Mystery Rays from Outer Space

Meddling with things mankind is not meant to understand. Also, pictures of my kids

May 20th, 2010

Cross-protection and flu vaccines

Gran'pop has a touch of the fluWe know that we need to make new vaccines against influenza each year, because new flu strains arise and spread each year and the previous year’s vaccines don’t give protection against the new strains.  Of course, there’s intense research toward developing cross-protective vaccines.  Ideally, flu vaccines would work like measles vaccines — get a shot as a child, be protected throughout life. That may not be a practical goal, but it’s a theoretical target.  More practically, even being able to vaccinate every five years or so would be a big step forward.    It’s clearly not going to be easy, though.  Natural infections don’t particularly offer a lot of cross-protection, and it’s hard1 to get vaccines that induce a stronger immune response than the natural infection.

The pandemic H1N1 influenza last year was an interesting test ground to see how much, if any, cross-protection seasonal influenza vaccines gave.  Unfortunately the results have been pretty confusing, with different studies finding some cross-protection, no cross-protection, or even some increased risk.

The increased risk thing has been hashed out quite extensively already, so if you follow flu stories much you’ve undoubtedly already seen it. This is from the Canadian study2 that found  that people vaccinated against flu in previous years –that is, against different flu strains — were somewhat more likely to get severe flu.

Influenza gargleNo one understands that finding, I think.  (The article itself is open-source, and there’s an excellent commentary on it3 here that’s also open-source, so check it out yourself.)  No one has been able to find any concrete problem with the study, other than its general nature — observational rather than randomized case/control.   But it’s clearly an outlier: Other studies looking at the same thing either find no effect either way, or a modest protective effect.

The latest in the series is a US Army study4 (open source, you can read it yourself) that finds a moderate protective effect of previous flu vaccinations against the pandemic H1N1 (pH1N1):

Our data also suggests that prior receipt of TIV [trivalent inactivated vaccine: IY] or LAIV [live attenuated influenza vaccine: IY] induces an association of protection against pH1N1-associated illness. This may reflect “priming” of the humoral immune system with influenza vaccine as demonstrated in immunologically-naïve children. … Additional findings from our study support the notion that vaccination with seasonal influenza vaccines in the preceding four years (2004–08) also conferred a certain degree of protective immunological memory relevant to the new viral strain. … Thus, it is reasonable to think that CMI [cell-mediated immunity: IY] plays a significant role and that cross-protective CMI to pH1N1 virus may actually exist in individuals who have been frequently immunized and/or exposed to seasonal influenza. 4

You always need to be a little cautious extrapolating army findings like this to the rest of the population. Military populations tend to be more crowded, more stressed, younger, fitter, and more homogeneous than the rest of the population. The vaccination rate among the service members in this study, for example, was much higher than in the general population.  There are a number of other possible sources of confusion that the authors carefully list. And of course, this is again an observational study, not a randomized prospective one.

But in the big picture, it (and similar studies) really do suggest that some cross-protection is possible in a natural population.  That’s really encouraging, because it shows there’s at least a foundation to build on for broadly cross-reactive vaccines.

  1. Though not impossible[]
  2. Skowronski, D., De Serres, G., Crowcroft, N., Janjua, N., Boulianne, N., Hottes, T., Rosella, L., Dickinson, J., Gilca, R., Sethi, P., Ouhoummane, N., Willison, D., Rouleau, I., Petric, M., Fonseca, K., Drews, S., Rebbapragada, A., Charest, H., Hamelin, M., Boivin, G., Gardy, J., Li, Y., Kwindt, T., Patrick, D., Brunham, R., & , . (2010). Association between the 2008–09 Seasonal Influenza Vaccine and Pandemic H1N1 Illness during Spring–Summer 2009: Four Observational Studies from Canada PLoS Medicine, 7 (4) DOI: 10.1371/journal.pmed.1000258[]
  3. Viboud, C., & Simonsen, L. (2010). Does Seasonal Influenza Vaccination Increase the Risk of Illness with the 2009 A/H1N1 Pandemic Virus? PLoS Medicine, 7 (4) DOI: 10.1371/journal.pmed.1000259[]
  4. Johns, M., Eick, A., Blazes, D., Lee, S., Perdue, C., Lipnick, R., Vest, K., Russell, K., DeFraites, R., & Sanchez, J. (2010). Seasonal Influenza Vaccine and Protection against Pandemic (H1N1) 2009-Associated Illness among US Military Personnel PLoS ONE, 5 (5) DOI: 10.1371/journal.pone.0010722[][]
May 10th, 2010

Careers, distractions, changes

CDC logoI’ve mentioned a couple of times recently that I’ve had some distractions in real life.  They’ve reached a level of confidence that I may as well explain them here.  Short version: I’ve had a job offer from the CDC, and I’m probably almost certainly going to leave my position at Michigan State University and join the CDC in Atlanta in the near future.

In handy pretend-question-and-answer format:

What’s the job? My title will be something like “Head of the Influenza Pandemic Preparedness and Vaccine Team“.  Being a government job, it probably sounds rather grander than it is. It’s a small to mid-sized research team  that covers various aspects of influenza pathogenesis, virology, and surveillance, focusing mainly but not only on the non-standard (i.e. non-seasonal) flu strains.

Why are you leaving MSU? I don’t think of it as “leaving MSU”, but rather as “going to the CDC”.  What I mean by that is that I’m very happy at MSU, it’s a great place, my research is going reasonably well, we are very fond of Michigan, and so on.  The only reason I’m changing positions is that I think the CDC position is going to be even more exciting and interesting.  And yes, I’m aware that I’m incredibly fortunate to be able to choose between these two wonderful opportunities.

When are you going? I’m probably moving in mid-June.

Do you have ten thousand and one things to do before then? Yes.

Are you looking forward to summers in Atlanta? No.  I’m Canadian.  I don’t deal well with heat.

What about this blog? There may be some hiccups as I have to worry about moving, selling and buying houses, and learning a bunch of new stuff.  But overall, I think it should keep going.

May 5th, 2010

Pandemics and publishing (and blogs?)

Egyptian scribes (NYPL)

A majority of the epidemiological articles on SARS were submitted after the epidemic had ended, although the corresponding studies had relevance to public health authorities during the epidemic.  … although the academic response to the SARS epidemic was rapid, most articles on the epidemiology of SARS were published after the epidemic was over even though SARS was a major threat to public health. 1

(My emphasis) This is an analysis of the published response to the SARS epidemic in 2003.   The conclusion is basically that, although SARS papers were clearly fast-tracked by journals, most papers didn’t see publication until after the epidemic was over.

They suggest that journals could speed up their fast-track systems for this sort of thing, and cite some of the subsequent attempts to speed up availability of publications (Nature Proceedings, Pandemic Flu Updates from the BMJ, and PLoS Current: Influenza), but point out that it’s not solely up to the journals: Most of the articles they looked at weren’t even submitted until the epidemic was over.  They suggest that authors could speed up data-collection and analysis:

This bottleneck could be reduced by developing a series of ready-to-use information technologies, to improve timeliness and, thus relevance, and further, to improve standardization, and thus comparability across studies in the event of an outbreak.1

That presumably means that epidemiologists should, right now, be preparing tools for the next pandemic.  I assume some are, but I don’t know how widespread that is.

I’d be very interested to compare the 2003 SARS response to the 2009/2010 pandemic flu response.  My impression was that the response was much faster — not only through the fast-tracked sites mentioned above, but through semi-formal channels as well.  Though it wasn’t a target of this paper (which focused on peer-reviewed papers) I’d also be interested to see how much (if any) impact blogs had for the flu response.

  1. Xing, W., Hejblum, G., Leung, G., & Valleron, A. (2010). Anatomy of the Epidemiological Literature on the 2003 SARS Outbreaks in Hong Kong and Toronto: A Time-Stratified Review PLoS Medicine, 7 (5) DOI: 10.1371/journal.pmed.1000272[][]
May 4th, 2010

Does immune evasion allow rapid HIV progression?

How not to be seenI was getting a little concerned and distressed by the lack of evidence for any function of viral MHC class I immune evasion. It’s kind of a relief to see articles demonstrating function coming out.

MHC class I is the target for cytotoxic T lymphocytes (CTL), which are generally believed to be pretty important in controlling viral infection. So when some viruses were shown to block MHC class I in cultured cells, it seemed pretty obvious that this would be a big benefit for the virus. You’d expect these viruses to be exceptionally resistant to CTL, for example.

But when people actually looked in animals (as opposed to in tissue culture), the ability to block MHC class I didn’t seem to do all that much. I’ve summarized some of those experiments here and here. For example, the MHC class I immune evasion genes in adenoviruses and in mouse cytomegalovirus (MCMV) didn’t show much effect on the actual infection at all.1 Mouse herpesvirus 68 (MHV68) had shown an effect, but not at the time point that you might expect — not early after infection, when CTL are kicking in and clearing virus, but rather later on, during the latent phase.2

We all believed there must be a function, because viruses don’t hang on to genes for millions of years unless those genes are important,3 but I was starting to wonder if perhaps we were looking in the wrong places — whether any immune effects might be spillover from some other function, say. But, as I say, we’re starting to get confirmation that these things really are doing more or less what we’d expected all along.

A little while ago, Klaus Fruh and Louise Pickert showed a significant effect of MHC class I immune evasion in rhesus cytomegalovirus: without that ability new viruses couldn’t superinfect hosts that already carry the virus. 4 (I talked about it here.) It’s quite possible — though of course not certain until it’s actually tested — that this is also true for human cytomegaloviruses (which are very closely related to the rhesus version) and for mouse CMV (which are less closely related but in the same family). So now we have functional data for MHC class I immune evasion for representatives of two broad groups of viruses, the betaherpesviruses (the cytomegaloviruses) and the gammaherpesviruses (the MHV68 story).

Now there’s another paper5 showing a function for the MHC class I immune evasion ability of HIV (actually for SIV, but again it’s probably true for the closely-related HIV).

HIV has a gene, nef, that can block MHC class I expression. This has been shown in cultured cells, but understanding its relevance in actual infections has been difficult:

Although these data suggest that Nef-mediated immune evasion could play an important role in AIDS pathogenesis, there has been little direct evidence linking disease progression with MHC-I downregulation in vivo. 5

Obviously you can’t make a nef-less HIV and just throw it into people to see what happens. Even doing the experiment in monkeys with SIV is complicated by the fact that nef is very polyfunctional — as well as downregulating MHC class I, it also targets a number of other molecules.

But you can take advantage of natural variation, both in the virus and the host.  Nef isn’t equally effective on all MHC class I types, for one thing. As well, nef can develop mutations within the host.  It turns out that rapid disease progression correlates with the extent of MHC class I downregulation, whereas effects on other genes affected by nef (CD3 and CD4) didn’t correlate:

The extent of MHC-I downregulation on SIV-infected cells varied among animals …  the level of MHC-I downregulation on SIV-infected cells was significantly greater in the rapid progressor animals than in normal progressors.  … high levels of MHC-I downregulation on SIV-infected cells are associated with uncontrolled virus replication and a lack of strong SIV-specific immune responses.5

This is strictly a correlation study, so we can’t confidently say that MHC downregulation causes disease progression. Still, it’s an interesting finding, and perhaps one that can be followed up in human studies.

  1. Gold MC, Munks MW, Wagner M, McMahon CW, Kelly A, Kavanagh DG, Slifka MK, Koszinowski UH, Raulet DH, & Hill AB (2004). Murine cytomegalovirus interference with antigen presentation has little effect on the size or the effector memory phenotype of the CD8 T cell response. Journal of immunology (Baltimore, Md. : 1950), 172 (11), 6944-53 PMID: 15153514
    Only slightly qualified by
    Lu, X., Pinto, A., Kelly, A., Cho, K., & Hill, A. (2006). Murine Cytomegalovirus Interference with Antigen Presentation Contributes to the Inability of CD8 T Cells To Control Virus in the Salivary Gland Journal of Virology, 80 (8), 4200-4202 DOI: 10.1128/JVI.80.8.4200-4202.2006[]
  2. Stevenson, P., May, J., Smith, X., Marques, S., Adler, H., Koszinowski, U., Simas, J., & Efstathiou, S. (2002). K3-mediated evasion of CD8+ T cells aids amplification of a latent ?-herpesvirus Nature Immunology DOI: 10.1038/ni818[]
  3. I will admit there’s a certain circular quality to this argument.  “The gene must be important, because viruses don’t carry unimportant genes.  We know that, because this gene that they’ve hung on to must be important.”[]
  4. Hansen, S., Powers, C., Richards, R., Ventura, A., Ford, J., Siess, D., Axthelm, M., Nelson, J., Jarvis, M., Picker, L., & Fruh, K. (2010). Evasion of CD8+ T Cells Is Critical for Superinfection by Cytomegalovirus Science, 328 (5974), 102-106 DOI: 10.1126/science.1185350[]
  5. Friedrich, T., Piaskowski, S., Leon, E., Furlott, J., Maness, N., Weisgrau, K., Mac Nair, C., Weiler, A., Loffredo, J., Reynolds, M., Williams, K., Klimentidis, Y., Wilson, N., Allison, D., & Rakasz, E. (2010). High Viremia Is Associated with High Levels of In Vivo Major Histocompatibility Complex Class I Downregulation in Rhesus Macaques Infected with Simian Immunodeficiency Virus SIVmac239 Journal of Virology, 84 (10), 5443-5447 DOI: 10.1128/JVI.02452-09[][][]
May 2nd, 2010

So that’s all right, then

Malaria is an annual production of nearly every section of the United States. No State is entirely free from it. The Western States for well-known reasons, have gained considerable notoriety for the number and frequency of Malarial diseases within their borders. These diseases in Michigan, among natives, are of the mildest forms, much milder than those on the Chesapeake peninsula, to say nothing of the severer forms seen on the Virginia low lands, or in the Carolinas.

–Magnetic & Mineral Spring of Michigan,
to which is
Prefixed an Essay
on the
Climate of Michigan

by Stiles Kennedy, MD

James & Webb, Wilmington, Delaware

(See also “Malaria in the USA, 1870“)