A team of scientists from Tel Aviv University has demonstrated that antibodies isolated from the immune system of recovered COVID-19 patients are effective in neutralising all known strains of the virus, the discovery raising the possibility not only of eliminating booster shots but strengthening the immune systems of populations at risk.
Dr Natalia Freund and doctoral students Michael Mor and Ruofan Lee of the Department of Clinical Microbiology and Immunology at the Sackler Faculty of Medicine led the research, conducted in collaboration with Dr Ben Croker of the University of California San Diego (UCSD). Professor Ye Xiang of Tsinghua University in Beijing as well as Professor Meital Gal-Tanamy and Dr Moshe Dessau of Bar-Ilan University also took part.
The current study is a continuation of a preliminary one done in October 2020, at the height of the COVID-19 crisis. At that time, Freund and her colleagues sequenced all of the B immune system cells from the blood of people in Israel who had recovered from the original COVID strain. They isolated nine antibodies the patients produced and have now found that some of these are exceptionally effective in neutralising both the Delta and Omicron variants.
“In the previous study, we showed that the various antibodies formed in response to infection with the original virus are directed against different sites of the virus,” said Freund. “The most effective antibodies were those that bound to the virus’ ‘spike’ protein, in the same place where the spike binds to the cellular receptor ACE2. Of course, we were not the only ones to isolate these antibodies, and the global health system made extensive use of them until the arrival of the different variants of the coronavirus, which in fact rendered most of those antibodies useless.
“In the current study, we proved that two other antibodies, TAU-1109 and TAU-2310, which bind the viral spike protein in a different area from the region where most of the antibodies were concentrated until now (and were, therefore, less effective in neutralising the original strain) are actually very effective in neutralising the Delta and Omicron variants. According to our findings, the effectiveness of the first antibody, TAU-1109, in neutralising the Omicron strain is 92%, and in neutralising the Delta strain, 90%. The second antibody, TAU-2310, neutralises the Omicron variant with an efficacy of 84%, and the Delta variant with an efficacy of 97%.”
Freund believes the surprising effectiveness of these antibodies might be related to the evolution of the virus.
“The infectivity of the virus increased with each variant because each time, it changed the amino acid sequence of the part of the spike protein that binds to the ACE2 receptor, thereby increasing its infectivity while evading the natural antibodies that were created after vaccinations. In contrast, the antibodies TAU-1109 and TAU-2310 don’t bind to the ACE2 receptor binding site, but to another region of the spike protein – an area of the viral spike that for some reason does not undergo many mutations – and they are therefore effective in neutralising more viral variants. These findings emerged as we tested all known COVID strains to date.”
The two antibodies, cloned in Freund’s laboratory at Tel Aviv University, were sent for tests to check their effectiveness against live viruses in laboratory cultures at the University of California San Diego (UCSD). They were also tested against pseudoviruses in the laboratories of the Faculty of Medicine of Bar-Ilan University in the Galilee. In both tests, the results were identical and equally encouraging
These antibodies can bring about a real revolution in the fight against COVID-19, according to Freund.
“We need to look at the pandemic in the context of previous disease outbreaks humankind has witnessed. People who were vaccinated against smallpox at birth and who today are 50 years old still have antibodies, so they are probably protected, at least partially, from the monkeypox virus that we have recently been hearing about.
“Unfortunately, this is not the case with the coronavirus. For reasons we still don’t yet fully understand, the level of antibodies against COVID-19 declines significantly after three months, which is why we see people getting infected again and again, even after being vaccinated three times.
“In our view, targeted treatment with antibodies and their delivery to the body in high concentrations can serve as an effective substitute for repeated boosters, especially for at-risk populations and those with weakened immune systems. COVID-19 infection can cause serious illness, and we know that providing antibodies in the first days after infection can stop the spread of the virus. It is, therefore, possible that by using effective antibody treatment, we will not have to provide booster doses to the entire population every time there is a new variant.”
Study details
Conformational flexibility in neutralization of SARS-CoV-2 by naturally elicited anti-SARS-CoV-2 antibodies
Ruofan Li, Michael Mor, Bingting Ma, Alex Clark, Joel Alter, Michal Werbner, Jamie Casey Lee, Sandra Leibel, Aaron Carlin, Moshe Dessau, Meital Gal-Tanamy, Ben Croker, Ye Xiang and Natalia Freund.
Published in Communications Biology on 5 August 2022
Abstract
As new variants of SARS-CoV-2 continue to emerge, it is important to assess the cross-neutralising capabilities of antibodies naturally elicited during wild type SARS-CoV-2 infection. In the present study, we evaluate the activity of nine anti-SARS-CoV-2 monoclonal antibodies (mAbs), previously isolated from convalescent donors infected with the Wuhan-Hu-1 strain, against the SARS-CoV-2 variants of concern (VOC) Alpha, Beta, Gamma, Delta and Omicron. By testing an array of mutated spike receptor binding domain (RBD) proteins, cell-expressed spike proteins from VOCs, and neutralisation of SARS-CoV-2 VOCs as pseudoviruses, or as the authentic viruses in culture, we show that mAbs directed against the ACE2 binding site (ACE2bs) are more sensitive to viral evolution compared to anti-RBD non-ACE2bs mAbs, two of which retain their potency against all VOCs tested. At the second part of our study, we reveal the neutralisation mechanisms at high molecular resolution of two anti-SARS-CoV-2 neutralising mAbs by structural characterisation. We solve the structures of the Delta-neutralising ACE2bs mAb TAU-2303 with the SARS-CoV-2 spike trimer and RBD at 4.5 Å and 2.42 Å resolutions, respectively, revealing a similar mode of binding to that between the RBD and ACE2. Furthermore, we provide five additional structures (at resolutions of 4.7 Å, 7.3 Å, 6.4 Å, 3.3 Å, and 6.1 Å) of a second antibody, TAU-2212, complexed with the SARS-CoV-2 spike trimer. TAU-2212 binds an exclusively quaternary epitope, and exhibits a unique, flexible mode of neutralisation that involves transitioning between five different conformations, with both arms of the antibody recruited for cross linking intra- and inter-spike RBD subunits. Our study provides additional mechanistic understanding about how antibodies neutralise SARS-CoV-2 and its emerging variants and provides insights on the likelihood of reinfections.
See more from MedicalBrief archives:
Nearly everyone in SA has COVID antibodies – SANBS study
COVID-19 antibodies persist at least nine months after infection — Assay tests in Italy
Super-potent human antibodies protect against COVID-19 in animal tests — Scripps