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

 

Polio could soon be wiped out—but only if scientists can track down the last carriers

By Helen Branswell

 


Image: GETTY IMAGES

Global eradication of polio has been the ultimate game of Whack-a-Mole for the past decade; when it seems the virus has been beaten into submission in a final refuge, up it pops in a new region. Now, as vanquishing polio worldwide appears again within reach, another insidious threat may be in store from infection sources hidden in plain view.

Polio’s latest redoubts are “chronic excreters,” people with compromised immune systems who, having swallowed weakened polioviruses in an oral vaccine as children, generate and shed live viruses from their intestines and upper respiratory tracts for years. Healthy children react to the vaccine by developing antibodies that shut down viral replication, thus gaining immunity to infection. But chronic excreters cannot quite complete that process and instead churn out a steady supply of viruses. The oral vaccine’s weakened viruses can mutate and regain wild polio’s hallmark ability to paralyze the people it infects. After coming into wider awareness in the mid-1990s, the condition shocked researchers.

Philip Minor, deputy director of the U.K.’s National Institute for Biological Standards and Control, describes the biomedical nightmare: Wild polioviruses stop circulating. Countries cut back on vaccination efforts. A chronic excreter kisses an unvaccinated baby, and the baby goes to day care. “And zappo,” he adds, “it’s all over the place, with babies drooling all over each other. So you could see a scenario where polio would come back from a developed country.” It could happen in the developing world as well. Although it was once thought that immunocompromised individuals could not survive for long in lower-income countries, circumstances are changing as those countries improve their health care systems. In 2009 an immunodeficient 11-year-old Indian boy was paralyzed by polio, five years after swallowing a dose of oral vaccine. It was only then that researchers recognized him as a chronic excreter.

Chronic excreters are generally only discovered when they develop polio after years of surreptitiously spreading the virus. Thankfully, such cases are rare. According to Roland W. Sutter, the World Health Organization scientist who heads research policy for the Global Polio Eradication Initiative, the initiative is pushing for the development of drugs that could turn off vaccine virus shedding. A few promising options are in the pipeline.

Drugs can only solve the problem if chronic excreters are identified, and that’s no easy task. For years scientists in Finland, Estonia and Israel monitored city sewers, watching for signs of shedders’ presence. In many samples, they have found the telltale viruses from chronic excreters, but they have failed to locate any of the individuals. These stealthy shedders may not be classic immunodeficient patients traceable through visits to immunologists. Instead they may be people who do not know they have an immunity problem at all and are under no specialized medical care. “We know that there’s really a Damocles sword hanging over them,” Sutter says. It hangs over the rest of us as well.

This article was originally published with the title Hidden and Dangerous.

 

http://www.scientificamerican.com/article.cfm?id=hidden-threat-that-could-prevent-polio-global-eradication

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

2010 study posted for filing

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

La Jolla Institute unlocks mystery of potentially fatal reaction to smallpox vaccine

Contact: Bonnie Ward contact@liai.org 619-303-3160 La Jolla Institute for Allergy and Immunology

Research team is part of NIH network working toward new smallpox vaccine for eczema sufferers

SAN DIEGO – (May 25, 2009) Researchers from the La Jolla Institute for Allergy & Immunology have pinpointed the cellular defect that increases the likelihood, among eczema sufferers, of developing eczema vaccinatum, a severe and potentially fatal reaction to the smallpox vaccine.  The research, conducted in mouse models, was funded under a special research network created by the National Institutes of Health in 2004.  The network is working toward the development of a new smallpox vaccine that could be administered to the millions of Americans who suffer from atopic dermatitis, a chronic, itchy skin condition commonly referred to as eczema.

The La Jolla Institute’s Toshiaki and Yuko Kawakami, M.D.s, Ph.D.s., a husband and wife scientific team, led the research group which found that activity levels of Natural Killer (NK) cells played a pivotal role in the development of eczema vaccinatum in the mice.  The activity of the NK cells, which are disease fighting cells of the immune system, was significantly lower in the mice that developed eczema vaccinatum than in normal mice that also received the smallpox vaccine.  This knowledge opens the door to one day developing therapies that could potentially boost NK cell activity in eczema sufferers.

“Since atopic dermatitis affects as many as 17 percent of children in the U. S. and since eczema vaccinatum carries a fatality rate of 5-10 percent, therapies that prevent or treat eczema vaccinatum successfully are crucial should the need for mass vaccination against smallpox arise in response to bioterrorism,” said Harvard pediatrics professor Raif S. Geha, M.D., chief of immunology at Boston Children’s Hospital and a principal investigator in the NIH funded network investigating eczema vaccinatum. “The discovery of the Kawakami team, who are participants in the NIH network, is an important step towards this goal.”

People with active atopic dermatitis (eczema), or who have outgrown atopic dermatitis, and the people they live with currently cannot receive smallpox vaccinations because of the risk of eczema vaccinatum.  While uncommon, eczema vaccinatum can develop when atopic dermatitis patients are given the smallpox vaccine or come into close personal contact with people who recently received the vaccine.  It is estimated that a significant portion of the U.S. population is currently not eligible for smallpox vaccination.

“This discovery answers an important question that has long eluded the scientific community, “why people with atopic dermatitis were susceptible to developing eczema vaccinatum upon receiving the smallpox vaccine, while the general population was not,” said Mitchell Kronenberg, the La Jolla Institute’s president & scientific director.  “It marks a significant advance toward the goal of ensuring that everyone can one day be protected against the smallpox virus.”

The finding was published today in the online version of the Journal of Experimental Medicine in a paper entitled, “Inhibition of NK cell activity by IL-17 allows vaccinia virus to induce severe skin lesions in a mouse model of eczema vaccinatum.”  La Jolla Institute scientist Shane Crotty, Ph.D., also contributed to the study.

Regarded as the deadliest disease ever known to man, smallpox was officially eradicated worldwide in 1980 and routine vaccinations against the disease ended in the U.S in 1972.   However, bioterrorism concerns have arisen over recent years regarding the deliberate distribution of the smallpox virus, which might make smallpox vaccinations once again necessary.  Such concerns led to the creation of the Atopic Dermatitis and Vaccinia Network (ADVN), a consortium of medical and research institutions nationwide developed by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.  The network, which provided grant funding for the Kawakami’s studies under NIH contact N01-AI40030C, was launched in 2004 with the goal of developing a new smallpox vaccine that would be safe for atopic dermatitis sufferers.  It includes three consortiums, involving data, clinical testing and animal studies, of which Drs. Kawakami and the La Jolla Institute are members.

The Animal Studies Consortium was created to establish animal models of atopic dermatitis and investigate their immune responses to vaccinia — the virus used in smallpox vaccine.  Drs. Kawakami were invited to join the consortium due to their creation of a new, more effective atopic dermatitis mouse model in 2004.

In their study, Drs. Kawakami showed that eczema-infected mice had higher levels of IL-17 cells, which are known to inhibit NK cell activity.  “This higher level of IL-17 cells slowed down the ability of the NK cells to kill the vaccinia virus,” said Yuko Kawakami, noting people with atopic dermatitis are also known to have higher numbers of IL-17 producing cells.  “This led to the development of eczema vaccinatum when these mice received the smallpox vaccine.”

Drs. Kawakami tested their theory by stimulating more NK cell activity in the eczema-infected mice.  The higher activity led to the elimination of the eczema vaccinatum infection.  “We are very excited by these findings, ” said  Toshiaki Kawakami.  “Developing a safer smallpox vaccine is the most important thing in this field.”

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About La Jolla Institute

Founded in 1988, the La Jolla Institute for Allergy & Immunology is a nonprofit medical research center dedicated to increasing knowledge and improving human health through studies of the immune system. Scientists at the institute carry out research searching for cures for cancer, allergy and asthma, infectious diseases, and autoimmune diseases such as diabetes, inflammatory bowel disease and arthritis. La Jolla Institute’s research staff includes more than 100 Ph.Ds and M.D.s.

Reposted at request