New study provides clues for future-proofing Covid-19 vaccines

New study explores how often our bodies produce a wide range of substances Neutralizing antibody The ability to block different SARS-CoV-2 variants (bnAbs) provides clues for fine-tuning strategies to enable future-proof COVID-19 vaccines.

To combat invading viruses, our bodies deploy specific antibodies, including neutralizing antibodies that target receptor binding domains (RBDs). “Velcro hooks” that pathogens use to attach themselves to our cells. As SARS-CoV-2 accumulates genetic mutations, new variants emerge in sneaky disguises to outsmart our defenses. So-called bnAbs are elite neutralizing antibodies that are capable of responding to the virus’ evolving tricks. Unfortunately, conventional COVID-19 vaccines have struggled to induce them.

“Conventional novel coronavirus infectious disease vaccines are known to be less effective against emerging SARS-CoV-2 variants due to the difficulty in generating bnAbs,” said corresponding author Hiroshima University Graduate School of Medicine. Professor Tomoharu Yasuda of the Graduate School of Health Sciences said. .

“To develop a vaccine with a sustained effect, efficacyIt is important to elucidate the mechanism of how bnAbs are generated after viral infection. “

A study by researchers from Hiroshima University, Kyoto University, and Hiroshima Prefectural Hospital was published in a journal communication biology in April.

Testing for bnAbs

The researchers looked at sera collected from 18 unvaccinated first-time COVID-19 patients 8 to 55 days later and found a sharp increase in neutralizing antibodies in the samples starting 17 days after diagnosis. I noticed that there is As hospitalization lengthened, sera collected on day 55 were found to be superior to the remaining sera, with the highest frequency of bnAb compared to sera collected at other time points.

By analyzing the samples, the researchers identified four therapeutic monoclonal antibody (mAb) candidates. NCV1SG17, NCV1SG23, NCV2SG48, and NCV2SG53 -; which neutralized the bona fide SARS-CoV-2 strain the patient was infected with. All study participants had long-term infection with the early B.1.1 strain of novel coronavirus, which contains the D614G spike mutation, which is thought to increase viral infectivity. The four mAbs also targeted only the original SARS-CoV-2 virus strain (Wuhan-Hu-1), alpha, delta, and K417, L452, or E484, which are known to reduce susceptibility to antibody neutralization. Mutants with point mutations were eliminated. However, of the several mAb treatments that act against this Omicron sublineage, all neutralize his Omicron BA.1, except his NCV2SG48, which showed potency against the variant comparable to that of sotrovimab. I could not do it. NCV2SG48 also beat off his Omicron BA.2 and BA.4/5.

A closer look at what makes it so powerful shows that long-term exposure to SARS-CoV-2, nearly two months, causes patients’ germinal centers (GCs) to develop a high rate of somatic hypermutation (SHM). It was found to have caused a change and provided NCV2SG48. It has an extensive binding interface.

NCV2SG48 specifically targets conserved residues in the receptor binding motif (RBM). The RBD subdomain directly interacts with the cell’s ACE2, the ‘loop’ through which the virus hooks for entry. These conserved residues tend not to change among mutants because they cannot tolerate mutation without affecting the pathogen’s ability to infect and replicate. Given its critical role in cell entry and the evolutionary pressure to keep the region associated with this role unchanged in future versions, RBM is an attractive Achilles heel for bnAbs to attack. NCV2SG48 took advantage of this coronavirus region vulnerability.

Due to its huge binding interface, NCV2SG48 was able to block not only the conserved residues of the target but also neighboring amino acids, effectively covering almost the entire viral surface that interacts with ACE2. Imagine a clump of lint sticking out in all directions and blocking the “Velcro hooks” of pathogens. Reverting to the original version, NCV2SG48 performed poorly in protecting alpha, beta, Omicron BA.1, BA.2, BA.2.12.1, and BA.4/5 mutants, and its potency confirmed the important role of SHM in .

Clues for a longer-lasting COVID-19 vaccine

The researchers also found that another bnAb, NCV2SG53, which gained a new interaction site by SHM, worked well with NCV2SG48. A cocktail made of these two antibodies broadly neutralized the mutants at low concentrations, showing promise as a treatment for COVID-19, especially as a pre-exposure therapy for immunocompromised patients.

“We discovered that bnAbs are created by an amino acid substitution called somatic hypermutation in the antibody’s antigen recognition site, which creates an additional binding site and increases the interaction between the antibody and the viral receptor.” The binding interface was significantly expanded, which contributed to the neutralization of a wide range of viral receptors,” explained Yasuda.

He believes their findings could help refine vaccination strategies that mimic sustained exposure for about two months.

“We don’t need to develop a completely new vaccine to induce bnAbs,” he said. “After one dose of vaccine, the germinal center reaction usually lasts for 2-3 weeks. Therefore, with 3 doses of the general vaccine, the total duration of the GC reaction can be about 2 months. ”

by switching antigen Yasuda said the vaccine could trigger reactions from different SARS-CoV-2 variants one after the other during the GC reaction, potentially inducing responses similar to those that occur during chronic infection. rice field. In chronic infection, the virus continuously mutates during replication, but no obvious symptoms are seen.

“We have previously shown that an antigen-shifting immunization approach enhances bnAbs,” he said, adding that Omicron’s boosters increase bnAbs levels in individuals previously vaccinated with the original SARS-CoV-2 antigen. We referred to previous studies in which the current authors were also involved in suggesting that

Researchers are now discussing the development of mRNA vaccines capable of inducing bnAbs based on their findings.

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