Science

Powerful new antibody neutralizes all known coronavirus variants

Posted on August 12, 2022 by Nancy Fliesler | Basic/Translational, Research

Tags: coronavirus, immunology, public health, vaccines


As the COVID-19 pandemic wears on, newer variants of the SARS-CoV-2 coronavirus have been evolving ways to evade the antibodies we make in response to vaccines or prior infections. As a result, we’ve seen breakthrough cases, antibody treatments that once worked have also become less effective over time. Scientists have been searching for an antibody that would be broadly neutralizing — able to fight off any virus variant that might emerge.

An antibody developed by researchers at Boston Children’s Hospital now seems to fit the bill. In lab tests, it neutralized all currently known SARS-CoV-2 variants of concern, including all Omicron variants.

“We hope this antibody will prove to be as effective in patients as it has been in pre-clinical evaluations thus far,” says Dr. Frederick Alt of the Program in Cellular and Molecular Medicine at Boston Children’s, a senior investigator on the study. “If it does, it might provide a new therapeutic and also contribute to new vaccine strategies.”

Led by Dr. Alt and Dr. Sai Luo at Boston Children’s, the team first modified a mouse model the Alt lab created to search for broadly neutralizing antibodies to HIV, another virus that frequently mutates. These mice essentially have built-in human immune systems. The modified model mimics — and refines — the trial-and-error process our own immune systems use to create increasingly effective antibodies when we encounter an invader.

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https://answers.childrenshospital.org/covid-19-neutralizing-antibody/

An antibody from single human VH-rearranging mouse neutralizes all SARS-CoV-2 variants through BA.5 by inhibiting membrane fusion

Science Immunology | 11 Aug 2022 | Vol 7, Issue 76 | DOI: 10.1126/sciimmunol.add5446

Sai Luo ... and Frederick W. Alt


Abstract


SARS-CoV-2 Omicron subvariants have generated a worldwide health crisis due to resistance to most approved SARS-CoV-2 neutralizing antibodies and evasion of vaccination-induced antibodies. To manage Omicron subvariants and prepare for new ones, additional means of isolating broad and potent humanized SARS-CoV-2 neutralizing antibodies are desirable. Here, we describe a mouse model in which the primary B cell receptor (BCR) repertoire is generated solely through V(D)J recombination of a human VH1-2 heavy chain (HC) and, substantially, a human Vκ1-33 light chain (LC). Thus, primary humanized BCR repertoire diversity in these mice derives from immensely diverse HC and LC antigen-contact CDR3 sequences generated by nontemplated junctional modifications during V(D)J recombination. Immunizing this mouse model with SARS-CoV-2 (Wuhan-Hu-1) spike protein immunogens elicited several VH1-2/Vκ1-33–based neutralizing antibodies that bound RBD in a different mode from each other and from those of many prior patient–derived VH1-2–based neutralizing antibodies. Of these, SP1-77 potently and broadly neutralized all SARS-CoV-2 variants through BA.5. Cryo-EM studies revealed that SP1-77 bound RBD away from the receptor-binding motif via a CDR3-dominated recognition mode. Lattice light-sheet microscopy–based studies showed that SP1-77 did not block ACE2-mediated viral attachment or endocytosis but rather blocked viral-host membrane fusion. The broad and potent SP1-77 neutralization activity and nontraditional mechanism of action suggest that it might have therapeutic potential. Likewise, the SP1-77 binding epitope may inform vaccine strategies. Last, the type of humanized mouse models that we have described may contribute to identifying therapeutic antibodies against future SARS-CoV-2 variants and other pathogens.


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https://www.science.org/doi/10.1126/sciimmunol.add5446