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V?2+ T cell response to malaria correlates with protection from infection but is attenuated with repeated exposure.

ABSTRACT: V?2⁺ ?? T cells are semi-innate T cells that expand markedly following P. falciparum (Pf) infection in naïve adults, but are lost and become dysfunctional among children repeatedly exposed to malaria. The role of these cells in mediating clinical immunity (i.e. protection against symptoms) to malaria remains unclear. We measured V?2⁺ T cell absolute counts at acute and convalescent malaria timepoints (n?=?43), and V?2⁺ counts, cellular phenotype, and cytokine production following in vitro stimulation at asymptomatic visits (n?=?377), among children aged 6 months to 10 years living in Uganda. Increasing age was associated with diminished in vivo expansion following malaria, and lower V?2 absolute counts overall, among children living in a high transmission setting. Microscopic parasitemia and expression of the immunoregulatory markers Tim-3 and CD57 were associated with diminished V?2⁺ T cell pro-inflammatory cytokine production. Higher V?2 pro-inflammatory cytokine production was associated with protection from subsequent Pf infection, but also with an increased odds of symptoms once infected. V?2⁺ T cells may play a role in preventing malaria infection in children living in endemic settings; progressive loss and dysfunction of these cells may represent a disease tolerance mechanism that contributes to the development of clinical immunity to malaria.

SUBMITTER: Jagannathan P

PROVIDER: S-EPMC5597587 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Vδ2+ T cell response to malaria correlates with protection from infection but is attenuated with repeated exposure.

Jagannathan Prasanna P Lutwama Fredrick F Boyle Michelle J MJ Nankya Felistas F Farrington Lila A LA McIntyre Tara I TI Bowen Katherine K Naluwu Kate K Nalubega Mayimuna M Musinguzi Kenneth K Sikyomu Esther E Budker Rachel R Katureebe Agaba A Rek John J Greenhouse Bryan B Dorsey Grant G Kamya Moses R MR Feeney Margaret E ME

Scientific reports 20170913 1

Vδ2+ γδ T cells are semi-innate T cells that expand markedly following P. falciparum (Pf) infection in naïve adults, but are lost and become dysfunctional among children repeatedly exposed to malaria. The role of these cells in mediating clinical immunity (i.e. protection against symptoms) to malaria remains unclear. We measured Vδ2+ T cell absolute counts at acute and convalescent malaria timepoints (n = 43), and Vδ2+ counts, cellular phenotype, and cytokine pro ...[more]

PMID: 28904345

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Project description:RTS,S/AS01 (GSK) is the world's first malaria vaccine. However, despite initial efficacy of almost 70% over the first 6 months of follow-up, efficacy waned over time. A deeper understanding of the immune features that contribute to RTS,S/AS01-mediated protection could be beneficial for further vaccine development. In two recent controlled human malaria infection (CHMI) trials of the RTS,S/AS01 vaccine in malaria-naïve adults, MAL068 and MAL071, vaccine efficacy against patent parasitemia ranged from 44% to 87% across studies and arms (each study included a standard RTS,S/AS01 arm with three vaccine doses delivered in four-week-intervals, as well as an alternative arm with a modified version of this regimen). In each trial, RTS,S/AS01 immunogenicity was interrogated using a broad range of immunological assays, assessing cellular and humoral immune parameters as well as gene expression. Here, we used a predictive modeling framework to identify immune biomarkers measured at day-of-challenge that could predict sterile protection against malaria infection. Using cross-validation on MAL068 data (either the standard RTS,S/AS01 arm alone, or across both the standard RTS,S/AS01 arm and the alternative arm), top-performing univariate models identified variables related to Fc effector functions and titer of antibodies that bind to the central repeat region (NANP6) of CSP as the most predictive variables; all NANP6-related variables consistently associated with protection. In cross-study prediction analyses of MAL071 outcomes (the standard RTS,S/AS01 arm), top-performing univariate models again identified variables related to Fc effector functions of NANP6-targeting antibodies as highly predictive. We found little benefit-with this dataset-in terms of improved prediction accuracy in bivariate models vs. univariate models. These findings await validation in children living in malaria-endemic regions, and in vaccinees administered a fourth RTS,S/AS01 dose. Our findings support a "quality as well as quantity" hypothesis for RTS,S/AS01-elicited antibodies against NANP6, implying that malaria vaccine clinical trials should assess both titer and Fc effector functions of anti-NANP6 antibodies.

Dataset Information

V?2+ T cell response to malaria correlates with protection from infection but is attenuated with repeated exposure.

Publications

Vδ2+ T cell response to malaria correlates with protection from infection but is attenuated with repeated exposure.

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