Two patients with mumps

Two patients, men aged 17 and 19 years respectively, were admitted with parotitis epidemica and orchitis caused by mumps. The second patient also had meningitis. PCR analysis revealed that, in both cases, the causative agentwas a mumps virus that was genetically related to a wild-type virus responsible for an outbreak in Singapore. This viral strain was also responsible for a mumps outbreak at Hotel School The Hague in September 2004. Both patients were not fully vaccinated. Both patients were from regions in which clustering of patients with clinical signs of mumps has been seen. Interestingly, a number of patients with confirmed mumps had been fully vaccinated. Possible explanations for the increase in mumps cases include low vaccination and immunity levels, primary and secondary vaccine failure and the emergence of genetically disparate mumps viruses.     

Transmission of mumps virus from mumps-vaccinated individuals to close contacts

During a recent mumps epidemic in the Netherlands caused by a genotype D mumps virus strain, we investigated the potential of vaccinated people to spread mumps disease to close contacts. We compared mumps viral titers of oral fluid specimens obtained by quantitative PCR from vaccinated (n = 60) and unvaccinated (n = 111) mumps patients. We also investigated the occurrence of mumps infection among the household contacts of vaccinated mumps patients. We found that viral titers are higher for unvaccinated patients than for vaccinated patients during the 1st 3 days after onset of disease. While no symptomatic cases were reported among the household contacts (n = 164) of vaccinated mumps patients (n = 36), there were cases with serological evidence of asymptomatic infection among vaccinated household contacts (9 of 66 vaccinated siblings). For two of these siblings, the vaccinated index patient was the most probable source of infection. We conclude that, in this particular outbreak, the risk of a close contact becoming infected by vaccinated patients was small, but present.     

Assessment of serological evidence for mumps virus infection in vaccinated children

It is estimated that at least one-third of mumps virus infections in non-vaccinated individuals are asymptomatic. Little information is available whether this proportion is the same among those vaccinated. We validated a commercial oral fluid mumps IgG-specific Enzyme Immunoassays (EIA) with vaccinated control groups to identify symptomatic and asymptomatic mumps virus infections in vaccinated individuals during a mumps outbreak in The Netherlands. A vaccinated control group was required to define a new cutoff value for the assay, because of the presence of low but significant levels of IgG antibodies in oral fluid as a result of mumps vaccination in the past. With a new cutoff, calculated using receiver operator characteristic analysis, we identified an attack rate of 7-10% compared to 2.7% based on clinical symptoms among vaccinated children. This finding has important implications when studying transmission patterns, strain virulence, as well as mumps vaccine effectiveness to protect from infection rather than disease.     

Genomic characterization of mumps viruses from a large-scale mumps outbreak in Arkansas, 2016

In 2016, a year-long large-scale mumps outbreak occurred in Arkansas among a highly-vaccinated population. A total of 2954 mumps cases were identified during this outbreak. The majority of cases (1676 (57%)) were school-aged children (5–17 years), 1536 (92%) of these children had completed the mumps vaccination schedule. To weigh the possibility that the mumps virus evaded vaccine-induced immunity in the affected Arkansas population, we established a pipeline for genomic characterization of the outbreak strains. Our pipeline produces whole-genome sequences along with phylogenetic analysis of the outbreak mumps virus strains. We collected buccal swab samples of patients who tested positive for the mumps virus during the 2016 Arkansas outbreak, and used the portable Oxford Nanopore Technology to sequence the extracted strains. Our pipeline identified the genotype of the Arkansas mumps strains as genotype G and presented a genome-based phylogenetic tree with superior resolution to a standard small hydrophobic (SH) gene-based tree. We phylogenetically compared the Arkansas whole-genome sequences to all publicly available mumps strains. While these analyses show that the Arkansas mumps strains are evolutionarily distinct from the vaccine strains, we observed no correlation between vaccination history and phylogenetic grouping. Furthermore, we predicted potential B-cell epitopes encoded by the Arkansas mumps strains using a random forest prediction model trained on antibody-antigen protein structures. Over half of the predicted epitopes of the Jeryl-Lynn vaccine strains in the Hemagglutinin-Neuraminidase (HN) surface glycoprotein (a major target of neutralizing antibodies) region are missing in the Arkansas mumps strains. In-silico analyses of potential epitopes may indicate that the Arkansas mumps strains display antigens with reduced immunogenicity, which may contribute to reduced vaccine effectiveness. However, our in-silico findings should be assessed by robust experiments such as cross neutralization assays. Metadata analysis showed that vaccination history had no effect on the evolution of the Arkansas mumps strains during this outbreak. We conclude that the driving force behind the spread of the mumps virus in the 2016 Arkansas outbreak remains undetermined.     

四川省首株腮腺炎病毒的分离

目的 为了解四川省腮腺炎病毒的基因特征,以填补四川省空白.方法 采集四川隆昌县腮腺炎暴发疫情中部分病例的咽拭子标本,进行病毒分离和核苷酸测序后,与腮腺炎病毒参考株SH基因序列做进化树分析.结果 该病毒分离株与F基因型参考株聚集在同一进化分枝上,bootstrap值为96％.与F基因型参考株的核苷酸和氨基酸序列同源性分别为96.8％ ～ 93.4％和94.7％～87.7％;与其他12个基因型参考株的核苷酸和氨基酸序列同源性分别为91.8％ ～ 84.2％和86％ ～71.9％.结论 该病毒分离株为F基因型腮腺炎病毒,即四川隆昌县腮腺炎暴发疫情流行是由F基因型腮腺炎病毒引起的.     

一起流行性腮腺炎爆发的血清学诊断和基因型别鉴定

目的对一起流行性腮腺炎(腮腺炎)爆发进行血清学证实,鉴定引起病毒性脑膜炎的腮腺炎病毒基因型别。方法用酶联免疫吸附试验(ELISA)检测临床诊断为腮腺炎患儿的血清和脑膜炎病人脑脊液(CSF)标本中的IgM抗体;从脑膜炎病人CSF标本中提取核糖核酸(RNA),用逆转录-套式聚合酶链反应(RT-Nest-PCR)方法扩增病毒小疏水蛋白(SH)基因255个核苷酸片段;序列测定结果与GenBank的8个基因型代表株做亲缘性关系树分析。结果15份血清中11份腮腺炎IgM阳性,5份CSF中2份IgM阳性。5份CSF标本中2份PCR扩增产物阳性。SH基因序列测定和分析表明该2株病毒为F基因型,与1995~1996年中国流行的腮腺炎野病毒基因型一致。结论此次疫情是由F基因型腮腺炎病毒引起的腮腺炎爆发,部分病例合并有病毒性脑膜炎。     

Cross-neutralization between vaccine and circulating wild-type mumps viruses in Korea

Mumps is a contagious disease caused by the mumps virus. It can be prevented using mumps vaccines, administered as a measles-mumps-rubella (MMR) vaccine. For first and second dose immunization, children aged 12–15 months and 4–6 years have been administered this vaccine since 1997 in Korea. Nevertheless, mumps outbreaks still occur in vaccinated populations worldwide. Hence, immunity against these diseases may be attenuated, or there are antigenic differences between currently available vaccine strains and circulating wild-type viruses. After the introduction of national immunization programs in Korea, mumps cases became sporadic. Viral genotypes F, H, and I have emerged since 1998 whereas the vaccine strains belong to genotype A. Here, we compared the amino acid sequences of the haemagglutinin-neuraminidase (HN) gene from wild-type viruses and the mumps vaccine and measured the cross-neutralization titers between them. We selected the F, H, and I wild-type mumps strains circulating in Korea from 1998 to 2016 and analyzed changes in the amino acid sequence of the protein encoded by the HN gene. We measured mumps virus-specific IgG and rapid focus reduction neutralization test (FRNT) titers in Korean isolates and sera obtained from 50 children aged 1–2 years who had been administered a single dose of MMR vaccine. Analysis of the HN protein sequences disclosed no changes in the glycosylation sites but did reveal 4–5 differences between the Korean isolates and the genotype A vaccine strain in terms of the neutralizing epitope sites on their HN proteins. Post-vaccination FRNT titers were significantly lower against genotypes F, H, and I than they were against genotype A. This finding highlights the possibility of a recurrence of mumps outbreaks in vaccinated populations depending on the degree of genetic conservation of the HN gene. Further research into this issue is needed to prevent the resurgence of mumps.     

Mumps outbreak and MMR IgG surveillance as a predictor for immunity in military trainees

In 2017, a mumps outbreak occurred in a barrack holding 249 service members. Suspected cases were evaluated with a combination of mumps IgG, IgM, viral culture, PCR and sequencing. Seven cases were diagnosed in febrile patients presenting with parotitis or orchitis. Mumps infection was confirmed by IgM or positive PCR with 5/7 cases having notable IgG levels before infection. Sequencing confirmed mumps genotype G strain. Serum from all 249 service members collected prior to the outbreak was withdrawn from the Department of Defense (DoD) Serum Repository and the IgG values of measles, mumps and rubella determined with 20.2%, 12.3% and 9.7% service members being seronegative, respectively. No specific IgG seronegativity combination predicted IgG marker levels to another virus within the same vaccine. This paper provides additional evidence that mumps serology is not a reliable surrogate for mumps immunity and that we need better laboratory correlates to confirm immunity.     

Investigation of mumps vaccine failures in Minsk, Belarus, 2001-2003

The purpose of this study was to investigate mumps vaccine failures (VF) in a highly vaccinated population of Minsk, Belarus, and to investigate a possible role for virus strain-specific immunity. During our 3-year study period, 22 adults were admitted to the Infectious Diseases Hospital in Minsk with a diagnosis of mumps. A genotype H1 mumps virus (MuV) strain was identified in all patients. Of 15 patients from whom the paired sera were collected, 9 were confirmed to have been previously vaccinated. Serological examinations indicated primary VF in seven of these cases and secondary VF in two. Despite almost all vaccinated patients possessing MuV specific IgG, few possessed neutralizing antibody to the vaccine strain and titers were nominal. Importantly, none of the sera were able to neutralize a genotype H MuV strain. Our results demonstrate the importance of assaying for neutralizing antibody and support the assertion that antigenic differences between wild type and vaccine MuV strains may play a role in cases of breakthrough infection in vaccinees.     

Genetic characterization of historical epidemic mumps viruses in northern Spain, 1987–1990

The mumps virus (MuV) is genetically diverse and is divided into 12 genotypes. The World Health Organization has recommended expanding virological surveillance for MuV, and therefore molecular characterization of circulating strains (i.e. genotypes) is increasingly performed. Nevertheless, little is known about the genotypes circulating before the massive vaccination of children and adolescents. The present study analyzed the strains causing the 1988–1989 mumps epidemic in the Basque Country, northern Spain, which occurred in the early vaccination period, before the endemic circulation of mumps virus was blocked. The epidemic reached an annual incidence rate of more than 400 cases/100,000 inhabitants, and caused a large number of cases of mumps meningitis. MuV RNA was amplified from the cerebrospinal fluid of 15 infected patients during the epidemic and from three more patients affected shortly before or after this epidemic (1987, early 1988 and 1990). Genotyping of the complete small hydrophobic gene (316 nucleotides), amplified in the 18 strains, as well as of the entire hemagglutinin-neuraminidase gene (1749 nucleotides), amplified in four strains, assigned all strains to genotype K, a genotype infrequently detected at present. Although the putative HN protein sequence differed by 4.8–5.5% in relation to Jeryl Lynn 5 strain (the main strain used in the vaccination program in this region), the vaccine was effective, and dramatically reduced the incidence of mumps over the following years. The presence of genotype K strains in Spain in the 1980s, together with their contemporary detection in Scandinavia, suggests that this genotype could have caused the Spanish epidemic and was also circulating widely in Europe at that time.     

Epidemic of complicated mumps in previously vaccinated young adults in the South-West of France

ObjectiveWe report the features and diagnosis of complicated mumps in previously vaccinated young adults.Patients and methodsWe retrospectively studied 7 cases of complicated mumps managed during 1 year at the Bordeaux University Hospital. The diagnosis was suggested by the clinical presentation and confirmed using specific RT-PCR.ResultsFive cases of meningitis, 1 of orchitis, and 1 of unilateral hearing impairment were identified. Each of the 7 patients had been previously vaccinated with MMR, 4 had received 2 doses of this vaccine. Blood tests revealed high rates of IgG antibodies, usually considered as sufficient for immunological protection, and every patient had at least 1 positive RT-PCR test for mumps.ConclusionOutbreaks of complicated mumps may still occur despite a broad coverage of MMR vaccination. The clinical presentation suggested mumps but the final diagnosis could only be confirmed by genomic detection of the virus. Unusual viral strains with increased neurovirulence, insufficient population coverage associated with immunity decrease over time may explain outbreaks of complicated mumps. A full vaccine scheme of contact people or a third injection of vaccine for previously vaccinated people who are at risk of developing mumps are required to prevent further spreading of the disease during the outbreak.     

Mumps-specific cross-neutralization by MMR vaccine-induced antibodies predicts protection against mumps virus infection

BackgroundSimilar to other recent mumps genotype G outbreaks worldwide, most mumps patients during the recent mumps genotype G outbreaks in the Netherlands had received 2 doses of measles, mumps and rubella (MMR) vaccine during childhood. Here, we investigate the capacity of vaccine-induced antibodies to neutralize wild type mumps virus strains, including mumps virus genotype G.MethodsIn this study, we tested 105 pre-outbreak serum samples from students who had received 2 MMR vaccine doses and who had no mumps virus infection (n = 76), symptomatic mumps virus infection (n = 10) or asymptomatic mumps virus infection (n = 19) during the mumps outbreaks. In all samples, mumps-specific IgG concentrations were measured by multiplex immunoassay and neutralization titers were measured against the Jeryl Lynn vaccine strain and against wild type genotype G and genotype D mumps virus strains.ResultsThe correlation between mumps-specific IgG concentrations and neutralization titers against Jeryl Lynn was poor, which suggests that IgG concentrations do not adequately represent immunological protection against mumps virus infection by antibody neutralization. Pre-outbreak neutralization titers in infected persons were significantly lower against genotype G than against the vaccine strain. Furthermore, antibody neutralization of wild type mumps virus genotype G and genotype D was significantly reduced in pre-outbreak samples from infected persons as compared with non-infected persons. No statistically significant difference was found for the vaccine strain. The sensitivity/specificity ratio was largest for neutralization of the genotype G strain as compared with the genotype D strain and the vaccine strain.ConclusionsThe reduced neutralization of wild type mumps virus strains in MMR vaccinated persons prior to infection indicates that pre-outbreak mumps virus neutralization is partly strain-specific and that neutralization differs between infected and non-infected persons. Therefore, we recommend the use of wild type mumps virus neutralization assays as preferred tool for surveillance of protection against mumps virus infection.     

Horizontal transmission of the Leningrad-3 live attenuated mumps vaccine virus

Here we describe symptomatic transmission of the Leningrad-3 mumps vaccine virus from healthy vaccinees to previously vaccinated contacts. Throat swab and serum samples were taken from six symptomatic mumps cases and from 13 family contacts. Assessment of serum IgG and IgM anti-mumps virus antibodies and IgG avidity testing was performed using commercial test kits. Sera neutralizing antibodies were measured by plaque reduction neutralization assay using the L-3 vaccine mumps virus as the target. All six of the symptomatic mumps cases and three contact subjects tested positive for mumps by RT-PCR. The genomic sequences tested (F, SH and HN genes) of all nine of these samples were identical to the L-3 mumps vaccine strain. All 13 contacts were asymptomatic; however clear serological evidence of mumps infection was found in some of them. The likely epidemiological source of the transmitted L-3 mumps virus was children who were recently vaccinated at the schools attended by the six symptomatic mumps patients described here. The L-3 mumps vaccine virus can be shed and transmitted horizontally, even to subjects previously vaccinated with the same virus.     

Epidemiological and molecular assessment of a measles outbreak in a highly vaccinated population of northeast Italy

Two distinct measles outbreaks, unrelated from the epidemiological point of view but caused by genetically related strains, occurred in the Friuli Venezia Giulia region of northeastern Italy. Forty-two cases were reported during the period April-May 2008. In the first outbreak the index case was a teacher who introduced the virus into the Pordenone area, involving eight adolescents and young adults. The other concomitant outbreak occurred in the city of Trieste with 33 cases. The containment of the epidemics can be explained by the high MMR vaccine coverage in an area where the first dose was delivered to 93·4% and the second dose to 88·3% of the target children. Phylogenetic analysis of 14 measles virus strains showed that they belonged to a unique D4 genotype indistinguishable from the MVs/Enfield.GBR/14.07 strain, probably introduced from areas (i.e. Piedmont and Germany) where this genotype was present or had recently caused a large epidemic.     

Greek measles epidemic strain, 2005-2006

The purpose of this work was the molecular study of the virus strain that caused the last measles outbreak in Greece. Twenty-four saliva specimens were obtained from selected patients serologically confirmed as measles cases between December 2005 and March 2006. Measles virus (MV) detection was performed by a nested RT-PCR. The 447-bp segment of the N gene of these MV strains was used for genotyping. The N gene sequences of the Greek MV strains were identical to each other, therefore a phylogenetic tree was constructed using one representative MV (ThesGRE/06). Our data show that the MV strain which caused the 2005-2006 outbreak in Greece belongs to genotype D6, and differs by 0.68% from the New Jersey D6 strain and by 5.5% from the MV vaccine strain Edmonston B (U03656) belonging to genotype A.     

Mumps outbreak in a highly vaccinated student population,The Netherlands, 2004

In September 2004 a mumps outbreak occurred at an international hotel school in The Netherlands. We investigated this outbreak to identify risk factors for mumps. There were 105 mumps cases (overall mumps attack rate (AR) 12% (95% CI: 10–15%)). The AR for Dutch vaccinated and unvaccinated participants was 12% (95% CI: 10–15%) and 15% (95% CI: 3–42%), respectively. Independent risk factor was mumps contact. Explanations for the relatively high AR among vaccinated participants include primary vaccine failure, waning immunity and incomplete vaccine-induced immunity in the context of high mumps virus exposure in a school party and a crowded boarding school.     

Comparison of the effectiveness of two mumps vaccines during an outbreak in Switzerland in 1999 and 2000: a case-cohort study

In two recent nation-wide outbreaks of mumps in Switzerland two-thirds of young children with clinical mumps had a history of primary vaccination. On average, measles–mumps–rubella (MMR) vaccination coverage is 80%. Two types of vaccine are commonly used: Jeryl-Lynn and Rubini. The effectiveness of the latter has been questioned in several publications. The authors therefore compared Rubini to Jeryl-Lynn in a case–cohort study. The study included 111 young children with clinical mumps who had been reported to the Swiss Federal Office of Public Health (SFOPH) by primary care physicians of the Swiss Sentinel Surveillance Network (SSSN) between January 1999 and May 2000. Sentinel physicians also sampled 661 children from the same birth cohort as the cases. While we found no evidence for the effectiveness of the Rubini strain, vaccination with the Jeryl-Lynn strain was 70% effective against clinical mumps. Furthermore, children vaccinated with the Rubini strain attended primary health care more frequently with clinical mumps than those who had received Jeryl-Lynn (odds ratio: 2.4; 95% confidence interval (CI): 1.3, 4.7). Restricting the analysis to laboratory confirmed cases increased the odds ratio to 18.4 (95% CI: 2.5, 811.2). Our study confirms the low effectiveness of the Rubini strain vaccine in the field. This vaccine should therefore be considered inappropriate for the control and elimination of mumps and its use should be discontinued. As other vaccines with comparable quality and safety standards and a substantially higher effectiveness are available the MMR vaccination program in Switzerland will not be compromised if the use of Rubini is no longer recommended.     

北京地区流行性腮腺炎野病毒与疫苗病毒基因特征比较

目的 比较北京地区流行性腮腺炎病毒流行株和疫苗株的基因特征,初步分析疫苗效果不佳的原因.方法 通过病例免疫史分析、病毒分离鉴定、SH基因序列分析,与其他基因型参考株进行同源性比较及血凝素-神经氨酸酶(HN)基因氨基酸关键位点变异分析.结果 病毒分离阳性病例共38例,其中IgM阴性7例.在2007和2008年,病毒分离率、RT-PCR阳性率、IgM抗体阳性率都有明显下降,同时有免疫史的病例增多.实验证明无免疫史的病例病毒分离和IgM抗体阳性率更高.38株病毒均属于F基因型,疫苗株属于A基因型.SH基因流行株之间核苷酸最大差异为5.6%,与疫苗株的差异为16.0%～18.1%.部分北京株SH蛋白中保守的疏水性氨基酸发生变化,如第8位:6株L→F.各流行株之间FIN蛋白氨基酸序列最大差异为2.3%,与疫苗株差异为4.2%～5.3%.在HN上决定交叉中和能力的氨基酸位点,北京株与疫苗株存在差异,如在354位和356位,所有北京株与疫苗株都不同.北京株在HN上的N-糖基化位点也和疫苗株存在差异,如在464～466位置上为NCS,疫苗株为NCR.另有18个未知功能的氨基酸位点,所有北京株与疫苗株不同.结论 近年北京地区流行的腮腺炎病毒优势株为F基因型,未发现基因型间变异,已存在较大型内差异.北京株和疫苗株在SH和HN蛋白上都存在较大差异.