Sanaria?s Plasmodium falciparum (Pf) sporozoite (SPZ) vaccines development program is receiving global support. Trials of PfSPZ Vaccine (radiation attenuated PfSPZ) or PfSPZ-CVac (PfSPZ Chemoprophylaxis Vaccine) administered by direct venous inoculation (DVI), including ~1,500 adults to infants were initiated in December 2015 (Tanzania, U.S.) or will be initiated in early 2016 in Mali, Kenya (~500 infants), Ghana, Equatorial Guinea, Germany and 3 additional U.S. sites. These trials will assess 3-, 2- or 1-dose regimens, as 100% protective efficacy at 9 weeks after last dose has been established with a 3-dose regimen. Protective efficacy has been shown to be durable against controlled malaria infection (CHMI) for at least a year, and against intense natural transmission in Mali of heterogeneous strains of Pf for at least 6 months. PfSPZ Vaccine and PfSPZ-CVac are comprised of PfSPZ of the NF54 strain of Pf. Short-term protection (3 weeks) by PfSPZ Vaccine against a heterologous (different from the vaccine strain) CHMI with Pf7G8 parasites was 80%, but despite a significant delay in onset of parasitemia, 6 month sterile protective efficacy was only 10%. Sanaria is taking two approaches to improving protective efficacy against heterologous/heterogeneous strains. The 1st is to increase the dose of PfSPZ (NF54) per immunization based on the hypothesis that this will broaden and strengthen the protective immune responses against shared dominant and sub-dominant epitopes. All of the trials described above utilize this approach. The 2nd and potentially more efficient approach will be to combine PfSPZ from different strains of Pf in the same vaccine. Our analysis of genomic sequence data, predicted proteomes, and predicted T cell epitopes indicates that using two strains of Pf should be sufficient. This project fills an important gap. We have funding from VRC, NIAID, NIH to conduct a clinical trial of a multivalent PfSPZ vaccine, but require the funds to manufacture, characterize, and release the multi-valent vaccine, and to navigate the regulatory/clinical affairs pathways required to initiate the trial. In this Phase IIB SBIR project, we propose to, 1) Manufacture and QC release chloroquine sensitive PfSPZ Challenge of a W African Pf clone (NF166) that can be used for CHMI studies and as a component of a multi-strain PfSPZ-CVac; 2) Manufacture and release PfSPZ Vaccine based on the Brazilian Pf clone (7G8) and PfSPZ Vaccine (NF54) for a two-strain/clone PfSPZ Vaccine combination; 3) Manufacture and release PfSPZ Challenge (7G8) and PfSPZ Challenge (NF54) for a two-strain combination PfSPZ-CVac; and 4) Conduct an end of phase 2 meeting with FDA to propose and finalize a plan for using phase 3 CHMI trials with PfSPZ Challenge (NF54, 7G8, NF135.C10, and NF166) to replace phase 3 field trials to establish protective efficacy of the vaccines. Success will reduce the time to licensure of a PfSPZ vaccine for travelers/military by at least a year and save > $50M. It will also facilitate more rapid development of all pre-erythrocytic stage vaccines intended to provide the high level (>80%) protection required for a vaccine for travelers, military, and elimination campaigns.

Public Health Relevance

Since inception this SBIR has been focused on providing the foundation for moving to a multivalent approach to vaccination if needed, a multi-strain/clone approach to controlled human malaria infection with Sanaria?s Plasmodium falciparum (Pf) sporozoite (SPZ)-based products. In this new project we will develop an optimized 2-strain/clone vaccine and multi-strain/clone controlled human malaria infection system, and an optimized approach for a travelers/military vaccine for pivotal phase 3 trials that takes advantage of these key parasites, and thereby significantly reduces the time and cost to achieve vaccine licensure and commercial launch.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
5R44AI058375-11
Application #
9484219
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
MO, Annie X Y
Project Start
2004-02-15
Project End
2019-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
11
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Sanaria, Inc.
Department
Type
DUNS #
131092715
City
Rockville
State
MD
Country
United States
Zip Code
20850
Scally, Stephen W; Murugan, Rajagopal; Bosch, Alexandre et al. (2018) Rare PfCSP C-terminal antibodies induced by live sporozoite vaccination are ineffective against malaria infection. J Exp Med 215:63-75
Murugan, Rajagopal; Buchauer, Lisa; Triller, Gianna et al. (2018) Clonal selection drives protective memory B cell responses in controlled human malaria infection. Sci Immunol 3:
Mpina, Maxmillian; Maurice, Nicholas J; Yajima, Masanao et al. (2017) Controlled Human Malaria Infection Leads to Long-Lasting Changes in Innate and Innate-like Lymphocyte Populations. J Immunol 199:107-118
Longley, Rhea J; Halbroth, Benedict R; Salman, Ahmed M et al. (2017) Assessment of the Plasmodium falciparum Preerythrocytic Antigen UIS3 as a Potential Candidate for a Malaria Vaccine. Infect Immun 85:
Lyke, Kirsten E; Ishizuka, Andrew S; Berry, Andrea A et al. (2017) Attenuated PfSPZ Vaccine induces strain-transcending T cells and durable protection against heterologous controlled human malaria infection. Proc Natl Acad Sci U S A 114:2711-2716
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Mordmüller, Benjamin; Surat, Güzin; Lagler, Heimo et al. (2017) Sterile protection against human malaria by chemoattenuated PfSPZ vaccine. Nature 542:445-449
Bastiaens, Guido J H; van Meer, Maurits P A; Scholzen, Anja et al. (2016) Safety, Immunogenicity, and Protective Efficacy of Intradermal Immunization with Aseptic, Purified, Cryopreserved Plasmodium falciparum Sporozoites in Volunteers Under Chloroquine Prophylaxis: A Randomized Controlled Trial. Am J Trop Med Hyg 94:663-73
Ishizuka, Andrew S; Lyke, Kirsten E; DeZure, Adam et al. (2016) Protection against malaria at 1 year and immune correlates following PfSPZ vaccination. Nat Med 22:614-23
Riedl, Julia; Mordmüller, Benjamin; Koder, Silvia et al. (2016) Alterations of blood coagulation in controlled human malaria infection. Malar J 15:15

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