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Engineered Receptor Binding Domain Immunogens Elicit Pan-Coronavirus Neutralizing Antibodies Outside the Receptor Binding Motif

35 Pages Posted: 26 Jan 2021 Publication Status: Review Complete

See all articles by Blake M. Hauser

Blake M. Hauser

Ragon Institute of MGH, MIT and Harvard

Maya Sangesland

Ragon Institute of MGH, MIT and Harvard

Evan Christopher Lam

Ragon Institute of MGH, MIT and Harvard

Jared Feldman

Ragon Institute of MGH, MIT and Harvard

Ashraf S. Yousif

Ragon Institute of MGH, MIT and Harvard

Timothy M. Caradonna

Ragon Institute of MGH, MIT and Harvard

Alejandro Benjamin Balazs

Ragon Institute of MGH, MIT and Harvard

Daniel Lingwood

Ragon Institute of MGH, MIT and Harvard

Aaron Schmidt

Ragon Institute of MGH, MIT and Harvard

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Abstract

Effective countermeasures are needed against emerging coronaviruses of pandemic potential, similar to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Designing immunogens that elicit broadly neutralizing antibodies to conserved viral epitopes on the major surface glycoprotein, spike, such as the receptor binding domain (RBD) is one potential approach. Here, we report the generation of homotrimeric RBD immunogens from different sarbecoviruses using a stabilized, immune-silent trimerization tag. We find that a cocktail of these homotrimeric sarbecovirus RBDs elicit antibodies to conserved viral epitopes outside of the ACE-2 receptor binding motif. Importantly, these responses neutralize all sarbecovirus components even in context of prior SARS-CoV-2 imprinting. This may be an effective strategy for eliciting broadly neutralizing responses leading to a pan-sarbecovirus vaccine.

Funding: We acknowledge funding from NIH R01s AI146779 (AGS), AI124378,AI137057 and AI153098 (DL), and a Massachusetts Consortium on Pathogenesis Readiness (MassCPR) grant (AGS); training grants: NIGMS T32 GM007753 (BMH and TMC); T32AI007245 (JF); F31 Al138368 (MS). A.B.B. is supported by the National Institutes for Drug Abuse (NIDA) Avenir New Innovator Award DP2DA040254, the MGH Transformative Scholars Program as well as funding from the Charles H. Hood Foundation. This independent research was supported by the Gilead Sciences Research Scholars Program in HIV.

Conflict of Interest: Authors declare no competing interests.

Ethical Approval: All experiments were conducted with institutional IACUC approval (MGH protocol 2014N000252).

Keywords: Receptor binding domain immunogen cocktails elicit pan-coronavirus neutralizing antibodies despite SARS-CoV-2 imprinting

Suggested Citation

Hauser, Blake M. and Sangesland, Maya and Lam, Evan Christopher and Feldman, Jared and Yousif, Ashraf S. and Caradonna, Timothy M. and Balazs, Alejandro Benjamin and Lingwood, Daniel and Schmidt, Aaron, Engineered Receptor Binding Domain Immunogens Elicit Pan-Coronavirus Neutralizing Antibodies Outside the Receptor Binding Motif. Available at SSRN: https://ssrn.com/abstract=3773801 or http://dx.doi.org/10.2139/ssrn.3773801
This version of the paper has not been formally peer reviewed.

Blake M. Hauser

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Maya Sangesland

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Evan Christopher Lam

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Jared Feldman

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Ashraf S. Yousif

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Timothy M. Caradonna

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Alejandro Benjamin Balazs

Ragon Institute of MGH, MIT and Harvard

25 Shattuck St
Boston, MA 02115
United States

Daniel Lingwood

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Aaron Schmidt (Contact Author)

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

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