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[Preprint]. 2023 May 23:2023.05.22.540829.
doi: 10.1101/2023.05.22.540829.

Vaccine-mediated protection against merbecovirus and sarbecovirus challenge in mice

David R Martinez  1   2 , Alexandra Schafer  3 , Tyler D Gavitt  4 , Michael L Mallory  3 , Esther Lee  4 , Nicholas J Catanzaro  3 , Haiyan Chen  4 , Kendra Gully  3 , Trevor Scobey  3 , Pooja Korategere  4 , Alecia Brown  4 , Lena Smith  4 , Rob Parks  4 , Maggie Barr  4 , Amanda Newman  4 , Cindy Bowman  4 , John M Powers  3 , Katayoun Mansouri  4 , Robert J Edwards  4 , Ralph S Baric  3 , Barton F Haynes  4 , Kevin O Saunders  4
Affiliations

Vaccine-mediated protection against merbecovirus and sarbecovirus challenge in mice

David R Martinez et al. bioRxiv. .

Update in

  • Vaccine-mediated protection against Merbecovirus and Sarbecovirus challenge in mice.
    Martinez DR, Schäfer A, Gavitt TD, Mallory ML, Lee E, Catanzaro NJ, Chen H, Gully K, Scobey T, Korategere P, Brown A, Smith L, Parks R, Barr M, Newman A, Bowman C, Powers JM, Soderblom EJ, Mansouri K, Edwards RJ, Baric RS, Haynes BF, Saunders KO. Martinez DR, et al. Cell Rep. 2023 Oct 31;42(10):113248. doi: 10.1016/j.celrep.2023.113248. Epub 2023 Oct 18. Cell Rep. 2023. PMID: 37858337 Free PMC article.

Abstract

The emergence of three distinct highly pathogenic human coronaviruses - SARS-CoV in 2003, MERS-CoV in 2012, and SARS-CoV-2 in 2019 - underlines the need to develop broadly active vaccines against the Merbecovirus and Sarbecovirus betacoronavirus subgenera. While SARS-CoV-2 vaccines are highly protective against severe COVID-19 disease, they do not protect against other sarbecoviruses or merbecoviruses. Here, we vaccinate mice with a trivalent sortase-conjugate nanoparticle (scNP) vaccine containing the SARS-CoV-2, RsSHC014, and MERS-CoV receptor binding domains (RBDs), which elicited live-virus neutralizing antibody responses and broad protection. Specifically, a monovalent SARS-CoV-2 RBD scNP vaccine only protected against sarbecovirus challenge, whereas the trivalent RBD scNP vaccine protected against both merbecovirus and sarbecovirus challenge in highly pathogenic and lethal mouse models. Moreover, the trivalent RBD scNP elicited serum neutralizing antibodies against SARS-CoV, MERS-CoV and SARS-CoV-2 BA.1 live viruses. Our findings show that a trivalent RBD nanoparticle vaccine displaying merbecovirus and sarbecovirus immunogens elicits immunity that broadly protects mice against disease. This study demonstrates proof-of-concept for a single pan-betacoronavirus vaccine to protect against three highly pathogenic human coronaviruses spanning two betacoronavirus subgenera.

Keywords: MERS-CoV; SARS-CoV; SARS-CoV-2; bat coronavirus; nanoparticle; neutralization; receptor binding domain; universal vaccine.

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Conflict of interest statement

Competing interests: B.F.H. and K.O.S. have filed US patents regarding the nanoparticle vaccine. R.S.B. is on the scientific advisory boards of VaxArt, Invivyd, and Takeda.

Figures

Figure 1.
Figure 1.. Design and characterization of trivalent RBD scNP vaccines.
(A) Ferritin nanoparticles were conjugated with sortase A tagged Group 2b SARS-CoV-2 RBD, Group 2b RsSHC014 RBD, and Group 2c MERS-CoV RBD. (B) Visualization of trivalent scNP was performed via negative stain electron microscopy. (C) Validation of trivalent scNP vaccine by Biolayer Interferometry. Trivalent RBD scNP antigenicity was done by assessing binding of the trivalent vaccine and various Group 2b and Group 2c spikes to human ACE2, MERS-CoV RBD mAbs, SARS-CoV-2 RBD mAbs, Group 2b cross-reactive RBD mAbs, and an S2 mAb. HIV-1 envelope was included as a negative control antigen.
Fig. 2.
Fig. 2.. IgG binding responses in mice immunized with monovalent SARS-CoV-2 RBD scNP vaccine, trivalent SARS-CoV-2/RsSHC014/MERS-CoV RBD scNP, and adjuvant alone.
Mouse sera was measured at pre-prime, pre-boost, and two-week post boost against the following spike antigens (A) SARS-CoV Tor2, (B) RsSHC014, (C) SARS-CoV-2, and (D) MERS-CoV. (E) Vaccine-elicited hACE2-blocking serum responses in monovalent, trivalent, and adjuvant-only vaccinated mice. (F) Vaccine-elicited hDPP4-blocking serum responses in monovalent, trivalent, and adjuvant-only vaccinated mice. (G) Cross-reactivity of monovalent, trivalent, vs adjuvant-only IgG responses against Group 1 (Canine CoV-HuPn), Group 2a (OC43), 2b (WIV-1, SARS-CoV GZ02, ZC45, GXP4L, and BANAL-236), 2c (MERS-CoV, NL140422, HKU4, and HKU5), 2d (BtKY06), and Group 4 (Porcine deltaCoV Haiti) coronavirus RBDs.
Figure 3.
Figure 3.. Neutralizing antibodies elicited against Group 2b and Group 2c betacoronaviruses.
Live virus neutralizing activity against SARS-CoV-2 BA.1, SARS-CoV Urbani, and MERS-CoV EMC. Mouse sera at baseline and post boost are shown in 2X vaccinated mice are shown. Blue circles denote monovalent SARS-CoV-2 RBD scNP vaccinated mice. Red squares denote trivalent SARS-CoV-2/RsSHC014/MERS-CoV RBD scNP vaccinated mice. Gray triangles denote adjuvant-only control mice. Numerical values in the graphs denote the median ID80 values (n = 16; *P < 0.05, **P < 0.005, ***P < 0.0005, and ****P < 0.0001).
Figure 4.
Figure 4.. Protective efficacy of monovalent vs trivalent RBD scNP vaccines against SARS-CoV challenge in mice.
(A) Weight loss in monovalent SARS-CoV-2 RBD, trivalent SARS-CoV-2/RsSHC014/MERS-CoV RBD vaccinated scNP, and adjuvant-only vaccinated mice. (B) Percent survival in vaccinated mice vs control following lethal SARS-CoV Urbani MA15 challenge. Statistical significance of the survival curves is from a Chi square log-rank test. (C) Infectious virus replication in the lung of vaccinated mice at day 2 following infection. Statistical significance is from a Kruskal-Wallis test following a Dunn’s multiple comparison correction test. (D) Infectious virus replication in nasal turbinates at day 2 post infection. Statistical significance is from a Kruskal-Wallis test following a Dunn’s multiple comparison correction test. Blue circles represent the monovalent vaccinated mice. Red squares represent the trivalent vaccinated mice. Grey triangles denote the adjuvant-only vaccinated mice. *P < 0.05, **P < 0.005, ***P < 0.0005, and ****P < 0.0001
Figure 5.
Figure 5.. Protective efficacy of monovalent vs trivalent RBD scNP vaccines against MERS-CoV challenge in mice.
(A) Weight loss in SARS-CoV-2 RBD monovalent, SARS-CoV-2/RsSHC014/MERS-CoV RBD vaccinated scNP, and adjuvant-only vaccinated mice following MERS-CoV intranasal challenge. Lung virus replication in monovalent, trivalent, and adjuvant-only controls at day 3 post infection. (C) Infectious virus replication in nasal turbinates at day 3 post infection. (D) Lung infectious virus replication at day 5 post infection. P values shown in all panels are from a Kruskal-Wallis test following a Dunn’s multiple comparisons test. *P < 0.05, **P < 0.005, ***P < 0.0005, and ****P < 0.0001
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