ABSTRACT
Heterogeneity in SARS-CoV-2 vaccine responses is not understood. Here, we identify four patterns of live-virus neutralizing antibody responses: individuals with hybrid immunity (with confirmed prior infection); rare individuals with low responses (paucity of S1-binding antibodies); and surprisingly, two further groups with distinct serological repertoires. One group - broad responders - neutralize a range of SARS-CoV-2 variants, whereas the other - narrow responders - neutralize fewer, less divergent variants. This heterogeneity does not correlate with Ancestral S1-binding antibody, rather the quality of the serological response. Furthermore, IgDlowCD27-CD137+ B cells and CCR6+ CD4+ T cells are enriched in broad responders before dose 3. Notably, broad responders have significantly longer infection-free time after their third dose. Understanding the control and persistence of these serological profiles could allow personalized approaches to enhance serological breadth after vaccination.
ABSTRACT
Introduction The impact of COVID-19 vaccination on disease in the community has been limited, as a result of both SARS-CoV-2 Variants of Concern that partially escape vaccine-induced immunity. We sought to characterise symptoms and viral loads over the course of COVID-19 infection in otherwise-healthy vaccinated adults, representative of the general population, to assess whether current self-isolation guidance remains justified. Methods In a prospective, observational cohort study, healthy vaccinated UK adults who reported a positive PCR or lateral flow test, self-swabbed on alternate days until day 10. We compared symptoms and viral kinetics between infections caused by VOCs Delta and Omicron (sub-variants BA.1 and BA.2) and investigated applicability of UK NHS isolation guidelines to these newer VOCs. Results 373 infection episodes were reported among 349 participants. Across VOCs, symptom duration was similar, however symptom profiles differed significantly among infections caused by Delta, Omicron BA.1 and BA.2. Anosmia was reported in <10% of participants with BA.1 and BA.2, compared to 42% with Delta infection, coryza fatigue and myalgia predominated. Most notably, viral load trajectories and peaks did not differ between Delta, BA.1 and BA.2, irrespective of symptom severity, VOC or vaccination status. Conclusion COVID-19 isolation guidance should not differ based on symptom severity or febrile illness and must remain under review as new SARS-CoV-2 VOCs emerge and population immunity changes. Our study emphasises the ongoing transmission risk of Omicron sub-variants in vaccinated adults with mild symptoms that may extend beyond current isolation periods.
Subject(s)
Hepatitis D , Fever , Olfaction Disorders , Common Cold , Myalgia , COVID-19ABSTRACT
Background: Concomitant administration of COVID-19 and influenza vaccines would reduce burden on healthcare systems. We assess the safety of concomitant administration. Methods: Adults in receipt of a single dose of ChAdOx1 or BNT162b2 were enrolled at 12 UK sites and randomised 1:1 to receive concomitant administration of either age-appropriate influenza or placebo alongside second COVID-19 vaccine. Three weeks later the group who received placebo received the influenza vaccine, and vice versa. Participants were followed to six weeks. The influenza vaccines were three seasonal, inactivated vaccines (trivalent, MF59C adjuvanted (aTIV) or a cellular or recombinant quadrivalent vaccine (QIVc/QIVr)). Participants and investigators were masked to the allocation. The primary endpoint was one or more participant-reported solicited systemic reaction in the seven days after first trial vaccination(s), with a difference of <25% considered non-inferior. Local and unsolicited systemic reactions and humoral responses were also assessed (ISRCTN14391248). Findings: Between 1st April and 26th June 2021, 679 participants were recruited to one of six cohorts: (129 ChAdOx1/QIVc; 139 BNT162b2/QIVc; 146 ChAdOx1/aTIV; 79 BNT162b2/aTIV; 128 ChAdOx1/QIVr; 58 BNT162b2/QIVr). Overall, 340 participants were randomised to concomitant administration of influenza and COVID-19 vaccine and 339 were randomised to placebo and COVID-19 vaccine. Non-inferiority was indicated in four cohorts; ChAdOx1/QIVc: risk difference (influenza vaccine minus placebo) -1·29% (95% confidence interval (CI) ‑14·7%, 12·1%); BNT162b2/QIVc: 6·17% (‑6·27%, 18·6%); BNT162b2/aTIV: -12·9% (‑34·2%, 8·37%); ChAdOx1/QIVr: 2·53% (‑13·3%, 18·3%). In two cohorts the upper limit of the 95%CI exceeded 25%; ChAdOx1/aTIV: 10·3% (‑5·44%, 26·0%) and BNT162b2/QIVr: 6·75% (‑11·8%, 25·3%). Most reactions were mild or moderate. Rates of local and unsolicited systemic reactions were similar between randomised groups. One serious adverse event, hospitalisation with severe headache, was considered related to the trial intervention. Immune responses were not adversely affected. Interpretation: Concomitant vaccination raises no safety concerns and preserves the immune response to both vaccines.Clinical Trial Registration Details: The trial is registered (ISRCTN14391248)Funding Information: The trial is commissioned and funded by the Department of Health and Social Care (DHSC) through the National Institute for Health Research (NIHR). This research was supported by the Vaccine Task Force (VTF) and NIHR Policy Research Programme (PR-R17-0916-22001, NIHR203243).Declaration of Interest: RL reports grants from National Institute for Health Research during the conduct of the trial, and grants from Elizabeth Blackwell Institute, AstraZeneca, Janssen and Valneva outside the submitted work. CR reports grants from National Institute for Health Research, during the conduct of the trial. JSN-V-T reports he is seconded to the Department of Health and Social Care, England. AF reports grants from Pfizer during the conduct of the trial, and grants from Elizabeth Blackwell Institute, Gates Foundation, Sanofi Pasteur, VBI Vaccines, Pfizer, Janssen, GSK, MedImmune, Novavax and Valneva outside the submitted work. Between May 2015 and May 2019 AF was President of the European Society for Paediatric Infectious Diseases which, during this period, received sponsorship from GSK for its annual congress. He currently serves as chief investigator on the Valneva (Covid-19) vaccine phase 1/2 and 2/3 studies .He also serves as co-investigator on the Janssen (Covid-19) vaccine 2 dose phase 3 study. He does advisory work related to vaccines for the UK government, the World Health Organisation and several companies developing vaccines. He also leads clinical trials of vaccines funded by the UK government, charities and vaccine manufacturers. He receives no personal remuneration or benefits in kind for any of this work apart from his salary via the University of Bristol from the Higher Education Funding Council and the NHS. He is a member of the UK Department of Health’s Joint Committee on Vaccination, Chair of the WHO European Technical Advisory Group of Experts in which capacity he attends SAGE. AM reports grants from National Institute for Health Research during the conduct of the trial, and grants from AstraZeneca, Janssen and Valneva outside the submitted work. 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, Pfizer, Janssen, Medimmune and MCM. The views in this paper are those of its authors and not necessarily those of the DHSC.Ethical Approval Statement: Approvals were received from the Medicines and Healthcare products Regulatory Agency (MHRA) (EudraCT number 2021-001124-18) and the South-Central Berkshire Research Ethics Committee (21/SC/0100).
Subject(s)
Encephalomyelitis, Acute Disseminated , Communicable Diseases , COVID-19ABSTRACT
Background: Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation, however we have previously reported that heterologous schedules incorporating an adenoviral-vectored vaccine (ChAd, Vaxzevria, Astrazeneca) and an mRNA vaccine (BNT, Comirnaty, Pfizer) at a 4-week interval are more reactogenic than homologous schedules. Here we report the immunogenicity of these schedules. Methods: Com-COV (ISRCTN: 69254139, EudraCT: 2020-005085-33) is a participant-blind, non-inferiority trial evaluating vaccine reactogenicity and immunogenicity. Adults ≥ 50 years, including those with well-controlled comorbidities, were randomised across eight groups to receive ChAd/ChAd, ChAd/BNT, BNT/BNT or BNT/ChAd, administered at 28- or 84-day intervals.The primary endpoint is geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG levels (ELISA) at one-month post boost between heterologous and homologous schedules given the same prime vaccine. We tested non-inferiority of GMR using a margin of 0.63. The primary analysis was on a per-protocol population, who were seronegative at baseline. Safety analyses were performed amongst participants receiving at least one dose of study vaccines.Findings: In February 2021, 830 participants were enrolled and randomised, including 463 with a 28-day prime-boost interval whose results are reported in this paper. Participant mean age was 57.8 years, 45.8% were female, and 25.3% from ethnic minorities.The geometric mean concentration (GMC) of day 28 post-boost SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12,906 ELU/ml) was non-inferior to that in ChAd/ChAd recipients (1,392 ELU/ml) with a geometric mean ratio (GMR) of 9.2 (one-sided 97.5% CI: 7.5, ∞). In participants primed with BNT, we failed to show non-inferiority of the heterologous schedule (BNT/ChAd, GMC 7,133 ELU/ml) against the homologous schedule (BNT/BNT, GMC 14,080 ELU/ml) with a GMR of 0.51 (one-sided 97.5% CI: 0.43, ∞). Geometric mean of T cell response at 28 days post boost in the ChAd/BNT group was 185 SFC/106 PBMCs (spot forming cells/106 peripheral blood mononuclear cells) compared to 50, 80 and 99 SFC/106 PBMCs for ChAd/ChAd, BNT/BNT, and BNT/ChAd, respectively. There were four serious adverse events across all groups, none of which were considered related to immunisation.Interpretation: Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the GMCs of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. These data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines.Trial Registration: The trial is registered at www.isrctn.com as ISRCTN: 69254139.Funding: Funded by the UK Vaccine Task Force (VTF) and National Institute for Health Research (NIHR)Declaration of Interest: 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 receives no personal financial payment for this work. JSN-V-T is seconded to the Department of Health and Social Care, England. 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 GSK, VPI, 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 vaccines, and 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 this SARS-CoV-2 vaccine 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-19Ethical Approval: The trial was reviewed and approved by the South-Central Berkshire Research Ethics Committee (21/SC/0022), the University of Oxford, and the Medicines and Healthcare Products Regulatory Agency MHRA). An independent data safety monitoring board (DSMB) reviewed safety data, and local trial- site physicians provided oversight of all adverse events in real-time.
Subject(s)
COVID-19ABSTRACT
Summary: Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is a novel technology formulated as a low dose vaccine against COVID-19.Methods: A phase I first-in-human dose-ranging trial of a saRNA COVID-19 vaccine candidate LNP-nCoVsaRNA, was conducted at Imperial Clinical Research Facility, and participating centres in London, UK. Participants received two intramuscular (IM) injections of LNP-nCoVsaRNA at six different dose levels, 0·1-10·0mg, given four weeks apart. An open-label dose escalation was followed by a dose evaluation. Solicited adverse events (AEs) were collected for one week from enrolment, with follow-up at regular intervals (1-8 weeks). The binding and neutralisation capacity of anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, immunoblot, SARS-CoV-2 pseudoneutralisation and wild type neutralisation assays.Findings: 192 healthy individuals with no history or serological evidence of COVID-19, aged 18-45 years were enrolled. The vaccine was well tolerated with no serious adverse events related to vaccination. Seroconversion at week six whether measured by ELISA or immunoblot was related to dose (both p<0·001), ranging from 8% to 61% in ELISA and 46% to 87% in the immunoblot assay.Concurrent anti-S IgG ranged from GM concentration (95% CI) 74 (45-119) at 0·1mg to 1023 (468-2236) ng/ml at 5·0mg (p<0·001) and was not higher at 10·0mg. Neutralisation of SARS-CoV-2 by participant sera was measurable in 15-48% depending on dose level received.Interpretation: Encapsulated saRNA is safe for clinical development and is immunogenic at low dose levels. Modifications to optimise humoral responses are required to realise its potential as an effective vaccine against SARS-CoV-2.Trial Registration: (ISRCTN17072692, EudraCT 2020-001646-20)Funding Statement: Medical Research Council UKRI (MC_PC_19076 and MC_UU_12023/23), National Institute for Health Research, Partners of Citadel and Citadel Securities, Sir Joseph Hotung Charitable Settlement, Jon Moulton Charity Trust.Declaration of Interests: P.F.M. and R.J.S. are co-inventors on a patent application covering this SARS-CoV-2 saRNA vaccine. All other authors have nothing to declare. Ethics Approval Statement: This study was approved in the UK by the Medicines and Healthcare products Regulatory Agency and the North East - York Research Ethics Committee (reference 20/SC/0145).
Subject(s)
COVID-19 , Pyruvate Carboxylase Deficiency Disease , Hemoglobin SC DiseaseABSTRACT
Background: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, MHRA, with a regimen of two standard doses given with an interval of between 4 and 12 weeks. The planned rollout in the UK will involve vaccinating people in high risk categories with their first dose immediately, and delivering the second dose 12 weeks later.Here we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered.Methods: We present data from phase III efficacy trials of ChAdOx1 nCoV-19 in the United Kingdom and Brazil, and phase I/II clinical trials in the UK and South Africa, against symptomatic disease caused by SARS-CoV-2. The data cut-off date for these analyses was 7th December 2020. The accumulated cases of COVID-19 disease at this cut-off date exceeds the number required for a pre-specified final analysis, which is also presented. As previously described, individuals over 18 years of age were randomised 1:1 to receive two standard doses (SD) of ChAdOx1 nCoV-19 (5x1010 viral particles) or a control vaccine/saline placebo. In the UK trial efficacy cohort a subset of participants received a lower dose (LD, 2.2x1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. All cases with a nucleic acid amplification test (NAAT) were adjudicated for inclusion in the analysis, by a blinded independent endpoint review committee. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov; NCT04324606, NCT04400838, and NCT04444674.Findings: 17,177 baseline seronegative trial participants were eligible for inclusion in the efficacy analysis, 8948 in the UK, 6753 in Brazil and 1476 in South Africa, with 619 documented NAAT +ve infections of which 332 met the primary endpoint of symptomatic infection >14 days post dose 2.The primary analysis of overall vaccine efficacy >14 days after the second dose including LD/SD and SD/SD groups, based on the prespecified criteria was 66.7% (57.4%, 74.0%). There were no hospitalisations in the ChAdOx1 nCoV-19 group after the initial 21 day exclusion period, and 15 in the control group.Vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 post vaccination was 76% (59%, 86%), and modelled analysis indicated that protection did not wane during this initial 3 month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 day (GMR 0.66, 95% CI 0.59, 0.74).In the SD/SD group, after the second dose, efficacy was higher with a longer prime-boost interval: VE 82.4% 95%CI 62.7%, 91.7% at 12+ weeks, compared with VE 54.9%, 95%CI 32.7%, 69.7% at <6 weeks. These observations are supported by immunogenicity data which showed binding antibody responses more than 2-fold higher after an interval of 12 or more weeks compared with and interval of less than 6 weeks GMR 2.19 (2.12, 2.26) in those who were 18-55 years of age.Interpretation: ChAdOx1 nCoV-19 vaccination programmes aimed at vaccinating a large proportion of the population with a single dose, with a second dose given after a 3 month period is an effective strategy for reducing disease, and may be the optimal for rollout of a pandemic vaccine when supplies are limited in the short term.Trial Registration: Studies are registered at ISRCTN89951424 and ClinicalTrials.gov; NCT04324606, NCT04400838, and NCT04444674.Funding: UKRI, NIHR, CEPI, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D’OR, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and Astra Zeneca.Conflict of Interest: Oxford University has entered into a partnership with Astra Zeneca for further development of ChAdOx1 nCoV-19. SCG is co-founder of Vaccitech (collaborators in the early development of this vaccine candidate) and named as an inventor on a patent covering use of ChAdOx1-vectored vaccines and a patent application covering this SARS-CoV-2 vaccine. TL is named as aninventor on a patent application covering this SARS-CoV-2 vaccine and was a consultant to Vaccitech for an unrelated project. PMF is a consultant to Vaccitech. AJP is Chair of UK Dept.Health and Social Care’s (DHSC) Joint Committee on Vaccination & Immunisation (JCVI), but does not participate in discussions on COVID-19 vaccines, and is a member of the WHO’sSAGE. AJP and SNF are NIHR Senior Investigator. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, NIHR or WHO. AVSH reports personal feesfrom Vaccitech, outside the submitted work and has a patent on ChAdOx1 licensed to Vaccitech, and may benefit from royalty income to the University of Oxford from sales of this vaccine by AstraZeneca and sublicensees. MS reports grants from NIHR, non-financial support fromAstraZeneca, during the conduct of the study; grants from Janssen, grants fromGlaxoSmithKline, grants from Medimmune, grants from Novavax, grants and non-financialsupport from Pfizer, grants from MCM, outside the submitted work. CG reports personal fees from the Duke Human Vaccine Institute, outside of the submitted work. SNF reports grants from Janssen and Valneva, outside the submitted work. ADD reports grants and personal fees from AstraZeneca, outside of the submitted work. In addition, ADD has a patent manufacturingprocess for ChAdOx vectors with royalties paid to AstraZeneca, and a patent ChAdOx2 vector with royalties paid to AstraZeneca. The other authors declare no competing interests.