Associations between cytokine/cytokine receptor single nucleotide polymorphisms and humoral immunity to measles, mumps and rubella in a Somali population.
ABSTRACT: We genotyped a Somali population (n = 85; age < or =30 years) for 617 cytokine and cytokine receptor single nucleotide polymorphisms (SNPs) using Illumina GoldenGate genotyping to determine associations with measles, mumps and rubella immunity. Overall, 61 significant associations (P < or = 0.01) were found between SNPs belonging to cytokine receptor genes regulating T helper (Th)1 (IL12RB2, IL2RA and B) and Th2 (IL4R and IL10RB) immunity, and cytokine (IL1B, TNFA, IL6 and IFNB1) and cytokine receptor (IL1RA, IFNAR2, IL18R1, TNFRSF1A and B) genes regulating innate immunity and variations in antibody levels to measles, mumps and/or rubella. SNPs within two major inflammatory cytokine genes, TNFA and interleukin (IL) 6, showed associations with measles-specific antibodies. Specifically, the minor allele variant of rs1799964 (TNFA -1211 C>T) was associated with primarily seronegative values (median enzyme immunoassay index values < or =0.87; P = 0.002; q = 0.23) in response to measles disease and/or vaccination. A heterozygous variant CT for rs2069849 (IL6 +4272C>T; Phe201Phe) was also associated with seronegative values and a lower median level of antibody response to measles disease and/or vaccination (P = 0.004; q = 0.36) or measles vaccination alone (P = 0.008). Several SNPs within the coding and regulatory regions of cytokine and cytokine receptor genes showed associations with mumps and rubella antibody levels but were less informative as strong linkage disequilibrium patterns and lower frequencies for minor alleles were observed among these SNPs. Our study identifies specific SNPs in innate immune response genes that may play a role in modulating antibody responses to measles vaccination and/or infection in Somali subjects.
Project description:Mumps outbreaks and breakthrough infections of measles and rubella have raised concerns about waning of vaccine-induced immunity after two doses of measles-mumps-rubella (MMR) vaccination. In the present follow-up study, serum IgG antibodies against mumps, measles and rubella, as well as the functional neutralizing antibodies against both the mumps vaccine strain and mumps outbreak strains were measured longitudinally in young adults that received a third MMR (MMR3) dose. The mumps-specific IgG and virus neutralizing antibody levels at 3 years after vaccination were still elevated compared to pre-vaccination antibody levels, although the differences were smaller than at earlier timepoints. Interestingly, subjects with low antibody levels to mumps before vaccination benefited the most as they showed the strongest antibody increase after an MMR3 dose. Three years after an MMR3 dose, all subjects had antibody levels to measles and rubella above the internationally agreed antibody cutoff levels for clinical protection. Our data support the recommendation that an MMR3 dose may provide additional protection for those that have become susceptible to mumps virus infection during outbreaks. MMR3 also resulted in an increase in anti-measles and rubella antibody levels that lasted longer than might have been expected.
Project description:Our objective was to replicate previously reported associations between cytokine and cytokine receptor SNPs and humoral and CMI (cell-mediated immune) responses to measles vaccine. All subjects (n=758) received two doses of MMR (measles/mumps/rubella) vaccine. From these subjects, candidate cytokine and cytokine receptor SNPs were genotyped and analyzed in 29-30 subjects falling into one of four "extreme" humoral (Ab(high/low)) and CMI (CMI(high/low)) response quadrants. Associations between seven SNPs (out of 11 in the discovery study) and measles-specific neutralizing antibody levels and IFN-? ELISPOT responses were evaluated using chi-square tests. We found one replicated association for SNP rs372889 in the IL12RB1 gene (P=0.03 for Ab(high)CMI(high) vs. Ab(low)CMI(low)). Our findings demonstrate the importance of replicating genotypic-phenotypic associations, which can be achieved using immunophenotypic extremes and smaller sample sizes. We speculate that IL12RB1 polymorphisms may affect IL-12 and IL-23 binding and downstream effects, which are critical cytokines in the CMI response to measles vaccine.
Project description:After the global implementation of national immunization programs for prevention of measles, mumps, and rubella (MMR), the prevalences of protective antibodies to these viruses are high in general population. However, there are limited data among human immunodeficiency virus (HIV)-1 infected individuals. This study aimed to determine the seroprevalence of antibodies to these viruses, and the serologic responses after vaccination among HIV-infected adults in Northern Thailand.A cross-sectional study was conducted in 500 HIV-infected adults, aged 20-59 years, receiving combination antiretroviral therapy, CD4 cell count ?200 cells/mm(3), and plasma HIV-1 RNA <50 copies/mL, and 132 HIV-uninfected controls, aged 20-59 years, at Chiang Mai University Hospital during July and August 2011. Prevalences of protective antibodies to these viruses as well as serologic responses after MMR vaccination in those without protective antibody to at least one of the three viruses were compared between groups.The prevalences of protective antibodies to measles, mumps, and rubella were 94.2, 55.0, and 84.6 % among HIV-infected adults, and 97.7, 67.5, and 89.4 % among HIV-uninfected controls, respectively. The prevalence of protective antibody to mumps was significantly lower in HIV-infected adults (p-value?=?0.010). MMR vaccination was done in 249 HIV-infected and 46 HIV-uninfected controls; at week 8 to 12 after vaccination, the seroprotective rates against measles, mumps, and rubella in HIV-infected adults were 96.4, 70.7, and 98.0 %, respectively, whereas those in HIV-uninfected controls were 100, 87, and 100 %, respectively. No serious adverse effects were observed.In contrast to measles and rubella, the prevalence of protective antibody to mumps was low in both HIV-infected adults and HIV-uninfected controls in northern Thailand. The seroprotective rates after MMR vaccination in both groups were considerably high, except only for mumps. Therefore, MMR vaccination should be considered in all HIV-infected adults receiving antiretroviral therapy with undetectable plasma HIV-1 RNA and CD4 cell count ?200 cells/mm(3).ClinicalTrials.gov: NCT02724852 , registered on March 31, 2016.
Project description:Single-nucleotide polymorphisms (SNPs) in candidate immune response genes were evaluated for associations with measles- and rubella-specific neutralizing antibodies, interferon (IFN)-?, and interleukin (IL)-6 secretion in two separate association analyses in a cohort of healthy immunized subjects. We identified six SNP associations shared between the measles-specific and rubella-specific immune responses, specifically neutralizing antibody titers (DDX58), secreted IL-6 (IL10RB, IL12B), and secreted IFN-? (IFNAR2, TLR4). An intronic SNP (rs669260) in the antiviral innate immune receptor gene, DDX58, was significantly associated with increased neutralizing antibody titers for both measles and rubella viral antigens post-MMR vaccination (p values 0.02 and 0.0002, respectively). Significant associations were also found between IL10RB (rs2284552; measles study p value 0.006, rubella study p value 0.00008) and IL12B (rs2546893; measles study p value 0.005, rubella study p value 0.03) gene polymorphisms and variations in both measles- and rubella virus-specific IL-6 responses. We also identified associations between individual SNPs in the IFNAR2 and TLR4 genes that were associated with IFN-? secretion for both measles and rubella vaccine-specific immune responses. These results are the first to indicate that there are SNP associations in common across measles and rubella vaccine immune responses and that SNPs from multiple genes involved in innate and adaptive immune response regulation may contribute to the overall human antiviral response.
Project description:An effective immune response to vaccination is, in part, a complex interaction of alleles of multiple genes regulating cytokine networks. We conducted a genotyping study of Th1/Th2/inflammatory cytokines/cytokine receptors in healthy children (n = 738, 11-19 years) to determine associations between individual single-nucleotide polymorphisms (SNPs)/haplotypes and immune outcomes after two doses of rubella vaccine. SNPs (n = 501) were selected using the ldSelect-approach and genotyped using Illumina GoldenGate and TaqMan assays. Rubella-IgG levels were measured by immunoassay and secreted cytokines by ELISA. Linear regression and post hoc haplotype analyses were used to determine associations between single SNPs/haplotypes and immune outcomes. Increased carriage of minor alleles for the promoter SNPs (rs2844482 and rs2857708) of the TNFA gene were associated with dose-related increases in rubella antibodies. IL-6 secretion was co-directionally associated (p < or = 0.01) with five intronic SNPs in the TNFRSF1B gene in an allele dose-related manner, while five promoter/intronic SNPs in the IL12B gene were associated with variations in IL-6 secretion. TNFA haplotype AAACGGGGC (t-statistic = 3.32) and IL12B promoter haplotype TAG (t-statistic = 2.66) were associated with higher levels of (p < or = 0.01) rubella-IgG and IL-6 secretion, respectively. We identified individual SNPs/haplotypes in TNFA/TNFRSF1B and IL12B genes that appear to modulate immunity to rubella vaccination. Identification of such "genetic fingerprints" may predict the outcome of vaccine response and inform new vaccine strategies.
Project description:Measles and rubella are highly contagious viral diseases transmitted via respiratory secretions and aerosolized droplets. Thailand has implemented universal vaccination against measles using the monovalent measles (M) or the trivalent measles-mumps-rubella (MMR) vaccine for the past 30 years. Nevertheless, incidence of measles and rubella remains in some parts of the country. We conducted a seroprevalence study to evaluate the antibodies to measles and rubella virus among Thais of all ages and to determine pre-existing immunity resulting from either vaccination and/or natural exposure. A total of 1,781 serum samples collected in 2014 was tested for IgG to measles and rubella virus by commercial enzyme-linked immunosorbent assays (ELISA). Percentages of individuals with protective antibody levels and the geometric mean concentrations (GMC) of IgG in each age group were analysed. The GMC of anti-measles IgG and anti-rubella IgG were 653.7 IU/L (95% confidence interval (CI); 555.9-751.4) and 39.5 IU/mL (95% CI;35.0-43.9), respectively. Thais between the ages of six months and 25 years did not demonstrate sufficient protective herd immunity for measles. This observation is consistent with the recent measles outbreaks in this age group. Lower prevalence of immunity against rubella was found among children ages 5-6 years who may not have completed vaccination as infants. Our findings identify gaps in rubella and measles immunity in specific age groups and support recommendations for catch-up MMR vaccination in individuals 30 years of age or younger.
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.
Project description:Immunity to measles, mumps, rubella, and varicella-zoster viruses (VZV; MMRV) is a common condition of employment for health care workers (HCWs) to ensure compliance with national standards and state laws. When documentation of complete vaccination or laboratory-confirmed infection is not available, Advisory Committee on Immunization Practices (ACIP) criteria are used to guide vaccination or anti-MMRV IgG testing. We assessed the performance of the BioPlex 2200 MMRV IgG multiplex flow immunoassay (MFI; Bio-Rad Laboratories, Hercules, CA) and matched immunofluorescence assays (IFAs; MBL Bion, Des Plaines, IL) in 220 HCWs categorized by ACIP criteria for presumptive immunity to MMRV. Among HCWs presumptively immune to measles, mumps, rubella, and VZV, the Bio-Rad MFI was positive in 77.3, 85.4, 84.3, and 91.1% of HCWs, respectively. Comparatively, the Bion IFA was positive in 92.9, 91.1, and 93.5% of HCWs presumptively immune to measles, mumps, and VZV (a rubella IFA was unavailable). Among HCWs fully vaccinated against measles, mumps, and VZV, Bio-Rad MFI/Bion IFA positivity rates were 77.4%/93%, 84.8%/90.7%, and 54.5%/90.9%, respectively. The Bio-Rad MFI was positive in 83.7% of HCWs fully vaccinated against rubella. For HCWs whose last vaccination event occurred within 15?years of enrollment, 83.3, 93.3, and 74.2% were positive by the Bio-Rad measles, mumps, and rubella IgG MFIs, respectively. We show significantly decreased Bio-Rad MFI sensitivity for detection of anti-measles and anti-mumps IgG-class antibodies in presumptively immune or fully vaccinated HCWs. Although negative results typically prompt revaccination, failure to recognize presumptive immunity in individuals unable to receive live, attenuated vaccines may have employment implications.
Project description:Although high measles, mumps, and rubella (MMR) vaccination coverage has been successful in dramatically reducing mumps disease in the United States, mumps (re)infections occasionally occur in individuals who have been either previously vaccinated or naturally infected. Standard diagnostics that detect virus or virus-specific antibody are dependable for confirming primary mumps infection in immunologically naïve persons, but these methods perform inconsistently for individuals with prior immune exposure. We hypothesized that detection of activated mumps-specific antibody-secreting B cells (ASCs) by enzyme-linked immunospot (ELISPOT) assay could be used as a more reliable diagnostic. To test this, a time course of virus-specific ASC responses was measured by ELISPOT assay following MMR vaccination of 16 previously vaccinated or naturally exposed adult volunteers. Mumps-specific ASCs were detectable in 68% of these individuals at some point during the first 3 weeks following revaccination. In addition, mumps-specific ASCs were detected in 7/7 previously vaccinated individuals who recently had been infected as part of a confirmed mumps outbreak. These data suggest that ELISPOT detection of mumps-specific ASCs has the potential for use as an alternative method of diagnosis when suspect cases cannot be confirmed by detection of IgM or virus. In addition, it was determined that mumps-specific memory B cells are detected at a much lower frequency than measles- or rubella-specific cells, suggesting that mumps infection may not generate robust B-cell memory.
Project description:Susceptibility to encapsulated bacteria is well known in sickle cell disease (SCD). Hydroxyurea use is common in adults and children with SCD, but little is known about hydroxyurea's effects on immune function in SCD. Because hydroxyurea inhibits ribonucleotide reductase, causing cell cycle arrest at the G1-S interface, we postulated that hydroxyurea might delay transition from naive to memory T cells, with inhibition of immunologic maturation and vaccine responses.T-cell subsets, naive and memory T cells, and antibody responses to pneumococcal and measles, mumps, and rubella vaccines were measured among participants in a multicenter, randomized, double-blind, placebo-controlled trial of hydroxyurea in infants and young children with SCD (BABY HUG).Compared with placebo, hydroxyurea treatment resulted in significantly lower total lymphocyte, CD4, and memory T-cell counts; however, these numbers were still within the range of historical healthy controls. Antibody responses to pneumococcal vaccination were not affected, but a delay in achieving protective measles antibody levels occurred in the hydroxyurea group. Antibody levels to measles, mumps, and rubella showed no differences between groups at exit, indicating that effective immunization can be achieved despite hydroxyurea use.Hydroxyurea does not appear to have significant deleterious effects on the immune function of infants and children with SCD. Additional assessments of lymphocyte parameters of hydroxyurea-treated children may be warranted. No changes in current immunization schedules are recommended; however, for endemic disease or epidemics, adherence to accelerated immunization schedules for the measles, mumps, and rubella vaccine should be reinforced.