Immune mechanisms targeting malaria transmission: opportunities for vaccine development

Abstract

Introduction: Malaria continues to remain a major global health problem with nearly a quarter of a billion clinical cases and more than 600,000 deaths in 2022. There has been significant progress toward vaccine development, however, poor efficacy of approved vaccines requiring multiple immunizing doses emphasizes the need for continued efforts toward improved vaccines. Progress to date, nonetheless, has provided impetus for malaria elimination.

Areas covered: In this review we will focus on diverse immune mechanisms targeting gametocytes in the human host and gametocyte-mediated malaria transmission via the mosquito vector.

Expert opinion: To march toward the goal of malaria elimination it will be critical to target the process of malaria transmission by mosquitoes, mediated exclusively by the sexual stages, i.e. male, and female gametocytes, ingested from infected vertebrate host. Studies over several decades have established antigens in the parasite sexual stages developing in the mosquito midgut as attractive targets for the development of transmission blocking vaccines (TBVs). Immune clearance of gametocytes in the vertebrate host can synergize with TBVs and directly aid in maintaining effective transmission reducing immune potential.

Keywords: Malaria; Plasmodium falciparum; Plasmodium vivax; combination vaccines; opsono-phagocytosis; transmission blocking immunity; transmission blocking vaccine.

Figure 1:. Malaria transmission cycles.

Mosquitoes acquire infectious male and female gametocytes in the blood meal which leads to sexual reproduction of parasites and formation of sporozoites. Infected mosquitoes inoculate sporozoites during the next blood feeding which initiates the hepatic stage of infection followed by erythrocytic infection as asexually replicating parasites responsible for all the clinical symptoms, including death. A small percentage of intraerythrocytic asexual stages differentiate into intraerythrocytic male and female sexual stages which continue the transmission cycles. Pre-erythrocytic vaccines target infection by sporozoites and transmission blocking vaccines target infectivity of gametocytes in the mosquitoes.

Figure 2:. Schematic representation of immune targets in gametocyte infected red blood cells (GiRBC).

The intraerythrocytic gametocytes (male and female) shaded in gray are enclosed within a parasitophorous vacuole and represent gametocyte infected red blood cells (GiRBC). Proteins represented as ‘a-f’ are produced in the developing gametocytes, expressed on the surface of the parasite, persist even on the surface of male and female gametes developing in the mosquito midgut after ingestion and are critical for fertilization between gametes. Most prominent antigens in this category are P230, P48/45, P47 and HAP2, and are important targets of antibodies interfering with gamete fertilization and sexual reproduction in the mosquito midgut (right box). Antigens on the surface of GiRBC (represented as ‘A-F,’ left box) are less well characterized and may be attractive targets of immune clearance by antibodies mediating opsonophagocytosis of imGiRBC and mGiRBC.

Figure 3:. Proposed immunologic role for antibodies directed against antigens represented as “A-F’ and ‘a-f’.

During maturation of gametocytes (i and vii) an antibody response (pre-existing or induced; shown in dark shaded boxes) against GSA in imGiRBC (stage I-III) indicated as (‘A-F’, Figure 2) may prevent adhesion of imGiRBC to microvasculature and/or entry of gametocyte into bone marrow (ii) where they sequester and such blocking antibodies may promote their opsonic phagocytosis (iii). Presentation of antigens after phagocytosis of imGiRBC (indicated by an X) to the immune system (iv) is expected to activate innate and adaptive immune responses directed against GSA represented as ‘A-F’ (Figure 2) and may promote clearance of imGiRBCs. Likewise, antibodies against surface antigens represented as ‘a-f’ on the surface of intracellular parasites (Figure 2) target sexual development of the parasites in the mosquito midgut (vi) and are well known candidates for the development of TBV. Importantly, antibodies against antigens represented as ‘A-F’ on the surface of mGiRBC (dashed arrow 1) could mechanistically promote opsonization of mGiRBC (viii). This is significant because live mature gametocytes critical for malaria transmission are otherwise known to resist phagocytosis (ix). In contrast, dead or extracellular mature gametocytes readily undergo phagocytosis (x) [52]. Presentation of antigens of opsonized mGiRBC or dead mGiRBC (indicated as Y and dashed arrows 2 and 3) is expected to further activate immune cells for continued production of anti-GSA antibodies. Phagocytosis of opsonized mature gametocytes (xi) leading to clearance from circulation (xii) is expected to result in overall reduced transmission of malaria (xiii).

Figure 4:

Target stages for combination vaccines