Measles virus, known commonly as one of the three viruses included in the MMR vaccine that infants typically receive (measles, mumps, and rubella), is a highly infectious disease that causes fever, coughing, runny nose, and a red, blotchy skin rash in children. Once declared eliminated in the U.S. in 2000, measles has unfortunately made a recent comeback. According to the CDC, there have been 704 cases of measles in the U.S since the beginning of 2019, the largest number in a single year since 1994. While the exact reason for measles’ sudden return is unknown, many attribute it to the rise of the anti-vaccination movement, as 71% of the cases so far this year were unvaccinated. Understanding the danger of a resurgence of such an infectious disease, it is imperative that the risks measles pose is thoroughly researched.
One feature of measles that contributes to the more than 100,000 deaths per year globally is its ability to suppress normal immune system function, making patients susceptible to more serious illnesses (1,4). This immunosuppression was first documented over 100 years ago when children infected with measles tested negative for tuberculosis antibody response in patients after previously testing positive (2). Since this discovery, virologists have linked the phenomenon to the infection of immune cells by measles virus, resulting in their depletion during infection (3). While the immune cells killed during the infection eventually recover, studies have shown the infection results in impaired immune memory (4). This phenomenon is commonly referred to as “immunological amnesia”, in which immune cells lose memory of pathogens that have caused previous infections. Until this study, however, no previous literature had successfully determined whether measles-induced immune amnesia exists.
By using a recent outbreak of measles in the Netherlands, researchers were able to effectively compare the diversity of antibodies pre- and post-infection for 77 unimmunized and infected and 5 immunized and uninfected children. To accomplish this, the researcher used VirScan, an assay that tracks antibodies to thousands of pathogen epitopes in the blood. Epitopes defend against future infection from a previous pathogen the immune system has encountered. Using this method, comparisons were made between the change in the number of epitopes across various groups of interest. This allowed the researchers to determine that measles caused a reduction in antibody diversity in unvaccinated children while uninfected, vaccinated children experienced an increase in diversity (Figure 1).
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| Figure 1: Measles virus infections reduce antibody diversity. VirScan of epitope hits pre- and post-infection measurement for Control groups A-C, measles virus (MV) negative, MMR vaccinated, and MV mild and severe children. MMR vaccinated children show a significant increase in epitope hits while MV mild and severe children show a significant decrease. |
Concentration of epitopes in the blood provides better insight into how measles is affecting the immune system. To analyze antibody abundance, the researchers looked at antibody epitope binding signals (EBS), which essentially measures how frequently an epitope is detected. With this form of analysis, they found that both the signal strength and general recognition of epitopes were disrupted by measles virus (Figure 2). This finding indicates that, even if an epitope for a particular pathogen remains present in the immune system, its frequency in the blood is drastically reduced by measles. As a result, the immune system’s ability to respond to a previously encountered infection may be compromised by measles, even if the antibody for the disease is present.
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| Figure 2: Measles virus infections are associated with diminished epitope binding signal. EMS was measured for each epitope and the signals were sorted into four groups of interest: Control group A, control group B, MV mild infections, and MV severe infections. (A) Each point depicted indicates one pathogen per child. The points obtained at post-infected were compared to a pre-infection baseline at 1 on the y-axis. Denisty curve distributions adjacent to the data points indicate the change in EMS, with MV mild and severe decreasing significantly. (B) Each point depicts one epitope across all children. Similar to (A), the points obtained at post-infected were compared to a pre-infection baseline at 1 on the y-axis. The EMS analysis found a decrease in binding among MV mild and severe children. |
While measles negatively impacted the antibody diversity of most unvaccinated children that were infected with measles, a small subset of them experienced an unusual increase in EBS post-infection. Suspecting that these cases may be due to exposure to other infectious pathogens in particular physical locations, the researchers analyzed the spatial clustering of transmissible pathogens by postal codes and housing identifiers. The researchers found that children from specific postal codes had a significantly greater likelihood of having certain antibodies, likely due to local exposure (Figure 4). This resulted in an increase in the general antibody counts in a small subset of individuals not linked to immune system recovery from measles virus.
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| Figure 3. Increases in antibody EBS cluster within postal codes and housing identifiers. (A-C) Observing antibody EBS for common viruses across various postal codes, researchers found increases in antibody EBS to be associated with a specific postal code across three viruses of interest: (A) adenovirus C, (B) influenza A virus, and (C) respiratory syncytial virus. Red circles represent children with significantly increased EBS for the pathogen while unchanged or decreased EBS is represented by gray. |
Overall, this paper offers exciting insight into a phenomenon that has been unconfirmed for decades: measles-induced immune amnesia. By analyzing the antibodies in children infected with measles, they determined that the disease had suppressed the immune system by significantly decreasing the number of unique antibodies and their abundance. This finding helps explain why a disease with such seemingly harmless symptoms is associated with historically heightened mortality rates (1).
As always, the best way to fight the measles virus is by getting vaccinated. MMR is approximately 97% effective at preventing measles according to the CDC. However, for children that do become infected with the virus, this study should provide some hope of immune recovery. By demonstrating that antibody reduction is less significant for mild cases of measles as opposed to severe, this study suggests that fighting the progression of the disease may be an effective means of preventing significant immune damage. Future research into the immunological consequences of measles is likely to explore the mechanism of this reduction in antibodies, investigating the driving forces and whether certain antibodies are more likely to be affected by the virus.
1. Portnoy, A., Jit, M., Ferrari, M., Hanson, M., Brenzel, L., and Verguet, S. (2019). Estimates of case-fatality ratios of measles in low-income and middle-income countries: A systematic review and modelling analysis. Lancet Glob. Health, 7:e472–e481, doi:10.1016/S2214-109X(18)30537-0pmid:30797735
2. Von Pirquet, C. (1908). Das Verhalten der Kutanen Tuberkulin-reaktion wahrend der Masern. Dtsch. Med. Wochenschr., 34:1297-1300
3. Laksono, B.M., Grosserichter-Wagener, C., de Vries, R.D., Langeveld, S.A.G., Brem, M.D., van Dongen, J.J.M., Katsikis, P.D., Koopmans, M.P.G., van Zelm, M.C., and de Swart, R.L. (2018). In Vitro Measles Virus Infection of Human Lymphocyte Subsets Demonstrates High Susceptibility and Permissiveness of both Naive and Memory B Cells. Journal of Virology, 92(8):e00131-18; doi: 10.1128/JVI.00131-18
4. Mina, M.J., Metcalf, C.J., de Swart, R.L., Osterhaus, A.D., and Grenfell B.T. (2015). Long-term measles-induced immunomodulation increases overall childhood infectious disease mortality. Science, 348(6235):694-9. doi: 10.1126/science.aaa3662
