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Low-dose intravenous and subcutaneous CIS43LS monoclonal antibody for protection against malaria (VRC 612 Part C): a phase 1, adaptive trial - 20/04/23

Doi : 10.1016/S1473-3099(22)00793-9 
Kirsten E Lyke, ProfMD a, , Andrea A Berry, MD a, Kaitlin Mason, RN a, Azza H Idris, MD b, Mark O’Callahan, BS b, Myra Happe, PhD b, Larisa Strom, MPH b, Nina M Berkowitz, MPH b, Mercy Guech, PhD b, Zonghui Hu, PhD c, Mike Castro, MS b, Manjula Basappa, BS b, Lu Wang, BA b, Kwang Low, PhD b, LaSonji A Holman, FNP b, Floreliz Mendoza, RN b, Ingelise J Gordon, RN b, Sarah H Plummer, MSN b, Olga Trofymenko, MD b, Kathleen S Strauss, BA a, Sudhaunshu Joshi, MS a, Biraj Shrestha, MS a, Matthew Adams, BS a, Andrezza Campos Chagas, PhD d, Jittawadee R Murphy, PhD d, Judy Stein, MBA b, Somia Hickman, PhD b, Andrew McDougal, PhD b, Bob Lin, BS b, Sandeep R Narpala, MS b, Sandra Vazquez, MS b, Leonid Serebryannyy, PhD b, Adrian McDermott, PhD b, Martin R Gaudinski, MD b, e, Edmund V Capparelli, ProfPharmD f, Emily E Coates, PhD b, Richard L Wu, MD b, e, Julie E Ledgerwood, DO b, Lesia K Dropulic, MD b, Robert A Seder, MD b
on behalf of the

VRC 612 Part C Study Team

  Members listed at the end of the Article
Cheryl Young, Colleen Boyce, Jennifer Winkler, Susan Holian, Nancy Greenberg, Shirley George, Alyson Kwon, Brenda Dorsey, Ana Raquel Da Costa, William Witt, Daryl Grays, Arren Gapasin, Paula Bernal, Jeffrey Floyd, Eric Goldstein, Leslie Howe, Myounghee Lee, Jennifer Marron, Kelly Brooks, Lisa Turek, Patricia Farley, Shantel Frels, Delores Booth, Jason Gall, Kevin Carlton, Gabriela Albright, Nadia Amharref, Kandace Atallah, Sashikanth Banappagari, Niutish Bastani, Daniel Blackstock, Bobby Boonyaratanakornkit, Elizabeth Carey, Adam Charlton, Rajoshi Chaudhuri, Alegria M. Caringal, Mingzhong Chen, Peifeng Chen, Wei Cheng, Daniel Gowetski, Krishana Gulla, Erica Hastings, Joe Horwitz, Vera Ivleva, Dan Kordella, Lisa A. Kueltzo, Sara Lagler, Matt Le, James Lee, Paula Lei, Yile Li, Attila Nagy, Aakash Patel, Peyi Runsewe, Will Shadrick, Shamitha Shetty, Hairong Wang, Calvin Webber, Farah Vejzagic, Yoo-Jung Yang

a Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA 
b Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA 
c Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA 
d Entomology Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA 
e United States Public Health Service Commissioned Corps, Rockville, MD, USA 
f School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, CA, USA 

* Correspondence to: Prof Kirsten E Lyke, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA Center for Vaccine Development and Global Health University of Maryland School of Medicine Baltimore MD 21201 USA

Summary

Background

Human monoclonal antibodies might offer an important new approach to reduce malaria morbidity and mortality. In the first two parts of a three-part clinical trial, the antimalarial monoclonal antibody CIS43LS conferred high protection against parasitaemia at doses of 20 mg/kg or 40 mg/kg administered intravenously followed by controlled human malaria infection. The ability of CIS43LS to confer protection at lower doses or by the subcutaneous route is unknown. We aimed to provide data on the safety and optimisation of dose and route for the human antimalaria monoclonal antibody CIS43LS.

Methods

VRC 612 Part C was the third part of a three-part, first-in-human, phase 1, adaptive trial, conducted at the University of Maryland, Baltimore Center for Vaccine Development and Global Health, Baltimore, MD, USA. We enrolled adults aged 18–50 years with no previous malaria vaccinations or infections, in a sequential, dose-escalating manner. Eligible participants received the monoclonal antibody CIS43LS in a single, open-label dose of 1 mg/kg, 5 mg/kg, or 10 mg/kg intravenously, or 5 mg/kg or 10 mg/kg subcutaneously. Participants underwent controlled human malaria infection by the bites of five mosquitoes infected with Plasmodium falciparum 3D7 strain approximately 8 weeks after their monoclonal antibody inoculation. Six additional control participants who did not receive CIS43LS underwent controlled human malaria infection simultaneously. Participants were followed-up daily on days 7–18 and day 21, with qualitative PCR used for P falciparum detection. Participants who tested positive for P falciparum were treated with atovaquone-proguanil and those who remained negative were treated at day 21. Participants were followed-up until 24 weeks after dosing. The primary outcome was safety and tolerability of CIS43LS at each dose level, assessed in the as-treated population. Secondary outcomes included protective efficacy of CIS43LS after controlled human malaria infection. This trial is now complete and is registered with ClinicalTrials.gov, NCT04206332.

Findings

Between Sept 1, 2021, and Oct 29, 2021, 47 people were assessed for eligibility and 31 were enrolled (one subsequently withdrew and was replaced) and assigned to receive doses of 1 mg/kg (n=7), 5 mg/kg (n=4), and 10 mg/kg (n=3) intravenously and 5 mg/kg (n=4) and 10 mg/kg (n=4) subcutaneously, or to the control group (n=8). CIS43LS administration was safe and well tolerated; no serious adverse events occurred. CIS43LS protected 18 (82%) of 22 participants who received a dose. No participants developed parasitaemia following dosing at 5 mg/kg intravenously or subcutaneously, or at 10 mg/kg intravenously or subcutaneously. All six control participants and four of seven participants dosed at 1 mg/kg intravenously developed parasitaemia after controlled human malaria infection.

Interpretation

CIS43LS was safe and well tolerated, and conferred protection against P falciparum at low doses and by the subcutaneous route, providing evidence that this approach might be useful to prevent malaria across several clinical use cases.

Funding

National Institute of Allergy and Infectious Diseases, National Institutes of Health.

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Vol 23 - N° 5

P. 578-588 - mai 2023 Retour au numéro
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