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The Epidemiological Features of the SARS-CoV-2 Omicron Subvariant BA.5 and Its Evasion of the Neutralizing Activity of Vaccination and Prior Infection

From December 2021 to May 2022, the Omicron BA.1 and BA.2 subvariants successively became the most dominant strains in many countries around the world. Subsequently, Omicron subvariants have emerged, and Omicron has been classified into five main lineages, including BA.1, BA.2, BA.3, BA.4, BA.5, and some sublineages (BA.1.1, BA.2.12.1, BA.2.11, BA.2.75, BA.4.6, BA.5.1, and BA.5.2). The recent emergence of several Omicron subvariants has generated new concerns about further escape from immunity induced by prior infection and vaccination and the creation of new COVID-19 waves globally. In particular, BA.5 (first found in southern Africa, February 2022) displays a higher transmissibility than other Omicron subvariants and is replacing the previously circulating BA.1 and BA.2 in several countries.

Since April 2022, BA.4 and BA.5 have rapidly replaced BA.2 and have initiated the fifth COVID-19 wave, accounting for more than 50% of sequenced cases in South Africa [4,11]. Several studies have reported that BA.5 exhibits a higher transmission advantage than BA.2 and increased evasion from neutralization antibodies elicited by vaccination and prior infection [4,[11][12][13][14][15]. Omicron BA.1 was displaced by BA.2, which in turn was displaced by BA.5, becoming the dominant strain in many regions [12,16,17]. As of 6 June 2022, it is noteworthy that more than 80% of the BA.5 sequences are found in the United States (33.25%), European countries, and South Africa [12]. The current review article aims to analyze the characteristics of key spike mutations, epidemic characteristics, and immune evasion of Omicron BA.5. We hope to provide a scientific reference for monitoring, control measures, and vaccine development strategies for the current or further Omicron subvariants.
Notably, F486 V decreased the binding activity of BA.5-RBD to hACE2 due to a reduced hydrophobic interaction, while the R493Q reversion mutation restored a hydrogen bond with H34 and avoided charge repulsion by K31 and increased the affinity between BA.5-RBD and hACE2, thus restoring receptor affinity and consequently the fitness of BA.5 [38]. Additionally, two recent reports claimed that BA.5-RBD showed higher binding affinity to hACE2 than BA.1 and BA.2 due to L452R and R493Q reversion [15]. Additionally, it was reported that F486 V broadly caused steric hindrance to binding by class 2 RBD mAbs, such as REGN10933 and LY-CoV555 [38]. Altogether, Omicron BA.5 has critical spike mutations that were previously reported in other VOCs (Alpha, Beta, Gamma, Delta, BA.1, and BA.2). Compared to BA.2, BA.5 has unique mutations, including L452R, F486 V, and R493Q, which can significantly affect the biological characteristics of BA.5, including increasing transmissibility and causing more immune evasion, as shown in Figure 3.

The Virological Characteristics of the SARS-CoV-2 Omicron BA.5
Cell-cell fusion experiments showed that BA.5 exhibited a higher propensity for fusion, with an average syncytia area 2.1-fold higher than that of BA.1 and BA.2 [39]. Similar to the fusion results, BA.5 could increase the S processing phenotype owing to the L452R mutation, and BA.5 exhibited comparable surface S expression, which was 1.4-fold higher than that of WT. Furthermore, the analysis of purified viral particles demonstrated that BA.5 increased S1 signals in purified virions compared to BA.2 [39] (with a similar intensity of p24 in the virions).
Pseudovirus infectivity experiments showed that the infectivity of BA.5 was 18.3-fold higher than that of BA.2 and that BA.5 was more efficiently replicated in human alveolar epithelial cells than BA.2, with the levels of viral RNA in the supernatant of rBA.5-infected cultures being 34-fold higher than those in rBA.2-infected cultures [40].
These results suggest that BA.5 exhibited higher fusogenicity and increased spike processing and that BA.5 has a higher transmission advantage than BA.2. In particular, the risk of BA.4 and BA.5 for global health is potentially higher than that of BA.2. These data highlighted that the number of BA.5 cases is rising worldwide and is becoming the dominant lineage, thus replacing BA. 2. It has been demonstrated that the viral load in the lungs infected with BA.1 is lower than that in the nasal airway [42], and BA.2 is more poorly replicated in CaLu-3 cells than in primary human nasal epithelial cells [43]. One study suggested that the BA.4/5 and BA.2.12.1 variants may retain the reduced pathogenicity of the BA.1 variant [39]. Epidemiologic surveillance [44][45][46][47] revealed that the risk of severe hospitalizations (admission to intensive care or mechanical ventilation or oral/intravenous steroid prescription) and deaths did not increase with the number of COVID-19 cases following the emergence of the Omicron variant globally, with a 20-80% reduction in risk of hospital admission compared to the WT and other VOCs. One clinical study revealed that, after controlling for factors associated with hospitalization and severity (age, sex, presence of comorbidity, previous SARS-CoV-2 infection, and SARS-CoV-2 vaccination status), the adjusted hazard ratio [aHR] of severe hospitalization or death of patients infected with BA.5 was 1.12 (95% confidence interval [CI]: 0.93-1.34) [48], as shown in Table 1. Although infection with BA.5 has a lower risk of severe clinical outcomes, the very higher transmission advantage poses overwhelming challenges to global healthcare systems.
Compared to the WT, BA.5 encoded the P314 L and the P3395H mutation in its RNAdependent RNA polymerase and its main protease, respectively. In vitro, 50% inhibitory concentration (IC50 with higher values indicating reduced susceptibility) of nirmatrelvir (an inhibitor of the main protease of SARS-CoV-2), molnupiravir, and remdesivir (an inhibitor of the RNA-dependent RNA polymerase of SARS-CoV-2) against BA.5 was 1.6-, 1.5-, and 1.2-fold higher than against WT, respectively [51].
One report published in Nature from a team of researchers from Columbia University reported that the nAbs elicited by BA.1 infection after vaccination could neutralize both WT and BA.1 but are largely evaded by BA.5 owing to D405N, L452R, and F486 V mutations [15]. Pseudovirus neutralization assays showed that the 50% neutralization titer (NT50) of plasma from individuals who had received three doses of CoronaVac (2-dose CoronaVac+ZF2001 or 3-dose CoronaVac+BA.1) against BA.5 was reduced by 1.62-, 2.27-, and 4.3-fold compared with BA.2 and was reduced by 1.62-, 2.39-, and 7.98-fold compared with BA.1, respectively [15].
Similarly, the median neutralizing antibody titer (GMT) six months after the initial two doses of BNT162b2 vaccination was 124 against WT but less than 20 against all the Omicron subvariants [16]. Two weeks after the booster, the GMT against BA.5 had decreased by 21.0-and 3.3-fold compared with WT and BA.1, respectively. Moreover, the GMT of plasma from individuals infected with BA.1 or BA.2 after vaccination against BA.5 was 18.7-and 2.9-fold lower than WT and BA.1, respectively [16]. Xie Xuping and colleagues indicated that the GMTs of the four doses of Pfizer or Moderna mRNA vaccine, two doses of vaccine + BA.1-infected sera and three doses of vaccine + BA.1-infected sera against BA.5 were 3.76-(GMTs: 95 vs. 236), 6.22-(GMTs: 274 vs. 1705), and 6.86-fold (GMTs: 297 vs. 2038) lower than those of BA.1, respectively [52].

Conclusions
BA.5 is becoming the dominant strain, replacing BA.2 and spreading rapidly in many countries, and will shortly cause the next COVID-19 wave. BA.5 has a much higher transmission advantage than other Omicron subvariants, leading to challenges to global