4. Benefits of malaria transmission-blocking vaccines

Current malaria vaccine approaches target various parasite lifecycle stages including liver and blood stages in the individual and sexual stages in the mosquito (Figure 1). Liver stage vaccines, best typified by whole sporozoite (SPZ) vaccines that induce sterile protection [12], presumably act through T cell responses [13] and possibly antibodies and prevent progression of liver stage infections to blood stage parasitemia. Blood stage vaccines on the other hand confer protection that reduces malaria episodes, disease severity, and/or parasitemia. Additionally, immunity against VAR2CSA, a member of the P. falciparum erythrocyte membrane protein 1 family that binds to chondroitin sulfate A, may prevent placental malaria [14].

mosquito bites and naturally acquire immunity that controls parasitemia and reduces clinical episodes of malaria over time. Responses against some parasite proteins have been associated

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Today, the most advanced malaria vaccine is RTS,S, a pre-erythrocytic stage vaccine consisting of a virus-like particle (VLP) that displays hepatitis B surface antigen alone (S) and fused with a P. falciparum circumsporozoite protein fragment containing its central repeats and T cell epitopes (RTS). RTS,S has completed Phase III clinical trial (vaccine given to thousands of people and tested for efficacy and safety) and showed an efficacy of 51.3% (95%CI, 47.5–54.9) against clinical malaria in 5- to 17-month children over 12 months after three doses of the vaccine. A fourth dose was required to sustain protection over longer periods [18]. RTS,S is currently in pilot implementation studies involving 360,000 young children, expected to be given the vaccine in Ghana, Kenya, and Malawi. Although this represents important progress given the absence of any other human vaccine against a eukaryotic pathogen, more research is needed to develop vaccines that meet the Malaria Vaccine Technology Roadmap goals of 50% efficacy against severe malaria for more than one year and ≥75% long lasting efficacy against clinical malaria. For example, alternative dosages, timing and number of doses, are being

Attenuated whole SPZ vaccines have shown high-level sterile protection (>90%) against homologous challenge in early clinical trials [21] and thus have been heralded as a promising malaria vaccine approach. The concept of immunization using the whole SPZ was first attempted in 1910 by the French scientist Sergent using an avian model of malaria [22]. Several decades later, protective immunity was induced in mice following inoculation of X-irradiated SPZ of P. berghei [12]. In 1973, this approach was shown to be protective in humans, using Xirradiated SPZ of P. falciparum to vaccinate, followed by challenge with the non-irradiated homologous strain delivered by mosquito bites [23]. More recently, inoculation of nonattenuated fully infectious SPZ from chemo-sensitive strains along with administration of effective antimalarial drugs, known as chemoprophylaxis vaccination, was shown to induce sterilizing immunity [24]. Immunity induced by chemoprophylaxis vaccination is dosedependent and requires substantially smaller SPZ inocula compared to irradiated SPZ [25].

Finally, genetic attenuation of parasites through the deletion of liver developmental stagespecific genes by homologous recombination is also being pursued to generate whole SPZ vaccines [26]. Numerous technologies may generate genetically attenuated parasite vaccines, including flippase (Flp)/Flp recognition target, Cre/loxP recombination, zing-finger nucleases, and the clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPRassociated protein 9 (CRISPR/Cas9) system [27–30]. Genetic attenuation enables generation of parasites that arrest at late liver stages, exposing a broader liver stage-specific antigen repertoire to the immune system over a longer duration. However, genetic attenuation can be incompletely effective for preventing breakthrough to blood stage parasitemia, and this needs to be monitored carefully in clinical studies. Further, the requirement for mosquitoes to deliver SPZ vaccines had been considered as an insuperable obstacle to development of a whole SPZ vaccine for mass immunization. This obstacle has been partially overcome by the production

of purified, aseptic, and cryopreserved SPZ for syringe injection by Sanaria Inc. [31].

with this natural protection, which makes them promising vaccine targets [17].

evaluated as strategies to improve RTS,S efficacy [19, 20].

Vaccines that target the sexual stages, known as TBVs, are the focus of this chapter. TBVs do not directly protect immunized individuals but specifically block onward transmission by preventing mosquito infection. TBVs utilize antigens expressed during mosquito parasite stages (gametocytes, gametes, zygotes and ookinetes) to induce functional antibodies that attack the parasite in the mosquito and impair its viability, inhibit its development, or impede its interaction with the mosquito midgut. The effector antibody responses involved in these types of vaccines include neutralization and complement-mediated lysis. A broader concept coined as a Vaccine to Interrupt Malaria Transmission (VIMT) by the Malaria Eradication Research Agenda (MalERA) includes not only TBVs but also pre-erythrocytic and blood stage vaccines, as well as mosquito molecules involved in parasite development [15] such as Anopheles gambiae aminopeptidase 1 (AnAPN1), carboxypeptidase, and saglin.

Ideally, TBVs will elicit effective antibodies that prevent malaria parasite development in mosquitoes after uptake of blood meals. This will reduce the number of circulating infectious mosquitoes below a threshold that sustains transmission. TBVs are among the tools being encouraged for use during pre-elimination and elimination phases of malaria eradication according to malERA [15] and could be an effective alternative or adjunct to vector control. Compared to vector control interventions, TBVs are ecologically safer, cost-effective, and readily enable high coverage of populations.

Most TBV antigens are genetically conserved, which may be due to limited immune pressure. The effect of immune pressure exerted by TBV against the parasite remains unknown and will need to be monitored in future. Notably, sexual stages are critical for the generation of parasite genetic diversity and regulation of parasite virulence, hence the effects of TBVs on these phenomena also warrant monitoring. In addition, malaria parasites experience a considerable population bottleneck in the mosquito for only a handful of parasite zygotes progressing to oocysts on the mosquito midgut. Altogether, while these observations make the mosquito phase an attractive target for vaccine development, much remains to be done to achieve implementable and effective TBVs.
