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Multicenter Study
. 2024 May;31(5-6):273-284.
doi: 10.1038/s41434-024-00441-5. Epub 2024 Feb 14.

Multicenter assessment and longitudinal study of the prevalence of antibodies and related adaptive immune responses to AAV in adult males with hemophilia

Ingrid Pabinger  1 , Mila Ayash-Rashkovsky  2 , Miguel Escobar  3 , Barbara A Konkle  4   5 , María Eva Mingot-Castellano  6   7 , Eric S Mullins  8 , Claude Negrier  9 , Luying Pan  2 , Kavitha Rajavel  10 , Brian Yan  2 , John Chapin  11
Affiliations
Multicenter Study

Multicenter assessment and longitudinal study of the prevalence of antibodies and related adaptive immune responses to AAV in adult males with hemophilia

Ingrid Pabinger et al. Gene Ther. 2024 May.

Abstract

Adeno-associated virus (AAV) based gene therapy has demonstrated effective disease control in hemophilia. However, pre-existing immunity from wild-type AAV exposure impacts gene therapy eligibility. The aim of this multicenter epidemiologic study was to determine the prevalence and persistence of preexisting immunity against AAV2, AAV5, and AAV8, in adult participants with hemophilia A or B. Blood samples were collected at baseline and annually for ≤3 years at trial sites in Austria, France, Germany, Italy, Spain, and the United States. At baseline, AAV8, AAV2, and AAV5 neutralizing antibodies (NAbs) were present in 46.9%, 53.1%, and 53.4% of participants, respectively; these values remained stable at Years 1 and 2. Co-prevalence of NAbs to at least two serotypes and all three serotypes was present at baseline for ~40% and 38.2% of participants, respectively. For each serotype, ~10% of participants who tested negative for NAbs at baseline were seropositive at Year 1. At baseline, 38.3% of participants had detectable cell mediated immunity by ELISpot, although no correlations were observed with the humoral response. In conclusion, participants with hemophilia may have significant preexisting immunity to AAV capsids. Insights from this study may assist in understanding capsid-based immunity trends in participants considering AAV vector-based gene therapy.

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Conflict of interest statement

MA-R was an employee of Takeda Development Center Americas, Inc. and Takeda stockholder at the time the study was conducted. JC, LP, KR and BY employees of Takeda Development Center Americas, Inc., and Takeda stockholders. ME honoraria for advisory boards or consulting (NovoNordisk, Takeda, Bayer, CSL Behring, Genentech/Roche, UniQure, Biomarin, Sanofi, Pfizer, Hemobiologics/LFB, NHF); research support (NovoNordisk, Uniqure, Baxalta, Bayer, Sanofi, Takeda, Pfizer, and OPKO Biologics). BK research support (CSL Behring, Pfizer, Sanofi, Spark, Takeda, and Uniqure); consulting fees (BioMarin, Novo Nordisk, Pfizer, Regeneron, Sanofi, Takeda, and Uniqure). MEM-C: none. ESM: research support (Takeda); consulting fees (Takeda). CN: research support (Roche, Sobi, and Takeda); advisory board/consulting fees (Bayer, Biomarin, CSL Behring, Novo Nordisk, Pfizer, Roche, Sanofi, Sobi, Takeda, and UniQure). IP research support (CSL Behring and Sobi and Roche Diagnostics to the Medical University of Vienna); honoraria for lectures, advisory boards, or participating as an advisor (CSL Behring, Takeda, Roche, Sobi, NovoNordisk, Bayer, Pfizer, Sandoz).

Figures

Fig. 1
Fig. 1. Participant disposition.
aNine participants had personal laboratory evidence of having developed inhibitors to FVIII or FIX protein at any time (≥0.6 Bethesda units on any single test), one participant had a bleeding disorder other than hemophilia A or B, and one participant did not have established severe hemophilia A (plasma FVIII activity <1%) or B (plasma FIX activity ≤2%). ICF informed consent form.
Fig. 2
Fig. 2. Prevalence of NAbs to AAV8, AAV2, and AAV5.
Prevalence of NAbs to AAV8, AAV2, and AAV5 in participants with A hemophilia A, B hemophilia B, and C total number of participants. Serology samples were all collected on a similar schedule, the staggered display is for graphical clarity only. aPrevalence is defined as the percentage of participants who tested positive for NAb (equal to or greater than the NAb assay cut point) or negative (less than the NAb assay cut point) at the minimum required dilution (1:5) to the specific AAV serotype in a group. bBinomial exact Clopper-Pearson method was used to calculate 95% CIs. cn represents the total number of participants who had positive NAb titers at a visit in a group. n1 represents the total number of participants with NAb titer results at that visit.
Fig. 3
Fig. 3. NAb and BAb titers at baseline.
A NAb titers and B BAb titers in enrolled participants at baseline. An NAb value of 163,840 for one participant (AAV2) has been removed because it was too high and skewed the output.
Fig. 4
Fig. 4. Prevalence of IgG BAbs to AAV8, AAV2, and AAV5.
Prevalence of BAbs to AAV8, AAV2, and AAV5 in participants with A hemophilia A, B hemophilia B, and C total number of participants. aPrevalence is defined as the percentage of participants who tested positive (equal to or greater than screening assay floating cut point) or negative (less than the screening assay floating cut point) at the minimum required dilution (1:20) in a specific AAV serotype group. bBinomial exact Clopper-Pearson method was used to calculate 95% CIs. cn represents the total number of participants who had positive BAb titers at a visit in a group. n1 represents the total number of participants with BAb titer results at that visit. + indicates positive.
Fig. 5
Fig. 5. Co-prevalence of NAb and corresponding IgG BAb.
Percentage of total study participants with co-prevalence of NAb and corresponding IgG BAb with A NAb positive and B NAb negative titers. Longitudinal follow-up is presented.
Fig. 6
Fig. 6. Prevalence of T cell–mediated immune response to AAV8 peptides.
aPrevalence is defined as the percentage of participants who tested positive (equal to or greater than screening assay floating cut point) or negative (less than the screening assay floating cut point). bBinomial exact Clopper-Pearson method was used to calculate 95% CIs. cn represents the total number of participants who presented with antigen-specific response (overall or by pool) at each visit. n1 represents the total number of participants with ELISpot assay titer results at that visit.
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