New adenovirus-based vaccine vectors targeting Pfs25 elicit antibodies that inhibit Plasmodium falciparum transmission

Kathleen A Mcguire,Kazutoyo Miura,Christopher M Wiethoff,Kim C Williamson

doi:10.1186/s12936-017-1896-7

Abstract

BackgroundAn effective malaria transmission-blocking vaccine (TBV) would be a major advance in the current efforts to eliminate and, ultimately, eradicate malaria. Antibodies against Plasmodium falciparum surface protein, Pfs25, are known to block parasite development in the mosquito vector. However, in initial clinical trials the limited immunogenicity of recombinant Pfs25 protein-in-adjuvant vaccines has been a challenge.MethodsNovel human adenovirus type 5 (Ad5) vectors were used in heterologous prime boost vaccination strategies to augment the immune response against Pfs25. Specifically, an Ad5 vector that directs expression of full-length, membrane-bound Pfs25 was used as a priming immunization followed by a boost with Ad5 viral particles displaying only the Pfs25 epitope targeted by transmission-blocking antibodies 4B7 and 1D2 (Pfs25 aa 122–134) in hypervariable region 5 of the hexon capsid protein.ResultsThis heterologous prime-boost vaccine strategy induced antibodies that significantly inhibit P. falciparum transmission to mosquitoes in a standard membrane-feeding assay. Further, immunized mice generated a robust anti-Pfs25 antibody response characterized by higher titer, higher relative avidity and a broader IgG subclass profile than observed with a homologous prime-boost with recombinant Pfs25/alum.ConclusionThe data suggest that focusing the immune response against defined epitopes displayed on the viral capsid is an effective strategy for transmission-blocking vaccine development.

Highlights

An effective malaria transmission-blocking vaccine (TBV) would be a major advance in the current efforts to eliminate and, eradicate malaria
Vaccination with adenovirus type 5 (Ad5) expressing Pfs25 generates high titer anti‐Pfs25 antibodies consistent with T cell help In this study, several novel Ad5-based transmission blocking vaccine vectors were generated in an effort to stimulate a high titer antibody response against Pfs25
After confirming the Ad5-pfs25 vector sequence, HeLa cells were transfected with the Ad5-pfs25 genome and 24 h post-transfection the majority of Pfs25 concentrated at the periphery of the cells using Pfs25-specific, transmission-blocking monoclonal ID2 suggestive of cell surface localization [28] (Fig. 1)

Summary

Introduction

An effective malaria transmission-blocking vaccine (TBV) would be a major advance in the current efforts to eliminate and, eradicate malaria. Antibodies against Plasmodium falciparum surface protein, Pfs, are known to block parasite development in the mosquito vector. In addition to the approximately 200 million clinical cases a year, many infections in endemic countries are asymptomatic Both symptomatic and asymptomatic infections produce sexual stage parasites, called gametocytes, required for malaria transmission [2,3,4]. Pfs is currently the most advanced transmissionblocking vaccine (TBV) candidate [8, 9]. This 25 kD surface protein is expressed after the gametocyte is taken up in a blood meal by a mosquito and stimulated to emerge as a gamete [10,11,12].

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