Adeno-associated virus delivery of Env-specific antibodies affords durable protection against simian immunodeficiency virus challenge

Potent broadly neutralizing antibodies (bnAbs) can protect against immunodeficiency virus infection. However, it is presently unclear how to elicit bnAbs by vaccination. As an alternative, we evaluated adeno-associated virus (AAV) delivery of rhesus macaque antibodies to the SIV envelope glycoprotein for protection of macaques against mucosal SIV challenge. AAV vectors encoding a bnAb or an antibody that only mediates antibody-dependent cellular cytotoxicity (ADCC) against SIV-infected cells were administered individually or together to separate groups of eight rhesus macaques. Sustained antibody expression with minimal anti-drug antibody responses was achieved in most animals. After sixteen weeks, the animals underwent twelve weekly low-dose, intrarectal (IR) challenges with SIV_mac239. All animals that received vectors encoding a control antibody or the antibody that only mediates ADCC became infected after four challenges. However, fourteen of the sixteen animals that received the bnAb, either alone or in combination with the ADCC antibody, resisted all twelve challenges. A year later, serum concentrations of the vectored antibodies were unabated, so the protected animals and six naïve control animals were rechallenged by repeated, low-dose IR inoculation with SIV_mac239. While all of the control animals became infected after six challenges, the fourteen animals that received the bnAb remain uninfected after nine challenges. Thus, sustained expression of a potent bnAb can afford durable protection against pathogenic SIV challenge.