Safety, Immunogenicity, and Protective Efficacy against Controlled Human Malaria Infection of Plasmodium falciparum Sporozoite Vaccine in Tanzanian Adults.

Adam J Ruben,Tobias Rutishauser,Natasha Kc,Maximillian Mpina,Catherine Mkindi,Tobias Schindler,Stephen L Hoffman,Munira Qassim,Sumana Chakravarty,B Kim Lee Sim,Salim Abdulla,Robert A Seder,Solomon Mwakasungula,Florence A Milando,Marcel Tanner,Beatus Simon,Peter F Billingsley,Claudia Daubenberger,Andrew S Ishizuka,Isabelle Zenklusen,Yonas Abebe,Bakari M Bakari,Eric R James,Said Jongo ,Kamaka R Kassim ,Ali Mtoro ,Anneth-Mwasi Tumbo ,Seif Shekalaghe ,Omar Juma ,Elizabeth Saverino,L W Preston Church,Julian Rothen

doi:10.4269/ajtmh.17-1014

Abstract

.We are using controlled human malaria infection (CHMI) by direct venous inoculation (DVI) of cryopreserved, infectious Plasmodium falciparum (Pf) sporozoites (SPZ) (PfSPZ Challenge) to try to reduce time and costs of developing PfSPZ Vaccine to prevent malaria in Africa. Immunization with five doses at 0, 4, 8, 12, and 20 weeks of 2.7 × 105 PfSPZ of PfSPZ Vaccine gave 65% vaccine efficacy (VE) at 24 weeks against mosquito bite CHMI in U.S. adults and 52% (time to event) or 29% (proportional) VE over 24 weeks against naturally transmitted Pf in Malian adults. We assessed the identical regimen in Tanzanians for VE against PfSPZ Challenge. Twenty- to thirty-year-old men were randomized to receive five doses normal saline or PfSPZ Vaccine in a double-blind trial. Vaccine efficacy was assessed 3 and 24 weeks later. Adverse events were similar in vaccinees and controls. Antibody responses to Pf circumsporozoite protein were significantly lower than in malaria-naïve Americans, but significantly higher than in Malians. All 18 controls developed Pf parasitemia after CHMI. Four of 20 (20%) vaccinees remained uninfected after 3 week CHMI (P = 0.015 by time to event, P = 0.543 by proportional analysis) and all four (100%) were uninfected after repeat 24 week CHMI (P = 0.005 by proportional, P = 0.004 by time to event analysis). Plasmodium falciparum SPZ Vaccine was safe, well tolerated, and induced durable VE in four subjects. Controlled human malaria infection by DVI of PfSPZ Challenge appeared more stringent over 24 weeks than mosquito bite CHMI in United States or natural exposure in Malian adults, thereby providing a rigorous test of VE in Africa.

Highlights

In 2015 and in 2016, there were an estimated 429,000–730,500 deaths caused by malaria.[1,2,3] Plasmodium falciparum (Pf) is the cause of > 98% of malaria deaths and > 80% of malaria cases in sub-Saharan Africa
Four of 20 (20%) recipients of five doses of 2.7 × 105 PfSPZ did not become infected after homologous controlled human malaria infection (CHMI) by direct venous inoculation (DVI) 3 weeks after the last immunization
12/13 (92.3%) volunteers in the United States who received five doses of 2.7 × 105 PfSPZ were protected after homologous CHMI by mosquito bite 3 weeks after the last vaccine dose.[11]

Summary

Introduction

In 2015 and in 2016, there were an estimated 429,000–730,500 deaths caused by malaria.[1,2,3] Plasmodium falciparum (Pf) is the cause of > 98% of malaria deaths and > 80% of malaria cases in sub-Saharan Africa. Plasmodium falciparum sporozoites (SPZ) are the only immunogens that have ever prevented Pf infection in > 90% of subjects.[5,6,7] Sanaria® PfSPZ Vaccine (Sanaria Inc., Rockville, MD) is composed of radiation-attenuated, aseptic, purified, cryopreserved PfSPZ.[8,9] When administered by rapid intravenous injection, PfSPZ Vaccine protected 100% (6/6) of malaria-naıve subjects in the United States against mosquito bite–controlled human malaria infection (CHMI) with Pf parasites similar to those in the vaccine (homologous) 3 weeks after the last immunization,[10] and 65% at 24 weeks.[11] Protection was durable against homologous mosquito bite CHMI for at least 59 weeks[12] and heterologous (parasites different than in vaccine) mosquito bite CHMI for at least 33 weeks.[13] PfSPZ Vaccine prevented naturally transmitted heterogeneous Pf in adults in Mali for at least 24 weeks (vaccine efficacy [VE] 52% by time to event and 29% by proportional analysis).[14]

Objectives

Methods

Results

Conclusion