​Pay close attention: Will "Delta Plus" trigger another global outbreak?

Recently, the number of confirmed cases of COVID-19 has been on the rise worldwide, and many countries have either tightened their epidemic prevention measures again or are actively preparing for widespread vaccination of vaccine boosters. At the same time, the new coronavirus has not stopped mutating, from the global mainstream Delta variant to the new "Delta Plus". Will the epidemic rage around the world again this winter?

Written by | Xiaoye

2021 is coming to an end, and the shadow of the COVID-19 pandemic has not yet dissipated. Vaccines, therapeutic drugs and intervention measures are our three major weapons against the virus, and the virus is constantly upgrading its "equipment" to seek breakthroughs. Recently, the new variant of the new coronavirus, the AY.4.2 sublineage, has attracted widespread attention from overseas media and has been dubbed "Delta Plus", which seems to imply its stronger transmission ability and potential threat.

AY.4.2 Sublineage—From the Western Hemisphere to the Eastern Hemisphere

Yes, another "new member" from the Delta variant family of the new coronavirus is spreading around the world. On October 26, the World Health Organization's weekly report on the COVID-19 epidemic specifically mentioned the AY.4.2 sublineage [1]. The report stated that since July this year, the number of AY.4.2 sublineage sequencing data submitted worldwide has continued to increase. As of October 25, more than 26,000 AY.4.2 virus strain sequences from 42 countries around the world have been uploaded to the Global Initiative on Sharing Influenza Data (GISAID) database.

Note: The Global Influenza Data Initiative database was established by some authoritative medical scientists. It is a public data platform accessible to the public and is dedicated to improving the sharing of data on influenza, coronavirus, etc. [2].

93% of the AY.4.2 virus strain sequence reports came from the UK. Subsequently, the UK Health Security Agency published a report titled "SARS-CoV-2 variants of concern and variants under investigation in England" at the end of October, pointing out that [3], although the virus strain sequencing data was incomplete, in October alone, the proportion of the AY.4.2 sublineage in Delta confirmed cases increased from 8.5% in early October to 11.3% at the end of the month. In the UK, the Delta variant is the main circulating coronavirus variant, and the increase in the proportion of the AY.4.2 sublineage indicates that this sublineage has the potential to develop into the mainstream virus. In addition to the UK, some European countries such as Denmark, Germany and Ireland have also reported the discovery of the AY.4.2 sublineage.

In the United States, as of November 11, 13 states[4] have reported confirmed cases of the AY.4.2 sublineage, but the cumulative prevalence caused by it is still less than 0.5%. On November 5, the Centre for Health Protection of the Department of Health of the Hong Kong Special Administrative Region Government announced that[5] the Centre had conducted whole genome sequencing on the sample of the previously announced imported case of the novel coronavirus variant (Case 12357), confirming that the sample belonged to the AY.4.2 sublineage of the Delta variant virus strain. The Centre has now launched an epidemiological investigation on the confirmed case.

Tracking of the spread of the AY.4.2 sublineage in the United States | Source: outbreak.info[4]

In the name of Delta Plus

As the novel coronavirus continues to spread and evolve, the virus evolution tree continues to “spread its branches and leaves”, including the Delta “Variant of Concern” (VOC) that has spread around the world this year with extremely strong infectious ability. It can be said to be a thick branch on the evolutionary tree, and the AY.4.2 sublineage is a new fork on this branch. Evans Rono, a molecular biologist who once worked at the Max Planck Institute for Infectious Disease Biology, described it as follows [6]: “There is a constant stream of new mutations in the novel coronavirus, but most of them are not enough to worry about. However, some will gain fitness advantages: either they have stronger transmission and infection capabilities, or they are more resistant to some therapies, or they can avoid the human immune response. Such variants will become unique virus sublineages.”

We already know that the new coronavirus uses the spike protein on the virus's surface to bind to the human ACE2 receptor to enter and infect human cells. The AY.4.2 sublineage comes from the most widely spread AY.4 lineage among the delta variants, and its spike protein has two major mutations at amino acid positions 145 and 222: Y145H mutation and A222V mutation. [7]

It is worth noting that the two characteristic mutations of the AY.4.2 sublineage do not appear simultaneously in other variants of concern. However, the A222V mutation has been seen in Delta's B.1.177 lineage, which may have first appeared in Spain in the summer of 2020. At the peak of summer vacation, the virus variants and tourists crossed mountains and seas. In just two or three months, it has become the main viral lineage spreading in countries such as Spain, Switzerland, Italy, Denmark, the United Kingdom, and Iceland[8]. A study published in Science[9] showed that compared with other lineages, the B.1.177 lineage has a 43% to 90% increased ability to spread. Although it will increase the incidence and hospitalization rates, there is currently no clear evidence that it will change the severity of the disease.

The mutation at position 145 was found in the Mu and Alpha variants of the novel coronavirus. Simply put, this region of the spike protein is the target for antibodies to recognize and eliminate. This mutation can "help the variant escape antibody attacks or (allow the variant virus) to enter human cells more smoothly," explained Olivier Schwartz, director of the Virus and Immunity Department at the Institut Pasteur in France [6].

Although the media named the AY.4.2 sublineage "Delta PLUS", since this sublineage has only recently gained attention, there are currently no clear research results showing that these two mutations affect the virus's ability to infect and ACE2 adhesion. Whether the above two situations are completely applicable to the AY.4.2 sublineage still requires in-depth scientific investigation.

A new threat?

In fact, the specific reasons why the AY.4.2 sublineage is on the rise in the UK are still not entirely clear, and different scientists have given different explanations.

One view is that the AY.4.2 sublineage may not be the most transmissible variant, but may just be spreading among people or areas where the number of confirmed cases in the UK has surged. Another view is that it is the biological changes of the virus itself (transmission ability or immune escape) that allow the AY.4.2 sublineage to run rampant. It is still unclear which reason is this.

Eric Topol, director of the Scripps Research Translational Institute in the United States, estimated[6] that the AY.4.2 sublineage may have a slight transmission advantage over the Delta strain, with a transmission capacity that is approximately 10% to 15% higher, but because the sequence changes are very small, it may not develop into a significant threat. Therefore, the AY.4.2 sublineage may not be the only reason to explain the current epidemic situation in the UK.

But to determine whether the AY.4.2 sublineage is more transmissible, "we need to see more differences between different regions and whether the virus can continue to spread for a longer period of time," said Jeremy Kamil, a virologist at Louisiana State University Health Shreveport [6].

Others have pointed out that the increase in the spread of the new variant in the UK is more likely related to the relaxation of public health intervention measures. In fact, since the outbreak of the new crown epidemic, there have been many controversies among the public and academia regarding policies on mask wearing, youth vaccination, and school transmission control. In addition, the immunity of people who were fully vaccinated a few months ago may decline, and after the arrival of winter, people are more willing to gather indoors with windows and doors closed. These factors may have led to an increase in the number of confirmed cases in the UK.

New variants, new warnings

Although the AY.4.2 sublineage has become increasingly prevalent in the UK, the situation in other European countries is better: although the AY.4.2 sublineage is still present in Denmark, it has not been found to be widespread and sustained in Germany and Ireland, so it has not become a major concern in these two countries. Another piece of “good news” is that so far, the AY.4.2 sublineage does not seem to cause more severe symptoms of infection or reduce the protective efficacy of existing vaccines. Kei Sato of Tokyo University in Japan said: “(Limited data show) that the hospitalization and mortality rates of the new crown epidemic in the UK are relatively stable, which also suggests that vaccines may be effective against the AY.4.2 sublineage.” [6]

However, the emergence of the AY.4.2 sublineage tells us that the new coronavirus still has the potential to find new ways to enhance its ability to spread through mutations. Some scientists want to investigate whether the transmissibility of the Delta virus has reached its peak. Other scientists have speculated that if the Delta mutant strain lineage acquires some new transmissibility, it may have to give up some other biological characteristics, such as those related to increased or decreased rates of severe illness. Undoubtedly, paying close attention to the development of the AY.4.2 sublineage can help scientists find the answers to these questions.

Since the end of last year, there have been various worrying new coronavirus variants, from Alpha to Delta, and the number has been increasing, but not all viruses can flourish all over the world. Many mutations depend on other local virus versions and the local environment. The transmission ability of the Alpha and Delta variants is stronger than other virus iterations that have existed. After their emergence, they infected a large number of susceptible people and eventually became the mainstream strains spreading around the world. The Beta and Gamma variants, which first became popular in South Africa and Brazil respectively, only caused infections and prevailed in the areas where they appeared, but there was no global pandemic.

Members of the new coronavirus variant family丨Source: Shireen Dooling

Today, the Delta variant is the dominant coronavirus variant worldwide, so experts estimate that variants that may pose new threats in the future are very likely descendants of the original Delta variant, such as the AY.4.2 sublineage. When a new pathogen enters a region and begins to spread, there is a lot of randomness, and many imported cases may disappear before a complete transmission chain is established. If the AY.4.2 sublineage is slightly more transmissible than Delta, then the probability results show that more imported cases are needed before the epidemic can break out again before it gains more transmissibility. [9]

In summary, this year's Delta mutant strain has caused repeated outbreaks in many countries around the world, but it is too early to assert that the AY.4.2 sublineage will set off a new round of global outbreaks after Delta. Scientists need to conduct experiments to study the immune evasion ability of virus variants, and health agencies need to continue genome sequencing to monitor virus evolution. The emergence of the AY.4.2 sublineage reminds us that the fight against the epidemic is not over yet, and winter is coming, so we still need to be prepared.

References

[1] https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---26-october-2021

[2] https://zh.wikipedia.org/wiki/%E5%85%A8%E7%90%83%E5%85%B1%E4%BA%AB%E6%B5%81%E6%84%9F%E6%95%B8%E6%93%9A%E5%80%A1%E8%AD%B0%E7%B5%84%E7%B9%94

[3] https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1029715/technical-briefing-27.pdf

[4] https://outbreak.info/situation-reports?pango=AY.4.2&loc=USA&selected=USA

[5] http://www.news.cn/gangao/2021-11/05/c_1128036184.htm

[6] https://www.nationalgeographic.com/science/article/an-offshoot-of-the-delta-variant-is-rising-in-the-uk

[7] https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1029715/technical-briefing-27.pdf

[8] https://www.nature.com/articles/s41586-021-03677-y

[9] https://www.science.org/doi/10.1126/science.abg3055