Moving targets: COVID-19 vaccine efficacy against Omicron subvariants.

The recent global spread of the Omicron variant of severe acute respiratory syndrome of coronavirus 2 (SARS-CoV-2) poses a critical challenge to the efficacy of COVID-19 vaccines and neutralizing therapeutic antibodies. This is due to multiple mutations in the spike protein (S), including its receptor-binding domain (RBD) and N-terminal domain.1, 2, 3 In April 2022, BA.1 was superseded by the BA.2 subvariant. Currently, the BA.2.12.1 and BA.4/5 subvariants have seen a dramatic increase and are dominant in the United States and South Africa, respectively. These variants contain RBD sequences of the S protein identical to that of BA.2, but with additional L452 and F486 mutations, namely L452Q (BA.2.12.1), L452M (BA.2.13), L452R, F486V, and 69–70 deletion (BA.4/5), and all showed a greater transmission advantage than BA.2. The mutation at spike residue F486V (L452) reported in BA.4/5 (both BA.2.12.1 and BA.4/5) facilitates escape from some antibodies targeting the so-called class 1 and class 2 (class 2 and class 3) of the RBD but impairs spike affinity for the cellular receptor angiotensin converting enzyme 2 (ACE2). However, reversion of L452R and R493Q restores binding affinity to hACE2 and thus fitness of BA.4/5.

Although BA.2.12.1 and BA.4/5 have comparable ACE2 binding affinity to BA.2, they show stronger neutralization avoidance than BA.2 against plasma from three-dose vaccinations and from BA.1 infections after vaccination, suggesting that an Omicron BA.1-based vaccine may not be the ideal antigen to induce broad-spectrum protection against emerging Omicron sublineages. In another study examining the efficacy of neutralizing antibodies (nAbs) following infection with BA.4 and BA.5 in both vaccinated (BNT162b2 or Ad26.CoV.2S) and unvaccinated individuals, there was a significant decrease (>2.6-fold and >7.5-fold, respectively) in nAbs titers against the newer sublineages as compared with BA.1. Similarly, Hachmann et al. reported that 6 months after two BNT162b2 immunizations (booster dose), nAbs titers against BA.1, BA.2.12.1, and BA.4/BA.5 were less than 20 (but significantly increased after the boost to 900, 410, and 275, respectively). Compared with the response to the BA.1 subvariant, the mean titer was 2.2 (3.3) times lower than for the BA.2.12.1 (BA.4/5) subvariant. For participants with prior Covid-19, the mean titer was 1.5 (2.9) times lower than for the BA.2.12.1 (BA.4/5) subvariant.

Because several key mutations are observed in the S proteins of the new SARS-CoV-2 variants, it is reasonable to speculate that these new Omicron subvariants may exhibit reduced sensitivity to therapeutic monoclonal antibodies (mAbs). To investigate this possibility, Yamasoba et al. examined the sensitivity of these new subvariants to eight mAbs, with BA.4 and BA.5 showing higher resistance to bamlanivimab, casirivimab, sotrovimab, imdevimab, etesevimab, and tixagevimab compared with BA.1, but not to bebtelovimab and cilgavimab. According to Guo et al., of the therapeutic antibodies approved for clinical use today, only bebtelovimab is fully effective against both BA.2.12.1 and BA.4/5, and more effective than the parental virus.

The efficacy of current vaccines against infections with the Omicron sublineages is unclear. Data available today suggest that the BA.2.12.1 and BA.4/5 subvariants escape neutralizing antibodies to a significant extent, triggered by both infection and vaccination. However, booster vaccination should increase neutralizing capacity against these emerging variants and will likely provide protection against severe disease. In parallel with the development of newer mAbs and next-generation vaccines, emerging SARS-CoV-2 variants need to be carefully and rapidly evaluated for potential enhancement of growth efficiency in the human population, pathogenicity, and/or evasion of antiviral immunity.