Early Rise of Blood T Follicular Helper Cell Subsets and Baseline Immunity as Predictors of Persisting Late Functional Antibody Responses to Vaccination in Humans

Abstract

CD4+ T follicular helper cells (TFH) have been identified as the T-cell subset specialized in providing help to B cells for optimal activation and production of high affinity antibody. We recently demonstrated that the expansion of peripheral blood influenza-specific CD4+IL-21+ICOS1+ T helper (TH) cells, three weeks after vaccination, associated with and predicted the rise of protective neutralizing antibodies to avian H5N1. In this study, healthy adults were vaccinated with plain seasonal trivalent inactivated influenza vaccine (TIIV), MF59®-adjuvanted TIIV (ATIIV), or saline placebo. Frequencies of circulating CD4+ TFH1 ICOS+ TFH cells and H1N1-specific CD4+IL-21+ICOS+ CXCR5+ TFH and CXCR5- TH cell subsets were determined at various time points after vaccination and were then correlated with hemagglutination inhibition (HI) titers. All three CD4+ T cell subsets expanded in response to TIIV and ATIIV, and peaked 7 days after vaccination. To demonstrate that these TFH cell subsets correlated with functional antibody titers, we defined an alternative endpoint metric, decorrelated HI (DHI), which removed any correlation between day 28/day 168 and day 0 HI titers, to control for the effect of preexisting immunity to influenza vaccine strains. The numbers of total circulating CD4+ TFH1 ICOS+ cells and of H1N1-specific CD4+IL-21+ICOS+ CXCR5+, measured at day 7, were significantly associated with day 28, and day 28 and 168 DHI titers, respectively. Altogether, our results show that CD4+ TFH subsets may represent valuable biomarkers of vaccine-induced long-term functional immunity.Trial RegistrationClinicalTrials.gov NCT01771367

Induction of IL21 in Peripheral T Follicular Helper Cells Is an Indicator of Influenza Vaccine Response in a Previously Vaccinated HIV-Infected Pediatric Cohort

“…The data presented herein regarding pTfh cells are, however, in line with two recent studies showing the value of circulating IL-21-producing CD4 T cells as biomarkers for vaccine induced responses (4, 30). Our study is novel in that it demonstrates the importance of IL-21 gene expression in response to antigen stimulation in memory CD4 T cells even before vaccination rather than days to weeks after vaccination.…”

Cell-Mediated Immunity Generated in Response to a Purified Inactivated Vaccine for Dengue Virus Type 1

“…These observations are in agreement with prior studies of CMI generated by other inactivated vaccine products such as the seasonal influenza vaccine. Inactivated influenza vaccine titers have been shown to be positively correlated with measurable CD4 ϩ T cell parameters, including in vivo expansion of CD4 ϩ T cells proximal to vaccination (33), increases in abundances of both total and antigenspecific CD4 ϩ T cells with a follicular helper-like phenotype (CXCR5 ϩ /ICOS ϩ /IL-21 ϩ ) (34,35), and the maintenance of long-term influenza virus strain cross-reactive T cell responses following repeated vaccinations (36,37). Studies performed with other nonreplicating vaccine products, such as recombinant proteins and virus-like particles (VLPs), have demonstrated the presence of de novo-generated CD4 ϩ T helper responses that correlate directly with enhanced antibody titers and vaccine performance (38)(39)(40)(41)(42)(43)(44).…”

Regulatory T cell frequencies and phenotypes following anti-viral vaccination

“…Both vaccines contained the recommended composition for the 2012/2013 northern hemisphere influenza season (as described in [16]). Vaccine or placebo was administered intramuscularly (i.m., m .…”