Immune amnesia: Another reason why measles is a serious illness

Basically everyone, even the antivaccine movement, concedes that the measles vaccine is highly effective at preventing the measles. (Actually, there are a few who try to deny this, but the efficacy of the MMR vaccine at preventing measles is such that they come off sounding ridiculous more than anything else.) That’s why what most antivaxers do is simply try to argue that measles isn’t a big deal, that it isn’t deadly, that it’s a harmless childhood disease, and that therefore the fantastical “risks” ascribed to the vaccine by antivaxers (autism, neurodevelopmental disorders, diabetes, sudden infant death syndrome, etc.) outweigh the benefits of presenting measles. It’s the kind of misinformation that led antivaxers to point to a 50-year-old episode of The Brady Bunch as “evidence” that people back then didn’t think the measles were a big deal because a sitcom played measles for laughs. I suppose that, by that “logic,” Hogan’s Heroes must also mean that life in Nazi prisoner of war camps wasn’t that bad. Be that as it may, the point is that the main benefit of vaccinating for measles has generally been believed to be the not-insignificant benefit of preventing the measles and its attendant complications, including the most dreaded SSPE. However, a new body of evidence is developing that the benefits of preventing measles go beyond just preventing measles and its known complications. In fact, it turns out that vaccinating against measles lowers all-cause mortality among children. The past and present rebuke antivaccinationists who claim measles is “benign.” Now, a new study suggest why the benefits of vaccinating against measles go beyond just preventing measles: Immune amnesia.

Let’s step back a minute. It’s basically been shown in a number of studies that the measles virus somehow damages the immune system, leading to immunosuppression, a phenomenon notices in developing countries where, after introduction of the MMR vaccine, mortality from all infectious diseases, including pneumonia and infectious diarrhea. More recent work suggests that it can last three years. Last Friday, two papers were published, one in Science (yes, that Science) and one in another Science journal, Science Immunology, that for the first time provided evidence for a potential mechanism by which immune amnesia due to measles infection occurs. The first is by a group led by Michael J. Mina at Harvard (whom we’ve met before) and Stephen Elledge, also at Harvard. Let’s take a look at it first.

The authors note in the introduction:

Immunosuppression was first documented when children with measles showed negative cutaneous tuberculin reactions after previously testing positive (5). Subsequent studies have shown decreased interferon signaling, skewed cytokine responses, lymphopenia, and suppression of lymphocyte proliferation shortly after infection (6). The MV receptor CD150/SLAMF1 (signaling lymphocytic activation molecule family member 1) is highly expressed on memory T, B, and plasma cells, resulting in their infection and depletion without an effect on total immunoglobulin G (IgG) levels (7–12). Recovery of the functional immune response, including resolution of lymphopenia, occurs 2 to 4 weeks after viral clearance (6, 10, 13, 14). However, MV replication in immune cells has been hypothesized to impair immune memory, potentially causing “immunological amnesia” (10, 15, 16).

And:

Epidemiological evidence has associated MV infections with increases in morbidity and mortality for as long as 5 years (15, 23) and suggests that in the pre-vaccine era, MV may have been associated with up to 50% of all childhood deaths from infectious diseases, mostly from non-MV infections (15). This phenomenon might be explained by immune amnesia. However, to date, no study has successfully resolved whether measles-induced immune amnesia—a reduction in the diversity of the immune memory repertoire after measles infections—indeed exists. To address this issue, we have studied paired blood samples collected before and after MV infection using a seroprofiling tool that allows the detection of thousands of pathogen-specific antibodies.

To study the effects of the measles virus on the immune system, the investigators studied a Dutch Orthodox Protestant Community in the Netherlands that refuses vaccines on religious grounds. As is often the case in such communities, in 2013 there was a measles outbreak, with more than 2600 cases reported, and it’s a community that has been studied before. An observational cohort study was performed during that measles outbreak, in which unvaccinated children 4 to 17 years of age at the time of sampling, without a history of natural measles, were recruited from schools with low vaccination coverage. Plasma was collected before and after laboratory-confirmed measles infection from 77 unimmunized children with a mean age of 9 years plus five unimmunized children who were lucky enough not to become infected during the study. Of the 77 children, 34 had mild cases and 42 severe cases. The mean time between sample collections was ten weeks, with the mean time after collection being 7 weeks. Elledge’s group used VirScan to measure antibody diversity before and after infection in these children. What is VirScan? The authors explain:

To measure the diversity and magnitude of the epitope-specific antibody repertoires in these children and controls, we used VirScan (25), a phage-display immunoprecipitation and sequencing (PhIP-Seq) technology (26) developed for virome-wide detection of antibodies against viral epitopes. VirScan primarily detects antibodies to short contiguous epitopes as opposed to conformational epitopes. The cells producing antibodies to all epitopes are phenotypically similar, aside from their antibody product. Thus, changes in the antibody repertoire detected by VirScan represent changes across the spectrum of antibodies, and these include neutralizing and non-neutralizing antibodies. For this study, we generated an expanded VirScan library that encodes the full proteomes of most known human pathogenic viruses (~400 species and strains) plus many bacterial proteins. For each sample, we obtained a comprehensive measure of the individual’s antipathogen antibody repertoire diversity (i.e., the total epitope hits across all pathogen peptides). We also derived an antibody epitope binding signal (EBS), which is a relative measure of antibody titer for each epitope.

I’ll translate. VirScan is a tool that Elledge and and Tomasz Kula, a PhD student in the Elledge Lab, developed in 2015. It detects antiviral and antibacterial antibodies in the blood that result from current or past encounters with viruses and bacteria, providing overall “snapshot” of the immune system at a given time. For those who can understand some of the more jargon-filled text above, PhIP-Seq uses oligonucleotide library synthesis to encode peptide libraries that can encompass an entire proteome (the entire number of proteins made by the body) for display on bacteriophage. These libraries are then immunoprecipitated using an individual’s antibodies for subsequent analysis by high-throughput DNA sequencing. How does that identify anything? Well, the DNA is “bar-coded,” so that each phage has a unique short DNA tag. It’s hard to explain if you don’t know how these systems work, but I found a nifty video that (I thought) explains the process pretty well. It’s not from the Elledge laboratory, but it is from the laboratory of one of the co-authors of this study:

All I can say after a video like this is: Damn! Science is cool! It can now in essence provide an immune profile listing every relevant antibody to every known pathogen to which a given person has been exposed, plus antibodies to self-antigens. In this case, the authors looked at antibodies to most known pathogenic viruses and many bacterial proteins. The authors also looked at paired samples from four control cohorts (n=119) from:

  • Approximately age-matched controls sampled at similar intervals (~3 months) as the measles cohorts (control A; n = 28 paired specimens)
  • Age-matched controls with samples collected ~1 year apart (control B; n = 31)
  • Adult controls with collection intervals similar to the measles-infected individuals (control C; n = 22)
  • Young children before and after their first measles-mumps-rubella (MMR) vaccination (MMR vaccinated; n = 33)
  • Unvaccinated children from the same community as the MV cases but who remained seronegative for MV (MV negative; n = 5)

Control cohorts A, B, and C were individuals with no known exposure to MV.

The authors observed that measles resulted in the elimination of 11% to 73% of the antibody repertoire across individuals. Notably, these effects were not observed in children vaccinated with the MMR but were observed in macaque monkeys intentionally infected with the measles virus. Recovery of these antibody populations only occur after reexposure to the pathogens that provoked the immune response in the first place. The authors suggested that this reduction in humoral immune memory after measles infection is what generates vulnerability to future infections.

But how does this immune amnesia happen? The cells that make antibodies are called B-lymphocytes. During an initial infection resulting in a primary immune response, naive follicular B-cells are activated by the immune system and undergo expansion to produce clones B cells producing antibodies specific for the antigen. Most of these cells differentiate into effector B cells, also known as plasma cells, which synthesize protective antibodies in order to fight and clear the infection. However, after the infection is cleared, a small fraction remain as “memory cells” that persist long-term and allow for a much more rapid second immune response when the same antigens are encountered again, as in a second exposure to the same pathogen. Yes, this is a simple (maybe simplistic) explanation, but it’s good enough for a lay person to understand what’s happening here. Somehow the measles virus attacks these memory cells, eliminating the cells that serve as the basis of a rapid secondary antibody response. Basically, for the relevant pathogens, it becomes as if the immune system had never seen that pathogen at all.

The authors explain further:

Using VirScan, we quantified the effects of measles on antipathogen antibody repertoires in plasma obtained before and after natural and experimental MV infections. We found that measles is associated with large reductions in both the diversity of the antibody repertoire and magnitude of the binding signal, likely reflecting reduced antibody titers resulting from diminished numbers of cells producing the respective antibody. The reduction of diversity may be greater than we report because even if particular antibody-producing cells have been eliminated, an antibody half-life of ~3 weeks (35) means that residual antibodies were still detectable at the time of sampling. Our findings show that after recovery from MV infections, individuals enter a state in which immune functionality is restored, but memory cell elimination induced by measles may alter previously acquired memory.

And:

Given the variation in the degree of immune repertoire modulation we observed, we anticipate that future risk of morbidity and mortality after measles would not be homogeneous but would be skewed toward individuals with the most severe elimination of immunological memory. These findings underscore the crucial need for continued widespread vaccination. More than 7 million people are estimated to have been infected with measles in 2018 (1–3). Comprehensive coverage with MV vaccine would not only help prevent the >120,000 deaths that will be directly attributed to measles this year, but, by preventing MV immune amnesia and thus preserving immunity, MV vaccines could also avert potentially hundreds of thousands of additional deaths attributable to the lasting damage to the immune system. The WHO recently reported that between 2000 and 2017, MV vaccines have prevented more than 21 million deaths directly attributable to measles (41). These findings suggest that the number of deaths averted might be much greater, and they attest to the immense public health value of the measles vaccine.

Elsewhere, it’s been noted that the conclusion that the immune amnesia lasting up to five years after a measles infection could be due to depletion of specific clones of memory cells is plausible, as that’s how long the immune system takes to reconstitute itself after administration of the powerful immunosuppressive drug rituximab, which depletes the same cells and is used to treat certain types of cancer.

That’s where the second study comes in, from Colin Russell at the University of Amsterdam, who published the second paper. He and his colleagues sequenced the DNA from the immune cells of 20 of the 77 children that Mina examined, allowing them to look at not just the cells producing antibodies but their naive precursors before exposure to antigen. To sum up a long study, they found that measles kills primarily the mature, differentiated, memory cells. As Russell himself says:

In our first few years of life, these naive cells mature, diversifying so they will rapidly recognise particular types of molecules on different pathogens. Russell’s team found that measles kills the mature cells. “It’s as if our immune system is reset back to infancy.”

That means, he says, that those who have had measles may need to be re-exposed to diseases multiple times to rebuild their antibody repertoire.

As a correlative study, Russell did an experiment in ferrets, in which the animals were infected with a virus similar to measles, morbillivirus. These animals had been vaccinated against the flu. The result? The animals infected with morbillivirus got repeated bouts of the flu after they recovered; the control group (not infected) did not. Immune amnesia strikes again.

Together these two studies are yet more evidence that, contrary to the claims of antivaxers pointing to 50 and 60 year old episodes of various sitcoms in which measles infections were made light of, measles is serious. It produces immune amnesia, which is why the benefits of vaccination against measles go beyond just protecting against measles. Let’s just put it this way, contrary to what antivaxers claim, “natural infection” with measles does not “boost the immune system”—quite the contrary.