Megha Mathakia
The Vaccine Revolution
Dr. Robert Siegel
June 5, 1998

An Evaluation of the Rubini, Urabe AM9, and Jeryl-Lynn Mumps Vaccines, Specifically Concerning Efficacy and Association with Aseptic Meningitis

 Introduction

Imagine a child painfully holding her head up high because of an incredible swelling in her parotid or salivary glands. Along with this excruciating enlargement in her neck region, she probably also has a fever, headache, sore throat, and maybe even a swelling in her temporomandibular area. This child is afflicted with a classic case of mumps, a disease that has largely been forgotten....

The mumps are caused by the mumps virus, a member of the Paramyxovirus family, which can be spread from person to person by saliva droplets or by direct contact with contaminated articles. Most research on the virus and disease is relatively recent, with the nature and size of the genome being determined in the 1970's and detailed information as to nucleotide sequences of various genes not being discovered until the mid-1980's. Conventional serology is still unable to distinguish between different strains of the virus so limited research efforts are now concentrating on sequencing selective regions of the genome that show variability between strains. These are regions such as the hemagglutinin-neuraminidase (HN) gene and other genes that code for surface proteins. For example, a method known as restriction fragment length polymorphism (RFLP) analysis was recently developed to identify mumps vaccine strains by the nucleotide sequence of a particular region of virus RNA, thus enabling a diagnosis of vaccine-related illness to be established. This and other newly-discovered methods have been instrumental in the development of vaccines against the mumps virus and in determining the efficacy and risks of particular strains of these vaccines.

All mumps vaccines in use today contain live, attenuated virus which has been derived by passage in chick fibroblasts. Vaccination produces a subclinical, noncommunicable infection with very few side effects. The mumps vaccine had previously been given as a monovalent dose, but recently the recommendation for vaccination has been universally changed, either formally or informally, to a trivalent measles, mumps, and rubella (MMR) vaccine. The three most popular strains of the virus used in this trivalent vaccine are the Rubini, Urabe AM9, and Jeryl-Lynn strains. Each of these differ slightly in nucleotide sequence and in the number of times they have been passaged through cells.

Since the introduction of the mumps vaccine, the number of mumps cases and complications due to mumps world-wide have decreased significantly. The vaccine has been estimated as being 95% efficacious in preventing mumps disease, and more than 97% of people known to be susceptible to mumps develop measurable antibody following vaccination. As a result, reported cases of mumps infection dropped to an all-time low of 4000 in the United States in 1991, and hospital admissions in England for mumps showed a 92% decline (down to 0.2 cases per 100,000 people ) compared to the prevaccination era. Results have been similar in every country throughout the world.

Although the vaccines have proven to be very effective in decreasing the overall incidence and prevalence of disease, the specific efficacy of the vaccines has come into question due to a number of recent cases of vaccine failure in specific populations that have been vaccinated. There has simultaneously been a general increase in the number of mumps cases since 1990 in areas such as Switzerland with high levels of circulating mumps virus, thus indicating vaccine failure. In one study conducted in Catania, Italy, the mumps vaccine failure rate was reported as 12.9%. Much debate surrounding mumps vaccine failure concerns whether the inefficacy is due to primary vaccine failure, in which the vaccine simply fails to induce an adequate initial immune response, or secondary vaccine failure, in which the immunity originally induced by the vaccine wanes with time. Many of the studies investigating outbreaks of disease have attempted to address this issue.

Mumps vaccination failure has not previously been considered a substantial public health problem, but in recent years, several mumps outbreaks which have led researchers to question efficacy of the vaccines have occurred among secondary school students, college students, and young working adults. This has been a surprising phenomenon because of school enrollment regulations for vaccine coverage. Although most of these outbreaks resulted largely from a failure to vaccinate susceptible individuals, a significant number were attributed to vaccine failure among a highly vaccinated population (at least 95%). This is a rate that is otherwise sufficient for protecting the entire population against wild mumps virus. However, one study by Cheek et al described an outbreak of mumps at a Texas high school where, according to school records, more than 98% of the students had been vaccinated.. Of the 54 students in the high school that developed mumps, 53 of the patients (98%) had been vaccinated with at least one dose of the vaccine. Similarly, in a study conducted in Maury County, Tennessee in 1991, vaccine effectiveness was estimated using the attack rate (AR) among vaccinated students as (1 - AR) X 100. It was found that an outbreak with an attack rate of 6.1% in a high school of 1116 students occurred when the vaccination rate was again 98%. Here most of the mumps cases were attributed to primary vaccine failure.

Furthermore, a complication that has recently and often been linked to the mumps vaccine is aseptic meningitis (AM). AM is a clinical illness characterized by headache, fever, and inflammation of the lining of the brain (meningitis). The illness is usually mild and runs its course without treatment, but in a few cases it can be quite severe and even life-threatening. According to Saito et al., AM is "the most common neurological reaction to live mumps vaccines..." and is well-recognized as typically occurring 2-4 weeks after immunization and resolving without sequelae. Unfortunately, no general statement can be made about the rates of post-vaccination aseptic meningitis because numbers vary form study to study and often depend on the level of effort on the part of the researchers. The one statement that is generally agreed upon is that the rate of vaccine-associated complications per dose of vaccine have remained relatively unchanged.

As is indicated by the number of recent mumps outbreaks, mumps vaccines in general have come under the eye of researchers and the informed general public. However, the many different strains of mumps vaccine virus have come under different levels of attack because of their differences in efficacy and overall levels of protection. Besides for general protective effects, there may also be significant social consequences of the general efficacy of vaccines. For example, inefficacious vaccines may discredit the value of other vaccines that may be otherwise quite efficacious. Efficacy thus becomes a very important issue.

Of the widely-used mumps vaccines, one of the most scrutinized mumps vaccine strains is the Rubini strain. The Rubini strain of mumps virus has been the most frequently used mumps component (72%) of MMR vaccines in Switzerland since 1986, and consequently, that country has been the site for much of the research done on this strain. Many of the recent mumps outbreaks have occurred in Switzerland, resulting in an incidence of disease of at least 200 cases per 100,000 inhabitants in 1993. Since 1990, there has been a continuous and marked increase in reports from a minimum of 0.7 mumps cases per physician per year to a nearly five-fold increase to 3.3 cases in 1993. Many studies done in Switzerland thus indicate a possible lack of efficacy of the Rubini strain.

For example, in an incidence study of cases on mumps in the schools of Geneva between March 18th and June 30th, 1994 done by Toscani et al, 195 children with mumps, ranging in age from 4 to 12 years, were surveyed. After adjusting for the confounding effect of age, an efficacy rate of a mere 12.4% was determined for the Rubini strain vaccine. In another study done on a kindergarten class in Geneva in June of 1991, seven of the nine children that got mumps had been vaccinated with the Rubini vaccine strain. This indicates a vaccine efficacy of just 22%.

Similarly, a case-control study done in Switzerland between January of 1992 and April of 1993 futher contributed to the perception of the Rubini vaccine strain as inefficacious. In this study, 72 of 88 (82%) patients virologically confirmed as infected with the mumps virus had been vaccinated with the Rubini strain vaccine. 21 out of 24 of those patients that had been vaccinated with Rubini also had a positive result for IgM antibodies to mumps virus. Since presence of IgM antibodies indicate recent or recurring infection, this finding indicates a possible primary vaccine failure in this group of patients. Additionally supporting the inefficacy of this strain was the finding that both the rate of seropositives and the pattern of IgG antibody index values (which indicate long-lasting immunity usually induced by exposure to wildtype or vaccine virus) were similar in those vaccinated with the Rubini strain and in those that were not vaccinated (unvaccinated-72% seropisitive, Rubini-vaccinated- 74% seropositive).

It can thus be concluded from the above three studies that the Rubini strain vaccines, which are most commonly used in Switzerland, have played an important role in the clear increase in mumps cases since 1990. These studies also offer little support for the efficacy of the Rubini strain of the mumps vaccine.

Another commonly used mumps vaccine strain is the Urabe AM9 strain, which consists of a mixture of mumps viruses that differ at a single codon of the hemagglutinin-neuraminidase (HN) gene. This was the first mumps vaccine to be licensed in Japan and was licensed in many European countries in the early 1980's. As indicated by a number of studies done in various countries, the Urabe vaccine is commonly accepted as the most efficacious of the available mumps vaccine strains. For example, the study done by Toscani et al. indicated the estimated efficacy of the Urabe strain to be 75.8%. Another study conducted in the United Kingdom in September of 1992, where the persistence of antibodies 4 years after single vaccination with one of three MMR vaccines was investigated, further supported the value of the Urabe strain of vaccine. This study determined that 85% of those vaccinated with the Urabe strain remained seropositive even 4 years after initial vaccination. The researchers did, however, raise the concern of possible secondary vaccine failure over time. Despite this concern, many studies again and again have supported this high rate of initial seroconversion with the Urabe strain (see Table 1 at end of section).

The third most widely-used strain of mumps vaccine whose efficacy must be investigated is the Jeryl-Lynn strain, another vaccine with a mixed virus population. This particular strain of vaccine, now used throughout the world, was introduced into the United States in 1967 and has been recommended for universal use in children 12 to 18 months of age since 1976. Although the Toscani study gave the Jeryl-Lynn strain an efficacy of just 64.7%, there has been a steady decrease in the incidence of mumps and mumps virus infection since its introduction. The efficacy of the vaccine is supported by the Miller et al study where 81% of those vaccinated with Jeryl- Lynn were still seropositive 4 years later. The Jeryl-Lynn strain therefore seems to be quite effective in preventing both incidence and prevalence of infection and disease.

Although all of the above studies seem to indicate some variation in the numbers presented and thus suggest a range in actual efficacies, it can be seen from the following two tables that the general trends are quite similar.

Table 1: Seropositivity rate findings

STUDY

Table 2: Efficacy

STUDY

It can be noted that, as indicated by the Miller et al study, the Jeryl-Lynn strain is slightly less efficacious than the Urabe strain of the vaccine. It was found that seropositivity rates are 4% lower with the Jeryl-Lynn vaccinees (81%) than with those vaccinated with the Urabe strain (85%). This data is similarly supported by a study conducted in Canada, in which seropositivity for those vaccinated with an MMR vaccine containing the Jeryl-Lynn strain (MMR II) was found to be 85% while that for those vaccinated with the Trivirix MMR vaccine containing the Urabe AM9 strain was 93%. Also, in a prospective, randomized clinical trial conducted in Austria, seroconversion for those vaccinated with the Urabe strain was 96.9% while those given the Jeryl-Lynn strain converted at a rate of 90%. Therefore, although there is substantial evidence for the efficacy of the Jeryl-Lynn vaccine, the Urabe strain seems to prevail in every study comparing the two strains.

From this data and the trends indicated by the above tables, it seems as though the Urabe strain should be used universally for vaccination because it has proven itself as the most effective and efficacious. It has also been suggested that the Rubini strain be used only in cases where there are contraindications to the other more effective vacinnes.

There are, however, a number of things to keep in mind when considering this data. One is how much is the actual difference in rates between the Urabe and Jeryl-Lynn strains. Although the Urabe strain seems to be slightly more efficacious in each case, it must be asked whether the differences between the two are significant. In addition, it is possible that many of the values and numbers obtained may be specific to a region since various strains of vaccine are often used in localized areas or countries and so the possibility of cofactors must be kept in mind. It should also be noted that most of these studies were retrospective. Otherwise, the data and conclusions presented seem to be quite valid and very supportive of the Urabe vaccine strain.

Although studies done on efficacy support the use of the Urabe strain of mumps vaccine, it is important to consider other factors as well, namely the risk of complications associated with use. One of the most common complications of mumps vaccines, one that should definitely be considered when evaluating the different strains, is the risk of post-vaccine aseptic meningitis. Overall, studies have shown that the risk of aseptic meningitis from wild virus is about four-fold higher than from vaccine. Risk of AM per dose of vaccine, however, also varies from study to study. It also seems to vary from region to region, depending on differences in methods of evaluation or vaccine strain used. The Rubini, Urabe, and Jeryl-Lynn strains have significantly different indications of aseptic meningitis that may heavily influence the use of one vaccine over the other.

Despite the inefficacy of the Rubini vaccines, there has actually been no documentation of any correlation of the Rubini strain with aseptic meningitis. Actually, one study found the estimated efficacy of the Rubini vaccines against all complications to be 50 to 81%. This is actually quite probable because of the hypothesized loss of virulence of the virus due to the high number of passages through cells in the attenuation process. Unfortunately, no studies have been done specifically concerning the risk of AM due to the Rubini strain of the mumps vaccine. This would be an interesting study even if there is no evidence of the Rubini strain causing AM; it would be nice to see a conformation of that theory.

Similarly, the Jeryl-Lynn strain according to a number of separate studies, has not been associated with post-vaccine aseptic meningitis. According to T. Forsey of the National Institute for Biological Standards and Control in England, "there has been no case of post-vaccine meningitis from which the Jeryl-Lynn strain has been isolated." One study done in the United States analyzed children who had received the Jeryl-Lynn strain of mumps vaccine in a monovalent dose. In this retrospective case study, no cases of AM occurring within the first 15 days of administration of the vaccine were identified in these children.

Another study that took place in the Unites States attempted to assess the level of increased risk, if any, of hospitalizations for AM after Jeryl-Lynn mumps strain MMR vaccine in the Vaccine Safety Datalink (VSD) population. The VSD project linked outcome and vaccine exposure information for 500,000 kids under the age of seven in Northern California. This particular study was run as a retrospective case-control study and used the first two years of available data in ascertaining the possible risk. Of the 59 cases of AM that were identified, it was found that none of these cases had apparent onset within 30 days of receiving the Jeryl-Lynn mumps vaccine. The researchers then concluded that "there was no increased risk of aseptic meningitis after MMR vaccine containing the Jeryl-Lynn strain of mumps. Thus, studies involving both the monovalent and trivalent vaccines support the assertion that the Jeryl-Lynn strain of mumps vaccine is not correlated with increased risk of post-vaccine aseptic meningitis. Because of this, the Jeryl-Lynn strain has become the acepted vaccine in many vaccination strategies throughout the world.

The Urabe strain, on the other hand, has been widely confirmed as a causative agent of post-vaccine AM. The VSD project analysis, for one, has indicated risk of hospitalization for aseptic meningitis after MMR vaccination containing the Urabe strain to be 1 per 3800 doses. Despite the high efficacy of the strain in preventing mumps disease, reasons such as this have led to the end of use of the vaccine in many countries. For instance, "use of the MMR vaccine containing the Urabe mumps strain was discontinued in the UK in September 1992 following the identification of an unacceptably high risk of aseptic meningitis 15-35 days after vaccination." Also, this same vaccine was removed from the Canadian market in 1987 due to the association between the Urabe mumps strain and aseptic meningitis. Here the risk of AM was calculated to be about 1 in 10,000 doses. However, according to a French study conducted from 1991-1993, where the associated risk was found to be 1 in 28,400 doses, the frequency of meningitis due to wild virus is still much higher at 1-3 cases per 1000 mumps cases. Thus, it can be argued that the benefit outweighs the apparently variable risk of vaccination.

Many research efforts have been concentrated on finding out the possible cause for this high correlation of AM with the Urabe strain of the mumps vaccine. A few of these studies have led to the suggestion of genetic factors as a possible cause. In a study done in Japan by Saito et al, mumps virus isolated from nonvaccine-associated AM cases were shown to lack the BamHI restriction cleavage sites of the P gene, a phenomenon also seen in the Urabe strain. The incidence of AM in those infected with this "Urabe-like" wild-type strain, termed the ODATE-1 strain, was shown to be 70%. This observation therefore indicates a possible genetic factor, specifically concerning the P gene, playing into the incidence of aseptic meningitis among those vaccinated with the Urabe strain of mumps virus.

In a separate study done in Canada, the nucleotide (nt) sequence of the hemagglutininin-neuraminidase (HN) gene from vaccine virus was compared to that of viruses isolated from persons with postvaccination aseptic meningitis. It was found that Urabe vaccinees who developed AM possessed predominantly a strain of virus that underwent a substitution of the nucleotide A for G at position 1081. This resulted in a substitution of the amino acid Lysine for Glucine at position 335 in the HN protein. This data indicates that the A form of the virus has a selective advantage to the G form during at least human infections that cause disease, and that the A form is thus pathogenic.

Although these studies seem to provide very convincing data and conclusions based on this data, it is important to keep in mind that they are not flawless. Particularly, the great majority of studies involving aseptic meningitis are retrospective in nature and thus may be subject to the "fishing expedition" bias. There is also a great range in the "risk per dose" calculations of each study. Furthermore, it would be valuable to study possible genetic factors contributing to the incidence of AM caused by the Urabe strain in areas throughout the world that have both higher levels of AM and different wild-type strains. Otherwise, all other indications point to the severity of the aseptic meningitis situation with the Urabe strain of mumps vaccine.

As seen here, there are a number of factors that must be considered when deciding which vaccine to use in a vaccination program. These factors often reach beyond general vaccine efficacy and risk of complications due to vaccination. As a result, there is often much controversy surrounding this issue, and questions are often raised as to why certain vaccines are used in certain countries and situations as opposed to others. There are a few possible explanations for this. One study, conducted by Germann et al, concluded that the Jeryl-Lynn strain should be used universally, and especially in areas of high levels of circulating virus, because of its demonstrated efficacy and low risk of complications. A second possible determinant is the country that the vaccine is being used in. For example, a possible explanation for the use of the Jeryl-Lynn strain in the United States is because the MMR vaccine containing this strain is manufactured by Merck, while the Rubini strain may be the most popular strain used in Switzerland because it is manufactured by a company located in Bern, Switzerland. A third possibility that has been raised has to do with possible vaccine shortage that may result in some countries if vaccines are withdrawn. This has specifically been suggested as a potential problem with the withdrawal of the Urabe strain in developing countries where this may be the only vaccine available. In cases such as this, the issues of potential risk with and without vaccination must be considered.

Despite the many concerns over the efficacy and risk of the different mumps vaccines, it is eveident that immunization for mumps must continue because of the high risk of infection from the wild-type mumps virus. There have been a few proposed solutions to remedy the problem of efficacy of these vaccines. Of these, the most promising and widely-accepted is the idea of a two-dose regimen of vaccination. Although not studied very well because it is relatively new, this strategy appears to be quite effective wherever it has been implemented. For example, in Finland, children vaccinated with the Rubini strain as infants and later (at age 10) were boosted with the Rubini strain once again, had a rise in titer that remained stable for the first yea of follow-up but then declined steadily thereafter. Similar results were seen in a study conducted in the United States with the Jeryl-Lynn strain. Although this approach is effective initially, a solution that maintains immunity must be found.

A possible solution that must be investigated is a possible two dose regimen, vaccinating with the Jeryl-Lynn strain at 12 months and later boosting this response with a vaccination of the Urabe strain when antibody levels decline to below a protective level. The theory behind this strategy is that an immune response will be elicited with the Jeryl-Lynn strain at an early age, but there will be no risk of complications due to vaccination. Later, when the immunity is no longer believed to be protective, the child will be immunized with the more efficacious but higher risk Urabe strain in an effort to maintain high levels of immunity. It is hypothesized that the immune response elicited by the Jeryl-Lynn strain will protect against any complications that may arise from immunization with the Urabe strain. This is a strategy that should be investigated in the effort to protect people from the largely-forgotten, but painful cases of the mumps.

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