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Computational investigations of the immune response to repeated influenza infections and vaccinations.

ABSTRACT: Previous studies have shown that repeated influenza vaccination can enhance susceptibility to subsequent infection with a drifted influenza virus strain. This paper seeks to further understanding of the interactions between influenza viruses and specific immune cells that accompany this phenomenon. The paper argues that repeated vaccination increases susceptibility to infection only in the context of a residual immunity induced by prior vaccination or infection. The results of computational analysis indicate that this is a dynamic consequence of interactions between vaccines, influenza viruses and specific immune cells. In particular, mathematical modelling was used to show that in the presence of residual immunity conferred by a vaccine administered in Canada in the 2013-2014 influenza season, the 2014-2015 season vaccine enhanced susceptibility to infection. Such infection enhancement occurs when the 2014-2015 vaccine boosts suppressive T-regulatory cells induced by the 2013-2014 vaccine, decreasing the strength of antibody responses to the infecting strain. Overall, the study suggests probable characteristics of infecting viruses and vaccines that make repeated influenza infections and vaccinations detrimental.

SUBMITTER: Adabor ES

PROVIDER: S-EPMC8074957 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The high genetic diversity of influenza viruses means that traditional serological assays have too low throughput to measure serum antibody neutralization titers against all relevant strains. To overcome this challenge, we have developed a sequencing-based neutralization assay that simultaneously measures titers against many viral strains using small serum volumes via a workflow similar to traditional neutralization assays. The key innovation is to incorporate unique nucleotide barcodes into the hemagglutinin (HA) genomic segment, and then pool viruses with numerous different barcoded HA variants and quantify infectivity of all of them simultaneously using next-generation sequencing. With this approach, a single researcher performed the equivalent of 2,880 traditional neutralization assays (80 serum samples against 36 viral strains) in approximately one month. We applied the sequencing-based assay to quantify the impact of influenza vaccination on neutralization titers against recent human H1N1 strains for individuals who had or had not also received a vaccine in the previous year. We found that the viral strain specificities of the neutralizing antibodies elicited by vaccination vary among individuals, and that vaccination induced a smaller increase in titers for individuals who had also received a vaccine the previous year-although the titers six months after vaccination were similar in individuals with and without the previous-year vaccination. We also identified a subset of individuals with low titers to a subclade of recent H1N1 even after vaccination. This study demonstrates the utility of high-throughput sequencing-based neutralization assays that enable titers to be simultaneously measured against many different viral strains. We provide a detailed experimental protocol (DOI: https://dx.doi.org/10.17504/protocols.io.kqdg3xdmpg25/v1) and a computational pipeline (https://github.com/jbloomlab/seqneut-pipeline) for the sequencing-based neutralization assays to facilitate the use of this method by others.

Project description:BackgroundImmune responses to pediatric vaccinations have been reported to differ according to sex. Such sex-differential responses may become more pronounced during adolescence due to hormonal differences. We investigated whether the vaccine response following primary vaccination against meningococcal serogroup A (MenA), MenW and MenY and booster vaccination against MenC differed between girls and boys using data from two clinical studies.MethodsChildren aged 10, 12, and 15 years, who had been primed with MenC vaccination between 14 months and 6 years of age, received a booster MenC vaccination or MenACWY vaccination. Polysaccharide-specific IgG concentrations and functional antibody titers [determined with the serum bactericidal antibody (SBA) assay] were measured at baseline, 1 month, 1 year, and 3 years (only MenC group) after vaccination. We calculated geometric mean concentrations and titers (GMC and GMT) ratios for girls vs. boys adjusted for age group. Additionally, we compared the proportion protected individuals between girls and boys at all timepoints.ResultsThis study included 342 girls and 327 boys from two clinical trials. While MenAWY antibody levels did not differ consistently 1 month after vaccination, all GMC- and GMT-ratios were in favor of girls 1 year after vaccination [range: 1.31 (1.02-1.70) for MenA IgG to 1.54 (1.10-2.16) for MenW IgG]. Overall, MenC antibody levels were slightly higher in girls at all postvaccination timepoints (GMC- and GMT-ratios: 1.16/1.17 at 1 month, 1.16/1.22 at 1 year and 1.12/1.15 3 years postvaccination). Higher MenC antibody levels were observed in 12- and 15-year-old girls compared to boys of the same age, whereas 10-year-old boys and girls had similar antibody levels. The percentage of participants protected (SBA titer ≥ 8) was very high (95-100%) at all timepoints, and did not differ significantly between boys and girls.ConclusionAntibody responses were higher in girls than in boys for all serogroups at most timepoints after primary MenAWY vaccination and booster MenC vaccination. The differences in average titers were however small and the percentage participants with protective titers was very high for both sexes.

Project description:BackgroundRacial/ethnic disparities in rates of influenza vaccinations in the US remain an issue even among those with access, no out-of-pocket costs, and after adjusting for confounders. We used an approach called the Oaxaca-Blinder (OB) decomposition method to ascertain the contribution of covariates individually and in aggregate to the racial disparity in influenza vaccination.MethodsWe included members > = 18 years of age as of 05/01/2014 with continuous enrollment through 04/30/2015. Influenza vaccination was defined by diagnosis, procedure, or medication codes, or documentation in the immunization table. Characteristics were reported by race. Logistic regression models estimated the odds of vaccination associated with: (1) race; and (2) covariates stratified by race. The Oaxaca-Blinder (OB) method calculated the contribution of covariates to the difference or disparity in vaccination between Blacks and Whites.ResultsWe found that among adults, 44% were vaccinated; 55% were Black; and 45% were White. Black members have 42% lower odds of vaccination than White members. The contribution of the differences in the average value of the study covariates between Black and White members (the OB covariate effect) accounted for 29% of the racial disparity. The contributions to the total White-Black disparity in vaccination included: age (16%), neighborhood median income (11%), and registration on the online patient portal (13%). The contribution of the differences in how the covariates impact vaccination (OB coefficient effect) accounted for 71% of the disparity in vaccination between Blacks and Whites.ConclusionIn conclusion, equalizing average covariate values in Blacks and Whites could reduce the racial disparity in influenza vaccination by 29%. For health system vaccine campaigns, improving registration on the patient portal may be a target component of an effective system-level strategy to reduce racial disparities in vaccination. Additional information on patient-centered factors could further improve the value of the OB approach.

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Computational investigations of the immune response to repeated influenza infections and vaccinations.

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