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Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses
Open accessAbstract
Recombinant adeno-associated viruses (AAVs) have unique gene-transfer properties that speak to their potential as carriers for gene therapy or vaccine applications. However, the presence of neutralizing antibodies to AAV as a result of previous exposure can significantly limit effective gene transfer. In this study, we obtained 888 human serum samples from healthy volunteers in 10 countries around the world. Samples were assayed for neutralizing antibodies to AAV1, AAV2, AAV7, and AAV8, as well as to a novel, structurally distinct AAV vector, rh32.33, in an in vitro transduction inhibition assay. Our data revealed that neutralizing antibodies to AAV2 were the most prevalent antibodies in all regions, followed by antibodies to AAV1. The seroprevalences of antibodies to AAV7 and to AAV8 were lower than that for antibodies to AAV1, and neutralization of AAVrh32.33 was only rarely detected. Our data also indicate a strong linkage of seroreactivity between apparently distinct serotypes that has not been predicted previously in animal models.
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“Seropositivity rate in our cohort was comparatively lower than that found in healthy human populations and in clinical trial patients, which ranged between 22-90% in different reports [7, 23, 24].”
From Characterization of anti-AAV2 neutralizing antibody levels in sheep prior to and following intravitreal AAV2.7m8 injection (2024) · cites this paper as [23]
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In the citing paper
“Another study analyzing over 800 patient samples from 4 continents and 10 countries also concluded that the NABs against AAV1 and AAV2 were higher than anti-AAV7 or anti-AAV8 NABs in humans.13”
From Systemic and local immune responses to intraocular AAV vector administration in non-human primates (2022) · cites this paper as [13]
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“In humans, anti-AAV2 NABs were found to be much higher than anti-AAV7 or -AAV8.12,13”
From Systemic and local immune responses to intraocular AAV vector administration in non-human primates (2022) · cites this paper as [13]
In the citing paper
“Antibodies against different AAV serotypes have been observed in human populations (Calcedo et al., 2009; Boutin et al., 2010).”
From AAV2 and AAV9 tropism and transgene expression in the mouse eye and major tissues after intravitreal and subretinal delivery (2023) · cites this paper as Calcedo et al., 2009
In the citing paper
“Of these, anti-AAV2 and AAV1 NAbs are the most prevalent NAbs among AAV capsid variants [69].”
From Immunogenicity of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Transfer (2023) · cites this paper as [69]
In the citing paper
“The prevalence of anti-AAV antibodies in the human population ranges from 40-70% depending on the serotype, geographical location, or ethnicity (3–5).”
From Pre-existing humoral immunity and complement pathway contribute to immunogenicity of adeno-associated virus (AAV) vector in human blood (2022) · cites this paper as [3]
In the citing paper
“Worldwide, a high level of AAV seropositivity is observed (40-70% depending on the serotype, geographical location, or ethnicity).[83][84][85]”
From Innate immune sensing of adeno-associated virus vectors (2024) · cites this paper as [83]
In the citing paper
“Most rAAV clinical trials exclude seropositive patients; given the high seroprevalence (60% for AAV2), limiting patients suitable for rAAV therapy (7, 8).”
From Immunomodulation in Administration of RAAV: Preclinical and Clinical Adjuvant Pharmacotherapies (2021) · cites this paper as [7]
In the citing paper
“Most rAAV clinical trials exclude seropositive patients; given the high seroprevalence (60% for AAV2), limiting patients suitable for rAAV therapy (7, 8).”
From Immunomodulation in Administration of RAAV: Preclinical and Clinical Adjuvant Pharmacotherapies (2021) · cites this paper as [7]
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Citations
Cites
Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy
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Self-citationClades of Adeno-Associated Viruses Are Widely Disseminated in Human Tissues
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Self-citationImmune responses to adenovirus and adeno-associated virus in humans
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Self-citationRecombinant adeno-associated virus for muscle directed gene therapy
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Self-citationGene therapy vectors based on adeno-associated virus type 1
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Self-citationAdeno-associated viruses undergo substantial evolution in primates during natural infections
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A STEP into Darkness or Light?
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Research works printed but not linked: 1
- Blacklow NR, 1968, J Natl Cancer Inst, 40, 319
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Adeno-associated virus vector as a platform for gene therapy delivery
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Self-citationCre-dependent selection yields AAV variants for widespread gene transfer to the adult brain
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Metadata
- Authors
- Calcedo, R., Vandenberghe, L. H., Gao, G., Lin, J., & Wilson, J. M.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Wilson, James M.
- Venue
- The Journal of Infectious Diseases
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-02
- Volume
- 199
- Issue
- 3
- Pages
- 381-390
- ISSN
- 0022-1899 (ISSN-L)
- 1537-6613
- PMC
- PMC10826927
- OpenAlex
- W2170205772
- Cited by
- 808
- References
- 23
- Citations by year
- 2026: 48 · 2025: 56 · 2024: 80 · 2023: 57 · 2022: 63 · 2021: 62 · 2020: 49 · 2019: 49 · 2018: 45 · 2017: 39 · 2016: 33 · 2015: 41 · 2014: 33 · 2013: 41 · 2012: 37
- FWCI
- 21.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Infectious Diseases (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- International AIDS Vaccine Initiative
- GlaxoSmithKline
- University of Pennsylvania
- Vlaamse regering
- National Institutes of Health
- National Heart, Lung, and Blood Institute (P01HL059407, P01HL051746)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK047757)
- Institute of Genetics
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Epidemiology › Virology and Viral Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- adeno-associated virus, neutralizing antibodies, seroprevalence, AAV1, AAV2, AAV8, gene therapy vectors, human serum samples
- MeSH terms
- Dependovirus, Africa, Antibodies, Viral, Australia, Europe, Humans, Parvoviridae Infections, Phylogeny, United States, Global Health, Seroepidemiologic Studies
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