Tuesday, July 28, 2015

PLoS Bio: Imperfect Poultry Vaccines, Unintended Results




When stories emerge about suspected links between an increased incidence of narcolepsy with taking the H1N1 Pandemrix vaccine, the elevated number of febrile reactions to CSL’s FluVax in Australia, or the possible impact of the (as-yet poorly understood) concept of Original Antigenic Sin on vaccines, it seems there is always a section of  the anti-vaccine movement who will twist both the importance and meaning of these studies to fit their own agenda.

An indignity, I suspect, that  yesterday’s PLoS Biology paper Imperfect Vaccination Can Enhance the Transmission of Highly Virulent Pathogens will also endure.


This immediate over-the-top `gotcha!’ response whenever researchers (or science writers) suggest that a vaccine might be less than perfect has a chilling effect, and I suspect serves as a barrier to development of better vaccines. 

First, a quick look at this study – which deals with poultry vaccines for a specific herpesvirus (MDV), not human vaccines – followed by some discussion of how all this may relate to the recent proliferation of HPAI viruses around the world. The whole article is worth reading, so follow the link to read:


Research Article

Imperfect Vaccination Can Enhance the Transmission of Highly Virulent Pathogens

Andrew F. Read , Susan J. Baigent, Claire Powers, Lydia B. Kgosana, Luke Blackwell, Lorraine P. Smith, David A. Kennedy, Stephen W. Walkden-Brown, Venugopal K. Nair

Published: July 27, 2015

DOI: 10.1371/journal.pbio.1002198


Could some vaccines drive the evolution of more virulent pathogens? Conventional wisdom is that natural selection will remove highly lethal pathogens if host death greatly reduces transmission. Vaccines that keep hosts alive but still allow transmission could thus allow very virulent strains to circulate in a population.

Here we show experimentally that immunization of chickens against Marek's disease virus enhances the fitness of more virulent strains, making it possible for hyperpathogenic strains to transmit. Immunity elicited by direct vaccination or by maternal vaccination prolongs host survival but does not prevent infection, viral replication or transmission, thus extending the infectious periods of strains otherwise too lethal to persist.

Our data show that anti-disease vaccines that do not prevent transmission can create conditions that promote the emergence of pathogen strains that cause more severe disease in unvaccinated hosts.

Author Summary

There is a theoretical expectation that some types of vaccines could prompt the evolution of more virulent (“hotter”) pathogens. This idea follows from the notion that natural selection removes pathogen strains that are so “hot” that they kill their hosts and, therefore, themselves. Vaccines that let the hosts survive but do not prevent the spread of the pathogen relax this selection, allowing the evolution of hotter pathogens to occur.

This type of vaccine is often called a leaky vaccine. When vaccines prevent transmission, as is the case for nearly all vaccines used in humans, this type of evolution towards increased virulence is blocked. But when vaccines leak, allowing at least some pathogen transmission, they could create the ecological conditions that would allow hot strains to emerge and persist. This theory proved highly controversial when it was first proposed over a decade ago, but here we report experiments with Marek’s disease virus in poultry that show that modern commercial leaky vaccines can have precisely this effect: they allow the onward transmission of strains otherwise too lethal to persist.

Thus, the use of leaky vaccines can facilitate the evolution of pathogen strains that put unvaccinated hosts at greater risk of severe disease. The future challenge is to identify whether there are other types of vaccines used in animals and humans that might also generate these evolutionary risks.

(Continue . . .)


This study suggests (at least with MDV and its imperfect vaccine) – to  paraphrase Nietzsche  – that which does not kill the virus, only makes it stronger.


Kai Kupferschmidt, writing for Science Magazine, has an excellent review of this article called Could some vaccines make diseases more deadly?, including reactions from other scientists.  Rather than re-invent that wheel, I’ll simply refer my readers to that report, and move on to a related subject.

While above research suggests that imperfect vaccines have have led to the creation of a `hotter’ MVD strains -  in the avian flu world we’ve recently seen a rapid rise in the number of novel flu subtypes -  which many researchers also attribute to the use of poorly matched, or inconsistently applied vaccines.

Three years ago, we essentially had only one HPAI (Highly Pathogenic Avian Influenza) virus of real concern; H5N1 – along with a handful of (mostly) low path (LPAI) H5, H7 and H9 viruses.


Since the spring of 2013 we’ve seen multiple new subtypes (H7N9, H10N8, H5N6, H6N1, H5N2, H5N3, H5N8, H5N9 (often with multiple clades)) emerge – mostly from China.  A new clade of H5N1 (see Eurosurveillance: Emergence Of A Novel Cluster of H5N1 Clade has appeared in Egypt, and that appears to be the driver for their unprecedented surge in human infections.


According to 2012’s Impact of vaccines and vaccination on global control of avian influenza by David Swayne, more than 113 billion poultry vaccine doses were used from 2002 to 2010. Two countries accounted for nearly 96% of all the vaccine used; 1) China (90.9%), 2) Egypt (4.6%).


Despite a decade’s heavy use of HPAI poultry vaccines, both Egypt and China continue to battle frequent outbreaks of HPAI in their poultry, and spillovers into the human population. The chart below is just for H5N1, and does not reflect the 640+ H7N9 cases in China, or the smattering of H5N6, H10N8, and H9N2 infections.



Over the past 8 months roughly 180 Egyptians have contracted H5N1 from contact with infected poultry, and we’ve seen  reports of large numbers of poultry outbreaks – even among previously vaccinated poultry (see Egypt H5N1: Poultry Losses Climbing, Prices Up 25%).


Not surprisingly, in 2012’s Egypt: A Paltry Poultry Vaccine, we saw a study conducted by the Virology department at St. Jude Children’s Research Hospital  that looked at the effectiveness of six commercially available H5 poultry vaccines then deployed in Egypt, and found only one (based on a locally acquired H5N1 seed virus) actually appeared to offer protection.


The reality is, poultry vaccines don’t always prevent disease – sometimes they only mask the symptoms of infection, and that can not only allow viruses to spread stealthily, it can also put human health at risk.


The story in China has been much the same. Last November the EID Journal dispatch Subclinical Highly Pathogenic Avian Influenza Virus Infection among Vaccinated Chickens, China  found evidence to suggest that `imperfect’ vaccines were driving the evolution of new clades, and and the creation of subtypes (bolding mine).


HPAI mass vaccination played a crucial role in HPAI control in China. However, this study demonstrated multiple disadvantages of HPAI mass vaccination, which had been suspected (13,14). For example, this study showed that H5N1 subtype HPAI virus has evolved into multiple H5N2 genotypes, which are all likely vaccine-escape variants, suggesting that this virus can easily evolve into vaccine-escape variants.

This observation suggests that HPAI mass vaccination, which is highly effective in the beginning of an outbreak, may lose its effectiveness with time unless the vaccine strains are updated. Moreover, this study showed that vaccinated chicken flocks can be infected with vaccine-escape variants without signs of illness.


Another study, released in February - Recombinant H5N2 Avian Influenza Virus Strains In Vaccinated Chickens - stated in its cautionary discussion (bolding mine):


In this study, three H5N2 influenza virus strains isolated from chickens were identified as novel reassortants with a highly pathogenic viral genotype. Surprisingly, the affected birds had been vaccinated with killed influenza vaccines but still showed characteristic clinical symptoms of avian influenza and eventually died.

These results are in agreement with previous work indicating that AIVs can continue genetic evolution under vaccination pressure [20]. Moreover, this study highlights the importance and necessity of periodic reformulation of the vaccine strain according to the strains circulating in the field in countries where vaccines are applied to control avian influenza.


Vaccines – even less than perfect ones – are often attractive options to poultry producers and governments facing serious social and economic disruptions from avian flu outbreaks (see Diseases of Food Animals Threaten Global Food Security).   


Quarantine and culling – which are the preferred control methods in most of the world – are particularly unattractive options in countries where there are high levels of food insecurity or a high reliance on poultry for income or personal wealth.


For more than a decade, however, the OIE has warned that vaccination of poultry cannot be considered a long-term solution to combating  avian flu. And that Any decision to use vaccination must include an exit strategy, i.e. conditions to be met to stop vaccination”.OIE on H7N9 Poultry Vaccines.


Despite these warnings, and the diminishing effectiveness of their vaccines these heavily impacted countries appear no closer to looking for that recommended `exit’.   The lesson here is that starting a vaccination program is infinitely easier than ending one.


With avian flu threatening to return this fall, many poultry producers in the United States are clamoring for the USDA to approve the use of an HPAI H5 vaccine, something that our government – and indeed most governments around the globe – have so far been reluctant to do.  

The most immediate concern is that deploying a bird flu vaccine could seriously impact our poultry exports, as many countries will refuse to accept vaccinated poultry products.  This could literally cost the industry billions.


While their are probably situations where limited (and hopefully temporary) use of a poultry vaccine may make sense - the track records of AI poultry vaccine use in China and Egypt show that poultry vaccines haven’t proved to be any sort of panacea for their poultry industry.   


Granted, their application may have reduced some short-term economic pain. But after ten years of vaccine use, their bird flu problems only appear to be getting worse. 


Meaning there are far more issues for the USDA to weigh this fall when it comes to authorizing a bird flu vaccine for the United States, than just how it might affect exports.