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Emergence and geographic dominance of Omicron subvariants XBB/XBB.1.5 and BF.7 – the public health challenges

  • Thirumalaisamy P. Velavan
    Correspondence
    Corresponding author: Dr Thirumalaisamy P. Velavan, Institute of Tropical Medicine, University of Tübingen, Wilhelmstrasse 27, 72074, Tübingen, Germany
    Affiliations
    Institute of Tropical Medicine, University Hospital Tübingen, Tübingen, Germany

    Vietnamese-German Center for Medical Research, VG-CARE, Hanoi, Vietnam

    Faculty of Medicine, Duy Tan University, Da Nang, Vietnam
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  • Francine Ntoumi
    Affiliations
    Institute of Tropical Medicine, University Hospital Tübingen, Tübingen, Germany

    Fondation Congolaise pour la Recherche Médicale, Brazzaville, Republic of Congo
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  • Peter G Kremsner
    Affiliations
    Institute of Tropical Medicine, University Hospital Tübingen, Tübingen, Germany

    Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon
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  • Shui Shan Lee
    Affiliations
    Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Hong Kong, China

    International Society for Infectious Diseases
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  • Christian G. Meyer
    Affiliations
    Institute of Tropical Medicine, University Hospital Tübingen, Tübingen, Germany

    Vietnamese-German Center for Medical Research, VG-CARE, Hanoi, Vietnam

    Faculty of Medicine, Duy Tan University, Da Nang, Vietnam
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Open AccessPublished:January 18, 2023DOI:https://doi.org/10.1016/j.ijid.2023.01.024

      Keywords

      Since the emergence of the SARS-CoV-2 Omicron variant in November 2021 [
      • Petersen E
      • Ntoumi F
      • Hui DS
      • Abubakar A
      • Kramer LD
      • Obiero C
      • et al.
      Emergence of new SARS-CoV-2 Variant of Concern Omicron (B.1.1.529) - highlights Africa's research capabilities, but exposes major knowledge gaps, inequities of vaccine distribution, inadequacies in global COVID-19 response and control efforts.
      ], it has rapidly replaced the former strains as the key driver of the pandemic. As of 27 October 2022, the Omicron variant was considered the only circulating variant of concern (VOC) by the World Health Organization (WHO) [

      WHO: TAG-VE statement on Omicron sublineages BQ.1 and XBB. In: World Health organization. 2022.

      ]. Omicron has spawned subvariants due to its propensity of engendering novel mutations. In January 2022, the original Omicron strain BA.1 was replaced by BA.2; and other subvariants – BA.3, BA.4, BA.5 and XE – have subsequently emerged. The WHO Technical Advisory Group on SARS-CoV-2 Virus Evolution (TAG-VE) concluded on 24 October 2022 that the phenotypes of XBB* and BQ.1* (BA.5 sublineage) were not sufficiently different from other Omicron lineages and did not warrant assignment of new VOC identifiers [

      WHO: TAG-VE statement on Omicron sublineages BQ.1 and XBB. In: World Health organization. 2022.

      ]. There is, however, evidence that the newer Omicron subvariants can re-infect people who were previously infected with earlier Omicron subvariants. Subvariants BA.4 and BA.5 (six spike mutations distinguishing them from BA.2) could be more contagious than the BA.2 subvariant [
      • Tallei TE
      • Alhumaid S
      • AlMusa Z
      • Fatimawali Kusumawaty D
      • Alynbiawi A
      • et al.
      Update on the omicron sub-variants BA.4 and BA.5.
      ].
      XBB is a recombinant of the BA.2.10.1 and BA.2.75 sublineages which was first documented on samples collected on 13 August 2022 [
      WHO: Tracking SARS-CoV-2 variants.
      ], with early evidence of an association with a higher risk of reinfection [

      WHO: TAG-VE statement on Omicron sublineages BQ.1 and XBB. In: World Health organization. 2022.

      ]. A recent study concluded that XBB evades neutralizing antibodies in recipients of BNT162b2 or CoronaVac vaccines [
      • Zhang X
      • Chen LL
      • Ip JD
      • Chan WM
      • Hung IF
      • Yuen KY
      • et al.
      Omicron sublineage recombinant XBB evades neutralising antibodies in recipients of BNT162b2 or CoronaVac vaccines.
      ]. XBB.1.5, a sublineage of XBB with an additional spike mutation (S486P) in the receptor binding domain, is currently estimated to have a large expansion advantage and is of considerable concern due to its rapid spread in December 2022. XBB.1.5 was estimated to have a growth advantage relative to previously circulating lineages in North America (109%) and Europe (113%), although these estimates have yet to be confirmed [
      ECDC: Update on SARS-CoV-2 variants: ECDC assessment of the XBB.1.5 sub-lineage.
      ]. The most likely explanation for this advantage is the high level of immune escape exhibited by XBB [
      • Wang Q
      • Iketani S
      • Li Z
      • Liu L
      • Guo Y
      • Huang Y
      • et al.
      Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants.
      ], combined with the effect of the spike variant S486P. Another study postulated that the enhanced transmissibility of XBB.1.5 is due to its strong ACE2 binding plus antibody evasion [

      Yue C, Song W, Wang L, Jian F, Chen X, Gao F, et al. Enhanced transmissibility of XBB.1.5 is contributed by both strong ACE2 binding and antibody evasion. bioRxiv. 2023:2023.01.03.522427; doi: 10.1101/2023.01.03.522427.

      ]. More recently, the monoclonal antibodies Evusheld and Bebtelovimab were shown to have failed to neutralize XBB.1/XBB.1.5 [

      Yue C, Song W, Wang L, Jian F, Chen X, Gao F, et al. Enhanced transmissibility of XBB.1.5 is contributed by both strong ACE2 binding and antibody evasion. bioRxiv. 2023:2023.01.03.522427; doi: 10.1101/2023.01.03.522427.

      ].
      Globally, the Omicron subvariants have dominated the current epidemiologic landscape of SARS-CoV-2 infection, the characteristics of which vary geographically. After the unanticipated lifting of virtually all lockdowns and almost all COVID-19 restrictions in China on 7 December 2022, an unprecedented surge in COVID-19 cases [
      WHO: TAG-VE statement on the meeting of 3 January on the COVID-19 situation in China.
      ] attributed to the highly transmissible Omicron strain BF.7 (BA.5.2.1.7, a substrain of BA.5) was reported. Omicron BF.7 carries the R346T substitution, a specific mutation in the SARS-CoV-2 spike protein, which is associated with the virus’ ability to evade neutralizing antibodies produced by current vaccines, including those produced in China, or following previous COVID-19 infections [
      • Hachmann NP
      • Miller J
      • Collier AY
      • Barouch DH.
      Neutralization Escape by SARS-CoV-2 Omicron Subvariant BA.4.6.
      ,
      • Wang Q
      • Li Z
      • Ho J
      • Guo Y
      • Yeh AY
      • Mohri H
      • et al.
      Resistance of SARS-CoV-2 omicron subvariant BA.4.6 to antibody neutralisation.
      ]. A recent study based on BF.7 neutralization assays in the sera of triple vaccinated individuals and patients infected during the BA.1 and BA.5 waves showed that BF.7 was resistant to neutralization, apparently also due to the R346T mutation [
      • Qu P
      • Evans JP
      • Faraone JN
      • Zheng YM
      • Carlin C
      • Anghelina M
      • et al.
      Enhanced neutralization resistance of SARS-CoV-2 Omicron subvariants BQ.1, BQ.1.1, BA.4.6, BF.7, and BA.2.75.2.
      ]. The basic reproductive number R0 has changed dramatically through generations of evolution of SARS-CoV-2. The Delta variant has a mean R0 of 5.1 compared to the original Wuhan strain (R0 2.8) [
      • Liu Y
      • Rocklov J.
      The reproductive number of the Delta variant of SARS-CoV-2 is far higher compared to the ancestral SARS-CoV-2 virus.
      ]. The Omicron variant has an average R0 of 8.2 [
      • Liu Y
      • Rocklov J.
      The effective reproductive number of the Omicron variant of SARS-CoV-2 is several times relative to Delta.
      ]. Symptoms of BF.7 infection appeared to be similar to those associated with other Omicron subvariants. The high transmission potential of these subvariants might however cause difficulties in implementing effective prevention and control measures.
      Full epidemiologic information on what currently happens in China is unavailable. What appears to be sure is that there are more than one million daily new infections, with a tendency of a further increase. China has suspended the previously widely applied mass testing and is no longer counting asymptomatic infections. The low fatality of COVID-19 derived from official data was criticized by WHO as the Chinese definition of COVID-19 deaths is far too narrow, since deaths in the presence of other concurrent illnesses, e.g. cardio- or cerebrovascular diseases and heart attacks are not considered to be attributable to COVID-19, despite the presence of SARS-CoV-2 positive test results. [
      • Dyer O.
      Covid-19: China stops counting cases as models predict a million or more deaths.
      ,
      • Mission EC
      China's Fight against COVID-19: Facts and Figures.
      ] Furthermore, not much information is available on the geographic distribution of virus variants and their temporal changes in China, and whether novel mutants have already emerged.
      The distribution of Omicron subvariants varies geographically, which has resulted from the interplay of the biological properties of SARS-CoV-2 that favors extensive genetic divergence, and the unique pattern of social networking across time and space. As of now, BF.7 might be the dominant subvariant in China, in contrast to the sequential dominance of Delta, followed by BA1/2, then BA4/5, and currently multiple Omicron sub-variants, including BQ.1 and XBB/XBB.1.5 in Europe and North America. While Omicron was first reported in South Africa, the epidemics have also evolved and the XBB.1.5 is also becoming identified lately. In Australia, the dominance of BR.2 in the last quarter of 2022 also appeared to be giving way to XBB.1.5 since January 2023. Given the current influenza season that has started earlier in the Northern Hemisphere in late 2022, the concomitant respiratory syncytial virus (RSV) epidemic and the immune evasion of novel Omicron subvariants, further studies are needed to inform public health interventions. While the vaccination coverage has increased globally, the protective efficacy of vaccines against emerging Omicron subvariants remains a concern. In China, for example, the widely used inactivated vaccines based on the Wuhan strain 2020 administered in two doses may provide only short-term protection from severe clinical diseases. Although scientific evidence is lacking it is possible that wide dissemination of BF.7 may be, to some extent, associated with suboptimal vaccination coverage. Practically, a broad population level coverage with boostered vaccine regimens targeting the wild type virus in conjunction with unavoidable natural infections in the community, probably provides the best protection to the population. Real-world data analyses would be important to evaluate the impacts of newer generation of COVID-19 vaccines that target Omicron subvariants, which would support the development of strategies to enhance preparedness of the health systems to guard against detrimental effects on population health.
      As the Lunar New Year approaches, mass movements in China and neighboring countries could exacerbate the spread of COVID-19, as was the case in early 2020 when the outbreak turned into a pandemic. With the “re-opening" of China, the passenger traffic with the rest of the world will increase exponentially, adding to the risk of the global dissemination of Omicron subvariants in Europe and the Americas where normal societal activities have resumed earlier on. In Africa, there is the concern of outbreaks as the population could be at risk due to lower vaccination coverage and limited surveillance, despite a higher proportion of younger age people who are less susceptable to severe diseases. Increased and coordinated efforts to safely monitor and contain the spread of various Omicron subvariants will contribute to the control of the pandemic as the world faces an ongoing risk of infections and the associated social disruptions and economic consequences.

      Declaration of Competing Interest

      The authors declare that they have no conflict of interest.

      Acknowledgments

      TPV acknowledges the PAN-ASEAN Coalition for Epidemic and Outbreak Preparedness (PACE-UP) (DAAD Project ID: 57592343). FN and TPV are supported by the Pan African Network for Rapid Research, Response, and Preparedness for Infectious Diseases Epidemics consortium (PANDORA ID-NET) (RIA2016E-1609). SSL is supported by the Health and Medical Research Fund, Hong Kong (COVID1903008). The funders had no influence on the decision to publish or the preparation.

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