Biodefense, Emerging Infectious Disease, and Malaria Monoclonal Antibody Studies

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

The Vaccine Research Center (VRC) Monoclonal Antibody Studies in Biodefense and Emerging Infectious Diseases research project is aimed at the clinical evaluation of monoclonal antibody (mAb) products related to infectious disease pathogens. Current targets include Ebola virus disease and malaria. Further evaluation will continue as the VRC develops additional monoclonal anitbody products aimed at emerging infectious disease targets. Published results on clinical products and trials include: VRC 608: Safety, tolerability, pharmacokinetics, and immunogenicity of the therapeutic monoclonal antibody mAb114 targeting Ebola virus glycoprotein (VRC 608): an open-label phase 1 study. Gaudinski MR, Coates EE, Novik L, Widge A, Houser KV, Burch E, Holman LA, Gordon IJ, Chen GL, Carter C, Nason M, Sitar S, Yamshchikov G, Berkowitz N, Andrews C, Vazquez S, Laurencot C, Misasi J, Arnold F, Carlton K, Lawlor H, Gall J, Bailer RT, McDermott A, Capparelli E, Koup RA, Mascola JR, Graham BS, Sullivan NJ, Ledgerwood JE; VRC 608 Study team. Lancet. 2019 Mar 2;393(10174):889-898. PALM Study: A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics. Mulangu S, Dodd LE, Davey RT Jr, Tshiani Mbaya O, Proschan M, Mukadi D, Lusakibanza Manzo M, Nzolo D, Tshomba Oloma A, Ibanda A, Ali R, Coulibaly S, Levine AC, Grais R, Diaz J, Lane HC, Muyembe-Tamfum JJ; PALM Writing Group, Sivahera B, Camara M, Kojan R, Walker R, Dighero-Kemp B, Cao H, Mukumbayi P, Mbala-Kingebeni P, Ahuka S, Albert S, Bonnett T, Crozier I, Duvenhage M, Proffitt C, Teitelbaum M, Moench T, Aboulhab J, Barrett K, Cahill K, Cone K, Eckes R, Hensley L, Herpin B, Higgs E, Ledgerwood J, Pierson J, Smolskis M, Sow Y, Tierney J, Sivapalasingam S, Holman W, Gettinger N, Valle D, Nordwall J; PALM Consortium Study Team. N Engl J Med. 2019 Dec 12;381(24):2293-2303. VRC 612: A Monoclonal Antibody for Malaria Prevention. Gaudinski MR, Berkowitz NM, Idris AH, Coates EE, Holman LA, Mendoza F, Gordon IJ, Plummer SH, Trofymenko O, Hu Z, Campos Chagas A, O'Connell S, Basappa M, Douek N, Narpala SR, Barry CR, Widge AT, Hicks R, Awan SF, Wu RL, Hickman S, Wycuff D, Stein JA, Case C, Evans BP, Carlton K, Gall JG, Vazquez S, Flach B, Chen GL, Francica JR, Flynn BJ, Kisalu NK, Capparelli EV, McDermott A, Mascola JR, Ledgerwood JE, Seder RA; VRC 612 Study Team. N Engl J Med. 2021 Aug 11. VRC 612 Part C: The antimalarial monoclonal antibody (mAb), CIS43, was derived from a subject immunized with the malaria species, Plasmodium Falciparum (Pf), whole-sporozoite (SPZO) vaccine and targets a conserved epitope within the junctional region of the Pf circumsporozoite protein. CIS43 was modified to contain a leucine to serine (LS) mutation in the Fc region of the heavy chain of the antibody that increases neonatal Fc-receptor binding and consequent antibody half-life. In Part B of the VRC 612 trial, a phase 1, dose escalation, open label trial, CIS43LS was found to confer a high level of protection at doses of 20 to 40 mg/kg intravenously (IV) following controlled human malaria infection (CHMI) in nave healthy volunteers. To assess whether CIS43LS could mediate protection at lower doses and by a subcutaneous (SC) route of administration, in Part C, it was administered to malaria-nave healthy volunteer participants 18 to 50 years of age at 1 (n=7), 5 (n=4) or 10 (n=3) mg/kg IV, and 5 (n=4) and 10 (n=4) mg/kg subcutaneously. Safety and pharmacokinetic analyses were performed. About 8 weeks following mAb administration, participants underwent CHMI by bites of 5 mosquitoes infected with the 3D7 strain of Pf. Six additional nave control participants underwent CHMI simultaneously. Participants were followed daily from Days 7 to 18 after CHMI by qualitative PCR used for Pf detection. Participants who tested positive were treated with atovaquone-proguanil and those who remained negative were treated on Day 21. Administration of CIS43LS was safe and well tolerated with mild adverse events reported. No serious adverse events occurred. All 6 control participants and 4 of the 7 participants dosed at 1 mg/kg IV developed parasitemia following CHMI. Participants dosed at 5 mg/kg or greater by the IV or SC route were protected from malaria infection approximately 8 weeks after administration of CIS43LS. This study provides proof of concept that a low dose of a malaria mAb administered by the IV or SC route provides high level protection against malaria in a controlled human infection model. Phase 1/2 studies have been conducted in malaria endemic regions. VRC 612 Part C manuscript is in preparation. Lancet Infect Dis 2023;23:578-88. PMID: 36708738 VRC 614: VRC 614 is a phase 1, open-label, dose-escalation trial that evaluated the safety, pharmacokinetic properties, and efficacy of a next-generation antimalarial mAb, L9LS. Eighteen adults without previous malaria infection or vaccination received L9LS either intravenously at 1 mg (n=5), 5 mg (n=4), or 20 mg (n=4) per kilogram or subcutaneously at 5 gm (n=5) per kilogram. Nine additional participants served as controls. Two to 6 weeks after administration of L9LS, participants underwent controlled human malaria infection (CHMI). Reactogenicity was mild to moderate in severity and self-limited. L9LS serum concentrations increased in a dose-dependent manner. Estimated half-life was 56 days. Among 17 L9LS recipients exposed to P.falciparum, parasitemia developed in 2 recipients, one who received a 1 mg per kilogram dose IV, and a second recipient who received 5 mg per kilogram subcutaneously. Parasitemia developed in all 6 controls. Protection after CHMI was observed with concentrations of L9LS as low as 9.2 ug per milliliter. Pharmacokinetic modeling indicated that a concentration of L9LS in the range of 5 to 11 ug per milliliter would remain in the circulation at 6 months in participants who received 5 mg per kg subcutaneously. These findings may have important public health and clinical implications because they establish the potential to advance protection against malaria in regions with seasonal and perennial transmission. This trial provides proof of principle that prevention of malaria can be achieved with a next generation mAb, L9LS. The subcutaneous regimen of a single low dose warrants further study to define its potential to limit malaria associated morbidity and mortality among infants and children where malaria is endemic. Phase 2 field studies are ongoing in malaria endemic regions. N Engl J Med. 2022 Aug 4;387(5):397-407. doi: 10.1056/NEJMoa2203067. PMID: 35921449.