Transmission-Blocking Vaccines: Old Friends and New Prospects

Abstract

In the progression of the life cycle of Plasmodium falciparum, a small proportion of asexual parasites differentiate into male or female sexual forms called gametocytes. Just like their asexual counterparts, gametocytes are contained within the infected host's erythrocytes (RBCs). However, unlike their asexual partners, they do not exit the RBC until they are taken up in a blood meal by a mosquito. In the mosquito midgut, they are stimulated to emerge from the RBC, undergo fertilization, and ultimately produce tens of thousands of sporozoites that are infectious to humans. This transmission cycle can be blocked by antibodies targeting proteins exposed on the parasite surface in the mosquito midgut, a process that has led to the development of candidate transmission-blocking vaccines (TBV), including some that are in clinical trials. Here we review the leading TBV antigens and highlight the ongoing search for additional gametocyte/gamete surface antigens, as well as antigens on the surfaces of gametocyte-infected erythrocytes, which can potentially become a new group of TBV candidates.

Keywords: Plasmodium falciparum; gametocytes; malaria; transmission blocking.

FIG 1

Life cycle of P. falciparum. Pre-erythrocytic-stage malaria vaccines target the sporozoites that are released from an infected mosquito into the human host and infected liver cells. Blood-stage vaccines target the merozoites released from the liver schizont as well as preventing the development of the asexual-stage-infected erythrocyte and the resulting merozoites produced from the erythrocytic schizont. Potential giRBC vaccines will target male and female gametocytes that develop within the erythrocyte. Transmission-blocking vaccines prevent the eventual development of oocysts and sporozoites within the mosquito. (Adapted from an Open Courseware image from the Johns Hopkins Bloomberg School of Public Health [188].)

FIG 2

Schematic of TBV gene structures. Brown segments represent the signal peptide motif; the gray segment represents the prodomain; blue segments represent the main structural domains; black segments represent the GPI motif or, for HAP2, the transmembrane domain. Thick red lines represent the regions containing the active epitopes.