measles infection diminishes other antibodies
Geoff A. Modest, M.D.
Wed 2/5/2020 7:05 AM
in 2015 i published a blog on measles infection and immunosuppression (see http://gmodestmedblogs.blogspot.com/2015/05/measles-and-immunosuppression.html ). a new study using more advanced techniques confirmed that native measles infection (which is unfortunately increasing because of parental declination of kids getting the MMR vaccine) results in "immune amnesia" from prior exposure to an array of prior infections. i will reprint/augment this older blog and add the new study.
From the old blog:
--measles remains endemic in most of the world: >7 million get it annually and >100,000 die
--because of reduced vaccination, the number of measles cases has increased in the US close to 300% since 2018
--measles infection is associated with increased morbidity and mortality for as long as 5 years, likely to be explained by the diverse effects of this infection, especially measles-induced immune amnesia
--mass measles vaccination in the past reduced overall 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.
--assessing 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. 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 mitigate 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 at least 4-6 weeks afterwards to get reliable results from a PPD test. or even studies from the 1940's finding that there were lasting remissions of autoimmune-related disorders after measles infections. so, it is important to look behyond 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 a 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.
the new measles study assessed the effect of measles infection on unimmunized children and noted a profound effect on the antibody titers of many other viral infections (see measles immunosuppression science2019 in dropbox, or Mina MJ Science 2019: 366; 599-606)
Details:
--77 unimmunized kids, mean age 9, who developed laboratory-confirmed measles infection, and 5 unimmunized kids who did not
--of the infected kids, 34 had mild measles and 43 severe
--blood samples were collected a mean of 10 weeks prior to infection and again a mean of 7 weeks after
--blood was analyzed using VirScan to detect antibodies to many viruses:
Results:
--measles infection was associated with a mean reduction of 20% in the overall diversity of the antibody repertoire measured
--the effect size varied between individuals: 16% of them lost >40% of their antibody diversity
--there was no difference in total IgG, IgA, or IgM levels: the researchers suggest that the reason the total IgG is unchanged is because there was a "restructuring of the antibody repertoire after measles"
--there was a differential effect in the loss of their total preexisting pathogen-specific antibody repertoires, depending on the severity of the clinical measles:
--mild cases: median loss of 33% (range: 12-73%)
--severe cases: median loss of 40% (11-62%)
--controls: retained 90% of their repertoires, even for those measured after a longer duration
--the most affected 20% of kids lost >50% of the pathogen-specific antibodies for most pathogens; in some up to 70% loss was found for some pathogens
--they also looked at antibody epitope binding sites by the VirScan, assessing 1100 epitopes (ie, the sites on the antibody that recognizes the antigen), finding that of approx 1100 epitopes assessed:
--controls: no significant changes
--after mild measles infection: 12% reduction
--after severe infection: 39% reduction
--comparing pre- and post-measles infection, they found that enterovirus, RSV, rhinovirus, influenza virus, coronavirus, herpesvirus, papillomavirus, and adenovirus all decreased with high statistical significance (7 of them with p<0.001 and one with p<0.05)
--giving the MMR vaccine did not affect the immune repertoire (ie, the vaccine was safe and did not confer the immunological havoc of the infection)
--epidemiologic investigation suggested that immune repertoire reconstruction was from new exposure to pathogens where the prior immunity was depleted; and that in a few cases cited, this entailed clinically significant infections (eg one kid developed pneumonia). ie, some people needed new exposures to old infections in order to redevelop antibody responses: the immunological amnesia from measles infection really did deplete immune memory from prior infections)
Commentary:
--these studies bring up a few issues:
--it seems pretty evident that the adverse effects of measles infection are profound and extend beyond the specifics of the measles virus: there seems to be immunologic amnesia to many other infections. and this might well explain the high general mortality both at the time of measles infection and even years after infection (studies in monkeys found that following a measles infection, researchers were no longer able to detect up to 60% of the antibody repertoire, and this persisted at least 5 months)
--perhaps the safest thing to do after someone gets measles is to revaccinate them with the routine childhood vaccinations (eg, the example above of a kid getting pneumococcal pneumonia)???
--per the CDC, one dose of MMR is 93% effective against the measles, 2 doses are 97% effective (see https://www.cdc.gov/vaccines/vpd/mmr/public/index.html )
--and, measles vaccine-acquired immunity is reported to wane in at least 5% of cases within 10-15 yrs after vaccination, per https://www.nvic.org/vaccines-and-diseases/Measles/measles-vaccine-effectiveness.aspx
--an older study in 1990 looked at antibody repsonse over time to live measles vaccine (the US went to a 2-dose vaccine regimen in kids in 1989) [there is both a cellular and humoral immune response, the latter being much easier to measure]. There are a few caveats here, including that there have been different lab tests to assess the antibody response, the prior studies were done on people with only 1 dose of vaccine, and it is not clear what the cutpoint of antibody response is associated with clinical immunity from the disease (though there is evidence that some people with low quantity of antibody may not be protected, as documented in the article: Markowitz LE. Pediatr Infect Dis J. 1990; 9:101-110)
--a few other issues:
--measles is perhaps the most contagious of all infections. For example, the R0 (the basic reproduction number, reflecting the average number of people who will get a disease from one contagious person: R0 projects the immunity level needed in the community to prevent spread of the virus). for ebola virus R0 is 2 (ie, 50% of the population needs to be immune to achieve herd immunity). for the novel coronavirus, it is felt to be around 2-3 (per NPR interview with Tony Fauci at the CDC). for measles it is 12-18 (so 92-95% of the population needs to be immune!!!). see http://gmodestmedblogs.blogspot.com/2017/11/herd-immunity-epidemics-and.html
--there are several immunological diseases associated with a prior measles infection (suggesting its widespread and longstanding generalized immunological perturbations), including postinfectious encephalomyelitis or the later-appearing subacute sclerosing panencephalitis
so, this does raise the issue to me that given the dramatic potential adverse consequences of measles virus infections, should we check antibody titers on people who might be exposed to measles?? the required herd immunity from measles vaccination is quite high (seems like in the 95% range), which would put at risk areas of the country where people are more likely to decline vaccination (these are indeed the areas of measles outbreaks). should those living in or near those communities be tested for immunity and reimmunized if needed?? (older studies of small numbers of patients confirm that revaccination does induce antibody response)? especially since even getting the appropriate childhood MMR vaccination does not seem to guarantee initial or sustained immunity.
from the above, perhaps measles vaccination is the most important of the vaccines we can give. ironic that it is the one targeted by the anti-vaccine groups....
geoff
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