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BA.2.87.1 represents a major shift in the BA.2 lineage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is unusual in having two lengthy deletions of polypeptide in the spike (S) protein, one of which removes a beta-strand. Here we investigate its neutralization by a variety of sera from infected and vaccinated individuals and determine its spike (S) ectodomain structure. The BA.2.87.1 receptor binding domain (RBD) is structurally conserved and the RBDs are tightly packed in an "all-down" conformation with a small rotation relative to the trimer axis as compared to the closest previously observed conformation. The N-terminal domain (NTD) maintains a remarkably similar structure overall; however, the rearrangements resulting from the deletions essentially destroy the so-called supersite epitope and eliminate one glycan site, while a mutation creates an additional glycan site, effectively shielding another NTD epitope. BA.2.87.1 is relatively easily neutralized but acquisition of additional mutations in the RBD could increase antibody escape allowing it to become a dominant sub-lineage., Competing Interests: Declaration of interests G.R.S. sits on the GSK Vaccines Scientific Advisory Board and is a founder member of RQ Biotechnology. D.I.S. consults for AstraZeneca. Oxford University holds intellectual property related to SARS-CoV-2 mAbs discovered in G.R.S.’s laboratory. S.J.D. is a Scientific Advisor to the Scottish Parliament on COVID-19., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Cellular processes are controlled by the thermodynamics of the underlying biomolecular interactions. Frequently, structural investigations use one monomeric binding partner, while ensemble measurements of binding affinities generally yield one affinity representative of a 1:1 interaction, despite the majority of the proteome consisting of oligomeric proteins. For example, viral entry and inhibition in SARS-CoV-2 involve a trimeric spike surface protein, a dimeric angiotensin-converting enzyme 2 (ACE2) cell-surface receptor and dimeric antibodies. Here, we reveal that cooperativity correlates with infectivity and inhibition as opposed to 1:1 binding strength. We show that ACE2 oligomerizes spike more strongly for more infectious variants, while exhibiting weaker 1:1 affinity. Furthermore, we find that antibodies use induced oligomerization both as a primary inhibition mechanism and to enhance the effects of receptor-site blocking. Our results suggest that naive affinity measurements are poor predictors of potency, and introduce an antibody-based inhibition mechanism for oligomeric targets. More generally, they point toward a much broader role of induced oligomerization in controlling biomolecular interactions., Competing Interests: Competing interests statement:P.K. is a nonexecutive director, shareholder of and consultant to Refeyn Ltd., J.L.P.B. and W.B.S. are shareholders of and consultants to Refeyn Ltd. W.B.S. and P.K. received the University of Oxford’s COVID-19 Research Response Fund. P.K. has filed a patent for the contrast enhancement methodology and its application to mass measurement of single biomolecules. G.R.S. is on the GSK Vaccines Scientific Advisory Board, a founder shareholder of RQ biotechnology and Jenner investigator. Oxford University holds intellectual property related to the Oxford-AstraZeneca vaccine.

Natural killer cells (NK cells) are the front line of immune cells to combat pathogens and able to influence the subsequent adaptive immune responses. One of the factors contributing to pathogenesis in dengue hemorrhagic fever (DHF) disease is aberrant immune activation during early phase of infection. This study explored the profile of NK cells in dengue infected pediatric patients with different degrees of disease severity. DHF patients contained higher frequency of activated NK cells but lower ratio of CD56 dim :CD56 bright NK subsets. Activated NK cells exhibited alterations in several NK receptors. Interestingly, the frequencies of NKp30 expressing activated NK cells were more pronounced in dengue fever (DF) than in DHF pediatric patients. In vitro functional analysis indicated that degranulation of NK cells in responding to dengue infected dendritic cells (DCs) required cell-cell contact and type I IFNs. Meanwhile, Interferon gamma (IFN-γ) production initially required cell-cell contact and type I IFNs followed by Interleukin-12 (IL-12), Interleukin-15 (IL-15) and Interleukin-18 (IL-18) resulting in the amplification of IFN-γ producing NK cells over time. This study highlighted the complexity and the factors influencing NK cells responses to dengue virus. Degree of activation, phenotypes of activated cells and the crosstalk between NK cells and other immune cells, could modulate the outcome of NK cells function in the dengue disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in variants that can escape neutralization by therapeutic antibodies. Here, we describe AZD3152, a SARS-CoV-2-neutralizing monoclonal antibody designed to provide improved potency and coverage against emerging variants. AZD3152 binds to the back left shoulder of the SARS-CoV-2 spike protein receptor binding domain and prevents interaction with the human angiotensin-converting enzyme 2 receptor. AZD3152 potently neutralized a broad panel of pseudovirus variants, including the currently dominant Omicron variant JN.1 but has reduced potency against XBB subvariants containing F456L. In vitro studies confirmed F456L resistance and additionally identified T415I and K458E as escape mutations. In a Syrian hamster challenge model, prophylactic administration of AZD3152 protected hamsters from weight loss and inflammation-related lung pathologies and reduced lung viral load. In the phase 1 sentinel safety cohort of the ongoing SUPERNOVA study (ClinicalTrials.gov: NCT05648110), a single 600-mg intramuscular injection of AZD5156 (containing 300 mg each of AZD3152 and cilgavimab) was well tolerated in adults through day 91. Observed serum concentrations of AZD3152 through day 91 were similar to those observed with cilgavimab and consistent with predictions for AZD7442, a SARS-CoV-2-neutralizing antibody combination of cilgavimab and tixagevimab, in a population pharmacokinetic model. On the basis of its pharmacokinetic characteristics, AZD3152 is predicted to provide durable protection against symptomatic coronavirus disease 2019 caused by susceptible SARS-CoV-2 variants, such as JN.1, in humans.

BA.2.86, a recently described sublineage of SARS-CoV-2 Omicron, contains many mutations in the spike gene. It appears to have originated from BA.2 and is distinct from the XBB variants responsible for many infections in 2023. The global spread and plethora of mutations in BA.2.86 has caused concern that it may possess greater immune-evasive potential, leading to a new wave of infection. Here, we examine the ability of BA.2.86 to evade the antibody response to infection using a panel of vaccinated or naturally infected sera and find that it shows marginally less immune evasion than XBB.1.5. We locate BA.2.86 in the antigenic landscape of recent variants and look at its ability to escape panels of potent monoclonal antibodies generated against contemporary SARS-CoV-2 infections. We demonstrate, and provide a structural explanation for, increased affinity of BA.2.86 to ACE2, which may increase transmissibility., Competing Interests: Declaration of interests G.R.S. sits on the GSK Vaccines Scientific Advisory Board, consults for AstraZeneca, and is a founder member of RQ Biotechnology. D.I.S. consults for AstraZeneca. Oxford University holds intellectual property related to SARS-CoV-2 mAbs discovered in G.R.S.’s laboratory. S.J.D. is a scientific advisor to the Scottish Parliament on COVID-19., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires ongoing monitoring to judge the ability of newly arising variants to escape the immune response. A surveillance system necessitates an understanding of differences in neutralization titers measured in different assays and using human and animal serum samples. We compared 18 datasets generated using human, hamster, and mouse serum and six different neutralization assays. Datasets using animal model serum samples showed higher titer magnitudes than datasets using human serum samples in this comparison. Fold change in neutralization of variants compared to ancestral SARS-CoV-2, immunodominance patterns, and antigenic maps were similar among serum samples and assays. Most assays yielded consistent results, except for differences in fold change in cytopathic effect assays. Hamster serum samples were a consistent surrogate for human first-infection serum samples. These results inform the transition of surveillance of SARS-CoV-2 antigenic variation from dependence on human first-infection serum samples to the utilization of serum samples from animal models.

The rapid evolution of SARS-CoV-2 is driven in part by a need to evade the antibody response in the face of high levels of immunity. Here, we isolate spike (S) binding monoclonal antibodies (mAbs) from vaccinees who suffered vaccine break-through infections with Omicron sub lineages BA.4 or BA.5. Twenty eight potent antibodies are isolated and characterised functionally, and in some cases structurally. Since the emergence of BA.4/5, SARS-CoV-2 has continued to accrue mutations in the S protein, to understand this we characterize neutralization of a large panel of variants and demonstrate a steady attrition of neutralization by the panel of BA.4/5 mAbs culminating in total loss of function with recent XBB.1.5.70 variants containing the so-called 'FLip' mutations at positions 455 and 456. Interestingly, activity of some mAbs is regained on the recently reported variant BA.2.86., (© 2024. The Author(s).)

Under pressure from neutralising antibodies induced by vaccination or infection the SARS-CoV-2 spike gene has become a hotspot for evolutionary change, leading to the failure of all mAbs developed for clinical use. Most potent antibodies bind to the receptor binding domain which has become heavily mutated. Here we study responses to a conserved epitope in sub-domain-1 (SD1) of spike which have become more prominent because of mutational escape from antibodies directed to the receptor binding domain. Some SD1 reactive mAbs show potent and broad neutralization of SARS-CoV-2 variants. We structurally map the dominant SD1 epitope and provide a mechanism of action by blocking interaction with ACE2. Mutations in SD1 have not been sustained to date, but one, E554K, leads to escape from mAbs. This mutation has now emerged in several sublineages including BA.2.86, reflecting selection pressure on the virus exerted by the increasing prominence of the anti-SD1 response., (© 2024. The Author(s).)

Inhibitor discovery for emerging drug-target proteins is challenging, especially when target structure or active molecules are unknown. Here, we experimentally validate the broad utility of a deep generative framework trained at-scale on protein sequences, small molecules, and their mutual interactions-unbiased toward any specific target. We performed a protein sequence-conditioned sampling on the generative foundation model to design small-molecule inhibitors for two dissimilar targets: the spike protein receptor-binding domain (RBD) and the main protease from SARS-CoV-2. Despite using only the target sequence information during the model inference, micromolar-level inhibition was observed in vitro for two candidates out of four synthesized for each target. The most potent spike RBD inhibitor exhibited activity against several variants in live virus neutralization assays. These results establish that a single, broadly deployable generative foundation model for accelerated inhibitor discovery is effective and efficient, even in the absence of target structure or binder information.

COVID-19 patients at risk of severe disease may be treated with neutralising monoclonal antibodies (mAbs). To minimise virus escape from neutralisation these are administered as combinations e.g. casirivimab+imdevimab or, for antibodies targeting relatively conserved regions, individually e.g. sotrovimab. Unprecedented genomic surveillance of SARS-CoV-2 in the UK has enabled a genome-first approach to detect emerging drug resistance in Delta and Omicron cases treated with casirivimab+imdevimab and sotrovimab respectively. Mutations occur within the antibody epitopes and for casirivimab+imdevimab multiple mutations are present on contiguous raw reads, simultaneously affecting both components. Using surface plasmon resonance and pseudoviral neutralisation assays we demonstrate these mutations reduce or completely abrogate antibody affinity and neutralising activity, suggesting they are driven by immune evasion. In addition, we show that some mutations also reduce the neutralising activity of vaccine-induced serum., (© 2023. The Author(s).)

Background: Heterologous COVID vaccine priming schedules are immunogenic and effective. This report aims to understand the persistence of immune response to the viral vectored, mRNA and protein-based COVID-19 vaccine platforms used in homologous and heterologous priming combinations, which will inform the choice of vaccine platform in future vaccine development., Methods: Com-COV2 was a single-blinded trial in which adults ≥ 50 years, previously immunised with single dose 'ChAd' (ChAdOx1 nCoV-19, AZD1222, Vaxzevria, Astrazeneca) or 'BNT' (BNT162b2, tozinameran, Comirnaty, Pfizer/BioNTech), were randomised 1:1:1 to receive a second dose 8-12 weeks later with either the homologous vaccine, or 'Mod' (mRNA-1273, Spikevax, Moderna) or 'NVX' (NVX-CoV2373, Nuvaxovid, Novavax). Immunological follow-up and the secondary objective of safety monitoring were performed over nine months. Analyses of antibody and cellular assays were performed on an intention-to-treat population without evidence of COVID-19 infection at baseline or for the trial duration., Findings: In April/May 2021, 1072 participants were enrolled at a median of 9.4 weeks after receipt of a single dose of ChAd (N = 540, 45% female) or BNT (N = 532, 39% female) as part of the national vaccination programme. In ChAd-primed participants, ChAd/Mod had the highest anti-spike IgG from day 28 through to 6 months, although the heterologous vs homologous geometric mean ratio (GMR) dropped from 9.7 (95% CI (confidence interval): 8.2, 11.5) at D28 to 6.2 (95% CI: 5.0, 7.7) at D196. The heterologous/homologous GMR for ChAd/NVX similarly dropped from 3.0 (95% CI:2.5,3.5) to 2.4 (95% CI:1.9, 3.0). In BNT-primed participants, decay was similar between heterologous and homologous schedules with BNT/Mod inducing the highest anti-spike IgG for the duration of follow-up. The adjusted GMR (aGMR) for BNT/Mod compared with BNT/BNT increased from 1.36 (95% CI: 1.17, 1.58) at D28 to 1.52 (95% CI: 1.21, 1.90) at D196, whilst for BNT/NVX this aGMR was 0.55 (95% CI: 0.47, 0.64) at day 28 and 0.62 (95% CI: 0.49, 0.78) at day 196. Heterologous ChAd-primed schedules produced and maintained the largest T-cell responses until D196. Immunisation with BNT/NVX generated a qualitatively different antibody response to BNT/BNT, with the total IgG significantly lower than BNT/BNT during all follow-up time points, but similar levels of neutralising antibodies., Interpretation: Heterologous ChAd-primed schedules remain more immunogenic over time in comparison to ChAd/ChAd. BNT-primed schedules with a second dose of either mRNA vaccine also remain more immunogenic over time in comparison to BNT/NVX. The emerging data on mixed schedules using the novel vaccine platforms deployed in the COVID-19 pandemic, suggest that heterologous priming schedules might be considered as a viable option sooner in future pandemics., Isrctn: 27841311 EudraCT:2021-001275-16., Competing Interests: Declaration of interests At the time of this study, MDS acted on behalf of the University of Oxford as an Investigator on studies funded or sponsored by vaccine manufacturers including AstraZeneca, GlaxoSmithKline, Pfizer, Novavax, Janssen, Medimmune, and MCM vaccines. He received no personal financial payment for this work. Subsequent to this study MDS is employed by Moderna Biotech UK and holds equity in this company. Moderna Biotech had no role in the study design, analysis of data or interpretation of results. JSN-V-T was seconded to the Department of Health and Social Care (DHSC), England from October 2017 to March 2022; since leaving DHSC he reports a lecture fee from AstraZeneca. AMC and DMF are investigators on studies funded by Pfizer and Unilever. They receive no personal financial payment for this work. AF is a member of the Joint Committee on Vaccination and Immunisation and chair of the WHO European Technical Advisory Group of Experts (ETAGE) on Immunisation. He is an investigator and/or provides consultative advice on clinical trials and studies of COVID-19 vaccines produced by AstraZeneca, Janssen, Valneva, Pfizer, and Sanofi, and of other vaccines from these and other manufacturers, including GlaxoSmithKline, VPI Pharmaceuticals, Takeda, and Bionet Asia. He receives no personal remuneration or benefits for any of this work. SNF acts on behalf of University Hospital Southampton NHS Foundation Trust as an investigator and/or providing consultative advice on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers, including Janssen, Pfizer, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Sanofi, Medimmune, Merck, and Valneva vaccines and antimicrobials. He receives no personal financial payment for this work. PTH acts on behalf of St. George's University of London as an investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers, including Janssen, Pfizer, AstraZeneca, Novavax, and Valneva. He receives no personal financial payment for this work. CAG acts on behalf of University Hospitals Birmingham NHS Foundation Trust as an investigator on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers, including Janssen, Pfizer, AstraZeneca, Novavax, CureVac, Moderna, and Valneva. He receives no personal financial payment for this work. VL acts on behalf of University College London Hospitals NHS Foundation Trust as an investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers including Pfizer, AstraZeneca, and Valneva. He receives no personal financial payment for this work. TL is named as an inventor on a patent application covering the ChAd vaccine and is an occasional consultant to Vaccitech, unrelated to this work. ALG is named as an inventor on a patent covering use of a particular promoter construct that is often used in -vectored vaccines and is incorporated in the ChAdOx1 nCoV-19 vaccine. ALG may benefit from royalty income paid to the University of Oxford from sales of this vaccine by AstraZeneca and its sublicensees under the University’s revenue sharing policy. Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19. All other authors declare no competing interests. The views expressed in this manuscript are those of its authors and not necessarily those of DHSC, VTF or NIHR., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Most existing studies characterizing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell responses are peptide based. This does not allow evaluation of whether tested peptides are processed and presented canonically. In this study, we use recombinant vaccinia virus (rVACV)-mediated expression of SARS-CoV-2 spike protein and SARS-CoV-2 infection of angiotensin-converting enzyme (ACE)-2-transduced B cell lines to evaluate overall T cell responses in a small cohort of recovered COVID-19 patients and uninfected donors vaccinated with ChAdOx1 nCoV-19. We show that rVACV expression of SARS-CoV-2 antigen can be used as an alternative to SARS-CoV-2 infection to evaluate T cell responses to naturally processed spike antigens. In addition, the rVACV system can be used to evaluate the cross-reactivity of memory T cells to variants of concern (VOCs) and to identify epitope escape mutants. Finally, our data show that both natural infection and vaccination could induce multi-functional T cell responses with overall T cell responses remaining despite the identification of escape mutations., Competing Interests: Declaration of interests A.J.P. is chair of the DHSC Joint Committee on Vaccination and Immunisation (JCVI) but does not take part in the JCVI COVID-19 committee. Oxford University has entered into a partnership with AstraZeneca for development of a COVID-19 vaccine. A.J.P. has provided advice to Shionogi & Co., Ltd., on the development of a COVID-19 vaccine., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

In November 2021, Omicron BA.1, containing a raft of new spike mutations, emerged and quickly spread globally. Intense selection pressure to escape the antibody response produced by vaccines or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection then led to a rapid succession of Omicron sub-lineages with waves of BA.2 and then BA.4/5 infection. Recently, many variants have emerged such as BQ.1 and XBB, which carry up to 8 additional receptor-binding domain (RBD) amino acid substitutions compared with BA.2. We describe a panel of 25 potent monoclonal antibodies (mAbs) generated from vaccinees suffering BA.2 breakthrough infections. Epitope mapping shows potent mAb binding shifting to 3 clusters, 2 corresponding to early-pandemic binding hotspots. The RBD mutations in recent variants map close to these binding sites and knock out or severely knock down neutralization activity of all but 1 potent mAb. This recent mAb escape corresponds with large falls in neutralization titer of vaccine or BA.1, BA.2, or BA.4/5 immune serum., Competing Interests: Declaration of interests G.R.S. sits on the GSK Vaccines Scientific Advisory Board, consults for AstraZeneca, and is a founding member of RQ Biotechnology. D.I.S. consults for AstraZeneca. Oxford University holds intellectual property related to SARS-CoV-2 mAbs discovered in G.R.S.’s laboratory. S.J.D. is a scientific advisor to the Scottish Parliament on COVID-19., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Effective public health measures against SARS-CoV-2 require granular knowledge of population-level immune responses. We developed a Tripartite Automated Blood Immunoassay (TRABI) to assess the IgG response against three SARS-CoV-2 proteins. We used TRABI for continuous seromonitoring of hospital patients and blood donors (n = 72'250) in the canton of Zurich from December 2019 to December 2020 (pre-vaccine period). We found that antibodies waned with a half-life of 75 days, whereas the cumulative incidence rose from 2.3% in June 2020 to 12.2% in mid-December 2020. A follow-up health survey indicated that about 10% of patients infected with wildtype SARS-CoV-2 sustained some symptoms at least twelve months post COVID-19. Crucially, we found no evidence of a difference in long-term complications between those whose infection was symptomatic and those with asymptomatic acute infection. The cohort of asymptomatic SARS-CoV-2-infected subjects represents a resource for the study of chronic and possibly unexpected sequelae., Competing Interests: TPJK is a member of the board of directors of Fluidic Analytics. AA is a member of the board of directors of Mabylon AG which has funded antibody-related work in the Aguzzi lab in the past. All other authors declare no competing interests., (© 2023 The Authors.)

Variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have caused successive global waves of infection. These variants, with multiple mutations in the spike protein, are thought to facilitate escape from natural and vaccine-induced immunity and often increase in affinity for ACE2. The latest variant to cause concern is BA.2.75, identified in India where it is now the dominant strain, with evidence of wider dissemination. BA.2.75 is derived from BA.2 and contains four additional mutations in the receptor-binding domain (RBD). Here, we perform an antigenic and biophysical characterization of BA.2.75, revealing an interesting balance between humoral evasion and ACE2 receptor affinity. ACE2 affinity for BA.2.75 is increased 9-fold compared with BA.2; there is also evidence of escape of BA.2.75 from immune serum, particularly that induced by Delta infection, which may explain the rapid spread in India, where where there is a high background of Delta infection. ACE2 affinity appears to be prioritized over greater escape., Competing Interests: Declaration of interests G.R.S. sits on the GSK Vaccines Scientific Advisory Board, consults for Astra Zeneca, and is a founding member of RQ Biotechnology. Oxford University holds intellectual property related to the Oxford-Astra Zeneca vaccine and SARS-CoV-2 mAbs discovered in G.R.S.’s laboratory. A.J.P. is Chair of UK Dept. Health and Social Care’s (DHSC) Joint Committee on Vaccination & Immunisation (JCVI) but does not participate in the JCVI COVID-19 committee and is a member of the WHO’s SAGE. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, or WHO. The University of Oxford has entered into a partnership with AstraZeneca on coronavirus vaccine development. T.L. is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and was a consultant to Vaccitech for an unrelated project whilst the study was conducted. S.J.D. is a scientific advisor to the Scottish Parliament on COVID-19., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Recent outbreaks of Zika virus (ZIKV) in South and Central America have highlighted significant neurologic side effects. Concurrence with the inflammatory neuropathy Guillain-Barré syndrome (GBS) is observed in 1:4,000 ZIKV cases. Whether the neurologic symptoms of ZIKV infection are immune mediated is unclear. We used rodent and human live cellular models to screen for anti-peripheral nerve reactive IgG and IgM autoantibodies in the sera of patients with ZIKV with and without GBS., Methods: In this study, 52 patients with ZIKV-GBS were compared with 134 ZIKV-infected patients without GBS and 91 non-ZIKV controls. Positive sera were taken forward for target identification by immunoprecipitation and mass spectrometry, and candidate antigens were validated by ELISA and cell-based assays. Autoantibody reactions against glycolipid antigens were also screened on an array., Results: Overall, IgG antibody reactivities to rat Schwann cells (SCs) (6.5%) and myelinated cocultures (9.6%) were significantly higher, albeit infrequent, in the ZIKV-GBS group compared with all controls. IgM antibody immunoreactivity to dorsal root ganglia neurones (32.3%) and SCs (19.4%) was more frequently observed in the ZIKV-GBS group compared with other controls, whereas IgM reactivity to cocultures was as common in ZIKV and non-ZIKV sera. Strong axonal-binding ZIKV-GBS serum IgG antibodies from 1 patient were confirmed to react with neurofascin 155 and 186. Serum from a ZIKV-infected patient without GBS displayed strong myelin-binding and putative antilipid antigen reaction characteristics. There was, however, no significant association of ZIKV-GBS with any known antiglycolipid antibodies., Discussion: Autoantibody responses in ZIKV-GBS target heterogeneous peripheral nerve antigens suggesting heterogeneity of the humoral immune response despite a common prodromal infection., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Dengue virus infection can cause dengue hemorrhagic fever (DHF). Dengue NS1 is multifunctional. The intracellular dimeric NS1 (iNS1) forms part of the viral replication complex. Previous studies suggest the extracellular secreted NS1 (sNS1), which is a major factor contributing to DHF, exists as hexamers. The structure of the iNS1 is well-characterised but not that of sNS1. Here we show by cryoEM that the recombinant sNS1 exists in multiple oligomeric states: the tetrameric (stable and loose conformation) and hexameric structures. Stability of the stable and loose tetramers is determined by the conformation of their N-terminal domain - elongated β-sheet or β-roll. Binding of an anti-NS1 Fab breaks the loose tetrameric and hexameric sNS1 into dimers, whereas the stable tetramer remains largely unbound. Our results show detailed quaternary organization of different oligomeric states of sNS1 and will contribute towards the design of dengue therapeutics., (© 2022. The Author(s).)

Background: Priming COVID-19 vaccine schedules have been deployed at variable intervals globally, which might influence immune persistence and the relative importance of third-dose booster programmes. Here, we report exploratory analyses from the Com-COV trial, assessing the effect of 4-week versus 12-week priming intervals on reactogenicity and the persistence of immune response up to 6 months after homologous and heterologous priming schedules using the vaccines BNT162b2 (tozinameran, Pfizer/BioNTech) and ChAdOx1 nCoV-19 (AstraZeneca)., Methods: Com-COV was a participant-masked, randomised immunogenicity trial. For these exploratory analyses, we used the trial's general cohort, in which adults aged 50 years or older were randomly assigned to four homologous and four heterologous vaccine schedules using BNT162b2 and ChAdOx1 nCoV-19 with 4-week or 12-week priming intervals (eight groups in total). Immunogenicity analyses were done on the intention-to-treat (ITT) population, comprising participants with no evidence of SARS-CoV-2 infection at baseline or for the trial duration, to assess the effect of priming interval on humoral and cellular immune response 28 days and 6 months post-second dose, in addition to the effects on reactogenicity and safety. The Com-COV trial is registered with the ISRCTN registry, 69254139 (EudraCT 2020-005085-33)., Findings: Between Feb 11 and 26, 2021, 730 participants were randomly assigned in the general cohort, with 77-89 per group in the ITT analysis. At 28 days and 6 months post-second dose, the geometric mean concentration of anti-SARS-CoV-2 spike IgG was significantly higher in the 12-week interval groups than in the 4-week groups for homologous schedules. In heterologous schedule groups, we observed a significant difference between intervals only for the BNT162b2-ChAdOx1 nCoV-19 group at 28 days. Pseudotyped virus neutralisation titres were significantly higher in all 12-week interval groups versus 4-week groups, 28 days post-second dose, with geometric mean ratios of 1·4 (95% CI 1·1-1·8) for homologous BNT162b2, 1·5 (1·2-1·9) for ChAdOx1 nCoV-19-BNT162b2, 1·6 (1·3-2·1) for BNT162b2-ChAdOx1 nCoV-19, and 2·4 (1·7-3·2) for homologous ChAdOx1 nCoV-19. At 6 months post-second dose, anti-spike IgG geometric mean concentrations fell to 0·17-0·24 of the 28-day post-second dose value across all eight study groups, with only homologous BNT162b2 showing a slightly slower decay for the 12-week versus 4-week interval in the adjusted analysis. The rank order of schedules by humoral response was unaffected by interval, with homologous BNT162b2 remaining the most immunogenic by antibody response. T-cell responses were reduced in all 12-week priming intervals compared with their 4-week counterparts. 12-week schedules for homologous BNT162b2 and ChAdOx1 nCoV-19-BNT162b2 were up to 80% less reactogenic than 4-week schedules., Interpretation: These data support flexibility in priming interval in all studied COVID-19 vaccine schedules. Longer priming intervals might result in lower reactogenicity in schedules with BNT162b2 as a second dose and higher humoral immunogenicity in homologous schedules, but overall lower T-cell responses across all schedules. Future vaccines using these novel platforms might benefit from schedules with long intervals., Funding: UK Vaccine Taskforce and National Institute for Health and Care Research., Competing Interests: Declaration of interests MDS acts on behalf of the University of Oxford as an investigator on studies funded or sponsored by vaccine manufacturers AstraZeneca, GlaxoSmithKline, Pfizer, Novavax, Janssen, Medimmune, and MCM vaccines, receiving no personal financial payment for this work. JSN-V-T was seconded to the Department of Health and Social Care (DHSC), England. AMC and DMF are investigators on studies funded by Pfizer and Unilever, receiving no personal financial payment for this work. AF is a member of the Joint Committee on Vaccination and Immunisation and Chair of the WHO European Technical Advisory Group of Experts on immunisation; he is an investigator, provides consultative advice, or both on clinical trials and studies of COVID-19 vaccines produced by AstraZeneca, Janssen, Valneva, Pfizer, and Sanofi and of other vaccines from these and other manufacturers GlaxoSmithKline, VPI, Takeda, and Bionet Asia, receiving no personal remuneration or benefits for any of this work. SNF acts on behalf of University Hospital Southampton NHS Foundation Trust as an investigator, provider of consultative advice, or both on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers Janssen, Pfizer, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Sanofi, Medimmune, Merck, and Valneva vaccines and antimicrobials, receiving no personal financial payment for this work. PTH acts on behalf of St George's University of London as an investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers Janssen, Pfizer, AstraZeneca, Novavax, and Valneva, receiving no personal financial payment for this work. CAG acts on behalf of University Hospitals Birmingham NHS Foundation Trust as an investigator on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers Janssen, Pfizer, AstraZeneca, Novavax, CureVac, Moderna, and Valneva vaccines, receiving no personal financial payment for this work. VL acts on behalf of University College London Hospitals NHS Foundation Trust as an investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers Pfizer, AstraZeneca, and Valneva, receiving no personal financial payment for this work. TL is named as an inventor on a patent application covering this SARS-CoV-2 vaccine (GB2003670.3) and is an occasional consultant to Vaccitech, unrelated to this work. Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Declaration of interests G.R.S. sits on the GSK Vaccines Scientific Advisory Board and is a founding member of RQ Biotechnology. Oxford University holds intellectual property related to the Oxford-AstraZeneca vaccine and SARS-CoV-2 mAb discovered in G.R.S.’s laboratory. A.J.P. is Chair of UK Dept. health and Social Care’s (DHSC) Joint Committee on Vaccination & Immunisation (JCVI) but does not participate in the JCVI COVID-19 committee and is a member of the WHO’s SAGE. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, or WHO. The University of Oxford has entered into a partnership with AstraZeneca on coronavirus vaccine development. T.L. is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and was a consultant to Vaccitech for an unrelated project while the study was conducted. S.J.D. is a scientific advisor to the Scottish Parliament on COVID-19., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of interests G.R.S. sits on the GSK Vaccines Scientific Advisory Board and is a founder member of RQ Biotechnology. Oxford University holds intellectual property related to the Oxford-Astra Zeneca vaccine. A.J.P. is Chair of UK DHSC Joint Committee on Vaccination & Immunisation (JCVI) but does not participate in the JCVI COVID-19 committee and is a member of the WHO’s SAGE. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, or WHO. The University of Oxford has entered into a partnership with AstraZeneca on coronavirus vaccine development. T.L. is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and was a consultant to Vaccitech for an unrelated project whilst the study was conducted. The University of Oxford has protected intellectual property disclosed in this publication. S.J.D. is a Scientific Advisor to the Scottish Parliament on COVID-19., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the persistence of immunogenicity three months after third dose boosters., Methods: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of seven COVID-19 vaccines used as a third booster dose. The analysis was conducted using all randomised participants who were SARS-CoV-2 naïve during the study., Results: Amongst the 2883 participants randomised, there were 2422 SARS-CoV-2 naïve participants until D84 visit included in the analysis with median age of 70 (IQR: 30-94) years. In the participants who had two initial doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd), schedules using mRNA vaccines as third dose have the highest anti-spike IgG at D84 (e.g. geometric mean concentration of 8674 ELU/ml (95% CI: 7461-10,085) following ChAd/ChAd/BNT162b2 (Pfizer-BioNtech, hearafter referred to as BNT)). However, in people who had two initial doses of BNT there was no significant difference at D84 in people given ChAd versus BNT (geometric mean ratio (GMR) of 0.95 (95%CI: 0.78, 1.15). Also, people given Ad26.COV2.S (Janssen; hereafter referred to as Ad26) as a third dose had significantly higher anti-spike IgG at D84 than BNT (GMR of 1.20, 95%CI: 1.01,1.43). Responses at D84 between people who received BNT (15 μg) or BNT (30 μg) after ChAd/ChAd or BNT/BNT were similar, with anti-spike IgG GMRs of half-BNT (15 μg) versus BNT (30 μg) ranging between 0.74-0.86. The decay rate of cellular responses were similar between all the vaccine schedules and doses., Conclusions: 84 days after a third dose of COVID-19 vaccine the decay rates of humoral response were different between vaccines. Adenoviral vector vaccine anti-spike IgG concentrations at D84 following BNT/BNT initial doses were similar to or even higher than for a three dose (BNT/BNT/BNT) schedule. Half dose BNT immune responses were similar to full dose responses. While high antibody tires are desirable in situations of high transmission of new variants of concern, the maintenance of immune responses that confer long-lasting protection against severe disease or death is also of critical importance. Policymakers may also consider adenoviral vector, fractional dose of mRNA, or other non-mRNA vaccines as third doses., Competing Interests: Declaration of Competing Interest KC acts on behalf of University Hospital Southampton as an investigator on studies funded or sponsored by vaccine manufacturers including AstraZeneca, GlaxoSmithKline, Janssen, Medimmune, Merck, Pfizer, Sanofi and Valneva. She receives no personal financial payment for this work. SNF acts on behalf of University Hospital Southampton NHS Foundation Trust as an Investigator and/or providing consultative advice on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers including Janssen, Pfizer, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Sanofi, Medimmune, Merck and Valneva vaccines and antimicrobials. He receives no personal financial payment for this work. ALG is named as an inventor on a patent covering use of a particular promoter construct that is often used in ChAdOx1-vectored vaccines and is incorporated in the ChAdOx1 nCoV-19 vaccine. ALG may benefit from royalty income paid to the University of Oxford from sales of this vaccine by AstraZeneca and its sublicensees under the University's revenue sharing policy. JH has received payments for presentations for AstraZeneca, Boehringer Ingelheim, Chiesi, Ciple & Teva. VL acts on behalf of University College London Hospitals NHS Foundation Trust as an Investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers including Pfizer, AstraZeneca and Valneva. He receives no personal financial payment for this work. PM acts on behalf of University Hospital Southampton NHS Foundation Trust and The Adam Practice as an investigator on studies funded or sponsored by vaccine manufacturers including AstraZeneca, GlaxoSmithKline, Novavax, Medicago and Sanofi. He received no personal financial payment for this work. JSN-V-T is seconded to the Department of Health and Social Care, England until 31st March 2022. MR has provided post marketing surveillance reports on vaccines for Pfizer and GSK for which a cost recover charge is made. MDS acts on behalf of the University of Oxford as an investigator on studies funded or sponsored by vaccine manufacturers including AstraZeneca, GlaxoSmithKline, Pfizer, Novavax. Janssen, Medimmune and MCM vaccines. He received no personal financial payment for this work., (Copyright © 2022. Published by Elsevier Ltd.)

Duration of protection from SARS-CoV-2 infection in people living with HIV (PWH) following vaccination is unclear. In a substudy of the phase II/III the COV002 trial (NCT04400838), 54 HIV+ male participants on antiretroviral therapy (undetectable viral loads, CD4+ T cells > 350 cells/μL) received 2 doses of ChAdOx1 nCoV-19 (AZD1222) 4-6 weeks apart and were followed for 6 months. Responses to vaccination were determined by serology (IgG ELISA and Meso Scale Discovery [MSD]), neutralization, ACE-2 inhibition, IFN-γ ELISpot, activation-induced marker (AIM) assay and T cell proliferation. We show that, 6 months after vaccination, the majority of measurable immune responses were greater than prevaccination baseline but with evidence of a decline in both humoral and cell-mediated immunity. There was, however, no significant difference compared with a cohort of HIV-uninfected individuals vaccinated with the same regimen. Responses to the variants of concern were detectable, although they were lower than WT. Preexisting cross-reactive T cell responses to SARS-CoV-2 spike were associated with greater postvaccine immunity and correlated with prior exposure to beta coronaviruses. These data support the ongoing policy to vaccinate PWH against SARS-CoV-2, and they underpin the need for long-term monitoring of responses after vaccination.

Introduction: The inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac, Sinovac) has been widely used in a two-dose schedule. We assessed whether a third dose of the homologous or a different vaccine could boost immune responses., Methods: RHH-001 is a phase 4, participant masked, two centre, safety and immunogenicity study of Brazilian adults (18 years and older) in São Paulo or Salvador who had received two doses of CoronaVac 6 months previously. The third heterologous dose was of either a recombinant adenoviral vectored vaccine (Ad26.COV2-S, Janssen), an mRNA vaccine (BNT162b2, Pfizer-BioNTech), or a recombinant adenoviral-vectored ChAdOx1 nCoV-19 vaccine (AZD1222, AstraZeneca), compared with a third homologous dose of CoronaVac. Participants were randomly assigned (5:6:5:5) by a RedCAP computer randomisation system stratified by site, age group (18-60 years or 61 years and over), and day of randomisation, with a block size of 42. The primary outcome was non-inferiority of anti-spike IgG antibodies 28 days after the booster dose in the heterologous boost groups compared with homologous regimen, using a non-inferiority margin for the geometric mean ratio (heterologous vs homologous) of 0·67. Secondary outcomes included neutralising antibody titres at day 28, local and systemic reactogenicity profiles, adverse events, and serious adverse events. This study was registered with Registro Brasileiro de Ensaios Clínicos, number RBR-9nn3scw., Findings: Between Aug 16, and Sept 1, 2021, 1240 participants were randomly assigned to one of the four groups, of whom 1239 were vaccinated and 1205 were eligible for inclusion in the primary analysis. Antibody concentrations were low before administration of a booster dose with detectable neutralising antibodies of 20·4% (95% CI 12·8-30·1) in adults aged 18-60 years and 8·9% (4·2-16·2) in adults 61 years or older. From baseline to day 28 after the booster vaccine, all groups had a substantial rise in IgG antibody concentrations: the geometric fold-rise was 77 (95% CI 67-88) for Ad26.COV2-S, 152 (134-173) for BNT162b2, 90 (77-104) for ChAdOx1 nCoV-19, and 12 (11-14) for CoronaVac. All heterologous regimens had anti-spike IgG responses at day 28 that were superior to homologous booster responses: geometric mean ratios (heterologous vs homologous) were 6·7 (95% CI 5·8-7·7) for Ad26.COV2-S, 13·4 (11·6-15·3) for BNT162b2, and 7·0 (6·1-8·1) for ChAdOx1 nCoV-19. All heterologous boost regimens induced high concentrations of pseudovirus neutralising antibodies. At day 28, all groups except for the homologous boost in the older adults reached 100% seropositivity: geometric mean ratios (heterologous vs homologous) were 8·7 (95% CI 5·9-12·9) for Ad26.COV2-S vaccine, 21·5 (14·5-31·9) for BNT162b2, and 10·6 (7·2-15·6) for ChAdOx1 nCoV-19. Live virus neutralising antibodies were also boosted against delta (B.1.617.2) and omicron variants (B.1.1.529). There were five serious adverse events. Three of which were considered possibly related to the vaccine received: one in the BNT162b2 group and two in the Ad26.COV2-S group. All participants recovered and were discharged home., Interpretation: Antibody concentrations were low at 6 months after previous immunisation with two doses of CoronaVac. However, all four vaccines administered as a third dose induced a significant increase in binding and neutralising antibodies, which could improve protection against infection. Heterologous boosting resulted in more robust immune responses than homologous boosting and might enhance protection., Funding: Ministry of Health, Brazil., Competing Interests: Declaration of interests AJP is chair of the UK Department of Health and Social Care's Joint Committee on Vaccination and Immunisation, but does not participate in policy advice on coronavirus vaccines, and is a member of the WHO Strategic Advisory Group of Experts. AJP is an National Institute for Health Research Senior Investigator. TL is named as an inventor on a patent application covering ChAdOx1 nCoV-19. Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

On 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 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., Competing Interests: Declaration of interests G.R.S. sits on the GSK Vaccines Scientific Advisory Board and is a founder member of RQ Biotechnology. J.Z. and G.S. declare the Israel patent application no. 23/09/2020—277,546 and United States patent application no. 16/12/2020—63/125,984, entitled methods and compositions for treating coronaviral infections. Oxford University holds intellectual property related to the Oxford-Astra Zeneca vaccine. A.J.P. is Chair of UK Dept. Health and Social Care’s (DHSC) Joint Committee on Vaccination & Immunisation (JCVI) but does not participate in the JCVI COVID-19 committee, and is a member of the WHO’s SAGE. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, or WHO. The University of Oxford has entered into a partnership with AstraZeneca on coronavirus vaccine development. The University of Oxford has protected intellectual property disclosed in this publication. S.C.G. is co-founder of Vaccitech (collaborators in the early development of this vaccine candidate) and is named as an inventor on a patent covering use of ChAdOx1-vectored vaccines and a patent application covering this SARS-CoV-2 vaccine (PCT/GB2012/000467). T.L. is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and was a consultant to Vaccitech for an unrelated project during the conduct of the study. S.J.D. is a Scientific Advisor to the Scottish Parliament on COVID-19., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Alpha-B.1.1.7, Beta-B.1.351, Gamma-P.1, and Delta-B.1.617.2 variants of SARS-CoV-2 express multiple mutations in the spike protein (S). These may alter the antigenic structure of S, causing escape from natural or vaccine-induced immunity. Beta is particularly difficult to neutralize using serum induced by early pandemic SARS-CoV-2 strains and is most antigenically separated from Delta. To understand this, we generated 674 mAbs from Beta-infected individuals and performed a detailed structure-function analysis of the 27 most potent mAbs: one binding the spike N-terminal domain (NTD), the rest the receptor-binding domain (RBD). Two of these RBD-binding mAbs recognize a neutralizing epitope conserved between SARS-CoV-1 and -2, while 18 target mutated residues in Beta: K417N, E484K, and N501Y. There is a major response to N501Y, including a public IgVH4-39 sequence, with E484K and K417N also targeted. Recognition of these key residues underscores why serum from Beta cases poorly neutralizes early pandemic and Delta viruses., Competing Interests: Declaration of interests M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals, Carnival Corporation, and on the Scientific Advisory Boards of Moderna and Immunome. The M.S.D. laboratory has received unrelated funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. G.R.S. sits on the GSK Vaccines Scientific Advisory Board and is a founder member of RQ Biotechnology. The University of Oxford has protected intellectual property disclosed in this publication., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

NP 105-113 -B*07:02-specific CD8 + T cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP 105-113 -B*07:02-specific T cell clones and single-cell sequencing were performed concurrently, with functional avidity and antiviral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with T cell receptor usage, transcriptome signature and disease severity (acute n = 77, convalescent n = 52). We demonstrated a beneficial association of NP 105-113 -B*07:02-specific T cells in COVID-19 disease progression, linked with expansion of T cell precursors, high functional avidity and antiviral effector function. Broad immune memory pools were narrowed postinfection but NP 105-113 -B*07:02-specific T cells were maintained 6 months after infection with preserved antiviral efficacy to the SARS-CoV-2 Victoria strain, as well as Alpha, Beta, Gamma and Delta variants. Our data show that NP 105-113 -B*07:02-specific T cell responses associate with mild disease and high antiviral efficacy, pointing to inclusion for future vaccine design., (© 2021. The Author(s).)

The human monoclonal antibody (HmAb) C10 potently cross-neutralizes Zika virus (ZIKV) and dengue virus. Analysis of antibody fragment (Fab) C10 interactions with ZIKV and dengue virus serotype 2 (DENV2) particles by cryoelectron microscopy (cryo-EM) and amide hydrogen/deuterium exchange mass spectrometry (HDXMS) shows that Fab C10 binding decreases overall ZIKV particle dynamics, whereas with DENV2, the same Fab causes increased dynamics. Testing of different Fab C10:DENV2 E protein molar ratios revealed that, at higher Fab ratios, especially at saturated concentrations, the Fab enhanced viral dynamics (detected by HDXMS), and observation under cryo-EM showed increased numbers of distorted particles. Our results suggest that Fab C10 stabilizes ZIKV but that with DENV2 particles, high Fab C10 occupancy promotes E protein dimer conformational changes leading to overall increased particle dynamics and distortion of the viral surface. This is the first instance of a broadly neutralizing antibody eliciting virus-specific increases in whole virus particle dynamics., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The human monoclonal antibody C10 exhibits extraordinary cross-reactivity, potently neutralizing Zika virus (ZIKV) and the four serotypes of dengue virus (DENV1-DENV4). Here we describe a comparative structure-function analysis of C10 bound to the envelope (E) protein dimers of the five viruses it neutralizes. We demonstrate that the C10 Fab has high affinity for ZIKV and DENV1 but not for DENV2, DENV3, and DENV4. We further show that the C10 interaction with the latter viruses requires an E protein conformational landscape that limits binding to only one of the three independent epitopes per virion. This limited affinity is nevertheless counterbalanced by the particle's icosahedral organization, which allows two different dimers to be reached by both Fab arms of a C10 immunoglobulin. The epitopes' geometric distribution thus confers C10 its exceptional neutralization breadth. Our results highlight the importance not only of paratope/epitope complementarity but also the topological distribution for epitope-focused vaccine design., Competing Interests: Declaration of interests F.A.R. is a board member and shareholder of EureKARE and MELETIUS Therapeutics. G.R.S. is member of the GSK Vaccines Scientific Advisory Board and a founding shareholder of RQ Biotechnology. G.R.S., F.A.R., P.G.-C., M.-C.V, A.R., S.D., and J.M. are authors in a patent concerning EDE mAbs, including C8 and C10:US20180037611A1 (2018): Anti-dengue vaccines and antibodies. G.R.S., F.A.R., M.-C.V., A.R., and J.M. are authors of patent CA3066488A1 (2017): Neutralising antibody against dengue for use in a method of prevention and/or treatment., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of interests G.R.S. is on the GSK Vaccines Scientific Advisory Board. Oxford University holds intellectual property related to the Oxford-AstraZeneca vaccine. A.J.P. is Chair of UK Department Health and Social Care’s (DHSC) Joint Committee on Vaccination & Immunisation (JCVI) but does not participate in the JCVI COVID19 committee and is a member of the WHO’s SAGE. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, or WHO. The University of Oxford has entered into a partnership with AstraZeneca on coronavirus vaccine development. The University of Oxford has protected intellectual property disclosed in this publication. S.C.G. is co-founder of Vaccitech (collaborators in the early development of this vaccine candidate) and is named as an inventor on a patent covering use of ChAdOx1-vectored vaccines and a patent application covering this SARS-CoV-2 vaccine (PCT/GB2012/000467). T.L. is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and was a consultant to Vaccitech for an unrelated project during the conduct of the study., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Data on vaccine immunogenicity against SARS-CoV-2 are needed for the 40 million people globally living with HIV who might have less functional immunity and more associated comorbidities than the general population. We aimed to explore safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine in people with HIV., Methods: In this single-arm open-label vaccination substudy within the protocol of the larger phase 2/3 trial COV002, adults aged 18-55 years with HIV were enrolled at two HIV clinics in London, UK. Eligible participants were required to be on antiretroviral therapy (ART), with undetectable plasma HIV viral loads (<50 copies per mL), and CD4 counts of more than 350 cells per μL. A prime-boost regimen of ChAdOx1 nCoV-19, with two doses was given 4-6 weeks apart. The primary outcomes for this substudy were safety and reactogenicity of the vaccine, as determined by serious adverse events and solicited local and systemic reactions. Humoral responses were measured by anti-spike IgG ELISA and antibody-mediated live virus neutralisation. Cell-mediated immune responses were measured by ex-vivo IFN-γ enzyme-linked immunospot assay (ELISpot) and T-cell proliferation. All outcomes were compared with an HIV-uninfected group from the main COV002 study within the same age group and dosing strategy and are reported until day 56 after prime vaccination. Outcomes were analysed in all participants who received both doses and with available samples. The COV002 study is registered with ClinicalTrials.gov, NCT04400838, and is ongoing., Findings: Between Nov 5 and Nov 24, 2020, 54 participants with HIV (all male, median age 42·5 years [IQR 37·2-49·8]) were enrolled and received two doses of ChAdOx1 nCoV-19. Median CD4 count at enrolment was 694·0 cells per μL (IQR 573·5-859·5). No serious adverse events occurred. Local and systemic reactions occurring during the first 7 days after prime vaccination included pain at the injection site (26 [49%] of 53 participants with available data), fatigue (25 [47%]), headache (25 [47%]), malaise (18 [34%]), chills (12 [23%]), muscle ache (19 [36%]), joint pain (five [9%]), and nausea (four [8%]), the frequencies of which were similar to the HIV-negative participants. Anti-spike IgG responses by ELISA peaked at day 42 (median 1440 ELISA units [EUs; IQR 704-2728]; n=50) and were sustained until day 56 (median 941 EUs [531-1445]; n=49). We found no correlation between the magnitude of the anti-spike IgG response at day 56 and CD4 cell count (p=0·93) or age (p=0·48). ELISpot and T-cell proliferative responses peaked at day 14 and 28 after prime dose and were sustained to day 56. Compared with participants without HIV, we found no difference in magnitude or persistence of SARS-CoV-2 spike-specific humoral or cellular responses (p>0·05 for all analyses)., Interpretation: In this study of people with HIV, ChAdOx1 nCoV-19 was safe and immunogenic, supporting vaccination for those well controlled on ART., Funding: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca., Competing Interests: Declaration of interests Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19 (AZD1222). SCG is cofounder of Vaccitech (a collaborator in the early development of this vaccine candidate) and named as an inventor on a patent covering use of ChAdOx1-vectored vaccines (PCT/GB2012/000467) and a patent application covering this SARS-CoV-2 vaccine. TL is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and was consultant to Vaccitech. PMF is a consultant to Vaccitech and has received research funding from the Brazilian Government. AJP is Chair of the UK Department of Health and Social Care's Joint Committee on Vaccination and Immunisation, but does not participate in policy advice on SARS-CoV-2 vaccines, and is a member of the WHO Strategic Advisory Group of Experts. AVSH is a cofounder of and consultant to Vaccitech and is named as an inventor on a patent covering design and use of ChAdOx1-vectored vaccines (PCT/GB2012/000467). SF is a consultant to Immunocore. GRS has received funding from Schmidt Futures and Wellcome Trust, consulting fees from GSK Vaccines Strategic Advisory Board, has patents on SARS-CoV-2 monoclonal antibodies, has leadership roles on Oxford University Council and Oxford University Hospitals NHS Foundation Trust, and holds stock in GSK. KP reports grants from the UK Medical Research Council UK Research and Innovation and National Institute of Health Research (NIHR) Vaccine Taskforce for RNA vaccine trial, COVAC1, and honoraria for Sanofi strategic advisory boards. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Declaration of interests G.R.S. sits on the GSK Vaccines Scientific Advisory Board. Oxford University holds intellectual property related to the Oxford-AstraZeneca vaccine. A.J.P. is chair of the UK Department Health and Social Care’s (DHSC) Joint Committee on Vaccination & Immunisation (JCVI) but does not participate in the JCVI COVID-19 committee and is a member of the World Health Organization’s (WHO’s) SAGE. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, or WHO. S.C.G. is co-founder of Vaccitech (collaborators in the early development of this vaccine candidate) and is named as an inventor on a patent covering use of ChAdOx1-vectored vaccines and a patent application covering this SARS-CoV-2 vaccine (PCT/GB2012/000467). T.L. is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and was a consultant to Vaccitech for an unrelated project during the conduct of the study. The University of Oxford has entered into a partnership with AstraZeneca on coronavirus vaccine development.The University of Oxford has protected intellectual property disclosed in this publication., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)