MuVs belong to the subfamily Rubulavirinae within the family Paramyxoviridae. Rubulaviruses are divided into the two genera Ortho- and Pararubulavirus. Whereas the genus Orthorubulavirus comprises different human pathogenic viruses including MuV as well as porcine and simian rubulaviruses, all members of the genus Pararubulavirus have their origin in bat species.
MuVs are further classified into 12 genotypes (A - N, excluding E and M) based on the sequence identity of the SH proteins (Yeo et al. 1993; Afzal et al. 1997; Orvell et al. 1997b;
Wu et al. 1998; Tecle et al. 2002). Each genotype contains different MuV strains that can be distinguished by variations in their protein sequences, mainly in the F and HN genes. Most
currently circulating MuV strains and isolates in Europe, the USA and Canada belong to genotype G (Gouma et al. 2014; Jin et al. 2015; Veneti et al. 2018a; Barrabeig et al. 2019).
Further, there is a correlation between MuV genotypes and their global occurrence: Besides genotype G, MuVs of the genotypes H, D, C and J are present in West Europe, the USA and Canada. A mixture of the genotypes C, F, G, H and I is circulating in Asia. With regard to South Africa, South America and Australia, the occurrence of MuV genotypes is more consistent with only one predominant genotype (B, K and J, respectively) (WHO 2012a; Cui et al. 2014; Cui et al. 2017; Willocks et al. 2017; Zengel et al. 2017; Gouma et al. 2018; Barrabeig et al. 2019).
1.4.1 The infectious disease mumps
The highly contagious disease mumps (parotitis epidemica) is the result of MuV infections.
Mumps is transmitted among humans by direct or indirect droplet infection with an infectivity rate up to 45% and an incubation period of two to four weeks (Levitt et al. 1970; CDC 2015).
Basically, mumps is a childhood disease, but during the last years several outbreaks among adolescents and adults have been reported (Veneti et al. 2018a; Carol et al. 2019; Ferenczi et al. 2020). MuV infections mainly result in mild symptoms such as fever, headache, joint pain and parotitis as the most characteristic clinical sign. One-third of mumps infections are asymptomatic but the virus can still be further transmitted (CDC 2015). In rare events, severe and even fatal complications including pancreatitis, orchitis, deafness or myocarditis can occur;
the CNS is involved in 50% of cases and meningitis or encephalitis have been observed (Russell et al. 1958; Vuori et al. 1962; Beard et al. 1977; Falk et al. 1989; Ozkutlu et al. 1989;
Taii et al. 2008; Rubin et al. 2015). The risk of such complications increases with the age of the infected individuals. However, the mortality rate of mumps is with one death per 10,000 cases still very low (Galbraith et al. 1984; Clemmons et al. 2012).
1.4.2 Vaccination
Given that no specific antiviral drug is available, vaccination is even more essential to prevent a MuV infection in the first place. Currently, a combined measles, mumps and rubella (MMR)
Robert Koch-Institut” from 2001, German children should be vaccinated with the first dose earliest at 11 months and with the second one latest at 23 months (RKI 2020).
There have been several issues in the history of developing a safe and efficient MuV vaccine.
In Canada in the 1970s, the MMR vaccine “Trivirix” produced with the Urabe AM9 strain came onto the market and replaced the so far used Jeryl Lynn strain containing vaccine. In 1988, Trivirix was withdrawn due to the incidence of vaccine-associated meningitis and the administration of the Urabe AM9 vaccine strain (Bonnet et al. 2006). Nevertheless, the same vaccine was simultaneously administered under the name “Pluserix” in the United Kingdome because the safe MMR vaccine formulated with the Jeryl Lynn strain was too expensive. In 1992, the production and sale of Pluserix has been ceased. However, Urabe AM9 is still a compound of an available vaccine called Trimovax Mérieux. The reason for the neurological complications has been assigned to the fact that the Urabe AM9 vaccine contained a mixture of viruses harboring differences in the HN gene that affected virulence (Brown et al. 1996;
Afzal et al. 1998). Similarly, a risk of meningitis following vaccination has been presumed for the vaccine strains Leningrad-3 or Leningrad-Zagreb that are primarily administered in Russia or India and Eastern Europe (da Silveira et al. 2002; Plotkin et al. 2013; Wakefield et al. 2017;
Tolzin 2019). Further, it has been documented that the Leningrad-3 vaccine strain has been transmitted from recently vaccinated individuals to contact persons resulting in clinical infections (Atrasheuskaya et al. 2006). Besides safety issues, in particular neurological complications, the increased frequency of mumps outbreaks in vaccinated populations raises the question whether new vaccines against MuV infections are needed.
1.4.3 Mumps virus outbreaks
Even though MuV vaccines are available, there are still mumps virus outbreaks which lately increase in number (Rubin et al. 2012; Isaac et al. 2017; Fields et al. 2019; Lau et al. 2019).
Mostly, places gathering plenty of people such as hospitals, schools or universities are hot spots of infection. From 2015 to 2017, multiple larger outbreaks in Arkansas, Iowa and Illinois have been reported (Albertson et al. 2016; Donahue et al. 2017; CDC 2020). In total, more than 9,000 mumps cases were registered during this time span, the largest outbreak which was reported in Arkansas resulted in 3,000 cases. From 2009 to 2010, New Jersey (mainly New York City) listed 3,000 mumps cases among two-dose vaccinated students (Dayan et al.
2008; Fiebelkorn et al. 2013b; Rota et al. 2013; CDC 2020). More than 6,500 people were infected mostly in several states in the Midwest in 2006 despite a vaccination coverage of 63%
(Dayan et al. 2008). In Norway from 2015 to 2016, 230 MuV infections were confirmed among students; the outbreak started with the infection of two international travelling students (Veneti et al. 2018b). Recently, in March 2019, outbreaks were observed in two universities in Nottingham, England, which expanded until June to more than 300 stated cases in the East
Midlands. Until end of 2019, a total of 5,000 cases across England were registered, the highest number of cases since 2009 (BBC 2019; England 2019). Most current, a small outbreak with 20 cases occurred in Phoenix, Arizona (PublicHealth 2019). General observations during recent MuV outbreaks were that either the vaccination rate has been declined in the affected area or that among vaccinated but infected people, the majority has obtained only one vaccine shot. Still, many cases occurred even in two-dose vaccine covered populations. Therefore, the impact of a third vaccine dose is increasingly discussed. It could be shown that in a population that is mainly composed of people with two-dose vaccination, a third dose may decline the risk of MuV infection and help in outbreak control (Ogbuanu et al. 2012; Fiebelkorn et al. 2013a;
Nelson et al. 2013). However, the number of administered vaccine doses might not be the only concern. A shift in the circulating MuVs might be hold responsible as well: While the vaccine strain Jeryl Lynn belongs to the genotype A, most circulating MuVs are genotype G or H viruses (Rubin et al. 2008; Jin et al. 2015; Gouma et al. 2018). Although all MuVs belong to one serogroup, the efficiency of cross-neutralization varies depending on the currently circulating strain leading to infection (Zengel et al. 2017). There are also speculations on the decrease of protective antibody levels over time leading to a waning immunity in vaccinated populations questioning again the effectiveness of the vaccination (Lewnard et al. 2018; Su et al. 2020).
Another explanation for mumps outbreaks in vaccinated populations was given by immunological investigations suggesting that naturally occurring MuV infections but not MuV vaccination results in the generation of memory B cells and CD8+ T cells (de Wit et al. 2018;
Rasheed et al. 2019). Therefore, the development of a new vaccine should be considered.