Higher Seroprevalence of Anti-Adeno-Associated Viral Vector Neutralizing Antibodies Among Racial Minorities in the United States

Abstract

Anti-adeno-associated viral vector (AAV) neutralizing antibodies (NAbs) can ablate efficacy of transgene expression following intravenous vector administration. This observation in both preclinical and clinical trials has led to exclusion of NAb-positive patients from receiving AAV gene therapy. AAV drug development includes selection of capsids with lower NAb seroprevalence that also possess other favorable traits. Often a limited number of healthy volunteers are screened to gauge NAb seroprevalence. However, limited data sets can be biased leading to inaccurate estimates of NAb incidence. In this study, we evaluated AAV NAbs against a panel of vectors among healthy donors within the United States. While the overall seroprevalence against most AAVs was lower, we did observe increased NAb incidence among black and Hispanic donors. These findings of increased NAb seroprevalence among the minority races were confirmed in a second set of donors who also demonstrated higher seroprevalence among these races. Interracial- and intraracial differences within genders were also observed among donors. The increased incidence of AAV NAb among racial minorities was unexpected. Our findings underscore the need for removing bias in sample data sets and evaluating seroprevalence within the patient population while selecting capsids.

The seroprevalence of neutralizing antibodies against the adeno-associated virus capsids in Japanese hemophiliacs

“…In some studies, total antibody binding with AAV capsid was measured, while others employed cell-based neutralizing assay. We used a cell-based assay because total antibody assays detect the binding antibody without any inhibitory effects 2,7,12 . On the other hand, the cell-based assay depends on the cells used in the experiments and the multiplicity of infection (MOI) of AAV 36 .…”

“…A recent global study of hemophilia A suggested the highest seropositivity to AAV5 in South Africa, Russia, Italy, and France compared with the United Kingdom, the United States, Germany, and Brazil 9 . Other factors, including race, age, and geographic location, are also known to affect the seroprevalence 3,7,9,10 . Previously, we reported that the seroprevalence in 40 years or older was much higher than those in younger populations in Japan 8 .…”

“…Surveys for the seroprevalence of anti-AAV Nabs have shown broadly varying results, ranging from 2.2% to 96.6% [2][3][4][5][6][7][8] . Several factors appear to account for the prevalence of Nabs, including the nationality.…”

“…Besides, seroprevalences differed among AAV serotypes. The seroprevalence against Clade B and C (AAV2 and AAV3B) that naturally infects humans displayed higher seropositivity than other serotypes, including Clade D and F (AAV8 and AAV9) 2,7,[11][12][13] . This study aimed to determine the seroprevalence of Nabs against various AAV serotypes and Nab titers in hemophiliacs and healthy individuals in Japan, in order to estimate the number of patients with hemophilia eligible for future gene therapy in this cross-sectional study.…”

“…Several factors appear to account for the prevalence of NAbs, including the geographical location. For example, high seroprevalence (∼96.6%) has been reported in India 4 , China 3 , and Korea 5 , compared with Europe 6 , the United States 7 , and Japan 8 . A recent global study of hemophilia A suggested the highest seropositivity to AAV5 in South Africa, Russia, Italy, and France compared with the United Kingdom, the United States, Germany, and Brazil 9 .…”