Antiviral efficacy of the SARS-CoV-2 XBB breakthrough infection sera against Omicron subvariants including EG.5

Abstract

As of July 2023, EG.5.1 (a.k.a. XBB.1.9.2.5.1), a XBB subvariant bearing the S:Q52H and S:F456L substitutions, alongside the S:F486P substitution (Figure S1A), has rapidly spread in some countries. On July 19, 2023, the WHO classified EG.5 as a variant under monitoring. First, we showed that EG.5.1 exhibits a higher effective reproduction number compared with XBB.1.5, XBB.1.16, and its parental lineage (XBB.1.9.2), suggesting that EG.5.1 will spread globally and outcompete these XBB subvariants in the near future. We then addressed whether EG.5.1 evades from the antiviral effect of the humoral immunity induced by breakthrough infection (BTI) of XBB subvariants and performed a neutralization assay using XBB BTI sera. However, the 50% neutralization titer (NT50) of XBB BTI sera against EG.5.1 was comparable to those against XBB.1.5/1.9.2 and XBB.1.16. Moreover, the sensitivity of EG.5.1 to convalescent sera of XBB.1- and XBB.1.5-infected hamsters was similar to those of XBB.1.5/1.9 and XBB.1.16. These results suggest that the increased Re of EG.5.1 is attributed to neither increased infectivity nor immune evasion from XBB BTI, and the emergence and spread of EG.5 is driven by the other pressures. We previously demonstrated that Omicron BTI cannot efficiently induce antiviral humoral immunity against the variant infected. In fact, the NT50s of the BTI sera of Omicron BA.1, BA.2, and BA.5 against the variant infected were 3.0-, 2.2-, and 3.4-fold lower than that against the ancestral B.1.1 variant, respectively. However, strikingly, we found that the NT50 of the BTI sera of XBB1.5/1.9 and XBB.1.16 against the variant infected were 8.7- and 8.3-fold lower than that against the B.1.1 variant. These results suggest that XBB BTI cannot efficiently induce antiviral humoral immunity against XBB subvariants.

Immune Evasion and Membrane Fusion of SARS-CoV-2 XBB Subvariants EG.5.1 and XBB.2.3

“…Though bivalent vaccination continues to protect better than the monovalent vaccine and natural infection, neutralization titers are markedly low against all XBB variants, particularly the newly emerged EG.5.1, in comparison to D614G and BA.4/5, as seen previously for XBB variants 3,5,7,9,12,14,16 . Neutralizing antibody titers stimulated by infection with either BA.4/5 or XBB.1.5 are minimal, with average neutralization titers against XBB variants clustering around the limit of detection for the assay, which is consistent with another study 33 . We found that the XBB.1.5-F456L mutation, rather than the XBB.1.5-Q52H mutation, drives the enhanced neutralization escape compared to XBB.1.5.…”

Antigenicity and infectivity characterization of SARS-CoV-2 BA.2.86

“…Indeed, we found that BA.2.86 can induce significant antibody evasion of XBB-stimulated plasma (Figure 2B). BA.2.86’s immune evasion capability even exceeds EG.5 and is comparable to “FLip” variants like HK.3 (XBB.1.5 + L455F & F456L) 9,10 . Interestingly, the relative activities against HK.3 and BA.2.86 vary from sample to sample, indicating a large antigenic distance despite a similar level of evasion.…”

Convergent evolution of SARS-CoV-2 XBB lineages on receptor-binding domain 455-456 synergistically enhances antibody evasion and ACE2 binding

“…These immune-evasive lineages are still continuously accumulating more S mutations, such as R403K, V445S, L455F, F456L and K478R, that may lead to further shift in antigenicity and escape from neutralizing antibodies elicited by repeated vaccination and infection [9, 10]. Some immune escape mutations, represented by F456L, even convergently appeared recently in multiple independent XBB derivative strains, such as EG.5, XBB.1.5.10, FE.1 and FD.1.1, indicating strong selection pressure due to herd immunity (Figure 1A) [11, 12]. By October 2023, over 70% of newly uploaded SARS-CoV-2 sequences carry F456L mutation.…”