Protective effect of vaccination against mumps complications, Czech Republic, 2007–2012

Mumps is an acute infection affecting humans and caused by the mumps virus, an RNA virus of the genus Rubulavirus, family Paramyxoviridae [1]. A third of mumps infections arise without recognised symptoms [2]. Clinically apparent mumps is manifested mainly by the swelling and inflammation of one or both parotid glands. Approximately ten percent of mumps cases develop complications. Epididymo-orchitis is the most frequent complication. Neurological complications as meningitis and less common encephalitis arise, seldom resulting in permanent unilateral deafness. Pancreatitis occurs rather commonly. Oophoritis or mastitis in females is diagnosed less frequently. Other complications as arthritis, myocarditis, nephritis, and polyneuropathy are infrequent. The case fatality rate is very low, with death reported in 1.5 % of mumps cases associated with encephalitis [2].

Complications of mumps worsen and prolong the course of disease, often require hospitalization and thus increase the economic and overall burden of the disease.

Mumps is transmitted by direct contact, droplet spread, or contaminated fomites. The incubation period averages about 16–18 days (range 12–25 days) [1‐4]. The spread of the mumps virus can cause mumps outbreaks in susceptible populations. An epidemic of mumps was described by Hippocrates as early as in the 5th century BC [4, 5]. Resurgence and outbreaks of mumps have been reported in many European countries in recent years [6‐15].

One mumps virus serotype [3] and based on the phylogenetic analysis, 12 genotypes of the mumps virus were identified (designated A-N, with E and M being unassigned) [16]. Mumps is preventable by immunization. Vaccines containing live attenuated mumps virus have been used worldwide, usually as part of the combined measles, mumps, and rubella vaccines known as MMR. Mumps is a common childhood infection in unimmunized individuals, but in highly vaccinated populations, the disease affects mainly adolescents and young adults [7, 8, 10, 15].

In the Czech Republic, the universal compulsory vaccination against mumps was introduced in 1987, with the measles and mumps vaccine MOPAVAC® and monovalent vaccine PAVIVAC®. The trivalent MMR vaccine TRIVIVAC® was administered since 1995. All previously named vaccines contained the Jeryl-Lynn vaccine strain. Since 2008, the MMR vaccine PRIORIX® comprising the RIT 4385 strain has been used in the vaccination calendar. In addition, on an optional basis, parents may purchase the PRIORIX TETRA® vaccine (against MMR and varicella) for their child, available on the market since 2007.

The national immunization schedule comprises two doses, the first one given from the 15th month of age and the second one given 6–10 months or more after the first dose [17‐20]. The vaccination coverage has been evaluated annually by administrative surveys and in the period 2007–2012 ranged from 97.76 to 98.51 % for two doses and from 1.64 to 0.92 % for one dose only [21].

The Czech national surveillance of mumps is comprehensive, countrywide with compulsory reporting. The EU case definition was enshrined in the legislation in the end of 2008. Hospital physicians and general practitioners report all clinical mumps cases to the regional public health authority. Regional epidemiologists bring together the patient's personal, demographic, clinical, laboratory, and epidemiological data, including the vaccination status. Data on each mumps case are entered with the International Classification of Diseases, Tenth revision (ICD10) code into the national electronic reporting system called EPIDAT. Case based data are transferred weekly from the regional to the national level where they are further analysed and outcomes are published monthly [22, 23]. Yearly anonymous case based data are reported to the European Surveillance System (TESSy) database operated by the European Centre for Disease Prevention and Control (ECDC). In the Czech Republic, the data from the national mandatory notification are accessible only for authorised personnel of the public health service including the National Institute of Public Health. For purpose of public health policy data are analysed, results published to inform professionals and public in order to support prevention of infectious diseases and health protection.

Before the introduction of the mumps vaccine to the Czech Republic, mumps epidemics occurred at regular 3–4-year intervals, with tens of thousands of reported cases and a maximum of over 100,000 mumps patients in the 1970s [4, 19, 23]. In the post-vaccination period, mumps incidence sharply declined. However, occasional regional and national outbreaks with several thousand cases occurred in 1995-96, 2005–2006, and 2011–2012 [17‐19, 23‐25]. Recent two large outbreaks were caused by genotype G mumps virus [18, 26]. In the latest years, mumps affects mainly adolescents, young adults, and school age children and various complications such as orchitis, meningitis, and pancreatitis arise quite frequently not only in unvaccinated but also in immunized individuals.

Despite the comprehensive surveillance and mandatory vaccination strategy with high vaccination coverage being in place in the Czech Republic, mumps cases and mumps complications continue to occur.

Various studies of vaccine effectiveness against mumps complications were conducted in some countries [7, 27, 28]; nevertheless, no relevant analysis to inquire more deeply the situation in the Czech Republic is available.

This study was the first investigation of the vaccine effectiveness against clinical complications of mumps and need for hospitalization in the Czech Republic, based on the national surveillance data.

A statistically significant effectiveness of the mumps vaccination on the prevention of orchitis, meningitis, encephalitis, and hospitalization was documented in this study. The most frequent clinical complication was orchitis. The most afflicted age groups were teenagers, adolescents, and young adults, similarly to some other studies [7, 10]. The findings of the risk of orchitis growing with age of male corresponds with the reference, in which the older age at infection is associated with a higher risk of certain complications, particularly orchitis [2].

The point estimates in this study are slightly different from the results reported by Dutch and British authors [7, 27]. Anyway, all three studies have proven the protective effect of mumps vaccination with two doses. In two-dose vaccine recipients the risk was reduced for orchitis (ORa 0.64, 0.26, 0.28) and for hospitalization (ORa 0.45, 0.18, 0.29) in England and Wales, the Netherlands, and the Czech Republic, respectively.

In addition, a significant protective effect against clinical complications and hospitalization was observed among single-dose vaccine recipients in this study. The national immunization calendar prescribes two MMR doses. The second dose of MMR vaccine is not a booster, but rather is given as another individual dose. In this study, there were small numbers of mumps cases and complications among the single-dose recipients. Even higher protective effect against all complications has been reported in the Netherlands [7] in single-dose and two-dose vaccine recipients, with ORa of 0.29 (95 % CI: 0.14, 0.62) and 0.24 (95 % CI: 0.14, 0.39), respectively. Therefore, the general importance of mumps vaccination should be emphasized. Each single dose of mumps vaccine can contribute to the protection against mumps complications.

To see if the outbreak period can somehow affect the occurrence of particular complications we compared epidemic and non-epidemic years. No substantial differences were seen in the occurrence of severe complications with exception of pancreatitis. The odds of hospitalization was lower during the epidemic period, this might be due to the limited capacities in the hospital health care settings.

Another important outcome of this investigation was the growing risk and thus decreasing protection against mumps complications with time from the second vaccine dose as prescribed in the national immunization schedule. Nevertheless, the risk still remained lower in comparison with the unvaccinated. Several patients who received the dose during the incubation period, mostly within the immunization campaign in response to the 2011 mumps outbreak in the Ústí nad Labem Region [24], developed mumps a few days later.

The patients immunized later than at four years of age had higher odds of complications. Unfortunately, routine surveillance data do not allow a clear interpretation of this finding. Various factors, e.g. an underlying or chronic disease, may have played a role in delayed vaccination [29].

When comparing the results of this study with those of the sero-epidemiological survey conducted in the population of the Czech Republic in 2013 [30], a similar downward trend in the specific antibody protection against mumps was revealed by the serosurvey in teenagers from the highly vaccinated general population. Thus the results of this study might indirectly support the probable impact of the waning immunity on increase in mumps cases and complications with time from the second vaccine dose in the vaccinated population. The issues of the waning immunity or secondary vaccine failure [31] and growing risk of developing mumps with increasing time after vaccination have been addressed [32, 33]. Due to the secondary vaccine failure after the previous vaccination the decreased or insufficient specific antibody level is unable to protect an individual infected by circulating wild strain of virus from disease development. Nevertheless, in the present study no laboratory data were analysed and the immunity status thus assumption of waning immunity couldn’t be validate directly. No uninfected comparison group was in the study. We also have to admit that orchitis as the most frequent complications contributed essentially to the number and proportion of all complications. Majority of the orchitis cases were among adolescents and young adults, and in the older age the risk of orchitis is higher [2]. It should be mentionded as a theoretical possibility of an intrinsic bias. Additionally, it was not possible to differentiate between primary and secondary vaccine failure in particular vaccinated cases included in this study.

This study does not investigate the impact of particular vaccine types on mumps complications. Vaccine effectiveness is not compared between different vaccine virus strains. Generally, both vaccine strains used in the Czech Republic (Jeryl Lynn and RIT 4385) are derived from genotype A [19]. Both vaccine strains are considered to be effective against the live mumps virus of genotype G, identified in some outbreak cases in 2006 and 2012 [26].

The authors are aware of the study limitations. Where appropriate, correction was applied for possible biases in particular steps of the present research protocol. To minimize the selection bias the data were collected directly from the national database. In the analyses, the multiple logistic regression adjusting for the important predictors (age, gender, year of onset, NUTS3 regions) was used to correct for possible information biases. The fact that the data originate from the routine surveillance system was taken into account. In the process of data collection and data cleaning, great efforts were made to clarify unclear, ambiguous, or missing data to minimize loss of records. Despite the notification is comprehensive, mandatory, enshrined in law [34, 35], and stable within the recent decades, the passive surveillance system might be subject to underreporting.

Another limitation might be that all reported mumps cases were included in this study regardless of their classification. The majority of cases were laboratory confirmed or epidemiologically linked to a confirmed case. Suspected cases are reported rarely based on typical clinical symptoms. Therefore, the notified mumps cases are unlikely to have been subject to misdiagnosis. The study relies on careful appraisal of each notified mumps case by the reporting physician and epidemiologist who performed epidemiological investigation of all reported cases.

This research might contribute to a better understanding of why mumps and mumps outbreaks occur in the Czech population with a high vaccination coverage. Recently, the Czech population has not been notably exposed to the natural booster by the wild virus. Supposing some gaps in the protection, herd immunity might drop to a certain threshold and then the wider spread of mumps might hit susceptible individuals. In the present investigation, the highest numbers of mumps cases and complications were in the age group 15–19 years.

The current Czech two-dose vaccination schedule is completed in children at the age of 21 to 25 months. The present results show that mumps and the clinical complications of mumps are quite rare during approx. 6-year period after the second dose. The epidemiological situation where mumps and complications affect predominantly teenagers and young adults evoke thinking about the need for updating the immunization calendar. The postponement of the second dose to an older age could be discussed. However, to determine the optimal age and adjust the schedule will require further investigation, taking into account laboratory and serological survey results. The epidemiological situation of measles and rubella should also be considered when speaking about the combined MMR vaccine routinely used in the Czech immunization practice.

Results of the present analysis confirm the positive preventive effect of vaccination on mumps complications in the context of the epidemiological situation of mumps, vaccination policy, and surveillance system in the Czech Republic.

The risk of clinical complications and hospitalization is lower in the vaccinated than in the unvaccinated patients with mumps. Immunization with two doses of mumps strain containing vaccines significantly reduces the risk of encephalitis, meningitis, orchitis and hospitalization. The risk of complications is not influenced substantially by the epidemic period. Orchitis, the most frequent complication of mumps, affects mainly teen-age, adolescent and young adult males. Within these age groups the vaccine effectiveness for orchitis declines with the growing age.

In two-dose recipients the risk of all complications increases and the protection declines with time interval since the previous vaccination. Additional studies would be needed to investigate the serological background of findings in the present study. To decrease the burden of mumps and mumps complications in the most affected age groups the adjustment of the vaccination schedule could be discussed. Further studies are required to determine the best approach to immunization in compliance with the current needs.