title: Sterile protection against human malaria by chemoattenuated PfSPZ vaccine.
abstract: A highly protective malaria vaccine would greatly facilitate the prevention and elimination of malaria and containment of drug-resistant parasites. 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 mosquitoes; by intravenous injection of aseptic, purified, radiation-attenuated, cryopreserved PfSPZ ('PfSPZ Vaccine'); or by infectious PfSPZ inoculated by mosquitoes to volunteers taking chloroquine or mefloquine (chemoprophylaxis with sporozoites). We assessed immunization by direct venous inoculation of aseptic, purified, cryopreserved, non-irradiated PfSPZ ('PfSPZ Challenge') to malaria-naive, healthy adult volunteers taking chloroquine for antimalarial chemoprophylaxis (vaccine approach denoted as PfSPZ-CVac). Three doses of 5.12 × 104PfSPZ of PfSPZ Challenge 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 × 104PfSPZ 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.
authors.affiliation: Institute of Tropical Medicine, University of Tübingen and German Center for Infection Research, partner site Tübingen, 72074 Tübingen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Mordmüller
authors.affiliation: Institute of Tropical Medicine, University of Tübingen and German Center for Infection Research, partner site Tübingen, 72074 Tübingen, Germany.
authors.forename: Güzin
authors.initials: G
authors.lastname: Surat
authors.affiliation: Institute of Tropical Medicine, University of Tübingen and German Center for Infection Research, partner site Tübingen, 72074 Tübingen, Germany.|Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Heimo
authors.initials: H
authors.lastname: Lagler
authors.affiliation: Sanaria Inc., Rockville, Maryland 20850, USA.
authors.forename: Sumana
authors.initials: S
authors.lastname: Chakravarty
authors.affiliation: Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Ishizuka
authors.affiliation: Institute of Tropical Medicine, University of Tübingen and German Center for Infection Research, partner site Tübingen, 72074 Tübingen, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Lalremruata
authors.affiliation: Institute of Tropical Medicine, University of Tübingen and German Center for Infection Research, partner site Tübingen, 72074 Tübingen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Gmeiner
authors.affiliation: Antigen Discovery Inc., Irvine, California 92618, USA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Campo
authors.affiliation: Institute of Tropical Medicine, University of Tübingen and German Center for Infection Research, partner site Tübingen, 72074 Tübingen, Germany.
authors.forename: Meral
authors.initials: M
authors.lastname: Esen
authors.affiliation: Sanaria Inc., Rockville, Maryland 20850, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Ruben
authors.affiliation: Institute of Tropical Medicine, University of Tübingen and German Center for Infection Research, partner site Tübingen, 72074 Tübingen, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Held
authors.affiliation: Institute of Tropical Medicine, University of Tübingen and German Center for Infection Research, partner site Tübingen, 72074 Tübingen, Germany.
authors.forename: Carlos Lamsfus
authors.initials: CL
authors.lastname: Calle
authors.affiliation: Institute of Tropical Medicine, University of Tübingen and German Center for Infection Research, partner site Tübingen, 72074 Tübingen, Germany.
authors.forename: Juliana B
authors.initials: JB
authors.lastname: Mengue
authors.affiliation: Institute of Tropical Medicine, University of Tübingen and German Center for Infection Research, partner site Tübingen, 72074 Tübingen, Germany.
authors.forename: Tamirat
authors.initials: T
authors.lastname: Gebru
authors.affiliation: Institute of Tropical Medicine, University of Tübingen and German Center for Infection Research, partner site Tübingen, 72074 Tübingen, Germany.
authors.forename: Javier
authors.initials: J
authors.lastname: Ibáñez
authors.affiliation: Institute of Tropical Medicine, University of Tübingen and German Center for Infection Research, partner site Tübingen, 72074 Tübingen, Germany.
authors.forename: Mihály
authors.initials: M
authors.lastname: Sulyok
authors.affiliation: Sanaria Inc., Rockville, Maryland 20850, USA.
authors.forename: Eric R
authors.initials: ER
authors.lastname: James
authors.affiliation: Sanaria Inc., Rockville, Maryland 20850, USA.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Billingsley
authors.affiliation: Sanaria Inc., Rockville, Maryland 20850, USA.|Protein Potential, LLC, Rockville, Maryland 20850, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Natasha
authors.affiliation: Sanaria Inc., Rockville, Maryland 20850, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Manoj
authors.affiliation: Sanaria Inc., Rockville, Maryland 20850, USA.
authors.forename: Tooba
authors.initials: T
authors.lastname: Murshedkar
authors.affiliation: Sanaria Inc., Rockville, Maryland 20850, USA.
authors.forename: Anusha
authors.initials: A
authors.lastname: Gunasekera
authors.affiliation: Sanaria Inc., Rockville, Maryland 20850, USA.
authors.forename: Abraham G
authors.initials: AG
authors.lastname: Eappen
authors.affiliation: Sanaria Inc., Rockville, Maryland 20850, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Sanaria Inc., Rockville, Maryland 20850, USA.|Protein Potential, LLC, Rockville, Maryland 20850, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Stafford
authors.affiliation: Sanaria Inc., Rockville, Maryland 20850, USA.|Protein Potential, LLC, Rockville, Maryland 20850, USA.
authors.forename: Minglin
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Medicine, University of California Irvine, Irvine, California 92697, USA.
authors.forename: Phil L
authors.initials: PL
authors.lastname: Felgner
authors.affiliation: Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Seder
authors.affiliation: Sanaria Inc., Rockville, Maryland 20850, USA.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Richie
authors.affiliation: Sanaria Inc., Rockville, Maryland 20850, USA.|Protein Potential, LLC, Rockville, Maryland 20850, USA.
authors.forename: B Kim Lee
authors.initials: BK
authors.lastname: Sim
authors.affiliation: Sanaria Inc., Rockville, Maryland 20850, USA.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hoffman
authors.affiliation: Institute of Tropical Medicine, University of Tübingen and German Center for Infection Research, partner site Tübingen, 72074 Tübingen, Germany.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Kremsner
mesh_terms: D000293:Adolescent; D000328:Adult; D000913:Antibodies, Protozoan / Q000097:blood / Q000276:immunology; D002738:Chloroquine / Q000627:therapeutic use; D004311:Double-Blind Method; D064368:Healthy Volunteers; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016778:Malaria, Falciparum / Q000097:blood / Q000276:immunology* / Q000469:parasitology / Q000517:prevention & control*; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000145:classification / Q000276:immunology*; D034101:Sporozoites / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology*; D055815:Young Adult
chemical_list: D000913:Antibodies, Protozoan; D017780:Malaria Vaccines; D014613:Vaccines, Attenuated; D002738:Chloroquine