Rare Antibodies Improve Effectiveness of COVID-19 Vaccines

What scientists discovered about the uncommon antibodies that target the Achilles’ heel of SARS-CoV-2 should help us fine-tune our COVID-19 vaccination strategy for longer-lasting immunity.

New research on how frequently our bodies develop broadly neutralizing antibodies (bnAbs) capable of repelling a variety of SARS-CoV-2 variants provides insights into strategy changes that could potentially future-proof COVID-19 vaccines.

To combat invading viruses, our bodies produce particular antibodies, including those that target the receptor-binding domain (RBD)—the “Velcro hooks” employed by infections to attach to our cells. As SARS-CoV-2 accumulates genetic changes, new variations develop dressed in deceptive disguises to elude human defenses. bnAbs are advanced neutralizing antibodies that can keep up with the virus’s ever-changing tactics. Unfortunately, traditional COVID-19 vaccinations have had difficulty eliciting them.

Conventional COVID-19 vaccines are known to be less effective against emerging SARS-CoV-2 variants due to the difficulty in producing bnAbs,” said study corresponding author Tomoharu Yasuda, professor at Hiroshima University’s (HU) Graduate School of Biomedical and Health Sciences.

“In order to develop a vaccine with sustained efficacy, it is important to clarify the mechanisms of how bnAbs are generated after virus infection.”

In April, researchers from HU, Kyoto University, and Hiroshima Prefectural Hospital published their findings in the journal Communications Biology.

Investigating bnAbs
The researchers found a spike in neutralizing antibodies in samples from 18 unvaccinated patients who had their first bouts of COVID-19 at 8-55 days after diagnosis. As the hospitalizations progressed, they discovered that sera collected on the 55th day outperformed the others, demonstrating the highest frequency of bnAbs when compared to those obtained at other times.

After analyzing the samples, the researchers discovered four therapeutic monoclonal antibody (mAb) candidates—NCV1SG17, NCV1SG23, NCV2SG48, and NCV2SG53—that neutralized the SARS-CoV-2 strain that infected the patients. All study participants had been infected with an earlier B.1.1 strain of the new coronavirus with the D614G spike mutation, which is thought to increase viral infectivity. The four mAbs also eliminated the original SARS-CoV-2 virus strain (Wuhan-Hu-1), alpha, delta, and variations with point mutations exclusively at K417, L452, or E484, which are known to reduce antibody neutralization sensitivity.

All, with the exception of NCV2SG48, failed to neutralize omicron BA.1, which demonstrated equal effectiveness against the variation as Sotrovimab, one of the only mAb therapies to operate against this omicron sublineage. NCV2SG48 was also able to repel omicron BA.2 and BA.4/5.

The researchers discovered that prolonged exposure to SARS-CoV-2 for nearly two months caused the patients’ germinal centers (GC) to introduce a high rate of changes known as somatic hypermutations (SHMs), providing NCV2SG48 with an extensive binding interface.

NCV2SG48 particularly targets conserved residues in the receptor-binding motif (RBM)—a RBD subdomain that interacts directly with the cell’s ACE2, the “loops” on which the virus latches for entry. Because these conserved residues cannot accept mutations without impairing the pathogen’s capacity to infect and multiply, they tend to remain intact among variations. Given its importance in cell entrance and the evolutionary urge to preserve sections associated with this role in future iterations, the RBM is an appealing Achilles’ heel for bnAbs to exploit. NCV2SG48 has exploited the vulnerability of this coronavirus area.

Because of its massive binding interface, NCV2SG48 was able to block not only its targeted conserved residues but also surrounding amino acids, effectively covering practically the whole virus surface while interacting with ACE2. Consider it a clump of lint with threads extending out in all directions, impeding the pathogen’s “Velcro hooks.” When NCV2SG48 was returned to its original form, it performed badly against the alpha, beta, omicron BA.1, BA.2, BA.2.12.1, and BA.4/5 variants, confirming the importance of SHMs in its potency.

Indications of longer-lasting COVID-19 vaccinations

NCV2SG53, another bnAb that obtained new interaction sites as a result of SHMs, also works effectively with NCV2SG48, according to the researchers. A mixture of these two antibodies substantially neutralized variations at low doses, indicating potential as a COVID-19 therapy, particularly as a pre-exposure medication for immunocompromised patients.

“We found that bnAbs are created by amino acid substitutions, called somatic hypermutation, in the antigen recognition site of antibodies. It produced additional binding sites and markedly extended the binding interface between the antibody and the viral receptor, which contributed to the neutralization of broad variants,” Yasuda explained.

He believes their findings could help refine our vaccination strategy to mimic sustained exposure of about two months.

“We do not need to develop a completely new vaccine to induce bnAbs,” he said. “A single vaccine shot generally maintains 2–3 weeks of germinal center reaction. So by getting a general vaccine three times, the duration of GC reaction could be around two months in total.”

Yasuda believes vaccines might induce a response similar to what occurs during chronic infection, where viruses continuously evolve as they multiply, but without the visible symptoms, by swapping antigens from various SARS-CoV-2 variants one after the other during the GC reaction.

“We previously showed that antigenic shift immunization approach enhances bnAbs,” he said, referring to a previous study the current authors were also involved in suggesting that an omicron booster elevates bnAbs levels in individuals earlier vaccinated with the original SARS-CoV-2 antigen.

Based on their findings, the researchers have begun conversations about producing an mRNA vaccine capable of eliciting bnAbs.

“We hope that our findings contribute to the development of effective vaccines and therapeutics against other pandemics and bioterrorism.”

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