Costa Clemens SA, Jepson B, Bhorat QE, Ahmad A, Akhund T, Aley PK, Bansal H, Bibi S, Kelly EJ, Khan M, Lambe T, Lombaard JJ, Matthews S, Pipolo Milan E, Olsson U, Ramasamy MN, Moura de Oliveira Paiva MS, Seegobin S, Shoemaker K, Szylak A, Villafana T, Pollard AJ, and Green JA
Background: AZD2816 is a variant-adapted COVID-19 vaccine that expresses the full-length SARS-CoV-2 beta variant spike protein but is otherwise similar to AZD1222 (ChAdOx1 nCoV-19). This study aimed to evaluate the safety and immunogenicity of AZD1222 or AZD2816 (or both) primary-series vaccination in a cohort of adult participants who were previously unvaccinated., Methods: In this phase 2/3, randomised, multinational, active-controlled, non-inferiority, immunobridging study, adult participants previously unvaccinated for COVID-19 were enrolled at 16 study sites in Brazil, South Africa, Poland, and the UK. Participants were stratified by age, sex, and comorbidity and randomly assigned 5:5:5:2 to receive a primary series of AZD1222 (AZD1222 group), AZD2816 (AZD2816 [4-week] group), or AZD1222-AZD2816 (AZD1222-AZD2816 group) at 4-week dosing intervals, or AZD2816 at a 12-week interval (AZD2816 [12-week] group) and evaluated for safety and immunogenicity through 180 days after dose 2. Primary outcomes were safety (rates of solicited adverse events occurring during 7 days and unsolicited adverse events occurring during 28 days after each dose) and immunogenicity (non-inferiority of pseudovirus neutralising antibody geometric mean titre [GMT], GMT ratio margin of 0·67, and seroresponse rate, rate difference margin of -10%, recorded 28 days after dose 2 with AZD2816 [4-week interval] against beta vs AZD1222 against ancestral SARS-CoV-2) in participants who were seronegative at baseline. This trial is registered with ClinicalTrials.gov, NCT04973449, and is completed., Findings: Between July 7 and Nov 12, 2021, 1449 participants were assigned to the AZD1222 group (n=413), the AZD2816 (4-week) group (n=415), the AZD1222-AZD2816 group (n=412), and the AZD2816 (12-week) group (n=209). Ten (2·6%) of 378 participants who were seronegative at baseline in the AZD1222 group, nine (2·4%) of 379 in the AZD2816 (4-week) group, eight (2·1%) of 380 in the AZD1222-AZD2816 group, and 11 (5·8%) of 191 in the AZD2816 (12-week) group had vaccine-related unsolicited adverse events. Serious adverse events were recorded in one (0·3%) participant in the AZD1222 group, one (0·3%) in the AZD2816 (4-week) group, two (0·5%) in the AZD1222-AZD2816 group, and none in the AZD2816 (12-week) group. Co-primary immunogenicity endpoints were met: neutralising antibody GMT (ratio 1·19 [95% CI 1·08-1·32]; lower bound greater than 0·67) and seroresponse rate (difference 1·7% [-3·1 to 6·5]; lower bound greater than -10%) at 28 days after dose 2 were non-inferior in the AZD2816 (4-week) group against beta versus in the AZD1222 group against ancestral SARS-CoV-2. Seroresponse rates were highest with AZD2816 against beta (12-week interval 94·3% [95% CI 89·4-97·3]; 4-week interval 85·7% [81·5-89·2]) and with AZD1222 (84·6% [80·3-88·2]) against ancestral SARS-CoV-2., Interpretation: Primary series of AZD1222 and AZD2816 were well tolerated, with no emergent safety concerns. Both vaccines elicited robust immunogenicity against beta and ancestral SARS-CoV-2 with greater responses demonstrated when testing against SARS-CoV-2 strains that matched those targeted by the respective vaccine. These findings demonstrate the continued importance of ancestral COVID-19 vaccines in protecting against severe COVID-19 and highlight the feasibility of using the ChAdOx1 platform to develop COVID-19 vaccines against future SARS-CoV-2 variants., Funding: AstraZeneca., Competing Interests: Declaration of interests SACC declares participation in the clinical development, with University of Oxford, of the vaccines described in this Article, membership on CureVac and Clover advisory boards, and institutional research grants from AstraZeneca. BJ is an employee of Cytel and is currently on assignment to AstraZeneca. QEB declares institutional funding, the provision of study materials, or both from the Wits Health Consortium, the Bill & Melinda Gates Foundation, the South African Medical Research Council, and AstraZeneca, as well as research grants or contracts from Regeneron, Novo Nordisk, Avillion, GlaxoSmithKline, Novavax, Sinovac, Johnson & Johnson, and Pfizer pharmaceuticals. PKA declares institutional grants to support the conduct of the study from AstraZeneca and the UK Vaccine Taskforce via the UK National Institute for Health Research (NIHR). HB is an employee of Bogier consulting and is currently on assignment to AstraZeneca. EJK is an employee of Sanofi. SM is an employee of Exploristics and is currently on assignment to AstraZeneca. EPM declares no competing interests. TL declares consulting fees from Vaccitech on an unrelated project, an honorarium from Seqirus on an unrelated project, an institutional grant from the UK Vaccine Taskforce via the NIHR, work-related investments, and is a named inventor on a patent application for a vaccine against SARS-CoV-2. JJL declares no competing interests. MNR declares institutional support for the study from AstraZeneca. AJP is Chair of the UK Department of Health and Social Care’s Joint Committee on Vaccination and Immunisation (JCVI) but does not participate in the JCVI COVID-19 committee. AJP also declares membership of the WHO’s Strategic Advisory Group of Experts on Immunization until January, 2022; provision of advice to Shionogi on COVID-19; and funding from the NIHR, AstraZeneca, the Bill & Melinda Gates Foundation, Wellcome, the UK Research and Innovation Medical Research Council, the Serum Institute of India, and the Coalition for Epidemic Preparedness Innovations. University of Oxford has entered a partnership with AstraZeneca for the development of COVID-19 vaccines; TL, MNR, SB, PKA, and AJP are contributors to the intellectual property licensed by Oxford University Innovation to AstraZeneca. AA, TA, EJK, MK, UO, SS, KS, AS, TV, and JAG are, or were, employees of and may hold (or have held) stock or stock options in AstraZeneca. MSMdOP declares no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)