Measles Vaccine Failure Research Articles

Measles Virus IgG Avidity Assay for Use in Identification of Measles Vaccine Failures in Tianjin, China

ObjectiveTo identify measles vaccine failures in Tianjin, China using a measles virus IgG avidity assay. MethodsThe China Information System for Disease Control and Prevention (CISDCP) was used to collect information about measles cases and blood specimens in Tianjin from 2013 to 2015. Measles-specific IgM and IgG antibodies were detected using Enzyme-Linked Immunosorbent Assay (ELISA). Avidity testing for measles IgG was performed using a commercial enzyme immunoassay (EIA). ResultsA total of 284 confirmed measles cases were identified. Of this total, 262 (92.25%) were in patients aged ≥ 20 years. High avidity was exhibited in 172 (60.56%) cases, while 80 (28.17%) cases demonstrated low avidity. High avidity was detected in only 21.43% of cases in patients aged < 1 year. The proportion of high avidity increased with age, and was significantly higher in patients aged 30–39 years at 70.07% (χ2 = 17.27, P = 0.002). Of the 52 measles cases in patients with a history of vaccinations, 41 (78.85%) cases showed high avidity, indicating secondary vaccine failures (SVF). In these vaccinations, there was no significant difference (P > 0.05) in clinical severity between high avidity and low avidity cases. However, regardless of vaccination status, clinical severity was significantly lower in high avidity cases (P < 0.001) than in low avidity cases. The percentages of positive measles IgM results in high avidity and low avidity cases were 66.28% and 91.25%, respectively. Geometric Mean Concentration (GMC) was significantly lower in high avidity cases at 33.73 U/mL, compared to 166.07 U/mL in low avidity cases. ConclusionsLow clinical severity and inconclusive IgM antibody results are more likely in high avidity measles cases. Measles cases were more common in adults. Therefore, a further dose of vaccines should be recommended for 30–39 years in Tianjin.

Measles, the need for a paradigm shift.

Measles vaccination schedules and targets of herd immunity have been designed according to the paradigm that the vaccine is as protective as natural infection, and the virus has remained of a single serotype over many decades. As a result, ongoing measles resurgence is mostly attributed to gaps in immunization. Using official data, we investigated the correlation between the rate of vaccine coverage reported and aggregated at the national level, and the incidence of cases. We discussed the limits of this indicator considered in isolation. We provide a literature overview of measles vaccine efficacy and failures. We questioned whether measles strains could escape the vaccine. Immunization tools and strategies for measles control deserve to be optimized in the current context.

The application of measles specific IgM and IgG antibody detection in classification measles vaccine failure, Tianjin

Objective: To study the application of measles specific IgM and IgG antibody detection in classification of primary vaccination failure (PVF) and secondary vaccination failure (SVF). Methods: Measles surveillance information system was used to collect measles confirmed cases in Tianjin, 2013-2015, and their blood specimens were collected, totally 284 cases were enrolled. Measles IgM and IgG were detected with enzyme-linked immunosorbent assay (ELISA), and the relative avidity index (RAI) was used to express the result of measles avidity. Measles IgM, IgG and IgM/IgG was analyzed with receiver operating characteristic (ROC) curve, the area under the ROC curve (AUC) as evaluation indicators. In addition, compared with a measles outbreak (26 cases) of a middle school in Tianjin in 2016, for making further verification on the diagnostic value of vaccination failure with IgM, IgG and IgM/IgG. Results: The age of cases ranged was 0-58 years old, the interval median (P(25), P(75)) of serum collection after rash onset was 2 (1, 4) days. The positive rate of measles IgM and IgG in acute phase specimens were 76.06% (216 cases) and 88.38% (251 cases). According to the ROC curve analysis, the area under the ROC curve (AUC) of IgM, IgG and IgM/IgG were 0.753, 0.891 and 0.952, indicating that IgM/IgG was the best index to distinguish PVF and SVF. The best cut off value for IgM/IgG was 0.06, the sensibility and specificity were 88.75% and 86.63%. When IgM/IgG >1, 96.30% cases were low-avidity (RAI <40%), only 1 case was equivocal response (RAI: 40%-60%). 97.14% cases were high-avidity (RAI >60%) when IgM/IgG <0.01, only 3 cases were equivocal response (RAI 40%-60%). The threshold of IgM/IgG was used to verify the measles outbreak of a middle school in Tianjin, 2016. In the acute phase specimens, 100% (26 cases) of IgM/IgG were <0.06, 84.62% (22 cases) of IgM/IgG were <0.01. Conclusion: The detection of measles IgM and IgG with ELISA, and IgM/IgG is a valuable diagnostic tool to distinguish PVF and SVF.

Assessing measles vaccine failure in Tianjin, China

Despite increasing global measles vaccination coverage, progress toward measles elimination has slowed in recent years. In China, children receive a measles-containing vaccine (MCV) at 8 months, 18–24 months, and some urban areas offer a third dose at age 4–6 years. However, substantial measles cases in Tianjin, China, occur among individuals who have received multiple MCV doses. This study describes the vaccination history of measles cases 8 months – 19 years old. Data came from measles cases in Tianjin’s reportable disease surveillance system (2009–2013), and from a case control study (2011–2015). Twenty-nine percent of those in the surveillance dataset and 54.4% of those in the case series received at least one dose of MCV. The minimum and median time-to-diagnosis since vaccination revealed an increase in time since vaccination for incremental doses. Considerable measles cases in Tianjin occur in vaccinated children, and further research is needed to understand the reasons for vaccine failure.

Clinical Characteristics of Measles in Previously Vaccinated and Unvaccinated Patients in California.

Measles vaccine failure was first described in 1972. Over the next 20 years, vaccine failure was extensively studied, but during the last 25 years few investigations have been performed. We describe the clinical characteristics of measles in previously vaccinated and unvaccinated patients in California. All confirmed measles cases reported to the California Department of Public Health from 1 January 2000 through 31 December 2015 were reviewed. Clinical characteristics (rates of hospitalization, cough, coryza, conjunctivitis, and fever) were compared between the previously unvaccinated, those who had had 1 dose of vaccine, and those who had had ≥2 doses of measles vaccine. There were 232 confirmed measles cases in whom vaccination status was verified; 80% were unvaccinated, 9% had had 1 dose of measles vaccine, and 11% had had ≥2 doses of measles vaccine. Subjects who had had ≥2 doses of measles vaccine had lower rates of hospitalization, cough, coryza, conjunctivitis, and fever than subjects who had 1 dose of measles vaccine or who were unimmunized. Vaccine failure measles cases were less ill than cases that occurred in unvaccinated patients. Nevertheless, these cases still required the same amount of public health effort in tracing contacts as in cases who were unvaccinated.

Genetic Variants in the IL-4/IL-13 Pathway Influence Measles Vaccine Responses and Vaccine Failure in Children from Mozambique.

Despite effective measles vaccines, measles still causes severe morbidity and mortality worldwide, particularly in developing countries. The Th2 pathway involving interleukin (IL)-4 and IL-13 cytokines, and their receptor IL-4Rα, play important roles in the Th1/Th2 balance and antibody production. A Th2 skewing of the cytokine milieu may affect vaccine responses. We investigated IL-4, IL-13, and IL-4Rα polymorphisms and their impact on measles IgG responses and measles vaccine failure, in two separate cohorts: 12-month-old Australian children immunized with measles-mumps-rubella vaccine (n = 137) and a case/control cohort of children aged 6 months-14 years from Mozambique, Africa (n = 89), some of whom were vaccinated, but still contracted measles (vaccine failure). We found that IL-4Rα haplotypes for Val75Ile, Ser503Pro, and Arg576Gln were associated with measles IgG in Mozambican children (p = 0.016 and p = 0.032 for Val.Pro.Arg and Val.Ser.Arg, respectively), but not Australian children. IL-4Rα 503Pro was more prevalent in Mozambique vaccine failure cases compared with controls (p = 0.008). We showed that the impact of Th2 genes on measles vaccine responses differs between ethnicities and IL-4Rα polymorphisms may work in combination to affect measles antibody responses and vaccine failure in Mozambican children. Studies in this area are particularly important in developing countries like Mozambique where measles is still a major health issue.

Genome-wide associations of CD46 and IFI44L genetic variants with neutralizing antibody response to measles vaccine.

Population-based studies have revealed 2-10% measles vaccine failure rate even after two vaccine doses. While the mechanisms behind this remain unknown, we hypothesized that host genetic factors are likely to be involved. We performed a genome-wide association study of measles specific neutralizing antibody and IFNγ ELISPOT response in a combined sample of 2872 subjects. We identified two distinct chromosome 1 regions (previously associated with MMR-related febrile seizures), associated with vaccine-induced measles neutralizing antibody titers. The 1q32 region contained 20 significant SNPs in/around the measles virus receptor-encoding CD46 gene, including the intronic rs2724384 (p value=2.64×10-09) and rs2724374 (p value=3.16×10-09) SNPs. The 1q31.1 region contained nine significant SNPs in/around IFI44L, including the intronic rs1333973 (p value=1.41×10-10) and the missense rs273259 (His73Arg, p value=2.87×10-10) SNPs. Analysis of differential exon usage with mRNA-Seq data and RT-PCR suggests the involvement of rs2724374 minor G allele in the CD46 STP region exon B skipping, resulting in shorter CD46 isoforms. Our study reveals common CD46 and IFI44L SNPs associated with measles-specific humoral immunity, and highlights the importance of alternative splicing/virus cellular receptor isoform usage as a mechanism explaining inter-individual variation in immune response after live measles vaccine.

Impact of Vaccination on Measles Transmission Patterns in Gweru City, Zimbabwe, 1960-89

A study was carried out in Gweru urban district (population-158233) in Zimbabwe to determine the impact of measles vaccine applied at 9 months of age on measles transmission patterns. A retrospective observational study that used data from measles vaccination records and measles disease surveillance was conducted. Linear regression analysis and the chi-squared test for linear trend (χ²) were used to investigate linear relationships at a 5% significance level. Vaccine coverage rates were 0% in pre-vaccination era in 1960-70 and 2-92% in 1971-89 (median=65, Q₁=34, Q₃=88) when they significantly linearly increased (p<0.001). In 1960-85 measles incidence rates significantly linearly increased (p<0.001) while in 1986-89 at vaccine coverage rates of >90% incidence rates significantly linearly declined (p<0.001). Proportion of vaccinated cases among measles notifications significantly linearly increased as vaccine coverage rates increased (Slope: +1.19, 95% CI [0.52, 1.86]). At vaccine coverage rates of >80% (1984-89), proportion of vaccine failures among cases aged 60-119 months was significantly higher than at vaccine coverage rates of <80% (1971-83) (p=0.011) while in age group 10-59 months proportions of vaccine failures were not different at vaccine coverage rates of <80% and >80%. In age group 60-119 months incidence rates significantly linearly increased as vaccine coverage rates increased (Slope: +29.88, 95 CI [13.95, 45.82]). In pre-vaccination era, and at vaccine coverage rates of <80% and >80% some 75% of all reported measles cases occurred by age 36-47 months, 48-59 months and 72-83 months respectively. In conclusion, measles incidence rates declined at vaccine coverage rates of >90%, while measles vaccine failures significantly increased as vaccine coverage rates increased. Increasing measles vaccination coverage led to shift of age at infection from age group <59 months to age group 60-119 months and decline in rates of measles transmission.

Monitoring the burden of respiratory syncytial virus in different age groups from 2011 to 2015 at National Influenza Centre in Slovenia

s / Journal of Clinical Virology 70 (2015) S1–S126 S43 transmission. Further surveillance and studies of measles vaccine failure are necessary to assess whether additional protective measures should be considered in these high exposure settings. It is clear, however, that unvaccinated HCWs pose a serious threat for nosocomial outbreaks, and that this group should be adequately vaccinated. http://dx.doi.org/10.1016/j.jcv.2015.07.103

Impact of CD14 promoter variants on measles vaccine responses and vaccine failure in children from Australia and Mozambique

Impact of <i><scp>CD14</scp></i> promoter variants on measles vaccine responses and vaccine failure in children from Australia and Mozambique

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

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

Polymorphisms in key innate immune genes and their effects on measles vaccine responses and vaccine failure in children from Mozambique

Despite an effective vaccine, measles remains a major health problem globally, particularly in developing countries. More than 30% of children show primary vaccine failure and therefore remain vulnerable to measles. Genetic variation in key innate pathogen recognition receptors, such as the measles cell entry receptors CD46 and SLAM, measles attachment receptor DC-SIGN, the antiviral toll-like receptors (TLR)3, TLR7 and TLR8, and the cytosolic antiviral receptor RIG-I, may significantly affect measles IgG antibody responses. Measles is still highly prevalent in developing countries such as those in Africa however there is no previous data on the effect of these innate immune genes in a resident African population. Polymorphisms (n=29) in the candidate genes were genotyped in a cohort of vaccinated children (n=238) aged 6 months–14 years from Mozambique, Africa who either had vaccine failure and contracted measles (cases; n=66) or controls (n=172). Contrasting previous associations with measles responses in Caucasians and/or strong evidence for candidacy, we found little indication that these key innate immune genes affect measles IgG responses in our cohort of Mozambican children. We did however identify that CD46 and TLR8 variants may be involved in the occurrence of measles vaccine failure. This study highlights the importance of genetic studies in resident, non-Caucasian populations, from areas where determining the factors that may affect measles control is of a high priority.

A review of measles vaccine failure in developing countries

Summary Measles is one of the major preventable childhood killer diseases in developing countries. Annually about 70 million cases occur worldwide. Measles vaccine has been developed over decades to prevent and control measles. Although national immunization programsprevent over 80 million cases of measles and 4.5 million deaths annu- ally, it is estimated that over 30 million cases and 875,000 d~ths still occur every yeat. High transmksion of measles despite high coverage with I-dose measles vaccine has been reported in some developing countries. Some of the reasons for vaccine failure in developing countries include; poor seroconversion, questionable potency of vaccines due to problem with cold chain that ultimately affect the quality of vaccine and waning immunity. To prevent outbreaks of measles in developing countries, there is needfor second dose of measles vaccine to take care of vaccine failures. This measure is necessary even in countries where there is high coverage with one dose of measles vaccine. The relevant International Agencies need to develop second dose measles vaccination policiesfor developing countries as obtains in some developed countries. Key words: Measles vaccine, failure, developing countries

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.

The genetic basis for measles vaccine failure

The genetic basis for measles vaccine failure

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.

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.

Acute disseminated encephalomyelitis with probable measles vaccine failure

The patient is a 10-year-old male who experienced somnolence and incomplete quadriplegia after headache and vomiting, without exanthema, for 3 days. The clinical course and magnetic resonance imaging findings of the brain and spinal cord were compatible with acute disseminated encephalomyelitis. The serologic examination revealed that the patient had rubeola because titers of IgM and IgG antibody to measles virus measured by enzyme immunoassay were 0.91 and 40 (cutoff = 0.80 and 2), respectively, at 5 weeks after the onset, the IgM titer had become negative (0.56), and the IgG titer had decreased to 17.7 at 13 weeks after the onset. Because the patient had received a measles-mumps-rubella vaccine at 12 months of age, the acute disseminated encephalomyelitis was thought to be attributed to the modified measles resulting from measles vaccine failure.

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.

Age for Routine Administration of the Second Dose of Measles–Mumps–Rubella Vaccine

This Policy Statement was retired May 2009. The purpose of this statement is to inform physicians of a modification in the recommendation of the appropriate age for routine administration of the second dose of measles–mumps–rubella (MMR) vaccine. The implementation of the two-dose measles vaccine schedule has improved the control of measles, but some outbreaks continue to occur in school children, although ≥95% of children in school have received one dose of vaccine. Because most measles vaccine failures are attributable to failure to respond to the first dose, that all children receive two doses of measles-containing vaccine is essential for the control of measles. Routine administration of the second dose of MMR vaccine at school entry (4 to 6 years of age) will help prevent school-based outbreaks. Physicians should continue to review the records of all children 11 to 12 years of age to be certain that they have received two doses of MMR vaccine after their first birthday. Documenting that all school children have received two doses of measles-containing vaccine by the year 2001 will help ensure the elimination of measles in the United States and contribute to the global effort to control and possibly eradicate measles.