|Human dorsal root ganglion infected with VZV|
A while ago, I talked about the influence of vaccination on Marek’s Disease Virus. Marek’s Disease Virus (MDV) is a ubiquitous chicken virus that causes tumors in infected birds. It’s a big problem for commercial flocks, and so vaccines against MDV are widely used. MDV is a herpesvirus, and in general it’s been hard to come up with really effective vaccines against herpesviruses. MDV is no exception; the vaccine prevents disease, but doesn’t prevent infection very well. As a result, there’s apparently been selection pressure on MDV to become more virulent over time.
There are quite a few vaccines against herpesvirus diseases, but most of them are in domestic animals rather than humans (and most of them would no be acceptable in humans, because of their lack of efficacy or their risk). In spite of a lot of research, there’s really only one human anti-herpesvirus vaccine, the chicken-pox vaccine. (There are eight known human herpesviruses, if you’re keeping count. Chicken-pox is caused by the varicella-zoster virus, VZV.) The MDV observation has left me wondering if the chicken-pox vaccine might lead to evolution of VZV virulence.
|Sandra Negro: “Cell infection by the Varicella Zoster Virus”|
A recent paper1 looks at a related issue: Evolution of the vaccine virus itself. Before talking about it, I should note that this is mainly a hypothetical concern; the VZV vaccine has been used widely for a long time, and has been clearly shown to be extremely safe and quite effective; whereas the actual disease — though usually fairly mild — used to hospitalize about 10,000 people per year (mostly children) and kill around a hundred people per year, in the USA alone.
The “vaccine strain” of VZV (the “vOka virus”) is not actually a single, pure, strain of virus. It’s a mixture of strains, each with a different set of changes, and with more or less similarity to wild-type virus. It’s also known that the vaccine occasionally causes a rash in vaccinees, although this disease is much milder than the natural infection.
So the question that Quinlivan et al1 asked was, What’s actually causing the rash? Is it a vaccine strain that’s relatively close to the wild-type virus? Is it a more variant strain? Is it caused by the same mix of strains as found in the original vaccine? Or is it something that wasn’t originally present in the vaccine — a revertant strain, that’s evolving back to become a virulent wild strain again?
It turns out that the rashes are not associated with new mutations: The virus is not reverting to wild-type or developing new virulence mechanisms. On the other hand, viruses associated with rashes are not identical to the original vaccine mixture. Instead, a particular subset of the vaccine strains seems to be better at causing rash:
The genotypes that carry one or more of the four selected mutations have outcompeted other components of the live vaccine inoculum. … the development of rash after vOka vaccination is due to selection of viral strains that occur infrequently in the vaccine and probably depends on specific interactions by these viruses with host immunity.
What can we learn from this? First, this may offer an opportunity to improve the vaccine. If the more virulent (rash-causing) variants can be removed from the vaccine strain, then presumably the vaccine will be safer. (We don’t know, though, whether these more virulent strains are also disproportionately responsible for immunity.) Second, the authors propose a mechanism that may make a strain more virulent — the ability to avoid T cell responses — and suggest that there may be a particular subgroup of people at greater risk of rash — those who don’t have a particular T cell recognition motif:
One corollary of this interpretation is the prediction that the vaccine virus will be found to spread more effectively in subjects who are HLA A2-negative or have lost immunity to this epitope.
More generally, this information may also be useful in understanding how viruses like VZV interact with the host immune response over long periods.
- M. L. Quinlivan, A. A. Gershon, M. M. Al Bassam, S. P. Steinberg, P. LaRussa, R. A. Nichols, J. Breuer (2007). From the Cover: Natural selection for rash-forming genotypes of the varicella-zoster vaccine virus detected within immunized human hosts Proceedings of the National Academy of Sciences, 104 (1), 208-212 DOI: 10.1073/pnas.0605688104[↩][↩]