Combination Respiratory Vaccine Containing Recombinant SARS-CoV-2 Spike and Quadrivalent Seasonal Influenza Hemagglutinin Nanoparticles with Matrix-M Adjuvant

  1. Michael J Massare
  2. Nita Patel
  3. Bin Zhou
  4. Sonia Maciejewski
  5. Rhonda Flores
  6. Mimi Guebre-Xabier
  7. Jing-Hui Tian
  8. Alyse D. Portnoff
  9. Louis Fries
  10. Vivek Shinde
  11. Larry Ellingsworth
  12. Gregory Glenn
  13. Gale Smith

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Abstract

The 2019 outbreak of a severe respiratory disease caused by an emerging coronavirus, SARS-CoV-2, has spread globally with high morbidity and mortality. Co-circulating seasonal influenza has greatly diminished recently, but expected to return with novel strains emerging, thus requiring annual strain adjustments. We have developed a recombinant hemagglutinin (HA) quadrivalent nanoparticle influenza vaccine (qNIV) produced using an established recombinant insect cell expression system to produce nanoparticles. Influenza qNIV adjuvanted with Matrix-M was well-tolerated and induced robust antibody and cellular responses, notably against both homologous and drifted A/H3N2 viruses in Phase 1, 2, and 3 trials. We also developed a full-length SARS-CoV-2 spike protein vaccine which is stable in the prefusion conformation (NVX-CoV2373) using the same platform technology. In phase 3 clinical trials, NVX-CoV2373 is highly immunogenic and protective against the prototype strain and B.1.1.7 variant. Here we describe the immunogenicity and efficacy of a combination quadrivalent seasonal flu and COVID-19 vaccine (qNIV/CoV2373) in ferret and hamster models. The combination qNIV/CoV2373 vaccine produces high titer influenza hemagglutination inhibiting (HAI) and neutralizing antibodies against influenza A and B strains. The combination vaccine also elicited antibodies that block SARS-CoV-2 spike protein binding to the human angiotensin converting enzyme-2 (hACE2) receptor. Significantly, hamsters immunized with qNIV/CoV2373 vaccine and challenged with SARS-CoV-2 were protected against weight loss and were free of replicating SARS-CoV-2 in the upper and lower respiratory tract with no evidence of viral pneumonia. This study supports evaluation of qNIV/CoV2373 combination vaccine as a preventive measure for seasonal influenza and CoVID-19.

Highlights

  • Combination qNIV/CoV2373 vaccine induced protective hemagglutination inhibition (HAI) responses to seasonal influenza A and B unchanged when formulated with recombinant spike.

  • Combination qNIV/CoV2373 vaccine maintained clinical and virologic protection against experimental challenge with SARS-CoV-2.

  • Combination qNIV/CoV2373 vaccine showed no clinical or histological sign of enhanced disease following experimental challenge with SARS-CoV-2.

  • Combination qNIV/CoV2373 vaccine induced antibodies against SARS-CoV-2 neutralizing epitopes common between US-WA and B.1.352 variant.

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  1. ScreenIT

    SciScore for 10.1101/2021.05.05.442782: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIACUC: Animal ethics statement: Noble Life Sciences performed the ferret (Musteia putorius furo) immunogenicity study (Sykesville, MD, USA).
    Field Sample Permit: The studies were conducted in accordance with each institutes’ IACUC approved protocol. 2.5.
    Sex as a biological variableBriefly, female BALB/c mice were immunized with SARS-CoV-2 US-WA recombinant spike (rS) protein adjuvanted with Matrix M1 on day 0 and day 14 by intramuscular injection.
    Randomizationnot detected.
    BlindingA board-certified pathologist (Experimental Pathology Laboratories, Inc. (EPI, Sterling, VA, USA) examined H&E slides in a blinded fashion. 2.15.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Hemagglutinin inhibiting antibodies (HAI): HAI responses against influenza A/Brisbane/02/2018 (H1N1), A/Kansas/14/17 (H3N2), and B strains (B/Maryland/15/16 and B/Phuket/3073/13) were evaluated in serum samples.
    H3N2
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Virus stock and receptor: The SARS-CoV-2 (strain 2019-nCoV/USA-WA1/2020) isolate was obtained from the Center for Disease Control and stock virus prepared by passage in Vero E6 cells.
    Vero E6
    suggested: RRID:CVCL_XD71)
    Sf9 cells cultures were infected with recombinant baculovirus expressing the HA genes.
    Sf9
    suggested: CLS Cat# 604328/p700_Sf9, RRID:CVCL_0549)
    At the end of incubation, 100 µL of 1.5×105 mL-1 MDCK cells were added to each well and the plates were incubated with 5% CO2 at 37°C for influenza A virus or 32°C for influenza B virus.
    MDCK
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    Briefly, female BALB/c mice were immunized with SARS-CoV-2 US-WA recombinant spike (rS) protein adjuvanted with Matrix M1 on day 0 and day 14 by intramuscular injection.
    BALB/c
    suggested: None
    Recombinant DNA
    SentencesResources
    pBac1 plasmids were transfected into Sf9 with Flash-bacGOLD bacmid containing the Autographa californica polydedrosis virus genome (Oxford Expression Technology, Oxford UK).
    pBac1
    suggested: None
    Software and Algorithms
    SentencesResources
    pBac1 plasmids were transfected into Sf9 with Flash-bacGOLD bacmid containing the Autographa californica polydedrosis virus genome (Oxford Expression Technology, Oxford UK).
    Oxford Expression Technology
    suggested: None
    Individual animal hACE2 receptor inhibiting titers, group GMT ± 95% CI were plotted using GraphPad Prism 8 software.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Statistical analysis: GraphPad Prism 7.05 software was used for statistical analysis.
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04368988Active, not recruitingEvaluation of the Safety and Immunogenicity of a SARS-CoV-2 …
    NCT04533399RecruitingA Study Looking at the Effectiveness and Safety of a COVID-1…
    NCT04583995RecruitingA Study Looking at the Effectiveness, Immune Response, and S…
    NCT04611802RecruitingA Study to Evaluate the Efficacy, Immune Response, and Safet…

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • No funding statement was detected.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2021.05.05.442782v1 on bioRxiv