IMRAS—A clinical trial of mosquito-bite immunization with live, radiation-attenuated P. falciparum sporozoites: Impact of immunization parameters on protective efficacy and generation of a repository of immunologic reagents

Abstract

Background Immunization with radiation-attenuated sporozoites (RAS) by mosquito bite provides >90% sterile protection against Plasmodium falciparum (Pf) malaria in humans. RAS invade hepatocytes but do not replicate. CD8+ T cells recognizing parasite-derived peptides on the surface of infected hepatocytes are likely the primary protective mechanism. We conducted a randomized clinical trial of RAS immunization to assess safety, to achieve 50% vaccine efficacy (VE) against controlled human malaria infection (CHMI), and to generate reagents from protected and non-protected subjects for future identification of protective immune mechanisms and antigens. Methods Two cohorts (Cohort 1 and Cohort 2) of healthy, malaria-naïve, non-pregnant adults age 18-50 received five monthly immunizations with infected (true-immunized, n = 21) or noninfected (mock-immunized, n = 5) mosquito bites and underwent homologous CHMI at 3

Systems analysis of immune responses to attenuated P. falciparum malaria sporozoite vaccination reveals excessive inflammatory signatures correlating with impaired immunity

“…The copyright holder for this preprint (which this version posted July 29, 2021. ; https://doi.org/10.1101/2021.07.28.454252 doi: bioRxiv preprint early timepoints, suggesting that Th1 responses contribute to PfRAS vaccination-induced immunity. This is consistent with studies in animal models which concluded that sterilizing protection involves Th1 cells which secrete IFNγ and, in co-ordination with with macrophages and liver resident cytotoxic CD8 T cells, eliminate intracellular pathogens (Cockburn et al, 2013;Fernandez-Ruiz et al, 2016a;Hickey et al, 2020;McNamara et al, 2017;Tse et al, 2014)(Perez-Mazliah andLanghorne, 2014). In addition, the correlation of CSP-specific, IFNγ-producing CD4 T cells with protection from infection following RTS,S/AS02 vaccination (Reece et al, 2004) also suggests that Th1 cells can contribute protective immunity in humans.…”

“…The IMRAS cohort analyzed consisted of eleven malaria-naïve adults immunized with five doses of approximately 200 bites from Pf RAS NF54 infected mosquitos (Hickey et al, 2020). The first four doses were given four weeks apart and the final dose was administered five weeks after the fourth.…”

“…Understanding mechanisms of protection is complicated by the likelihood that protective effector processes are multi-functional, due to the large breadth of potential antigens, and protection may occur at multiple points between the introduction of SPZs and the establishment of a blood stage infection. Both antibody and cellular mediated mechanisms may contribute to protection: monoclonal antibodies derived from attenuated SPZ vaccination can protect humanized mice although antibody levels variably correlate with protection (Epstein et al, 2017; Hickey et al, 2020) and liver resident CD8+ T-cells and IFNγ correlate with protection in non-human primates (Pichyangkul et al, 2017). The complex balance of responses associated with protection are illustrated here by the differential early inflammatory responses between P and NP subjects and the potential effects on Th1 and Th2 responses.…”

“…In this study, we applied a systems immunology approach to identify correlates of protection that are identifiable up to 28 days after initial vaccination in malaria naïve human trial subjects that participated in the Immunization by Mosquito with Radiation Attenuated Sporozoites (IMRAS) trial (Hickey et al, 2020). Participants were immunized by PfRAS delivered by mosquito bite with was not certified by peer review) is the author/funder.…”

In vitro and in vivo inhibition of malaria parasite infection by monoclonal antibodies against Plasmodium falciparum circumsporozoite protein (CSP)

“…A pediatric formulation of RTS,S/AS01 is currently undergoing Phase 4 trials at several field sites across Africa 10 . Immunization via mosquito bite with radiation-attenuated sporozoites (IMRAS vaccine) 11 , cryopreserved irradiated sporozoites (PfSPZ vaccine) 12 or sporozoites delivered under chloroquine prophylaxis (PfSPZ-C vaccine) 13 also elicit protection against CHMI that is in part mediated by inhibitory CSP antibodies. Highly protective polyclonal and monoclonal antibodies have been mapped to the central repeats and junctional sequence, but not to the N- or C-terminal regions of CSP 2 , 14 – 16 .…”