Vectored Immunoprophylaxis (VIP) is a gene-based approach to vaccination that delivers genetic instructions for an antibody, enabling the host to produce an immune response without engaging the traditional humoral pathway. Adeno-associated virus (AAV) vectors are well-suited for in vivo antibody gene delivery due to their low pathogenicity, minimal genome integration, sustained transgene expression, and liver/muscle tropism—optimal sites for monoclonal antibody (mAb) production. AAV has been used in non-human primates (NHPs) and clinical trials, but studies report transient antibody expression due to anti-drug antibodies (ADAs) and anti-capsid immune responses, limiting repeat dosing.

A study by the Wootton lab demonstrated AAV6.2FF-mediated expression of the anti-Marburg virus mAb MR191 in sheep for over 1100 days with low ADA and anti-capsid responses, contradicting findings in NHPs. This discrepancy may be due to differences in AAV serotype, host age, or the sequence divergence from the germline of the expressed mAb. Notably, NHP studies primarily tested highly somatically hypermutated broadly neutralizing HIV mAbs (bNAbs), whereas MR191 was derived from a patient recovering from acute Marburg infection and would therefore have undergone less hypermutation. The higher divergence from the germline in bNAbs may contribute to increased immunogenicity.

This study will assess these factors in a sheep model to better understand their role in ADA development. Determining how mAb sequence divergence, host age, and AAV serotype influence immune responses to VIP will hopefully help decrease the incidence of ADAs and improve the durability of AAV-mediated antibody expression.