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OVID-19 is caused by the recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While the majority of COVID-19 infections are relatively mild, with recovery typically within 2-3 weeks 1,2 , a significant number of patients develop severe illness, which is postulated to be related to both an overactive immune response and viral-induced pathology 3,4. The role of T cell immune responses in disease pathogenesis and longer-term protective immunity is currently poorly defined, but essential to understand in order to inform therapeutic interventions and vaccine design. Currently, there are many ongoing vaccine trials, but it is unknown whether they will provide long-lasting protective immunity. Most vaccines are designed to induce antibodies to the SARS-CoV-2 spike protein, but it is not yet known if this will be sufficient to induce full protective immunity to SARS-CoV-2 (refs. 5-8). Studying natural immunity to the virus, including the role of SARS-CoV-2specific T cells, is critical to fill the current knowledge gaps for improved vaccine design. For many primary virus infections, it typically takes 7-10 d to prime and expand adaptive T cell immune responses in order to control the virus 9. This coincides with the typical time it takes for patients with COVID-19 to either recover or develop severe illness. There is an incubation time of 4-7 d before symptom onset and a further 7-10 d before individuals progress to severe disease 10 .

The race to produce vaccines against 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 which 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.

On the 24 th 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 titres of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic as well as Alpha, Beta, Gamma, Delta are substantially reduced or fail to neutralize. Titres against Omicron are boosted by third vaccine doses and are high in cases both vaccinated and infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of a large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses, combining mutations conferring tight binding to ACE2 to unleash evolution driven by immune escape, leading to a large number of mutations in the ACE2 binding site which rebalance receptor affinity to that of early pandemic viruses.

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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: 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 RBD impact neutralisation. Monoclonal antibody 222 neutralises 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.

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 UK. Here we study the ability of monoclonal antibodies, convalescent and vaccine sera to neutralize B.1.617.1 and B.1.617.2 and complement this with structural analyses of Fab/RBD complexes and map the antigenic space of current variants. Neutralization of both viruses is reduced when 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 previously infected by these variants may be more susceptible to reinfection by B.1.617.2. This observation provides important new insight for immunisation policy with future variant vaccines in non-immune populations.

he SARS-CoV-2 virus is thought, based on sequence identity, to have crossed from bats to humans in 2019 1 . Similar to SARS-CoV-1 (2002-2003 and MERS-CoV (2012), SARS-CoV-2 presents as a respiratory disease but can progress into internal organs and cause organ failure 2,3 . A recent report from France estimates a fatality rate of 0.7% and a hospitalization rate of 3.6% 4 . Both these rates are much higher in elderly populations 4,5 . Around 33% of those admitted to UK hospitals with COVID-19 have died 6 . Because SARS-CoV-2 also spreads rapidly in the naive human population 7 , the current COVID-19 pandemic has presented an unprecedented challenge to modern human society. Although there is currently no 'cure' or vaccine for the disease, passive immune therapy by transfusing critically ill COVID-19 patients with serum from COVID-19 convalescent individuals has been shown to improve clinical outcomes 8,9 . This would suggest that neutralization of the virus, even at a relatively late stage in the disease, may be a useful COVID-19 therapy.The single-positive-strand RNA genome of SARS-CoV-2, like SARS-CoV, encodes four major structural proteins: spike, envelope, membrane and nucleocapsid. The spike protein comprises an N-terminal (S1) subunit, which contains the roughly 200-residue receptor binding domain (RBD) 10,11 , and a C-terminal subunit (S2), which contains the fusion protein 12 (Fig. 1a). The RBD of SARS-CoV-2 binds more tightly to the extracellular domain of angiotensin-converting enzyme 2 (ACE2) (Fig. 1a) than the homologous SARS-CoV-1 RBD 13 . The higher affinity results from sequence changes in RBD (Fig. 1b) and this has been proposed to underlie the higher transmissibility of SARS-CoV-2 14 . Antibodies raised to the spike protein of SARS-CoV-1 can neutralize the virus both in vitro and in vivo, by binding to the RBD and blocking binding to ACE2 15 . Unfortunately, most of these antibodies do not cross-react with the SARS-CoV-2 RBD 13 . The CR3022 antibody derived from a convalescent SARS-CoV-1 patient is cross-reactive to both SARS-CoV-1 and SARS-CoV-2 RBD (reported apparent K D of 6 nM, ref. 16 ). Two studies have reported crystal structures of CR3022 bound to SARS-CoV-2 RBD and show that the target epitope is distant from the ACE2 binding region 17,18 , which is consistent with the observation that CR3022 does not block RBD binding to ACE2. Another study on CR3022 has reported highly effective SARS-CoV-2 neutralizing activity that appears to arise from destabilization of the spike trimer, a novel mechanism for neutralizing SARS-CoV-2 18 . Destabilization of viral proteins by antibodies has been observed for influenza 19 and human immunodeficiency virus 20 .Mammalian, including human, antibodies generally have two chains (heavy and light), but camelids, in addition to two-chain antibodies, also possess a single-heavy-chain antibody variant 21 .