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Principal Investigator: James J Kobie
Organization: UNIVERSITY OF ALABAMA AT BIRMINGHAM
Fiscal Year: 2024
Award: $841,341
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
SARS-CoV-2 has infected over 138 million people and resulted in over 2.8 million deaths so far, with the
expectation the pandemic will continue for many more months, and the virus will persist endemically for years,
exacerbated by emerging variants of concern (VoC). Although several vaccines are being used wide-spread, it
is unclear if they will be able to induce effective long-term immunity against emerging VoC. Highly effective anti-
viral therapeutics for SARS-CoV-2 remain elusive, although several monoclonal antibodies (mAbs) targeting the
Receptor Binding Domain (RBD) of the Spike (S) protein have been granted EUA for mild to moderate infection,
their effectiveness against severe disease has not yet been evident. With the slow pace of global vaccination,
limited anti-viral use/efficacy, and the emergence of antigenic drift variants, the trajectory of this pandemic and
future resurgences of the virus is of great concern. Fundamental understanding of the mechanisms of inducing
and sustaining protective humoral immunity to SARS-CoV-2 will be critical to its mitigation. The virus is now
classified into several clades, numerous VoC emerging, and indications including our work and others that some
of this antigenic drift is the result of the virus escaping from immune pressure and increased transmissibility. Drift
within the RBD is of the utmost concern as it can enhance the infectivity of the virus and negate the activity of
NAbs that may have developed from previous vaccination or infection. Numerous reports have emerged of
repeated SARS-CoV-2 infections in patients, and breakthrough infections in fully vaccinated individuals,
highlighting the imperfection of naturally acquired SARS-CoV-2 immunity. Utilizing our rationally designed
RBD/RBD-ACE2 fusion protein variants, we have identified epitopic and phenotypic heterogeneity amongst
RBD-specific human B cells and have isolated several potent RBD-specific human neutralizing monoclonal Abs
(NmAbs) (IC50<50 ng/ml) against SARS-CoV-2 which are entering into a Phase 1/2 clinical trial using inhaled
delivery in the coming months. We hypothesize that within RBD, the highly conserved regions (RBD-CR),
epitopes desirable for mediating broad and potent humoral protection, are surrounded by variable regions (RBD-
VR) that are structurally dynamic and highly susceptible to antigenic drift. Further, we hypothesize that RBD-VR
mitigate the development of potent and broad RBD-CR specific humoral responses through their
immunodominance and direct occlusion of RBD-CR. This RBD-CR/RBD-VR evolutionary dynamic is likely to
regulate the sustained protection (or failure) of humoral responses against future viral variants. We will 1) define
the ontological and phenotypic diversity of the human RBD-specific neutralizing antibody response, 2) define the
dynamics of maintenance of ACE2 binding and immunological pressure on constraining RBD evolution, and 3)
determine RBD Ab tolerance for and contribution to SARS-CoV-2 drift. Defining the limits of natural infection and
vaccination induced RBD neutralizing antibodies to drive antigenic drift and confer protection from divergent
SARS-CoV-2 viruses will inform the development next generation SARS-CoV-2 vaccines and therapeutics.
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