The new Omicron variant is more contagious and has increased immune escape. What is the ultimate antidote?

Since the emergence of the novel coronavirus Omicron variant at the end of last year, new sub-strains have emerged one after another, triggering another wave of epidemics in countries around the world. The infectivity and ability to escape antibody neutralization of these new variants have greatly increased compared to the past. Fortunately, the severity and mortality rates caused by Omicron and its sub-strains have been greatly reduced compared to the previous novel coronavirus original strain and Delta variant.

Written by | Kestrel

Produced by: Science Popularization China

Crazy mutation

In the past six months, scientists have found multiple sub-strains of the novel coronavirus Omicron variant. Among them, BA.4, BA.2.12.1, and BA.5 were first discovered in South Africa and the United States, causing a new increase in confirmed cases there. These new Omicron sub-strains have stronger immune escape capabilities, and so far, it is unclear whether these new sub-strains will cause a surge in the number of infections worldwide last winter, as did the previous BA.1 and BA.2.

John Moore, an immunologist at Weil Cornell Medicine, said there is no need to panic. These new strains will certainly bring new troubles, but there is no evidence that they are more dangerous or more pathogenic than the previous Omicron strains. And vaccination or infection with the new coronavirus can still reduce the severity of most new sublineages. However, new sublineages may change pharmaceutical companies' plans to release vaccines for specific sublineages [1]. Although the number of infections and hospitalizations in South Africa and the United States is increasing, researchers believe that waves of infections caused by specific mutant sublineages will become more and more predictable.

The Omicron variant of the coronavirus (B.1.1.529) was first discovered in Botswana in November 2021 and was soon discovered in South Africa.[3] Omicron replicates faster than the Delta variant and has a higher rate of reinfection. A study in Qatar showed that people who had COVID-19 had an 85% to 90% lower risk of reinfection with Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2) than those who had their first infection, while the risk of reinfection with Omicron was only reduced by 56%. It is not yet clear whether Omicron is inherently more contagious, but unpublished in vitro studies have shown that Omicron prefers to replicate in nasal epithelial cells and bronchial tissues compared to Delta, which may be one of the reasons why it is more contagious.[6] In addition, the symptoms of Omicron infection are relatively less severe. An analysis in England showed that the risk of hospitalization and death from infection with Omicron is about one-third of that of Delta.[2]

Shortly after the Omicron variant appeared, its two sub-strains, BA.1 and BA.2, were also discovered in South Africa at about the same time. BA.2 quickly replaced the previously prevalent BA.1 as soon as it appeared. In January 2022, BA.2 first appeared in the United States; the large-scale infection discovered in Shanghai in March was also caused by BA.2. Compared with the initial version of the new coronavirus (SARS-CoV-2), BA.2 and BA.1 have 32 mutations in common; BA.2 has another 28 mutations that are different from BA.1, some of which are located in gene fragments responsible for encoding the receptor binding domain (RBD), which affects the binding of the virus to the host receptor. Because the nucleic acid test results are difficult to distinguish from the Delta test results, BA.2 is also called "stealth Omicron", and its infectiousness is about 1.5 times stronger than the original version. As of mid-April, BA.2 infections accounted for 90% of all new crown infections in the United States, but did not cause a new round of large-scale transmission, partly because of the immune protection brought by the previous BA.1 infection.

In April this year, the BA.2.12.1 sublineage of the Omicron strain was discovered in New York. It is closely related to BA.2, but 25% more contagious. On April 30, the first case of BA.2.12.1 infection was discovered in my country, an imported case from Guangzhou[8]. According to data released by the US CDC on May 17, BA.2.12.1 infections now account for 48% of all cases in the United States. CNBC (Consumer News and Business Channel) reported that as of May 11, BA.2.12.1 had appeared in 23 countries[12].

However, Omicron did not stop mutating, nor did it stop spreading. On April 29, the first case of BA.5 infection was discovered in my country, an imported case from Shanghai. The patient recovered on May 12[10]. On May 4, the first case of BA.4 infection was discovered, an imported case from Guangzhou[9].

In fact, BA.4 and BA.5 showed signs in South Africa as early as January this year, but the surge in cases has only recently occurred: from April 17 to May 7, the number of confirmed cases per day soared 10 times (from 1,000 cases per day to 10,000 cases per day), indicating that these two sublineages are more contagious than BA.2. "South Africa's epidemic has definitely resurfaced, and it seems to be completely driven by BA.4 and BA.5. The number of infections has exploded again. In my lab alone, six students have taken sick leave." As of May 17, in addition to South Africa, BA.4 infections have occurred in 17 countries around the world, with a total of no more than 700 cases; BA.5 infections have occurred in 16 countries, with a total of no more than 300 cases.

Figure 1 Phylogenetic tree of recently discovered SARS-CoV-2 variants. [10]

Immune escape

A preprint article published on medRxiv on May 2 this year stated that compared with BA.1, BA.4 and BA.5 have stronger immune escape capabilities, and even if you have been vaccinated or have been infected with BA.1, you may not be able to avoid being infected with BA.4 or BA.5 again. Researchers in South Africa collected blood samples from patients who had been infected with BA.1 in November and December 2021, including cases with or without vaccination. After testing, the antibodies in these blood samples were found to be several times less capable of neutralizing BA.4 and BA.5 substrains than other Omicron substrains. However, despite this, the antibodies of vaccinated people are still a little more effective. This may be because after the wave of the BA.1 substrain epidemic in South Africa, people's immunity to BA.1 gradually subsided.

On the same day, another preprint article published on bioRxiv also reported that the antibodies of patients who recovered from infection with BA.1 were less capable of neutralizing BA.4, BA.5 and BA.2.12.1 sublineages than BA.1 sublineages under laboratory conditions. In this study, a domestic team synthesized its spike protein based on the DNA sequence of the new mutant strain, and then tested the ability of different antibodies to prevent it from binding to cell surface receptors. The researchers collected 156 blood samples, each of whom had received a vaccine and a booster shot. Some of them had been infected with BA.1, and some were survivors of the SARS-CoV-1 virus 20 years ago. Similar to the South African team, they also found that the blood samples of subjects infected with BA.1 were less capable of neutralizing BA.4, BA.5 and BA.2.12.1 than BA.1. Interestingly, they also found that among the subjects infected with BA.1, the neutralizing ability of the blood samples of the vaccinated subjects was even worse than that of the unvaccinated subjects.

Last December, Professor David Ho of Columbia University in New York published an article in Nature stating that the Omicron variant has significant antibody escape ability against the four previously widely used vaccines. Currently, his team has published a preprint reporting that the sublineages BA.2.12.1 and BA.4/5 developed from BA.2 have stronger antibody escape ability.

Figure 2 Mutations in the spike protein of each Omicron substrain. [11]

The aforementioned article published on bioRxiv pointed out that the new variant has the ability to escape immunity by evading antibody neutralization. The mutations carried by BA.4, BA.5 and BA.2.12.1 changed the leucine (L452) at position 452 of the spike protein. The virus enters the cell by binding to the cell surface receptor through its spike protein, so the change in the amino acid sequence of the spike protein leads to a change in the binding properties of the spike protein. The domain where L452 is located is also a key site for antibody binding. L452 is in the highly variable region of the virus, where four different mutations have appeared. Researchers suspect that this is the result of the selection pressure brought about by the high herd immunity brought about by vaccination and large-scale Omicron infection, and mutations that can escape immunity have been concentrated and retained. The Delta mutant also has an important mutation at position 452, so many scientists are paying close attention to this site [4].

Ho believes that the emergence of these strains suggests that the Omicron variants have and will continue to evolve into sublineages that are more contagious and capable of evading antibodies.

Figure 3 Surface structure of spike protein trimers of various Omicron sublineage strains. [11]

A preprint article published on bioRxiv on May 26 reported that compared with the BA.2 substrain, BA.2.12.1 is only 1.8 times more resistant to the vaccine recipient's serum, while BA.4 and BA.5 are 4.2 times more resistant, making the latter two more likely to cause breakthrough infections. Mutations at amino acid site L452 in BA.2.12.1, BA.4, and BA.5 can help them escape antibodies targeting the class 2 and class 3 receptor binding domains. The F486V mutation carried by BA.4 and BA.5 can help them escape antibodies targeting the class 1 and class 2 receptor binding domain regions, while also impairing their affinity for the cell receptor ACE2. However, the R493Q reversion mutation restored their affinity for ACE2. Among the therapeutic antibodies currently in clinical use, only bebtelovimab (LY-COV1404) developed by Eli Lilly still maintains complete neutralizing efficacy against BA.2.12.1, BA.4, and BA.5. [7]

Vaccine development and antibody therapy

In laboratory studies, the immunity that people develop after being infected with BA.1 has limited effect on the new sublineage, so there are voices questioning whether the vaccines being developed by Moderna, Pfizer/BioNTech and other pharmaceutical companies against Omicron are effective. Moderna has tested two versions of the mRNA vaccine, one containing sequences of the original new coronavirus and the Beta strain, and the other containing sequences of the original new coronavirus and the Omicron BA.1 sublineage, but has not yet reported the effects of these two versions on the new sublineage. Pfizer/BioNTech has also tested the effects of a booster shot and another BA.1-based vaccine, and the results are not expected until the end of June. The FDA will analyze the data and recommend the vaccine for use in the fall on June 28.

Wang Linfa, a virologist at Duke-NUS Medical School, believes that the virus is evolving too quickly and the development of vaccines targeting specific substrains cannot keep up. In the future, a better way to deal with mutant strains may be a broad-spectrum monoclonal antibody cocktail targeting multiple substrains (i.e., the combination of multiple monoclonal antibodies).

Studies have found that antibody F61 isolated from the blood of recovered patients infected with the original strain of the new coronavirus can neutralize five variants, including BA.1, BA.1.1, BA.2, BA.3 and BA.4. Another antibody D2 that binds to different antigenic epitopes (epitopes, sites that determine the specificity of antigen-antibody binding) can neutralize several mutant strains except BA.1.1 and BA.4. If the two antibodies are used in combination, they will show a synergistic effect and can neutralize all the above subtypes in vitro [5]. The use of this type of broad-spectrum neutralizing antibody will become the mainstream of antibody therapy.

For people who are vulnerable to severe illness, including those with immune deficiencies, the cocktail treatment may provide protection for up to several months. Wang Linfa believes that protecting these vulnerable groups is important because many researchers suspect that new mutant strains emerge from those who have been infected for a long time and whose immune systems are unable to clear the virus.

The main obstacle to cocktail therapy is its extremely high price - $1,000 per person per dose. In addition, its research and development cycle may not be short. If someone can reduce the cost to $50 or $100, cocktail therapy may become an effective strategy to prevent the long-term spread of the new crown. This may even be more cost-effective than constantly updating vaccines.

Prediction: The next wave of epidemic

Although BA.4 and BA.5 mutants have been found in Europe and North America, they may not cause a new wave of epidemics, at least not yet. Tom Wenseleers, an evolutionary biologist at the Catholic University of Leuven in Belgium, believes that they are closely related to BA.2, which has just swept through Europe, so the immunity of the population there may still be high. Therefore, their impact on Europe may be smaller.

If the new coronavirus continues to evolve along its current path, it could become a seasonal respiratory disease. The pattern of new coronavirus infection will become increasingly traceable, as new mutations always exploit defects in the herd's immune mechanism to invade and drive its cyclical spread. Scientists may be able to predict more and more accurately how long the population's immunity to COVID-19 will last and when a new wave of the epidemic will come. Jesse Bloom, a viral evolutionary biologist at the Fred Hutchinson Cancer Research Center in Seattle, believes that this is a way to interpret the current epidemic observations, but we should be cautious because the observation time scale is too short to be extrapolated to more widely applicable laws.

References

[1] https://www.the-scientist.com/news-opinion/what-you-should-know-about-new-omicron-subvariants-70012

[2] https://www.uptodate.cn/contents/covid-19-epidemiology-virology-and-prevention

[3] https://www.yalemedicine.org/news/5-things-to-know-omicron

[4] https://www.science.org/content/article/new-versions-omicron-are-masters-immune-evasion

[5] https://www.biorxiv.org/content/10.1101/2022.05.27.493682v1

[6] https://www.biorxiv.org/content/10.1101/2021.12.31.474653v1

[7] https://www.biorxiv.org/content/10.1101/2022.05.26.493517v1

[8] https://weekly.chinacdc.cn/en/article/doi/10.46234/ccdcw2022.094

[9] https://weekly.chinacdc.cn/en/article/doi/10.46234/ccdcw2022.095

[10] https://weekly.chinacdc.cn/en/article/doi/10.46234/ccdcw2022.104

[11] https://www.biorxiv.org/content/10.1101/2022.04.30.489997v1

[12] https://www.cnbc.com/2022/05/11/who-says-omicron-bapoint4-and-bapoint5-subvariants-have-spread-to-over-a-dozen-countries.html#:~:text=A nonether%20omicron%20subvariant%20called%20BA.2.12.1%20has%20been%20detected,subvariant%2C%20most%20of%20which%20comes%20from%20the%20U.S.

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