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Author Notes:

Ursula J. Buchholz, phone: (301) 594 1533. Email: ubuchholz@niaid.nih.gov

Cyril Le Nouën, phone: (240) 669 5907. Email: lenouenc@niaid.nih.gov

Conceptualization: H.-S.P., X.L., Y.M., C.LN, and U.J.B.. Methodology, formal analysis, visualization: H.-S.P., X.L., Y.M., C.S., L.Y., C.L., I.N.M., P.Z., P.L., C.LN and U.J.B.. Investigation: H.-S.P., X.L., Y.M., C.S., L.Y., C.L., I.N.M., P.Z., P.L., and C.LN.. Resources: R.J., N.L.G., and S.M.B.. Writing – Original Draft: X.L., H.-S.P., C.LN. and U.J.B.. Writing – Review and Editing: All authors.

The authors thank the staff of the NIAID Comparative Medicine Branch for animal study support. We thank Barney Graham and Kizzmekia Corbett, Vaccine Research Center, NIAID, NIH, and Jason McLellan, University of Texas, Austin, TX, for providing plasmid 2019-nCoV S-2P_dFurin_F3CH2S encoding the prefusion-stabilized version of the SARS-CoV-2 S ectodomain which was used to generate ELISA antigen for our studies. The SARS-CoV-2 S protein containing the receptor-binding domain (RBD) was obtained from David Veesler through BEI Resources, NIAID, NIH. We thank Ruturaj Masvekar and Bibi Bielekova, Laboratory of Clinical Immunology & Microbiology, NIAID, NIH for their help with the MSD plate reader.

U.J.B., C.L., X.L, and C.LN. are inventors on the provisional patent application number 63/180,534, entitled “Recombinant chimeric bovine/human parainfluenza virus 3 expressing SARS-CoV-2 spike protein and its use”, filed by the United States of America, Department of Health and Human Services.

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Research Funding:

This research was supported by the Intramural Research Program of the NIAID, NIH (Project number ZIA AI001298–01).

Keywords:

  • parainfluenza virus vaccines
  • pediatric vaccines
  • COVID-19
  • SARS-CoV-2
  • intranasal immunization

Live-attenuated pediatric parainfluenza vaccine expressing 6P-stabilized SARS-CoV-2 spike protein is protective against SARS-CoV-2 variants in hamsters

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bioRxiv

Volume:

Volume 2022

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Type of Work:

Article | Preprint: Prior to Peer Review

Abstract:

The pediatric live-attenuated bovine/human parainfluenza virus type 3 (B/HPIV3)-vectored vaccine expressing the prefusion-stabilized SARS-CoV-2 spike (S) protein (B/HPIV3/S-2P) was previously evaluated in vitro and in hamsters. To improve its immunogenicity, we generated B/HPIV3/S-6P, expressing S further stabilized with 6 proline mutations (S-6P). Intranasal immunization of hamsters with B/HPIV3/S-6P reproducibly elicited significantly higher serum anti-S IgA/IgG titers than B/HPIV3/S-2P; hamster sera efficiently neutralized variants of concern (VoCs), including Omicron variants. B/HPIV3/S-2P and B/HPIV3/S-6P immunization protected hamsters against weight loss and lung inflammation following SARS-CoV-2 challenge with the vaccine-matched strain WA1/2020 or VoCs B.1.1.7/Alpha or B.1.351/Beta and induced near-sterilizing immunity. Three weeks post-challenge, B/HPIV3/S-2P- and B/HPIV3/S-6P-immunized hamsters exhibited a robust anamnestic serum antibody response with increased neutralizing potency to VoCs, including Omicron sublineages. B/HPIV3/S-6P primed for stronger anamnestic antibody responses after challenge with WA1/2020 than B/HPIV3/S-2P. B/HPIV3/S-6P will be evaluated as an intranasal vaccine to protect infants against both HPIV3 and SARS-CoV-2.
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