measles and immunosuppression

of late, it seems that I have been mostly trashing immunization, specifically the pertussis component of Tdap. so, i thought i should highlight a really interesting (to me) article from the journal Science on the mysteries of the remarkably successful measles vaccine (see measles and immunosuppression science 2015 in dropbox, or doi: 10.1126/science.aaa3662). here is a brief review of the article.

--mass measles vaccination in the past reduced childhood mortality by 30-50% in resource-poor countries and up to 90% in the most impoverished countries. this benefit could not be explained simply by preventing measles infection alone.

--measles virus (MV) infection is associated with profound immunosuppression, and recent data challenge the prior notion that this is a transient phenomenon:

    --data (mostly animal) suggest that measles infection leads to a loss in immune memory cells, and that this is prevented by vaccination

    --in macaques, measles infection leads to systemic depletion of lymphocytes and reduced innate immune cell proliferation. MV leads to replacement of "the previous memory cell repertoire with measles virus-specific lymphocytes, resulting in 'immune amnesia' to non-measles pathogens". recovery of these memory cells requires restimulation by the appropriate antigens

    --in the current study, they looked at 4 sets of data from resource-rich countries with adequate data on the pre- and post-measles vaccination period (England, Wales, US, Denmark) to test the hypothesis that MV infection leads to immune amnesia, findings:

         ​--there was a significant correspondence between measles disease incidence and mortality overall

         --there was significant reduction in nonmeasles infectious disease mortality associated with the introduction of the measles vaccine (vaccination programs occurred at different times in the different countries, 20 years later in Denmark)

        --the data from England and Wales suggested that the duration of MV-immunomodulation lasted 28 months on average. in the US data it was 31 months, and 30 months in Denmark

        --this time lag was consistent for age groups 1-4 yo and 5-9 yo.

        ​--the increase in mortality was consistent for different diseases (pneumonia, dysentery/diarrhea) and different organisms (bacteria --eg strep, pneumococcus, typhoid, meningococcus -- as well as fungal and viral pathogens), though not so for septicemia and rubella, which seemed to have shorter periods of immunologic amnesia (3 months and 12 months, respectively). this suggests a pretty  global immune amnesia.

        --looking at pertussis, which is not associated with immunosuppression,  vaccination did not influence non-pertussis mortality in England and Wales

    ​    --one interesting corollary of the above finding is that MV infection could diminish the herd immunity effect (ie, population immunity) from other infections (ie, not only increase the susceptibility of an individual infected with MV to a non-measles infection, but also of a non-measles infection being more likely to spread throughout the population, even to those who did not get MV but are susceptible to other infections). or to put that more concretely, if you need 80% immunity in a community to prevent the spreading of infectious disease XXX, and the level is 90% in that community, a measles outbreak may bring that immunity level down to 50-60%, making the whole community more susceptible to the spread of infection XXX.

so, again, the above data challenge the usual (simplistic) understanding about vaccination -- its effects are not simply increasing immunity to its targeted specific microbial species, but that any immunologic manipulation may have collateral effects on the functioning of the immune system overall (sort of like medication effects -- the adverse effects found are just collateral effects on other cells in the body, and are above and beyond the desired targeted effects). what are the implications of this? 

    ​-- the reverse could be true: vaccination could conceivably cause profound alterations of the immune system or other systemic effects which undercut the protection from the vaccine. examples might include the earlier rotavirus vaccine, associated with documented increased risk of intusseseption in kids; and even the measles vaccine, which is associated with enough immunosuppression itself that you need to wait 4-6 weeks afterwards to get reliable results from a PPD test. so, it is important to look at even more than vaccine-specific clinical benefits but at a much larger picture (such as the overall mortality effects noted in the measles study above)

    -- there may not be much of a correlation between a robust antibody response and clinical disease protection. for example the recent dengue vaccine achieved robust immunologic response from all 4 serotypes included in the vaccine, but there was no significant clinical protection in those with serotype 2 infection.

    ​--and, yet again, this measles article brings up the importance of our always challenging and modifying our understanding of physiologic processes.