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      A PfSPZ vaccine immunization regimen equally protective against homologous and heterologous controlled human malaria infection

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          Abstract

          Immunization with radiation-attenuated Plasmodium falciparum (Pf) sporozoites (SPZ) in PfSPZ Vaccine, has provided better vaccine efficacy (VE) against controlled human malaria infection (CHMI) with the same parasites as in the vaccine (homologous) than with genetically distant parasites (heterologous). We sought to identify an immunization regimen that provided similar VE against CHMI with homologous and heterologous Pf for at least 9 weeks in malaria-naïve adults. Such a regimen was identified in part 1 (optimization), an open label study, and confirmed in part 2 (verification), a randomized, double-blind, placebo-controlled study in which VE was assessed by cross-over repeat CHMI with homologous (PfNF54) and heterologous (Pf7G8) PfSPZ at 3 and 9–10 weeks. VE was calculated using Bayesian generalized linear regression. In part 1, vaccination with 9 × 10 5 PfSPZ on days 1, 8, and 29 protected 5/5 (100%) subjects against homologous CHMI at 3 weeks after the last immunization. In part 2, the same 3-dose regimen protected 5/6 subjects (83%) against heterologous CHMI at both 3 and 9–10 weeks after the last immunization. Overall VE was 78% (95% predictive interval: 57–92%), and against heterologous and homologous was 79% (95% PI: 54–95%) and 77% (95% PI: 50–95%) respectively. PfSPZ Vaccine was safe and well tolerated. A 4-week, 3-dose regimen of PfSPZ Vaccine provided similar VE for 9–10 weeks against homologous and heterologous CHMI. The trial is registered with ClinicalTrials.gov, NCT02704533.

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          Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial.

          (2015)
          The efficacy and safety of the RTS,S/AS01 candidate malaria vaccine during 18 months of follow-up have been published previously. Herein, we report the final results from the same trial, including the efficacy of a booster dose.
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            Live attenuated malaria vaccine designed to protect through hepatic CD8⁺ T cell immunity.

            Our goal is to develop a vaccine that sustainably prevents Plasmodium falciparum (Pf) malaria in ≥80% of recipients. Pf sporozoites (PfSPZ) administered by mosquito bites are the only immunogens shown to induce such protection in humans. Such protection is thought to be mediated by CD8(+) T cells in the liver that secrete interferon-γ (IFN-γ). We report that purified irradiated PfSPZ administered to 80 volunteers by needle inoculation in the skin was safe, but suboptimally immunogenic and protective. Animal studies demonstrated that intravenous immunization was critical for inducing a high frequency of PfSPZ-specific CD8(+), IFN-γ-producing T cells in the liver (nonhuman primates, mice) and conferring protection (mice). Our results suggest that intravenous administration of this vaccine will lead to the prevention of infection with Pf malaria.
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              Sterile protection against human malaria by chemoattenuated PfSPZ vaccine

              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 × 104 PfSPZ 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 × 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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                Author and article information

                Contributors
                benjamin.mordmueller@radboudumc.nl
                slhoffman@sanaria.com
                Journal
                NPJ Vaccines
                NPJ Vaccines
                NPJ Vaccines
                Nature Publishing Group UK (London )
                2059-0105
                23 August 2022
                23 August 2022
                2022
                : 7
                : 100
                Affiliations
                [1 ]GRID grid.411544.1, ISNI 0000 0001 0196 8249, Institut für Tropenmedizin, , Universitätsklinikum Tübingen, ; Tübingen, Germany
                [2 ]GRID grid.452463.2, Deutsches Zentrum für Infektionsforschung, Standort Tübingen, ; Tübingen, Germany
                [3 ]GRID grid.452268.f, Centre de Recherches Médicales de Lambaréné, ; Lambaréné, Gabon
                [4 ]GRID grid.10417.33, ISNI 0000 0004 0444 9382, Department of Medical Microbiology, , Radboud University Medical Center, ; Nijmegen, The Netherlands
                [5 ]GRID grid.280962.7, Sanaria Inc., ; Rockville, MD USA
                [6 ]GRID grid.423438.a, Protein Potential, LLC, ; Rockville, MD USA
                Author information
                http://orcid.org/0000-0001-9101-2768
                http://orcid.org/0000-0002-4692-7835
                http://orcid.org/0000-0002-6766-1765
                http://orcid.org/0000-0001-9508-1787
                http://orcid.org/0000-0001-6215-6332
                http://orcid.org/0000-0003-4716-0311
                http://orcid.org/0000-0002-2946-5456
                http://orcid.org/0000-0002-0700-9505
                http://orcid.org/0000-0002-3926-4113
                Article
                510
                10.1038/s41541-022-00510-z
                9396563
                35999221
                7065e2c3-6c8a-49cb-9f37-79c71ab78a6b
                © The Author(s) 2022

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 19 October 2021
                : 24 June 2022
                Funding
                Funded by: FundRef https://doi.org/10.13039/100000060, U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID);
                Award ID: 5R44AI055229
                Award ID: 5R44AI058375
                Award Recipient :
                Funded by: U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
                Funded by: FundRef https://doi.org/10.13039/100009139, Deutsches Zentrum für Infektionsforschung (German Center for Infection Research);
                Award ID: TTU 03.902
                Award ID: TTU 03.902
                Award Recipient :
                Categories
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                © The Author(s) 2022

                malaria,live attenuated vaccines
                malaria, live attenuated vaccines

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