Hilleman, Enders, Hayflick, Plotkin and How They Saved Humanity

In this 2-part series, we partner with STEMHiss, an international student-led organisation based in Canada, to delve into all things vaccines. In this first part, STEMHiss’s vice-president Cindy Liu looks into the history of measles, mumps and rubella (MMR) vaccine development and its lifesaving impact worldwide. This will be followed by Project BioLogical writer Wei Zhanghao’s article on recent technological developments and rising anti-vaccine sentiments.

Prior to the vaccines, measles, mumps, and rubella led to large-scale outbreaks with catastrophic effects. Measles alone was estimated to kill 2.6 million people every year worldwide prior to 1963, states the World Health Organization. In the US, it led to an estimated 500 deaths, 48,000 hospitalizations, and 1,000 cases of brain inflammation (encephalitis) every year. Mumps infected around 186,000 Americans each year before the introduction of the vaccine in 1967, leading to complications such as meningitis in 15% of infections and deafness in a few. Rubella, while typically mild in children, was disastrous during pregnancy. During the 1964–1965 rubella epidemic in the U.S., 12.5 million cases led to 11,000 miscarriages, 2,100 deaths of infants, and 20,000 instances of Congenital Rubella Syndrome (CRS), resulting in deafness, blindness, and heart defects. These statistics highlight how terrifying and deadly these viruses were before vaccination.

Figure 1: Child with Measles by Larry Duncan

John Enders developed the first measles vaccine in 1963 by isolating the virus in 1954 from a sick child and weakening it through repeated cultivation in chick embryo cells. This favored virus specimens that would be better at infecting chicken cells and not at human cells, creating a weakened virus–that is capable of triggering immunity without causing severe disease. However, this early vaccine had side effects like fever and rashes. Maurice Hilleman later improved it by weakening the virus in a lab. He used Enders’s method but used a cold environment. This favoured virus specimens that were better adapted to the cold and not the heat of the human body to flourish, further weakening the virus. He created the “Edmonston-Enders” strain, which was much safer than previous measles vaccinations and became the standard used in the modern measles vaccine. Overall, Hilleman’s refinements made the vaccine safer for immunization.

Figure 2: Electron micrograph of measles virus (Semantic Scholar)

Maurice Hilleman developed the mumps vaccine in 1967 using a live virus strain he obtained from his 5-year-old daughter, Jeryl Lynn, when she was sick with mumps. He weakened this virus by passing it through chicken embryo cells, reducing its ability to cause disease while keeping it effective at generating immunity. This vaccine, known as the “Jeryl Lynn strain,” remains in use today and is considered incredibly effective. Hilleman’s method ensured the vaccine was both safe and potent, helping to reduce mumps cases by over 99% in countries where it was widely administered.

Figure 3: Dr. Maurice Hilleman, one of the greatest vaccinologists of all time

Stanley Plotkin and Leonard Hayflick improved vaccine safety by culturing the virus in WI-38 human diploid fibroblast cells, a more stable and safe cell line derived from fetal tissue. This weakens the virus, as it favors virus specimens that are adept at infecting fibroblasts rather than respiratory epithelium (the primary target of the virus in the human body). Since this experimentally allowed for more predictable and reproducible vaccine batches. It must be noted that this cell line is used to “breed” the virus and weaken and not actually included in the vaccine. Furthermore, the fetal tissue is derived from a legal abortion done in 1962 and is not actually in the vaccine but merely used to weaken the virus. Plotkin’s RA27/3 vaccine, licensed in 1969, was the vaccine of choice because it was more efficacious with fewer risks of side effects. Overall, they made the vaccine safe to prevent the congenital abnormalities caused by rubella infections during pregnancy.

Figure 4: Dr. Leonard Hayflick, created the WI38 cell line to attenuate (weaken) rubella virus

Maurice Hilleman developed the MMR vaccine in 1971 by combining three separate live virus vaccines for measles, mumps, and rubella into a single injection. He used the improved Edmonston-Enders strain for measles, the Jeryl Lynn strain for mumps, and the RA27/3 strain for rubella. By merging these vaccines, Hilleman simplified immunization schedules and increased vaccination rates. Thus, the MMR vaccine was a major breakthrough in public health, offering protection against three dangerous diseases with one safe, effective shot, reducing the burden of viral infections in children across the globe.

The introduction of the MMR vaccine in 1971 led to a dramatic decline in deaths and complications caused by measles, mumps, and rubella. In the U.S., widespread vaccination reduced measles deaths by over 99%, with only a few dozen cases reported annually by the 2000s, compared to hundreds of thousands before vaccination. Mumps and rubella cases also plummeted by over 98%, with congenital rubella syndrome becoming almost nonexistent in many developed countries. Globally, measles vaccination alone has prevented an estimated 56 million deaths between 2000 and 2021. Therefore, the MMR vaccine played a key role in eliminating these diseases as endemic threats in many regions.

Figure 5: MMR Vaccine for injection

Thimerosal is a mercury-containing compound used as a preservative in some multi-dose vaccine vials to prevent bacterial contamination. It was discovered in 1927 by Morris Selig Kharasch, a chemist at the University of Maryland, who developed it while researching antiseptics. Thimerosal contains ethylmercury, which is quickly eliminated from the body and is different from toxic methylmercury. Importantly, the measles, mumps, and rubella (MMR) vaccine has never contained thimerosal, as it is produced in single-dose vials that do not require preservatives.

References

1. Hilleman, M. R. (2000). Vaccines in historic evolution and perspective: a narrative of vaccine discoveries. Vaccine, 18(15), 1436–1447. https://doi.org/10.1016/s0264-410x(99)00434-x

2. J. Olshansky, S., & Hayflick, L. (2017). The Role of the WI-38 Cell Strain in Saving Lives and Reducing Morbidity. AIMS Public Health, 4(2), 127–138. https://doi.org/10.3934/publichealth.2017.2.127

3. Narodowego, K., Zdrowia Publicznego -Państwowego, I., Higieny, Z., Towarzystwa, P., Lekarzy, E., & Zakaźnych, C. (2015). PRZEGLĄD EPIDEMIOLOGICZNY EPIDEMIOLOGICAL REVIEW ZDROWIE PUBLICZNE, EPIDEMIOLOGIA I PROBLEMY KLINICZNE CHORÓB ZAKAŹNYCH Rok 2015 Tom 69 Nr 1 NARODOWY INSTYTUT ZDROWIA PUBLICZNEGO -PAŃSTWOWY ZAKŁAD HIGIENY WARSZAWA. https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=d218dd3f8b27716d942796f2198499aa81bce843#page=73

4. Newman, L. (2005). Maurice Hilleman. BMJ : British Medical Journal, 330(7498), 1028. https://pmc.ncbi.nlm.nih.gov/articles/PMC557162/