No fear of virus mutation: Lanke/Xu Ke's team proposed a new strategy for the design of a broad-spectrum vaccine for the new crown

The epidemic caused by the novel coronavirus (SARS-CoV-2) is still ongoing, and so far the number of new coronavirus infections worldwide has reached more than 640 million, and more than 6.
6 million people have died (according to the official website of the World Health Organization).

With the longer the virus spreads and circulates, the virus continues to accumulate and mutate, coupled with the selection pressure of human immunity and vaccine immunity, the new coronavirus has evolved from the original original strain to a multi-lineage variant strain
.
The World Health Organization has named important variants of interest (VOCs), including: Alpha, Beta, Gamma, Delta and Omicron
.

However, what does not match the speed of virus mutation is that vaccine research and development requires a long cycle, and most of the vaccines currently on the market (inactivated vaccines, subvaccines, nucleic acid vaccines, viral vector vaccines, etc.
) still use the new coronavirus prototype strain as the antigen, and the neutralization ability of the now circulating Omicron and its sublineage strains has decreased
to varying degrees.
Even when vaccine companies can update vaccines based on changes in epidemic strains, they tend to lag behind the speed at which
the virus mutates.
Therefore, how to develop a relatively broad-spectrum vaccine that can fight both the current epidemic strains and the possible variants of the future is an important scientific question
.

On January 4, 2023, Lan Ke and Xu Ke's research group from the State Key Laboratory of Virology and the State Key Laboratory of Virology of Wuhan University published a report in Science Translational Medicine entitled Vaccination with Span, an antigen guided by SARS-CoV-2 S protein evolution, protects against challenge A research paper with viral variants in mice that proposes a new strategy
for designing broad-spectrum vaccines to deal with the constant mutation of the new coronavirus.

By tracking the evolution and mutation law of the new coronavirus spike protein (S protein), the research team proposed a new broad-spectrum vaccine design strategy of "optimizing the design of vaccine immunogen based on viral evolution consensus sequence", and developed a broad-spectrum vaccine immunogen Span (pan-new coronavirus S antigen) covering "common mutations", which can induce the production of Alpha, Beta, Gamma, Eta, Kappa, Delta, Lambda and Omicron and its sublineage of broad-spectrum neutralizing antibodies protected the mice against lethal attacks by multiple novel coronavirus variants, including Omicron (Figure 1).

Figure 1.
Span vaccine effect science map, broad-spectrum vaccine immunogen (Span) like a strong castle to protect against a variety of new coronavirus variants

The study, which reported for the first time the evolutionary path of the new coronavirus, found that mutations in the Spike (S) protein in virus isolates that survived in the population were not completely random, but evolved along three directional pathways (Figure 2).

Figure 2.
Evolutionary law of S protein of the new coronavirus (containing 11,650,487 sequences).

The x-axis indicates the immune evasion ability of the SARS-CoV-2 variant, and the y-axis represents the cellular infectivity
of the SARS-CoV-2 variant.
The sector color marks the separation time
of the shown variant documented in the GISAID database.
The size of the area per sector represents the number of
individual variants isolated as of July 2022 (each month).
Shades of gray indicate evolutionary pathways
.

The different paths of S protein mutations lead to changes
in antigenicity.
Therefore, the vaccine components of a single strain cannot effectively protect the population against other variants along different evolutionary pathways
.
In order to obtain a broad-spectrum immunogen that can cover the vast majority of variants, the research team analyzed 2675 new coronavirus S protein sequences in the NCBI database, calculated the frequency of occurrence of all mutation sites (Figure 3B) through evolutionary clustering (Figure 3A), and finally designed a fitted neoantigen (Span) covering common mutations (Figure 3C).

The results show that the Span sequence is located at the center of the S protein phylogenetic tree (Figure 3D).

Figure 3.
Span is located at the center of the phylogenetic tree

Interestingly, Span was designed before the Delta and Omicron outbreaks, but it covers evolutionarily calculated common mutations and represents the convergence law of S protein mutations, so it is clustered with later Omicron, indicating that Span has the potential to cover future variants (Figure 3E).

Further analysis showed that the above six common mutation sites obtained by the research team were retained in the Omicron subline strains that later broke out, showing strong common regularity and predictability (Figure 4).

The above common mutation sites and broad-spectrum vaccine antigen design scheme have been authorized by China invention patent on August 5, 2022 (patent name: novel coronavirus mutant strain S protein and its subvaccine; Patent No.
: ZL 2021 1 1181856.
X).

Figure 4.
The 6 common mutation sites (transverse markers) identified by the research team were largely preserved in later outbreaks of Omicron epidemic strains (longitudinal markers) (red indicates that the site was preserved).

In line with design expectations, the research team found that Span immunogen showed obvious broad-spectrum neutralization advantages over prototype immunogen (Swt): after immunizing 2 shots of prototype S protein and then 1 shot of Span protein, Span induced more efficient and widely neutralizing antibodies against WT, Beta, Delta, Omicron strains and their sublines (Figure 5A, Figure 5B) compared with immunization of 3 shots of prototype S protein, Span induced more efficient and widely neutralizing antibodies against WT, Beta, Delta, Omicron strains and their sublines, and was 100% Protect mice from lethal attack by the Omicron strain (Figure 5C).

This suggests that Span provides broad-spectrum protection
as a booster shot.
Even a simple 2-shot Span immune can provide cross-immune protection across lineages while resisting lethal attacks
by WT, Beta and Delta strains.
The researchers also observed that the prototype strain immunogen (Swt) was unable to provide effective cross-protection across Beta strains
.

This research work has carried out a proof of concept for this innovative broad-spectrum vaccine design concept, and the pan-novel coronavirus S protein immunogen (Span) designed based on the common evolutionary law of the new crown is expected to become a broad-spectrum vaccine
candidate to prevent existing and potential future epidemic strains of the new coronavirus.

Figure 5.
Span vaccine immunity provides broad-spectrum immunoprotection in mice

Professor Lan Ke and Professor Xu Ke, State Key Laboratory of Virology, School of Life Sciences, Wuhan University, are co-corresponding authors
of the paper.
Zhao Yongliang, postdoctoral fellow of the State Key Laboratory of Virology, Ni Wenjia, Liang Simeng, Dong Lianghui, Xiang Min, Niu Danping, and Dr.
Cai Zeng, experimentalist of the Animal Level III Biosafety Laboratory of Wuhan University, are co-first authors
of the paper.
The research was supported by the National Natural Science Foundation of China, the Hubei Provincial Innovation Team, the Wuhan University New Coronary Pneumonia Special Research Fund, and the Beijing Taikang Yicai Public Welfare Foundation
.