A MERS-CoV antibody neutralizes a pre-emerging group 2c bat coronavirus

Abstract

The repeated emergence of zoonotic human betacoronaviruses (β-CoVs) dictates the need for broad therapeutics and conserved epitope targets for countermeasure design. Middle East respiratory syndrome (MERS)–related coronaviruses (CoVs) remain a pressing concern for global health preparedness. Using metagenomic sequence data and CoV reverse genetics, we recovered a full-length wild-type MERS-like BtCoV/ li /GD/2014-422 (BtCoV-422) recombinant virus, as well as two reporter viruses, and evaluated their human emergence potential and susceptibility to currently available countermeasures. Similar to MERS-CoV, BtCoV-422 efficiently used human and other mammalian dipeptidyl peptidase protein 4 (DPP4) proteins as entry receptors and an alternative DPP4-independent infection route in the presence of exogenous proteases. BtCoV-422 also replicated efficiently in primary human airway, lung endothelial, and fibroblast cells, although less efficiently than MERS-CoV. However, BtCoV-422 shows minor signs of infection in 288/330 human DPP4 transgenic mice. Several broad CoV antivirals, including nucleoside analogs and 3C-like/M pro protease inhibitors, demonstrated potent inhibition against BtCoV-422 in vitro. Serum from mice that received a MERS-CoV mRNA vaccine showed reduced neutralizing activity against BtCoV-422. Although most MERS-CoV–neutralizing monoclonal antibodies (mAbs) had limited activity, one anti-MERS receptor binding domain mAb, JC57-11, neutralized BtCoV-422 potently. A cryo–electron microscopy structure of JC57-11 in complex with BtCoV-422 spike protein revealed the mechanism of cross-neutralization involving occlusion of the DPP4 binding site, highlighting its potential as a broadly neutralizing mAb for group 2c CoVs that use DPP4 as a receptor. These studies provide critical insights into MERS-like CoVs and provide candidates for countermeasure development.

Hybrid immunity to SARS-CoV-2 arises from serological recall of IgG antibodies distinctly imprinted by infection or vaccination

“…Antibodies that exhibit β-sheet–like binding properties, as well as other backbone-backbone contacts such as those in the SC27 CDR-L3, might thus be uniquely situated to adapt to emerging SARS-CoV-2 variants. Indeed, the β-strand-like binding of SC27 has been observed for broadly neutralizing antibodies directed at other β-CoVs 72 and HIV 73 .…”

Mapping immunodominant sites on the MERS-CoV spike glycoprotein targeted by infection-elicited antibodies in humans

“…However, as far fewer neutralizing RBDdirected antibodies for MERS-CoV (29)(30)(31)(32)34) have been characterized than for SARS-CoV-2 (44,69,70), it is likely that there are additional neutralizing epitopes on the MERS-CoV RBD that contribute to the neutralizing activity of plasma. Additional studies focused on discovering and characterizing antibodies targeting the MERS-CoV RBD will further resolve immunodominant epitopes as well as elucidate those epitopes that are resilient to viral evolution and contribute to the cross-neutralization of related merbecoviruses (42).…”

“…Several monoclonal neutralizing antibodies (mAbs) targeting MERS-CoV S have been isolated and characterized to date (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). They recognize epitopes located in the RBD, NTD, or S2 subunit, indicating that each of these MERS-CoV S domains are targets of neutralizing mAbs.…”

Protein nanoparticle vaccines induce potent neutralizing antibody responses against MERS-CoV

“…S2A). Two weeks post-boost, all groups but the bare I53-50 nanoparticle control showed high antibody titers, ranging from 3.2-8.4×10 4 , that slightly waned by week 8 (7.0×10 3 -1.9×10 4 ). S-2P and S-2P-T33_dn10 elicited cross-reactive serum antibodies that bound to SARS-CoV and SARS-CoV-2 HexaPro trimers ( 71), but we did not observe similar cross-reactivity from the nanoparticles displaying the domain-based antigens (Fig.…”

“…Although the success of vaccine development efforts in response to the pandemic were a triumph of modern vaccinology, SARS-CoV-2 remains the only coronavirus for which licensed vaccines are available. To date, nine coronaviruses are known to infect humans, three of which have caused epidemics or pandemics in the last 20 years and two of which have been identified in humans in only the past two years, underscoring that more coronaviruses than previously appreciated currently circulate in humans and pose zoonotic threats (1)(2)(3)(4). Developing vaccines for additional coronaviruses, both known and unknown, is therefore a public health priority (5).…”