Structure-guided and epitope-based design of potent and broadly neutralizing nanobodies for COVID-19 mucosal immunotherapy

Project Summary
The coronavirus disease 2019 (COVID-19) rapidly disseminated through the human population
and became a global pandemic. Significant efforts have been put into developing vaccines or
antibody therapies based on the spike glycoprotein of SARS-CoV-2. One challenge of such
strategies is to identify conserved epitopes on the Spike and predict viral mutations that could
diminish the effectiveness of the vaccine and immunotherapy. To date, over 20 variant of SARS-
CoV-2 genome sequences have been reported. Therefore, structure guided and epitope based
design are crucial to generate effective medicines for current and future outbreaks of SARS-CoV-
2 or related coronavirus. Nanobodies can recognize conserved epitopes on hypervariable
pathogens. Here, we propose that anti-spike nanobodies can be utilized for rapid identification of
protective epitopes to inform design of vaccine and therapeutics. Further, we hypothesize that
potent and broadly protective nanobodies against SARS-CoV-2 can be developed as an inhaled
prophylactic or therapeutic medicine.
In this proposal, we will leverage our complementary strengths through a multi-disciplinary
approach combining mucosal immunology, structural biology, and virology, to characterize the
molecular interactions and differential specificities of a diverse panel of nanobodies against spike
of SARS-CoV-2 and other members of the Betacoronaviruese family (Aim 1). A comprehensive
list of conserved and non-conserved epitopes (Aim 2) will be used for structure-based design of
potent nanobody multimers for in vivo characterization (Aim 3).

Grant Number: 4R01AI159182-04
NIH Institute/Center: NIH
Principal Investigator: Lisa Cavacini