Research identifies a highly potent monoclonal antibody that neutralizes multiple sarvecoviruses

In a recent article published in scientific translational medicine According to the Journal, researchers isolated a highly potent monoclonal antibody ( mAb) were isolated long-term.

These mAbs are effective against multiple sarvecoviruses and all severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) Neutralized the mutant.

study: Broadly neutralizing antibodies to sarvecovirus generated by immunization of macaque monkeys with AS03-adjuvanted COVID-19 vaccine. Image credit: MattL_Images/Shutterstock.com

Background

Sarbecoviruses have caused three human epidemics in the last 20 years, of which the SARS-CoV-2 pandemic was the worst. Over 6.8 million deaths by 2023, despite widespread population-level immunity.

Omicron mutants and their substrains pose the most serious challenges to current COVID-19 vaccination strategies, owing to their extraordinary ability to evade immune responses. Studies have shown that mRNA monovalent vaccines have the following effects: efficacy It was below 50% on the recent BA.4/5 wave, but a 4th booster shot may improve it temporarily and minimally.

Furthermore, all available mAb therapeutics failed to combat Omicron submutants, highlighting the urgent need for next-generation vaccines and mAbs with broader protective coverage.

About research

In the present study, researchers investigated the evolutionary trajectory of memory B cell (MBC) responses in AS03-adjuvanted vaccinated rhesus monkeys. subunit vaccine The ability of the SARS-CoV-2 vaccine to enhance protective immunity was studied over a period of more than a year and a half using samples from previous studies that benchmarked clinically relevant adjuvants.

A previous study had two cohorts of 5 and 6 male rhesus monkeys (M. Mulatta), respectively.

The former group received a first boost of two doses of receptor-binding domain nanoparticles (RBD-NPs) with AS03 adjuvant on days 0 and 21. Similarly, the latter group of 6 animals received two doses of AS03-adjuvanted HexaPro. -NP vaccine.

The research team used the Mann-Whitney unpaired rank sum test and two-way analysis of variance (ANOVA) to measure the difference between any two groups at one and different time points, respectively. A two-tailed chi-square test measured the difference between different categories.

In addition, we performed a serological evaluation of the 15 most potent mAbs isolated between 3 weeks and 6 months after primary vaccination. Additionally, the team performed extensive structural analysis on some of the isolated mAbs and demonstrated their efficacy in mice.

During structural analysis, they determined the crystal structures of mAbs: 25F9, 20A7 and 21B6 and the binding modes of SARS-CoV-2 to the RBD at 3.05, 2.58 and 1.75 angstrom (Å) resolution, respectively.

Results and conclusions

Vaccines adjuvanted with AS03 provided long-term protection against omicron challenge in all test animals used in this study.

The degree of protection was 100% at 6 weeks after priming and 6 months after boosting. The latter showed rapid evolution of the encoded extensive antibody repertoire. antigen– Specific memory B cells (MBC).

The authors found that the vaccine induced a more extensive and stronger progressive antibody evolution over 12 months of follow-up, and antigen-antibody complexes on dendritic cells (DCs) may have facilitated this phenomenon. pointed out.

Nearly 4.4% of the 338 mAbs isolated between 1.4 and 6 months after primary vaccination had good potency against SARS-CoV-2 BA.1. Seven broadly neutralizing monoclonal antibodies (bnAbs) demonstrated potent neutralization against the ancestral SARS-CoV-2 strain, Wuhan Hu1, with half-maximal inhibitory concentrations below 10 ng/ml (IC₅₀).

They also neutralized variants of SARS-CoV-2 that emerged before Omicron, without significant loss of potency.

Four mAbs, 25F9, 21B6, 20A7, and 27A12, neutralized Omicron BA.1 at IC₅₀ Values ​​were 42, 11, 6, and 5 ng/ml, respectively. 27A12 showed slightly reduced neutralizing activity against other Omicron substrains, whereas BA.2-BA.5, XBB, BQ.1, BQ.1.1, and XBB 20A7 were showed a slight decrease in neutralizing activity.

However, among all other monoclonal antibodies tested, 25F9 and 20A7 exhibited the most potent neutralizing activity against all SARS-CoV-2 variants and multiple omicron substrains, indicating that these It may be a promising prophylactic candidate against viral infections.

Strikingly, 25F9 neutralized bona fide clade 1 sarbecovirus and provided broad protection against infection in mice, highlighting its clinical utility. Furthermore, 20A7 showed good neutralizing activity against pseudotyped clade 3 sarbecoviruses.

Most of the mAbs, including ADG20, DH1047, S2X259, 20A7 and SA55, targeted the same region of the RBD, namely RBS-D/CR3022, as observed in several previous studies. ADG20, DH1047 and S2X259 mAbs lost their neutralizing ability against Omicron and its substrains, whereas 20A7 and SA55 remained resistant to all Omicron submutants.

Nonetheless, this finding highlighted that this RBD region, which can induce broad-spectrum and potent mAbs, may provide insights into next-generation vaccine design.

In particular, several structural factors, such as the angle of approach to the epitope, influence the loss of neutralizing potency or resistance of mAbs. Similarly, reliance on specific amino acid residues within the epitope affects mAb binding.