Recent Advancements in AAV-Vectored Immunoprophylaxis in the Nonhuman Primate Model

Abstract

Monoclonal antibodies (mAbs) are important treatment modalities for preventing and treating infectious diseases, especially for those lacking prophylactic vaccines or effective therapies. Recent advances in mAb gene cloning from naturally infected or immunized individuals has led to the development of highly potent human mAbs against a wide range of human and animal pathogens. While effective, the serum half-lives of mAbs are quite variable, with single administrations usually resulting in short-term protection, requiring repeated doses to maintain therapeutic concentrations for extended periods of time. Moreover, due to their limited time in circulation, mAb therapies are rarely given prophylactically; instead, they are generally administered therapeutically after the onset of symptoms, thus preventing mortality, but not morbidity. Adeno-associated virus (AAV) vectors have an established record of high-efficiency in vivo gene transfer in a variety of animal models and humans. When delivered to post-mitotic tissues such as skeletal muscle, brain, and heart, or to organs in which cells turn over slowly, such as the liver and lungs, AAV vector genomes assume the form of episomal concatemers that direct transgene expression, often for the lifetime of the cell. Based on these attributes, many research groups have explored AAV-vectored delivery of highly potent mAb genes as a strategy to enable long-term expression of therapeutic mAbs directly in vivo following intramuscular or intranasal administration. However, clinical trials in humans and studies in nonhuman primates (NHPs) indicate that while AAVs are a powerful and promising platform for vectored immunoprophylaxis (VIP), further optimization is needed to decrease anti-drug antibody (ADA) and anti-capsid antibody responses, ultimately leading to increased serum transgene expression levels and improved therapeutic efficacy. The following review will summarize the current landscape of AAV VIP in NHP models, with an emphasis on vector and transgene design as well as general delivery system optimization. In addition, major obstacles to AAV VIP, along with implications for clinical translation, will be discussed.

Keywords: adeno-associated virus (AAV) vectors; human immunodeficiency virus (HIV); infectious diseases; nonhuman primate (NHP) model; passive immunization; therapeutic monoclonal antibodies; vectored immunoprophylaxis (VIP).

Figure 1

Immunoprotection by AAV-vectored immunoprophylaxis (AAV VIP): Infection of a healthy person with a virus triggers the production of antibodies as part of the host immune response. B cells are harvested from the convalesced individual, and potent neutralizing antibody clones are isolated so that their antibody genes can be cloned and sequenced. Subsequently, the variable-heavy and variable-light chains of neutralizing monoclonal antibodies (mAbs) are cloned into an AAV vector. AAV vectors engineered to express the desired mAbs are manufactured and administered intramuscularly. The transduced muscle cells then secrete these mAbs into the bloodstream, enabling them to circulate throughout the body, providing the host with durable and comprehensive protection against the target pathogen.

Figure 2

Long-term monitoring of AAV6.2FF-mediated expression of mAb MR191 in sheep serum following intramuscular administration of 5 × 10¹² vg/kg of AAV6.2FF-MR191.