Novel coronavirus "Omicron subtype variant strain BA.2": The latest research progress

You-Cheng Xie, Yin-Nan Kang, Chun Gao, Shan-Shan Liu, Li-Ting Zheng,Xiao-Hui Yu, Jiu-Cong Zhang

1. The First Clinical Medical School, Gansu University of Chinese Medicine, Lanzhou 730000, China

2. Department of Gastroenterology, The 940 Hospital of Joint Service Support Forces of the Chinese People's Liberation Army, Lanzhou 730050, China

ABSTRACT Since the outbreak of COVID-19, with the emergence of a series of novel coronavirus variants of different types, COVID-19 has continued to spread across the globe, posing a huge threat to the lives and health of people around the world and posing a severe challenge to global public health security. Recently, the World Health Organization (WHO) announced that novel coronavirus variant strain "Omicron" subtype variant strain BA.2 has been found in 57 countries and regions. It has higher vaccine and antibody tolerance and is more infectious than omicron (B.1.1.529). In this paper, we briefly review the recent studies on the omicron subtype variant strain BA.2.

Keywords:Novel coronavirus pneumonia SARS-CoV-2 Variants Omicron BA.2 Progress

Corona Virus Disease 2019 (COVID-19) is an acute respiratory infectious Disease caused by a newly emerged coronavirus type 2(SARS-COV-2). The main manifestations of COVID-19 are fever,fatigue and dry cough. Severe cases can rapidly progress to acute respiratory distress syndrome, septic shock, and refractory metabolic acidosis and coagulopathy[1]. Since the end of 2019, there have been more than 300 million confirmed cases and 5.62 million deaths as of 28 January. While vaccines and monoclonal antibodies are being applied to fight the epidemic, the Novel Coronavirus itself is also in constant change, producing a variety of mutant strains (also known as mutant strains). The "Omicron ba.2 subtype variant" was first discovered in South Africa in November 2021. According to the weekly epidemiological update of the World Health Organization,the "Omicron subtype BA.2" has rapidly spread to 57 countries and regions around the world. Therefore, the study of Omicron BA.2 subtype mutation is of great importance for public health and epidemic prevention and control.

1. Novel Coronavirus etiology and pathogenesis

Sars-cov-2 is a linear single-stranded plus stranded RNA virus belonging to β coronaviruses, with a spherical envelope of 100-160 nm in diameter and a genome size of 27-32 KB[2]. Starting from the 5 'end of the genome, the anterior 2/3 region is an open reading frame that encodes a polymeric protein (PP1AB), which cleaves itself into 16 non-structural proteins[3] and participates in the transcription and replication of the viral genome. Sequences near the 3 'end encode structural proteins, including spike surface proteins (S), envelope proteins (E), membrane proteins (M), and nucleocapsid proteins (N)[4]. The S1 subunit of S mediates the recognition of host receptors and the S2 subunit promotes the fusion of viral envelope and cell membrane. E and M proteins are responsible for immunological transmembrane frontier transport assembly, germination and release of progeny viruses, and viral envelope formation, all of which play important roles in virus production and maturation. The N protein binds to viral RNA and the virus infects host cells by participating in the replication cycle of viral genes and the immune response. In addition, there are some species-specific accessory genes that are also required for viral replication[5].

2. The novel coronavirus mutation causes

Coronaviruses such as SARS-COV-2 are relatively stable in the replication process due to the proofreading mechanism, but they still have small probability of errors, including mutations and deletions[]. Moreover, the RNA polymerase replication correction function on which RNA virus replication depends is limited, making RNA virus mutation faster. These errors can lead to an accumulation of mutations that, by natural selection, produce more harmful variants,making the virus more infectious and lethal. The large number of mutated strains and unknown new variants are increasingly different from each other, making it difficult for vaccines or drugs to be effective against all strains[7-8], which will also pose a formidable challenge in designing effective vaccines and diagnostics.

Since the beginning of the outbreak, the Novel Coronavirus pathogen (SAR-COV-2) has continued to evolve and mutate,producing transmissible and virulent variants. Such as Alpha(B.1.1.7), Beta(B.1.351), Gamma(p.1), Delta(B.1.617.2) and Omicron(B.1.1.529) variants[ ]. The Omicron variant has recently become the dominant variant in the world, with four lineages: BA.1,BA.2, BA.3 and B.1.1.529. Among them, the cases of Omicron ba.2 variant are gradually increasing and have rapidly spread to 57 countries and regions around the world, attracting widespread attention.

3. Omicron BA.2 subtype mutant

3.1 Discovery and epidemiology of Omicron BA.2 subtype mutant

According to WHO brief, 58.5% of the genetic sequences uploaded globally in the past 30 days were the Omicron strain, which is fast spreading and highly infectious and is rapidly replacing other variants[10]. The genetic lineage of the Omicron strain, b.1.1.529,was first identified in South Africa in November 2021 and designated by the World Health Organization as a "Variant strain of Concern (VOC)", named after the Greek alphabet of Omicron(O)[11]. Ba.1 accounts for the vast majority of omicron infections worldwide, which is the main reason why the omicron strain is listed as VOC. However, cases of BA.2 infection are rapidly increasing in many countries. In the United Kingdom, the BA.2 strain has been identified as the "mutant strain under investigation (VUI)[12].

The genome of the BA.2 strain was found in a sample collected in Gauteng province, South Africa on 27 November 2021, and has been identified in several countries since its discovery. As of 1 February 2022, the omicron subtype variant strain BA.2 has been found in 57 countries and regions[13]. Japan confirmed 7 COVID-19 patients infected with the Omicron subtype variant strain BA.2 on 17 February 2022, including 2 locally infected cases[14]. At present,the SUBvariant ba.2 strain has become the main epidemic strain in 10 countries and regions including the UK, Philippines, Canada and Germany[15]. The UK Health Safety Agency (UKHSA) announced on January 21 that ba.2 had been classified as "VUI". As of January 21, 426 cases of BA.2 had been detected in the UK, up from 53 cases on January 10[16]; Norway also reported a "rapid increase" in BA.2,with only 7 cases on 4 January, but this had risen to 611 cases on 19 January. In Denmark, from 30 December to 2 January, the proportion of the BA.2 variant in the total number of novel coronavirus samples uploaded in the country increased from 14.1% to 30%, while the proportion of the BA.1 variant decreased from 76.6% to 65.1%[17].As of January 28, 2022, nearly half of the STATES in the United States have reported at least 127 confirmed cases of infection with the ba.2 subtype variant strain[18]. On February 17, 2022, the first infection with ormicronia variant BA.2 was found in Guangzhou[19]. Subsequently, sporadic cases of BA.2 were found in Shenzhen,Guangxi, Yunnan, Hainan and other provinces, posing a serious threat to the health and life safety of the public. Although the BA.2 strain has not yet been listed as A VOC by WHO, countries must remain vigilant against the BA.2 strain.

3.2 Infectivity of Omicron BA.2 subtype variant

Compared with the reference genome reported in Wuhan, Omicron BA.2 had 50 mutations in non-structural proteins (NSP3), NSP4,NSP5, NSP6, NSP12, NSP14, S protein, E protein, M protein and N protein[20]. Thirty-two mutations occurred in the S protein, which is the main antigen target of antibodies produced by infection or inoculation, of which 16 mutations affected the receptor binding domain (RBD), 12 were identical to ba.1 and ba.2 had four unique mutations. Previous studies have demonstrated that SARS-COV-2 initiation of cell entry and infection relies on the binding between the viral S protein RBD and the host angiotensin-converting enzyme 2(ACE2) target cell receptor[21], and is the primary target of vaccines and monoclonal antibodies (mAbs)[22]. In contrast, the Delta variant had only 2 RBD mutations[23]. The high mutation of BA.2 in RBD enables it to enhance its infectivity through stronger binding to ACE2.

Due to natural selection, the virus increases the change of BFE through mutation, thus enhancing the binding affinity of ACE2-RBD complex[24]. The greater the change of BFE, the stronger the infectivity. Because natural selection favors mutations that increase the infectivity of the virus[25], the most infectious mutations will dominate the population under the same competitive conditions.Zhang L et al. [21] compared the other major variants of SARscoV-2(Alpha, Beta, Gamma, Delta, Theta, Kappa, Lambda and Mu) and found that the Delta variant had the highest change in BFE among the early variants. And the Omicron variant was the most infectious before it appeared, which explains the advantage of the Delta variant in 2021. The BFE changes of Omicron BA.1, BA.2 and Ba.3 were 2.60, 2.98 and 2.88 kcal/mol, respectively, which were much higher than those of other srAS-COV-2 varieties. Omicron BA.2 was the most infectious, 20 times as infectious as SARS-COV-2 and 4.2 times as infectious as Delta, respectively.

Model predictions also suggested that BA.2 was about 1.5 times as infectious as BA.1[26], and another report also confirmed that Omicron BA.2 was more infectious than BA.1[27]. At the same time, ba.2 is unofficially known as the "stealth" variant because of the difficulty of early PCR identification. In the identification of omicron, B.1.1.529 mutant, PCR identification was carried out by using the region targeting "S gene target failure" (SGTF), but BA.2 lacked S gene deletion in the region encoding 69/70 amino acid,making it difficult to quickly identify in clinical samples[28]. As a result, only genetic sequencing technology can identify ba.2, which often spreads quickly in the early stages of an epidemic because of the increased difficulty of detection.

The incidence of BA.2 has been soaring in more than 57 countries,suggesting it is more infectious than its "predecessor" BA.1. In Israel, a small number of patients infected with the original Omicron ba.1 strain have been reported to reinfect the Ba.2 strain within a short period of time[29], which means that antibodies produced by early infection with Omicron BA.1 may be avoided by the Ba.2 strain.

Omicron BA.1 is known for its ability to evade existing vaccines[30], and its 15 mutations on RBD enable it not only to enhance its infectiity through stronger binding to host ACE2, but also to produce mismatches with most directly neutralizing antibodies produced by vaccination or prior infection. Although ba.1, Ba.2, and Ba.3 had a total of 12 RBD mutations, ba.1 had three additional RBD mutations, Ba.2 had four additional RBD mutations, ba.3 had one identical mutation to Ba.1 and two identical mutations to Ba.2.

Sensitivity tests were performed on Omicron, Alpha, Beta, Gamma,Delta, Lambda, and Mu in serum samples from 28 convalescence COVID-19 patients infected with the early SARS-COV-2 strain(D614G)[31]. The results showed that Omicron BA.1, BA.2 and Ba.3 could lead to an approximately 21-fold, 27-fold and 18-fold increase in vaccine breakthrough capacity under the same conditions. As a result, ba.2 is approximately 30% higher than BA.1 and 17 times higher than Delta. Because of its highest infectivity and highest vaccine escape potential, Omicron Ba.2 will replace Omicron Ba.1 in infecting the world's population.

3.4 Antibody tolerance of Omicron BA.2 subtype mutant

The design and discovery of monoclonal antibodies is one of the important achievements in combating COVID-19[32]. Unfortunately,like vaccines, monoclonal antibodies are susceptible to viral mutations, especially those with antibody resistance[33]. Early studies predicted and confirmed that Omicron BA.1 will impair monoclonal antibodies against COVID-19 developed by Eli Lilly, Regeneron,Astrazeneca, Celltrion and Rockefeller University[34]. The FDA has stopped using monoclonal antibodies for COVID-19 from Eli Lilly and Regeneron. However, the effect of Omicron BA.1 on GlaxoSmithKline's sotrovimab is expected to be modest[35].

Sotrovimab[36] is the only antibody drug approved in the United States for the treatment of COVID-19 patients infected with Omicron variants. All monoclonal antibodies to human ACE2 competing receptor binding motifs (RBM) are severely impaired by Omicron subvariants, as most RBD mutations are located in RBM.One possible reason is that the Omicron subvariant optimizes the RBD mutation of RBM, enhances the infectivity of the virus, and evades direct neutralizing antibodies. As a result, all monoclonal antibodies against RBM are severely compromised by subvariants of Omicron. Antibody S309 is the mother antibody of Sotrovimab[37]. C135 and S309 antibodies do not directly compete with ACE2 for RBM. However, C135 is still very close to RBM and is significantly weakened by some Omicron mutations. In contrast, S309 is further away from RBM and escapes Omicron's RBD mutation. The ba.2 mutation had little effect on S309. Therefore, some scholars predict that sotrovimab is still effective against the BA.2 subtype.

Similarly, in a deep learning model for Ba.2 [12], scientists investigated the effect of BA.2 RBD mutation on RBD-ACE2 binding, and found that BA.2 was 1.5 times and 4.2 times more infectious than Ba.1 and Delta, respectively, and predicted that ba.2 would destroy most existing monoclonal antibodies. Except for Sotrovimab developed by GlaxoSmithKline [10].

4. Summary and prospect

Due to natural selection, cases of infection with the Omicron variant BA.2 variant of severe acute respiratory syndrome coronavirus 2(SARS-COV-2) are increasing globally, with higher infectivity,greater vaccine breakthrough capacity and severe antibody escape rates. In South Africa, the BA.2 strain has become the dominant circulating strain, and in Denmark[38], the BA.2 strain has accounted for 69% of new confirmed cases, and it is expected that all new cases will soon be ba.2 infected. Despite this, Denmark has one of the highest vaccination rates in the world[39]: 83.4% of people over the age of five have received at least one dose of COVID-19 vaccine,81.5% have received two doses and 62.2% have received booster shots. Ninety-eight percent of people over 55 have had booster shots.Denmark is also the first country to cancel quarantine measures,so we urge people to keep physical distance, wear masks correctly,avoid mass gatherings, and follow quarantine rules even if they get vaccinated against COVID-19. At present, information on the BA.2 strain is still in the process of groping. We believe that through the efforts of governments, medical staff, scientists and ordinary people,we can find out more about the ba.2 strain. The epidemic will be defeated by mankind, and victory will belong to the people of the world.