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. 2023 Oct 31;42(10):113248.
doi: 10.1016/j.celrep.2023.113248. Epub 2023 Oct 18.

Vaccine-mediated protection against Merbecovirus and Sarbecovirus challenge in mice

David R Martinez  1 , Alexandra Schäfer  2 , Tyler D Gavitt  3 , Michael L Mallory  2 , Esther Lee  3 , Nicholas J Catanzaro  2 , Haiyan Chen  3 , Kendra Gully  2 , Trevor Scobey  2 , Pooja Korategere  3 , Alecia Brown  3 , Lena Smith  3 , Robert Parks  3 , Maggie Barr  3 , Amanda Newman  3 , Cindy Bowman  3 , John M Powers  2 , Erik J Soderblom  4 , Katayoun Mansouri  3 , Robert J Edwards  3 , Ralph S Baric  5 , Barton F Haynes  6 , Kevin O Saunders  7
Affiliations

Vaccine-mediated protection against Merbecovirus and Sarbecovirus challenge in mice

David R Martinez et al. Cell Rep. .

Abstract

The emergence of three highly pathogenic human coronaviruses-severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003, Middle Eastern respiratory syndrome (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 protect against severe COVID-19, 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. The trivalent RBD scNP elicited serum neutralizing antibodies against bat zoonotic Wuhan Institute of Virology-1 (WIV-1)-CoV, SARS-CoV, SARS-CoV-2 BA.1, SARS-CoV-2 XBB.1.5, and MERS-CoV live viruses. The 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. This study demonstrates proof of concept for a single pan-sarbecovirus/pan-merbecovirus vaccine that protects against three highly pathogenic human coronaviruses spanning two betacoronavirus subgenera.

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

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Conflict of interest statement

Declaration of 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 NPs 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 2c spikes to hACE2, 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.
Figure 2.
Figure 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
(A) BALB/c mice were immunized intramuscularly at weeks 0 and 4 with either monovalent or trivalent vaccines adjuvanted with GLA-SE. Mice were bled 1 day before priming (pre-prime), 1 day before boosting (pre-boost), and 2 weeks post-boost (peak) against the following spike antigens: (B) SARS-CoV Tor2, (C) RsSHC014, (D) SARS-CoV-2, and (E) MERS-CoV. (F) Vaccine-elicited hACE2-blocking serum responses in monovalent-, trivalent-, and adjuvant-only-vaccinated mice. (G) Vaccine-elicited hDPP4-blocking serum responses in monovalent-, trivalent-, and adjuvant-only-vaccinated mice. Error bars represent group standard deviation in (F) and (G).
Figure 3.
Figure 3.. Neutralizing antibodies elicited against group 2b and 2c betacoronaviruses
Live-virus neutralizing activity against (A) SARS-CoV-2 BA.1, (B) bat zoonotic WIV-1-CoV, (C) SARS-CoV Urbani, and (D) MERS-CoV EMC. Mouse sera at baseline and post-boost are shown in 2× vaccinated mice for SARS-CoV-2 BA.1, SARS-CoV Urbani, and MERS-CoV. Mouse sera post second boost were used against WIV-1. Blue circles denote monovalent SARS-CoV-2 RBD scNP-vaccinated mice. Magenta 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. ID80 values are reported as reciprocal serum dilution that inhibits 80% of virus replication. A Kruskal-Wallis non-parametric test with Dunn’s multiple comparisons test was used throughout to compare the median ID80 values across vaccine groups (*p < 0.05, **p < 0.005, ***p < 0.0005, and ****p < 0.0001).
Figure 4.
Figure 4.. Vaccination of mice with monovalent and trivalent RBD scNP-induced modest neutralization of SARS-CoV-2 XBB1.5 live virus
(A–C) Serum inhibition of virus replication determined by virus reporter luminescence for the (A) monovalent, (B) trivalent, and (C) adjuvant-only vaccines. A reduction in luminescence by more than half of the value seen in control cells that lack serum but are infected is shown as the half-maximal value. Neutralization curves that reach the half-maximal value are considered positive. Each curve shows neutralization by an individual mouse serum sample collected 1 week after the third immunization. (D and E) The reciprocal dilution of serum required to inhibit (D) 50% or (E) 80% of virus replication. Each symbol represents the value for an individual mouse, with the horizontal bar indicating group geometric mean.
Figure 5.
Figure 5.. Protective efficacy of monovalent versus trivalent RBD scNP vaccines against SARS-CoV challenge in mice
(A) Weight loss in monovalent SARS-CoV-2 RBD scNP-, trivalent SARS-CoV-2/RsSHC014/MERS-CoV RBD scNP-, and adjuvant-only-vaccinated mice. Error bars represent SEM. (B) Percentage of survival in vaccinated mice versus control mice following lethal SARS-CoV Urbani MA15 challenge. Statistical significance of the survival curves is from a chi-squared log-rank test. (C) Infectious virus replication (plaque forming units: PFU) 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. Magenta squares represent the trivalent-vaccinated mice. Gray triangles denote the adjuvant-only-vaccinated mice. *p < 0.05, **p < 0.005, ***p < 0.0005, and ****p < 0.0001.
Figure 6.
Figure 6.. Protective efficacy of monovalent versus trivalent RBD scNP vaccines against MERS-CoV challenge in mice
(A) Cross-reactivity of monovalent and trivalent versus adjuvant-only IgG responses at 1 week post-second boost (peak) against group 1 (canine CoV-HuPn); 2a (OC43); 2b (WIV-1, SARS-CoV GZ02, ZC45, GXP4L, and BANAL-236); 2c (MERS-CoV, NL140422, HKU4, and HKU5); 2d (BtKY06); and 4 (porcine DeltaCoV Haiti) coronavirus RBDs. Bars indicate the group median, and error bars indicate the interquartile range. (B) Weight loss in SARS-CoV-2 RBD monovalent-, SARS-CoV-2/RsSHC014/MERS-CoV RBD scNP-, and adjuvant-only-vaccinated mice following MERS-CoV intranasal challenge. Error bars represent SEM. (C) Lung virus replication in monovalent, trivalent, and adjuvant-only controls at day 3 post-infection. (D) Infectious virus replication in nasal turbinates at day 3 post-infection. (E) Lung infectious virus replication at day 5 post infection. p values shown 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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