Measles Virus and B-cell memory

The re-emergence of diseases that were thought to be part of our history, defeated by immunisation, and hoped to be found only in category 4 labs deep underground and textbooks, are now increasingly common in headlines covering new epidemics.

Of current popular concern is Measles, the virus not to be confused with German Measles nor Rubella, which prior to a vaccintation program beginning in 1963, killed 2.6M people annually [1]. In 2018 more than 140,000 people died from the virus [1], an incredible decrease since the 1960s but this number has been increasing.

Image: Measles Virus Micrograph

The reason for the rise in measles cases is not only because of the recent fall-off in immunisation program uptake, thanks to baseless claims linking autism with the combination vaccine, MMR (Measles, Mumps and Rubella), but also because of the virulence of the virus. Measles is the most infectious virus known to the human race, and before vaccination programs were in effect, infection with inevitable, with 90% of people displaying immunity by the age of 15 [2].

The prevention of measles epidemics is reliant on “herd immunity”, where enough of a population are immune to prevent further infection and spread. However herd immunity to measles relies on greater than 95% immunisation rates, and currently many European countries have less than 85% coverage [3].

Measles Virus Pathology

The pathology of the virus centres around its immunosuppressive effects. Viral cell surface haemagluttinin binds with high infectivity to host nucleated cells via CD46, but also CD150, aka SLAM, expressed on macrophages and dendritic cells. The concurrent circulation of the virus in these white blood cells via the lymphatic system ensures many host immune cells are infected, and soon undergo cell death by lysis upon the release of newly synthesised virus. In turn, the host is susceptible to co-infection by often non-pathogenic virus and bacteria that can now cause disease, leading to increased host morbidity and mortality.

Recently, Mina and colleagues published just how devastating and far reaching the effect of measles-induced immunosuppression is. Their study published in Science, overviewed below, solidifies the already undeniable need for increasing public confidence in vaccination programs and adds weight to the argument for compulsory vaccinations for children wishing to attend school, to ensure our populations’s herd immunity.

Targeting B-cell Memory

Mina et al [4] go further than previous studies identifying the lymphopenia caused by measles virus, and monitor actual antibody titres in the blood, reactive against peptides derived from a large panel of pathogens. The study highlighted a phenomenon when a cohort of non-vaccinated children had their blood taken, and then several years later after a measles outbreak hit their community, had their blood taken again. When assessing antibody reactivity they noticed something unusual. While newly generated antibodies against measles virus were found in the blood after infection, titres of antibodies reactive to other pathogens were often not found after measles infection. Infected individuals lost their immunity to pathogens they were previously exposed to, as they lacked an immune response after the measles outbreak.

The depletion of circulating antibodies in the blood was hypothesised to be due to measles virus destroying bone-marrow residing memory B-cells, the body’s reservoir of learned defenders left from the host’s first exposure to an infectious agent, and ready to quickly create neutralising antibodies upon reinfection, preventing host pathology. This was later confirmed in animal models.

The disappearance of memory cells implies that individuals who have been infected with measles virus may need to be re-immunised against previously vaccinated pathogens, and will also succumb to infectious agents they previous gained immunity to, such is the far-reaching immunosuppressive destruction caused by measles virus.

But why?!

What I had wondered, and often do wonder when reading about viruses, is their evolutionarily derived biological imperative. What increased survival pressure has led to the virus targeting bone-marrow dwelling memory B-cells? 

Is the virus able to maintain a longer period of infectivity among those the host associates with, due to co-infections? Is the host less able to mount an immune response as it is having to mount de novo responses to commonly encounter viruses and bacteria due to this depletion of memory?

References:

1. "Measles Fact sheet N°286". World Health Organization (WHO) https://www.who.int/en/news-room/fact-sheets/detail/measles 5th December 2019
2. "Pinkbook Measles Epidemiology of Vaccine Preventable Diseases". Centers for Disease Control and Prevention (CDC).https://www.cdc.gov/vaccines/pubs/pinkbook/meas.html
3. Gary Finnegan., "France Measles outbreak: babies hit hardest". Vaccines Today. November 7th 2018
4. Review on measles outbreaks in France, also covering other European countries included The UK - https://www.vaccinestoday.eu/stories/france-measles-outbreak-babies-hit-hardest/
5. Michael J. Mina et al. "Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens." Science. Published online October 31, 2019. doi: 10.1126/science.aay6485