Impacts of Ecology, Parasite Antigenic Variation, and Human Genetics on RTS,S/AS01e Malaria Vaccine Efficacy

Abstract

Purpose of Review Global malaria elimination has little chance of success without an effective vaccine. The first malaria vaccine, RTS,S/AS01e, demonstrated moderate efficacy against clinical malaria in phase III trials and is undergoing large-scale effectiveness trials in Africa. Importantly, the vaccine did not perform equally well between phase III study sites. Though reasons for the moderate efficacy and this variation are unclear, various mechanisms have been suggested. This review summarizes the recent literature on such mechanisms, with a focus on those involving landscape ecology, parasite antigenic variation, and human host genetic differences. Recent Findings Transmission intensity may have a role pre- and post-vaccination in modulating immune responses to the vaccine. Furthermore, malaria incidence may “rebound” in vaccinated populations living in high transmission intensity settings. There is growing evidence that both genetic variation in the parasite circumsporozoite protein and variation of human host genetic factors affect RTS,S vaccine efficacy. These genetic factors may be interacting in complex ways to produce variation in the natural and vaccine-induced immune responses that protect against malaria. Summary Due to the modest efficacy of RTS,S/AS01e, the combinations of factors (ecological, parasite, human host) impacting its effectiveness must be clearly understood, as this information will be critical for implementation policy and future vaccine designs.

Global diversity and balancing selection of 23 leading Plasmodium falciparum candidate vaccine antigens

“…Nonetheless, numerous Bcell epitopes have been found within disordered regions [28] and many of these appear to elicit functional immune responses [70,71,75,[89][90][91][92]. For instance, the protective effect of RTS,S appears to be predominantly mediated by generation of antibody responses to the disordered central NANP repeat region [90,93]. Our observation of immune-mediated selection pressure in the N-terminal disordered region of SERA5, is also supported by the finding that in vitro parasite growth was inhibited by anti-SERA5 antibodies raised in squirrel monkeys (Saimiri sciureus) [72].…”

Primate malarias as a model for cross-species parasite transmission

“…Understanding the strain-specific immune responses and range of natural genetic variation is particularly important because var genes such as PfEMP1 have been proposed as vaccine targets, and expression of var genes has been shown to change in response to treatments ( Bachmann et al, 2019 ; Jensen et al, 2020 ). Similarly, vaccines developed against P. falciparum have had mixed success based on the genetic diversity of parasites ( Thera et al, 2011 ; Neafsey et al, 2015 ; Ouattara et al, 2015 ; Graves et al, 2016 ; Laurens et al, 2017 ; Bailey et al, 2020 ; Bell et al, 2021 ). Su et al, 2020 further discuss the role of these gene families in host-parasite interaction, and future work expanding to nonhuman malarias will be important to understand the role of these genes in between-species susceptibility and host switching.…”

Malaria Vaccine Impact on Cases, Drug-resistant Cases, and Deaths in Africa: A Modeling Study

“…The rate at which vaccine e cacy (VE) wanes depends on many factors, including pathogen replication time and rate of exposure, the effect on antibodies as well as B and T cell responses in the human host, and the number and timing of doses (23). Additionally, VE may vary across regions due to geographical differences in these ecological, parasite, and human host factors (23). In the Phase III trial of RTS,S among children 5-17 months old, VE against clinical malaria was highest (~ 60-70%) six months after three primary doses (24) then waned to ~ 45%, ~ 35%, and ~ 28% at 20, 32, and 48 months follow-up, respectively (25).…”

“…The rate at which vaccine e cacy (VE) wanes depends on many factors, including pathogen replication time and rate of exposure, the effect on antibodies as well as B and T cell responses in the human host, and the number and timing of doses (23). Additionally, VE may vary across regions due to geographical differences in these ecological, parasite, and human host factors (23).…”

“…A booster at 18 months increased VE at 48 months to ~ 36%. Additionally, VE varied across study sites ranging from 22% in Mozambique to ~ 75% in Kenya (23). In a Phase IIb trial, R21 showed ~ 77% e cacy at 12 months follow-up and may be the rst malaria vaccine to reach WHO's target of over 75% e cacy (22,26).…”