thousands of deaths, mainly among the elderly, in the UK each year but the vaccine is of limited effectiveness, especially for older people. One expert told The Independent the Government should be held accountable for “wasting taxpayer’s money” on the annual £120m national vaccination campaign.

But scientists stressed it was still worth getting the jab as it is currently “the best we have”.

A report published by the Centre for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota, US, says the misperception that existing flu vaccines are highly effective has become a barrier to developing new and better vaccines.

It also risks undermining public trust in mass immunisation campaigns if Governments fail to tell the truth about the vaccine.

Michael Osterholm, director of CIDRAP and professor of Environmental Health Sciences, said: “I have been a strong proponent of vaccination in general and flu vaccine in particular for many years. I still recommend its use as the best we have. But we have over-promoted this vaccine. For certain age groups in some years its effectiveness has been severely limited relative to what has been previously reported.”

The vaccine is offered free on the NHS to everyone in the UK over 65, to patients of all ages with chronic illnesses such as asthma, to pregnant women and front-line healthcare workers in what is an annual bonanza for drug companies.

Latest figures from the Health Protection Agency show 60.8 per cent of over-65s have had their flu shot this winter and 37.5 per cent of those with chronic illnesses. Among pregnant women uptake is running at 29.8 per cent with healthcare workers at 28.4 per cent.

Flu vaccine has to be re-formulated every year on the basis of an educated guess by experts who attempt to match it with the strains of the rapidly mutating flu virus likely to be circulating that season.

A 2010 review by the highly respected Cochrane Collaboration, an international network of experts, concluded that the vaccine had little impact in years, like the winter of 2011-12, when the vaccine and the viruses were mismatched.

On average, flu vaccine shortened the illness by about half a day but did not reduce the number of people hospitalised, it said.

Tom Jefferson, an author of the Cochrane reviews, said: “We have conducted four reviews since the late 1990s. We calculated that you need to vaccinate between 33 and 99 people to prevent one case of flu, depending on the match between the vaccine and the circulating strains of the virus. I want people held accountable for wasting taxpayer’s money on these vaccines. The reviews have been available for years and nothing has been done.”

Influenza vaccine was first introduced in the 1940s and protection rates of between 70 to 90 per cent were frequently cited. The CIDRAP report found that the flu shots given in the UK, using trivalent inactivated flu vaccine, provided 59 per cent protection in healthy adults aged 18 to 64 but there were no good studies demonstrating its effectiveness in adults of 65 and over.

Professor Osterholm, an US public health adviser whose report “The Compelling need for game changing influenza vaccines” was published last month, said: “Our report is very comprehensive. It took three years, we reviewed 12,000 peer reviewed papers and interviewed 88 experts from around the world. We took no money from the private sector or governments – we had no conflicts of interest.

“The most striking outcome is that we have over-stated the effectiveness of the influenza vaccine. That has had a very dampening effect on the development of new vaccines.”

“It is important to state: we support using flu vaccine in all age groups. Even among the over 65s although it is of limited benefit it is still a benefit. We surely have overstated the level of protection but it still offers some protection.”

Douglas Fleming, of the Royal College of General Practitioners’ Influenza Monitoring Unit in Birmingham, said: “No vaccines are perfect. Last year’s flu vaccine was a bad match with the circulating strains. Its effectiveness varies from year to year and with different age groups. Amongst the elderly it is widely recognised that its effectiveness decreases. Better vaccines are needed for this reason particularly. It has been over-hyped by many people.”

A Department of Health spokesperson said evidence on the effectiveness of the vaccine had been reviewed within the last year. “There is no doubt that the flu programme saves lives. We strongly encourage scientists and the vaccine industry in their efforts to develop new and more effective flu vaccines and do not agree that these efforts are being discouraged. Each year thousands of people die after catching flu and we urge everyone that is in an at risk group to get the vaccine.”

 

http://www.independent.co.uk/life-style/health-and-families/health-news/scientists-urge-ministers-tell-truth-on-overhyped-flu-vaccine-8336184.html#

Seasonal flu vaccination increase the risk of infection with pandemic H1N1 flu by 68%

2010 study posted for filing

Contact: Andrew Hyde press@plos.org 44-122-346-3330 Public Library of Science

Did seasonal flu vaccination increase the risk of infection with pandemic H1N1 flu?

Press release from PLoS Medicine

Did seasonal flu vaccination increase the risk of infection with pandemic H1N1 flu?

In September 2009, news stories reported that researchers in Canada had found an increased risk of pandemic H1N1 (pH1N1) influenza in people who had previously been vaccinated against seasonal influenza. Their research, consisting of four different studies, has now undergone further scientific peer review and is published in the open access journal PLoS Medicine.

Did previous vaccination against seasonal flu increase the risk of getting pH1N1 flu? Based on these studies – conducted by a large network of investigators across Canada led by Principal Investigator Danuta Skowronski of the British Columbia Centre for Disease Control in Vancouver, in collaboration with provincial leads Gaston De Serres in Quebec, Natasha Crowcroft in Ontario and Jim Dickinson in Alberta – the answer remains: “possibly.”

In a school outbreak of pH1N1 in spring 2009, people with cough and fever were found to have received prior seasonal flu vaccination more often than those without. Several public health agencies in Canada therefore undertook four additional studies during the summer of 2009 to investigate further. Taken together, the four studies included approximately 2,700 people with and without pH1N1.

The first of the studies used an ongoing sentinel monitoring system to assess the frequency of prior vaccination with the 2008󈝵 seasonal vaccine in people with pH1N1 influenza (cases) compared to people without evidence of infection with an influenza virus (controls). This study confirmed that the seasonal vaccine provided protection against seasonal influenza, but found it to be associated with an increased risk of approximately 68% for pH1N1 disease.

The further 3 studies (which included additional case-control investigations in Ontario and Quebec, as well as a transmission study in 47 Quebec households where pH1N1 influenza had occurred) similarly found between 1.4𔃀.5 times increased likelihood of pH1N1 illness in people who had received the seasonal vaccine compared to those who had not. Prior seasonal vaccination was not associated with an increase in hospitalization among those who developed pH1N1 illness.

These studies do not show whether there was a true cause-and-effect relationship between seasonal flu vaccination and subsequent pH1N1 illness (as might occur if, for example, the seasonal vaccine modified the immune response to pH1N1), or whether the observed association was not a result of vaccination, but was instead due to differences in some unidentified factor(s) among the groups being studied.

If the findings from these studies are real they raise important questions about the biological interactions between pre-existing and novel pandemic influenza strains. The researchers note, however, that the World Health Organization has recommended that pH1N1 be included in subsequent seasonal vaccine formulations. This will provide direct protection against pH1N1 and thereby obviate any risk that might have been due to the seasonal vaccine in 2009, which did not include pH1N1.

In an accompanying commentary in PLoS Medicine, Lone Simonsen and Cécile Viboud, who were not involved in the studies, write: “Given the uncertainty associated with observational studies, we believe it would be premature to conclude that increased the risk of 2009 pandemic illness, especially in light of six other contemporaneous observational studies in civilian populations that have produced highly conflicting results.” They conclude that “this perplexing experience should teach us how to best react to disparate and conflicting studies and prepare us for the next public health crisis, so that we can better manage future alerts for unexpected risk factors.”

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Citation: Skowronski DM, De Serres G, Crowcroft NS, Janjua NZ, Boulianne N, et al. (2010) Association between the 2008󈝵 Seasonal Influenza Vaccine and Pandemic H1N1 Illness during Spring–Summer 2009: Four Observational Studies from Canada. PLoS Med 7(4): e1000258. doi:10.1371/journal.pmed.1000258

Funding: This project was funded by the Canadian Institutes of Health Research, the British Columbia Ministry of Health and the British Columbia Centre for Disease Control, Alberta Health and Wellness, the Ontario Agency for Health Protection and Promotion, the Ontario Ministry of Health and Long Term Care, the Ministère de la santé et des services sociaux du Québec, the Institut national de santé publique du Québec and the Fonds de la recherche en santé du Québec (FRSQ). Although agencies of the investigators provided infrastructure in support of the reported studies, the funders did not have a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: DMS has previously received research grant funding from GlaxoSmithKline and Sanofi-Pasteur for separate studies. GDS and NB have received research grant funding from GlaxoSmithKline and Sanofi-Pasteur for separate studies. GB has received funding from GlaxoSmithKline for unrelated projects. SAVOIR contributor Allison McGeer has received investigator initiated research grant funding from GlaxoSmithKline, and speaking honoraria from GlaxoSmithKline and Sanofi-Pasteur.

IN YOUR COVERAGE PLEASE USE THIS URL TO PROVIDE ACCESS TO THE FREELY AVAILABLE PAPER: http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1000258

PRESS-ONLY PREVIEW OF THE ARTICLE: www.plos.org/press/plme-07-04-skowronski.pdf

CONTACTS:

Danuta Skowronski BC Centre for Disease Control Epidemiology Services
655 West 12th Avenue Vancouver, British Columbia V5Z 4R4 Canada
+1 604-707-2511 +1 604-707-2516 (fax) Danuta.Skowronski@bccdc.ca

Ritinder Harry Communications Leader, BC Centre for Disease Control (BCCDC) 655 West 12th Avenue Vancouver, BC V5Z 4R4 Canada +1 604 707-2412 ritinder.harry@bccdc.ca

Perspective article by Cecile Viboud:

Citation: Viboud C, Simonsen L (2010) Does Seasonal Influenza Vaccination Increase the Risk of Illness with the2009 A/H1N1 Pandemic Virus? PLoS Med 7(4): e1000259. doi:10.1371/journal.pmed.1000259

Competing Interests:CV declares no competing interests. LS is a paid consultant for SDI health (a health data business), and has received research support since 2008 from Wyeth (now Pfizer) for pneumococcal vaccine modelling.

IN YOUR COVERAGE PLEASE USE THIS URL TO PROVIDE ACCESS TO THE FREELY AVAILABLE PAPER: http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1000259

PRESS-ONLY PREVIEW OF THE ARTICLE: http://www.plos.org/press/plme-07-04-viboud.pdf

CONTACT:

Cécile Viboud National Institutes of Health Fogarty International Center 16 Center Drive Bethesda, MD 20892 United States of America
1-301-496-2146 1-301-496-8496 (fax) viboudc@mail.nih.gov

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

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

France halts sale of Novartis flu vaccine

Fri, 26 Oct 2012 14:18 GMT

Source: reuters

(Adds comment from European Medicines Agency)

PARIS, Oct 26 (Reuters) – France said it was halting sales of an influenza vaccine made by Swiss drugmaker Novartis as a precaution after potential impurities were found in batches of the product in Italy.

Health Minister Marisol Touraine said on Friday she had asked for all doses of Agrippal to be withdrawn from the market.

“At this stage no impurities have been found in France … There is no known risk for patients who have used this brand in France,” Touraine said in a statement.

France said it had taken the action pending a decision by the European Medicines Agency (EMA), although the London-based agency said it was not taking a lead in investigations since the flu vaccine was authorised by national governments.

The EMA is responsible for medicines that are authorised centrally, although it may be called on to help with issues concerning nationally approved products if requested by the European Commission or governments.

“At the moment there is no regulatory action from our side,” an EMA spokeswoman said.

The French decision follows the announcement by Swiss and Italian authorities on Wednesday that they were banning some flu vaccines produced by Novartis after small white particles were discovered in Italy in injections.

German and Spanish authorities also imposed a ban on certain Novartis flu vaccines on Thursday.

Agrippal is the only Novartis flu vaccine marketed in France. The ban in Switzerland concerns Novartis’ Fluad as well as Agrippal, while Italy has also withdrawn subunit Influpozzi and adjuvanted Influpozzi.

Novartis said on Thursday it believed its flu vaccines were safe, despite the discovery of aggregated protein in a batch of vaccine which was not released to the market.  (Reporting By Vicky Buffery and Ben Hirschler; Editing by Keiron Henderson and Helen Massy-Beresford)

http://www.trust.org/alertnet/news/france-halts-sale-of-novartis-flu-vaccine/

No significant influenza (FLU) vaccine effectiveness could be demonstrated for any season, age or setting after adjusting for county, sex, insurance, chronic conditions recommended for influenza vaccination and timing of influenza vaccination

2008 study posted for filing

Contact: Heather Hare
585-273-2840
JAMA and Archives Journals

Use of the influenza vaccine was not associated with preventing hospitalizations or reducing physician visits for the flu in children age 5 and younger during two recent seasons, perhaps because the strains of virus in the vaccine did not match circulating strains, according to a report in the October issue of Archives of Pediatrics & Adolescent Medicine, one of the JAMA/Archives journals.

Influenza causes substantial illness among young children; therefore, the United States and other countries have expanded their childhood vaccination requirements, according to background information in the article. As of June 2006, U.S. health officials recommend annual vaccinations for all children age 6 to 59 months. “An inherent assumption of expanded vaccination recommendations is that the vaccine is efficacious in preventing clinical influenza disease,” the authors write.

Peter G. Szilagyi, M.D., M.P.H., of the University of Rochester School of Medicine and Dentistry and Strong Memorial Hospital, Rochester, N.Y., and colleagues studied 414 children age 5 and younger who developed influenza during the 2003-2004 or 2004-2005 seasons (245 seen in hospitals or emergency departments, and 169 seen in outpatient practices). Their vaccination status was compared with that of more than 5,000 children from the same three counties who did not have influenza during those seasons.

Before the researchers considered any other factors, children with influenza appeared to have lower vaccination rates than children without influenza. “However, significant influenza vaccine effectiveness could not be demonstrated for any season, age or setting after adjusting for county, sex, insurance, chronic conditions recommended for influenza vaccination and timing of influenza vaccination (vaccine effectiveness estimates ranged from 7 percent to 52 percent across settings and seasons for fully vaccinated 6- to 59-month olds),” the authors write.

A suboptimal match between the strain of influenza in the vaccine and that circulating in the public during those two seasons may have contributed to the poor effectiveness, the authors note. In 2003-2004, 99 percent of circulating influenza strains were caused by the influenza A virus, but only 11 percent of influenza A strains across the United States were similar to those in the vaccine. “The 2004-2005 season was less severe and the vaccine was a better match to circulating strains than in 2003-2004, but still only 36 percent of virus isolates were antigenically similar to vaccine strains,” they write.

This study comparing cases with controls adds important information about vaccine effectiveness in children but should be combined with additional research, including studies of years with good vaccine match, they conclude. “Further studies of influenza vaccine effectiveness are needed using a variety of study designs (that adjust for confounders) to assess the yearly impact of influenza vaccination programs for children, particularly as higher rates of vaccination are achieved in the study population,” the authors write.

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(Arch Pediatr Adolesc Med. 2008;162[10]:943-951. Available pre-embargo to the media at www.jamamedia.org.)

Editor’s Note: This work was funded by the Centers for Disease Control and Prevention as part of the New Vaccine Surveillance Network and the National Vaccine Program Office, and some subjects in Cincinnati were recruited through a study funded by QuickVue Influenza Test (Quidel Corp., San Diego, Calif.). Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc

Flu shot does not reduce risk of death

2008 Study posted for filing

Contact: Keely Savoie
ksavoie@thoracic.org
212-315-8620
American Thoracic Society

The widely-held perception that the influenza vaccination reduces overall mortality risk in the elderly does not withstand careful scrutiny, according to researchers in Alberta. The vaccine does confer protection against specific strains of influenza, but its overall benefit appears to have been exaggerated by a number of observational studies that found a very large reduction in all-cause mortality among elderly patients who had been vaccinated.

The results will appear in the first issue for September of the American Journal of Respiratory and Critical Care Medicine, a publication of the American Thoracic Society.

The study included more than 700 matched elderly subjects, half of whom had taken the vaccine and half of whom had not. After controlling for a wealth of variables that were largely not considered or simply not available in previous studies that reported the mortality benefit, the researchers concluded that any such benefit “if present at all, was very small and statistically non-significant and may simply be a healthy-user artifact that they were unable to identify.”

“While such a reduction in all-cause mortality would have been impressive, these mortality benefits are likely implausible. Previous studies were likely measuring a benefit not directly attributable to the vaccine itself, but something specific to the individuals who were vaccinated—a healthy-user benefit or frailty bias,” said Dean T. Eurich,Ph.D. clinical epidemiologist and assistant professor at the School of Public Health at the University of Alberta. “Over the last two decades in the United Sates, even while vaccination rates among the elderly have increased from 15 to 65 percent, there has been no commensurate decrease in hospital admissions or all-cause mortality. Further, only about 10 percent of winter-time deaths in the United States are attributable to influenza, thus to suggest that the vaccine can reduce 50 percent of deaths from all causes is implausible in our opinion.”

Dr. Eurich and colleagues hypothesized that if the healthy-user effect was responsible for the mortality benefit associated with influenza vaccination seen in observational studies, there should also be a significant mortality benefit present during the “off-season”.

To determine whether the observed mortality benefits were actually an effect of the flu vaccine, therefore, they analyzed clinical data from records of all six hospitals in the Capital Health region in Alberta. In total, they analyzed data from 704 patients 65 years of age and older who were admitted to the hospital for community-acquired pneumonia during non-flu season, half of whom had been vaccinated, and half of whom had not. Each vaccinated patient was matched to a non-vaccinated patient with similar demographics, medical conditions, functional status, smoking status and current prescription medications.

In examining in-hospital mortality, they found that 12 percent of the patients died overall, with a median length of stay of approximately eight days. While analysis with a model similar to that employed by past observational studies indeed showed that patients who were vaccinated were about half as likely to die as unvaccinated patients, a finding consistent with other studies, they found a striking difference after adjusting for detailed clinical information, such as the need for an advanced directive, pneumococcal immunizations, socioeconomic status, as well as sex, smoking, functional status and severity of disease. Controlling for those variables reduced the relative risk of death to a statistically non-significant 19 percent.

Further analyses that included more than 3,400 patients from the same cohort did not significantly alter the relative risk. The researchers concluded that there was a difficult to capture healthy-user effect among vaccinated patients.

“The healthy-user effect is seen in what doctors often refer to as their ‘good’ patients— patients who are well-informed about their health, who exercise regularly, do not smoke or have quit, drink only in moderation, watch what they eat, come in regularly for health maintenance visits and disease screenings, take their medications exactly as prescribed— and quite religiously get vaccinated each year so as to stay healthy. Such attributes are almost impossible to capture in large scale studies using administrative databases,” said principal investigator Sumit Majumdar, M.D., M.P.H., associate professor in the Faculty of Medicine & Dentistry at the University of Alberta.

The finding has broad implications:

 

  • For patients: People with chronic diseases such as chronic respiratory diseases such as chronic obstructive pulmonary disease, immuno-compromised patients, healthcare workers, family members or friends who take care of elderly patients and others with greater exposure or susceptibility to the influenza virus should still be vaccinated. “But you also need to take care of yourself. Everyone can reduce their risk by taking simple precautions,” says Dr. Majumdar. “Wash your hands, avoid sick kids and hospitals during flu season, consider antiviral agents for prophylaxis and tell your doctor as soon as you feel unwell because there is still a chance to decrease symptoms and prevent hospitalization if you get sick— because flu vaccine is not as effective as people have been thinking it is.”
  • For vaccine developers: Previously reported mortality reductions are clearly inflated and erroneous–this may have stifled efforts at developing newer and better vaccines especially for use in the elderly.
  • For policy makers: Efforts directed at “improving quality of care” are better directed at where the evidence is, such as hand-washing, vaccinating children and vaccinating healthcare workers. 

Finally, Dr. Majumder said, the findings are a reminder to researchers that “the healthy-user effect is everywhere you don’t want it to be.”

 

 

 

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Flu Vaccine offers no Protection in seniors

Respost 2008

Contact: Rebecca Hughes hughes.r@ghc.org 206-287-2055 Group Health Research Institute

Flu vaccine may not protect seniors well

Group Health study in Lancet finds no less risk of pneumonia with vaccine

SEATTLE—A Group Health study in the August 2 issue of The Lancet adds fuel to the growing controversy over how well the flu vaccine protects the elderly.

The study of more than 3,500 Group Health patients age 65󈟊 found no link between flu vaccination and risk of pneumonia during three flu seasons. “This suggests that the flu vaccine doesn’t protect seniors as much as has been thought,” said Michael L. Jackson, PhD, MPH, a postdoctoral fellow at the Group Health Center for Health Studies.

“Ours is by far the largest case-control study of flu vaccine in the elderly,” Jackson added. This kind of study compares “cases” with “controls.” The cases were patients with “community-acquired” pneumonia treated in a hospital or elsewhere. The controls were people matched to cases by sex and age, but with no pneumonia. Both groups were found to have similar rates of flu vaccination. All had intact immune systems and none lived in a nursing home.

Jackson and his colleagues carefully reviewed medical records to reveal details of seniors’ health and ability to do daily activities. “We tried to overcome the limits of previous studies done by others,” he explained. “Those studies may have overestimated the benefits of the flu vaccine in the elderly for various reasons.” For instance, those studies looked only at pneumonia cases treated in a hospital. They also included seniors who had immune problems, which limit potential benefit from vaccination. And they didn’t review medical records to get information on chronic diseases, such as heart or lung disease, which raise the risk of pneumonia.

Most importantly, those previous studies also failed to account for differences between healthier seniors and those who were “frail,” Jackson said. Frail seniors are older and have chronic  diseases and difficulty walking. “They are less likely than younger, healthier seniors to go out and get vaccinated—and more apt to develop pneumonia,” he said.

Pneumonia is a common and potentially life-threatening complication of the flu, Jackson said. But pneumonia can happen without the flu. “That’s why our study used a control time period, after flu vaccine became available but before each flu season actually started,” he said. During those pre-flu-season periods, people who had been vaccinated were much less likely to get pneumonia. Why? “Because those who got the vaccine happened to be healthier—not because the flu vaccine was protecting them from pneumonia caused by the flu, since it wasn’t present yet,” he explained.

“Despite our findings, and even though immune responses are known to decline with age, I still want my grandmother to keep getting the flu vaccine,” said Jackson. “The flu vaccine is safe. So it seems worth getting, even if it might lower the risk of pneumonia and death only slightly.”

His co-author Lisa A. Jackson, MD, MPH (no relation), a senior investigator at the Group Health Center for Health Studies, agreed. “People age 65 and older should still get yearly flu vaccines as usual,” she advised. But she said that researchers should work to understand better how well the current flu vaccines work in seniors—and to explore other options for controlling flu in the “old old.” Examples include bigger doses or stronger types of vaccines, and conducting randomized controlled trials comparing them.

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Other co-authors are Group Health’s Jennifer C. Nelson, PhD and William Barlow, PhD; Noel S. Weiss, MD, DrPH of the Fred Hutchinson Cancer Research Center and University of Washington; and Kathleen M. Neuzil, MD, MPH, of the Program for Appropriate Technology in Health (PATH), University of Washington, and the Group Health Center for Health Studies, all in Seattle.

A fellowship grant from the Group Health Foundation and internal funds from the Group Health Center for Health Studies funded this study.

Group Health Center for Health Studies

Founded in 1947, Group Health Cooperative is a Seattle-based, consumer-governed, nonprofit health care system that coordinates care and coverage. For 25 years, the Group Health Center for Health Studies has conducted research on preventing, diagnosing, and treating major health problems. Government and private research grants provide its main funding.

Please visit the virtual newsroom on our Web site, www.ghc.org under “Newsroom.”

Influenza Vaccine Failure among Highly Vaccinated Military Personal, No protection against Pandemic Strains.

Introduction

Following the 2009 influenza A/H1N1 (pH1N1) pandemic, both seasonal and pH1N1 viruses circulated in the US during the 2010–2011 influenza season; influenza vaccine effectiveness (VE) may vary between live attenuated (LAIV) and trivalent inactivated (TIV) vaccines as well as by virus subtype.

Materials and Methods

Vaccine type and virus subtype-specific VE were determined for US military active component personnel for the period of September 1, 2010 through April 30, 2011. Laboratory-confirmed influenza-related medical encounters were compared to matched individuals with a non-respiratory illness (healthy controls), and unmatched individuals who experienced a non-influenza respiratory illness (test-negative controls). Odds ratios (OR) and VE estimates were calculated overall, by vaccine type and influenza subtype.

Results

A total of 603 influenza cases were identified. Overall VE was relatively low and similar regardless of whether healthy controls (VE = 26%, 95% CI: −1 to 45) or test-negative controls (VE = 29%, 95% CI: −6 to 53) were used as comparison groups. Using test-negative controls, vaccine type-specific VE was found to be higher for TIV (53%, 95% CI: 25 to 71) than for LAIV (VE = −13%, 95% CI: −77 to 27). Influenza subtype-specific analyses revealed moderate protection against A/H3 (VE = 58%, 95% CI: 21 to 78), but not against A/H1 (VE = −38%, 95% CI: −211 to 39) or B (VE = 34%, 95% CI: −122 to 80).

Conclusion

Overall, a low level of protection against clinically-apparent, laboratory-confirmed, influenza was found for the 2010–11 seasonal influenza vaccines. TIV immunization was associated with higher protection than LAIV, however, no protection against A/H1 was noted, despite inclusion of a pandemic influenza strain as a vaccine component for two consecutive years. Vaccine virus mismatch or lower immunogenicity may have contributed to these findings and deserve further examination in controlled studies. Continued assessment of VE in military personnel is essential in order to better inform vaccination policy decisions.

Discussion

The results of this assessment suggest there is a low to moderate degree of protection against A/H3 and B, but not against A/H1 strains that circulated in the US during the 2010–11 season. The low VE against clinically-apparent, laboratory-confirmed influenza illnesses among active component US military service members is somewhat unexpected. However, this is the first study among a primarily US-based population to report VE estimates for the 2010–11 season and may end up being comparable as other data are released on the general US population.

VE estimates for the 2010–11 [12]–[18] and early for 2011–12 season [19], [20] have been reported for the European Union (EU). Although the overall estimates of VE in this study are somewhat lower than those reports from the EU, when the findings are restricted to TIV VE compared to test-negative controls (a more appropriate comparison as the vaccines used in the EU studies are inactivated vaccines), the results are more similar. A study by Kissling et al reported adjusted VE for eight EU states to be 52% overall and 41% for the 15 to 59 year age group [15]. Similar estimates were also reported by Steens et al for the Netherlands (46%) and by Savulescu et al for Spain (50%), both of which used a test-negative control comparison group [13], [14]. Contrary to our findings of no VE for the A/H1 subtype, Kissling et al reported a VE of 27% for A/H1 among 15 to 59 year olds, however, this did not reach statistical significance [15].

There are a number of factors that may have played a role in the low to moderate VE estimates found in this study. There is the potential that the vaccine viruses were a mismatch with the circulating viruses. This has been reported in some previous seasons and has resulted in low VE [24], [25]. Although isolates from the general US population reported by the CDC for the 2010–11 season indicated a close match between the circulating and vaccine viruses [26], this genetic drift could have occurred later in the season and perhaps among strains which circulated among military personnel [27]. This may be especially true for the A/H1 strains where there was an apparent lower immunogenicity and protection provided by vaccines among recruits as described by Myers et al [27]. An additional study by US military collaborators at the US Naval Health Research Center which investigated the genetic characteristics of the A/H1 viruses that circulated in the military recruit population during the 2010–11 season and associated comparisons of the immune responses generated by LAIV and TIV vaccines in this same population is in the publication stage. Noteworthy to mention, however, is the fact that this study has found modest amino acid differences in circulating strains compared to the vaccine strain and could provide much needed answers to these questions (personal communication, Commander Patrick Blair).

Lower than expected VE may also be due to population factors. The military population is highly immunized against influenza, typically at greater than 90% [28]; while the US civilian population of a similar age range (18 to 49 years) has overall vaccination rates of no more than 40% [29]. Previous studies have found decreased VE among highly immunized military populations, especially for the LAIV vaccine, but higher LAIV VE among vaccine-naïve populations, such as military recruits [9]–[11]. For this study, stratification of VE by vaccine type revealed lower and non-significant VE for LAIV recipients compared to TIV. Since almost twice as many of our cases received LAIV compared to TIV, this difference in vaccine type VE may help to explain the overall finding of lower than expected VE in this population. The case-control design of this study may also partially explain the overall lower than expected VE estimates. A simulation model by Ferdinands and Shay, found that case-control studies of VE underestimate true VE by as much as 11.9%, principally due to biases introduced by the lack of diagnostic specificity of tests used (not a factor in our study since we based our cases on RT-PCR and/or culture diagnosis) [30]. All of these explanations warrant additional investigation, perhaps using populations with varying immunization rates and controlled cohort-based studies, to confirm and better understand the mechanisms at play. In addition, VE estimates need to be examined with relation to the degree of severity of influenza-associated illnesses, that is to say, comparison for hospitalized (more severe) versus non-hospitalized outcomes.

One important factor which we could control for was the sensitivity of the influenza-detecting assays given that their sensitivity are known to decrease over time (eg, lower sensitivity of RT-PCR and culture after 48 to 72 hours of illness). In our study, time from symptom onset to specimen collection did not differ between test-positive and test-negative cases (median = 2 days for both groups). Thus, there should have been no difference in influenza detection between test-positive and test-negative cases, given this very narrow sampling window.

There are several strengths and limitations to this study. The use of laboratory-confirmed, clinically-diagnosed influenza cases strengthens this study by providing a more specific case definition. A second strength is the use of both “healthy” and “test-negative” controls for comparison, which provided different methodologies to account for potential biases that can occur in case-control studies of VE [31]. The military population also provides a robust population to study VE as they represent a relatively healthy, young-to-middle aged adult population that is sometimes overlooked in other VE studies. Additionally, medical encounters and vaccines have near complete capture electronically for all active component personnel.

Of note, it is difficult to directly compare the healthy control population to the test-negative control population because the healthy controls were matched to the cases based on demographic characteristics. However, prior history of vaccination does appear to be different between the two control populations. The test-negative controls were more similar to the cases with regards to prior vaccination history (80% with one or more prior influenza vaccinations) than the healthy control population (96%). This probably reflects evidence of better health care seeking behavior and/or opportunities for prior vaccination in healthy controls, thus, comparisons using test-negative controls may represent a more appropriate comparison population in the military population for this and future influenza VE case-control studies.

One important limitation is the fact that the military population is highly immunized, thus, the results of this study may not be generalizable to the general US population. The study was also limited by the number of influenza cases that were laboratory-confirmed. There were probably many more influenza cases that occurred among military personnel, but not all were laboratory-confirmed or sought medical attention. If the cases selected for laboratory confirmation were different from other influenza cases, perhaps due to severity of illness, then the findings may be biased and may not be generalizable to all influenza infections occurring in the military. There may also be unknown biases and confounders that were not accounted for in the adjusted models.

In conclusion, a low level of protection against clinically-apparent, laboratory-confirmed, influenza-associated illness was found for the 2010–11 seasonal influenza vaccines in this military population. TIV immunization was associated with higher protection than LAIV, however, no protection against A/H1 was noted, even though a pandemic virus strain was a vaccine component for the second year in a row. These findings may provide justification towards preferential use of inactivated vaccines as a primary option for “seasoned” (eg, highly-immunized) US military personnel. Continued future annual assessments of influenza vaccine efficacy and/or effectiveness are necessary in the military setting in order to better guide vaccination policies and influenza infection control efforts.

Angelia A. Eick-Cost1,3*, Katie J. Tastad2,3, Alicia C. Guerrero2, Matthew C. Johns1, Seung-eun Lee1, Victor H. MacIntosh2, Ronald L. Burke1, David L. Blazes1, Kevin L. Russell1, Jose L. Sanchez1,3*

1 Armed Forces Health Surveillance Center (AFHSC), Silver Spring, Maryland, United States of America, 2 US Air Force School of Aerospace Medicine (USAFSAM), 711th Human Performance Wing, Wright Patterson Air Force Base, Ohio, United States of America, 3 Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., (HJF), Bethesda, Maryland, United States of America