On July 5, the Omicron BA.5 subtype, which is better at evading the human immune response, was first reported to cause local transmission in the mainland. Xi’an became the first city in the mainland to be attacked by BA.5. The next day, the Beijing Center for Disease Control and Prevention also notified the gene sequencing results of 3 infected specimens, and BA.5 also appeared in Beijing.
At a press conference on July 8, Lei Zhenglong, deputy director and first-level inspector of the National Health Commission’s Bureau of Disease Control and Prevention, pointed out that recently Beijing, Tianjin, Shaanxi and other places have successively reported local cases caused by imported cases of BA.5 mutants. Due to the epidemic, the pressure on China to prevent imports from abroad continues to increase. On July 10, Shanghai also reported a case of infection caused by the BA.5 clade variant, which was an infected person associated with overseas entry; from July 12 to 14, several districts in Shanghai carried out “3-day 2-checks”.
”Hello BA.5″, also on July 5, Eric Topol, an American expert in genetics and genetic science, posted such a tweet. In the picture, the number of people infected with the new crown in the United States, the United Kingdom, Greece, New Zealand, France and other countries has rebounded significantly in the near future, and the new mutant strain BA.5 of Omicron is an important driving force behind it.
In the Omikron virus family with strong immune escape ability, BA.5 has evolved even better, setting off a new wave of infection internationally. The emergence of this new strain makes it more difficult to block the spread of the virus, and the effect of existing vaccines is also declining, and the prevention and control of the new crown epidemic is facing a new test.
BA.5 “R0 is greater than 18, the transmission ability is faster than measles”?
It is not surprising that BA.5 came to China, as it has gradually become a mainstream strain globally.
On July 6, according to the latest data from the World Health Organization (WHO)’s latest global new crown epidemic weekly report, from June 27 to July 3, there were more than 4.6 million new new crown cases worldwide, reaching a new high since April. Among them, the new sub-variants BA.4 and BA.5 of the Omicron variant are the main reasons for the aggravation of the epidemic. According to WHO monitoring, BA.5 has been detected in 83 countries. From June 19th to 25th, among all the sequences submitted by countries to the Global Influenza Shared Database “GISAID” every week, BA.5 accounted for The proportion rose from 37% to 52%.
The Omicron BA.5 sequence was first uploaded to the Global Influenza Shared Database on March 15 this year from a nasopharyngeal swab collected from a patient in South Africa on February 25. BA.4 and BA.5 became the main SARS-CoV-2 variants in South Africa in May.
BA.5 is not far from us. At the press conference of the Joint Prevention and Control Mechanism of the State Council held on June 28, Wang Wenling, a researcher at the Institute of Viral Diseases of the Chinese Center for Disease Control and Prevention, introduced that since February this year, the main virus strain circulating in China is the sub-branch of Omicron BA.2 series. In May, BA.4 and BA.5 were detected for the first time from imported cases in China.
BA.4 and BA.5 are often studied and paid attention to together, because their mutation sites on the new coronavirus S protein are the same, and their relationship can be regarded as a pair of very close “twins”, however, BA.5 Spreads a bit faster than its brother BA.4.
”BA.4/5 is a subtype of Omicron, however, the reason for concern is because it has appeared a lot different than the original Omicron, because it has combined some of the characteristics of Delta.” Liu Shanju, a virologist at Ohio State University, told China News Weekly. BA.4/5 is evolved from BA.2. Originally, BA.2 has more spreading advantages than the original strain of Omicron, and BA.4/5 is stronger on its basis.
Omicron is currently the virus with the largest number of mutations on the key S protein of the new coronavirus, and the subtype BA.4/5 continues to evolve. Eric Topol, an American expert in genetics and genetic science, described: “The Omicron variant BA.5 is the worst version of the virus we have ever seen.” Because it takes immune escape to a new level, and , because of this change, its spread has also been enhanced, far exceeding the other variants of the Omicron family.
BA.4/5 and BA.2 differ in only 6 mutation sites on the spike protein of the new coronavirus, however, the mutation of one of the sites, L452R, is critical, and this mutation appears in the delta strain. Kei Sato, a virologist at the University of Tokyo, said the mutation may cause the virus to more easily bind to cells and replicate better.
According to the analysis in the briefing updated by the British Health Security Agency on June 24, the growth rate of Omicron BA.5 is 35.1% faster than that of BA.2; while the growth rate of Omicron BA.4 is about 19.1% faster than that of BA.2 .
On July 6, a nucleic acid detection sampling point in Hongkou District, Shanghai. Figure / Surging Image
However, an “appalling” statement is that the basic infection number R0 of BA.5, an important indicator for measuring the ability of the virus to spread, is as high as 18.6. Many media quoted this data and described that the transmission ability of BA.5 has “exceeded that of measles, the virus with the highest transmission ability in human records”. However, this claim has been widely questioned in academic circles.
The source of this figure is often described as: recent research from South Africa. However, if you carefully trace the source of this number, you will find that it comes from an article published in the academic media “Dialogue” on July 4. An epidemiologist from the University of South Australia estimates that the transmission capacity of BA.2 is 1.4 times that of BA.1, R0 is about 13.3; and he cited a non-peer-reviewed, preprinted paper in South Africa that pointed out that BA.4/5 has a dissemination advantage over BA.2, similar to that of BA.2. BA.1, therefore, the scholar concluded that the R0 value of BA.4/5 is 18.6.
The R0 value is the basic reproduction number, which refers to the average number of how many people an infected person will transmit the disease to other people without any intervention of epidemic prevention and at the same time everyone is not immune. Jin Dongyan, a professor at the School of Biomedical Sciences at the University of Hong Kong and an expert in virology, told China News Weekly that it is obvious that the R0 value is no longer suitable for measuring the infectivity of the new coronavirus in the real world, because most people have been vaccinated and become immune. According to the real data provided by various countries, it took BA.1/2 about a month to replace Delta to become a global epidemic strain, and BA.4/5 took 3 to 4 months, indicating that in the past natural infection, vaccine protection and Under the public health measures, its transmission power is not so exaggerated.
Zhang Zuofeng, director of the Department of Epidemiology at the School of Public Health at the University of California, Los Angeles, analyzed the peak incidence of South Africa, France and Portugal on July 7 and found that the average daily incidence of these three countries was mainly caused by BA.5 The highest peaks are 33%, 33% and 47% of the peak incidence of BA.1/BA.2, respectively. The outbreak curve does not support the statement that the R0 value is 18.
master of immune evasion
However, the consensus of the academic community is that BA.4/5 is indeed a “master” in terms of immune evasion.
Multiple laboratory studies have now consistently shown that antibodies elicited by vaccination are less effective at blocking BA.4 and BA.5 than earlier Omicron strains. Even people with mixed immunity, that is, people who have been vaccinated and infected with Omicron BA.1, produce antibodies that are difficult to neutralize BA.4 and BA.5.
On June 17, the journal Nature published papers from Peking University Biomedical Frontier Innovation Center, Peking University School of Life Sciences, and Institute of Biophysics, Chinese Academy of Sciences. The study found that the Omikron sub-variants BA.2.12.1, BA.4, and BA.5 showed stronger immune escape ability, and showed a significant increase in the plasma of Omikron BA.1 infected patients after recovery. Neutralize escape phenomena.
In Portugal, BA.5 already accounted for 80% of all confirmed cases of the virus in June. Although Portugal’s vaccination rate exceeds 85%, and it has just experienced a large number of infections in Omicron BA.1 and BA.2 from the end of 2021 to the beginning of 2022, there is still a new wave of infections in Portugal, with new deaths. It also returned to the level at the peak of Omicron infection in January-February 2022.
On July 5, He Dayi’s team from the Department of Microbiology and Immunology at Columbia University published “Antibody Escape Phenomenon of Omicoron Sub-Variants BA.2.12.1, BA.4, and BA.5” in the journal “Nature” , concluded that BA.4/5 immune escape was 4.2 times that of BA.2 and 19.2 times that of the original strain; the study also evaluated the neutralizing ability of 21 neutralizing antibody drugs, and in vitro experiments found that , 19 mAbs completely or partially lost their neutralizing activity against BA.4/5. Lan Ke, director of the State Key Laboratory of Virology at Wuhan University, told China News Weekly that this shows that BA.4/5 is evolving towards a stronger immune escape ability, which will directly affect the immune protection titer of the new crown vaccine.
A laboratory animal study raised concerns about its pathogenicity. A preprint study published by researchers from Kumamoto University, Tokyo University and other institutions on the BioRxiv website at the end of May showed that three to five days after hamsters were infected with BA.4 and BA.5, the viral load around their lungs was Infect BA.2 hamsters 5.7 and 4.2 times. This means that, for hamsters, BA.4/5 is more likely to cause lung infections.
However, Jin Dongyan believes that this result should not be over-interpreted. The upper respiratory tract of golden hamsters is different from that of the human body, and the harm of a new wave of epidemics in many countries has not been observed in the real world. Organizations including the WHO and the European Center for Disease Control and Prevention all pointed out in their reports in late June that there is currently no evidence that Omicron BA.4 and BA.5 cause more severe disease than previous variants.
Vaccination remains key in the face of BA.4/5. Figure/Visual China
On June 28, South African scientists released the first real-world study on the severity of the disease of infected persons with Omikron BA.4/5 on the preprinted open platform medRxiv, including nearly 3,800 Omikron BA.4/ 5 cases and nearly 191,000 confirmed cases of previous infections caused by mutant strains. The study found that compared with BA.1 cases, BA.4/5 cases had no difference in the risk of death and critical illness, and were all lower than earlier versions of the new coronavirus strain; at the same time, vaccination could still effectively prevent BA .4/5 developed critical illness and died after infection.
Zhang Zuofeng compared the case fatality rates caused by BA.5 and BA.1/BA.2 in South Africa, Portugal and France. In South Africa, the average case fatality rate for BA.5 is 0.65%, while BA.1/BA.2 is 1.33%; in Portugal, the average case fatality rate for BA.5 is 0.17%, while BA.1/BA.2 is 0.13 %; In France, the average case fatality rate of BA.5 is also lower than that of BA.1/BA.2. Looking at the numbers, none of the three countries observed an increase in the average case fatality rate, or even lower than Omicron’s earlier version.
Liu Shansu believes that further results are still pending on how pathogenic the mutant strain is in the real world, because large-scale population data always lag behind virological studies by several weeks, or even a month or two, requiring Be vigilant. However, he emphasized that BA.4/5 has not changed dramatically compared with other strains of the same family. Although some characteristics such as immune evasion ability have been enhanced, it is possible that these characteristics will gradually weaken. He stressed that vaccination remains the key.
BA.4/5 is likely to become the next popular strain in China. Wei Sheng, a professor at the School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, told China News Weekly. However, the current domestic measures to clear the current situation are still not effective for new mutant strains. Effective, because domestic policy is not entirely dependent on vaccines and drugs, current biological changes in the Omicron strain should not have much impact. He believes that normalized nucleic acid testing, combined with rapid epidemiological investigations and public health control measures, is still the key to keeping major cities from breaking out.
Jin Dongyan suggested that more efforts and resources need to be concentrated so that everyone can at least complete the whole course of vaccination, especially the third shot for the elderly; at the same time, special attention should be paid to those areas with insufficient medical resources such as rural areas that do not have the conditions for normalized nucleic acid. Prevention and control, if an outbreak occurs in the suburbs and rural areas, it will in turn affect the big cities.
Two-pronged approach to booster needles and second-generation vaccines
In late June, infections caused by BA.4/5 already accounted for more than half of those infected in the UK. In a June 24 briefing, the UK Health Security Agency pointed out that the rise in infections in the UK so far, thanks to vaccinations, has not led to an increase in severe illness and deaths, and the agency urged people that eligible people should Get vaccinated as soon as possible.
Scientists agree that the vaccine and booster needles have not completely expired, and the immunity activated by the current vaccine can still provide effective protection against severe illness, hospitalization and death in the face of BA.4/5. However, as the new coronavirus continues to mutate and the level of vaccine protection continues to weaken over time, it is also necessary to study the protective effect of existing vaccines and formulate more detailed vaccination strategies.
Zhang Linqi, director of the Center for Global Health and Infectious Diseases at Tsinghua University, told China News Weekly that in the face of BA.4/5, there are currently three levels of response to vaccine development and vaccination strategies at home and abroad. The first is to continue to promote booster shots, especially heterologous or sequential vaccination, that is, the “mixed fight” of different technical routes of booster shots and basic immunization vaccines, which is more effective than only vaccinating the same type of vaccine.
According to a paper published on July 7 in the New England Journal of Medicine by the Gao Fu team of the Institute of Microbiology of the Chinese Academy of Sciences, after two doses of inactivated vaccine basic immunization, the protein subunit vaccine was used as a heterologous booster for booster vaccination. The neutralizing antibody titers of the original strain and all Omicron subtype variants were higher than those of the group vaccinated with three doses of the same inactivated vaccine. Among subjects vaccinated with three doses of Zhifei protein subunit vaccine, compared with those vaccinated with a 1-month interval between the second and third doses, the vaccinated subjects with an interval of 4 to 6 months were more resistant to early primary The neutralizing antibody titers of the strains increased by nearly 10 times, and the neutralizing antibody titers against all Omicron subtype variants were increased by about 30 times.
Furthermore, Zhang Linqi said that both domestic and international vaccine research and development companies have begun to focus on adding anti-BA.4/5 vaccines to booster vaccinations as much as possible in the autumn and winter of this year. Gao Fu et al. also pointed out that in order to better prevent the immune escape of the current subtype variant strains (especially BA.4 and BA.5) and the subtype variant strains that may be popular in the future, it is still necessary to develop an updated version of the vaccine as a booster shot. .
Since this year, domestic and foreign vaccine manufacturers have been developing second-generation new crown vaccines for Omicron. The four technical routes of domestic inactivated vaccine, recombinant protein vaccine, adenovirus vector vaccine and mRNA vaccine are all developing the Austrian strain vaccine. On May 9, Sinopharm China Bio-Beijing Institute launched a sequential inoculation clinical study of booster injections with Austrian strain vaccine in Hunan Province; on July 9, Sinopharm Zhongsheng Wuhan Institute’s new crown inactivated vaccine entered the clinical research stage.
On May 31, the Faculty of Medicine of the University of Hong Kong and Sinopharm Group announced a collaboration to launch a vaccine clinical trial of the second-generation Ormicon strain, aiming to recruit 1,800 adult volunteers who have been vaccinated with two or three doses of inactivated or mRNA new crown vaccine. . According to Jin Dongyan’s understanding, the above-mentioned clinical trials should disclose relatively complete data in 2 to 3 months, and it happens to be autumn and winter, and this vaccine is expected to come in handy as a booster shot.
The research and development of two mainstream mRNA vaccines in foreign countries is also working hard. On June 8 and June 25, Modera and Pfizer announced the phase II/III trial data of their bivalent vaccines based on the original strain and Omicron BA.1 antigens, respectively. The bivalent vaccines of the two companies were used as booster shots to increase the serum neutralizing antibody titers of the subjects to a certain extent. However, the studies of both vaccine companies pointed out that the bivalent vaccine can produce neutralizing antibodies to BA.4 and BA.5, but the antibody level is lower than that of BA.1 and BA.2.
In view of the strong prevalence of BA.4/5 and the characteristics of the virus, the US FDA has held consecutive meetings since the end of June, requiring vaccine companies to make adjustments in the research and development of the new crown vaccine, and the specificity of the vaccine against BA.4/5 needs to be seriously considered. On the afternoon of June 28, after an 8-hour public discussion, the FDA Vaccine and Related Biological Products Advisory Committee overwhelmingly voted 19:2 in favor of the future US new crown vaccine booster shot must contain Ormicon variant components. The majority of the committee also expressed hope that the new booster will be a bivalent vaccine against both the early original strain and the Omicron BA4/BA.5 strain.
But there are also uncertain factors. Zhang Linqi pointed out that the virus is mutating too fast now, and it is hard to say whether BA.4/5 is still popular in the world in autumn and winter. Vaccine development is still relatively passive in catching up with virus mutations. Therefore, many laboratories around the world, including his team, are working on developing a universal or broad-spectrum vaccine to adapt to changes. This is the third direction of effort.
The Alliance for Innovation in Infectious Disease Prevention, an international organization, and the National Institute of Allergy and Infectious Diseases announced in March last year and $43 million respectively in March last year and $43 million in research and development of broad-spectrum vaccines aimed at preventing infections including the new coronavirus. Various coronaviruses. However, domestic and foreign research and development progress in this regard is very early.
A domestic scientist involved in the development of a broad-spectrum new crown vaccine introduced in an interview with “China News Weekly” that so far, on the new crown antigen, there has not been found a relatively strong immunogenicity, not easy to mutate, and able to activate broad-spectrum neutralization. Ideal epitope for antibodies. Because the new coronavirus mutates so fast, it even surpasses the flu virus. So their team’s idea is to design a vaccine by adding T-cell epitopes to a relatively good antigenic epitope.
He said that in fact, they had designed a broad-spectrum vaccine as early as the beginning of last year, and then they have been improving and verifying it, and some companies have the intention to complete the commercial transformation of this vaccine. However, a vaccine may need to invest more than one billion yuan from research and development to listing. It is difficult to say how the new crown will go, what strategies the government will adopt for prevention and control, etc. Therefore, the capital market and enterprises are not very optimistic about the prospects of the vaccine market. If you are sure, you will not be actively advancing. This is another main reason why broad-spectrum vaccines are not progressing fast.
The new coronavirus has not stopped its evolution, and BA.5 will not be the last mutant. As of July 2, researchers from various countries have found a total of 85 gene sequences of BA.2.75 variants in international new coronavirus genome databases such as “GISAID”. The variant first appeared in the genetic sequence from India in early June, and then quickly appeared in seven other countries including the United Kingdom, the United States, Japan, Canada, Australia, New Zealand, and Germany. BA.2.75 is the “second generation variant” evolved from the BA.2 variant. Some experts said, “This new variant strain may be more infectious.”
