A highly protective malaria vaccine would greatly facilitate the prevention and elimination of malaria and containment of drug-resistant parasites1. A high level (more than 90%) of protection against malaria in humans has previously been achieved only by immunization with radiation-attenuated Plasmodium falciparum (Pf) sporozoites (PfSPZ) inoculated by mosquitoes2,3,4; by intravenous injection of aseptic, purified, radiation-attenuated, cryopreserved PfSPZ (‘PfSPZ Vaccine’)5,6; or by infectious PfSPZ inoculated by mosquitoes to volunteers taking chloroquine7,8,9,10 or mefloquine11 (chemoprophylaxis with sporozoites). We assessed immunization by direct venous inoculation of aseptic, purified, cryopreserved, non-irradiated PfSPZ (‘PfSPZ Challenge’12,13) to malaria-naive, healthy adult volunteers taking chloroquine for antimalarial chemoprophylaxis (vaccine approach denoted as PfSPZ-CVac)14. Three doses of 5.12 × 104 PfSPZ of PfSPZ Challenge12,13 at 28-day intervals were well tolerated and safe, and prevented infection in 9 out of 9 (100%) volunteers who underwent controlled human malaria infection ten weeks after the last dose (group III). Protective efficacy was dependent on dose and regimen. Immunization with 3.2 × 103 (group I) or 1.28 × 104 (group II) PfSPZ protected 3 out of 9 (33%) or 6 out of 9 (67%) volunteers, respectively. Three doses of 5.12 × 104 PfSPZ at five-day intervals protected 5 out of 8 (63%) volunteers. The frequency of Pf-specific polyfunctional CD4 memory T cells was associated with protection. On a 7,455 peptide Pf proteome array, immune sera from at least 5 out of 9 group III vaccinees recognized each of 22 proteins. PfSPZ-CVac is a highly efficacious vaccine candidate; when we are able to optimize the immunization regimen (dose, interval between doses, and drug partner), this vaccine could be used for combination mass drug administration and a mass vaccination program approach to eliminate malaria from geographically defined areas.
The authors thank the vaccine trial participants for their contribution and commitment to vaccine research. We thank F. Adomat, S. Adukpo, M. Aldejohann, S. Bolte, S. Borrmann, A. Bouyoukou Hounkpatin, S. Brückner, E. Bruske, J. Fernandes, P. Granados Bayón, J. Hass, S. Jeyaraj, J. Keim, A. Knoblich, R. Köllner, A. Kreidenweiss, D. N. Ndungu, R. Ritter, J. A. Selvaraj, Z. Sulyok, S. Theil, N. Theurer, and I. Westermann for support in conducting the trial, and P. Darrah and M. Roederer for assistance with the interpretation of the T-cell data. We thank the Sanaria and Protein Potential teams for manufacture and shipping of investigational products, PfSPZ Challenge and diluents, regulatory, quality, and clinical site activities, and legal and administrative support, including especially D. Cheney (née Padilla), Y. Abebe, E. Saverino, Y. Wu, E. Fomumbod, A. Awe, M. King, M. Orozco, A. Patil, Y. Wen, K. Nelson, J. Overby, S. Matheny, V. Pitch, B. Jiang, L. Gao, R. Xu, T. T. Wai, S. Monsheimer, P. De La Vega, M. Laskowski, H. Huang, M. Marquette, J. Jackson, F. Beams, R. Douglas, R. C. Thompson, D. Dolberg and A. Hoffman. We thank J. Inglese and P. Dranchak of the National Center for Advancing Translational Sciences (NCATS), NIH for support with the automated immunofluorescence assay and inhibition of sporozoite invasion assays. We appreciate the expert reviews of the Safety Monitoring Committee (W. Chen, P. Coyne and P. Zanger). The clinical trial was funded by the German Federal Ministry of Education and Research (BMBF) through the German Center for Infection Research (DZIF). Manufacture of investigational product by Sanaria was supported in part by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under SBIR award numbers 5R44AI058375 and 5R44AI055229. T cell studies were supported by the intramural research program of the VRC, NIAID, NIH. Proteome microarray studies were supported by NIAID SBIR grant 5R44AI066791 and funding from the Bill & Melinda Gates Foundation.
Extended data figures
Extended data tables
This file contains Supplementary Figure 1, Supplementary Tables 1-5 and 7-9.
Supplementary Table 6 shows logistic regression of peak antibody levels (2 weeks after final immunization) and baseline antibody levels on probability of sterile protection against CHMI, adjusted by dose of PfSPZ-CVac.