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[Preprint]. 2024 Mar 14:2024.03.13.584735.
doi: 10.1101/2024.03.13.584735.

Protein nanoparticle vaccines induce potent neutralizing antibody responses against MERS-CoV

Cara W Chao  1   2   3 , Kaitlin R Sprouse  2 , Marcos C Miranda  1   2 , Nicholas J Catanzaro  4 , Miranda L Hubbard  4 , Amin Addetia  2 , Cameron Stewart  2 , Jack T Brown  2 , Annie Dosey  1   2 , Adian Valdez  1   2 , Rashmi Ravichandran  1   2 , Grace G Hendricks  1   2 , Maggie Ahlrichs  1   2 , Craig Dobbins  1   2 , Alexis Hand  1   2 , Catherine Treichel  1   2 , Isabelle Willoughby  1   2 , Alexandra C Walls  2 , Andrew T McGuire  2 , Elizabeth M Leaf  1   2 , Ralph S Baric  4 , Alexandra Schäfer  4 , David Veesler  2   5 , Neil P King  1   2
Affiliations

Protein nanoparticle vaccines induce potent neutralizing antibody responses against MERS-CoV

Cara W Chao et al. bioRxiv. .

Update in

  • Protein nanoparticle vaccines induce potent neutralizing antibody responses against MERS-CoV.
    Chao CW, Sprouse KR, Miranda MC, Catanzaro NJ, Hubbard ML, Addetia A, Stewart C, Brown JT, Dosey A, Valdez A, Ravichandran R, Hendricks GG, Ahlrichs M, Dobbins C, Hand A, McGowan J, Simmons B, Treichel C, Willoughby I, Walls AC, McGuire AT, Leaf EM, Baric RS, Schäfer A, Veesler D, King NP. Chao CW, et al. Cell Rep. 2024 Dec 24;43(12):115036. doi: 10.1016/j.celrep.2024.115036. Epub 2024 Dec 6. Cell Rep. 2024. PMID: 39644492 Free PMC article.

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic betacoronavirus that causes severe and often lethal respiratory illness in humans. The MERS-CoV spike (S) protein is the viral fusogen and the target of neutralizing antibodies, and has therefore been the focus of vaccine design efforts. Currently there are no licensed vaccines against MERS-CoV and only a few candidates have advanced to Phase I clinical trials. Here we developed MERS-CoV vaccines utilizing a computationally designed protein nanoparticle platform that has generated safe and immunogenic vaccines against various enveloped viruses, including a licensed vaccine for SARS-CoV-2. Two-component protein nanoparticles displaying MERS-CoV S-derived antigens induced robust neutralizing antibody responses and protected mice against challenge with mouse-adapted MERS-CoV. Electron microscopy polyclonal epitope mapping and serum competition assays revealed the specificities of the dominant antibody responses elicited by immunogens displaying the prefusion-stabilized S-2P trimer, receptor binding domain (RBD), or N-terminal domain (NTD). An RBD nanoparticle vaccine elicited antibodies targeting multiple non-overlapping epitopes in the RBD, whereas anti-NTD antibodies elicited by the S-2P- and NTD-based immunogens converged on a single antigenic site. Our findings demonstrate the potential of two-component nanoparticle vaccine candidates for MERS-CoV and suggest that this platform technology could be broadly applicable to betacoronavirus vaccine development.

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Figures

Fig. 1.
Fig. 1.. Production and characterization of nanoparticle immunogens.
(A) Schematics of MERS-CoV nanoparticle immunogen assembly. (B) Size exclusion chromatograms of MERS-CoV nanoparticle components (dotted lines) and assembled nanoparticles (solid lines) on a Superose 6 10/300 GL. (C) Left, raw micrographs and right, 2D class averages of negatively stained SEC-purified nanoparticles. For S-2P-T33_dn10, class averages of the nanoparticle core and displayed S-2P trimer are shown on top and bottom, respectively. Scale bar, 50 nm. (D) Binding of left, antigen-bearing components prior to assembly and right, SEC-purified nanoparticle immunogens to mAbs G2 (NTD-specific), S41 (RBD-specific), 4C2 (RBD-specific), and CV-30 (SARS-CoV-2 S RBD-specific; negative control).
Fig. 2.
Fig. 2.. Antibody responses elicited by MERS-CoV nanoparticle immunogens in mice
(A) Study design and groups. Groups of 10 BALB/c mice were immunized at weeks 0 and 4, and serum was obtained at weeks 0, 2, 6, and 8. (B) Serum antibody binding titers against vaccine-matched (EMC) MERS-CoV S-2P, measured by ELISA. (C) Serum antibody titers against SARS-CoV HexaPro, SARS-CoV-2 HexaPro, and OC43 S-2P. (D) Vaccine-elicited neutralizing activity against VSV pseudotyped with closely related MERS-CoV EMC, London variant, Kenya variant, or South Korea variant spikes. Groups were compared using Kruskal-Wallis followed by Dunn’s multiple comparisons. ****, p < 0.0001; ***, p < 0.001; **, p < 0.01; *, p < 0.1. The mouse immunization study was performed twice, and representative data from one study are shown.
Fig. 3.
Fig. 3.. Epitope mapping of vaccine-elicited antibodies
(A) Serum competition of study groups with hDPP4 (top) and G2 (bottom) against MERS-CoV S-2P. (B) 3D reconstructions of MERS S-2P with no bound Fabs and selected 2D class averages. Scale bar, 27 nm. (C to F) Representative reconstructions from week 8 sera from mice immunized with S-2P (C), S-2P-I53-50 (D), NTD-I53-50 (E), and RBD-I53-50 (F).
Fig. 4.
Fig. 4.. Protection against challenge with mouse-adapted MERS-CoV
(A) Challenge study design and groups. Groups of 288/330+/+ mice were immunized at weeks 0 and 4, serum was obtained at weeks 0, 2, and 6, and the mice were challenged at week 15. (B) Serum antibody binding titers against vaccine-matched (EMC) MERS-CoV S-2P, measured by ELISA. (C) Vaccine-elicited neutralizing activity against VSV pseudotyped with closely related MERS-CoV EMC, London variant, Kenya variant, or South Korea variant spikes. Groups were compared using Kruskal-Wallis followed by Dunn’s multiple comparisons. ****, p < 0.0001; ***, p < 0.001; **, p < 0.01; *, p < 0.1. (D) Changes in body weight after maM35c4 challenge. (E) Lung congestion score. Data analyzed with two-way ANOVA or mixed model followed by Sidak’s multiple comparison. ****, p < 0.0001; *** p < 0.001; ** p < 0.01. (F) Viral titers in the lungs of challenged mice from (3 dpi: n = 5 for bare I53-50, S-2P, S-2P-T33_dn10, and S-2P-I53-50; n = 6 for RBD-I53-50. 5 dpi: n = 4 for bare I53-50; n = 5 for S-2P and S-2P-I53-50; n = 6 for S-2P-T33_dn10 and RBD-I53-50. Data were analyzed with two-way ANOVA or mixed model followed by Dunnett’s multiple comparison. ****, p < 0.0001. (G) Viral titers in nasal turbinates of challenged mice. n = 5 for bare I53-50, S-2P, S-2P-T33_dn10, and S-2P-I53-50; n = 6 for RBD-I53-50. Data analyzed with one-way ANOVA with Geisser-Greenhouse correction followed by Dunnett’s multiple comparison.
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