DEVELOPMENT AND OPTIMIZATION OF A P47-BASED PLASMODIUM VACCINE TO BLOCK MALARIA TRANSMISSION

Abstract

Malaria is an infectious disease caused by Plasmodium parasites that are transmitted to

hosts by infected Anopheles mosquitoes. Over the last two decades, the widespread

deployment of effective interventions, such as drugs and insecticides, has resulted in

significant reductions of malaria cases. However, without an effective vaccine, the

recent emergence of drug-resistant parasites and insecticide-resistant mosquitoes are

threats to this progress, motivating the need for newer tools to control and ultimately

eliminate malaria. Recently, reducing Plasmodium transmission from humans to

mosquitoes has become an actively pursued approach to eradicate malaria. One unique strategy to achieve this goal is through transmission-blocking vaccines (TBVs). TBVs

generate antibodies in immunized individuals that are transferred to mosquitoes during

a blood meal to block the Plasmodium life cycle.

Recently, our laboratory discovered that the P. falciparum surface protein P47 (Pfs47)

allows parasites to evade mosquito immune system. This makes Pfs47 critical for the

parasite’s survival, and a valuable target for a TBV. The work in this dissertation

reveals the potential of P47 as a TBV target in two models of malaria. In the first aim,

the development, optimization, and efficacy of a P47 vaccine were investigated using

Pfs47 as an antigen. Recombinant Pfs47 protein was expressed in Escherichia coli, and

vaccine immunogenicity was assessed in mice. Antibodies targeting a key region of

Pfs47 reduced Plasmodium density in mosquito. This result supports TBV as an

effective approach to control the spread of malaria. Since delivering vaccines using

traditional injection is challenging in developing countries, new technologies that

improve vaccine accessibility are also needed. Thus, Pfs47 vaccine was loaded into

microneedles, dissolvable micron-scale structures, and tested for function. In the

second aim, the efficacy of a P47 vaccine was evaluated in a challenge model of malaria

using the Plasmodium berghei mouse malaria antigen Pbs47. The key region in Pbs47

where antibody binding confers protection was mapped. This in vivo system provides

preclinical evidence that a vaccine targeting Pfs47 could be effective in humans.

Together, this thesis presents P47 as a new malaria vaccine target and introduces MNs

as an effective platform to deliver vaccines in resource-poor settings.