Secondary Vaccine Failure Research Articles

Detection of secondary mumps vaccine failure by means of avidity testing for specific immunoglobulin G

The aim of this study was to discriminate between primary and secondary vaccine failure in children with mumps using IgG avidity testing. Thirty-nine serum samples from children with mumps, confirmed by specific IgM, were studied. The patients were grouped according to their immunization status. The secondary immune response was defined by IgG with an avidity index >32%. A secondary response in infected children previously immunized was considered as a secondary vaccine failure. Vaccinated children presented higher IgG titers and IgG avidity than unvaccinated children. The proportion of secondary immune responses in unvaccinated patients was lower than that obtained in previously vaccinated infected patients. Avidity testing can be a useful tool to detect secondary vaccine failure in mumps.

Measles in Minsk, Belarus, 2001–2003: Clinical, virological and serological parameters

Background: A number of cases of measles have been reported in the Republic of Belarus despite vaccine coverage of 98%. The absence of information on measles virus genotypes circulating in the Republic of Belarus has made it difficult to asses the situation. Objectives: The purpose of this study was to isolate and sequence measles virus strains from clinical cases in Minsk, Belarus, and to estimate the role of vaccine failure in those cases. Study design: Between 2001 and 2003 years, 14 measles cases admitted to the Hospital of Infectious Diseases of Minsk were enrolled in our study. Clinical, routine laboratory, as well as serological and virological examinations were carried out. Detection of measles antibodies and IgG avidity testing was performed using commercial test kits. All measles cases were confirmed by RT-PCR and phylogenetically characterized. Results: Only 42.9% of the cases met the WHO laboratory criteria for measles, however, all cases were confirmed by RT-PCR. Most of the measles cases were attributed to secondary vaccine failure (SVF). Phylogenetic analysis revealed the presence of genotype A virus strains in 2001 and 2002 with D6 and D7 genotypes in 2003. Conclusions: For the first time, MVs were genetically characterized in Belarus. Our results suggest that in a highly vaccinated population, most of measles cases represent vaccine failures and are vaccine-modified. Our results also indicate that confirmation of a clinical diagnosis of vaccine-modified measles requires a combination of serological and virological tests.

Rapid Diagnostic Method for Detection of Mumps Virus Genome by Loop-Mediated Isothermal Amplification

Most mumps patients are clinically diagnosed without any virological examinations, but some diagnosed cases of mumps may be caused by other pathogens or secondary vaccine failure (SVF). To clarify these issues, a sensitive, specific, and rapid diagnostic method is required. We obtained 60 salivary swabs from 34 patients with natural infection during the course of the illness, 10 samples from patients with vaccine-associated parotitis, and 5 samples from patients with SVF. Total RNA was extracted and subjected to reverse transcription-PCR (RT-PCR) and loop-mediated isothermal amplification (LAMP) for genome amplification. We detected mumps virus RNA corresponding to 0.1 PFU by LAMP within 60 min after RNA extraction, with the same sensitivity as RT-nested PCR. Mumps virus was isolated in 30 of 33 samples within day 2, and mumps virus genome was amplified by LAMP in 32 of them. The quantity of virus titer was calculated by monitoring the time to reach the threshold of turbidity. The viral load decreased after day 3 and was lower in patients serologically diagnosed as having SVF with milder illness. Accuracy of LAMP for the detection of mumps virus genome was confirmed; furthermore, it is of benefit for calculating the viral load, which reflects disease pathogenesis.

A simple method for the detection of measles virus genome by loop-mediated isothermal amplification (LAMP)

Approximately 20,000–30,000 measles patients were reported in a surveillance of infectious diseases because of low vaccine coverage of 80% in Japan. Among them, some were thought to be secondary vaccine failure (SVF) with generally mild or non‐typical measles illness and sometimes became a source of further transmission. We have developed a new, sensitive, and rapid method to detect the measles virus genome by reverse transcription loop‐mediated isothermal amplification (RT‐LAMP). We examined 50 nasopharyngeal secretion (NPS) samples that were obtained during the 1999 outbreak and stored at −70°C and fresh NPS, lymphocytes and sera from 11 patients in 2003. Total RNA was extracted from the samples and subjected to reverse transcription‐polymerase chain reaction (RT‐PCR) and RT‐LAMP. We detected the genomic RNA corresponding to at least 0.01–0.04 TCID50, 30–100 copies in samples by RT‐LAMP within 60 min after extraction of RNA, and all four genotypes isolated in Japan were equally amplified. Specific DNA amplification was monitored spectrophotometrically by real time turbidimeter and the quantity of RNA was calculated. Measles virus genome was detected in 44 of 50 stored NPS by RT‐PCR and in 49 by RT‐LAMP. The vaccine strain was discriminated from wild strains after sequencing the LAMP products. RT‐LAMP is a useful rapid diagnostic method for the detection of measles virus without any special apparatus, showing higher sensitivity than RT‐PCR, and expected to be applied for hospital‐based infection control and for laboratory‐based measles surveillance. J. Med. Virol. 76:406–413, 2005. © 2005 Wiley‐Liss, Inc.

Prevalence of measles antibody in children of different ages in Shiraz, Islamic Republic of Iran

An outbreak of measles due to secondary vaccine failure prompted this investigation into the prevalence of measles antibody in children. We studied 608 children in 7 different age groups: 6, 9, 14 and 18 months and 6, 10 and 15 years. Children in the 2 youngest groups received no vaccination; the rest were vaccinated at 9 months and 15 months. The 15-year-old age group received an additional vaccination. Transplacental measles antibody (Ab) decreased from 10.0% at 6 months to 0% at 9 months. Measles Ab was positive in 52.9% (14 months), 89.4% (18 months), 60.8% 96 years), 45.0% (10 years) and 96.8% (15 years). To increase Ab levels, a booster vaccination is recommended, administered either with the second DPT booster or at pre-high school age.

Dengue virus: molecular basis of cell entry and pathogenesis, 25–27 June 2003, Vienna, Austria

Multivalent dengue vaccines now in late stage development pose unique vaccine safety challenges in that primary or secondary vaccine failures might place vaccines at risk to antibody-dependent enhanced (ADE) wild-type dengue infections. This conference was organized to address this unique vaccine safety issue. New data were presented on the structure of dengue and other flaviviruses, the cellular receptors of dengue virus for biologically relevant cells, dengue viral cell entry mechanisms and mechanisms underlying in vivo protection, neutralization and enhancement of dengue virus infection. It was concluded that a targeted research program should aim to develop an in vitro test to characterize persons immunized with dengue vaccines as completely or partially protected. Achievement of this aim will require a better understanding of the basic mechanisms by which dengue viruses recognize, attach, enter and infect relevant human cells and how antibodies protect against dengue infections.

Measles virus receptors: SLAM and CD46.

The success of vaccination against measles in developed countries has significantly reduced the incidence of measles-related morbidity and mortality. However, measles is still the leading cause of mortality in children from underdeveloped countries due to low vaccination coverage, high transmissibility of the measles virus as well as primary and secondary vaccine failure. As with any viral disease, the identification of the host molecule to which the measles virus binds and gains entry into the host cell is a major step in understanding the molecular pathology of the disease. Two cell surface receptors, CD46 and signaling lymphocyte-activation molecule (SLAM), have been identified as measles virus receptors. CD46 is ubiquitously expressed on all nucleated cells and acts as a receptor for the Edmonston strain and all vaccine strains derived from it. SLAM is selectively expressed on some T and B cells and is utilised by the Edmonston strain and wild-type strains that cannot use CD46 for cell entry. Understanding the structural and functional variations in measles virus receptors with regard to host response can facilitate the development of new vaccines as well as provide new insights into measles virus tropism and pathogenesis and, importantly, into possible mechanisms for vaccine non-response. Our review focuses on the structure of measles virus receptors, measles virus receptor function, isoforms and polymorphic forms.

The genetic basis for measles vaccine failure.

The US measles epidemics of 1989-1991 included a series of outbreaks resulting from vaccine failure. A series of studies was launched aimed at elucidating the mechanisms of this vaccine failure. A meta-analysis of the literature examining epidemics in vaccinated populations was conducted, which showed that the secondary vaccine failure rate (development of the disease despite an initial or primary vaccine success) is no more than 0.2%. The overwhelming proportion of measles vaccine failure was due to primary vaccine failure (failure to ever generate antibody from antigenic stimulation). This comparison of two geographically distinct communities revealed that 10% of children previously vaccinated against measles lacked antibody on follow-up and that these vaccine failures clustered in families. A study of monozygotic and dizygotic twins revealed a high degree of heritability of measles vaccine antibody level. Subsequent studies found associations with both class I and class II alleles in these population-based studies. In the future, detection of the specific peptides that interact with human leukocyte antigen (HLA) molecules may serve as the basis for improved vaccines and address vaccine failure that results from cold-chain problems, immaturity of the immune system, malnutrition and maternal immunity.

Outbreak of mumps in a vaccinated child population: a question of vaccine failure?

In Belgium, children are immunized against measles–mumps–rubella (MMR) in a two-dose schedule at the age of 15 months and 11 years. Despite these recommendations, epidemics of mumps still occur. During an outbreak of mumps in Bruges (Belgium), 105 cases were registered in seven schools (age group 3–12 years). Lower than optimal vaccination coverage, inadequate vaccination schedule and a combination of primary and/or secondary vaccine failure are considered as possible reasons for the outbreak as described in the article. The role of secondary vaccine failure is highlighted.

Identification of primary and secondary measles vaccine failures by measurement of immunoglobulin G avidity in measles cases during the 1997 São Paulo epidemic.

Despite almost universal use of measles vaccines in recent decades, epidemics of the disease continue to occur. Understanding the role of primary vaccine failure (failure to seroconvert after vaccination) and secondary vaccine failures (waning immunity after seroconversion) in measles epidemics is important for the evaluation of measles control programs in developing countries. After a measles epidemic in São Paulo, Brazil, 159 cases previously confirmed by detection of specific immunoglobulin M (IgM) antibodies were tested for IgG avidity, and a secondary immune response, defined by an IgG avidity index of at least 30%, was established in 30 of 159 (18.9%) patients. Among the 159 patients, 107 (67.3%) had not been vaccinated and 52 (32.7%) had received one or more doses of measles vaccine. Of the 107 unvaccinated patients, 104 (97.2%) showed a primary immune response, defined as an IgG avidity index of less than 30%. Among the 52 patients with documented vaccination, 25 (48.1%) showed a primary immune response and 27 (51.9%) showed a secondary immune response, thereby constituting a secondary vaccine failure. Primary vaccine failure was observed in 13 of 13 patients vaccinated prior to 1 year of age and in 43.5 and 12.5%, respectively, of patients receiving one or two doses after their first birthdays. These results provide evidence that measurement of IgG avidity can be used to distinguish between primary and secondary vaccine failures in vaccinated patients with measles; the method can also be a useful tool for the evaluation of measles control programs.

Current status of measles in Japan.

Approximately 20,000 to 30,000 cases of measles are reported annually in Japan, although the actual number of measles infections is considered to be five to ten times higher than the number of reported cases. Despite the availability of effective and safe live attenuated vaccines, regional outbreaks in Okinawa, transmission in adults, and secondary vaccine failures continue. Recent advances in molecular technology have contributed to molecular epidemiological studies, new concepts of asymptomatic infection, and the identification of different characteristics among measles virus genotypes. Measles virus strains isolated in Japan since 1984 were classified into the genotypes C1 (-1985), D3 (1985-1990), D5 (1990-1997), and Chicago-type D3 (1997-1999) from the results of sequencing the hemagglutinin gene. After 2000, the D5 genotype emerged, and, recently, the H1 genotype, which is now dominant, was introduced from Korea. Some of the currently circulating wild-types have different characteristics (high growth rate at 39 degrees C-40 degrees C). The cumulative vaccine coverage has reached 81%, but most measles cases involved unvaccinated individuals. Measles is a preventable disease and can be eradicated by increasing the vaccine coverage, and promoting the motivation for vaccination, in accordance with the worldwide measles strategy.

Measles elimination: old and new challenges?

Life attenuated measles vaccines have dramatically reduced measles morbidity and mortality world-wide. Despite high vaccination coverage, measles outbreaks continue to occur both in developed and developing countries. While secondary vaccine failure may be responsible for disease in some seroconverted individuals, evidence suggests that many more vaccinees who are protected against disease may not be fully protected against virus infection. In low-income developing countries protection by maternal antibodies seems to erode faster than previously estimated especially in infants who were born to vaccinated mothers. Problems of infectivity and susceptibility of vaccinees will be compounded in case wild-type viruses become less sensitive to vaccine induced immunity. These observations suggest that elimination may be more easily achieved as long as large proportions of populations are protected by wild-type virus-induced immunity.

Secondary measles vaccine failures identified by measurement of IgG avidity: high occurrence among teenagers vaccinated at a young age.

Failure to seroconvert (primary vaccine failure) is believed to be the principal reason (approx. > 95%) why some vaccinees remain susceptible to measles and is often attributed to the persistence of maternal antibodies in children vaccinated at a young age. Avidity testing is able to separate primary from secondary vaccine failures (waning and/or incomplete immunity), but has not been utilized in measles epidemiology. Low-avidity (LA) and high-avidity (HA) virus-specific IgG antibodies indicate primary and secondary failure, respectively. Measles vaccine failures (n = 142; mean age 10.1 years, range 2-22 years) from an outbreak in 1988-9 in Finland were tested for measles-virus IgG avidity using a protein denaturating EIA. Severity of measles was recorded in 89 failures and 169 non-vaccinees (mean age 16.2 years, range 2-22 years). The patients with HA antibodies (n = 28) tended to have clinically mild measles and rapid IgG response. Among failures vaccinated at < 12, 12-15 and > 15 months of age with single doses of Schwarz-strain vaccine in the 1970s, 50 (95% CI 1-99), 36 (CI 16-56) and 25% (CI 8-42) had HA antibodies, respectively. When a single measles, mumps and rubella (MMR) vaccine had been given after 1982 at 15 months of age, only 7% (CI 0-14) showed HA antibodies. Omitting re-vaccinees and those vaccinated at < 15 months, Schwarz-strain recipients had 3.6 (CI 1.1-11.5) higher occurrence of HA responses compared to MMR recipients. Apart from one municipality, where even re-vaccinees had high risk of primary infection, 89% (CI 69 to approximately 100) of the infected re-vaccinees had an HA response. Secondary measles-vaccine failures are more common than was more previously thought, particularly among individuals vaccinated in early life, long ago, and among re-vaccinees. Waning immunity even among individuals vaccinated after 15 months of age, without the boosting effect of natural infections should be considered a relevant possibility in future planning of vaccination against measles.

Measles Outbreak in a Junior High School in November-December 1998

year in 199 I I 998 (3)・ Thoughthefrequency of large.Outbreaks has lately been seen to decrease, measles remainsanlmPOrtant EPI target disease in Japan. Fromthe end of November to the end of December 1998, an outbreak or measles occumd in a Junior high school in Tokyo・ Among 630 students enrolled in the school, 28 were diagnosed as having measles. The measles vims was isolated from four patients byusing B95a cells (4). Among 476 students who responded our questionnaire, 345 (72.4%) had received measles vaccineand 61 (12.8%) had past-histories of measles. Among the 345 vaccinees, only two students were affected by the present measles outbreak (0.6%). On the other hand, among 59 non-vaccinees without past-histories of measles, 22 students were affected (37.3%), indicating that the present outbreak affected mainly non-vaccinees. The number of measles patients among vaccinees was 2 in 345 (2.6%) (Table 1). The two students with histories of measles vaccination had measles in the present outbreak. It was not clear whether this was due to a pnmary vaccine failure or secondary vaccine failure (5). We measuredthe HI antibody titers of 174 students by HI test (6) three months after the outbreak. The average HI titer in the group with histories of natural infection was 82, while that in the vaccinees was 32. It was evident that the vaccination could not elevate the antibody liter to the level obtained by naturalinfection・ The distribution of serum HI titers of 169 students who escaped the outbreak is shown in Figure I ・ Among l30 vaccinees in this group, 19 (15%) had no detectable HI antibody and 74 (56.9%) had only low levels of the antibody (X8-16). Namely, 72% of the vaccinees had no or showed only low levels of measles antibody・ It was suggested that an outbreak of this size had no txnster effect onthe herd immunity, producing a condition for secondary vaccine failure・ This may be related to the recent increase of measles cases among the adults (7).

Measles elimination: progress and challenges

The accelerating progress in reducing measles incidence and mortality in many parts of the world has led to calls for its global eradication during the next 10–15 years. Three regions have established goals of elimination of indigenous transmission of measles. The strategy used in the Americas of a mass ‘catchup’ campaign of children 9 months to 15 years of age, high coverage through routine vaccination of infants, intensive surveillance and follow-up campaigns to prevent excessive build-up of susceptibles has had great success in reducing measles transmission close to zero. However, while these developments are impressive, much remains to be done to reduce measles-associated mortality in western and central Africa, where less than half of children are currently receiving measles vaccine and half a million children die from measles each year. The obstacles to global measles eradication are perceived to be predominantly political and financial. There are also technical questions, however. These include the refinement of measles elimination strategies in the light of recent outbreaks in the Americas; the implications of the HIV epidemic for measles elimination, issues around injection safety, and concerns about the possibility that secondary vaccine failures will contribute in sustaining transmission in highly vaccinated populations. The global priorities are to improve measles control in low income countries, increase awareness among industrialized countries of the importance of measles, and conduct studies to answer the technical questions about measles elimination strategies.

Analysis of mumps vaccine failure by means of avidity testing for mumps virus-specific immunoglobulin G.

To characterize patients with mumps vaccine failure, avidity testing was performed with the Enzygnost Anti-Parotitis Virus/IgG kit using a single-dilution-6 M urea denaturation method. Five groups of patients were tested. Group 1 consisted of 29 patients with primary mumps infections; group 2 was 20 children and adults with a definite history of natural infection; group 3 was 7 patients with a recent mumps vaccination, 1 of whom developed parotid gland swelling and aseptic meningitis; group 4 was 14 patients with mumps vaccine failure; and group 5 was 6 patients with recurrent episodes of parotitis in addition to a history of vaccination. On the basis of the results of groups 1 and 2, an avidity of </=31% was determined to be low, and >/=32% was determined to be high. Avidity maturation from low to high appears to occur around 180 days after the acute illness. The results of group 3 showed that the vaccine-induced immunoglobulin G (IgG) had very low avidity. Among the 14 patients in group 4, 12 patients, including 7 with a positive IgM response, were diagnosed as having secondary vaccine failures. The results of group 5 suggested the possibility that the avidity of the mumps vaccine-induced IgG remains low or borderline. These results showed that secondary mumps vaccine failure occurs not infrequently, even among school age children under condition in which the vaccine coverage is low (i.e., 33% in our study population), and therefore, vaccinees are prone to be exposed to wild-type viruses. Avidity testing should provide information useful for the analysis of mumps virus infections.

Estimated susceptibility to asymptomatic secondary immune response against measles in late convalescent and vaccinated persons.

Serological evidence indicates that measles virus (MV) could circulate in seropositive, fully protected populations. Among individuals fully protected against disease, those prone to asymptomatic secondary immune response are the most likely to support subclinical MV transmission. The serological characteristics of protected subjects who developed secondary immune response after reexposure to measles have been described recently [Huiss et al. (1997): Clinical and Experimental Immunology 109:416-420]. On the basis of these data, a threshold of susceptibility was defined to estimate frequencies of secondary immune response competence in different populations. Among measles, late convalescent adults (n = 277) and vaccinated high school children (n = 368), 3.2-3.9% and 22.2-33.2%, respectively, were considered susceptible to secondary immune response. A second vaccination did not seem to lower this incidence. Even when estimates of symptomatic secondary immune response (e.g., secondary vaccine failure) were taken into account, susceptibility to subclinical secondary immune response was still 5-8 times higher after vaccination than after natural infection. Although viral transmission between protected individuals has never been directly demonstrated, the data describe a population in which protected but infectious persons could potentially be of epidemiological importance.

Decline of measles-specific immunoglobulin M antibodies after primary measles, mumps, and rubella vaccination.

Detection of measles-specific immunoglobulin M (IgM) has become the standard diagnostic method for laboratory confirmation of measles. In outbreaks, the interpretation of an IgM-positive result can be complicated when persons with suspected measles receive a dose of measles vaccine as part of outbreak control measures. This investigation evaluated the decay of measles-specific IgM antibodies 1 to 4 months after primary vaccination with measles, mumps, and rubella vaccine (MMRII). Serum samples were obtained from 536 infants vaccinated when they were 15 months old as part of a study to assess primary and secondary measles vaccine failure. Sixty serum specimens per week were selected from specimens collected between 4 and 9 weeks after MMRII vaccination; all 176 available serum specimens collected between 10 and > or = 16 weeks were included. Specimens were tested for the presence of measles-specific IgM by an antibody-capture enzyme immunoassay. The proportion of IgM-positive specimens dropped from 73% at 4 weeks after vaccination to 52% at 5 weeks after vaccination and then declined to 7% by 8 weeks after vaccination. Less than 10% of children remained IgM positive between 9 and 11 weeks. An IgM-negative result helps rule out the diagnosis of measles in a person with suspected infection and a history of recent vaccination. The interpretation of a positive IgM result from a person with a clinically suspected case of measles and a recent history of measles vaccination (especially within 8 weeks) is problematic, and the diagnosis of measles should be based on epidemiologic linkage to a confirmed case or on detection of wild-type measles virus.

Variability in Immune Response to Pathogens: Using Measles Vaccine to Probe Immunogenetic Determinants of Response

“The measles had not prevailed on the Faroes since 1781; they broke out early in April, 1846. … of the 7,782 inhabitants, about 6,000 were taken with measles … 225 persons in all died … of the many old people still living on the Faroes who had had the measles in 1781, not one … was attacked the second time.” [P. L. Panum, Observations Made during the Epidemic of Measles on the Faroe Islands in the Year 1846]

A serological survey of measles vaccine in a rural region of Eskişehir in Turkey

We designed this longitudinal study as a response to measles outbreaks which occur occasionally in Eskişehir in Turkey to investigate the incidence of primary and secondary vaccine failure. The investigation was conducted over two periods (December 1993 to October 1994 and April 1995 to October 1995). Two study groups were involved, infants aged 9–11 months and children aged 18 months to 9 y. During December 1993 to October 1994 prevaccination sera was collected from 35 infants aged 9–11 months and tested to determine if maternally derived antibodies were present. The infants were vaccinated and subsequently the 31 infants who could be traced were retested 30–40 d later to determine their response to vaccination. The following was done to determine whether seropositivity rates alter over time. The second group, a randomised sample of 117 children aged between 18 months to 9 y was chosen; all of whom had been previously vaccinated and who had no history of measles. Sera was taken and tested during December 1993 to October 1994 in order to determine whether seropositivity rates varied with time. During April 1995 to October 1995 out of all the children in both groups 123 children were retested. All sera samples were studied by an enzyme-lined immunosorbent assay (ELISA). Out of the 35 infants in group 1 only four (11.4%) had maternal antibody against measles on initial testing. Out of 31 infants followed up 30–40 d after vaccination (61.3%) were found to be seropositive for measles. In the second group, of the 117 previously vaccinated children ninety-three (71.5%) had measles IgG antibody. Seropositivity rates did not show significant difference with time after vaccination. There was no association between first and second screening seropositivity rates. We conclude that the presence of maternal antibody reduces the success of vaccination. These results suggest the vaccination policy in Turkey should be re-examined with a view to revision.