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.

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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.

Author information

Author notes

    • Stephen L. Hoffman
    •  & Peter G. Kremsner

    These authors contributed equally to this work.


  1. Institute of Tropical Medicine, University of Tübingen and German Center for Infection Research, partner site Tübingen, 72074 Tübingen, Germany

    • Benjamin Mordmüller
    • , Güzin Surat
    • , Heimo Lagler
    • , Albert Lalremruata
    • , Markus Gmeiner
    • , Meral Esen
    • , Jana Held
    • , Carlos Lamsfus Calle
    • , Juliana B. Mengue
    • , Tamirat Gebru
    • , Javier Ibáñez
    • , Mihály Sulyok
    •  & Peter G. Kremsner
  2. Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, 1090 Vienna, Austria

    • Heimo Lagler
  3. Sanaria Inc., Rockville, Maryland 20850, USA

    • Sumana Chakravarty
    • , Adam J. Ruben
    • , Eric R. James
    • , Peter F. Billingsley
    • , KC Natasha
    • , Anita Manoj
    • , Tooba Murshedkar
    • , Anusha Gunasekera
    • , Abraham G. Eappen
    • , Tao Li
    • , Richard E. Stafford
    • , Minglin Li
    • , Thomas L. Richie
    • , B. Kim Lee Sim
    •  & Stephen L. Hoffman
  4. Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA

    • Andrew S. Ishizuka
    •  & Robert A. Seder
  5. Antigen Discovery Inc., Irvine, California 92618, USA

    • Joseph J. Campo
  6. Protein Potential, LLC, Rockville, Maryland 20850, USA

    • KC Natasha
    • , Richard E. Stafford
    • , Minglin Li
    •  & B. Kim Lee Sim
  7. Department of Medicine, University of California Irvine, Irvine, California 92697, USA

    • Phil L. Felgner


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B.M. designed the study, analysed the data, contributed to data collection and wrote the manuscript; B.K.L.S., E.R.J., A.J.R., A.G.E., T.L., R.E.S. and M.L manufactured the investigational products; A.M., R.S., T.M., A.G. and P.F.B. assured quality and regulatory compliance; C.L.C. and J.B.M. performed PfSPZ formulations; G.S., M.G., M.S. and H.L. collected data; A.L., M.E., J.I., T.G. and J.H. performed laboratory analyses; S.C., N.K, M.L. and A.J.R. performed and analysed all ELISA, IFA, and inhibition of sporozoite invasion studies; J.J.C. and P.L.F. performed and analysed protein array data; A.S.I. and R.A.S. performed and analysed cytometry experiments; T.L.R. oversaw the clinical trial; A.J.R., T.L.R., P.F.B., B.K.L.S. and S.L.H. analysed data; S.L.H. and P.G.K supervised the project, interpreted data, and wrote the manuscript. S.L.H. was the clinical trial sponsor representative and B.M. the principal investigator of the trial. S.L.H. and P.G.K. contributed equally to the work. All authors discussed the results and commented on the manuscript.

Competing interests

S.C., A.J.R., E.R.J., P.F.B., N.K, A.M., T.M., A.G., A.G.E., T.L., R.E.S, M.L., T.L.R., B.K.L.S. and S.L.H. are salaried employees of Sanaria Inc., the developer and owner of PfSPZ Challenge and the sponsor of the clinical trial. In addition, S.L.H. and B.K.L.S. have a financial interest in Sanaria Inc. J.J.C. is an Antigen Discovery Employee. P.L.F. owns stock and is a board member at Antigen Discovery, Inc. All other authors declare no conflicts of interest.

Corresponding author

Correspondence to Stephen L. Hoffman.

Reviewer Information Nature thanks L. Rénia and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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    Supplementary Information

    This file contains Supplementary Figure 1, Supplementary Tables 1-5 and 7-9.

  2. 2.

    Supplementary Table 6

    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.

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