Title: Emergence of the Omicron SARS-CoV-2 subvariants during the COVID-19 pandemic
Abstract: Dear Editor, Since December 2019, more than 6.6 million deaths and at least 640 million infection cases (approximately 8% of the world population) have been officially linked to the coronavirus disease 2019 (COVID-19) due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Like other viruses, SARS-CoV-2, an RNA virus, is highly prone to mutations. Naturally, the mutations that ensure a high survival rate for the virus to propagate among its human hosts prove the viral genetic fitness. Thanks to genetic sequencing, multiple genetic alterations and mutations have been identified that characterize the new SARS-CoV-2 (sub)variants. Since 2019, several SARS-CoV-2 variants had emerged but only a limited number could survive and circulate among the community, thanks to such fitness advantages including high virulence, high transmissibility, and evasion of neutralizing antibodies. The World Health Organization, in collaboration with its expert teams of clinicians and scientists, actively monitor for new significantly mutated (sub)variants that may gravely threaten the public health during the course of the pandemic. Indeed, each identified variant of concern (VOC) was found to cause a new surge in positive cases and hospital admissions. After the emergence of B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta) as the initial few SARS-CoV-2 variants, a new VOC, Omicron (B.1.5291), was discovered in South Africa and Botswana. The rapid spread of Omicron into many countries was the focus of sophisticated studies worldwide [1–3] as it produces new subvariants. For example, B.1.1.529.1 (BA.1), an Omicron subvariant, possesses critical genetic alterations and higher transmissibility [3] than the ancestral Omicron strain [4,5]. During the latest waves of COVID-19, the variants were found to spread faster but cause less-severe illness among infected subjects, changing the profile of the pandemic. Assessing the SARS-CoV-2 antigenic drift by studying the effectiveness of the neutralizing antibodies against all the VOCs has shown that Omicron resists neutralization by antisera which were elicited by all the VOCs preceding it [6,7]. Thus, the pre-Omicron VOCs apparently belong to one antigenic cluster, whereas Omicron carries a new antigenic cluster which enables the virus to escape the convalescent sera [7]. The spike protein of Omicron carries almost 30 mutations that facilitate immune evasion [8]; the transmissibility of the Omicron subvariants (BA.1, BA.2, BA.3, BA.4.6, BA.5, and BA.2.75) have also been gradually increasing [1,9]. The above evidence led to an ongoing redesign of the vaccine formulations to maintain high vaccine efficacy (https://www.nbcnews.com/health/health-news/fda-recommends-omicron-subvariants-ba4-ba5-fall-covid-boosters-rcna36125). To have a better understanding of the presently evolving pandemic, we briefly discuss the pandemic situation after the emergence of the two recent Omicron subvariants. BA.2.75 A new subvariant of Omicron (Fig. 1), informally called “Centaurus,” has emerged, causing a new surge of the COVID-19 cases first reported in India [10,11]. The peaks in case numbers have caused a considerable public-health scare (https://science.thewire.in/the-sciences/ba-2-75-sub-variant-new-covid-19-wave). Within a short period, the neutralizing antibodies have been shown to be less effective against BA.2.75 [12]. At least nine of the mutations including (W152R, I210V, G257S, G446S, N460K, G662S, G339H, N4060S, S1221L, P1640S) reported in this subvariant (https://outbreak.info/situation-reports?pango=BA.2 and https://outbreak.info/situation-reports?pango=BA.2.75) are not seen in BA.2 (Fig. 2), casting doubts on the effectiveness of the therapies and neutralizing antibodies elicited by natural infections or vaccines [13,14]. So far, 42 countries and 32 U.S. states have reported this subvariant (https://outbreak.info/situation-reports?pango=BA.2.75&loc=GBR&loc=USA&selected) [15–17]. BA.2.75 has been speculated to have a fast transmission efficiency but cause less-severe disease and a low hospitalization rate. BA.2.75 is more resistant to neutralization by polyclonal sera than other Omicron subvariants [13].Fig. 1.: Phylogenetic relationships of Nextstrain SARS-CoV-2 clades and the rising number of BA.2 subvariants. Adopted from https://nextstrain.org.Fig. 2.: Mutations in the sequence of the spike protein compared between BA.4.6 and BA.2.75 Omicron subvariants [15–17].BA.4.6 In August 2022, new peaks of COVID-19-positive cases were reported mainly in the United States (https://www.cidrap.umn.edu/news-perspective/2022/08/omicron-subvariants-gain-more-ground-including-ba46-midwest). Until the first week of September 2022, outbreak.info (https://outbreak.info/situation-reports?pango=BA.4.6&loc=ZAF&loc=GBR&loc=USA&selected) reported that BA.4.6 (Fig. 2) was found in 66 countries and 53 U.S. states. This subvariant has now surpassed the previous subvariants. Though our knowledge of BA.4.6 is still limited, some experts surmised that the variant had already emerged in early May 2022 and had circulated among some communities undetected. BA.4.6 has been shown to resist neutralizing antibodies [14] highlighting the urgency of developing new, updated vaccines against the Omicron subvariants. Similarly, tixagevimab and cilgavimab were reported to be ineffective against BA.4.6 [14]. In many U.S. states, the prevalence of BA.4.6 represents up to 5% of the cases; however, continued surveillance is necessary to determine the real prevalence of the subvariant. The future of the pandemic To determine what threats the Omicron subvariants could pose, several viral characteristics, including transmissibility rate, disease severity, and virulence, particularly compared with ancestral strains, should be studied (https://reliefweb.int/report/world/enhancing-response-omicron-sars-cov-2-variant). The more-rapid spread of Omicron and its subvariants than the previous strains, including the Delta VOC, shows that Omicron and its subvariants have a favorable growth advantage but cause less-severe disease than by the Delta VOC. Over the course of the pandemic, the SARS-CoV-2 subvariants have been shown to be less virulent but highly transmissible [18]. Indeed, the emergence of Omicron subvariants can be considered optimistically because they have spread to large parts of the world, thus inducing herd immunity (if population vaccination coverage is low). While Omicron has caused a steady number of hospitalizations, emergence of new SARS-CoV-2 variants during the winter of 2023 in the northern hemisphere may present a new picture. The rapidly evolving Omicron subvariants have implications for the efficacy of some available vaccines. Therefore, updated and potentially effective vaccines are necessary to maintain an acceptable level of immunity among many communities [19,20]. Mass-vaccination is the short-term solution for minimalizing a speedy spread of SARS-CoV-2 infections in the community. Undoubtedly, constant genomic surveillance warrants the successful and preventive management of the COVID-19 pandemic in the future. Provenance and peer review Not commissioned, internally peer-reviewed. Conflicts of interest Authors have no competing interests to declare. Funding None. Ethical approval This article does not require any human/animal subjects to acquire such approval. Sources of funding This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Author contribution Farid Rahimi: Conceptualization, Data Curation, Writing – Original Draft, Writing – review & editing. Amin Talebi Bezmin Abadi: Conceptualization, Data Curation, Writing – Original Draft, Writing – review & editing. All authors critically reviewed and approved the final version of the manuscript before submitting. Research registration Unique Identifying number (UIN) 1.Name of the registry: Not applicable. 2.Unique Identifying number or registration ID: Not applicable. 3.Hyperlink to your specific registration (must be publicly accessible and will be checked): Not applicable. Guarantor All authors. Farid Rahimi Amin Talebi Bezmin Abadi 1Research School of Biology, The Australian National University, Ngunnawal and Ngambri Country, Canberra, Australia 2Department of Bacteriology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran E-mail addresses:[email protected]