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

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.

[1]  P. Zhang,et al.  Intranasal pediatric parainfluenza virus-vectored SARS-CoV-2 vaccine is protective in monkeys , 2022, Cell.

[2]  Gheyath K Nasrallah,et al.  Duration of mRNA vaccine protection against SARS-CoV-2 Omicron BA.1 and BA.2 subvariants in Qatar , 2022, Nature Communications.

[3]  H. Feldmann,et al.  SARS-CoV2 variant-specific replicating RNA vaccines protect from disease following challenge with heterologous variants of concern , 2022, eLife.

[4]  K. Gersing,et al.  Characteristics, Outcomes, and Severity Risk Factors Associated With SARS-CoV-2 Infection Among Children in the US National COVID Cohort Collaborative , 2022, JAMA network open.

[5]  J. Mascola,et al.  SARS-CoV-2 Omicron Variant Neutralization after mRNA-1273 Booster Vaccination , 2022, The New England journal of medicine.

[6]  J. Yewdell,et al.  A single intranasal dose of a live-attenuated parainfluenza virus-vectored SARS-CoV-2 vaccine is protective in hamsters , 2021, Proceedings of the National Academy of Sciences.

[7]  Robert J. Fischer,et al.  ChAdOx1 nCoV-19 (AZD1222) protects Syrian hamsters against SARS-CoV-2 B.1.351 and B.1.1.7 , 2021, Nature Communications.

[8]  H. Schuitemaker,et al.  Immunity elicited by natural infection or Ad26.COV2.S vaccination protects hamsters against SARS-CoV-2 variants of concern , 2021, Science Translational Medicine.

[9]  J. Mascola,et al.  Durability of mRNA-1273 vaccine–induced antibodies against SARS-CoV-2 variants , 2021, Science.

[10]  T. Randall,et al.  Scent of a vaccine , 2021, Science.

[11]  P. Dormitzer,et al.  BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans , 2021, Nature.

[12]  J. Mascola,et al.  Antibody Persistence through 6 Months after the Second Dose of mRNA-1273 Vaccine for Covid-19 , 2021, The New England journal of medicine.

[13]  Robert J. Fischer,et al.  ChAdOx1 nCoV-19 (AZD1222) protects Syrian hamsters against SARS-CoV-2 B.1.351 and B.1.1.7 , 2021, bioRxiv.

[14]  Nguyen H. Tran,et al.  T cell and antibody responses induced by a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine in a phase 1/2 clinical trial , 2020, Nature Medicine.

[15]  R. Baric,et al.  Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults , 2020, The New England journal of medicine.

[16]  Sijia He,et al.  A systematic review and meta‐analysis of children with coronavirus disease 2019 (COVID‐19) , 2020, Journal of medical virology.

[17]  G. Ippolito,et al.  Structure-based design of prefusion-stabilized SARS-CoV-2 spikes , 2020, Science.

[18]  W. Self,et al.  Parainfluenza Virus Types 1-3 Infections Among Children and Adults Hospitalized with Community-Acquired Pneumonia. , 2020, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[19]  J. Matthijnssens,et al.  A single-dose live-attenuated YF17D-vectored SARS-CoV-2 vaccine candidate , 2020, Nature.

[20]  Tokiko Watanabe,et al.  Syrian hamsters as a small animal model for SARS-CoV-2 infection and countermeasure development , 2020, Proceedings of the National Academy of Sciences.

[21]  Adam J. Schweickert,et al.  Epidemiology, Clinical Features, and Disease Severity in Patients With Coronavirus Disease 2019 (COVID-19) in a Children's Hospital in New York City, New York. , 2020, JAMA pediatrics.

[22]  P. Sorger,et al.  SARS-CoV-2 infection protects against rechallenge in rhesus macaques , 2020, Science.

[23]  H. Yen,et al.  Peer Review File Manuscript Title: Pathogenesis and transmission of SARS-CoV-2 in golden Syrian hamsters , 2020 .

[24]  G. Gao,et al.  Plasma IP-10 and MCP-3 levels are highly associated with disease severity and predict the progression of COVID-19 , 2020, Journal of Allergy and Clinical Immunology.

[25]  P. Vollmar,et al.  Virological assessment of hospitalized patients with COVID-2019 , 2020, Nature.

[26]  K. To,et al.  Simulation of the clinical and pathological manifestations of Coronavirus Disease 2019 (COVID-19) in golden Syrian hamster model: implications for disease pathogenesis and transmissibility , 2020, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[27]  A. Walls,et al.  Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein , 2020, Cell.

[28]  B. Graham,et al.  Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation , 2020, Science.

[29]  M. Killerby,et al.  Human parainfluenza virus circulation, United States, 2011–2019 , 2020, Journal of Clinical Virology.

[30]  Victor M Corman,et al.  Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR , 2020, Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin.

[31]  S. Madhi,et al.  Global patterns in monthly activity of influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus: a systematic analysis. , 2019, The Lancet. Global health.

[32]  P. Kwong,et al.  Improved Prefusion Stability, Optimized Codon Usage, and Augmented Virion Packaging Enhance the Immunogenicity of Respiratory Syncytial Virus Fusion Protein in a Vectored-Vaccine Candidate , 2017, Journal of Virology.

[33]  P. Kwong,et al.  Packaging and Prefusion Stabilization Separately and Additively Increase the Quantity and Quality of Respiratory Syncytial Virus (RSV)-Neutralizing Antibodies Induced by an RSV Fusion Protein Expressed by a Parainfluenza Virus Vector , 2016, Journal of Virology.

[34]  P. Kwong,et al.  Enhanced Neutralizing Antibody Response Induced by Respiratory Syncytial Virus Prefusion F Protein Expressed by a Vaccine Candidate , 2015, Journal of Virology.

[35]  P. Collins,et al.  Chimeric Bovine/Human Parainfluenza Virus Type 3 Expressing Respiratory Syncytial Virus (RSV) F Glycoprotein: Effect of Insert Position on Expression, Replication, Immunogenicity, Stability, and Protection against RSV Infection , 2014, Journal of Virology.

[36]  J. Falloon,et al.  Phase 1 Study of the Safety and Immunogenicity of a Live, Attenuated Respiratory Syncytial Virus and Parainfluenza Virus Type 3 Vaccine in Seronegative Children , 2012, The Pediatric infectious disease journal.

[37]  Brian R. Murphy,et al.  Evaluation of two chimeric bovine-human parainfluenza virus type 3 vaccines in infants and young children , 2011, Vaccine.

[38]  H. Ebihara,et al.  Validation of assays to monitor immune responses in the Syrian golden hamster (Mesocricetus auratus) , 2011, Journal of Immunological Methods.

[39]  P. Collins,et al.  Nonstructural Proteins 1 and 2 of Respiratory Syncytial Virus Suppress Maturation of Human Dendritic Cells , 2008, Journal of Virology.

[40]  Michelle M. Packard,et al.  Prior Infection and Passive Transfer of Neutralizing Antibody Prevent Replication of Severe Acute Respiratory Syndrome Coronavirus in the Respiratory Tract of Mice , 2004, Journal of Virology.

[41]  Murray Leaf,et al.  WHAT IS “FORMAL” ANALYSIS? , 2004, Cybern. Syst..

[42]  B. Murphy,et al.  Recombinant Bovine/Human Parainfluenza Virus Type 3 (B/HPIV3) Expressing the Respiratory Syncytial Virus (RSV) G and F Proteins Can Be Used To Achieve Simultaneous Mucosal Immunization against RSV and HPIV3 , 2001, Journal of Virology.

[43]  J. McAuliffe,et al.  Bovine Parainfluenza Virus Type 3 (BPIV3) Fusion and Hemagglutinin-Neuraminidase Glycoproteins Make an Important Contribution to the Restricted Replication of BPIV3 in Primates , 2000, Journal of Virology.

[44]  Ed Zintel,et al.  Resources , 1998, IT Prof..

[45]  B. Murphy,et al.  Attenuation of bovine parainfluenza virus type 3 in nonhuman primates and its ability to confer immunity to human parainfluenza virus type 3 challenge. , 1988, The Journal of infectious diseases.

[46]  Norma Banas,et al.  Virtual Reality Visualization of 3-D Electromagnetic Fields , 2000 .