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Genetic associations with a fever after measles-containing vaccines.

ABSTRACT: Children have elevated fever risk 1 to 2 weeks after the first dose of a measles-containing vaccine (MCV), which is likely affected by genetic, immunologic, and clinical factors. Fever after MCV is associated with febrile seizures, though may also be associated with higher measles antibody titers. This exploratory study investigated genetic and immunologic associations with a fever after MCV. Concurrent with a randomized Phase 3 clinical trial of 12-15-month-olds who received their first measles-mumps-rubella (MMR) vaccine in which parents recorded post-vaccination temperatures daily, we consented a subset to collect additional blood and performed human leukocyte antigens (HLA) typing. Association between fever 5-12 days after MMR ("MMR-associated") and HLA type was assessed using logistic regression. We compared 42-day post-vaccination geometric mean titers (GMT) to measles between children who did and did not have fever using a t-test. We enrolled 86 children and performed HLA typing on 82; 13 (15.1%) had MMR-associated fever. Logistic regressions identified associations between MMR-associated fever and HLA Class I loci A-29:02 (P = .036), B-57:01 (P = .018), C-06:02 (P = .006), C-14:02 (P = .022), and Class II loci DRB1-15 (P = .045). However, Bonferroni's adjustment for multiple comparisons suggests that these associations could have been due to chance. Ninety-eight percent of children had protective antibody titers to measles; however, GMT was higher among those with fever compared with children without fever (P = .006). Fever after the measles vaccine correlated with genetic factors and higher immune response. This study suggests a possible genetic susceptibility to MMR-associated fever.

SUBMITTER: Klein NP

PROVIDER: S-EPMC8115494 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:OBJECTIVES: To evaluate the effects on non-specific and all cause mortality, in children under 5, of Bacillus Calmette-Guérin (BCG), diphtheria-tetanus-pertussis (DTP), and standard titre measles containing vaccines (MCV); to examine internal validity of the studies; and to examine any modifying effects of sex, age, vaccine sequence, and co-administration of vitamin A. DESIGN: Systematic review, including assessment of risk of bias, and meta-analyses of similar studies. STUDY ELIGIBILITY CRITERIA: Clinical trials, cohort studies, and case-control studies of the effects on mortality of BCG, whole cell DTP, and standard titre MCV in children under 5. DATA SOURCES: Searches of Medline, Embase, Global Index Medicus, and the WHO International Clinical Trials Registry Platform, supplemented by contact with experts in the field. To avoid overlap in children studied across the included articles, findings from non-overlapping birth cohorts were identified. RESULTS: Results from 34 birth cohorts were identified. Most evidence was from observational studies, with some from short term clinical trials. Most studies reported on all cause (rather than non-specific) mortality. Receipt of BCG vaccine was associated with a reduction in all cause mortality: the average relative risks were 0.70 (95% confidence interval 0.49 to 1.01) from five clinical trials and 0.47 (0.32 to 0.69) from nine observational studies at high risk of bias. Receipt of DTP (almost always with oral polio vaccine) was associated with a possible increase in all cause mortality on average (relative risk 1.38, 0.92 to 2.08) from 10 studies at high risk of bias; this effect seemed stronger in girls than in boys. Receipt of standard titre MCV was associated with a reduction in all cause mortality (relative risks 0.74 (0.51 to 1.07) from four clinical trials and 0.51 (0.42 to 0.63) from 18 observational studies at high risk of bias); this effect seemed stronger in girls than in boys. Seven observational studies, assessed as being at high risk of bias, have compared sequences of vaccines; results of a subset of these suggest that administering DTP with or after MCV may be associated with higher mortality than administering it before MCV. CONCLUSIONS: Evidence suggests that receipt of BCG and MCV reduce overall mortality by more than would be expected through their effects on the diseases they prevent, and receipt of DTP may be associated with an increase in all cause mortality. Although efforts should be made to ensure that all children are immunised on schedule with BCG, DTP, and MCV, randomised trials are needed to compare the effects of different sequences.

Project description:Host antiviral genes are important regulators of antiviral immunity and plausible genetic determinants of immune response heterogeneity after vaccination. We genotyped and analyzed 307 common candidate tagSNPs from 12 antiviral genes in a cohort of 745 schoolchildren immunized with two doses of measles-mumps-rubella (MMR) vaccine. Associations between SNPs/haplotypes and measles virus-specific immune outcomes were assessed using linear regression methodologies in Caucasians and African-Americans. Genetic variants within the DDX58/RIG-I gene, including a coding polymorphism (rs3205166/Val800Val), were associated as single-SNPs (p≤0.017; although these SNPs did not remain significant after correction for false discovery rate/FDR) and in haplotype-level analysis, with measles-specific antibody variations in Caucasians (haplotype allele p-value=0.021; haplotype global p-value=0.076). Four DDX58 polymorphisms, in high LD, demonstrated also associations (after correction for FDR) with variations in both measles-specific IFN-γ and IL-2 secretion in Caucasians (p≤0.001, q=0.193). Two intronic OAS1 polymorphisms, including the functional OAS1 SNP rs10774671 (p=0.003), demonstrated evidence of association with a significant allele-dose-related increase in neutralizing antibody levels in African-Americans. Genotype and haplotype-level associations demonstrated the role of ADAR genetic variants, including a non-synonymous SNP (rs2229857/Arg384Lys; p=0.01), in regulating measles virus-specific IFN-γ Elispot responses in Caucasians (haplotype global p-value=0.017). After correction for FDR, 15 single-SNP associations (11 SNPs in Caucasians and 4 SNPs in African-Americans) still remained significant at the q-value<0.20. In conclusion, our findings strongly point to genetic variants/genes, involved in antiviral sensing and antiviral control, as critical determinants, differentially modulating the adaptive immune responses to live attenuated measles vaccine in Caucasians and African-Americans.

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Genetic associations with a fever after measles-containing vaccines.

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