What is behind the rapid demise of the delta variant in Japan? It could be a self-extinction.

Why has the fifth and largest wave of the coronavirus pandemic in Japan, driven by the supercontagious delta variant, suddenly come to an end following a seemingly unrelenting rise in new infections? And what made Japan different from other developed countries that are now seeing a new wave of new cases?

According to a group of researchers, the surprising answer could be that the delta variant took care of itself in an act of “self-extinction.”

Three months after the delta variant resulted in a record daily nationwide number of nearly 26,000, new COVID-19 infections in Japan have plummeted, falling below 200 in recent weeks. This drop was underscored by the fact that no deaths were reported on November 7 – the first time in about 15 months.

Many researchers point to various possibilities, including one of the highest vaccination rates among advanced countries with 75.7% of residents fully vaccinated on Wednesday. Other potential factors are social distancing and mask-wearing measures which are now deeply entrenched in Japanese society.

But the main reason may be related to the genetic changes the coronavirus undergoes during reproduction, at a rate of about two mutations per month. According to a potentially revolutionary theory proposed by Ituro Inoue, a professor at the National Institute of Genetics, the delta variant in Japan has accumulated too many mutations in the non-structural error-correcting protein of the virus called nsp14. As a result, the virus struggled to fix errors in time, ultimately leading to “self-destruction”.

Studies have shown that more people in Asia have a defense enzyme called APOBEC3A which attacks RNA viruses, including the SARS-CoV-2 virus which causes COVID-19, compared to people in Europe and Africa.

Researchers from the National Institute of Genetics and the University of Niigata therefore set out to find out how the APOBEC3A protein affects the nsp14 protein and whether it can inhibit the activity of the coronavirus. The team conducted an analysis of genetic diversity data for alpha and delta variants from infected clinical samples in Japan from June to October.

They then visualized the relationships between the DNA sequences of the SARS-CoV-2 virus to show genetic diversity in a diagram called the haplotype network. In general, the larger the network, the more positive cases it represents.

Osaka’s Minami district on October 25. | KYODO

The alpha variant network, which was the main driver of Japan’s fourth wave from March to June, featured five large clusters with many branching mutations, confirming a high level of genetic diversity. Researchers believed that the delta variant, which the US Centers for Disease Control and Prevention says is more than twice as contagious as previous variants and could cause more severe disease in unvaccinated people, would have a diversity much more dynamic genetics.

Surprisingly, they found the opposite to be true. The haplotype network had only two main groups and the mutations seemed to stop abruptly in the middle of its evolutionary development process. When the researchers looked at the error-correcting enzyme from the nsp14 virus, they found that the vast majority of nsp14 specimens in Japan appeared to have undergone many genetic changes at mutation sites called A394V.

“We were literally shocked to see the results,” Inoue told the Japan Times. “The delta variant in Japan was highly transmissible and excluded other variants. But as the mutations accumulated, we believe it eventually became a faulty virus and was unable to copy itself. Considering that the cases have not increased, we believe that at some point during such mutations it headed straight for its natural extinction. “

Inoue’s theory, while innovative, would support the mysterious disappearance of the spread of the delta variant in Japan. While much of the rest of the world with equally high vaccination rates, including South Korea and some Western countries, suffer from record waves of new infections, Japan appears to be a special case as COVID-19 cases have remained low despite trains and restaurants filling up after the last state of emergency ended.

“If the virus were alive and well, the cases would surely increase, as masking and vaccination does not prevent breakthrough infections in some cases,” said Inoue.

Ituro Inoue, professor at the National Institute of Genetics |  THE NATIONAL INSTITUTE OF GENETICS
Ituro Inoue, professor at the National Institute of Genetics | THE NATIONAL INSTITUTE OF GENETICS

Indeed, the unexpected drop in new cases after the summer wave has been a hot topic of discussion among many experts, including those who do not conduct studies on the coronavirus, according to Takeshi Urano, professor at the medical school of Shimane University which was not involved in the research carried out by Inoue.

“Nsp14 works with other viral proteins and has a critical function in protecting virus RNA from disruption,” he said when asked about Inoue’s findings. “Studies have shown that a virus with a paralyzed nsp14 has a drastically reduced capacity for replication, so this may be a factor behind the rapid decline in new cases. Nsp14 is derived from a virus, and the chemical agent to curb this protein could become a promising drug, which is already in development.

Japan appears to be an anomaly as the delta variant practically excluded alpha and other variants at the end of August. On the other hand, other countries including India and Indonesia, both of which have been particularly affected by the delta variant, have reported a mix of alpha and delta strains among the cases.

A similar natural extinction of the coronavirus could possibly be observed abroad, says Inoue, adding that it would be difficult to detect this because no other country seems to have accumulated as many mutations in the nsp14 of the virus as in Japan, although similar mutations at the A394V site have been found in at least 24 countries.

Pedestrians walk past bars on a street at night in Tokyo's Shimbashi district on October 29.  |  BLOOMBERG
Pedestrians walk past bars on a street at night in Tokyo’s Shimbashi district on October 29. | BLOOMBERG

But Inoue’s theory may also help explain why the outbreak of severe acute respiratory syndrome (SARS) ended abruptly in 2003. An in vitro experiment in which researchers caused mutations in nsp14 in the virus that causes SARS led to the discovery that the virus ultimately could not replicate as mutations accumulate.

“No genomic data exists, so it’s just a hypothesis, but because it’s gone, it will never see the light of day again,” he said.

So what are the chances that we may see a similar natural extinction overseas of the SARS-CoV-2 virus causing COVID-19?

“The chances are not zero, but it seems too optimistic for now as we are not able to obtain such evidence, although we have looked at various data from other countries,” he said. .

Since peaking in mid-August, daily COVID-19 cases in Japan have continued to decline, falling below 5,000 in mid-September and below 200 in late October. The country has had one of the lowest infection rates of any advanced country for some time, but it is not immune to the next wave of the pandemic, Inoue said.

A high school student is vaccinated in Saitama on October 7.  |  KYODO
A high school student is vaccinated in Saitama on October 7. | KYODO

“There is clearly a threat,” he said. “We were good because there was a delta variant. Other variants were introduced little by little but the delta of Japan kept them away. But because there is nothing left to keep them at bay, there is room for new ones, as vaccines alone would not solve the problem. In this sense, I think the quarantine measures for immigration control are very important because we never know what comes from foreign countries. “

Some people may wonder if the self-extinction of the delta variant in Japan was caused by something special in the genetic makeup of the Japanese, but Inoue disagrees.

“I don’t think so,” he said. “The people of East Asia, like the Koreans, are ethnically the same as the Japanese. But I don’t know why this observation was made in Japan.

Inoue said the team of researchers from the National Institute of Genetics and the University of Niigata planned to compile a study on their findings by the end of November.

People drink at a bar in Saitama on October 25.  |  KYODO
People drink at a bar in Saitama on October 25. | KYODO

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