Imprinted antibody responses against SARS-CoV-2 Omicron sublineages

Abstract

SARS-CoV-2 Omicron sublineages carry distinct spike mutations and represent an antigenic shift resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters result in potent plasma neutralizing activity against Omicron BA.1 and BA.2 and that breakthrough infections, but not vaccination-only, induce neutralizing activity in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1 and BA.2 receptor-binding domains whereas Omicron primary infections elicit B cells of narrow specificity. While most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant antibody, that is unaffected by any Omicron lineage spike mutations and is a strong candidate for clinical development.

Omicron spike function and neutralizing activity elicited by a comprehensive panel of vaccines

“…The emergence of the SARS-CoV-2 Delta and subsequently Omicron variants of concern led to an increasing number of reinfections and vaccine breakthrough cases ( 5 , 46 – 48 ). Public health policies were therefore updated worldwide to recommend administration of an additional vaccine dose (booster) several months after the primary vaccine series, which has been shown to increase the breadth and potency of neutralizing antibodies ( 5 , 12 , 17 , 49 ).…”

“…As SARS-CoV-2 progressively becomes endemic in the human population, vaccination strategies will need to be carefully considered and optimized to provide long-lasting immunity. So far, elicitation of high titers of variant-neutralizing antibodies and protection against severe disease can be accomplished by dosing with the Wuhan-Hu-1 S antigen, as shown in animal models and studies of vaccine efficacy in humans ( 5 , 48 , 65 , 66 ). In fact, an Omicron BA.1 (or other variant) S boost does not offer mice or non-human primates significantly more BA.1 protection than a Wuhan-Hu-1 S boost ( 67 – 71 ), and Omicron primary infections elicit neutralizing antibody and memory responses of narrow breadth ( 72 – 74 ).…”

Broadly Neutralizing Antibodies to SARS-CoV-2 Provide Novel Insights Into the Neutralization of Variants and Other Human Coronaviruses

“…By contrast, few RBD conserved region-directed nAbs (e.g. S2X324, S2K146, S2X259 and S2H97) have shown broad in vitro cross-neutralization potential and in vivo protective efficacy at low doses against sarbecoviruses ( Starr et al., 2021 ; Tortorici et al., 2021 ; Park et al., 2022 ; Park et al., 2022 ). Interestingly, a rare class of nAbs (e.g.…”

“…Recently, an affinity matured RBD specific nAb CAB-A17 targeting the ACE2 binding region have been shown to neutralize highly mutated Omicron without losing the potency ( Sheward et al., 2022 ). Interestingly, two RBM specific ACE2 blocking SARS-CoV-2 bnAbs S2K146 and S2X324 with cross-reactivity to other SARS-related viruses have been reported to potently neutralize broad SARS related viruses and Omicron variants ( Park et al., 2022 ; Park et al., 2022 ). Considering all that is known about the structure-function relationship between antibodies and SARS-CoV-2, the following strategies could be effective to combat highly mutated SARS-CoV-2 variants and any coronavirus outbreak(s) in the future: (1) by developing more potent bnAbs targeting RBD conserved regions (e.g.…”

Molecular analysis of a public cross-neutralizing antibody response to SARS-CoV-2

“…In fact, the binding mode of LY-CoV1404 is identical to the cross-neutralizing antibody 2-7, which is also encoded by IGHV2-5/IGLV2-14 [9]. More recently, Veesler and colleagues reported another potently cross-neutralizing antibody with similar sequences and binding mode as LY-CoV1404 [10]. As IGHV2-5 was shown to be an important contributor to cross-neutralizing antibody response [11], the observations above stimulated a systematic analysis of IGHV2-5/IGLV2-14-encoded RBD antibodies to SARS-CoV-2.…”