ABSTRACT
Background: Human monoclonal antibodies from convalescent individuals that target the SARS-CoV-2 spike protein have been deployed as therapeutics against SARS-CoV-2. However, nearly all of these antibodies have been rendered obsolete by SARS-CoV-2 variants that evolved to resist similar, naturally occurring antibodies. Moreover, Most SARS-CoV-2 specific antibodies are inactive against divergent sarbecoviruses Methods: By immunizing mice that carry human immunoglobulin variable gene segments we generated a suite of fully human monoclonal antibodies that bind the human ACE2 receptor (hACE2) rather than the viral spike protein and were engineered to lack effector functions such as ADCC. Result(s): These ACE2 binding antibodies block infection by all hACE2 binding sarbecoviruses, including emergent SARS-CoV-2 variants, with a potency that of the most potent spike binding therapeutic antibodies. Structural and biochemical analyses revealed that the antibodies target an hACE2 epitope that engages SARS-CoV-2 spike. Importantly, the antibodies do not inhibit hACE2 enzymatic activity, nor do they induce ACE depletion from cell surfaces. The antibodies exhibit favorable pharmacology in human ACE2 knock in mice and provide near complete protection of hACE2 knock-in mice against SARS-CoV-2 infection. Conclusion(s): ACE2 binding antibodies should be useful prophylactic and treatment agents against any current and future SARS-CoV-2 variants, as well as hACE2-binding sarbecoviruses that might emerge as future pandemic threats.
ABSTRACT
Background: Two years after its onset, the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains difficult to control despite the availability of several vaccines. Progress in controlling the pandemic is complicated by the emergence of variants with antibody-resistance. Methods: Here we report on the evolution of antibody and memory B cell responses in a cohort of SARS-CoV-2 naïve individuals who received two doses of the Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) vaccines against SARS-CoV-2 and were boosted with a third mRNA vaccine dose thereafter. Results: Plasma neutralizing antibody titers in individuals vaccinated with two mRNA vaccines doses decrease over time, but can be restored by a third, i.e., a booster dose. A third vaccine dose also results in dramatically increased plasma neutralizing activities against viral variants, including the delta and omicron variants. Boosting vaccinated individuals also increases the number of RBD-specific memory B cells, which display clonal turnover after the third dose of the vaccine. The mononclonal antibodies generated by those cells have greater somatic hypermutation and increased neutralizing activity when compared to antibodies generated after the second dose, indicative of continued evolution of the humoral response to SARS-CoV-2. A substantial fraction of the monoclonal antibodies isolated after the third dose of an mRNA vaccine are able to neutralize pseudoviruses representing the delta and omicron variants, at low antibody concentrations. Conclusion: The data suggest that boosting vaccinated individuals with mRNA vaccines provides dramatically increased and broadened plasma neutralizing activity. This is the result of antibody evolution and the consequent production of potent and broadly active neutralizing antibodies.