Safety and immunogenicity of a plant-produced Pfs25 virus-like particle as a transmission blocking vaccine against malaria: A Phase 1 dose-escalation study in healthy adults

Jessica A Chichester, Brian J Green, R Mark Jones, Yoko Shoji, Kazutoyo Miura, Carole A Long, Cynthia K Lee, Christian F Ockenhouse, Merribeth J Morin, Stephen J Streatfield, Vidadi Yusibov, Jessica A Chichester, Brian J Green, R Mark Jones, Yoko Shoji, Kazutoyo Miura, Carole A Long, Cynthia K Lee, Christian F Ockenhouse, Merribeth J Morin, Stephen J Streatfield, Vidadi Yusibov

Abstract

Malaria continues to be one of the world's most devastating infectious tropical diseases, and alternative strategies to prevent infection and disease spread are urgently needed. These strategies include the development of effective vaccines, such as malaria transmission blocking vaccines (TBV) directed against proteins found on the sexual stages of Plasmodium falciparum parasites present in the mosquito midgut. The Pfs25 protein, which is expressed on the surface of gametes, zygotes and ookinetes, has been a primary target for TBV development. One such vaccine strategy based on Pfs25 is a plant-produced malaria vaccine candidate engineered as a chimeric non-enveloped virus-like particle (VLP) comprising Pfs25 fused to the Alfalfa mosaic virus coat protein. This Pfs25 VLP-FhCMB vaccine candidate has been engineered and manufactured in Nicotiana benthamiana plants at pilot plant scale under current Good Manufacturing Practice guidelines. The safety, reactogenicity and immunogenicity of Pfs25 VLP-FhCMB was assessed in healthy adult volunteers. This Phase 1, dose escalation, first-in-human study was designed primarily to evaluate the safety of the purified plant-derived Pfs25 VLP combined with Alhydrogel® adjuvant. At the doses tested in this Phase 1 study, the vaccine was generally shown to be safe in healthy volunteers, with no incidence of vaccine-related serious adverse events and no evidence of any dose-limiting or dose-related toxicity, demonstrating that the plant-derived Pfs25 VLP-FhCMB vaccine had an acceptable safety and tolerability profile. In addition, although the vaccine did induce Pfs25-specific IgG in vaccinated patients in a dose dependent manner, the transmission reducing activity of the antibodies generated were weak, suggesting the need for an alternative vaccine adjuvant formulation. This study was registered at www.ClinicalTrials.gov under reference identifier NCT02013687.

Keywords: Malaria; Pfs25; Plant-produced; Transmission blocking vaccine; Virus-like particle.

Copyright © 2018. Published by Elsevier Ltd.

Figures

Fig. 1
Fig. 1
Anti-Pfs25 IgG responses in serum samples collected from the 30 and 100 µg dose groups. Data are shown as median with interquartile range. **: p < 0.01, ***: p < 0.001, and ****: p < 0.0001 when compared to pre-immune data using the Friedman test followed by the Dunn’s multiple comparison test.
Fig. 2
Fig. 2
Results of SMFA on sera collected from the 30 and 100 µg dose groups on Study Days 84 (1-month post 2nd dose) and 196 (1-month post 3rd dose). Purified IgG was tested at 3.75 mg/mL in the assay. Data are shown as median with interquartile range. Results are shown as the best estimates from 2 or 3 independent SMFA. *: p < 0.05 by the binomial test.

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