High Prevalence of Preexisting Neutralizing Antibodies Against Adeno-Associated Virus Capsids in Mongolian People with Hemophilia

<jats:p>Adeno-associated virus (AAV) vector–mediated gene therapy for hemophilia offers the potential for sustained therapeutic benefit after a single administration and is particularly attractive in regions with limited access to standard therapies. However, the prevalence of anti-AAV neutralizing antibodies (NAbs), which can impair therapeutic efficacy, varies geographically and remains poorly characterized in Mongolia. Here, we evaluated the seroprevalence of NAbs against clinically relevant AAV serotypes in Mongolia. NAbs against AAV3B, AAV5, and AAV8 were assessed in serum samples from 23 healthy volunteers and 52 people with hemophilia (PwH) using a validated cell-based transduction inhibition assay. A high seroprevalence of anti-AAV NAbs was observed across all three serotypes in both healthy volunteers (69.6%–87.0%) and PwH (78.9%–84.6%), with no significant differences between groups. NAbs were detected across all age groups, including early childhood, and frequently exhibited neutralization against multiple AAV serotypes, which was associated with higher NAb titers. Taken together, anti-AAV NAbs are highly prevalent and acquired early in life in the Mongolian population, with multiserotype neutralization patterns. These findings identify a substantial population-specific barrier to AAV-mediated gene therapy and highlight the need for alternative therapeutic strategies beyond AAV-based platforms to overcome immunological constraints in this setting.</jats:p>