Delineating antibody escape from Omicron sublineages

Abstract

SummarySARS-CoV-2-neutralizing antibodies play a critical role for protection and treatment of COVID-19. Viral antibody evasion therefore threatens essential prophylactic and therapeutic measures. The high number of mutations in the Omicron BA.1 sublineage results in markedly reduced neutralization susceptibility. Consistently, Omicron is associated with lower vaccine effectiveness and a high re-infection rate. Notably, newly emerging Omicron sublineages (BA.1.1, BA.2) have rapidly become dominant. Here, we determine polyclonal serum activity against BA.1, BA.1.1 and BA.2 in 50 convalescent or vaccinated individuals as well as delineate antibody sensitivities on a monoclonal level using 163 antibodies. Our study reveals a significant but comparable reduction of serum activity against Omicron sublineages which markedly increases after booster immunization. However, notable differences in sensitivity to individual antibodies demonstrate distinct escape patterns of BA.1 and BA.2 that also affect antibodies in clinical use. The results have strong implications for vaccination strategies and antibody use in prophylaxis and therapy.

Structural and functional characteristics of SARS-CoV-2 Omicron subvariant BA.2 spike

“…Nevertheless, the clinical outcomes of infection by these two Omicron subvariants do not appear to be very different ( 6 ). Both BA.1 and BA.2 are antigenically distant from the Wuhan-Hu-1 stain that initiated the pandemic ( 7, 8 ), and they evade neutralizing antibodies elicited by the Wuhan-Hu-1 based vaccines or by infection of early viral strains to a similar degree ( 9 ), but with some qualitative differences ( 10, 11 ). Vaccinated individuals infected with BA.1 can induce cross-reactive immunity to BA.2, and reinfection with BA.2 after BA.1 infection is rare ( 12–14 ).…”

Imprinted antibody responses against SARS-CoV-2 Omicron sublineages

“…The BA.3 S glycoprotein comprises a combination of mutations found in BA.1 S and BA.2 S (4), whereas BA.4 S and BA.5 S comprise a deletion of residues 69-70, L452R and F486V and reversion to Q493 compared to BA.2 S (5). We characterized the emergence of Omicron (BA.1) as a major antigenic shift due to the unprecedented magnitude of immune evasion associated with this variant of concern (3,(6)(7)(8)(9)(10). Mutations in the BA.1 S glycoprotein N-terminal domain (NTD) and RBD, which are the main targets of neutralizing antibodies (3,(11)(12)(13)(14)(15)(16), explain the markedly reduced plasma neutralizing activity of previously infected or vaccinated subjects, especially those that have not received booster doses, and escape from most monoclonal antibodies (mAbs) used in the clinic.…”

VH3-53/66-Class RBD-Specific Human Monoclonal Antibody iB20 Displays Cross-Neutralizing Activity against Emerging SARS-CoV-2 Lineages

“…Only a fewnAbs from this class, including those isolated from a patient infected with a Beta-variant of SARS-CoV-2, have been reported to be resistant to K417N/T and/or N501Y effects [ 6 , 24 ]. Nonetheless, to our knowledge, the vast majority of nAbs from this class display no or very weak neutralization of the Omicron variant [ 6 , 7 , 25 ].…”