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Principal Investigator: Blake Marie Hauser
Organization: HARVARD MEDICAL SCHOOL
Fiscal Year: 2023
Award: $52,694
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract
Since the emergence of the novel severe acute respiratory syndrome virus 2 (SARS-CoV-2) coronavirus, the
need for better frameworks to rapidly develop vaccines in response to emerging viral threats, including other
coronaviruses of potential pandemic concern, is clear. One approach is to develop an immunogen design
platform that leverages the often-conserved interface between viral surface glycoproteins and their host cellular
receptor(s). For SARS-CoV-2, elicited antibodies would target the interaction between its “spike” glycoprotein
and the human angiotensin-converting enzyme 2 (ACE-2) receptor. Other coronaviruses like SARS-CoV-1 and
the common cold-causing NL63 also use ACE-2, thus antibodies that interfere with this conserved interaction
might also protect against future novel coronaviruses that also use this receptor. The goal of this proposed work
is to use structure-guided, rational design of novel immunogens to focus the immune response to the ACE-2
receptor binding interface of SARS-CoV-2. This may provide a generalizable framework of immunogen design
strategies that can be rapidly used to combat novel emerging viruses in the future. I will use the following two
design approaches: 1) I will use molecular scaffolds that are structurally homologous to the SARS-CoV-2
receptor binding domain (RBD) and “resurface” them with the ACE-2 receptor binding motif (RBM) from SARS-
CoV-2. As a result, the antigenically distinct scaffolds will uniformly present the conserved SARS-CoV-2 RBM
and will focus the immune response to the conserved interface. 2) I will use hyperglycosylation to mask
immunodominant, non-protective epitopes on the SARS-CoV-2 RBD to direct the immune response to the
SARS-CoV-2 RBM. For both approaches, I will analyze the elicited immune response to determine the extent of
immune focusing to the SARS-CoV-2 RBM, obtain neutralization profiles and structurally characterize down-
selected elicited antibodies. Collectively, these data will provide insight into how masking and resurfacing can
determinatively direct the immune response to a conserved viral epitope. While I use SARS-CoV-2 as a model
virus, this could provide a vaccine design framework for future viral pathogens with the potential for rapid
deployment.
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