Date Published: December 5, 2018
Publisher: Public Library of Science
Author(s): Hugh C. Welles, Madeleine F. Jennewein, Rosemarie D. Mason, Sandeep Narpala, Lingshu Wang, Cheng Cheng, Yi Zhang, John-Paul Todd, Jeffrey D. Lifson, Alejandro B. Balazs, Galit Alter, Adrian B. McDermott, John R. Mascola, Mario Roederer, Katie J Doores.
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 1012 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.
Antibodies mediate protection against infection for nearly all traditional licensed vaccines. To achieve protective antibody titers, active immunization has historically been employed. More recently, given advances in monoclonal antibody isolation and production technologies, delivery of prophylactic antibodies via passive vaccination is being considered for pathogens where active vaccination strategies have not succeeded. Advantages of passive immunization include better efficacy, enhanced coverage against multiple disease strains or serotypes, greater tolerability, and economics. Strategies to prevent infection via prophylactic administration of monoclonal antibodies are advancing clinically, with success against a variety of diseases (primarily in animal models): respiratory syncytial virus, Influenza A, hepatitis C, herpes simplex, Ebola, Rabies, cytomegalovirus, Hendravirus, and HIV.[1–3] As with all protein-based regimens, obstacles include cost of production[4,5], maintenance of functional drug levels[6–8], and rejection by anti-drug antibody responses.[7,9–11]
Our study demonstrates the utility of NHP to model passive immunization delivering native anti-viral mAbs via infusion or AAV. Infused mAbs behave as expected for native antibodies and were detected at the mucosal surfaces within a short timeframe following infusion.[7,36,37,39] The successful translocation of infused and AAV delivered mAb to the rectal mucosal is encouraging and the protective effect of AAV delivered antibodies against viral challenge represents an example of species matched AAV vectored immunoprophylaxis against infectious diseases.