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Abstract

An attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) vaccine, PfSPZ Vaccine, is highly protective against controlled human malaria infection (CHMI) 3 weeks after immunization, but the durability of protection is unknown. We assessed how vaccine dosage, regimen, and route of administration affected durable protection in malaria-naive adults. After four intravenous immunizations with 2.7 × 105 PfSPZ, 6/11 (55%) vaccinated subjects remained without parasitemia following CHMI 21 weeks after immunization. Five non-parasitemic subjects from this dosage group underwent repeat CHMI at 59 weeks, and none developed parasitemia. Although Pf-specific serum antibody levels correlated with protection up to 21–25 weeks after immunization, antibody levels waned substantially by 59 weeks. Pf-specific T cell responses also declined in blood by 59 weeks. To determine whether T cell responses in blood reflected responses in liver, we vaccinated nonhuman primates with PfSPZ Vaccine. Pf-specific interferon-γ-producing CD8 T cells were present at 100-fold higher frequencies in liver than in blood. Our findings suggest that PfSPZ Vaccine conferred durable protection to malaria through long-lived tissue-resident T cells and that administration of higher doses may further enhance protection.

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  • 18 May 2016

    In the version of this article initially published online, the authors omitted a funding source, The Bill and Melinda Gates Foundation (Investment ID: 24922). The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

The authors thank the vaccine trials participants for their contribution and commitment to vaccine research. We acknowledge the contributions of: our US National Institutes of Health (NIH) Clinical Center (CC) and National Institute of Allergy and Infectious Diseases (NIAID) colleagues, especially J. Stein, J. Pierson, R. Eckes, P. Driscoll, L. Ediger, and the nursing staff of the 5NW, SCSU, 5SE-S, and 5SE-N units; our VRC colleagues, especially A. Mittelman, H. Harvey, M. Young, C. Artis, R. Hicks, P. Darrah, and T. Abram; our Sanaria and Protein Potential colleagues, especially Y. Abebe, J. Jackson, A. Awe, M. King, H. Huang, A. Patil, S. Matheny, J. Overby, Y. Wen, K. Nelson, V. Pich, M. Orozco, D. Padilla, E. Saverino, B. Jiang, L. Gao, R. Xu, E. Fomumbod, M. Laskowski, T.T. Wai, F. Beams, R. Thompson, and A. Hoffman for administrative, operations, and legal support, and T. Luke for insight and inspiration; the EMMES Corporation; the NIAID Institutional Review Board; the NIAID Office of Communications and Government Relations; the NIH CC Department of Laboratory Medicine; the NIH CC IND Pharmacy, and the NIH CC Patient Recruitment and Public Liaison Office. We appreciate the expert reviews of the Safety Monitoring Committee (A. Durbin, K. Kester, and A. Cross) and the assistance from the US Military Malaria Vaccine Program, the Walter Reed Army Institute of Research Entomology Branch, and the Naval Medical Research Center (NMRC), especially A. Reyes, Y. Alcorta, G. Banania, C. Fedders, M. Dowler, T. Savransky, D. Patel, C. Brando, K. Kobylinski, and K. Walker. This work was supported by the intramural research program of the VRC, NIAID, NIH. Production and characterization of the PfSPZ Vaccine were supported in part by NIAID Small Business Innovation Research grants 5R44AI055229-11 (S.L.H.), 5R44AI058499-08 (S.L.H.), and 5R44AI058375-08 (S.L.H.). The humanized mouse experiments reported here were funded by the Bill and Melinda Gates Foundation (Investment ID: 24922; to S.H.I.K.).

The findings and conclusions in this report are those of the authors and do not necessarily reflect the views of the funding agency or collaborators. The views expressed in this article are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, the Department of the Army, the Department of Defense, or the US Government. This work was supported in part by work unit number 6000.RADI.F.A0309 to NMRC. J.E.E. and S.A.D. are military service members, and this work was prepared as part of their official duties. Title 17 U.S.C. §101 defines a US Government work as a work prepared by a military service member or employee of the US Government as part of that person's official duties.

Author information

Author notes

    • Lee-Jah Chang
    • , Uzma N Sarwar
    •  & Srinivas Rao

    Present addresses: Sanofi, Swiftwater, Pennsylvania, USA (L.-J.C.), Albert Einstein College of Medicine, Montefiore Medical Center, New York, New York, USA (U.N.S.), Sanofi, Cambridge, Massachusetts, USA (S.R.).

    • Andrew S Ishizuka
    •  & Kirsten E Lyke

    These authors contributed equally to this work.

    • Stephen L Hoffman
    • , Julie E Ledgerwood
    •  & Robert A Seder

    These authors jointly directed this work.

Affiliations

  1. Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda (NIH), Maryland, USA.

    • Andrew S Ishizuka
    • , Adam DeZure
    • , Floreliz H Mendoza
    • , Mary E Enama
    • , Ingelise J Gordon
    • , Lee-Jah Chang
    • , Uzma N Sarwar
    • , Kathryn L Zephir
    • , LaSonji A Holman
    • , Sarah H Plummer
    • , Cynthia S Hendel
    • , Laura Novik
    • , Pamela J M Costner
    • , Jamie G Saunders
    • , Barbara Flynn
    • , William R Whalen
    • , J P Todd
    • , Jay Noor
    • , Srinivas Rao
    • , Kailan Sierra-Davidson
    • , Geoffrey M Lynn
    • , Barney S Graham
    • , Mario Roederer
    • , Julie E Ledgerwood
    •  & Robert A Seder
  2. Institute for Global Health, Center for Vaccine Development and Division of Malaria Research, University of Maryland School of Medicine, Baltimore, Maryland, USA.

    • Kirsten E Lyke
    • , Andrea A Berry
    • , Matthew B Laurens
    •  & Christopher V Plowe
  3. Sanaria Inc., Rockville, Maryland, USA.

    • Thomas L Richie
    • , Eric R James
    • , Peter F Billingsley
    • , Anusha Gunasekera
    • , Sumana Chakravarty
    • , Anita Manoj
    • , MingLin Li
    • , Adam J Ruben
    • , Tao Li
    • , Abraham G Eappen
    • , Richard E Stafford
    • , Natasha K C
    • , Tooba Murshedkar
    • , B Kim Lee Sim
    •  & Stephen L Hoffman
  4. Protein Potential, LLC, Rockville, Maryland, USA.

    • MingLin Li
    • , Richard E Stafford
    • , Natasha K C
    •  & B Kim Lee Sim
  5. Pharmaceutical Development Section, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.

    • Hope DeCederfelt
  6. Naval Medical Research Center (NMRC), Malaria Department, Silver Spring, Maryland, USA.

    • Judith E Epstein
  7. Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.

    • Margaret A Kemp
    •  & Gary A Fahle
  8. Center for Infectious Disease Research, Seattle, Washington, USA.

    • Sebastian A Mikolajczak
    • , Matthew Fishbaugher
    • , Brandon K Sack
    •  & Stefan H I Kappe
  9. Entomology Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.

    • Silas A Davidson
    •  & Lindsey S Garver
  10. Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

    • Niklas K Björkström
  11. Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

    • Martha C Nason

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Contributions

A.S.I., K.E.L., T.L.R., B.K.S., M.C.N., B.S.G., M.R., B.K.L.S., S.L.H., J.E.L., and R.A.S. designed the research studies; A.S.I., K.E.L., A.D., A.A.B., T.L.R., F.H.M., M.E.E., I.J.G., L.-J.C., U.N.S., K.L.Z., L.A.H., E.R.J., P.F.B., A.G., S.C., A.M., M.L., A.J.R., T.L., A.G.E., R.E.S., N.K., T.M., H.D., S.H.P., C.S.H., L.N., P.J.M.C., J.G.S., M.B.L., C.V.P., B.F., W.R.W., J.P.T., J.N., S.R., K.S.-D., G.M.L., J.E.E., M.A.K., G.A.F., S.A.M., M.F., B.K.S., S.H.I.K., S.A.D., L.S.G., N.K.B., M.C.N., B.S.G., M.R., B.K.L.S., S.L.H., J.E.L., and R.A.S. performed the research, analyzed data, and discussed the results and implications; and A.S.I., K.E.L., S.L.H., and R.A.S. wrote the paper.

Competing interests

T.L.R., E.R.J., P.F.B., A.G., S.C., A.M., M.L., A.J.R., T.L., A.G.E., R.E.S., N.K., T.M., B.K.L.S., and S.L.H. are salaried employees of Sanaria Inc., the developer and owner of PfSPZ Vaccine and the sponsor of the clinical trials. In addition, S.L.H. and B.K.L.S. have a financial interest in Sanaria Inc. All other authors declare no competing financial interests.

Corresponding author

Correspondence to Robert A Seder.

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https://doi.org/10.1038/nm.4110

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