Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.816131
Title: Immunoprophylaxis of influenza using AAV vector delivery of cross-subtype neutralizing nanobodies
Author: Del Rosario, Joanne Marie M.
ISNI:       0000 0004 9353 5249
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2020
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Abstract:
Cross-subtype neutralizing single domain antibodies against influenza present new opportunities for immunoprophylaxis and pandemic preparedness. Their simple modular structure and single open reading frame format are highly amenable to gene therapy-mediated delivery. R1a-B6, an alpaca-derived single domain antibody (nanobody), that is capable of potent cross-subtype neutralization in vitro of H1N1, H5N1, H2N2, and H9N2 influenza viruses, through binding to a highly conserved epitope in the influenza hemagglutinin stem region, was previously described. To evaluate the potential of R1a-B6 for immunoprophylaxis via adeno-associated viral (AAV) vector delivery, it was reformatted as Fc fusions of mouse IgG1 (ADCC-) and IgG2a (ADCC+) isotypes. This is also to extend R1a-B6’s half-life and to assess the requirement for ADCC for efficacy of R1a-B6 in vitro and in vivo. It was found that reformatted R1a-B6 of either mouse IgG isotype retained its potent binding and neutralization activity against different Group I influenza A subtypes in vitro. The findings in this study also demonstrate that a single intramuscular injection in mice of AAV encoding R1a-B6-Fc was able to drive sustained high-level expression (0.5–1.1 mg/mL) of the nanobody-Fc in sera with no evidence of reduction for up to 6 months. R1a-B6-Fc fusions of both isotypes gave complete protection against lethal challenge with both pandemic A/California/07/2009 (H1N1)pdm09 and mouse-adapted avian influenza A/Vietnam/1194/2004 (H5N1). These data suggest that R1a-B6-Fc delivered via AAV is capable of cross-subtype protection and ADCC was not essential for protection. These findings reveal that AAV delivery of cross-subtype neutralizing nanobodies may be an effective strategy to prevent influenza infection and provide long-term protection independent of a host induced immune response.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.816131  DOI: Not available
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