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Antibody-based protection against respiratory syncytial virus in mice and their offspring through vectored immunoprophylaxis

Gene Therapy (2023)Cite this article

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Abstract

Respiratory syncytial virus (RSV) causes acute lower respiratory tract infections, with potential lower respiratory tract infections, which can be particularly problematic in infants and the elderly. There are no approved vaccines for RSV. The current standard of care for high-risk individuals is monthly administration of palivizumab, a humanized murine monoclonal antibody (mAb) targeting the RSV fusion protein. Adeno-associated virus (AAV)-mediated expression of mAbs has previously led to sustained expression of therapeutic concentrations of mAbs in several animal models, representing an alternative to repetitive passive administration. Intramuscular (IM) administration of AAV6.2FF expressing RSV antibodies, palivizumab or hRSV90, resulted in high concentrations of human (h)IgG1 mAbs in the serum and at various mucosal surfaces, while intranasal administration limited hIgG expression to the respiratory tract. IM administration of AAV6.2FF-hRSV90 or AAV6.2FF-palivizumab in a murine model provided sterilizing immunity against challenge with RSV A2. Evidence of maternal passive transfer of vectorized hRSV90 was detected in both murine and ovine models, with circulating mAbs providing sterilizing immunity in mouse progeny. Finally, addition of a “kill switch” comprised of LoxP sites flanking the mAb genes resulted in diminished serum hIgG after AAV-DJ-mediated delivery of Cre recombinase to the same muscle group that was originally transduced with the AAV-mAb vector. The ability of this AAV-mAb system to mediate robust, sustained mAb expression for maternal transfer to progeny in murine and ovine models emphasizes the potential of this platform for use as an alternative prophylactic vaccine for protection against neonatal infections, particularly in high-risk infants.

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Fig. 1: Human IgG expression at various mucosal surfaces and in the serum after IM or IN administration of AAV6.2FF-hRSV90 or AAV6.2FF-palivizumab.
Fig. 2: Mice expressing AAV6.2FF-palivizumab and AAV6.2FF-hRSV90 were completely protected from RSV challenge.
Fig. 3: AAV6.2FF-hRSV90 administered mice successfully transfer human IgG to offspring.
Fig. 4: Maternally transferred hRSV90 from AAV6.2FF-hRSV90 transduced mice provides sterilizing immunity against RSV infection.
Fig. 5: Maternal transfer of human IgG in sheep administered an AAV6.2FF-expressing mAb.
Fig. 6: Addition of Cre-recombinase provides variable depression of human IgG levels AAV-mAb administration.

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Acknowledgements

We would like to thank all those who were involved in the care of the animals for these studies. This research was funded by grants from the Canadian Institutes of Health Research (CIHR grant # PJ4 179807) and Mitacs Accelerate (IT27042). ADR, JGEY and JAL are all recipients of the OVC scholarship, ADR and JGEY are recipients of the Ontario Graduate Scholarship. ADR was the recipient of a Mitacs Accelerate Studentship.

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Authors and Affiliations

  1. Department of Pathobiology, University of Guelph, Guelph, ON, N1G 2W1, Canada

    Amira D. Rghei, Jacob G. E. Yates, Jordyn A. Lopes, Matthew M. Guilleman, Yanlong Pei, Laura P. van Lieshout, Lisa A. Santry, Byram W. Bridle, Khalil Karimi, Leonardo Susta & Sarah K. Wootton

  2. Vanderbilt Vaccine Center, Vanderbilt University, Nashville, TN, 37232-0417, USA

    Xuiaoyan Zhan & James E. Crowe Jr.

  3. Avamab Pharma Inc., Calgary, AB, T2T 2P9, Canada

    Brad Thompson

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Contributions

Conceptualization, ADR and SKW; methodology, ADR produced the vector and executed the study designs.; ADR and JGEY propagated RSV virus.; JAL, XZ, MMG, YP, LPvL, and LAS assisted with vector cloning, animal work and/or data analysis. Writing-original draft preparation, ADR; writing-review and editing, JGEY, KK, BWB, LS and SKW; supervision, SKW; funding acquisition, SKW. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Sarah K. Wootton.

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Competing interests

LPvL and SKW are inventors on a US patent for the AAV6.2FF capsid. This patent (US20190216949) is licensed to Avamab Pharma Inc., where BT, LPvL and SKW are co-founders and BT serves as an executive. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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This study was conducted according to the guidelines set forth by the Canadian Council on Animal Care (CCAC) and approved by the Animal Care Committee of the University of Guelph (Animal Use Protocol number 4664).

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Rghei, A.D., Yates, J.G.E., Lopes, J.A. et al. Antibody-based protection against respiratory syncytial virus in mice and their offspring through vectored immunoprophylaxis. Gene Ther (2023). https://doi.org/10.1038/s41434-023-00385-2

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