Search

Background: The emergence of SARS-CoV-2 variants and COVID-19 vaccination have resulted in complex exposure histories. Rapid assessment of the effects of these exposures on neutralising antibodies against SARS-CoV-2 infection is crucial for informing vaccine strategy and epidemic management. We aimed to investigate heterogeneity in individual-level and population-level antibody kinetics to emerging variants by previous SARS-CoV-2 exposure history, to examine implications for real-time estimation, and to examine the effects of vaccine-campaign timing., Methods: Our Bayesian hierarchical model of antibody kinetics estimated neutralising-antibody trajectories against a panel of SARS-CoV-2 variants quantified with a live virus microneutralisation assay and informed by individual-level COVID-19 vaccination and SARS-CoV-2 infection histories. Antibody titre trajectories were modelled with a piecewise linear function that depended on the key biological quantities of an initial titre value, time the peak titre is reached, set-point time, and corresponding rates of increase and decrease for gradients between two timing parameters. All process parameters were estimated at both the individual level and the population level. We analysed data from participants in the University College London Hospitals-Francis Crick Institute Legacy study cohort (NCT04750356) who underwent surveillance for SARS-CoV-2 either through asymptomatic mandatory occupational health screening once per week between April 1, 2020, and May 31, 2022, or symptom-based testing between April 1, 2020, and Feb 1, 2023. People included in the Legacy study were either Crick employees or health-care workers at three London hospitals, older than 18 years, and gave written informed consent. Legacy excluded people who were unable or unwilling to give informed consent and those not employed by a qualifying institution. We segmented data to include vaccination events occurring up to 150 days before the emergence of three variants of concern: delta, BA.2, and XBB 1.5. We split the data for each wave into two categories: real-time and retrospective. The real-time dataset contained neutralising-antibody titres collected up to the date of emergence in each wave; the retrospective dataset contained all samples until the next SARS-CoV-2 exposure of each individual, whether vaccination or infection., Findings: We included data from 335 participants in the delta wave analysis, 223 (67%) of whom were female and 112 (33%) of whom were male (median age 40 years, IQR 22-58); data from 385 participants in the BA.2 wave analysis, 271 (70%) of whom were female and 114 (30%) of whom were male (41 years, 22-60); and data from 248 participants in the XBB 1.5 wave analysis, 191 (77%) of whom were female, 56 (23%) of whom were male, and one (<1%) of whom preferred not to say (40 years, 21-59). Overall, we included 968 exposures (vaccinations) across 1895 serum samples in the model. For the delta wave, we estimated peak titre values as 490·0 IC 50 (95% credible interval 224·3-1515·9) for people with no previous infection and as 702·4 IC 50 (300·8-2322·7) for people with a previous infection before omicron; the delta wave did not include people with a previous omicron infection. For the BA.2 wave, we estimated peak titre values as 858·1 IC 50 (689·8-1363·2) for people with no previous infection, 1020·7 IC 50 (725·9-1722·6) for people with a previous infection before omicron, and 1422·0 IC 50 (679·2-3027·3) for people with a previous omicron infection. For the XBB 1.5 wave, we estimated peak titre values as 703·2 IC 50 (415·0-3197·8) for people with no previous infection, 1215·9 IC 50 (511·6-7338·7) for people with a previous infection before omicron, and 1556·3 IC 50 (757·2-7907·9) for people with a previous omicron infection., Interpretation: Our study shows the feasibility of real-time estimation of antibody kinetics before SARS-CoV-2 variant emergence. This estimation is valuable for understanding how specific combinations of SARS-CoV-2 exposures influence antibody kinetics and for examining how COVID-19 vaccination-campaign timing could affect population-level immunity to emerging variants., Funding: Wellcome Trust, National Institute for Health Research University College London Hospitals Biomedical Research Centre, UK Research and Innovation, UK Medical Research Council, Francis Crick Institute, and Genotype-to-Phenotype National Virology Consortium., Competing Interests: Declaration of interests CSw receives grants from Bristol Myers Squibb, Ono Pharmaceuticals, Boehringer Ingelheim, Roche-Ventana, Pfizer, and Archer Dx; receives personal fees from Genentech, the Sarah Canon Research Institute, Medicxi, Bicycle Therapeutics, GRAIL, Amgen, AstraZeneca, Bristol Myers Squibb, Illumina, GlaxoSmithKline, MSD, and Roche-Ventana; holds stock options in Apogen Biotech, Epic Biosciences, GRAIL, and Achilles Therapeutics; is a member of a scientific advisory board for Bicycle Therapeutics, GRAIL, Relay Therapeutics, SAGA Diagnostics, and Achilles Therapeutics; is a co-founder of Achilles Therapeutics; receives consulting fees from Genentech, Medicxi, MetaboMed, Novartis, the China Innovation Centre of Roche, and the Sarah Cannon Research Institute; and receives honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Illumina, and Incyte. DLVB receives grants, paid to their institution, from AstraZeneca. EJC is an unpaid member of the Infection, Prevention and Control Committee of the UK Kidney Association. RB and DLVB are members of the Genotype-to-Phenotype 2 Consortium. AJK received the Sir Henry Dale Fellowship, jointly funded by the Wellcome Trust and the Royal Society (grant number 206250/Z/17/Z). AJK and DH were supported by the National Institutes of Health (1R01AI141534–01A1). All other authors declare no competing interests., (Copyright © 2025 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.)

Patients with blood cancer continue to have a greater risk of inadequate immune responses following three COVID-19 vaccine doses and risk of severe COVID-19 disease. In the context of the CAPTURE study (NCT03226886), we report immune responses in 80 patients with blood cancer who received a fourth dose of BNT162b2. We measured neutralizing antibody titers (NAbTs) using a live virus microneutralization assay against wild-type (WT), Delta, and Omicron BA.1 and BA.2 and T cell responses against WT and Omicron BA.1 using an activation-induced marker (AIM) assay. The proportion of patients with detectable NAb titers and T cell responses after the fourth vaccine dose increased compared with that after the third vaccine dose. Patients who received B cell-depleting therapies within the 12 months before vaccination have the greatest risk of not having detectable NAbT. In addition, we report immune responses in 57 patients with breakthrough infections after vaccination., Competing Interests: Declaration of interests The authors declare no competing interest., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Several variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged during the current coronavirus disease 2019 (COVID-19) pandemic. Although antibody cross-reactivity with the spike glycoproteins (S) of diverse coronaviruses, including endemic common cold coronaviruses (HCoVs), has been documented, it remains unclear whether such antibody responses, typically targeting the conserved S2 subunit, contribute to protection when induced by infection or through vaccination. Using a mouse model, we found that prior HCoV-OC43 S-targeted immunity primes neutralizing antibody responses to otherwise subimmunogenic SARS-CoV-2 S exposure and promotes S2-targeting antibody responses. Moreover, vaccination with SARS-CoV-2 S2 elicited antibodies in mice that neutralized diverse animal and human alphacoronaviruses and betacoronaviruses in vitro and provided a degree of protection against SARS-CoV-2 challenge in vivo. Last, in mice with a history of SARS-CoV-2 Wuhan-based S vaccination, further S2 vaccination induced broader neutralizing antibody response than booster Wuhan S vaccination, suggesting that it may prevent repertoire focusing caused by repeated homologous vaccination. These data establish the protective value of an S2-targeting vaccine and support the notion that S2 vaccination may better prepare the immune system to respond to the changing nature of the S1 subunit in SARS-CoV-2 variants of concern, as well as to future coronavirus zoonoses.

CAPTURE (NCT03226886) is a prospective cohort study of COVID-19 immunity in patients with cancer. Here we evaluated 585 patients following administration of two doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after two doses were 85% and 59% in patients with solid and hematological malignancies, respectively. A lower proportion of patients had detectable neutralizing antibody titers (NAbT) against SARS-CoV-2 variants of concern (VOCs) vs wildtype (WT). Patients with hematological malignancies were more likely to have undetectable NAbT and had lower median NAbT vs solid cancers against both WT and VOCs. In comparison with individuals without cancer, patients with haematological, but not solid, malignancies had reduced NAb responses. Seroconversion showed poor concordance with NAbT against VOCs. Prior SARS-CoV-2 infection boosted NAb response including against VOCs, and anti-CD20 treatment was associated with undetectable NAbT. Vaccine-induced T-cell responses were detected in 80% of patients, and were comparable between vaccines or cancer types. Our results have implications for the management of cancer patients during the ongoing COVID-19 pandemic., Competing Interests: Competing interests ST has received speaking fees from Roche, Astra Zeneca, Novartis and Ipsen. ST has the following patents filed: Indel mutations as a therapeutic target and predictive biomarker PCTGB2018/051892 and PCTGB2018/051893 and Clear Cell Renal Cell Carcinoma Biomarkers P113326GB. N.Y. has received conference support from Celegene. A.R. received a speaker fee from Merck Sharp & Dohme. J.L. has received research funding from Bristol-Myers Squibb, Merck, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar Therapeutics, Covance, Immunocore, Pharmacyclics, and Aveo, and served as a consultant to Achilles, AstraZeneca, Boston Biomedical, Bristol-Myers Squibb, Eisai, EUSA Pharma, GlaxoSmithKline, Ipsen, Imugene, Incyte, iOnctura, Kymab, Merck Serono, Nektar, Novartis, Pierre Fabre, Pfizer, Roche Genentech, Secarna, and Vitaccess. I.C. has served as a consultant to Eli-Lilly, Bristol Meyers Squibb, MSD, Bayer, Roche, Merck-Serono, Five Prime Therapeutics, Astra-Zeneca, OncXerna, Pierre Fabre, Boehringer Ingelheim, Incyte, Astella, GSK, Sotio, Eisai and has received research funding from Eli-Lilly & Janssen-Cilag. He has received honorarium from Eli-Lilly, Eisai, Servier. A.O. acknowledges receipt of research funding from Pfizer and Roche; speakers fees from Pfizer, Seagen, Lilly and AstraZeneca; is an advisory board member of Roche, Seagen, and AstraZeneca; has received conference support from Leo Pharmaceuticals, AstraZeneca/Diachi-Sankyo and Lilly. C.S. acknowledges grant support from Pfizer, AstraZeneca, Bristol Myers Squibb, Roche-Ventana, Boehringer-Ingelheim, Archer Dx Inc (collaboration in minimal residual disease sequencing technologies) and Ono Pharmaceutical, is an AstraZeneca Advisory Board member and Chief Investigator for the MeRmaiD1 clinical trial, has consulted for Amgen, Pfizer, Novartis, GlaxoSmithKline, MSD, Bristol Myers Squibb, Celgene, AstraZeneca, Illumina, Genentech, Roche-Ventana, GRAIL, Medicxi, Metabomed, Bicycle Therapeutics, and the Sarah Cannon Research Institute, has stock options in Apogen Biotechnologies, Epic Bioscience, GRAIL, and has stock options and is co-founder of Achilles Therapeutics. Patents: C.S. holds European patents relating to assay technology to detect tumour recurrence (PCT/GB2017/053289); to targeting neoantigens (PCT/EP2016/059401), identifying patent response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA LOH (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221), identifying patients who respond to cancer treatment (PCT/GB2018/051912), a US patent relating to detecting tumour mutations (PCT/US2017/28013) and both a European and US patent related to identifying insertion/deletion mutation targets (PCT/GB2018/051892). L.P. has received research funding from Pierre Fabre, and honoria from Pfizer, Ipsen, Bristol-Myers Squibb, and EUSA Pharma. S.B. has recieved institutional research funding from Astrazeneca, Tesaro, GSK; speakers fees from Amgen, Pfizer, Astrazeneca, Tesaro, GSK, Clovis, Takeda, Immunogen, Mersana and has an advisor role for Amgen, Astrazeneca, Epsilogen, Genmab, Immunogen, Mersana, MSD, Merck Serono, Oncxerna, Pfizer, Roche. W.C. has received honoraria from Janssen and AstraZeneca. Remaining authors have no conflicts of interest to declare.

Patients with cancer are currently prioritized in coronavirus disease 2019 (COVID-19) vaccination programs globally, which includes administration of mRNA vaccines. Cytokine release syndrome (CRS) has not been reported with mRNA vaccines and is an extremely rare immune-related adverse event of immune checkpoint inhibitors. We present a case of CRS that occurred 5 d after vaccination with BTN162b2 (tozinameran)-the Pfizer-BioNTech mRNA COVID-19 vaccine-in a patient with colorectal cancer on long-standing anti-PD-1 monotherapy. The CRS was evidenced by raised inflammatory markers, thrombocytopenia, elevated cytokine levels (IFN-γ/IL-2R/IL-18/IL-16/IL-10) and steroid responsiveness. The close temporal association of vaccination and diagnosis of CRS in this case suggests that CRS was a vaccine-related adverse event; with anti-PD1 blockade as a potential contributor. Overall, further prospective pharmacovigillence data are needed in patients with cancer, but the benefit-risk profile remains strongly in favor of COVID-19 vaccination in this population., (© 2021. The Author(s).)

There is need for effective and affordable vaccines against SARS-CoV-2 to tackle the ongoing pandemic. In this study, we describe a protein nanoparticle vaccine against SARS-CoV-2. The vaccine is based on the display of coronavirus spike glycoprotein receptor-binding domain (RBD) on a synthetic virus-like particle (VLP) platform, SpyCatcher003-mi3, using SpyTag/SpyCatcher technology. Low doses of RBD-SpyVLP in a prime-boost regimen induce a strong neutralising antibody response in mice and pigs that is superior to convalescent human sera. We evaluate antibody quality using ACE2 blocking and neutralisation of cell infection by pseudovirus or wild-type SARS-CoV-2. Using competition assays with a monoclonal antibody panel, we show that RBD-SpyVLP induces a polyclonal antibody response that recognises key epitopes on the RBD, reducing the likelihood of selecting neutralisation-escape mutants. Moreover, RBD-SpyVLP is thermostable and can be lyophilised without losing immunogenicity, to facilitate global distribution and reduce cold-chain dependence. The data suggests that RBD-SpyVLP provides strong potential to address clinical and logistic challenges of the COVID-19 pandemic.

• Detects antibodies which prevent the virus receptor from attaching to cells. • Predicts and measures virus-neutralising antibody. • Very high specificity and sensitivity. • Identifies risk persons who would benefit from immune plasma therapy. • Species and class neutral. Accurate and sensitive detection of antibody to SARS-CoV-2 remains an essential component of the pandemic response. Measuring antibody that predicts neutralising activity and the vaccine response is an absolute requirement for laboratory-based confirmatory and reference activity. The viral receptor binding domain (RBD) constitutes the prime target antigen for neutralising antibody. A double antigen binding assay (DABA), providing the most sensitive format has been exploited in a novel hybrid manner employing a solid-phase S1 preferentially presenting RBD, coupled with a labelled RBD conjugate, used in a two-step sequential assay for detection and measurement of antibody to RBD (anti-RBD). This class and species neutral assay showed a specificity of 100 % on 825 pre COVID-19 samples and a potential sensitivity of 99.6 % on 276 recovery samples, predicting quantitatively the presence of neutralising antibody determined by pseudo-type neutralization and by plaque reduction. Anti-RBD is also measurable in ferrets immunised with ChadOx1 nCoV-19 vaccine and in humans immunised with both AstraZeneca and Pfizer vaccines. This assay detects anti-RBD at presentation with illness, demonstrates its elevation with disease severity, its sequel to asymptomatic infection and its persistence after the loss of antibody to the nucleoprotein (anti-NP). It also provides serological confirmation of prior infection and offers a secure measure for seroprevalence and studies of vaccine immunisation in human and animal populations. The hybrid DABA also displays the attributes necessary for the detection and quantification of anti-RBD to be used in clinical practice. An absence of detectable anti-RBD by this assay predicates the need for passive immune prophylaxis in at-risk patients. [ABSTRACT FROM AUTHOR]