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

Since the emergence of the SARS-CoV-2 Omicron variant in November 2021 [1], it has rapidly replaced 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) [2]. 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 [2]. 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 [3].

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 [4], with early evidence of an association with a higher risk of reinfection [2]. A recent study concluded that XBB evades neutralizing antibodies in recipients of BNT162b2 or CoronaVac vaccines [5]. 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 [6]. The most likely explanation for this advantage is the high level of immune escape exhibited by XBB [7], 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 [8]. More recently, the monoclonal antibodies Evusheld and Bebtelovimab were shown to have failed to neutralize XBB.1/XBB.1.5 [8].

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 [9] 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 [10,11]. 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 [12]. 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) [13]. The Omicron variant has an average R₀ of 8.2 [14]. 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. [15,16] 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 evolved now 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 disease. 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 susceptible 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.