Malaria Vaccines: Recent Advances and New Horizons

Abstract

The development of highly effective and durable vaccines against the human malaria parasites Plasmodium falciparum and P. vivax remains a key priority. Decades of endeavor have taught that achieving this goal will be challenging; however, recent innovation in malaria vaccine research and a diverse pipeline of novel vaccine candidates for clinical assessment provides optimism. With first-generation pre-erythrocytic vaccines aiming for licensure in the coming years, it is important to reflect on how next-generation approaches can improve on their success. Here we review the latest vaccine approaches that seek to prevent malaria infection, disease, and transmission and highlight some of the major underlying immunological and molecular mechanisms of protection. The synthesis of rational antigen selection, immunogen design, and immunization strategies to induce quantitatively and qualitatively improved immune effector mechanisms offers promise for achieving sustained high-level protection.

Figure 1

Malaria Vaccine Candidates in Clinical Development Data sources for this figure included the WHO Malaria Vaccine Rainbow Table and Clinicaltrials.gov. Vaccines for P. vivax are colored blue. The life cycle figure was adapted from Nilsson et al. (2015).

Figure 2

CHMI Models for Vaccine Efficacy Testing Blood-stage parasitemia is monitored by qPCR with lower limit of quantification ∼20 parasites/mL blood (black dotted line), typically for a 21 day study period. Malaria-naïve volunteers are usually diagnosed and treated at ∼10,000 parasites/mL when patent by thick-film microscopy (black dashed line). Following sporozoite CHMI, sterile protection is measured or a partial vaccine effect can be assessed by analysis of the liver-to-blood inoculum (LBI) leading to a delay in time to diagnosis. For blood-stage CHMI, an inoculum of ∼1,000 parasites is administered IV on day 0, with parasites growing ∼10-fold per 48 hr (red line) (Payne et al., 2016). For an effective blood-stage vaccine, a reduction in the parasite multiplication rate (PMR) would be expected. To assess transmission, CHMI is initiated by sporozoites or blood-stage inoculum (the figure depicts the latter). A low-dose drug regimen is used to treat asexual parasitemia, followed by a curative regimen if recrudescence occurs. A wave of gametocytemia then ensues, with all volunteers receiving drug treatment to clear parasites at the end of the study period (Collins et al., 2018).

Figure 3

A Structure-Guided Approach to Malaria Vaccine Development Structures of essential Plasmodium surface proteins in complex with Fab fragments from mAbs provide a potential starting point for structure-guided vaccine development. Inhibitory mouse mAbs (9AD4 and QA1) binding on PfRH5 are shown (Wright et al., 2014). A mouse binding-inhibitory antibody (2D10), which can prevent PvDBP_RII from binding to human erythrocytes, has been shown to bind to the tip of its third subdomain (Chen et al., 2016). Antibodies that bind the NANP repeats of PfCSP prevent hepatocyte invasion by sporozoites (Oyen et al., 2017). Structural studies have also revealed Pfs25 bound to six different mouse mAbs, identifying two transmission-blocking epitopes, illustrated by the complexes with 1190 (epitope I) and 1260 (epitope II) (Scally et al., 2017).

Figure 4

Functional Analysis of Human Antigen-Specific IgG Reported EC₅₀ [±95% CI] data from Phase Ia clinical trials of vaccine-induced human antigen-specific IgG, as assessed for functional activity against blood-stage (GIA) or sexual-stage parasites (SMFA). Vaccine-induced polyclonal IgG responses are carefully quantified using affinity-purified ELISA standards (Cheru et al., 2010, Miura et al., 2009) or calibration-free concentration analysis (Hodgson et al., 2014).

Figure 5

Examples of Approaches to Next-Generation Malaria Vaccine Discovery