Secondary Vaccine Failure Research Articles

Guest Editorial: The public health implications of secondary measles vaccine failure

Guest Editorial: The public health implications of secondary measles vaccine failure

Measles virus genotyping an important tool in measles outbreak investigation in Norway, 2011

This study describes 33 laboratory-confirmed cases of measles that occurred in Norway in 2011, mainly among unvaccinated children between seven months and 10 years of age. Laboratory testing included detection of anti-measles IgM- and IgG antibodies by enzyme-linked immunosorbent assay (ELISA) and molecular detection and characterisation of measles virus by polymerase chain reaction (PCR) and sequencing. Epidemiological data and genotyping revealed that the measles cases originated from eight separate importations, resulting in four outbreaks and four sporadic cases. Except for the first outbreak which affected 18 cases, limited secondary spread occurred in each of the three other outbreaks. The outbreaks were caused by measles virus genotypes B3, D4 and D9, whereas genotypes D8 and B3 were detected in the sporadic cases. This study highlights that genetic characterisation of measles virus is an essential tool in the laboratory surveillance of measles, especially in countries like Norway which are approaching the measles elimination goal. The investigation revealed that importation of measles resulted in subsequent transmission within Norway to non-vaccinated individuals, and twelve cases occurred in healthcare settings, involving both staff and children. The four cases detected among healthcare workers (HCWs) emphasised that the coverage of measles-mumps-rubella (MMR) vaccination among healthcare personnel needs to be improved and both primary and secondary vaccine failure was demonstrated in two fully immunised HCWs.

Measles Virus IgG Avidity Assay for Use in Classification of Measles Vaccine Failure in Measles Elimination Settings

In regions where endemic measles virus has been eliminated, diagnostic assays are needed to assist in correctly classifying measles cases irrespective of vaccination status. A measles IgG avidity assay was configured using a commercially available measles-specific IgG enzyme immunoassay by modifying the protocol to include three 5-min washes with diethylamine (60 mM; pH 10.25) following serum incubation; serum was serially diluted, and the results were expressed as the end titer avidity index. Receiver operating characteristic analysis was used for evaluation and validation and to establish low (≤30%) and high (≥70%) end titer avidity thresholds. Analysis of 319 serum specimens expected to contain either high- or low-avidity antibodies according to clinical and epidemiological data indicated that the assay is highly accurate, with an area under the curve of 0.998 (95% confidence interval [CI], 0.978 to 1.000), sensitivity of 91.9% (95% CI, 83.2% to 97.0%), and specificity of 98.4% (95% CI, 91.6% to 100%). The assay is rapid (<2 h) and precise (standard deviation [SD], 4% to 7%). In 18 samples from an elimination setting outbreak, the assay identified 2 acute measles cases with low-avidity results; both were IgM-positive samples. Additionally, 11 patients (15 samples) with modified measles who were found to have high-avidity IgG results were classified as secondary vaccine failures; one sample with an intermediate-avidity result was not interpretable. In elimination settings, measles IgG avidity assays can complement existing diagnostic tools in confirming unvaccinated acute cases and, in conjunction with adequate clinical and epidemiologic investigation, aid in the classification of vaccine failure cases.

The re-emergence of measles in developed countries: Time to develop the next-generation measles vaccines?

The re-emergence of measles in developed countries: Time to develop the next-generation measles vaccines?

Mumps virus diagnosis and genotyping using a novel single RT-PCR

BackgroundIgM detection is considered as the gold standard for mumps diagnosis. Currently, most cases in developed countries occur in highly vaccinated populations due to secondary vaccine failure. In these patients, pre-existing vaccine-induced antibodies are not able to neutralise the virus, but prevent the typical primary response, so that specific IgM is not always elicited. Consequently, acute infection has to be demonstrated by direct detection of the virus by viral isolation or genomic amplification. RT-PCR allows a diagnosis with the maximum sensitivity to be made and also forms the basis for genotype characterisation by sequencing the SH gene, according to WHO recommendations. However, none of the RT-PCR techniques properly evaluated for the diagnosis of acute mumps infection yields an amplification fragment useful for genotyping, and none of the amplification techniques described for genotyping has proved to be sensitive enough for diagnosis. ObjectivesDevelopment of a RT-PCR for the mumps virus diagnosis and genotyping, properly evaluated in comparison with serological gold-standard technique. Study design195 suspected mumps cases and six wild type MuV genotypes were studied. ResultsOur method was able to detect 0.001 TCID50 of mumps virus. Fifty-eight of these showed positive results, of which 54 (93.3%) showed mumps RNA in saliva, while only 20 (34.5%) had mumps IgM in serum. Genotypes G1, G2, H1, H2, D1 and C were identified in positive samples. ConclusionsThe technique described could be a very useful tool for mumps surveillance, management and control.

Laboratory Characterization of Measles Virus Infection in Previously Vaccinated and Unvaccinated Individuals

Waning immunity or secondary vaccine failure (SVF) has been anticipated by some as a challenge to global measles elimination efforts. Although such cases are infrequent, measles virus (MeV) infection can occur in vaccinated individuals following intense and/or prolonged exposure to an infected individual and may present as a modified illness that is unrecognizable as measles outside of the context of a measles outbreak. The immunoglobulin M response in previously vaccinated individuals may be nominal or fleeting, and viral replication may be limited. As global elimination proceeds, additional methods for confirming modified measles cases may be needed to understand whether SVF cases contribute to continued measles virus (MeV) transmission. In this report, we describe clinical symptoms and laboratory results for unvaccinated individuals with acute measles and individuals with SVF identified during MeV outbreaks. SVF cases were characterized by the serological parameters of high-avidity antibodies and distinctively high levels of neutralizing antibody. These parameters may represent useful biomarkers for classification of SVF cases that previously could not be confirmed as such using routine laboratory diagnostic techniques.

Mumps outbreaks in four universities in the North West of England: Prevention, detection and response

Evidence suggests that primary and secondary vaccine failure have contributed to recent university-based mumps outbreaks. We describe the epidemiology and public health management of two such outbreaks that occurred simultaneously in two areas of the North West of England, affecting four universities, using data from routine surveillance, serology testing, and telephone interviews and electronic questionnaires. Vaccination status was obtained from GP records. Cases were predominantly first year students living in university halls of residence. Public health response involved active surveillance, isolation advice and targeted vaccination clinics. Many students lack natural immunity and mumps vaccination. Factors hindering the public health response include delayed notifications, inability to readily define the ‘at risk’ population, low vaccine uptake, and lack of an evidence-based, cost effective strategy.

Control of Varicella Disease, Version 2.0

Control of Varicella Disease, Version 2.0

Mumps Outbreak in the Republic of Moldova, 2007–2008

Moldova experienced a nationwide mumps outbreak between 2007 and 2008. Single-dose monovalent mumps vaccination at 15 to 18 months was introduced in 1983, replaced by a 2-dose MMR schedule at age 1 and 6 to 7 years in 2002. We investigated the outbreak to quantify its extent, explore the role of primary and secondary vaccine failure, and provide control recommendations. We analyzed national mumps surveillance and vaccination coverage data to estimate vaccine effectiveness (VE) using the screening method. A retrospective cohort study in 5 educational institutions was conducted to determine age-specific attack rates (ARs) and VE. We compared vaccine strain-specific ARs. Isolation and genotyping of mumps virus strains were performed. Of 31,142 cases reported during October 2007 and July 2008, 80% were in 15- to 24-year-olds. Of cases with information (66%), 92% were vaccinated once, 4% twice. One-dose mumps VE estimates based on surveillance data over 1997-2001 declined from 91% (95% CI: 88%-92%) in 2-year-olds to 72% (70%-74%) in 15- to 19-year-olds. In the cohort study (n = 1589), VE was -40% (-120% to 20%) for 1 dose. For 2 doses it was 62% (-43% to 90%) in 13- to 15-year-olds. ARs were higher in individuals vaccinated with Urabe strains (43%) than with Leningrad-Zagreb strains (14%, P < 0.001). Mumps virus genotype G5 was identified. Low effectiveness of single-dose mumps vaccination was the main cause of the outbreak. Waning immunity may have contributed to this. The risk of mumps in 2-dose vaccinees was low. Other countries in which large population groups have received <2 doses of mumps vaccine may face similar outbreaks.

Investigation of a mumps outbreak among university students with two measles–mumps–rubella (MMR) vaccinations, Virginia, September–December 2006

Following the clinical diagnosis of the first case of mumps on September 22, 2006 at the University of Virginia (UVA), 52 suspected cases were identified through active surveillance for mumps by the end of December 2006. Samples were collected from 47 students who presented with parotitis despite a documented history of two doses of measles, mumps, and rubella (MMR) vaccine. Six of 47 serum samples (13%) were positive for mumps IgM, and 46/47 specimens were positive for mumps IgG. Endpoint titration of acute phase serum samples from laboratory-confirmed cases did not provide evidence that elevated serum IgG is a consistent marker for infection among cases due to secondary vaccine failure. Buccal swab samples from 39 of the 47 students were tested by real-time reverse transcription-polymerase chain reaction (RT-PCR) and/or viral culture. Mumps virus or mumps RNA was detected in 12 of 39 buccal samples (31%). Genetic analysis of the virus from the outbreak at UVA indicated that the outbreak was not linked to the large mumps outbreak in the Midwestern US that occurred earlier in 2006. Our findings support the use of viral detection to improve laboratory diagnosis of mumps among persons who have received two doses of MMR.

Measles cases in highly vaccinated population of Novosibirsk, Russia, 2000–2005

While the proportion of measles cases in vaccinees is expected to increase as vaccine coverage increases, such cases must be carefully investigated. The present study was conducted to examine possible contributions to vaccine failures (VFs) and to genetically characterize measles virus (MV) strains circulating in Novosibirsk, Russia during 2000-2005. Totally, 27 adult measles patients admitted to a regional hospital were prospectively enrolled in our study. Genetic characterization of the MV strains revealed circulation of genotypes A, D4 and D6 between 2000 and 2003 years; a genotype D6 MV was associated with the 2005 measles outbreak. Based on IgG avidity testing, half of the vaccinated patients demonstrated evidence of secondary vaccine failure (SVF). Patients, representing both levels of vaccine failure in our study were characterized by the lack of protective titers of neutralizing antibodies against circulating MVs, despite high IgG levels in many cases and high IgG avidity in SVF cases.

Mumps virus reinfection is not a rare event confirmed by reverse transcription loop‐mediated isothermal amplification

Clinically apparent mumps reinfection is considered extremely rare, but several cases have been suspected of reinfection in an out-patient clinic. In this study, virological examination, virus isolation, the reverse transcription loop-mediated isothermal amplification (RT-LAMP), and IgG and IgM EIA antibodies, were examined in order to identify mumps reinfection. Patients were divided into three categories; the reinfection group comprised 29 patients with a history of natural infection, the vaccine-failure group consisted of 37 patients with an immunization history, and two patients had histories of both immunization and mumps infection. Another 25 patients were enrolled as a primary infection group. Mumps virus was isolated in 5 (17%) and the genome was detected in 12 (41%) of 29 in the reinfection group. Reinfection was confirmed in 21/28, demonstrating high avidity of IgG EIA. Mumps virus was isolated in 15 (41%) and there was a higher positivity of genome amplification in 25 (68%) of 37 patients in the vaccine-failure group. Among these, 23 were confirmed as secondary vaccine failure by high avidity IgG EIA serology. In the primary infection group, the isolation rate and genome detection rate was higher in 16 (64%) and in 18 (72%) of 25 patients, respectively. There was no significant difference in virus load among the three groups but high mumps virus load was suspected in the IgM EIA-positive group based on the shorter amplification time on RT-LAMP. Mumps virus reinfection was confirmed by RT-LAMP and an IgG avidity test and was not a rare event.

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

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

Mumps outbreak in a highly vaccinated school population: Assessment of secondary vaccine failure using IgG avidity measurements

From March to April 2006, an outbreak of mumps occurred in Gyeonggi, Korea. The aim of this study was to describe and discriminate between primary and secondary vaccine failure in a highly vaccinated population for mumps using IgG avidity testing. Fifteen clinical mumps cases occurred among 41 students. Among these 15 patients, 11 vaccinated patients were considered secondary vaccine failures with high IgG titers and a high avidity index (AI, > or =32%); an unvaccinated patient was considered to have primary infection with high IgG titers and low AI, and three vaccinated patients were considered as other infections with low IgG titers and low AI. Among 26 unaffected students, 5 vaccinated patients were retrospectively diagnosed as sub-clinical infection with high IgG titers and high AI; the remaining students had low IgG titers and low AI except for one previously infected student. The results of this study show that secondary vaccine failure played an important role in this mumps outbreak. Therefore, booster immunization for mumps should be considered in immunized adolescents to prevent further outbreaks.

P1074 Evaluation of seroconversion to measles vaccine in vaccinated infants in Ibadan, Nigeria

The development and wide-spread use of mumps vaccine resulted in a dramatic and sustained decrease in the incidence of mumps disease; however, since 2000, an increase in the size and number of mumps outbreaks in the United States and other countries has sparked renewed interest in the durability of mumps-specific immunity elicited by mumps vaccination. The most likely explanation for mumps cases in previously immunized persons may be secondary vaccine failure, or waning immunity. In the current study, we examined changes in markers of measles and mumps immunity at two timepoints, approximately 7 and 17 years after two-dose MMR-II® vaccination, in a cohort of 98 healthy adults.Our results indicate that mumps IgG titers exhibited a large and significant decline during this time period, while mumps neutralizing Ab titers were relatively stable. There was a similar discrepancy with measles-specific immune responses. For both pathogens, neutralizing antibody titers were fairly low and, given the length of time since vaccination, may have already declined. These data suggest that specific immune outcomes may wane at different rates and highlight our currently incomplete understanding of protective immune responses to mumps and measles.

High CD4/CD45RO+ and CD8/CD45RO+ frequencies in children with vaccine‐modified measles

Despite availability and wide vaccine coverage, measles infections still occur especially in developing countries. An outbreak of measles occurred among previously immunized older Ghanaian children who had milder clinical symptoms with measles-specific IgG antibodies that could have been attributed to secondary vaccine failure, suggesting that the infection was vaccine-modified measles (VMM). Two-color immunophenotyping of the peripheral blood mononuclear cells was performed at acute, recovery and convalescence phases for 19 VMM patients (mean age 6.2 +/- 3.5 years) using flow cytometry, and compared with that of 20 healthy, sex- and age-matched controls. The results showed a significantly higher memory helper (CD4(+)/CD45RO(+)) cell frequency and increased suppressor cell (CD8(+)/CD45R0(+)) frequency in VMM patients compared to healthy controls. There were no complications and all the patients recovered completely. These findings show that the mild symptoms in patients with VMM may have correlated with the increase of memory T cells, which is in sharp contrast with previous reports on acute measles infection. This may suggest that the intact immunologic memory cells could have been crucial for the resolution of VMM.

The changing epidemiology of hospitalized pediatric patients in three measles outbreaks

To assess the demographic and clinical findings of measles patients during three epidemics from 1989 to 2001. A total 520 medical records of measles patients were analyzed retrospectively and divided into three groups; those who were admitted during 1989-1990 (group I, 116 patients), those admitted during 1993-1994 (group II, 127 patients), and those admitted during 2000-2001 (group III, 277 patients). For the age distribution, there was no difference in the proportion of < 2 years of age (61%, 58% and 57%, respectively) for the three groups. However, in each outbreak, there were significant differences in the distribution of > or = 2 years children who had mostly received one-dose measles-mumps-rubella (MMR) vaccination. The age distribution had changed with a significant increase in older children in subsequent outbreaks. In the last 2000-2001 outbreak, there was a pattern for increased attack rates with increasing interval since the initial vaccination. There was no statistical difference between the three groups in gender ratio, MMR vaccination rate in > or = 2 years of age, duration of fever, and complications. No difference was found in all the clinical and laboratory parameters between the anti-measles IgM antibody negative patients and the positive patients. The age distribution of admitted children with measles in each outbreak has changed over time since the introduction of one-dose MMR vaccination. This finding suggests that the secondary vaccine failure may have played a large role in the last measles outbreak.

Evaluation of Diagnostic Markers for Measles Virus Infection in the Context of an Outbreak in Spain

A measles outbreak occurred from January to July 2003 in Spain, despite the fact that the Plan of Eradication of Measles and its surveillance program had been set up in 2001. Different diagnostic markers for measles virus infection were compared for 246 patients in tests of serum, urine, and pharyngeal exudate specimens. Measles virus immunoglobulin M (IgM) and IgG and rubella virus and parvovirus IgM levels in serum were assayed. Multiplex PCR was done on urine, serum, and pharyngeal exudates, and isolation of measles virus in the B 95 a cell line from urine was attempted. At least one positive marker for measles virus was obtained from 165 patients (67.1%; total number of patients, 246). A total of 136 cases (82.4% of the patients showing positive markers) were diagnosed by PCR and/or isolation and IgM detection methods. The results for 27 patients (16.4%) were positive only by direct methods. The results for two patients (1.2%) were positive only by IgM detection. In the case of the first group (136 cases), the time elapsed from appearance of the rash was significantly longer than in the case of the group which was only positive by PCR. Besides, 8 out of 27 PCR-positive IgM-negative cases showed specific IgG results, suggesting either secondary vaccine failure or reinfection. Numbers resulting from PCR performed with pharyngeal exudates proved to be significantly higher than those obtained with other specimens. Phylogenetic analysis showed the presence of genotype B3. The results strongly back the World Health Organization recommendation that detection of IgM should be supplemented by PCR and isolation for the diagnosis of measles virus infection.

Evaluating the impact of the HIV pandemic on measles control and elimination.

To estimate the impact of the HIV pandemic on vaccine-acquired population immunity to measles virus because high levels of population immunity are required to eliminate transmission of measles virus in large geographical areas, and HIV infection can reduce the efficacy of measles vaccination. A literature review was conducted to estimate key parameters relating to the potential impact of HIV infection on the epidemiology of measles in sub-Saharan Africa; parameters included the prevalence of HIV, child mortality, perinatal HIV transmission rates and protective immune responses to measles vaccination. These parameter estimates were incorporated into a simple model, applicable to regions that have a high prevalence of HIV, to estimate the potential impact of HIV infection on population immunity against measles. The model suggests that the HIV pandemic should not introduce an insurmountable barrier to measles control and elimination, in part because higher rates of primary and secondary vaccine failure among HIV-infected children are counteracted by their high mortality rate. The HIV pandemic could result in a 2-3% increase in the proportion of the birth cohort susceptible to measles, and more frequent supplemental immunization activities (SIAs) may be necessary to control or eliminate measles. In the model the optimal interval between SIAs was most influenced by the coverage rate for routine measles vaccination. The absence of a second opportunity for vaccination resulted in the greatest increase in the number of susceptible children. These results help explain the initial success of measles elimination efforts in southern Africa, where measles control has been achieved in a setting of high HIV prevalence.

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.