Vectored delivery of anti-SIV envelope targeting mAb via AAV8 protects rhesus macaques from repeated limiting dose intrarectal swarm SIVsmE660 challenge

• Published in: PLoS pathogens Vol. 14; no. 12; p. e1007395
• Main Authors: Welles, Hugh C., Jennewein, Madeleine F., Mason, Rosemarie D., Narpala, Sandeep, Wang, Lingshu, Cheng, Cheng, Zhang, Yi, Todd, John-Paul, Lifson, Jeffrey D., Balazs, Alejandro B., Alter, Galit, McDermott, Adrian B., Mascola, John R., Roederer, Mario
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.12.2018; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; AIDS; Animal models; Animals; Antibodies; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - immunology; Antibodies, Neutralizing - administration & dosage; Antibodies, Neutralizing - immunology; Antibodies, Viral - administration & dosage; Antibody response; Antigens; Binding sites; Biology and Life Sciences; Clinical trials; Constraining; Dependovirus; Drug dosages; Expression vectors; Feasibility studies; Gene expression; Gene therapy; Genetic aspects; Genetic Therapy - methods; Genetic Vectors; Genomes; Glycosylation; Health risks; HIV; Human immunodeficiency virus; Immunity; Immunization; Immunization (passive); Immunization, Passive - methods; Immunoglobulins; Infections; Infectious diseases; Influenza; Macaca mulatta; Medical research; Medicine and Health Sciences; Monoclonal antibodies; Mucosa; Muscles; Neutralization; Proteins; Publishing; Quantitation; Research and Analysis Methods; Rhesus monkey; SAIDS Vaccines; Simian Acquired Immunodeficiency Syndrome - prevention & control; Simian Immunodeficiency Virus; Supervision; Transgenes; Vaccines; Viral Envelope Proteins - immunology; Viruses; United States > US; Maryland; Massachusetts
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1007395

Gene based delivery of immunoglobulins promises to safely and durably provide protective immunity to individuals at risk of acquiring infectious diseases such as HIV. We used a rhesus macaque animal model to optimize delivery of naturally-arising, autologous anti-SIV neutralizing antibodies expressed by Adeno-Associated Virus 8 (AAV8) vectors. Vectored transgene expression was confirmed by quantitation of target antibody abundance in serum and mucosal surfaces. We tested the expression achieved at varying doses and numbers of injections. Expression of the transgene reached a saturation at about 2 x 10(12) AAV8 genome copies (gc) per needle-injection, a physical limitation that may not scale clinically into human trials. In contrast, expression increased proportionately with the number of injections. In terms of anti-drug immunity, anti-vector antibody responses were universally strong, while those directed against the natural transgene mAb were detected in only 20% of animals. An anti-transgene antibody response was invariably associated with loss of detectable plasma expression of the antibody. Despite having atypical glycosylation profiles, transgenes derived from AAV-directed muscle cell expression retained full functional activity, including mucosal accumulation, in vitro neutralization, and protection against repeated limiting dose SIVsmE660 swarm challenge. Our findings demonstrate feasibility of a gene therapy-based passive immunization strategy against infectious disease, and illustrate the potential for the nonhuman primate model to inform clinical AAV-based approaches to passive immunization.