WHO Immunological Basis for Immunization Series

Module 16: Mumps Update 2020

Department of Immunization, Vaccines and Biologicals

World Health Organization 20, Avenue Appia CH-1211 Geneva 27, Switzerland [email protected] http://www.who.int/immunization/en/

Immunization, Vaccines and Biologicals WHO Immunological Basis for Immunization Series

Module 16: Mumps Update 2020

Immunization, Vaccines and Biologicals The immunological basis for immunization series: module 16: mumps. Update 2020 (Immunological basis for immunization series ; module 16)

ISBN 978-92-4-001750-4 (electronic version) ISBN 978-92-4-001751-1 (print version)

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Abbreviations and acronyms...... v Preface ...... vi Acknowledgements ...... vii Conflict of interest ...... viii

1. Mumps disease, virus and vaccine...... 1 1.1 Mumps disease ...... 1 1.2 Mumps virus ...... 2 1.3 Mumps vaccines ...... 3 2. Immunological response to natural infection...... 6 2.1 Antibody response to mumps infection in unvaccinated persons...... 6 2.2 Cell-mediated immunity following natural mumps disease...... 6 2.3 Maternal antibody...... 7 2.4 Duration of immunity to natural mumps infection...... 7 3. Immunological response to vaccination...... 8 3.1 Antibody response following vaccination...... 8 3.2 Immune responses to revaccination...... 10 3.3 Cell-mediated immunity following mumps vaccination...... 10 3.4 Duration of immunity to mumps vaccination ...... 10 3.5 Correlates of immunity...... 12 4. Laboratory diagnosis of mumps...... 14 4.1 Virological methods...... 14 4.2 Serological methods...... 15 4.3 Diagnostic challenges...... 16 5. Vaccine performance ...... 17 5.1 Vaccine efficacy...... 17 5.2 Vaccine effectiveness...... 17 5.3 Vaccine failure among two- and three-dose vaccine recipients ...... 20 References...... 22

iii iv Abbreviations and acronyms

EPI Expanded Programme on Immunization CMI Cell-mediated immunity CDC (United States) Centers for Disease Control and Prevention CI Confidence interval CTL Cytotoxic T cell DNA Deoxyribonucleic acid EIA Enzyme immunoassay ELISA Enzyme-linked immunosorbent assay F Fusion protein HN Haemagglutinin-neuraminidase HLA Human leukocyte antigen IFN Interferon L Large protein M Matrix protein MMR Measles, mumps and rubella Nm Nanometre NP Nucleoprotein P Phosphoprotein PRN Plaque reduction neutralization RNA Ribonucleic acid RT-PCR Reverse transcription polymerase chain reaction SH Short hydrophobic membrane-associated protein TNF Tumour necrosis factor UNICEF United Nations Children’s Fund WHO World Health Organization

v Preface

This module is part of the WHO series The immunological basis for immunization, which was initially developed in 1993 as a set of eight modules comprising one module on general immunology and seven modules each devoted to one of the vaccines recommended for the Expanded Programme on Immunization – i.e. vaccines against diphtheria, measles, pertussis, polio, tetanus, tuberculosis and yellow fever. Since then, this series has been updated and extended to include other vaccines of international importance. The main purpose of the modules is to provide national immunization managers and vaccination professionals with an overview of the scientific basis for vaccination against a range of important infectious diseases. The modules developed since 1993 continue to be vaccine-specific, reflecting the biological differences in immune responses to the individual pathogens and the differing strategies employed to create the best possible level of protection that can be provided by vaccination. The modules also serve as a record of the immunological basis for the WHO recommendations on vaccine use, published in the WHO vaccine position papers.1

1 See: http://www.who.int/immunization/documents/positionpapers_intro/en/index.html, accessed 31 July 2018.

vi Acknowledgements

The preparation of this publication was coordinated by the World Health Organization (WHO) Department of Immunization, Vaccines and Biologicals. WHO thanks the donors whose unspecified financial support has made the production of this document possible.

This module was updated for WHO by Carole J Hickman and Mariel A Marlow (US Centers for Disease Control and Prevention). The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

WHO also expresses its thanks to those who provided expert and technical reviews for the initial preparation of the module and the 2020 update, namely Kelly Moore (Vanderbilt School of Medicine, USA).

vii Conflict of interest

None.

viii 1. Mumps disease, virus and vaccine

1.1 Mumps disease

Mumps is an acute viral illness characterized by unilateral or bilateral tenderness or swelling of the parotid or other salivary glands. Mumps is transmitted from person to person through direct contact with respiratory droplets or saliva from an infected person. Mumps is less infectious than measles and varicella, both of which can be transmitted by aerosol spread (Simpson, 1952). The mumps virus replicates in the salivary glands and local lymph nodes, with a secondary viraemia occurring late in the incubation period. During those 3–5 days of viraemia, the virus spreads into the major target organs. The salivary glands are most commonly affected; however, the central nervous system, pancreas, liver, spleen, kidneys and genital organs can also be involved. The average incubation period is 16–18 days, with a range from 12 to 25 days (Clemmons et al., 2018). Mumps is most infectious from a few days before the onset of parotid swelling to 5 days afterwards (CDC, 2008). However, the mumps virus has been isolated from saliva 7 days prior to the onset of parotitis to 9 days afterwards (Ennis & Jackson, 1968; Tan et al., 2011). Mumps virus has been isolated from urine (Utz, Szwed & Kasel, 1958) and seminal fluids (Jalal et al., 2004) up to 14 days after the onset of parotitis. The clinical presentation of mumps is age-dependent and ranges from asymptomatic infection or nonspecific – mainly respiratory – symptoms to complications with or without parotitis. Mumps typically presents as parotitis or other salivary gland swelling lasting about 2 days but may persist for longer than 10 days (Plotkin & Rubin, 2017). Parotitis may initially be unilateral but it becomes bilateral in some 64% of patients (Sullivan et al., 1985). Prodromal symptoms are nonspecific, consisting of myalgia, anorexia, malaise, headache and low-grade fever. Among unvaccinated populations, on average about 20% of mumps infections are asymptomatic (Reed et al., 1967; Philip et al., 1959; Falk et al., 1989). Two studies evaluated asymptomatic infection among vaccinated persons: one study found that 1 out of 5 laboratory- confirmed cases were asymptomatic, while the other found that 66% (29 out of 44 cases) were asymptomatic (Hahné et al., 2017; Gouma et al., 2014). Since vaccination is likely to alter clinical presentation, more studies are needed to assess the rate of asymptomatic infection among vaccinated patients. Complications of mumps infection include orchitis, oophoritis, mastitis, meningitis, encephalitis, pancreatitis and hearing loss. Cases of nephritis, myocarditis and other sequelae – including paralysis, seizures, cranial nerve palsies and hydrocephalus – have also been reported in mumps patients, although they are rare. The frequency of complications is higher among patients aged 15 years or older (Falk et al., 1989; Ma et al., 2018). Mumps is less severe, and complications occur less frequently, in vaccinated patients (Yung et al., 2011; Barskey et al., 2012; Zamir et al., 2015; Orlikova et al., 2016; Gouma et al., 2016; Havlickova et al., 2016; Ma et al., 2018).

1 Orchitis is the most common complication, occurring in some 30% of unvaccinated and 6–7% of vaccinated post-pubertal men infected with mumps (Havlickova et al., 2016; Orlikova et al., 2016). Among patients with orchitis, about half develop testicular atrophy of the affected testicles that may lead to oligospermia, azoospermia or asthenospermia (Masarani, Wazait & Dinneen, 2006; Rubin et al., 2015). While these sequelae may lead to subfertility, studies have not been conducted to determine if mumps orchitis can cause sterility. Oophoritis and mastitis have been reported to occur in 7% (Reed et al., 1967) and 30% (Philip et al., 1959) of unvaccinated post-pubertal women, and in ≤ 1% of vaccinated post-pubertal women (Dayan et al., 2008; Donahue et al., 2017; Havlickova et al., 2016; Orlikova et al., 2016). Results from a study that compared self-reported adolescent mumps infection between pregnant women and women seeking infertility treatment suggested an association between mumps oophoritis and infertility (Prinz & Taubert 1969). More studies are needed to determine if mumps oophoritis can cause infertility.

Mumps virus is highly neurotropic (Rubin et al., 2015), with asymptomatic meningitis occurring in up to 55% of patients in studies where lumbar punctures were performed routinely (Bang & Bang, 1943; Brown, Kirkland and Hein, 1948). However, symptomatic meningitis and encephalitis usually occur in ≤ 1% of mumps cases (Witte & Karchmer, 1968; Hayden et al., 1978; Dayan et al., 2008; Yung et al., 2011; Takla et al., 2013; Sane et al., 2014; Havlickova et al., 2016; Orlikova et al., 2016; Ma et al., 2018).

Pancreatitis and hearing loss, which is usually transient, occur in < 1% of mumps patients (Dayan et al., 2008; Yung et al., 2011; Takla et al., 2013; Sane et al., 2014; Orlikova et al., 2016; Ma et al., 2018). Few estimates are available in the literature for the proportion of permanent deafness resulting from mumps infection, and these estimates are likely to vary according to the rate of vaccination among the study population (Cohen, Durstenfeld & Roehm, 2014). In the United States of America (USA) prior to the introduction of vaccine, permanent deafness was estimated to occur in 0.5% of mumps cases (Everberg, 1957). One study in Japan, a country with a low rate of mumps vaccination, found that permanent deafness occurred in 7 out of 24 patients with hearing loss; overall, 0.1% of all mumps cases included in the study experienced permanent deafness (Hashimoto et al., 2009). Among the 6 584 mumps cases reported in the USA in 2006, 11 cases were reported to have experienced hearing loss but none of these had permanent deafness (Dayan et al., 2008). In countries without a mumps vaccination programme, mumps continues to be a notable and preventable cause of sensorineural hearing loss in children (Cohen, Durstenfeld & Roehm, 2014; WHO, 2020). Death from mumps is rare.

1.2 Mumps virus

Mumps virus is a single-stranded, negative-sense, enveloped ribonucleic acid (RNA) virus in the Paramyxoviridae family, Rubulavirinae subfamily, Orthorubulavirus genus. Mumps virions are pleomorphic but generally they are spherical structures and range in size from 85 nm to 300 nm in diameter (Cantell, 1961). The viral genome is 15 384 nucleotides in length and encodes nine proteins from seven genes. The mumps genome is encapsidated by nucleoprotein (NP); the phosphoprotein (P) and large (L) protein are associated with the encapsidated RNA to form the ribonucleoprotein complex. The envelope is a lipid bilayer membrane and contains the two surface glycoproteins – a haemagglutinin-neuraminidase (HN) and fusion (F, haemolysin) protein as

2 WHO immunological basis for immunization series - Module 16: Mumps well as a matrix (M) and a short hydrophobic (SH) membrane-associated protein (Wilson et al., 2006). The last two proteins – i.e. the V and I proteins – are nonstructural proteins. The V protein plays a role in interferon signalling and production, while the role of the I protein is not known. The SH protein is believed to play a role in modulating the host immune response and is thought to interfere with TNFα-mediated signalling and apoptosis (Xu et al., 2011; Wilson et al., 2006). The gene encoding the SH protein is highly variable and has been used as the basis for genotyping mumps viruses for molecular epidemiological purposes (Jin, Beard & Brown, 1999; Muhlemann, 2004). Genotypes show nucleotide variation of 2−4% within genotypes and up to 20% between genotypes within the SH gene and a maximum of 9% within the HN gene (Johansson, Tecle & Orvell, 2002). There is one mumps virus serotype; however, 12 genotypes (A−N, excluding E and M), have been described (Jin et al., 2005). Only eight of the 12 genotypes (G, H, C, F, K, I, J and D) are known to have been detected in the USA since 2010 (McNall et al., 2020). Since 2006, the predominant circulating genotype in the USA has been genotype G (Marin et al., 2018; McNall, et al., 2020). Genotype G has been reported in numerous countries, including Canada, India, Israel, Japan, Netherlands, Norway, Scotland and Spain (Bodewes et al., 2019; Gavilan et al., 2018; Indenbaum et al., 2017; Kuba et al., 2017; Nunn et al., 2018; Vaidya et al., 2018; Veneti et al., 2018; Willocks et al., 2017). Genotype C has been detected in India, genotype H in Mexico and Mongolia, genotype K in Viet Nam and genotype F is endemic in China (Vaidya et al., 2013; Del Valle, Garcia & Barron, 2016; Kidokoro et al., 2011; Liu et al., 2018; Cui et al., 2017).

1.3 Mumps vaccines

The first mumps vaccine was developed in 1946 (Habel, 1946), based on formalin- inactivated virus. However, it was discontinued because immunity was short-lived (Habel, 1951). Since then, numerous mumps vaccine strains have been developed and used in vaccines throughout the world. These vaccines have varied safety and effectiveness profiles. As of 2017, mumps virus-containing vaccine is routinely used in 122 countries (WHO, 2018).

1.3.1 Jeryl Lynn The first live attenuated mumps vaccine using the Jeryl Lynn strain was developed in the USA using an isolate from the throat of a child with mumps and passaged in embryonated hens’ eggs and chick embryo cell cultures (Buynak & Hilleman, 1966). Vaccines containing the Jeryl Lynn strain (genotype A) contain two distinct but genetically related substrains (Afzal et al., 1993). The Jeryl Lynn vaccine is distributed worldwide and has been the only mumps vaccine used in the USA since it was licensed in 1967.

1.3.2 RIT 4385 The mumps RIT 4385 vaccine strain, developed by limiting the dilution of a monovalent commercial vaccine, is a pure virus clone of the dominant virus component in the Jeryl Lynn vaccine strain (Usonis, Bakasenas & Denis, 2001). Vaccines containing this strain began circulating in the early 2000s and are now used routinely in more than 30 countries. These vaccines appear to have safety and efficacy profiles similar to vaccines containing the Jeryl Lynn strain (MMR-161 Study Group, 2018).

3 1.3.3 Urabe Am 9 Another mumps vaccine that was formerly distributed widely used the Urabe Am 9 strain. The vaccine was developed in Japan from an isolate obtained from the saliva of a child with mumps and was passaged in chick embryo amniotic cavity or quail embryo fibroblasts (Yamanishi, 1973). The strain contains two variants, one being more neurovirulent than the other (Santos-López et al., 2006). Vaccine containing the Urabe Am 9 strain was used primarily in Canada, Japan and European countries in the 1980s. However, the vaccine was withdrawn from most of these countries because of increased incidence of aseptic meningitis following vaccination. Since 2015, this vaccine has no longer been available as the manufacturer exited the market.

1.3.4 Rubini The isolate for the mumps vaccine containing the Rubini strain was attenuated in WI-38 (human diploid cell line), hens’ eggs and MRC-5 cells (Gluck et al., 1986). The vaccine containing the Rubini strain was introduced in some countries that had discontinued the use of vaccines containing the Urabe Am 9 strain. However, increased mumps incidence, including outbreaks in highly vaccinated populations (Toscani et al., 1996; Chamot et al., 1998; Gonçalves et al., 1998; Goh, 1999; Schlegel et al., 1999; Pons et al., 2000) and reports of high attack rates among children vaccinated with the Rubini vaccine strain (Goh, 1999; Ciofi Degli Atti et al., 2002; Montes et al., 2002) in countries using vaccines containing the Rubini vaccine strain (Italy, Portugal, Singapore, Spain and Switzerland) indicated low efficacy of the vaccine. Subsequent investigations confirmed that the vaccine had little or no efficacy and WHO recommended that the Rubini strain vaccine should not be used in national immunization programmes (WHO, 2001). The vaccine was consequently withdrawn.

1.3.5 Leningrad-3 and Leningrad-Zagreb The mumps vaccine containing the Leningrad-3 strain was developed in the former Union of Soviet Socialist Republics (USSR) in 1967. It was obtained from a combination of five isolates of mumps viruses and was attenuated through passages in chick embryos or Japanese quail embryo cultures (Smorodintsev, Luzyanina & Mikutskaya, 1965). The Leningrad-Zagreb (L-Zagreb) vaccine strain, a further attenuation of the Leningrad-3 mumps vaccine strain, was developed in the 1970s in Croatia (which at the time was a part of the former Yugoslavia). It was passaged on specific pathogen- free chick embryo fibroblast cell cultures (Beck et al., 1989). Leningrad-3 vaccine has been used primarily in Russia as part of the national immunization programme since 1981 (Atrasheuskaya et al., 2006). Vaccine using the L-Zagreb strain is used as a less expensive alternative to Jeryl Lynn vaccines in many middle-income countries that have mumps vaccination programmes.

1.3.6 Other mumps vaccines Many more mumps vaccines have been developed using other vaccine strains but have had limited distribution. They include: Sofia 6, developed in Bulgaria; S-12; BBM-18, a strain derived from the S-12 strain; S79, derived from the Jeryl Lynn vaccine strain and licensed in China; PAVIVAC, used in the Czech Republic; and the Japanese strains, Hoshino, Torii Miyahara and NK-M46 (Odisseev, 1966; Makino et al., 1976; Sasaki et al., 1976; Fedova et al., 1987; Odisseev & Gacheva, 1994; Feiterna-Sperling et al., 2005; Fu, Liang & Wang, 2008; Plotkin & Rubin 2008). Given the resurgence of mumps

4 WHO immunological basis for immunization series - Module 16: Mumps in countries with high vaccination coverage, researchers have begun to develop new strains from circulating wild-type genotypes that are different from the more widely used vaccine strain genotypes (genotypes A, B and N), including SP vaccine strain (genotype F) in China (Liang et al., 2019), RS-12 (genotype H) in Iran (Shahkarami et al., 2012), and a recombinant mumps virus (genotype G) in the USA (Xu et al., 2014).

1.3.7 Mumps vaccine formulations The trivalent measles, mumps and rubella (MMR) vaccine is the most commonly used formulation for mumps vaccine. However, mumps vaccine is also available in monovalent, bivalent (measles and mumps) and tetravalent (measles, mumps, rubella and varicella) formulations.

1.3.8 Significant adverse reactions to mumps vaccination Adverse reactions to mumps vaccination are rare, occurring 2−4 weeks after vaccination and resolving without sequelae. The most common adverse reactions are parotitis and low-grade fever. However, post-vaccine aseptic meningitis may occur; it is generally mild-to-moderate and resolves within a week. It is challenging to compare rates of reported post-vaccination aseptic meningitis since the rates vary according to the vaccine strain, case definitions, ascertainment methods, clinical suspicion, age of the vaccine recipient, and whether the vaccine recipient received the first or subsequent dose (Bonnet et al., 2006). The rates of reported aseptic meningitis following mumps vaccination range from the lowest with the Jeryl Lynn strain (< 1 per 100 000 doses) to rates ranging from 13 to 1000 per 100 000 doses for vaccines containing the Urabe Am 9, Leningrad-3 and L-Zagreb strains (UNICEF, 2015). Although studies have reported incidence of aseptic meningitis following vaccination with the L-Zagreb strain below 1 per 100 000 doses (PAHO, 1999; Phadke et al., 2004; Kulkarni et al., 2005), several studies with baseline incidence data on aseptic meningitis found elevated incidence at 2−4 weeks following mass vaccination campaigns with MMR vaccine containing the L-Zagreb strain (da Cunha et al., 2002; da Silveira et al., 2002). Furthermore, a prospective study in Croatia using virally confirmed cases of aseptic meningitis found that the incidence of aseptic meningitis at 15−31 days following vaccination with the L-Zagreb strain vaccine was 49 per 100 000 (Tesovic & Lesnikar, 2006). Two studies of reported aseptic meningitis following vaccination with Torii and Hoshino strains have shown rates ranging from 107 to 187 per 100 000 doses (Kimura et al., 1996; Ueda et al., 1995).

5 2. Immunological response to natural infection

The immune response to mumps virus infection is most likely the result of a complex interplay between the humoral and cellular arms of immunity. No definitive correlates of protection have yet been identified.

2.1 Antibody response to mumps infection in unvaccinated persons

In mumps naïve individuals, IgM antibodies are measurable within a few days of the onset of symptoms. IgM peaks at about 1 week after the onset of parotitis or symptoms and is detectable for weeks or months after parotitis onset (Ukkonen, Granstrom & Penttinen, 1981; Benito et al., 1987). Low-avidity IgG may also be present at the time of symptom onset, although generally at a minimal level (Narita et al., 1998). IgG antibody increases rapidly and reaches maximum levels about 3 weeks after onset of symptoms. IgG antibodies remain at that level for about 2−3 months before they decrease again (Gotlieb et al., 1953; Ukkonen, Granstrom & Penttinen, 1981); they have been assumed to persist for life although some more recent data question this assumption (section 2.4). Neutralizing antibody titres that are detectable after vaccination are lower than those produced after natural infection (Weibel et al., 1967; Hilleman et al., 1968). Additionally, wild-type mumps infection generally results in higher-avidity IgG than that seen in response to vaccination; however, average avidity indices in response to both natural disease and vaccination are lower than avidity indices observed for other viral pathogens such as measles (Narita et al., 1998; Park et al., 2007; Mercader et al., 2018). IgG antibody that is specific for NP is non-neutralizing, appears first and is more abundant than IgG antibody specific for haemagglutinin which is less plentiful but neutralizing (Linde, Granstrom & Orvell, 1987; Matsubara, Iwata & Nakayama, 2012; Latner et al., 2014). A study predominantly of naturally infected persons demonstrated that 41 of those 45 persons (91%) had steady long-lived antibody responses for up to 26 years; moreover, their memory B cell frequencies were significantly correlated with antibody titres (Amanna, Carlson & Slifka, 2007). Mumps-specific salivary IgA antibodies can be detected up to 5 weeks after onset of illness and gradually decrease, becoming undetectable at around 10 weeks after onset (Chiba et al., 1973; Friedman, 1982).

2.2 Cell-mediated immunity following natural mumps disease

Lymphocytes are known to play an important role in the host response to viral infections and are also believed to have a significant function in the immune response to mumps and the recovery from mumps infection. While the presence of a plaque reduction neutralization titre to mumps appears to be associated with the development of mumps immunity, less is known about the development, significance and function

6 WHO immunological basis for immunization series - Module 16: Mumps of mumps-specific cell-mediated immunity (CMI). Specific lymphocyte-mediated cytotoxicity has been shown to correlate well with the presence of detectable humoral responses to mumps but not with the magnitude of the antibody response (Rola-Pleszczynski et al., 1976; Chiba et al., 1976). Mumps-specific cytotoxic T cell (CTL) activity has been observed in persons with natural mumps disease with a peak response at 2−4 weeks after disease onset and has been associated with an antecedent lymphocyte proliferative response. Mumps-specific antibody titres and interferon–gamma (IFN-γ) release from lymphocytes was higher among naturally infected versus vaccinated persons; however, neither vaccination nor wild-type mumps infection induced both CMI and humoral immunity in all subjects (Terada et al., 2017; Hanna-Wakim et al., 2008). In a small group of IgG-positive persons, mumps-specific T-cell activation and IFN-γ production were detected in 80% of naturally infected persons compared to 70% of vaccinated ones (Hanna-Wakim et al., 2008).

2.3 Maternal antibody

Maternal antibody (IgG) to mumps following natural infection is transferred across the placenta and is believed to provide protection to infants against clinical mumps. Titres of transplacentally transferred antibodies generally reflect maternal IgG antibody titres which are typically lower when induced by vaccination compared to natural disease (Gans & Maldonado, 2013). Clinical mumps occurs less frequently in infants aged less than 12 months (12−17%) compared to children aged 1−4 years (68%) (Philip et al., 1959; Meyer, 1962; Reed et al., 1967). During an outbreak, 2 of every 3 infants under 12 months of age born to mothers with no history of clinical mumps developed mumps when exposed; however, for every 10 infants under 12 months of age born to mothers with a prior history of clinical mumps, none developed the disease (Meyer, 1962). In a separate study among 18 infants, most had detectable neutralizing antibodies at age 2 months (94%) and also at 5 months (66%), but by 12 months of age none of the infants had detectable antibodies (Hodes & Brunell, 1970). Similarly, two other studies found that 4% of 74 infants (Leineweber et al., 2004) and 25% of 32 infants (Sato et al., 1979) had detectable neutralizing antibodies at 12 months of age. In studies of infants born to predominantly vaccinated mothers, the duration of protection via maternal antibody was estimated to be from 2.4 to 2.7 months (Waaijenborg et al., 2013; Leuridan, Sabbe & Van Damme, 2012). In contrast, the median duration of protection derived from naturally immune mothers was 3.8 months. Placental transfer of mumps IgG antibodies was found to be lower among pre-term infants, resulting in lower antibody levels at birth, compared to infants born at term (Van den Berg et al., 2014).

2.4 Duration of immunity to natural mumps infection

Natural mumps virus infection is believed to provide long-lasting immunity for most persons. Twenty or more years after their mumps illness, most (82%) persons still had detectable haemagglutination-inhibiting antibodies (Levitt et al., 1970). However, there have been reports of cases of clinically apparent mumps reinfection that have been confirmed with epidemiological links or laboratory tests (Meyer, 1962; Biedel et al., 1978; Gut et al., 1995; Narita et al., 1998; Crowley & Afzal, 2002; Yoshida et al., 2008; Terada et al., 2017) and that appear to be more common than previously thought. During recent outbreaks there were several reports of persons developing parotitis that resolved but was followed 2 weeks to 7 months later by parotitis on either the same or opposite side, even among twice-vaccinated persons (Fields et al., 2019).

7 3. Immunological response to vaccination

3.1 Antibody response following vaccination

In general, over 90% of infants and children develop detectable antibodies against mumps following vaccination with mumps vaccines (Table 1). Seroconversion rates are comparable for vaccine combinations with Jeryl Lynn and RIT 4385 and slightly lower for vaccine combinations with L-Zagreb. However, studies that directly compare these vaccine strains are needed in order to determine differences in seroconversion rates since the available serological tests for mumps antibodies are not consistent and rates vary depending on the method used. Seroconversion rates vary from 74% to 100% for vaccines containing the Jeryl Lynn strain, 88% to 99% for vaccines containing the RIT 4385 strain, and 84% to 100% for vaccines containing the L-Zagreb strain (Table 1). Cui et al. (2018) reported that neutralizing antibody responses to vaccine virus were low following 1 dose of MMR and cross-neutralizing responses to circulating wild- type strains were lower. There is no difference in seroconversion between monovalent, bivalent, trivalent or tetravalent formulations of the mumps vaccine (Weibel et al., 1973; Lerman, Bollinger & Brunken, 1981; Shinefield et al., 2005; Bernstein et al., 2007).

8 WHO immunological basis for immunization series - Module 16: Mumps Table 1. Seroconversion following mumps vaccination

Seroconversion Number of (%) Strain References studies Median Range

Jeryl Lynn, 6 96 74, 100 (Weibel et al., 1967; Hilleman et al., 1968; Sugg et al., 1968; monovalent Brunell, Brickman & Steinberg, 1969; Vesikari et al., 1983b; Fedova et al., 1987) Jeryl Lynn, 3 90 84, 91 (Weibel et al., 1973; Vesikari et al., 1983a; Popow-Kraupp et al., bivalent 1986) Jeryl Lynn, 11 94 89, 97 (Borgono et al., 1973; Ehrenkranz et al., 1975; Schwarz et al., trivalent 1975; Lerman, Bollinger & Brunken, 1981; Popow-Kraupp et al., 1986; Schwarzer et al., 1998; Usonis et al., 1998; Usonis et al., 1999; Klinge et al., 2000; Redd et al., 2004; Feiterna-Sperling et al., 2005) Jeryl Lynn, 4 100 98, 100 (Watson et al., 1996; Shinefield et al., 2005; Kuter et al., 2006; tetravalent Bernstein et al., 2007) RIT 4385, 7 96 90, 99 (Usonis et al., 1998; Usonis et al., 1999; Crovari et al., 2000; trivalent Lee et al., 2002; Nolan et al., 2002; Lim, Han & Bock, 2007; MMR-161 Study Group, 2018) RIT 4385, 3 96 86, 97 (Nolan et al., 2002; Schuster et al., 2008; Lalwani et al., 2015) tetravalent Urabe Am 9, 3 95 83, 97 (Isomura et al., 1973; Ehrengut, Georges & Andre, 1983; monovalent Vesikari et al., 1983b) Urabe Am 9, 2 84 79, 97 (Vesikari et al., 1983a; Popow-Kraupp et al., 1986) bivalent Urabe Am 9, 5 99 97, 100 (Berger, Just & Gluck, 1988; Robertson et al., 1988; trivalent Dunlop et al., 1989; Schoub et al., 1990; Forleo-Neto et al., 1997) Rubini 5 93 23, 95 (Gluck et al., 1986; Just et al., 1986; Berger, Just & Gluck, 1988; Schwarzer et al., 1998; Khalil et al., 1999; Crovari et al. 2000) Leningrad-3 4 94 (Smorodintsev, Nasibov & Jakovleva, 1970) Leningrad- 3 91 84, 100 (Beck et al., 1989; dos Santos et al., 2006; Díaz-Ortega et al., Zagreb 2014) BBM-18 1 85 (Feiterna-Sperling et al., 2005) Sofia 6 2 93 93, 94 (Odisseev & Gacheva, 1994) Hoshino 2 97 95, 100 (Makino et al., 1990; Sood et al., 2017) S-12 1 93 (Sassani et al., 1991)

Infants aged 6 months who were vaccinated in the presence of maternal antibody had lower neutralizing antibody titres and seroconversion rates than infants vaccinated at 9 and 12 months of age. Lower seroconversion was seen not only when vaccination took place in the presence of passive antibody but also when it happened in the absence of maternal antibody, which suggests an intrinsic deficiency in antiviral antibody production in young infants (Gans et al., 2003). Seroconversion rates did not differ between infants vaccinated at 9 months, 12 months and 15 months of age (Schoub et al., 1990; Forleo-Neto et al., 1997; Klinge et al., 2000; Pebody et al., 2002; Redd et al., 2004).

9 3.2 Immune responses to revaccination

In studies that examined the presence of antibodies prior to and following the second dose of mumps vaccine, most children who received one dose of mumps vaccine mounted a secondary immune response to revaccination, as evidenced by a few study subjects (< 2%) who had a detectable IgM response against mumps following vaccination with a second dose (Pebody et al., 2002; LeBaron et al., 2009). Although up to 30% of persons were reported to be seronegative prior to revaccination in other studies, 75−97% seroconverted following the second dose of mumps vaccine (Broliden et al., 1998; Gothefors, Bergstrom & Backman, 2001). In these studies, there was no assessment to determine whether seronegativity was caused by primary vaccine failure or by having antibody below the level of test detection.

Among individuals with neutralizing antibodies prior to receipt of a second or a third dose, an increase in antibody levels generally occurred following revaccination. More than 50% of those revaccinated had a four-fold increase in antibody titres (LeBaron et al., 2009). Increases in antibody observed by ELISA and plaque reduction neutralization (PRN) at 1 month and 1 year after receipt of a third dose were modestly higher than the baseline but were nevertheless statistically significant increases (Latner et al., 2017). In addition, the proportion of persons with low titres was significantly reduced following a second or third dose.

3.3 Cell-mediated immunity following mumps vaccination

Following vaccination with live attenuated mumps vaccine, most – though not all – children with anti-mumps antibody in their sera demonstrated a lymphocyte proliferative response to mumps antigen (Ilonen, 1979; Ilonen et al., 1984). Mumps lymphoproliferative responses to a second dose of MMR were higher than measles and rubella responses (Dhiman et al., 2005). Responses returned to baseline by approximately 5 weeks after receipt of the second MMR dose. Unlike the humoral immune response to mumps, cellular responses were equivalent in all age groups and were independent of the presence of maternal antibody (Gans et al., 2001). Mumps virus-specific lymphoproliferative responses could be detected up to 10−21 years post-vaccination (Jokinen et al., 2007; Hanna-Wakim et al., 2008). Subjects with higher levels of IgG antibody were more likely to have positive proliferative responses (Vandermeulen et al., 2009). Mumps virus-specific memory CD4+ T cells have been detected in the bone marrow of healthy adults with unknown mumps exposure histories (Okhrimenko et al., 2014). In addition, associations of specific human leukocyte antigen (HLA) haplotypes with higher or lower frequencies of mumps antigen-reactive T lymphocytes have been observed (Bruserud & Thorsby, 1985; Hyoty et al., 1986; Bruserud, Paulsen & Thorsby, 1987; Tan et al., 2001; Ovsyannikova et al., 2008), suggesting that host genetic factors may influence the immune response to mumps.

3.4 Duration of immunity to mumps vaccination

One dose of MMR vaccine can provide persistent antibodies to mumps. Between 70% and 99% of persons had detectable anti-mumps antibodies as shown by ELISA or neutralization tests approximately 10 years after initial vaccination (Broliden et al., 1998; Gothefors, Bergstrom & Backman, 2001; LeBaron et al., 2009;

10 WHO immunological basis for immunization series - Module 16: Mumps Poethko-Müller & Mankertz, 2012) (Table 2). In two-dose recipients, mumps antibodies were detectable in 74–92% of children tested by ELISA and 91–99% of children tested by neutralization tests 10 or more years after receipt of a second dose of MMR vaccine (Table 2) (Davidkin et al., 2008; LeBaron et al., 2009). Differences in laboratory methods may account for the wide variation in detection rates.

Table 2. Long-term persistence of mumps antibodies following vaccination with mumps Jeryl Lynn vaccine

Number Years after Serological method Reference Country seropositive/ vaccination used Number tested (%) 1 dose (LeBaron et al., 2009) USA 10 304/308 (99) Plaque-reduction neutralization (Gothefors, Sweden ~10 230/299 (70) ELISA Bergstrom & Backman, 2001) (Poethko-Müller & Germany 3-6 (93) ELISA Mankertz, 2012) (Poethko-Müller & Germany >6 (89) ELISA Mankertz, 2012) (Broliden et al., 1998) Sweden ~11 167/229 (73) Neutralizing antibodies 2 doses (LeBaron et al., 2009) USA 7 17/189 (91) Plaque-reduction neutralization (Date et al., 2008) USA ≥11 134/146 (92) Commercial EIA (LeBaron et al., 2009) USA 12 146/154 (95)* Plaque-reduction neutralization (Seagle et al., 2018) USA 12 260/296 (88)† Plaque-reduction neutralization (Rubin et al., 2008) USA 10 87/88 (99)§ Plaque-reduction neutralization (Kontio et al., 2012) Finland 20 (74-92) Commercial EIA (Davidkin et al. 2010) Finland 20§ (77) Commercial EIA (Poethko-Müller & Germany 3-6 (93) ELISA Mankertz, 2012) (Poethko-Müller & Germany >6 (87) ELISA Mankertz, 2012) (Gonçalves et al., Portugal ~10 (82) ELISA 2016) (Gonçalves et al., Portugal ~13 (74) ELISA 2016) (Davidkin et al., Finland 15 67/90 (74) Commercial EIA 2008)

* All subjects were seropositive prior to receipt of the second mumps vaccine dose. † Only subjects who were consistently seropositive at all study time points. § Years since first dose of MMR vaccine.

11 Studies on the duration of immunity following mumps vaccination consistently show a notable decline in mumps antibodies by approximately 10 years after receipt of the second MMR dose. In studies using PRN to detect antibodies in persons vaccinated as children, neutralizing antibody titres against mumps declined by 9% per year between 6 months and 12 years after receipt of the second MMR dose (Seagle et al., 2018) and declined to near pre-second dose levels by 7–12 years (LeBaron et al., 2009; Rubin et al., 2008). There was considerable individual variation in the antibody responses to mumps and a fast rate of decline, although no demographic or clinical predictors were identified (Seagle et al., 2018). In another study, the geometric mean neutralizing antibody titre in persons vaccinated within 5 years before the blood collection was higher than in those vaccinated 15 or more years earlier (Date et al., 2008). In studies using commercial enzyme immunoassays (EIAs), compared with the titre levels at 6 months to 1 year after vaccination with the second dose, titres decreased by about 70% after 8 years and 75% or more after 15–20 years following the second dose (Davidkin et al., 2010; Kontio et al., 2012). In another study, compared with persons vaccinated with the second dose less than 2 years previously, patients who were vaccinated more than 8 years previously were 76% more likely to be seronegative, respectively (Poethko-Müller & Mankertz, 2012). A longitudinal study compared neutralizing antibody titres against Jeryl Lynn (genotype A) and wild-type genotype G mumps virus; it reported that, while all recipients had neutralizing antibody to both virus strains 10 years after receipt of the second MMR dose, the geometric mean titres of antibodies against genotype G were about half those against Jeryl Lynn (Rubin et al., 2008).

In three-dose recipients, studies suggest that the increase in antibodies following receipt of a third dose might not persist longer than 1 year after vaccination (Latner et al., 2017; Fiebelkorn et al., 2014; Date et al., 2008). Results from three different ELISA methods and by PRN demonstrate that, while there is a modest increase in mumps antibody at 1 month after receipt of the third dose, mumps antibody declined to near baseline levels after 1 year (Latner et al., 2017). Among persons who received a third dose of MMR vaccine, a longer time since the second dose (15 years or more versus less than 15 years) was significantly associated with having negative or low antibody titres at 1 year after receipt of the third dose (Fiebelkorn et al., 2014).

3.5 Correlates of immunity

Humoral immunity is important in protecting against mumps. Antibody measurements are often used as a surrogate measure of immunity to viral infections. However, there is poor correlation between assays that measure functional neutralizing antibody and less labour-intensive methods such as ELISA that measure both neutralizing and non-neutralizing antibody (Pipkin et al., 1999). While there is no serological test available that consistently and reliably predicts protection against mumps, neutralizing antibodies appear to be a reasonable marker for immunity. Antibodies directed against HN have been shown to neutralize the infectivity of mumps virus, and animal models suggest that antibodies against fusion protein, the other mumps surface glycoprotein, may also be involved in neutralization (Orvell, 1978; Love et al., 1986; Houard et al., 1995). Early studies of outbreaks among unvaccinated persons indicated correlations between neutralizing antibodies and the susceptibility to mumps, where those with neutralizing antibody titres above 1:2 (Brunell et al., 1968) and 1:4 (Meyer, Stifler & Joseph, 1966; Ennis, 1969) were protected from mumps infection. In addition, the vaccinated children who developed mumps during prelicensure studies had low (< 1:2) or undetectable neutralizing antibodies after vaccination (Hilleman et al., 1968).

12 WHO immunological basis for immunization series - Module 16: Mumps More recent studies suggest that higher neutralizing antibody titres may be needed to give protection (Cortese et al., 2011; Gouma et al., 2014). In one study, more case patients than exposed nonpatients had pre-outbreak anti-Jeryl Lynn titres < 31 and an anti-genotype G titre < 8 (55% versus 14%) and more case patients than exposed nonpatients had pre-outbreak EIA results < 1.7 (73% versus 14%) (Cortese et al., 2011). A second study found that pre-outbreak mumps-specific IgG titres were lower among cases than among non-cases but, as with the previous study, titres overlapped and it was not possible to identify cut-off points that separated all mumps case patients from non-patients (Gouma et al., 2014). NP appears to be the immunodominant antigen and the major target of the humoral immune response as well as the predominant antigen detected by ELISA (Matsubara, Iwata & Nakayama, 2012; Latner et al., 2014). As such, an ELISA can provide an overestimate of anti-mumps antibody if all positive results are considered as indications of protection against disease since both neutralizing and non-neutralizing antibodies give positive results (Christenson & Bottiger, 1990). Commercial ELISAs using whole virus as the detecting antigen predominantly detect antibody to NP (Matsubara, Iwata & Nakayama, 2012; Latner et al., 2014). An ELISA specific for the mumps HN was developed in order to better correlate to PRN, but the partial correlation of the HN-specific ELISA with PRN was of limited predictive value (Latner et al., 2014). It is noteworthy that 41 of 43 military personnel who developed mumps disease within 3 months to 5 years of joining the military were positive for mumps IgG antibodies measured by ELISA upon intake (Eick et al., 2008). Potential explanations for this include the possibility that total mumps IgG does not necessarily correlate with protection from mumps infection or that immunity waned below protective levels during the short time from blood screening to mumps infection. Cases of mumps among persons who received a third dose of MMR more than 21 days prior to exposure have occurred during several recent outbreaks, which suggests that certain persons may not respond with a protective response despite additional doses (Cardemil et al., 2017; Shah et al., 2018). More studies are needed on both humoral and cellular correlates of immunity. Recent advances, such as determining immunosignatures in response to infection or vaccination, may help to identify immune correlates and better define and predict susceptibility.

13 4. Laboratory diagnosis of mumps

A clinical diagnosis of mumps is frequently made if parotitis is evident when the patient is examined. However, since parotitis may be caused by other viral or nonviral diseases or conditions, laboratory confirmation using virological or serological techniques may be required, especially as mumps disease becomes less frequent due to vaccination.

4.1 Virological methods

Mumps virus and viral RNA can be detected from blood, saliva, cerebrospinal fluid and urine. In confirmed mumps cases tested by multiple diagnostic methods, detection of mumps virus RNA using reverse transcription polymerase chain reaction (RT-PCR) on buccal swabs has the highest diagnostic yield (Hatchette et al., 2009; Rota et al., 2013; Nunn et al., 2018). The sensitivity of mumps RNA detection in urine is poor (Krause, Eastick & Ogilvie, 2006) and the incremental value of collecting and testing urine specimens is small and results in significantly increased cost (Nunn et al., 2018; Tan et al., 2011; Hatchette et al., 2009). Urine specimens may be more useful in patients presenting with mumps complications such as orchitis or if specimens are collected many days after the onset of parotitis (Nunn et al., 2018). Mumps virus is stable for several days at 4 °C. Stability increases with decreasing temperature and the virus can be stored indefinitely at −70 °C. The quality and timing of the specimen collection and the quality of specimen itself appear to have a major impact on the ability to culture mumps virus and to detect mumps RNA using RT-PCR (Utz, Szwed & Kasel, 1958; Rota et al., 2013). Efforts to train providers in proper collection, storage and shipment of specimens have improved mumps detection (Rota et al., 2013; Nunn et al., 2018). Since mumps virus replication is transient, there is a limited time frame for isolating the virus. This appears to be most successful within the first 2 days of parotitis onset (CDC, 2008) although mumps virus RNA can be detected up to 9 days following parotitis onset (Nunn et al., 2018; Hatchette et al., 2009). Mumps viral load and mumps RNA detection decrease during the first 3 days after onset of symptoms and the viral load is lower in persons who have been vaccinated or who had prior history of the disease (Okafuji et al., 2005; Bitsko et al., 2008; Rota et al., 2009). One study of suspected mumps cases demonstrated that the highest isolation rates were among unvaccinated cases (64%; 15/25), followed by vaccinated cases (41%; 15/37) and cases with previous history of mumps (17%; 5/29) (Yoshida et al., 2008). The detection of mumps RNA is generally more sensitive than culture-based virus detection methods (Poggio et al., 2000; Uchida et al., 2005). Importantly, and in contrast to mumps IgM detection, laboratory diagnosis of mumps via RT-PCR works equally well among previously vaccinated and unvaccinated persons (Hatchette et al., 2009; Rota et al., 2013; Nunn et al., 2018). Detection rates for RT-PCR in outbreak settings range from approximately 60% to around 90%. The use of RT-PCR primers that target the N gene, as opposed to use of primers that target the SH gene, resulted in a 14% higher rate of detection among 205 virus isolation positive cases (94% versus 79%) (Rota et al., 2013) and has been widely adopted.

14 WHO immunological basis for immunization series - Module 16: Mumps 4.2 Serological methods

The detection of mumps-specific IgM antibody in serum or saliva is a reasonable diagnostic measure in unvaccinated patients. IgM detection was higher in unvaccinated persons compared to those with a history of vaccination (90% versus 51%) in one study using an IgM capture assay (Rota et al., 2013) and 64% versus 34% in a second study (Nunn et al., 2018) using an indirect EIA. Most mumps cases among vaccinated persons are caused by secondary vaccine failure (waning of vaccine-induced immunity to nonprotective levels) rather than primary vaccine failure (failure to seroconvert) and have delayed or blunted IgM responses. The percent positivity of IgM tests among previously vaccinated persons is low compared to RT-PCR, with IgM detection rates ranging from 14% to 51% depending on the IgM assay used (Hatchette et al. 2009; Rota et al. 2013; Nunn et al. 2018). Timing of specimen collection is important to consider in interpreting laboratory results. Negative IgM ELISA results may occur when serum is collected prior to day 4 of clinical presentation (Cunningham et al. 2006; Krause et al. 2007). In contrast, patients who mount a secondary immune response, as occurs in the majority of vaccinated mumps cases, may have an IgM response that is transient, delayed or not detected, depending on the timing of specimen collection. Consequently, a high number of false-negative results may occur in previously vaccinated persons, and the absence of an anti-mumps IgM response in a vaccinated or previously infected individual presenting with clinically compatible mumps does not rule out mumps as a diagnosis. Failure to detect mumps IgM in previously vaccinated persons has been well documented (Rota et al., 2013; Nunn et al., 2018). The ability to detect IgM varies by vaccination status and is highest in unvaccinated cases (80−100%), intermediate in one-dose recipients (60−80%) (Briss et al., 1994; Narita et al., 1998) and lowest in two-dose recipients (13−51%) (Bitsko et al., 2008; Rota et al., 2009; Rota et al., 2013; Nunn et al., 2018). IgM test methods and kits vary considerably in their sensitivity and specificity, with some indirect EIA and immunofluorescent assays detecting only 12–15% of confirmed mumps cases. The capture IgM ELISA is the most sensitive method, but its commercial availability is limited.

When IgM is negative in unvaccinated persons, a convalescent serum demonstrating seroconversion or a significant rise (four-fold) in IgG titre between the acute and convalescent serum sample can be used to confirm a diagnosis of mumps. However, paired serum samples from previously-vaccinated persons, even if appropriately timed, may not show a rise in IgG titre. At the time of symptom onset IgG may already be elevated such that it is not possible to detect a four-fold rise in titre. IgG avidity testing is an important tool that can be used to differentiate between primary and secondary vaccine failure (Narita et al., 1998; Sanz-Moreno et al., 2005; Park et al., 2007) and can assist in determining the role of waning immunity in current outbreaks. In the case of reinfection or mumps infection in previously-vaccinated persons, an elevated titre of high avidity mumps-specific IgG is observed (Gut et al., 1995) (Table 3).

15 Table 3. Serological response to mumps wild-type infection based on previous exposure history

Previous IgM IgG Avidity Comments References Infection History Unvaccinated No + + or – Low IgM may be detected for (Meurman et al., 1982; history of mumps weeks to months Sakata et al., 1985; Low levels of low-avidity Rota et al., 2013; IgG may be present at Nunn et al., 2018 disease onset. Narita et al., 1998; Mercader et al., 2018) Avidity matures from low < 30% to high > 30% by 6 months Previously + or – Likely + Low: primary Serum collected: (Narita et al., 1998; vaccinated vaccine failure 1–10 days: 50% IgM + Jin et al., 2004; Krause et al., 2007; 1 dose High: secondary > 10 days: 50–80% IgM + vaccine failure Rota et al., 2013) Previously + or – Likely + Low: primary Serum collected: (Bitsko et al., 2008; vaccinated vaccine failure 0–2 days: 12–46% IgM + Rota et al., 2009; Rota et al., 2013; 2 doses High: secondary > 3 days: 71–83% vaccine failure Hatchette et al., 2009; Nunn et al., 2018) Wild-type mumps + or – + High IgM infrequently detected

4.3 Diagnostic challenges

Mumps outbreaks occur in countries that do not immunize against mumps, those with low vaccine coverage, and in numerous countries with high two-dose vaccine coverage. Laboratory confirmation of mumps in highly vaccinated populations was initially challenging because existing test methodologies were designed to detect mumps in naïve patients whereas vaccinated persons shed less virus and have blunted serological responses. Diagnostic methods to detect mumps virus infection have improved significantly in the past 10 years and attention to factors such as testing method, timing of specimen collection, proper collection technique, and proper storage and shipment of specimens has increased laboratory confirmation of mumps cases. RT-PCR and cell culture are the best diagnostic tests that are currently available to detect mumps infection in previously vaccinated persons (Rota et al., 2009; Bitsko et al., 2008; Rota et al., 2013; Hatchette et al., 2009; Nunn et al., 2018). Attention to collection techniques and proper storage and shipment is critical.

16 WHO immunological basis for immunization series - Module 16: Mumps 5. Vaccine performance 5.1 Vaccine efficacy

Prelicensure randomized-controlled trials conducted in more than 3000 children enrolled in nursery or elementary schools found that a single dose of mumps vaccines containing the Jeryl Lynn strain was approximately 95% effective in preventing mumps disease (Hilleman et al., 1967; Weibel et al., 1967; Sugg et al., 1968). However, duration of follow-up was short (up to 20 months), and in the largest study (Sugg et al., 1968), cases were diagnosed clinically and not laboratory confirmed. In a smaller study, with 193 children exposed to persons with clinical mumps, the efficacy of the mumps vaccine containing the Leningrad-3 strain was 94% (95% CI: 76–98%) (Smorodintsev, Luzyanina & Mikutskaya, 1965). Additional studies using vaccines containing the Leningrad-3 strain found efficacy between 97% and 99% (Smorodintsev, Nasibov & Jakovleva, 1970).

5.2 Vaccine effectiveness

5.2.1 Vaccine effectiveness of one dose In postlicensure studies, estimates of vaccine effectiveness for the prevention of mumps disease have been lower than vaccine efficacy found in prelicensure trials. In 21 studies in Singapore, Europe and North America, the median estimate for vaccine effectiveness of one dose of the Jeryl Lynn mumps vaccine was 80% (range: 49–92%) (Table 4). Similarly, the median vaccine effectiveness estimates for vaccines containing the Urabe Am 9 strain in five studies was 73% (range: 54–87%) (Toscani et al., 1996; Chamot et al., 1998; Gonçalves et al., 1998; Schlegel et al., 1999; Ong et al., 2005). Although there are several studies that include populations that may have received mumps vaccines containing the RIT 4385 strain (Harling et al., 2005; Cohen et al., 2007), no studies have examined vaccine effectiveness exclusively for mumps vaccines containing the RIT 4385 strain. The vaccine effectiveness of vaccines containing the RIT 4385 strain is expected to be similar to that of the Jeryl Lynn strain because RIT 4385 was derived from the Jeryl Lynn strain and has been shown to be non-inferior in prelicensure immunogenicity and safety trials.

Several studies in outbreak settings have indicated that the Rubini strain vaccine had little or no effectiveness against disease (Table 4). The vaccine effectiveness estimates from Switzerland, Singapore, Spain and Portugal ranged from −55% to 50% (Paccaud et al., 1995; Toscani et al., 1996; Chamot et al., 1998; Gonçalves et al., 1998; The Benevento and Compobasso Pediatricians Network for the Control of Vaccine-Preventable Diseases, 1998; Goh, 1999; Schlegel et al., 1999; Pons et al., 2000; Richard et al., 2003; Ong et al., 2005). Mumps vaccine containing the Rubini strain is no longer licensed or available. Limited studies with the L-Zagreb (Beck et al., 1989), Leningrad-3 (Smorodintsev,

Luzyanina & Mikutskaya, 1965), S79 (Fu, Liang & Wang, 2008; Fu et al., 2009), and Sofia 6 (Odisseev & Gacheva, 1994) strains estimate the vaccines to be between 77% and 100% effective (Table 4). Data on vaccine effectiveness of other strains are not available in English-language peer-reviewed publications.

17 Table 4. Mumps vaccine effectiveness

Number in Vaccine effectiveness Reference Country Population study (%) Jeryl Lynn – one dose (Chamot et al., 1998) Switzerland Close contacts 62 (95% CI: 0, 85) (Harling et al., 2005) England Population 353 64 (95% CI: 40, 78) (Toscani et al., 1996) Switzerland School 65 (95% CI: 11, 86) (Sartorius et al., 2005) Sweden Population Screening 65 method (Castilla et al., 2009) Spain Population (children) 1057 66 (95% CI: 25, 85) (Richard et al., 2003) Switzerland Population (young children) 324 70 (95% CI: 50, 80) (Lewis et al., 1979) Canada School 495 75 (Wharton et al., 1988) USA School 385 78 (95% CI: 65, 86) (Schlegel et al., 1999) Switzerland Population (children) 44 78 (95% CI: 64, 82) (Schaffzin et al., 2007) USA Camp attendees and staff 67 80 (95% CI: 42, 93) (Sullivan et al., 1985) USA School 434 81 (95% CI: 71, 88) (Ong et al., 2005) Singapore Child-care centre and school 1325 81 (95% CI: 58, 91) (Cheek et al., 1995) USA School 307 82 (95% CI: 77, 86) (Marin et al., 2008) USA College population 235 82 (95% CI: 0, 98) (Hersh et al., 1991) USA School 1721 83 (95% CI: 57, 94) (Kim-Farley et al., 1985) USA School 66 85 (95% CI: 39, 94) (Cohen et al., 2007)* England Population Screening 88 (95% CI: 83, 91) method (Chaiken et al., 1987) USA School 165 91 (95% CI: 77, 93) (Vygen et al., 2016)† France Population (young adults) 406 49 (Domínguez et al., 2010)§ Spain Population Screening 85 (95% CI: 67, 93) method (Snijders et al., 2012) Netherlands School 1175 92 (95% CI: 83, 96) Jeryl Lynn – two doses (Marin et al., 2008) USA College population 2141 79 (95% CI: 0, 97) (Castilla et al., 2009) Spain Population (children) 425 83 (95% CI: 54, 94) (Harling et al., 2005)* England Population 153 88 (95% CI: 62, 96) (Marin et al., 2008) USA Close contacts 74 88 (95% CI: 63, 96) (Sartorius et al., 2005) Sweden Population Screening 91 method (Schaffzin et al., 2007) USA Camp population 461 92 (95% CI: 83, 96) (Cohen et al., 2007)* England Population Screening 95 (95% CI: 93, 96) method (Cardemil et al., 2017) USA College population (< 13 years 20 496 89 (95% CI: −3, 99) since second dose) (Cardemil et al., 2017) USA College population (≥ 13 years 20 496 32 (95% CI: −389, 91) since second dose) (Domínguez et al., 2010)§ Spain Population Screening 85 (95% CI: 67, 93) method (Greenland et al., 2012) Netherlands College population 989 68 (95% CI: 41, 82) (Takla et al., 2014) Germany School 100 92 (95% CI: 81, 97) (Vygen et al., 2016)† France Population (young adults) 406 55 (Livingston et al., 2014) USA Close contacts 2176 86 (95% CI: 63, 95) (Snijders et al., 2012) Netherlands School 1175 93 (95% CI: 85, 97)

18 WHO immunological basis for immunization series - Module 16: Mumps Number in Vaccine effectiveness Reference Country Population study (%) Jeryl Lynn – three doses (incremental vaccine effectiveness; 3 doses versus 2 doses) (Cardemil et al., 2017) USA College population 20 496 78 (95% CI: 61, 88) (Nelson et al., 2013) Guam School 3239 61 (Ogbuanu et al., 2012) USA School 2178 88 (95% CI: -32, 99) Urabe Am 9 (Ong et al., 2005) Singapore Child-care centre and school 804 54 (95% CI: -16, 82) (Gonçalves et al., 1998 Portugal Population 242 70 (95% CI: 25, 88) (Chamot et al., 1998) Switzerland Close contacts 73 (95% CI: 42; 88) (Toscani et al., 1996) Switzerland School 76 (95% CI: 36, 91) (Schlegel et al., 1999) Switzerland Population 48 87 (95% CI: 76, 94) Rubini (Pons et al., 2000) Spain School 422 −340 (Ong et al., 2005) Singapore Child-care centre and school 2308 −55 (95% CI: −122, -9) (Schlegel et al., 1999) Switzerland Population 87 −4 (95% CI: −218, 15) (Gonçalves et al., 1998) Portugal Population 369 1 (95% CI: −108, 53) (Chamot et al., 1998) Switzerland Close contacts 6 (95% CI: −46; 40) (Toscani et al., 1996) Switzerland School 12 (95% CI: −102, 62) (Pons et al., 2000) Spain School 124 40 (95% CI: −66, 78) (Richard et al., 2003) Switzerland Population (young children) 213 30 (95% CI: −30, 60) (Paccaud et al., 1995) Switzerland School 156 50 (95% CI: −19, 81) Leningrad-Zagreb (Beck et al., 1989) Yugoslavia Pre-school 97−100 Leningrad-3 (Beck et al., 1989) School 193 94 (95% CI: 76, 98)

S79 – one dose (Fu, Liang & Wang, 2008) China Population (8 months to 937 86 (95% CI: 77, 92) 12 years) (Fu et al., 2009) China Population (8 months to 366 83 (95% CI: 68, 91) 12 years) (Ma et al., 2018) Population (birth cohort 80 (95% CI: 67, 88) 2006−2007) (Ma et al., 2018) Population (birth cohort 89 (95% CI: 82, 94) 2008−2009)

S79 – two doses (Ma et al., 2018) Population (birth cohort 89 (95% CI: 83, 92) 2006−2007) (Ma et al., 2018) Population (birth cohort 94 (95% CI: 89, 95) 2008−2009) Sofia 6 (Odisseev & Gacheva, Bulgaria Contacts 98 1994)

* Some of the study population may have received mumps vaccine containing the RIT 4385 strain. † Some of the study population may have received mumps vaccine containing the Urabe Am 9 strain. § Some of the study population may have received mumps vaccine containing the Rubini strain.

19 5.2.2 Vaccine effectiveness of two doses Studies on vaccine effectiveness of two doses have been conducted only for vaccines containing the Jeryl Lynn strain and the S79 strain. Fifteen estimates of vaccine effectiveness of two doses of Jeryl Lynn mumps vaccine are available from 13 studies, with a median estimate of 88% (range: 32–95%) (Table 4). These studies vary in methods, setting, sample size and other factors that may affect the vaccine effectiveness, so the median estimate should be interpreted with caution. Vaccine effectiveness of two doses of Jeryl Lynn strain vaccine has been shown to be significantly lower among persons with a longer period since vaccination (Cardemil et al., 2017). One study evaluated the vaccine effectiveness of two doses of S79 strain vaccine and found that vaccine effectiveness was 89% or 94%, depending on the birth cohort (Ma et al., 2018).

5.2.3 Vaccine effectiveness of three doses Three studies reported on the incremental vaccine effectiveness of three MMR doses compared with two doses; all three studies were for vaccines containing the Jeryl Lynn strain among populations with high two-dose MMR coverage (> 96%) during outbreaks (Table 4). In these studies, incremental vaccine effectiveness of the third versus the second dose of MMR vaccine ranged from 61% to 88% (Cardemil et al., 2017; Nelson et al., 2013; Ogbuanu et al., 2012); one estimate was found to be a statistically significant increase (78.1%, 95% CI: 61–88%) (Cardemil et al., 2017). The majority of the participants in these three studies had received the third dose within the past year. No studies have assessed the duration of protection of a third dose of MMR vaccine against mumps.

5.3 Vaccine failure among two- and three-dose vaccine recipients

Several countries which have had mumps vaccination in their routine immunization programmes since the 1970s and 1980s have seen periodic mumps epidemics, with most cases occurring among young adults who previously received two doses of MMR vaccine. Cases among persons who previously received three doses of MMR vaccine were also documented in some outbreaks (Cardemil et al., 2017; Shah et al., 2018). The first large mumps outbreaks in countries with high mumps vaccination coverage began in the mid-2000s (Dayan, 2008; ECDC, 2010). Because mumps is not a nationally notifiable disease in most countries, it is unknown whether the epidemics in developed countries have accompanied a global epidemic in developing countries where mumps typically has a 2–5-year periodicity (Galazka, Robertson & Kraigher, 1999).

The reemergence of mumps among highly vaccinated populations is believed to be due to waning humoral immunity, an average two-dose vaccine efficacy of 88% (range 32–95%), residence in close contact settings that facilitate transmission, and antigenic variation of circulating wild-type strains (Rubin et al., 2008; Gouma et al., 2018; Vermeire et al., 2018). A number of studies documented increased risk of developing mumps with increasing time after vaccination (Vandermeulen et al., 2004; Cortese et al., 2008; Castilla et al., 2009; Cardemil et al., 2017). Data from the United Kingdom indicate that vaccine effectiveness may decrease with age, which most likely reflects increasing time since vaccination (Cohen et al., 2007). Antigenic variation between mumps viruses has also been cited as a possible explanation for vaccine failure or reinfection, and reduced cross-neutralization has been observed between strains of different genotypes (Nojd et al., 2001; Crowley & Afzal, 2002; Orvell et al., 2002;

20 WHO immunological basis for immunization series - Module 16: Mumps Rubin et al., 2006; Rubin et al., 2008). The significance of these differences is unclear. While antigenic differences could lead to decreases in vaccine effectiveness, mumps vaccine (genotype A virus) has been effective in preventing mumps during outbreaks due to genotype G in the USA and Europe (Cohen et al., 2007; Schaffzin et al., 2007; Cardemil et al., 2017). Mumps vaccines manufactured from different strains/genotypes have also been highly effective in controlling mumps around the world. Differences in neutralization capability between mumps virus strains may become significant when levels of neutralizing antibody are already low and the force of infection is high. Additional studies are needed to establish a link between protection and a particular level of neutralizing anti-mumps antibodies and to investigate the role of heterotypic mumps strains in decreasing vaccine effectiveness Further, while 2 doses of the current mumps vaccines appears to be sufficient for mumps control in the general population, more research is needed to determine the potential for a new vaccine or a booster dose to enhance immunity and prevent mumps epidemics.

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41 Department of Immunization, Vaccines and Biologicals

World Health Organization 20, Avenue Appia CH-1211 Geneva 27, Switzerland [email protected] http://www.who.int/immunization/en/