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Potent cross-reactive antibodies following Omicron breakthrough in vaccinees.

ABSTRACT: Highly transmissible Omicron variants of SARS-CoV-2 currently dominate globally. Here, we compare neutralization of Omicron BA.1, BA.1.1, and BA.2. BA.2 RBD has slightly higher ACE2 affinity than BA.1 and slightly reduced neutralization by vaccine serum, possibly associated with its increased transmissibility. Neutralization differences between sub-lineages for mAbs (including therapeutics) mostly arise from variation in residues bordering the ACE2 binding site; however, more distant mutations S371F (BA.2) and R346K (BA.1.1) markedly reduce neutralization by therapeutic antibody Vir-S309. In-depth structure-and-function analyses of 27 potent RBD-binding mAbs isolated from vaccinated volunteers following breakthrough Omicron-BA.1 infection reveals that they are focused in two main clusters within the RBD, with potent right-shoulder antibodies showing increased prevalence. Selection and somatic maturation have optimized antibody potency in less-mutated epitopes and recovered potency in highly mutated epitopes. All 27 mAbs potently neutralize early pandemic strains, and many show broad reactivity with variants of concern.

SUBMITTER: Nutalai R

PROVIDER: S-EPMC9120130 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Potent cross-reactive antibodies following Omicron breakthrough in vaccinees.

Nutalai Rungtiwa R Zhou Daming D Tuekprakhon Aekkachai A Ginn Helen M HM Supasa Piyada P Liu Chang C Huo Jiandong J Mentzer Alexander J AJ Duyvesteyn Helen M E HME Dijokaite-Guraliuc Aiste A Skelly Donal D Ritter Thomas G TG Amini Ali A Bibi Sagida S Adele Sandra S Johnson Sile Ann SA Constantinides Bede B Webster Hermione H Temperton Nigel N Klenerman Paul P Barnes Eleanor E Dunachie Susanna J SJ Crook Derrick D Pollard Andrew J AJ Lambe Teresa T Goulder Philip P Paterson Neil G NG Williams Mark A MA Hall David R DR Mongkolsapaya Juthathip J Fry Elizabeth E EE Dejnirattisai Wanwisa W Ren Jingshan J Stuart David I DI Screaton Gavin R GR

Cell 20220520 12

Highly transmissible Omicron variants of SARS-CoV-2 currently dominate globally. Here, we compare neutralization of Omicron BA.1, BA.1.1, and BA.2. BA.2 RBD has slightly higher ACE2 affinity than BA.1 and slightly reduced neutralization by vaccine serum, possibly associated with its increased transmissibility. Neutralization differences between sub-lineages for mAbs (including therapeutics) mostly arise from variation in residues bordering the ACE2 binding site; however, more distant mutations S ...[more]

PMID: 35662412

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Project description:Despite the success of COVID-19 vaccines in preventing infection and/or severe disease, there has been an increase in SARS-CoV-2 infections in vaccinated individuals owing to the waning vaccine-derived immunity, and the emergence of new variants which encode escape mutations in Spike. Following breakthrough infection in vaccinated individuals, an increase in neutralization breadth has been observed in sera/plasma. However, how exposure to a heterologous Spike broadens the neutralizing response at the monoclonal antibody (mAb) level is not fully understood. Through isolation of 119 mAbs from three individuals receiving two doses of BNT162b2 vaccine before becoming Delta or Omicron/BA.1 infected, we show that serum breadth occurs due to the presence of somatically mutated mAbs with broad neutralization activity indicative of re-activation and maturation of B cells generated through previous COVID-19 vaccination. Isolated mAbs frequently show reduced neutralization of current circulating variants including BA.2.75.2, XBB, XBB.1.5, and BQ.1.1 confirming continuous selective pressure on Spike to evolve and evade neutralization. However, isolation of mAbs that display effective cross-neutralization against all variants indicates the presence of conserved epitopes on the receptor binding domain and a lesser extent the N-terminal domain. These findings have implications for the selection of Spike antigens for next-generation COVID-19 vaccines. IMPORTANCE With the emergence of SARS-CoV-2 viral variants, there has been an increase in infections in vaccinated individuals. Here, we isolated monoclonal antibodies (mAbs) from individuals experiencing a breakthrough infection (Delta or BA.1) to determine how exposure to a heterologous Spike broadens the neutralizing antibody response at the monoclonal level. All mAbs isolated had reactivity to the Spike of the vaccine and infection variant. While many mAbs showed reduced neutralization of current circulating variants, we identified mAbs with broad and potent neutralization of BA.2.75.2, XBB, XBB.1.5, and BQ.1.1 indicating the presence of conserved epitopes on Spike. These results indicate that variant-based vaccine boosters have the potential to broaden the vaccine response.

Dataset Information

Potent cross-reactive antibodies following Omicron breakthrough in vaccinees.

Publications

Potent cross-reactive antibodies following Omicron breakthrough in vaccinees.

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