Michael Mina is an Assistant Professor of Epidemiology and of Immunology & Infectious Diseases at the Harvard T.H. Chan School of Public Health and is an associate medical director in clinical pathology, focusing on infectious disease diagnostics, at the Brigham and Women’s Hospital / Harvard Medical School. His work aims to understand the interface of immunity and public health, particularly surrounding vaccines and childhood infectious diseases.
by Michael Mina
Historically, measles was so common it was considered a near right-of-passage into adulthood. Until the introduction of the measles-containing vaccine in the 1960s, the measles virus, arguably the most transmissible pathogen to infect humans, infected nearly 100% of children by their 5th birthday. Today, approximately 7 million cases continue to occur annually – that amounts to approximately 5% of the annual global birth cohort. Though 7 million is a sobering number, it reflects a massive reduction in the share of children infected (approximately 95%!), which can be attributed to global measles vaccination efforts.
Though most children who become infected with measles recover within a few weeks, physicians and public health experts have long recognized the dangers of contracting the virus. Of the estimated 7 million cases that occurred in 2018, approximately 140,000 (2%) were fatal. In high-income countries, where mortality rates are considerably lower (1 death per 5000 cases or 0.05%), between 10%-20% of infected children nevertheless end up in the hospital, many of them in intensive care, as seen in the New York State outbreak this past year. These children are lucky to have access to healthcare that can generally keep them alive through discharge. In low- and middle-income countries, on the other hand, 1 death per 50-100 cases (1 to 2%) is common. In 2018-2019, for example, the mortality associated with a large outbreak of measles in Samoa, which infected 5,500 people, or >2% of the population, led to at least 79 deaths – a mortality rate of approximately 1 per 70 cases (1.4%).
Measles increases risk of other infectious diseases for 2-3 years
While these measles-specific mortality rates are very high, research we reported in 2015 suggests that the overall death rate associated with measles may be even higher. In that report, using population level data, we discovered that after large measles epidemics, the numbers of deaths from other infections (not including measles) increased for 2-3 years. The effect was remarkably strong and consistent across countries, decades, and ages. We concluded then that measles infections may increase risk from other infectious diseases for 2-3 years and that measles may have been implicated in as many as 50% of all childhood infectious disease deaths. If proven further (i.e. biologically), the finding would place measles elimination through vaccination as a clear top global priority.
This work was supported by an additional retrospective cohort study using data collected from approximately 50% of the general practitioners in the U.K. Analyzing over 2,200 measles cases in the U.K. through the 1990s and 2000s, we found that after a measles infection, children experienced increased risk of requiring medical visits and being prescribed antibiotics, both of which are potential markers of increased infectious disease incidence. Excess risk lasted as long as 5 years following measles.
These findings brought us to ask the obvious question – how? How could a famously acute viral infection like measles result in a years-long increased risk of other infectious diseases? How could measles possibly be connected to almost half of all childhood deaths from infectious diseases? Answering these questions required understanding the biology of the virus.
Measles is a respiratory virus that invades the cells of the body using a specific molecular receptor called CD150. The CD150 receptor is expressed on the surface of immune cells – including the B, T, and plasma cells that produce immunological memory and help us to fight off infections that we have already seen. Thus, by preferentially infecting CD150-expressing immune cells, measles destroys the cells that hold onto immunological memory. The potential effect is something we termed “immune-amnesia” (credit goes to Rik de Swart for deriving the term). Discovery or proof of immune-amnesia would help explain the long-term increases in mortality we previously detected with a biological mechanism.
Measles causes immunological amnesia
With support from the Value of Vaccination Research Network (VoVRN), we sought to test for immune amnesia among natural-measles-infected children. To do this, we looked towards the Netherlands during an ongoing measles outbreak among a community that refuses vaccines on religious grounds. Despite refusal to vaccinate, the parents were interested in participating in better understanding measles and consented for us to obtain blood samples from their child before the epidemic hit their school system. They additionally agreed to our returning to obtain follow-up samples should their child become infected.
By the end of the collection period, we obtained blood samples from 77 children, both before and approximately 2-3 months after measles infection. To test for immune amnesia we made use of a recently described technology called VirScan, which allows us to assess the presence and quantity of antibodies against hundreds of different pathogens, simultaneously, in each sample. By comparing the VirScan antibody results from before and after measles, we found that among the 77 children studied, measles was associated with a remarkable 20% to 70% decline in antibodies that could protect against other infectious diseases. Although there was a range of effects, we found that the most-affected 20% of children lost over half of all of their pre-existing antibody memory. In contrast, we found that over a full year, controls retained 90% of their antibodies on average. We additionally tested this in measles-infected macaques and found that measles led to the rapid decline of about 50% of all of their protective antibodies, and that the antibodies remained diminished even 5 months post-measles (the last point in time that we checked).
Overall, we concluded from this recent study that measles eliminates between 20% and 70% of an individual’s antibody memory. Because antibodies are produced primarily by long-lived memory cells, which do not return once killed, we concluded further that it is most likely that to reacquire immune memory following measles would require re-infections or revaccinations and that this process could take years. During this time, children would be at elevated risk for other infectious diseases. Measles, therefore, is a master childhood infection – precipitating excess susceptibility to other diseases. These findings highlight the importance of measles elimination as a key public health priority and provide a crucial evidence of a biological basis for an increasingly recognized phenomenon of excess infectious disease mortality lasting years after measles. Taken together, the population and biological work I’ve described suggest that the measles vaccine may serve to preserve individual and population (herd) immunity against all other infectious diseases, with the effect of reducing all-cause child mortality by nearly 50%. Thus, measles vaccines are perhaps the greatest buy in public health interventions.
[…] amnesia. Here, she also states the fact that a large chunk of the deaths caused by the secondary infections is due to a lack of immunological memory caused by the measles infection. This was found […]