From King Nebuchadnezzar of Babylon to Mumps Genotyping and Vaccination 26 Centuries Later

Jeryl Lynn Hilleman was diagnosed with mumps infection in 1963. Her father, Maurice Hilleman, a virologist at Merck, collected a throat swab from his 5-year-old daughter, isolated the mumps virus in his laboratory, passaged the virus several times to attenuate the virus, and subsequently produced the Jeryl Lynn strain of mumps vaccine virus.¹  In this issue of Pediatrics, investigators from the Centers for Disease Control and Prevention in Atlanta, Georgia, present an update on mumps infections in the United States in the 21st century.² 

But where did mumps virus come from in the beginning? The origin of mumps virus has not yet been determined. But we can turn to measles virus for clues. Measles is another member of the paramyxovirus family of negative-stranded enveloped RNA viruses. Measles originated when rinderpest virus jumped from cattle into humans in 600 before common era (BCE).³  Circa 600 BCE, the city-state of Babylon with its famous hanging gardens ruled by King Nebuchadnezzar was the largest city in the world, with an estimated population >100 000.⁴  This region, changing from an agrarian to urban society, was a likely site for measles dispersal from infected farmers living near the city. Mumps probably originated in a similar manner in a similar location, perhaps from an ancestor of the closely related Newcastle disease virus, a paramyxovirus in chickens.^5,6  Mumps as a disease was clearly described by Hippocrates in classic Greece (460–370 BCE). Therefore, it is certain that mumps arose as a human disease earlier than 460 BCE. In addition, having lost their ability to jump back into animal hosts, measles and mumps could only become endemic diseases with the rise of cities such as Babylon, with populations >100 000, because that minimal population size is needed to maintain an infectious disease that only infects humans.^3,5 

Mumps has been an endemic disease in the United States since its founding. Mumps epidemics harmed soldiers in the Civil War and led to an astonishing 230 356 hospitalizations of American troops during World War I.⁷  The mumps vaccine made by Dr Hilleman’s group at Merck was first marketed in 1967 and subsequently incorporated into the measles-mumps-rubella vaccine product after 1971.⁸  The number of mumps cases in the United States dropped precipitously but the mumps vaccine was never as effective as the measles vaccine. In a recent Cochrane analysis of mumps vaccination in multiple countries, researchers stated that 1 dose of mumps vaccine was 72% effective and 2 doses of mumps vaccine were 86% effective.⁹  Several investigators have concluded that mumps likely remains endemic in the United States.^2,10  One of the larger outbreaks included in these analyses occurred at the University of Iowa in 2015.¹¹ 

Mumps viruses around the world are divided into 12 genotypes.¹²  Genotyping is based on single nucleotide polymorphisms found in the gene encoding the small hydrophobic protein of mumps. Altogether, there are 12 genotypes, designated by the letters A through N. Each of the 12 genotypes differs from another genotype by at least 8% on the basis of the small hydrophobic nucleotide variation.

An approach for management of some mumps outbreaks is to administer a third dose of the Merck measles-mumps-rubella vaccine.¹³  Perhaps it is time to consider an alternative strategy. There are other live attenuated mumps vaccines being used elsewhere in the world. One is based on the Urabe strain from Japan (genotype B) and another called the Zagreb strain was derived from a Russian strain (Leningrad strain); the genotype of the Russian strain is less clear because it was isolated so early in the 20th century.¹⁴  The American Jeryl Lynn strain belongs to genotype A, but genotype A strains are no longer circulating in the United States.¹⁰  Therefore, should we consider a third immunization with the Urabe strain or the Zagreb strain of the mumps vaccine?¹⁵  That strategy presumably would broaden the neutralization antibody response in vaccine recipients.

A final comment is a comparison with the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that we have experienced in the year 2020 in the United States and to the earlier outbreak of severe acute respiratory syndrome coronavirus 1. Both SARS-CoV-2 and severe acute respiratory syndrome coronavirus 1 jumped from bats into humans, possibly with an intermediate host such as a civet cat or a pangolin.^16–18  In both cases, 1 mode of transmission appeared to be spread to humans while they prepared meals from infected civet cats or pangolins. (For this commentary, I will leave aside the additional question of whether SARS-CoV-2 had undergone manipulation in a virology research laboratory.) Measles and mumps likely jumped from infected farmyard animals and birds, as they were slaughtered to prepare meals for their owners >2 millennia ago. The question remains whether variants of SARS-CoV-2 may adapt, as did mumps long ago, and become an endemic human disease with periodic outbreaks.