Longitudinal immune profiling after radiation-attenuated sporozoite vaccination reveals coordinated immune processes correlated with malaria protection

Abstract

BackgroundIdentifying immune processes required for liver-stage sterilizing immunity to malaria remains an open problem. The IMRAS trial comprised 5x immunizations with radiation-attenuated sporozoites resulting in 55% protection from subsequent challenge.MethodsTo identify correlates of vaccination and protection, we performed detailed systems immunology longitudinal profiling of the entire trial time course including whole blood transcriptomics, detailed PBMC cell phenotyping and serum antigen array profiling of 11 IMRAS radiation-attenuated sporozoite (RAS) vaccinees at up to 21 timepoints each.ResultsRAS vaccination induced serum antibody responses to CSP, TRAP, and AMA1 in all vaccinees. We observed large numbers of differentially expressed genes associated with vaccination response and protection, with distinctly differing transcriptome responses elicited after each immunization. These included inflammatory and proliferative responses, as well as increased abundance of monocyte and DC subsets after each immunization. Increases in Vδ2 γδ; T cells and MAIT cells were observed in response to immunization over the course of study, and CD1c+ CD40+ DC abundance was significantly associated with protection. Interferon responses strongly differed between protected and non-protected individuals with high interferon responses after the 1st immunization, but not the 2nd-5th. Blood transcriptional interferon responses were correlated with abundances of different circulating classical and non-classical monocyte populations.ConclusionsThis study has revealed multiple coordinated immunological processes induced by vaccination and associated with protection. Our work represents the most detailed immunological profiling of a RAS vaccine trial performed to date and will guide the design and interpretation of future malaria vaccine trials.

Human transcriptional signature of protection after Plasmodium falciparum immunization and infectious challenge via mosquito bites

“…Previous studies have reported on the whole blood transcriptional response after immunization with irradiated SPZ ( Pf SPZ). 24 , 26 To potentially increase the resolution of the analysis, we focused our analysis of the transcriptional response on antigen-specific cells by stimulating cells in vitro with NF54 Pf- SPZ or media control and then magnetically enriching for CD69 + cells, an activation marker that can be used as surrogate marker for antigen-specific cells. 27 After quality control and filtering out lowly expressed genes, 15,923 genes survived for further analysis.…”

“…Similar analyses have been done following the five successive immunization sessions, and the transcriptome responses to RAS differed strongly after each immunization. 26 Notably, as opposed to the first immunization session, the subsequent four immunizations revealed a positive correlation between IFN-associated gene transcription and protection. Nevertheless, the authors described that the biggest factor driving variability in transcriptome and circulating cell phenotype populations was inter-subject variability.…”

“…Nevertheless, the authors described that the biggest factor driving variability in transcriptome and circulating cell phenotype populations was inter-subject variability. 26 Our approach, using in vitro SPZ-stimulation and sorting CD69 + activated cells, was designed to study the specific transcriptomic response to Plasmodium SPZ induced by RAS immunization. Ex vivo transcriptomic signatures reflect the state of the host, whereas antigen-specific stimulation allows the identification of transcriptional events triggered in antigen-specific lymphocytes that could occur in vivo after encounter with the pathogen.…”

γδ T‐cell–mediated immune responses to malaria

“…CHMI could help better understand naturally acquired immunity as well as the development of protective immunity. Indeed, immunization studies of chemically attenuated whole PfSPZ vaccine and radiation‐attenuated sporozoite vaccination 16 revealed induced overall proportion of CD3 + γδ T cells, especially Vγ9Vδ2 T cells 17–19 . CHMI after irradiation‐attenuated PfSPZ vaccination in previously malaria‐exposed population expanded Vδ1 + and Vδ1 − Vδ2 − T cells with multiple clonotypes during blood‐stage Plasmodium infection 20 .…”

Sporozoite immunization: innovative translational science to support the fight against malaria

“…To date, however, the protective antigen repertoire has not been identified, motivating an ongoing effort to use reagents from individuals immunized with PfSPZ for antigen discovery [ 50 , 63 , 64 ]. The role of γδ T cells, particularly the Vδ2 subset [ 4 , 65 – 69 ], and of NK cells [ 70 , 71 ] in the induction of protective immunity by PfSPZ vaccines are important areas of ongoing investigation. A reappraisal of the role of antibodies is also underway [ 72 – 74 ], with the tools of systems serology offering an innovative approach to elucidate antibody-associated protective mechanisms following SPZ immunization [ 72 , 73 ].…”