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expert reaction to Marek’s disease in chickens, imperfect vaccines and virulence of viruses

The possibility that vaccines which do not block transmission of their target virus to un-vaccinated hosts encourage the evolution of more virulent pathogens is the subject of a  study published in the journal PLOS Biology. The researchers examined this scenario in chickens using the Marek’s disease virus, and report that in this model this could indeed be the case.

 

Dr Philip Minor, Head of the Division of Virology, National Institute of Biological Standards and Control (NIBSC), said:

“This is a good piece of scientific research on vaccination against the virus that causes Marek’s disease in poultry, an important agricultural disease. It has shown that under experimental conditions a Marek’s vaccine that does not completely block replication of the virus can allow chickens infected with highly virulent strains to transmit the virus on to other birds instead of dying before this could happen.

“The paper speculates that the use of ‘imperfect’ vaccines might drive changes in the virus population over time. Though, as far as I am aware, there is no direct evidence that this has actually happened in the field, it is a plausible risk that needs to be taken into account in designing vaccines, as well as in the implementation of new vaccine programmes and in monitoring their impact. These risks are already carefully considered, for example, in implementing new human vaccine programmes such as those against HPV, pneumococcal and meningitis vaccines.

“Extensive surveillance programmes have been set up to look for any unexpected disease patterns and changes in the distribution of infectious agents in the environment following the introduction of vaccination.”

 

Dr Michael Skinner, Reader in Virology, Imperial College London, said:

“The authors have been careful to emphasise the various provisos that apply to their work. Nevertheless, there are several ways in which their work could be misinterpreted or mistakenly assumed to apply more broadly than it actually does. It is therefore necessary to be clear what their work shows and what it does not.

“So, what have they shown?  Put simply, they have shown that chickens infected with a lethal strain of the virus (Marek’s disease virus, MDV) can only transmit it until they die (whereas those infected with a non-lethal strain can transmit it over a prolonged period). If chickens were immunised with a “perfect vaccine”, it would both protect them and prevent them transmitting MDV to other chickens. Current vaccines against MDV, however, are “imperfect”, in that vaccinated chickens will be protected and will survive but will still be able to transmit the virus to other chickens (which will, unless they too have been vaccinated, die). Vaccinated chickens therefore present a mechanism for prolonged shedding and transmission of the lethal virus.

“What have they not shown?  As the authors acknowledge, they have not demonstrated evolution of MDV from non-lethal to lethal forms in vaccinated chickens. Their work does, however indicate that, if such a mutant virus arose, it could be maintained in chickens vaccinated with the “imperfect vaccine” but not in unvaccinated chickens.

“The authors discuss the considerable speculation in the field that the introduction of MDV vaccines since the 1950s contributed to evolution of more lethal forms of MDV. However, as they acknowledge, there have been many other changes to the poultry industry over that period, which could have provided selection pressure for evolution of those viruses, so we cannot be certain which factor (or combination of factors) was most important. For example, flock size and density increased tremendously – a chicken infected with lethal MDV will infect more unvaccinated chickens in the 10 days before it dies if it is in a shed with tens of thousands of chickens rather than out in the field.

“Does their work have wider implications?  It only applies to generally lethal infections, transmission of which would normally be limited by death of all infected animals.

“It does not therefore apply to our common childhood vaccines against viruses such as such as polio, mumps, rubella, and measles. Because these viruses cause, at worst, death in a relatively small proportion of those infected, they continue to be transmitted in the majority of non-vaccinated individuals. Moreover, these vaccines would not be described as “imperfect”, as they do both protect the vaccinee and prevent them transmitting virus. Nor does it apply to the vaccine that eradicated smallpox because it is close to a “perfect” vaccine in this regard. This helps explain why these human vaccines have not led to evolution of more lethal descendants.

“In the future, it could apply to vaccines that we hope will be developed against generally lethal viruses (e.g. HIV, Ebola), encouraging scientists to strive towards “perfect vaccines” for them. However, these viruses are very different from MDV. Without intervention, both of these are generally lethal already. Ebola, as we have so tragically seen recently, can also be effectively transmitted even after death.

“Some background: Vaccines are widely used in the poultry industry to combat viruses. They have been available for many years and will almost certainly remain cheaper than any antivirals that might be developed in the future. Antivirals are also likely to be unacceptable to consumers who do not want pharmaceutical residues in their food. Veterinary vaccines in general are not derived, produced and tested under the level of strict controls that are applied to human clinical vaccines. Cheaper “therapeutic vaccines” that protect the flock until slaughter (just a few weeks for broiler, meat chickens) are often more acceptable to the industry than considerably more expensive vaccines that would stop transmission. There is, as the authors discuss, a known cost to this approach, that antigenic variants of some viruses occur every few years, requiring the introduction of updated vaccines. This is conceptually similar to the evolution of antibiotic resistant bacteria if we misuse antibiotics.

“A word of warning on terminology – the authors use various terms to describe the vaccines: “sterilising” versus “non-sterilising”, “perfect” versus “imperfect” and “leaky” (versus presumably “non-leaky”). Apart from the matter that technically it is the immunity induced by vaccines that is “sterilising “ or “non-sterilising”, the term “leaky” is to me the least desirable as it could be seen to imply an implicit defect of the vaccine, which could be translated by some as meaning that the vaccine itself poses some threat – this is not the case.”

 

Prof. Adrian Hill, Director of the Jenner Institute, University of Oxford, said:

“The change in Marek’s disease virus after vaccination is the rare textbook example of vaccine-driven viral evolution, and has been known about for many years. This paper provides experimental data consistent with that understanding. But it does not explain why, importantly, there is no evidence of this happening with other vaccines especially in humans, where many vaccines are used safely in millions of individuals every month. The suggestion that altered pathogen virulence should be looked for after vaccinating people is not new, and there is no evidence that human vaccines have produced more virulent pathogens. So, it is important not to claim from this example in chickens that this is a problem with vaccines in humans. There is strong evidence that widely used human vaccines are not producing any such effect.”

 

Prof. Peter Openshaw, President of the British Society for Immunology and Professor of Experimental Medicine at Imperial College London, said:

“The effects of innovations are hard to anticipate, and this is an example. Many viruses circulate widely and generally do little or no harm – swine flu being an example. However, some unlucky individuals are highly susceptible to disease, including the un-vaccinated. This article shows a new twist to this effect, whereby chickens vaccinated against Marek’s disease might harbour and spread infection and yet not suffer from it. Clearly, vaccines that allow this to happen are not ideal and need to be improved so that they confer widespread benefits to the population as a whole via ‘herd immunity’. Fortunately, most vaccines don’t do this and just protect everyone, including those who are not actually vaccinated.

“It’s important not to interpret this study as an argument against vaccination of our children against flu or any other disease. The standard vaccines that are in current use are safe and effective, and not prone to cause the emergence of more dangerous strains of viruses. Vaccines are amongst the safest and most cost-effective measures that we have to improve public health and protect from disease and it is vital that we achieve high vaccination rates to prevent the return of the many and terrible diseases that they prevent.”

 

‘Imperfect vaccination can enhance the transmission of highly virulent pathogens’ by Andrew F. Read et al. published in PLOS Biology on Monday 27 July 2015. 

 

Declared interests

Dr Philip Minor declares no interests.

Dr Michael Skinner: “I lead a small research group looking at interactions between poultry vaccines and their chicken host. I coordinate a larger, academic consortium (of which one of the authors, Prof. Venugopal Nair, is a member) interested in improving poultry and human vaccine production. I have no commercial funding.”

Prof. Adrian Hill is Director of the Jenner Institute, a large vaccine research institute, dedicated to developing new vaccines, and is also a developer of next generation malaria vaccines.

Prof. Peter Openshaw’s research is funded by the Wellcome Trust, the MRC, BBSRC and the European Union. He has received honoraria or consultancy fees from GSK, Janssen, Johnson & Johnson and Sanofi.

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