Functional Analysis of Human and Feline Coronavirus Cross-Reactive Antibodies Directed Against the SARS-CoV-2 Fusion Peptide

Abstract

To face the continuous emergence of SARS-CoV-2 variants, broadly protective therapeutic antibodies are highly needed. We here focused on the fusion peptide (FP) region of the viral spike antigen since it is highly conserved among alpha- and betacoronaviruses. First, we found that coronavirus cross-reactive antibodies are commonly formed during infection, being omnipresent in sera from COVID-19 patients, in ~50% of pre-pandemic human sera (rich in antibodies against endemic human coronaviruses), and even in feline coronavirus-infected cats. Pepscan analyses demonstrated that a confined N-terminal region of the FP is strongly immunogenic across diverse coronaviruses. Peptide-purified human antibodies targeting this conserved FP epitope exhibited broad binding of alpha- and betacoronaviruses, besides weak and transient SARS-CoV-2 neutralizing activity. Being frequently elicited by coronavirus infection, these FP-binding antibodies might potentially exhibit Fc-mediated effector functions and influence the kinetics or severity of coronavirus infection and disease.

Broadly neutralizing antibodies target the coronavirus fusion peptide

“…Furthermore, depletion of fusion peptide-specific antibodies from the serum of COVID-19 convalescent patients resulted in a 20% reduction in SARS-CoV-2 neutralization ( 37 ), and reactivity to the fusion peptide correlated with neutralization titer ( 38 ), indicating that polyclonal antibodies to the fusion peptide can play an appreciable role. Thus, our findings are consistent with previous studies highlighting the potential utility of the fusion peptide as a target epitope ( 37 – 40 ) and the fusion peptide-targeted mAbs provide additional tools to combat COVID-19 and enhance pandemic preparedness.…”

Cellular electrical impedance to profile SARS-CoV-2 fusion inhibitors and to assess the fusogenic potential of spike mutants

“…In contrast, the inhibitory effect of a S-neutralizing antibody (Ab) that binds to the RBD of S (Ab R001) was rather limited and depended strongly on the intrinsic efficiency and kinetics of the experimental cell-cell fusion ( Figure 4B and Supplementary Figure 2B ). Even a saturating Ab concentration of 10 μg/ml, that completely prevents virus entry of authentic SARS-CoV-2 virus in Vero E6 and Calu-3 cells, as shown earlier (29, 30), reduced the fusion response by only 45% ( Figure 4B ). Furthermore, when Ab R001 was tested in an additional experiment in which cell-cell fusion occurred more efficiently and rapidly because of exogenous TMPRSS2 (as evidenced by the CI response), no reduction in maximum impedance response could be recorded and only a delay in the fusion kinetics was observed ( Supplementary Figure 2B ).…”

Cellular electrical impedance to profile SARS-CoV-2 fusion inhibitors and to assess the fusogenic potential of spike mutants

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