Outer membrane protein complex as a carrier for malaria transmission blocking antigen Pfs230

Puthupparampil V Scaria,Bob J Lucas,Debbie D Nahas,Lynn E Lambert,Emma K Barnafo,Patrick E Duffy,Elizabeth R Fischer,Charles F Anderson,Christopher G Rowe,Irfan U Zaidi,Beth B Chen,David L Narum,Olga V Muratova

doi:10.1038/s41541-019-0121-9

Abstract

Malaria transmission blocking vaccines (TBV) target the mosquito stage of parasite development by passive immunization of mosquitoes feeding on a vaccinated human. Through uptake of vaccine-induced antibodies in a blood meal, mosquito infection is halted and hence transmission to another human host is blocked. Pfs230 is a gametocyte and gamete surface antigen currently under clinical evaluation as a TBV candidate. We have previously shown that chemical conjugation of poorly immunogenic TBV antigens to Exoprotein A (EPA) can enhance their immunogenicity. Here, we assessed Outer Membrane Protein Complex (OMPC), a membrane vesicle derived from Neisseria meningitidis, as a carrier for Pfs230. We prepared Pfs230-OMPC conjugates with varying levels of antigen load and examined immunogenicity in mice. Chemical conjugation of Pfs230 to OMPC enhanced immunogenicity and functional activity of the Pfs230 antigen, and OMPC conjugates achieved 2-fold to 20-fold higher antibody titers than Pfs230-EPA/AdjuPhos® at different doses. OMPC conjugates were highly immunogenic even at low doses, indicating a dose-sparing effect. EPA conjugates induced an IgG subclass profile biased towards a Th2 response, whereas OMPC conjugates induced a strong Th1-biased immune response with high levels of IgG2, which can benefit Pfs230 antibody functional activity, which depends on complement activation. OMPC is a promising carrier for Pfs230 vaccines.

Highlights

Malaria transmission blocking vaccines (TBV) are designed to interrupt the mosquito stage of the Plasmodium parasite life cycle; vaccinated humans pass antibodies to mosquitos during their blood meals which block parasite development in the midgut.[1,2,3] By halting transmission from humans to mosquitos, TBVs could contribute to malaria elimination from affected communities and malaria eradication worldwide
Pfs230-Outer Membrane Protein Complex (OMPC) conjugates were synthesized by methods similar to those described earlier for chemical conjugation of Pfs[25] to OMPC43 (Method 1; Supplementary Fig. 1)
Pfs[230] is a large protein expressed on the gametocyte and gamete surface, and immunization with this antigen induces potent transmission blocking antibodies

Summary

Introduction

Malaria transmission blocking vaccines (TBV) are designed to interrupt the mosquito stage of the Plasmodium parasite life cycle; vaccinated humans pass antibodies to mosquitos during their blood meals which block parasite development in the midgut.[1,2,3] By halting transmission from humans to mosquitos, TBVs could contribute to malaria elimination from affected communities and malaria eradication worldwide. Several proteins expressed during parasite sexual stages have been explored as TBV antigens.[4,5,6,7,8,9,10,11,12,13,14,15,16,17] Among them, the zygote surface protein Pfs[25] has undergone extensive preclinical studies[4,6] and advanced to clinical testing and field trials.[18,19,20,21] Two gametocyte/gamete surface antigens, Pfs[230] and Pfs48/45, shown to be potent TBV antigens, are leading vaccine candidates.[8,9,13,14,15,17] Other TBV antigens under preclinical evaluation include the mosquito antigen AnAPN1 involved in ookinete invasion of the mosquito midgut,[10] the zygote/ookinete surface antigen Pfs[28,7,11] and the gametocyte surface antigen Pfs[47] involved in evasion of the mosquito immune system.[5,12,16]

Methods

Results

Conclusion