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Neutralization titers against BA.4.6 were significantly reduced compared to BA.4/5 for both breakthrough BA.1 (1.5-fold; I P i = 0.0006) and BA.2 (1.2-fold; I P i = 0.0384) serum samples. A small non-significant increase in neutralization titers against BA.4.6 was observed in the BA.4/5 breakthrough cohort compared to BA.4/5. It is not clear why the BA.2 and BA.4/5 neutralization titers using BA.2 and BA.4/5 serum respectively were not higher than titers for other SARS-CoV-2 variants as one might expect. [Extracted from the article]

Enterovirus 71 (EV71)-neutralizing antibodies correlate with protection and have potential as therapeutic agents. We isolate and characterize a panel of plasmablast-derived monoclonal antibodies from an infected child whose antibody response focuses on the plateau epitope near the icosahedral 3-fold axes. Eight of a total of 19 antibodies target this epitope and three of these potently neutralize the virus. Representative neutralizing antibodies 38-1-10A and 38-3-11A both confer effective protection against lethal EV71 challenge in hSCARB2-transgenic mice. The cryo-electron microscopy structures of the EV71 virion in complex with Fab fragments of these potent and protective antibodies reveal the details of a conserved epitope formed by residues in the BC and HI loops of VP2 and the BC and HI loops of VP3 spanning the region around the 3-fold axis. Remarkably, the two antibodies interact with the epitope in quite distinct ways. These plateau-binding antibodies provide templates for promising candidate therapeutics. To date, no therapeutic agents against enterovirus 71, the causative agent of hand, foot and mouth disease, exist. Here, using Cryo-EM Huang et al. characterize two plasmablast-derived plateau-binding neutralizing antibodies conferring effective protection against lethal EV71 challenge in vivo. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • Potent RBD antibodies from Omicron breakthrough vaccinees broadly neutralize VoC • These, possible recall antibodies, are focused in two main clusters • Somatic maturation adapts public antibodies to recover potency • BA.2 > BA.1 ACE2 affinity. BA.2 < BA.1 neutralization by vaccine serum and Vir-S309 Analysis of antibodies from SARS-CoV-2 Omicron breakthrough infections reveals their structural and functional properties as well as ability to neutralize different pandemic strains. [ABSTRACT FROM AUTHOR]

Terminating the SARS-CoV-2 pandemic relies upon pan-global vaccination. Current vaccines elicit neutralizing antibody responses to the virus spike derived from early isolates. However, new strains have emerged with multiple mutations, including P.1 from Brazil, B.1.351 from South Africa, and B.1.1.7 from the UK (12, 10, and 9 changes in the spike, respectively). All have mutations in the ACE2 binding site, with P.1 and B.1.351 having a virtually identical triplet (E484K, K417N/T, and N501Y), which we show confer similar increased affinity for ACE2. We show that, surprisingly, P.1 is significantly less resistant to naturally acquired or vaccine-induced antibody responses than B.1.351, suggesting that changes outside the receptor-binding domain (RBD) impact neutralization. Monoclonal antibody (mAb) 222 neutralizes all three variants despite interacting with two of the ACE2-binding site mutations. We explain this through structural analysis and use the 222 light chain to largely restore neutralization potency to a major class of public antibodies. [Display omitted] • Despite similar RBD mutations, P.1 is easier to neutralize than B.1.351 • P.1, B.1.351, and B.1.1.7 partially or fully escape most VH3-53 antibodies • mAb 222 (VH3-53) retains neutralization against all three variants • Neutralization is restored in VH3-53 chimeric antibodies with mAb 222 LC Structural and functional analysis of the P.1 variant of SARS-CoV-2 from Brazil reveals less resistance to antibodies generated from natural infection or vaccination compared to another similar variant, B.1.351. A monoclonal antibody, mAb 222, is able to neutralize all three variants (P.1, B.1.351, and B.1.1.7), with its light chain able to restore neutralization potency to a broad group of antibodies. [ABSTRACT FROM AUTHOR]

The race to produce vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began when the first sequence was published, and this forms the basis for vaccines currently deployed globally. Independent lineages of SARS-CoV-2 have recently been reported: UK, B.1.1.7; South Africa, B.1.351; and Brazil, P.1. These variants have multiple changes in the immunodominant spike protein that facilitates viral cell entry via the angiotensin-converting enzyme-2 (ACE2) receptor. Mutations in the receptor recognition site on the spike are of great concern for their potential for immune escape. Here, we describe a structure-function analysis of B.1.351 using a large cohort of convalescent and vaccinee serum samples. The receptor-binding domain mutations provide tighter ACE2 binding and widespread escape from monoclonal antibody neutralization largely driven by E484K, although K417N and N501Y act together against some important antibody classes. In a number of cases, it would appear that convalescent and some vaccine serum offers limited protection against this variant. [Display omitted] • Reduced B.1.351 neutralization by mAbs and sera induced by early SARS-CoV-2 isolates • B.1.351 neutralization titer reduced 8- to 9-fold for Pfizer and AstraZeneca vaccinees • E484K, K417N, and N501Y cause widespread escape from mAbs • NTD deletion in B.1.351 abrogates neutralization by a potent neutralizing human mAb Structure-function analysis of the SARS-CoV-2 variant B.1.351 using serum samples from convalescent and vaccinated individuals reveals how mutations in the viral spike protein result in tighter binding to the receptor ACE2 and allow escape from monoclonal antibody neutralization. [ABSTRACT FROM AUTHOR]

Antibodies are crucial to immune protection against SARS-CoV-2, with some in emergency use as therapeutics. Here, we identify 377 human monoclonal antibodies (mAbs) recognizing the virus spike and focus mainly on 80 that bind the receptor binding domain (RBD). We devise a competition data-driven method to map RBD binding sites. We find that although antibody binding sites are widely dispersed, neutralizing antibody binding is focused, with nearly all highly inhibitory mAbs (IC 50 < 0.1 μg/mL) blocking receptor interaction, except for one that binds a unique epitope in the N-terminal domain. Many of these neutralizing mAbs use public V-genes and are close to germline. We dissect the structural basis of recognition for this large panel of antibodies through X-ray crystallography and cryoelectron microscopy of 19 Fab-antigen structures. We find novel binding modes for some potently inhibitory antibodies and demonstrate that strongly neutralizing mAbs protect, prophylactically or therapeutically, in animal models. [Display omitted] • Map 377 mAbs: 19 of 80 recognizing the RBD are potent neutralizers; 1 potent NTD binder • 19 Fab-antigen complex structures; 80 mAbs mapped on RBD and clustered into 5 epitopes • Most potent mAbs are ACE2 blockers, neutralize with few ACE2s, some Fabs glycosylated • mAbs reveal unique examples of NTD binding, RBD binding mode, and LC optimization Dejnirattisai et al. present an in-depth study of the human antibody response to SARS-CoV-2 infection. By characterizing 377 human mAbs from recovered COVID-19 patients, and determining 19 protein structures, they construct a map of antibody footprints on the RBD that describes in great detail its antigenic anatomy. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 has caused over 2 million deaths in little over a year. Vaccines are being deployed at scale, aiming to generate responses against the virus spike. The scale of the pandemic and error-prone virus replication is leading to the appearance of mutant viruses and potentially escape from antibody responses. Variant B.1.1.7, now dominant in the UK, with increased transmission, harbors 9 amino acid changes in the spike, including N501Y in the ACE2 interacting surface. We examine the ability of B.1.1.7 to evade antibody responses elicited by natural SARS-CoV-2 infection or vaccination. We map the impact of N501Y by structure/function analysis of a large panel of well-characterized monoclonal antibodies. B.1.1.7 is harder to neutralize than parental virus, compromising neutralization by some members of a major class of public antibodies through light-chain contacts with residue 501. However, widespread escape from monoclonal antibodies or antibody responses generated by natural infection or vaccination was not observed. [Display omitted] • Original strain convalescent and vaccine sera show reduced B.1.1.7 neutralization • N501Y enhances RBD: ACE2 binding affinity • N501Y compromises neutralization by many antibodies with public V-region IGHV3-53 • No widespread escape by B.1.1.7 was observed The SARS-CoV-2 B.1.1.7 variant is not neutralized as easily as the original form of the virus. Some public antibodies cannot neutralize B.1.1.7, due to altered light-chain contacts with residue 501. However, B.1.1.7 does not show widespread escape from monoclonal antibodies, natural antibody responses, or vaccines. [ABSTRACT FROM AUTHOR]

On 24th November 2021, the sequence of a new SARS-CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titers of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic Alpha, Beta, Gamma, or Delta are substantially reduced, or the sera failed to neutralize. Titers against Omicron are boosted by third vaccine doses and are high in both vaccinated individuals and those infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of the large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses and uses mutations that confer tight binding to ACE2 to unleash evolution driven by immune escape. This leads to a large number of mutations in the ACE2 binding site and rebalances receptor affinity to that of earlier pandemic viruses. [Display omitted] • Large reduction in Omicron neutralization titers, ameliorated by the 3rd booster vaccine • Failure of many potent mAbs to neutralize Omicron • Complex pattern of mutations balances ACE2 binding and antibody escape • Omicron RBD is structurally similar but the most antigenically distant variant A comprehensive analysis of sera from vaccinees, convalescent patients previously infected by multiple variants, and potent monoclonal antibodies from early in the COVID-19 pandemic reveals a substantial overall reduction in the ability to neutralize the SARS-CoV-2 Omicron variant, which seems to ameliorate with a third vaccine dose. Structural analyses of the Omicron RBD suggest that selective pressure balances key changes that increase affinity for ACE2 with other changes in the receptor-binding motif that disfavor ACE2 binding but facilitate immune escape. [ABSTRACT FROM AUTHOR]

The Omicron lineage of SARS-CoV-2, which was first described in November 2021, spread rapidly to become globally dominant and has split into a number of sublineages. BA.1 dominated the initial wave but has been replaced by BA.2 in many countries. Recent sequencing from South Africa's Gauteng region uncovered two new sublineages, BA.4 and BA.5, which are taking over locally, driving a new wave. BA.4 and BA.5 contain identical spike sequences, and although closely related to BA.2, they contain further mutations in the receptor-binding domain of their spikes. Here, we study the neutralization of BA.4/5 using a range of vaccine and naturally immune serum and panels of monoclonal antibodies. BA.4/5 shows reduced neutralization by the serum from individuals vaccinated with triple doses of AstraZeneca or Pfizer vaccine compared with BA.1 and BA.2. Furthermore, using the serum from BA.1 vaccine breakthrough infections, there are, likewise, significant reductions in the neutralization of BA.4/5, raising the possibility of repeat Omicron infections. [Display omitted] • BA.4/5 resist neutralization by triple-dosed vaccinee serum more than BA.1 and BA.2 • BA.1 vaccine breakthrough serum shows reduced neutralization of BA.4/5 • Activity of SARS-CoV-2 therapeutic antibodies against BA.4/5 is reduced • L452R and F486V mutations both make major contributions to BA.4/5 escape SARS-CoV-2 Omicron BA.4 and BA.5 sublineages bear mutations that lead to their reduced neutralization by sera from triple-vaccinated individuals when compared with the more recent BA.1 and BA.2. Importantly, sera from individuals with breakthrough BA.1 infections also show reduced neutralization, suggesting that repeat Omicron infections are likely in the population. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has undergone progressive change, with variants conferring advantage rapidly becoming dominant lineages, e.g., B.1.617. With apparent increased transmissibility, variant B.1.617.2 has contributed to the current wave of infection ravaging the Indian subcontinent and has been designated a variant of concern in the United Kingdom. Here we study the ability of monoclonal antibodies and convalescent and vaccine sera to neutralize B.1.617.1 and B.1.617.2, complement this with structural analyses of Fab/receptor binding domain (RBD) complexes, and map the antigenic space of current variants. Neutralization of both viruses is reduced compared with ancestral Wuhan-related strains, but there is no evidence of widespread antibody escape as seen with B.1.351. However, B.1.351 and P.1 sera showed markedly more reduction in neutralization of B.1.617.2, suggesting that individuals infected previously by these variants may be more susceptible to reinfection by B.1.617.2. This observation provides important new insights for immunization policy with future variant vaccines in non-immune populations. [Display omitted] • Vaccine/convalescent sera show reduced neutralization of B.1.617.1 and B.1.617.2 • Sera from B.1.351and P.1 show markedly reduced neutralization of B.1.617.2 • B.1.351, P.1, and B.1.617.2 are antigenically divergent • Vaccines based on B.1.1.7 may protect broadly against current variants The B.1.617 lineage of SARS-CoV-2, especially the delta strain, which is B.1.617.2, has contributed to the wave of infection in the Indian subcontinent. Structural and serological analyses show some evidence of antibody escape, and individuals infected previously with the B.1.351 (beta) and P.1 (gamma) variants are likely more susceptible to reinfection by the delta strain. Vaccines based on B.1.1.7 (alpha) are likely to provide the broadest protection against current variants. [ABSTRACT FROM AUTHOR]