Safety analysis of a live attenuated mumps vaccine in healthy adolescents in China: A phase 4, observational, open-label trial.

Mumps is an acute infectious disease, which was well controlled in the past, but recently it has resurged in some areas. This study aimed to evaluate the safety profile of the live attenuated mumps vaccine after large-scale vaccination. We conducted an observational, open-label phase 4 trial in Shaanxi, China from October 2020 to March 2021. Eligible participants were freshmen of junior high school who were not above 14 years old. Adverse events following immunization (AEFI) monitoring was carried out by active and passive surveillance. Safety follow-ups were conducted during the study participation. Overall, 10057 subjects were enrolled in the active surveillance analysis. A total of 214 subjects reported adverse reactions with an incidence of 2.13% (214/10057). Most adverse reactions were grade 1, and the incidence of grade 1 adverse reactions was 1.44% (145/10057); 0.60% for grade 2 (60/10057); and 0.09% for grade 3 (9/10057). The majority of adverse reactions were solicited (1.73%, 174/10057). Injection-site pain was the most frequently reported local adverse reaction (0.71%, 71/10057), followed by redness (0.29%, 29/10057). The most common systemic adverse reactions were nausea (0.19%, 19/10057) and fever (0.16%, 16/10057). For passive AEFI surveillance, 57 AEFI cases were reported, with an incidence of 19.28/100000 (57/287608). And most AEFI cases were common adverse reactions (66.67%, 38/57). In total, the live attenuated mumps vaccine evaluated in this trial has a favorable safety profile and can be used for large-scale inoculation.

Annual trends in adverse events following mumps vaccination in Japan: A retrospective study.

BACKGROUND: In Japan, a monovalent mumps vaccine is provided on a voluntary basis. Due to public concerns over post-vaccination aseptic meningitis, the vaccination coverage is not high enough. The present study investigated the incidence of adverse events, including aseptic meningitis, after Torii strain-derived mumps vaccination. METHODS: This retrospective, observational study used data collected by a vaccine manufacturer regarding adverse events following mumps vaccinations at medical institutions between 1992 and 2018. In addition, the number of Torii strain-derived mumps vaccines shipped each year was obtained. The incidence (per 100,000 doses) and 95% confidence intervals (CIs) were calculated for all adverse events and each adverse event, categorized as aseptic meningitis, encephalitis, mumps, mumps complications, and others. RESULTS: During the study period, 8,262,121 mumps vaccine doses were shipped, and 688 subjects reported adverse events. The incidence for all adverse events (per 100,000 doses) was 8.33, and the incidence was 4.19 for aseptic meningitis, 0.33 for encephalitis, 0.80 for mumps, 0.25 for mumps complications, and 3.78 for others. The incidence of aseptic meningitis (per 100,000 doses) was 7.90 (95% CI: 5.61-10.18) between 1998 and 2000 but declined by half, to 3.91 (2.46-5.36), between 2001 and 2003. The most recent incidence (per 100,000 doses) of aseptic meningitis, for the period 2016 to 2018, was 2.78 (1.94-3.62). CONCLUSION: The incidence of post-vaccination aseptic meningitis has declined significantly since 2001, and the incidence has remained stable at fewer than 3 cases per 100,000 doses since 2010. Multiple factors might have contributed to the decline in aseptic meningitis incidence, including (i) lowered misclassification of aseptic meningitis resulting from echovirus infection; (ii) changes in the vaccine manufacturing process in 2000; and (iii) publication in 2008 of the recommendation for vaccination of children at 1 year of age.

Parents' views on mumps, mumps vaccine, and the factors associated with vaccination in Japan.

BACKGROUND: The measles-mumps-rubella vaccine was withdrawn from the National Immunization Program in 1993 because aseptic meningitis was reported as a post-vaccination adverse reaction in Japan. This study aimed to measure the uptake of and determinants influencing mumps vaccination, including concerns about adverse reactions. METHODS: We conducted this cross-sectional survey for all parents whose children underwent 18-month health checkups in Kanazawa City between October 2019 and February 2020. Community nurses interviewed the parents using a unified questionnaire, and 1422 parents responded. RESULTS: Based on records from maternal and child health handbooks, the mumps vaccination rate was 55.6%. The most common reason for parents not vaccinating their children against mumps was that "it is not a routine vaccine" (35.9%), whereas "concern about adverse reactions" accounted for only 2.2%. In multivariate analysis, the significantly positive factors associated with vaccination against mumps were children whose parents knew that adverse reactions were fever, rash, diarrhea, and vomiting; had received a recommendation for vaccination from their family members; had read the Vaccination Guide issued by the city; vaccinated with other voluntary vaccines or treated for gastroenteritis; and had a deep general understanding of vaccination. Conversely, the significantly negative factor was children whose parents had not received any recommendation for vaccination. CONCLUSION: The mumps vaccination rate could be improved by adding the mumps vaccine in the routine vaccination program and educating parents by disseminating correct information on mumps and the mumps vaccine, and by primary care physicians routinely recommending vaccination.

Cases of aseptic meningitis after vaccination against mumps in Russia (2009-2019).

OBJECTIVES: Mumps is a highly contagious viral infection prevented by immunization with live attenuated vaccines. Mumps vaccines have proven to be safe and effective; however, rare cases of aseptic meningitis (AM) can occur after vaccination. The range of meningitis occurrence varies by different factors (strain, vaccine producer, and so on). Monovaccines or divaccines (mumps-measles vaccine), prepared from the strain Leningrad-3 (L-3), are used in Russia. Meningitis occurrence after vaccination has been established previously as very low. Nevertheless, with the number of children being vaccinated every year, vaccine-associated AM cases still occur. There is no official statistics on AM incidence after mumps vaccines, and information on AM features as an adverse event of mumps vaccination is limited and mostly devoted to vaccines, prepared from strains other than L-3. STUDY DESIGN: The study included patients with AM who were vaccinated against mumps in the previous 30 days before the present disease onset during 2009-2019. METHODS: Patients admitted to Infectious Clinical Hospital No. 1, Moscow, Russia, with AM were observed by a pediatrician and were screened for etiological agents of meningitis. RESULTS: Seven patients were enrolled, and clinical features and the course of infection are presented. CONCLUSIONS: Detection of only 7 cases of AM associated with mumps vaccination during the 10-year period supports very low occurrence of this adverse event after immunization with the L-3 strain-based mumps vaccines. Nevertheless, the annual number of AM cases that occur after mumps vaccination remains unknown and poorly diagnosed in practice because of the low awareness of physicians of this adverse reaction. Detection and objective coverage of such cases can lead to a weakening of 'antivaccination' moods in a society and to restoration of confidence in the healthcare system.

Meningitis aguda posterior a vacuna tresvírica / Acute meningitis following mumps vaccine

Resumen En Chile, la cepa del virus parotídeo utilizada en la vacuna es Leningrad-Zagreb (L-Z). Aunque la relación entre meningitis y la cepa L-Z sigue siendo controvertida, la mayoría de los casos reportados han presentado un cuadro de curso benigno y sin secuelas neurológicas. Presentamos el caso de una paciente que tres semanas post-inmunización con la vacuna tresvírica evolucionó con una meningitis aséptica de predominio mononuclear, con serología para IgM positiva contra el virus parotídeo. En este caso clínico, existió una relación temporal entre la vacunación, el inicio del cuadro parotídeo y posteriormente el meníngeo; la curva de inmunoglobulinas demostró una infección aguda posterior a la vacuna. Si bien no se logró aislar el virus en LCR, es razonable atribuir el cuadro a una infección post-vacunal.

In Chile, the strain of the mumps virus used in the vaccine is Leningrad-Zagreb (L-Z). Although the relationship between meningitis and the L-Z strain remains controversial, most of the reported cases have shown a benign course without permanent neurological sequelae. We present a case of a patient who presented an aseptic meningitis three weeks after immunization with a mumps vaccine; and laboratory confirmation showed positive serum mumps IgM antibody. In this clinical case, there was a temporal relationship between vaccination and the onset of the mumps and subsequently the meningeal involvement; the immunoglobulin curve demonstrates acute infection after vaccination. Although it was not possible to isolate the virus in CSF, it is reasonable to attribute the picture to a post-vaccinal infection.

Effects of a Public Subsidy Program for Mumps Vaccine on Reducing the Disease Burden in Nagoya City, Japan.

Nagoya City initiated a public subsidy program for mumps vaccination using either the Torii or Hoshino strains in August 2010. To determine the effects of the program, we used publicly available information from Nagoya City to investigate the changes in immunization rates and numbers of patients who developed post-immunization adverse reactions, including post-vaccinal aseptic meningitis, in the 7 years since its initiation. We also investigated the numbers of mumps patients reported by sentinel sites in a national database during this period. The immunization rate in one-year-old children increased from 24.3% before the program to 91.0% after 7 years. The mean numbers of reported mumps cases per sentinel site in one-year-old to preschool children-the age groups targeted by the program- were 12.9 in the 7 years before the program and 4.93 in the 7 years after initiation of the program, showing a significant decrease of 1/2.6 (p = 0.01). The number of vaccinations during the 6.5-year period was 140,316, with only one case of aseptic meningitis reported (0.7 cases/100,000 vaccinations). No other serious adverse reactions were observed. The present findings demonstrate that the public subsidy program in Nagoya City is an effective and safe measure against mumps in children.

[Acute meningitis following mumps vaccine]. / Meningitis aguda posterior a vacuna tresvírica.

In Chile, the strain of the mumps virus used in the vaccine is Leningrad-Zagreb (L-Z). Although the relationship between meningitis and the L-Z strain remains controversial, most of the reported cases have shown a benign course without permanent neurological sequelae. We present a case of a patient who presented an aseptic meningitis three weeks after immunization with a mumps vaccine; and laboratory confirmation showed positive serum mumps IgM antibody. In this clinical case, there was a temporal relationship between vaccination and the onset of the mumps and subsequently the meningeal involvement; the immunoglobulin curve demonstrates acute infection after vaccination. Although it was not possible to isolate the virus in CSF, it is reasonable to attribute the picture to a post-vaccinal infection.

Bilateral Deafness as a Complication of the Vaccination-A Case Report.

The vaccination has much profit for an infectious disease. On the other hand, there is little frequency, side effects may appear. It includes severe complication. We reported the case that resulted in bilateral acute profound hearing loss after mumps alone and measles and rubella (MR) vaccination. The case was a 5 years old girl. She inoculated mumps alone and MR vaccine. After 18days later, both sides profound hearing loss occurred in her. The hearing loss was not improved by the intravenous feeding of the steroid. Three months later, cochlea implantation was carried out to her right ear. She got hearing again. As for the hearing loss, mumps vaccine was considered as a cause from a latency period until the onset. The bilateral profound hearing loss that was a very rare complication was occurred by vaccination. The care of the hearing is important, but the mental care of an affected child and the parent is important, too.

Enhancing global vaccine pharmacovigilance: Proof-of-concept study on aseptic meningitis and immune thrombocytopenic purpura following measles-mumps containing vaccination.

New vaccines designed to prevent diseases endemic in low and middle-income countries (LMICs) are now being introduced without prior record of utilization in countries with robust pharmacovigilance systems. To address this deficit, our objective was to demonstrate feasibility of an international hospital-based network for the assessment of potential epidemiological associations between serious and rare adverse events and vaccines in any setting. This was done through a proof-of-concept evaluation of the risk of immune thrombocytopenic purpura (ITP) and aseptic meningitis (AM) following administration of the first dose of measles-mumps-containing vaccines using the self-controlled risk interval method in the primary analysis. The World Health Organization (WHO) selected 26 sentinel sites (49 hospitals) distributed in 16 countries of the six WHO regions. Incidence rate ratios (IRR) of 5.0 (95% CI: 2.5-9.7) for ITP following first dose of measles-containing vaccinations, and of 10.9 (95% CI: 4.2-27.8) for AM following mumps-containing vaccinations were found. The strain-specific analyses showed significantly elevated ITP risk for measles vaccines containing Schwarz (IRR: 20.7; 95% CI: 2.7-157.6), Edmonston-Zagreb (IRR: 11.1; 95% CI: 1.4-90.3), and Enders'Edmonston (IRR: 8.5; 95% CI: 1.9-38.1) strains. A significantly elevated AM risk for vaccines containing the Leningrad-Zagreb mumps strain (IRR: 10.8; 95% CI: 1.3-87.4) was also found. This proof-of-concept study has shown, for the first time, that an international hospital-based network for the investigation of rare vaccine adverse events, using common standardized procedures and with high participation of LMICs, is feasible, can produce reliable results, and has the potential to characterize differences in risk between vaccine strains. The completion of this network by adding large reference hospitals, particularly from tropical countries, and the systematic WHO-led implementation of this approach, should permit the rapid post-marketing evaluation of safety signals for serious and rare adverse events for new and existing vaccines in all settings, including LMICs.

Deep sequencing reveals persistence of cell-associated mumps vaccine virus in chronic encephalitis.

Routine childhood vaccination against measles, mumps and rubella has virtually abolished virus-related morbidity and mortality. Notwithstanding this, we describe here devastating neurological complications associated with the detection of live-attenuated mumps virus Jeryl Lynn (MuVJL5) in the brain of a child who had undergone successful allogeneic transplantation for severe combined immunodeficiency (SCID). This is the first confirmed report of MuVJL5 associated with chronic encephalitis and highlights the need to exclude immunodeficient individuals from immunisation with live-attenuated vaccines. The diagnosis was only possible by deep sequencing of the brain biopsy. Sequence comparison of the vaccine batch to the MuVJL5 isolated from brain identified biased hypermutation, particularly in the matrix gene, similar to those found in measles from cases of SSPE. The findings provide unique insights into the pathogenesis of paramyxovirus brain infections.

Effect of age on the incidence of aseptic meningitis following immunization with monovalent mumps vaccine.

OBJECTIVE: The purpose of this study was to determine the risk of aseptic meningitis after mumps vaccination in younger children compared with older children. METHODS: This prospective cohort study included a total of 21,465 children under 18 years of age who had received the first dose of three of the Japanese mumps monovalent vaccine. We compared the cumulative incidence of aseptic meningitis for 30 days after vaccination among the following age groups: ≤ 1, 2, 3-4, and ≥ 5 years old. We also investigated the cumulative incidence of salivary gland swelling, a fever (≥ 38°C) lasting at least 3 days during the 10 to 25 days following immunization, vomiting of 3 times or more, headache, and seizure. RESULTS: A total of 10 aseptic meningitis, 551 salivary gland swelling, 844 fevers, 669 vomiting, 757 headaches, and 29 seizure cases were identified. The cumulative incidence of aseptic meningitis increased with age (0.016%, 0.021%, 0.066%, and 0.096%, respectively). Statistical significance was observed between children ≥ 3 years old and those < 3 years of age [0.078% vs. 0.018%, RR 4.35 (95% CI 1.05-18.2), p=0.04]. The cumulative incidence of salivary gland swelling also increased with age (1.8%, 3.0%, 3.5%, and 4.5%, respectively). For non-specific adverse events, the cumulative incidence of fever or seizure decreased with age. In contrast, the cumulative incidence of headache increased with age. The cumulative incidence of vomiting was similar among children ≤ 4 years of age; however, that in those children ≥ 5 years old was significantly lower. CONCLUSIONS: The first dose of mumps vaccine that is currently available for use in Japan may be administered in children less than 3 years of age in order to complicate a less aseptic meningitis after immunization.

Virus genotypes and responses of serum-specific antibodies in children with primary mumps and mumps reinfection.

BACKGROUND: Research on children with mumps reinfection after natural infection is limited; there are currently no studies on virus-specific antibody responses in paired sera or genotyping of isolated viruses. METHODS: This study included 281 children (147 boys and 134 girls, age: 1.2-15.9 y) with primary mumps (240), mumps reinfection after natural infection (9), mumps after previous vaccination (26), and vaccine-associated mumps (6). We measured mumps-specific serum antibodies and analyzed isolated virus genes. RESULTS: During acute illness, series-specific IgM and IgG titers exceeded cutoff values in 240 and 232 children with primary mumps, respectively. During convalescence, IgM antibodies were positive in seven and negative in two of nine children with mumps reinfection occurring after natural infection; among 26 previously vaccinated children, 13 were positive and 13 negative. Mumps viruses were isolated from viral cultures from 42 of the 51 children. Except for 6 vaccine-associated cases, all remaining 36 cases of isolated mumps virus were identified as genotype G. CONCLUSION: These results suggest that measurement of IgM antibody on any day of acute illness may be indicative of primary mumps but may be inconsistent for diagnosing mumps reinfection after natural infection or previous vaccination.

Clinically mild encephalitis with a reversible splenial lesion (MERS) after mumps vaccination.

We retrospectively collected three patients with clinically mild encephalitis with a reversible splenial lesion (MERS) after mumps vaccination, and reviewed five patients, including two patients previously reported. The five patients (all males, aged 1 to 9) presented with fever, vomiting, or headache as the initial symptoms (day 0), suggesting meningitis, at 13 to 21 days after mumps vaccination. Consciousness disturbance, delirious behavior, seizures, or dysarthria was observed on days 1 to 3, which had completely resolved before day 11. Hyponatremia was observed in all patients. A cerebrospinal fluid study showed pleocytosis, and confirmed the vaccine strain genome. MRI revealed reduced diffusion in the splenium of the corpus callosum on days 2 to 4, which had completely disappeared on the follow-up studies performed on days 7-15. EEG showed high voltage slow wave in three patients, which later normalized. These findings led to a diagnosis of MERS after mumps vaccination. MERS after mumps vaccination may be more common than previously considered. MERS is suspected when a male patient after mumps vaccination presents with neurological symptoms with hyponatremia, following symptoms of aseptic meningitis, and MRI would be performed to examine the splenium of the corpus callosum.

Adventitious agents in viral vaccines: lessons learned from 4 case studies.

Since the earliest days of biological product manufacture, there have been a number of instances where laboratory studies provided evidence for the presence of adventitious agents in a marketed product. Lessons learned from such events can be used to strengthen regulatory preparedness for the future. We have therefore selected four instances where an adventitious agent, or a signal suggesting the presence of an agent, was found in a viral vaccine, and have developed a case study for each. The four cases are: a) SV40 in polio vaccines; b) bacteriophage in measles and polio vaccines; c) reverse transcriptase in measles and mumps vaccines; and d) porcine circovirus and porcine circovirus DNA sequences in rotavirus vaccines. The lessons learned from each event are discussed. Based in part on those experiences, certain scientific principles have been identified by WHO that should be considered in regulatory risk evaluation if an adventitious agent is found in a marketed vaccine in the future.

Safety and immunogenicity of a live attenuated mumps vaccine: a phase I clinical trial.

BACKGROUND: Mumps, a communicable, acute and previously well-controlled disease, has had recent and occasional resurgences in some areas. METHODS: A randomized, double-blind, controlled and multistep phase I study of an F-genotype attenuated mumps vaccine produced in human diploid cells was conducted. A total of 300 subjects were enrolled and divided into 4 age groups: 16-60 years, 5-16 years, 2-5 years and 8-24 months. The groups were immunized with one injection per subject. Three different doses of the F-genotype attenuated mumps vaccine, A (3.5 ± 0.25 logCCID50), B (4.25 ± 0.25 logCCID50) and C (5.0 ± 0.25 logCCID50), as well as a placebo control and a positive control of a licensed A-genotype vaccine (S79 strain) were used. The safety and immunogenicity of this vaccine were compared with those of the controls. RESULTS: The safety evaluation suggested that mild adverse reactions were observed in all groups. No serious adverse event (SAE) was reported throughout the trial. The immunogenicity test showed a similar seroconversion rate of the neutralizing and ELISA antibody in the 2- to 5-year-old and 8- to 24-month-old groups compared with the seroconversion rate in the positive control. The GMT of the neutralizing anti-F-genotype virus antibodies in the vaccine groups was slightly higher than that in the positive control group. CONCLUSIONS: The F-genotype attenuated mumps vaccine evaluated in this clinical trial was demonstrated to be safe and have effective immunogenicity vs. control.

Case of mumps orchitis after vaccination.

We present a case of mumps orchitis after vaccination. A 35-year-old man visited the emergency unit of our hospital for fever and right testicular pain on 7 January 2012. Two weeks before the visit, he underwent vaccination for mumps. After 7 days of hospitalization, the patient recovered from fever and testicular pain. Scrotal magnetic resonance imaging suggested right orchitis, and an increased level of serum mumps immunoglobulin M and immunoglobulin G indicated an initial infection of mumps virus. The peak value of immunoglobulin G showed 106 enzyme immunoassay unit 5 weeks after vaccination, which was 10-fold higher than the ordinary rise of a vaccinated individual. This fact leads to two possibilities. One is this happened as an adverse event of vaccination, and the other is that he actually had a wild-type infection at the same time as vaccination. There are some reports regarding adverse events of mumps vaccine; however, they might include wild-type infection.

Mumps Hoshino and Torii vaccine strains were distinguished from circulating wild strains.

Aseptic meningitis and acute parotitis have been observed after mumps vaccination. Mumps outbreaks have been reported in Japan because of low vaccine coverage, and molecular differentiation is required to determine whether these cases are vaccine associated. RT-nested PCR was performed in the small hydrophobic gene region, and viruses were differentiated by restriction fragment length polymorphism assay. A total of 584 nucleotides were amplified. The PCR product of the Hoshino strain was cut into two fragments (313 and 271 nucleotides) by MfeI; that of the Torii strain was digested with EcoT22I, resulting in 332- and 252-nucleotide fragments. Both strains were genotype B and had an XbaI site, resulting in two fragments: 299 and 285 nucleotides. Current circulating wild types were cut only by XbaI or MfeI. However, the MfeI site of the wild types was different from that of the Hoshino strain, resulting in 451- and 133-nucleotide fragments. Using three restriction enzymes, two mumps vaccine strains were distinguished from wild types, and this separation was applied to the identification of vaccine-related adverse events.

Characterizing vaccine-associated risks using cubic smoothing splines.

Estimating risks associated with the use of childhood vaccines is challenging. The authors propose a new approach for studying short-term vaccine-related risks. The method uses a cubic smoothing spline to flexibly estimate the daily risk of an event after vaccination. The predicted incidence rates from the spline regression are then compared with the expected rates under a log-linear trend that excludes the days surrounding vaccination. The 2 models are then used to estimate the excess cumulative incidence attributable to the vaccination during the 42-day period after vaccination. Confidence intervals are obtained using a model-based bootstrap procedure. The method is applied to a study of known effects (positive controls) and expected noneffects (negative controls) of the measles, mumps, and rubella and measles, mumps, rubella, and varicella vaccines among children who are 1 year of age. The splines revealed well-resolved spikes in fever, rash, and adenopathy diagnoses, with the maximum incidence occurring between 9 and 11 days after vaccination. For the negative control outcomes, the spline model yielded a predicted incidence more consistent with the modeled day-specific risks, although there was evidence of increased risk of diagnoses of congenital malformations after vaccination, possibly because of a "provider visit effect." The proposed approach may be useful for vaccine safety surveillance.

[Combined or coadministred Measles, Mumps, Rubella and Varicella Vaccines? That is the question!]. / Vaccini contro Morbillo, Parotite, Rosolia e Varicella: combinazione o associazione? Questo è il problema!

In November 2011, the Medicine's Italian Agency published the Pediatric Working Group's recommendation; that is do not use the quadruple vaccine against measles, rubella, mumps and varicella as first dosage in children from 12 to 23 months, because it involves an increase of febrile convulsions risks. It caused a big discussion between international and national Scientific and Institutional Bodies. In Italy, varicella is the most common vaccine preventable disease and preventive measures are not uniform. Clear and universally accepted indication is needed.

Horizontal transmission of the Leningrad-Zagreb mumps vaccine strain: a report of six symptomatic cases of parotitis and one case of meningitis.

Here we report horizontal symptomatic transmission of the Leningrad-Zagreb (L-Zagreb) mumps vaccine virus. Children who were the source of transmission had been vaccinated with the MMR vaccine (Serum Institute of India) contained L-Zagreb mumps virus. This is the first report of horizontal symptomatic transmission of this vaccine. The etiology of all seven contact cases was confirmed by epidemiological linking, serology and by F, SH, NP and HN mumps virus genes sequencing.