Adeno-associated viruses have emerged as one of the most promising viral vectors for gene therapy. In the last six years, the U.S. FDA has approved drugs using different serotypes of recombinant AAV vectors, including AAV2, AAV5 and AAV9 (FDA submission tracking numbers 125610, 125694, 125772, 125720, 125781 and 125786, respectively, in chronological order). However, as preexisting NAbs jeopardize effective treatment18,19, knowing the population seroprevalence profile has practical value in a clinical setting and for AAV drug development. This study was designed to stratify the seroprevalence of the Basque population. To the best of our knowledge, no prior study of this nature has been conducted in the Basque region. We showed that the population of the Basque Autonomous Region possesses the highest seroprevalence of neutralizing antibodies against AAV3, compared to the AAV2 seroprevalence found in previous reports for cohorts in the U.S., Belgium, Greece, Italy, Kenya, Rwanda, South Africa, Uganda, Zambia, Australia, France, China and Japan10,12,13,14,20,21,22. In addition, our study revealed that, in the Basque cohort, there was a statistically significant decrease in the AAV1, AAV2, AAV4, AAV5, AAV6, AAV8, and AAV9 seroprevalence versus the AAV3 seroprevalence. Moreover, less than 50% of the residents in the Basque Country possess neutralizing antibodies against AAV4, AAV6 and AAV9. In this context, these serotypes might be more suitable targets for gene therapy development.
We also observed co-seroreactivity across different AAV serotypes within the Basque cohort. Co-seroreactivity occurs when (i) an individual has been infected with different AAV serotypes throughout her/his life, thus possessing both specific NAbs, and/or (ii) a NAb raised against a specific serotype recognizes multiple serotypes. The latter difference may be explained by the structural and/or primary sequence homology of the VP1-VP2-VP3 capsid proteins across the different serotypes. An example of this could be those sera positive for neutralizing anti-AAV6 antibodies that are also positive for neutralizing antibodies against AAV1, AAV2 and AAV3 [largest structural pairwise root-mean-square-deviation (rmsd) = 0.8 Å between 518 equivalent Cα in AAV6 versus AAV3 and a minimal sequence identity > 83% between AAV6 versus AAV2; PDB ids for AAV6, AAV1, AAV2 and AAV3: 3OAH, 6JCR, 6IH9 and 3KIE, respectively].
However, this rationale has its limitations as it does not explain the significant differences, such as the low prevalence percentage observed for AAV9 among the AAV8-positive serum samples, despite displaying a rmsd of 1.1 Å between 518 equivalent Cα and a sequence identity > 85% (PDB ids for AAV9 and AAV8: 7MT0 and 6V12, respectively)23. It is important to consider that most NAbs interact with the receptor binding domains located at the threefold axis of symmetry on the capsid, and these interactions typically involve a few key residues conformationally competent.
Posttranslational modifications, such as glycosylation, though less common in nonenveloped viruses, remain largely unexplored in AAV research and might modulate NAb recognition24.
When analysing our results derived from the Basque cohort against those available from other EU cohorts (France, Belgium, Italy and Greece), we noticed that only seroprevalence data for AAV1, AAV2 and AAV8 were common. A comparison of the percentages of seropositivity against AAV1 showed that in the Basque cohort, there was a statistically significant increase (42%) relative to that in the Italian cohort (13%), which was more in line with the seropositivity values of other EU countries.
In the case of NAbs against AAV2, the Basque cohort (54%) had seroprevalences similar to those of the French and Belgian cohorts but significantly different from the lower percentages of the Italian (23%) and Greek (37%) cohorts. Notably, for the remaining serotypes, when we compared the Basque cohort against the French cohort (which is the closest country geographically), there were large statistically significant differences in AAV5 (42% vs. 4%) and AAV9 (17% vs. 34%)10,13.
When all European data were combined, AAV2 (44%) and AAV8 (29%) were the serotypes that exhibited the most significant differences, with a decrease in prevalence for both serotypes in the U.S. (28% and 14%), an increase in both serotypes in China (92% and 69%, respectively) and an increase in AAV2 in Africa (56%). Regarding the prevalence of AAV1, only the U.S. (20%) showed a decrease when compared to Europe (37%). Finally, only one previous study analysed NAbs against the AAV3 serotype, revealing that there is a large statistical increase in NAbs in China (89%) compared to Europe (52%). Intriguingly, Australia, the furthest location from Europe, showed no significant differences from the EU cohort in any of the serotypes analysed.
In conclusion, our AAV seroprevalence study in a cohort of residents of the Basque Country provides an epidemiological picture that supports a seroprevalence profile closer to that of countries geographically located in Western Europe rather than in Southern Europe. Nevertheless, as in many countries worldwide, the Basque region is experiencing transformation due to widespread migration movements. Consequently, these studies require constant updates to determine the evolving seroprevalence profile of NAbs against AAVs worldwide, which is crucial for developing AAV-based gene therapies.
- SEO Powered Content & PR Distribution. Get Amplified Today.
- PlatoData.Network Vertical Generative Ai. Empower Yourself. Access Here.
- PlatoAiStream. Web3 Intelligence. Knowledge Amplified. Access Here.
- PlatoESG. Carbon, CleanTech, Energy, Environment, Solar, Waste Management. Access Here.
- PlatoHealth. Biotech and Clinical Trials Intelligence. Access Here.
- Source: https://www.nature.com/articles/s41598-024-66546-4