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Irradiated sporozoite vaccination induces sex-specific immune responses and protection against malaria in mice.

ABSTRACT: In both preclinical animal studies and human clinical trials, adult females tend to develop greater adaptive immune responses than males following receipt of either viral or bacterial vaccines. While there is currently no approved malaria vaccine, several anti-sporozoite vaccines, including RTS,S/AS01 and attenuated sporozoite vaccines, are in development, but the impact of sex and age on their efficacy remains undefined. To examine sex differences in the efficacy of anti-sporozoite stage malaria vaccination, adult (10?weeks of age) or juvenile (11?days of age) male and female C3H mice were twice vaccinated with irradiated transgenic Plasmodium berghei sporozoites expressing the P. falciparum circumsporozoite (CSP) protein and 45?days post boost vaccination, mice were challenged with transgenic P. berghei via mosquito bite or intradermal challenge. Immunization with irradiated sporozoites resulted in greater protection against challenge in adult females, which was associated with greater anti-CSP antibody production and avidity, as well as greater hepatic, but not splenic, CD8⁺ T cell IFN? production in adult females than adult males. No sex differences in adaptive immune responses or protection were observed in mice vaccinated prior to puberty, suggesting a role for sex steroid hormones. Depletion of testosterone in males increased, whereas rescue of testosterone decreased, anti-CSP antibody production, the number of antigen-specific CD8⁺ T cells isolated from the liver, and protection following parasite challenge. Conversely, depletion of sex steroids in female mice did not alter vaccine-induced responses or protection following challenge. These data suggest that elevated testosterone concentrations in males reduce adaptive immunity and contribute to sex differences in malaria vaccine efficacy.

SUBMITTER: Vom Steeg LG

PROVIDER: S-EPMC7862922 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Irradiated sporozoite vaccination induces sex-specific immune responses and protection against malaria in mice.

Vom Steeg Landon G LG Flores-Garcia Yevel Y Zavala Fidel F Klein Sabra L SL

Vaccine 20190628 32

In both preclinical animal studies and human clinical trials, adult females tend to develop greater adaptive immune responses than males following receipt of either viral or bacterial vaccines. While there is currently no approved malaria vaccine, several anti-sporozoite vaccines, including RTS,S/AS01 and attenuated sporozoite vaccines, are in development, but the impact of sex and age on their efficacy remains undefined. To examine sex differences in the efficacy of anti-sporozoite stage malari ...[more]

PMID: 31262583

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Project description:Understanding immune mechanisms that mediate malaria protection is critical for improving vaccine development. Vaccination with radiation-attenuated Plasmodium falciparum sporozoites (PfRAS) induces high level of sterilizing immunity against malaria and serves as a valuable tool for the study of protective mechanisms. To identify vaccine-induced and protection-associated responses during malarial infection, we performed transcriptome profiling of whole blood and in-depth cellular profiling of PBMCs from volunteers who received either PfRAS or noninfectious mosquito bites, followed by controlled human malaria infection (CHMI) challenge. In-depth single-cell profiling of cell subsets that respond to CHMI in mock-vaccinated individuals showed a predominantly inflammatory transcriptome response. Whole blood transcriptome analysis revealed that gene sets associated with type I and II interferon and NK cell responses were increased in prior to CHMI while T and B cell signatures were decreased as early as one day following CHMI in protected vaccinees. In contrast, non-protected vaccinees and mock-vaccinated individuals exhibited shared transcriptome changes after CHMI characterized by decreased innate cell signatures and inflammatory responses. Additionally, immunophenotyping data showed different induction profiles of vδ2+ γδ T cells, CD56+ CD8+ T effector memory (Tem) cells, and non-classical monocytes between protected vaccinees and individuals developing blood-stage parasitemia, following treatment and resolution of infection. Our data provide key insights in understanding immune mechanistic pathways of PfRAS-induced protection and infective CHMI. We demonstrate that vaccine-induced immune response is heterogenous between protected and non-protected vaccinees and that inducted-malaria protection by PfRAS is associated with early and rapid changes in interferon, NK cell and adaptive immune responses. Trial Registration: ClinicalTrials.gov NCT01994525.

Dataset Information

Irradiated sporozoite vaccination induces sex-specific immune responses and protection against malaria in mice.

Publications

Irradiated sporozoite vaccination induces sex-specific immune responses and protection against malaria in mice.

Similar Datasets

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