He Liping, chief reporter of The Paper
According to the latest data released by the US Centers for Disease Control and Prevention (CDC) on June 21, the new variant BA.4/5 of the Ami kerong new variant has accounted for 34.9% of the new cases in the United States in the week of June 18, a surge of 61.57% over the previous week. BA.4/5 is by far the most immune-escaping strain of the new coronavirus. What is more worrying is that BA.4/5 can also be efficiently replicated in human alveolar epithelial cells, while previously, Omikron BA.1 and BA.2 were mainly replicated in the upper respiratory tract.
Specifically, BA.5 accounted for about 23.5%, and BA.4 accounted for about 11.4%, which has the potential to replace BA.2.12.1. The proportion of BA.2.12.1, which had previously rapidly replaced BA.2, fell to 56% from 62.7% in the previous week. Ba.1, which was rapidly replaced by BA.2, is close to extinction.
The United States just experienced the Omicron tsunami last winter and this spring, with BA.1 in the first half and BA.2 in the second half. However, the high immunity level of the population brought about by the infection of a large number of people plus vaccination can not stop the WAVES of BA.2.12.1. BA.2.12.1 has not been flattened, and BA.4/5 has rolled in.
Mutations in BA.2.12.1, BA.4, and BA.5 at the L452 site of spike protein are not present in the Omiljung BA.1 and BA.2 sub-variants, while the Delta strain has the spike protein mutation site. The difference is that the mutation in BA.2.12.1 is L452Q, and the mutation in BA.4/5 is L452R. Delta is also L452R.
This means that the Ormicron variant has under strong positive selection pressure, and has a convergent evolution with the Delta strain on the spike protein gene. The mutation on the spike protein is particularly noteworthy because the spike protein plays a key role in the entry of the new crown virus into human cells: the spike protein can bind to the ACE2 receptor of human cells, invade across the cell membrane, is the "key" to open the cell door, and is also the main target of mRNA vaccine and antibody drug design.
Regarding the pathogenicity of BA.4/5, 27 scientific research units from the University of Tokyo, Kyoto University, Hokkaido University, Kyushu University, Kobe University, and the Weizmann Institute of Science in Israel jointly published a blockbuster study on the medical preprint website bioRxiv, showing that the replication efficiency in human alveolar epithelial cells is higher than that of BA.2, especially BA.4 and BA.5 have stronger cell fusion ability in alveolar epithelial cells than BA.2.
In order to test the replication ability of many variant strains of Omikeron in human alveolar epithelial cells, the research team prepared a chimeric recombination sars-CoV-2 virus with L452R mutation through reverse genetics, and the experiment showed that the plaque formed by BA.4 and BA.5 on human alveolar epithelial cell infection was larger than that formed by BA.2 infection. Through experiments, the researchers also found that BA.4 and BA.5 replicate much more efficiently in human iPSC-derived alveolar epithelial cells than BA.2.
Under the wave of BA.4 and BA.5 infections, the US aviation industry is falling into disorder due to the frequent recruitment of crew members, and a large number of flights have been cancelled. June is the traditional summer vacation month in the United States, and on June 19, travelers suffered a new round of flight chaos across the United States, and about 1,000 flights were cancelled. Together with Friday and Saturday the day before, u.S. arrivals and departures and domestic flights were cancelled or delayed in total about 14,000 flights.
The BA.4/5 Atlanta Hartsfield-Jackson Airport was particularly affected. As Delta cancels or changes dozens of scheduled flights, a large number of passengers stay at the airport over the weekend.
The huge overseas COVID-19 infection base provides a steady stream of opportunities for mutations, so new mutant strains emerge like a tidal wave: strains with stronger immune escape ability and stronger transmission have emerged.
Immune escape is stronger, meaning that infections can be repeated. The dangers of repeated COVID-19 infections have attracted the attention of the academic community. Recently, washington university school of medicine and st. Louis veterans health care system jointly released a blockbuster study: Outcomes of SARS-CoV-2 Reinfection. By studying a large sample of 5.69 million people, they found that reinfected people showed an increased risk of all-cause mortality, hospitalization and many diseases compared to those who were infected with COVID-19 for the first time. And with each infection, the above risk increases dramatically. Whether they are unvaccinated or have had 1 or 2 or more injections before their second infection, the risk increases significantly.
And the weaker the toxicity of the so-called mutant strain with stronger propagation ability, the weaker it is. A review in the May issue of Nature Reviews Microbiology, an authoritative international academic journal, pointed out that the low severity of disease in patients after infection with the Omikeron strain is just a coincidence. The antigen evolution of the new crown virus is continuous and rapid, which allows the endless stream of new variants of the virus to increase the severity of infection by evading immunity.
Nature Reviews Microbiology is the journal with the highest impact factor in the microbial field, with an impact factor of 60.633 in 2021. The authors of this review are Peter V. Markov of the European Commission's Joint Research Centre (JRC), Professor Aris Katzourakis of the Department of Zoology at the University of Oxford, and Nikolaos I. Stilianakis of the European Commission's Joint Research Centre and Department of Biometrics and Epidemiology at the University of Erlangen-Nuremberg.
Corresponding author Markov's European Commission Joint Research Centre supports EU policymaking. Professor Katzourakis is also a big name in the field of virus evolution, his research mainly focuses on the long-term evolutionary biology of viruses, and he found a rich genomic "fossil record" of ancient viral sequences in the host genome, which promoted the development of this research, thus giving birth to the emerging field of paleovirology. Professor Katzourakis also studies the evolution and epidemiology of viral pathogens today (such as HIV/HTLV), as well as evolutionary inferences from animal and viral genome sequence data.
In this review article, they wrote that the new crown virus (SARS-CoV-2) is highly contagious, rapidly reduced immunity after infection, antigen evolution, plus a series of potential animal hosts, which allows the new crown virus to continue to spread in human society. From the perspective of disease prevention and control, a key issue is to predict the epidemiological characteristics of the new crown virus, the clinical parameters and the burden of diseases to be borne by human society.
The Opichron variant produces relatively mild symptoms compared to the Delta variant, which is also defined by WHO as a "Concerned Variant (VOC)". This, the authors mention, in turn ignited all sorts of wishful thinking about the epidemic and evolution of the virus: for example, new variant strains are "harmless" epidemics; Widespread immunization from large numbers of vaccinations and infections will make the wave of outbreaks safe; Viruses are promising to evolve benignly.
The most widespread and persistent misconception, they mention, is that viruses evolve to be less lethal to protect their hosts. In fact, viruses have been under intense evolutionary pressure, which affects the virus's immune ability to escape and spread, and the virulence of viruses is usually just a byproduct of this process.
The virulence of viruses is formed by a complex interaction between various factors in the host and pathogen. Viruses evolve to maximize their ability to spread, which, unlike popular belief, may sometimes be associated with higher virulence, for example, higher viral loads that both facilitate transmission and increase the severity of the disease. If so, the virus may evolve into a more virulent strain. If the severity of the strain is only manifested in the later stages of infection, that is, after the typical transmission window, then the role of virulence in virus adaptability is limited, and the strength of toxicity will not be the key to the survival of the fittest. There are many viruses like this that appear after the transmission window, such as the new crown virus, influenza virus, HIV, hepatitis C virus and so on.
That is to say, in fact, predicting the evolution of the virulence of the virus is a complex task, and the low severity of the Omikejong mutation is just a coincidence, and it is difficult to predict future mutations based on this. The authors also point out that unfortunately, the more likely future evolutionary path of the new coronavirus is highly dependent on the potentially catastrophic combination of re-infection ability and high virulence brought about by immune escape.
The authors also point out that another common and naïve belief is that widespread vaccination or infection-induced immunity in populations can guarantee only mild symptoms when new strains of the new virus are contracted in the future. However, this idea ignores a core feature of the biology of the new coronavirus – antigen evolution, the constant modification of the viral antigen spectrum in response to host immune pressures. High rates of antigen evolution can lead to immune escape, i.e., new variants of the virus strain reduce the immune system's ability to respond, leading to reinfection and the potentially serious disease that comes with it. At the population level, antigen evolution and escape increase the burden of medical resources by increasing the rate of reinfection and severe illness.
The Omiljung strain clearly shows that the new coronavirus can produce a large number of mutations in a relatively short period of time to achieve antigen escape. Compared with the original strain, the Omikeron strain has at least 50 amino acid mutations and has a high degree of antigenicity difference with earlier popular strains such as Alpha, Beta, Gamma, Delta, etc. The transmigrant tsunami caused by Omi kerong in highly immune populations suggests that these mutations allow the variant to easily infect individuals who are immune to previous infections or vaccinations. Genetic differences between the various subfamilies under Omikejong are also quite large, and the functional importance of this difference is being demonstrated by the large spread of the Omikeron BA.2 strain.
The authors recall that in September 2020, after an initial period of relative evolutionary stability, variants with considerable antigenic differences from the original strain of the new coronavirus began to emerge. At least three of the earlier VOCs— beta, gamma, delta— have strong immune escape mutations. There is currently no indication that the antigen evolution of the new coronavirus will slow down in the future. Instead, these "concerned variant strains (VOCs)" are just the tip of the "evolutionary iceberg." Over time, hundreds of subtree lines of the new crown virus continue to diverge from each other, and according to evolutionary theory, the chances of immune escape mutations of the new crown virus in the future will be greatly increased.
The degree of adaptability of a virus can be reflected in its effective regeneration number (Rt). Rt is the total number of secondary infections produced by cases of infection in a population. Therefore, the most adaptable variant strain is the one that spreads most to the host. In populations where everyone is susceptible, the virus can do this by becoming more contagious. This is how the early "Concerned Variant Strains " ( VOCs ) evolved : both Alpha and Delta were about 50 % more contagious than the previous dominant strain. In a process where a large infected population is dominated by epidemics, each VOC quickly replaces another.
They also note that, however, in highly immune populations, the contribution of merely increasing intrinsic infectivity to expanded transmission is relatively small, because in this case, the main factor hindering transmission is the host's immunity to infection. Therefore, as humans transition to high levels of immunity, it is expected that COVID-19 will increasingly optimize its transmissibility (Rt) by increasing its ability to reinfect immunized individuals, rather than optimizing its transmissibility (Rt) by being highly contagious. Therefore, increased immunity levels may accelerate the rate of antigen evolution of the virus, thereby increasing the risk of reinfection and possibly increasing the severity of the disease of reinfection. In fact, the rapid spread of Omikeron, thanks to its extraordinary ability to reinfect immune individuals, exemplifies this evolutionary strategy.
Editor-in-Charge: Li Yuequn
Proofreader: Yan Zhang