Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 46; pp. 18921 - 18925
• Main Authors: Moldt, Brian, Rakasz, Eva G, Schultz, Niccole, Chan-Hui, Po-Ying, Swiderek, Kristine, Weisgrau, Kimberly L, Piaskowski, Shari M, Bergman, Zachary, Watkins, David I, Poignard, Pascal, Burton, Dennis R
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 13.11.2012; National Acad Sciences
• Subjects: Animals; Antibodies; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antibodies, Neutralizing - immunology; Antibodies, Neutralizing - pharmacology; antigens; Biological Sciences; blood serum; Female; HIV; HIV 1; HIV Antibodies - immunology; HIV Antibodies - pharmacology; HIV Infections - immunology; HIV Infections - prevention & control; HIV-1 - immunology; Human immunodeficiency virus; Humans; Immunization; Immunization, Passive; Immunology; Inhibitory concentration 50; Macaca mulatta; Monkeys & apes; Monoclonal antibodies; neutralization; Neutralizing antibodies; Shivs; Sterilization; sterilizing immunity; Vaccination; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1214785109

Most animal studies using passive administration of HIV broadly neutralizing monoclonal antibodies (bnMAbs) have associated protection against high-dose mucosal viral challenge with relatively high serum concentrations of antibody. We recently identified several bnMAbs remarkable for their in vitro potency against HIV. Of these bnMAbs, PGT121 is one of the most broad and potent antibodies isolated to date and shows 10- to 100-fold higher neutralizing activity than previously characterized bnMAbs. To evaluate the protective potency of PGT121 in vivo, we performed a protection study in rhesus macaques. Animals were i.v. administered 5 mg/kg, 1 mg/kg, or 0.2 mg/kg PGT121 24 h before being vaginally challenged with a single high dose of chimeric simian-human immunodeficiency virus (SHIV) SF₁₆₂P₃. Sterilizing immunity was achieved in all animals administered 5 mg/kg and 1 mg/kg and three of five animals administered 0.2 mg/kg PGT121, with corresponding average antibody serum concentrations of 95 µg/mL, 15 µg/mL, and 1.8 µg/mL, respectively. The results suggest that a protective serum concentration for PGT121 is in the single-digit µg/mL for SHIV SF₁₆₂P₃, showing that PGT121 can mediate sterilizing immunity at serum concentrations that are significantly lower than those observed in previous studies and that may be achievable through vaccination with the development of a suitable immunogen.