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. 2025 Jul 11;9(4):100642.
doi: 10.1016/j.mayocpiqo.2025.100642. eCollection 2025 Aug.

Immunogenicity and Safety of ChAdOx1 nCoV-19 (AZD1222) as a Homologous Fourth-Dose Booster: A Substudy of the Phase 3 COV003 Trial in Brazil

Sue Ann Costa Clemens  1   2 , Sagida Bibi  1 , Natalie G Marchevsky  1 , Parvinder K Aley  1 , Federica Cappuccini  1 , Sophie A Davies  1 , Isabela Gonzalez  2 , Sarah C Kelly  1 , Yama F Mujadidi  1 , Eveline Pipolo Milan  3 , Alexandre V Schwarzbold  4 , Eduardo Sprinz  5 , Merryn Voysey  1 , Lily Y Weckx  6 , Daniel Wright  1 , Himanshu Bansal  7 , Maria A S Bergagård  8 , Abby J Isaacs  7 , Elizabeth J Kelly  9   10 , Dongmei Lan  7 , Shethah Morgan  11 , Nirmal Kumar Shankar  12 , Kathryn Shoemaker  1 , Tonya L Villafana  13 , Teresa Lambe  1   14 , Justin A Green  11 , Andrew J Pollard  1
Affiliations

Immunogenicity and Safety of ChAdOx1 nCoV-19 (AZD1222) as a Homologous Fourth-Dose Booster: A Substudy of the Phase 3 COV003 Trial in Brazil

Sue Ann Costa Clemens et al. Mayo Clin Proc Innov Qual Outcomes. .

Abstract

Objective: To address that, despite widespread use of ChAdOx1 nCoV-19 (AZD1222) as a COVID-2019 booster, fourth-dose clinical outcomes data are limited. We report immunogenicity and safety for ChAdOx1 nCoV-19 as a homologous fourth-dose booster.

Participants and methods: Participants (aged ≥18 years) who had received 2 doses of ChAdOx1 nCoV-19 in phase 3 COV003 trial in Brazil were offered a third dose after a planned dose interval from 11 to 13 months and a fourth dose after a planned interval from 6 to 15 months (both 5 × 1010 viral particles). All fourth doses were administered to substudy participants between August 18 and October 28, 2022. The data cutoff was December 9, 2022. The primary immunogenicity outcome was noninferiority of ancestral severe acute respiratory syndrome coronavirus (SARS-CoV)-2-neutralizing antibody responses 28 days after dose 4 versus dose 3. Solicited and unsolicited adverse events were recorded 7 and 28 days postdose 4, respectively.

Results: 172 participants received a fourth dose (median interval postthird dose, 10.7 months). Ancestral SARS-CoV-2-neutralizing antibody titers postdose 4 were noninferior to those postdose 3; geometric mean fold rise was 1.9 (95% CI, 1.6-2.4; n=112). Immunogenicity results were consistent across all variants analyzed. Local and systemic solicited adverse events were reported in 60.3% (n=35/58) and 43.1% (n=25/58) of participants, respectively.

Conclusion: Immune responses after a fourth dose of ChAdOx1 nCoV-19 were noninferior to those after a third dose across SARS-CoV-2 variants. The fourth dose was well tolerated with no emergent safety concerns, supporting the continued development of the ChAdOx1 platform in preparation for future pandemics.

Trial registration: clinicaltrials.gov Identifier: NCT04536051.

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Conflict of interest statement

Sara Kelly is a contributor to intellectual property licensed by Oxford University Innovation to AstraZeneca. Merryn Voysey reports receiving institutional grants from AstraZeneca to University of Oxford. Dr Lambe reports consulting fees from Vaccitech for an unrelated project, an honorarium from Seqirus for an unrelated influenza meeting, work-related investments, and grants from Vaccine Taskforce via NIHR and AstraZeneca and is named as an inventor on a patent application for a vaccine against SARS-CoV-2. Dr Kelly, Dr Green, Dr Shoemaker, Maria Bergagård, Dr Shankar, Dr Morgan, and Dr Villafana are current or former employees of AstraZeneca and may hold AstraZeneca stock or stock options. Dr Isaacs, Dr Lan, and Dr Bansal were contracted to AstraZeneca at the time of the study. Dr Isaacs is an employee of Phastar (Durham, NC); Dr Lan is an employee of Cytel, Inc (Cambridge, MA); Dr Bansal is an employee of Bogier Consulting (Raleigh, NC). Dr Kelly is a former employee of AstraZeneca and now an employee of Sanofi (Swiftwater, PA, USA) and has held AstraZeneca stocks. Dr Pollard was a member of WHO’s Strategic Advisory Group of Experts on Immunization until January 2022, remains Chair of WHO’s salmonella Technical Advisory Group, and Chair of the UK Department of Health and Social Care’s Joint Committee on Vaccination and Immunisation (JCVI) but did not participate in the JCVI COVID-19 committee during the pandemic and reports providing advice to Shionogi on COVID-19, receiving mRNA from Moderna, and funding from the National Institute for Health and Care Research (NIHR), AstraZeneca, the Bill & Melinda Gates Foundation, Wellcome, the Medical Research Council, the Coalition for Epidemic Preparedness Innovations, the Serum Institute of India, and the European Commission. The University of Oxford entered into a partnership with AstraZeneca for the development of COVID-19 vaccines. Grants to support the conduct of this study were provided by AstraZeneca and the UK Vaccine Taskforce via NIHR. The other authors report no competing interests.

Figures

Figure 1
Figure 1
Participant disposition. Flow chart showing the number of participants randomized and vaccinated with ChAdOx1 nCoV-19 primary series or control; the number of participants vaccinated with third and fourth doses of ChAdOx1 nCoV-19 in the substudy; and the number of participants included in the substudy and exploratory subgroup analysis populations. DCO: December 9, 2022, unless otherwise specified. aAnalyses in these populations were performed by The University of Oxford. bAnalyses in these populations were performed by AstraZeneca. COVID-19, coronavirus disease 2019; DCO, data cutoff.
Figure 2
Figure 2
nAb titers against (A) ancestral SARS-CoV-2 and (B) Omicron BA.4/5 before and 28 days postprimary series, third dose, and fourth-dose of ChAdOx1 nCoV-19. nAb titers were assessed before and 28 days postprimary series (dose 2), dose 3, and dose 4 of ChAdOx1 nCoV-19 in the immunogenicity population. The bottom and top edges of the box indicate the first and third quartiles (the difference is the IQR), and the line inside the box is the median. Whiskers extend to the minimum and maximum values, excluding outliers. Any points with a log-transformed value of more than 1.5× IQR from the respective edges of the box were considered outliers. Boxplots were created based on the log-normal distribution. GMFRs were calculated in participants with Ab measurements at both compared time points; for a full listing of GMTs associated with the provided GMFRs, see Supplemental Table 1. CI, confidence interval; GMFR, geometric mean fold rise; GMT, geometric mean titer; LLoQ, lower limit of quantification; nAb, neutralizing antibody; SARS-CoV, severe acute respiratory syndrome coronavirus; ULoQ, upper limit of quantification.
Figure 3
Figure 3
Anti-ChAdOx1 nAb titers over time and the impact on ChAdOx1 nCoV-19-induced humoral immunogenicity against ancestral SARS-CoV-2. (A) Anti-ChAdOx1 nAb titers were assessed before and 28 days postprimary series (dose 2), dose 3, and dose 4 of ChAdOx1 nCoV-19 in the immunogenicity population. Correlations of after third and fourth dose (B) anti-SARS-CoV-2 nAb titers and (C) anti-SARS-CoV-2 spike Ab titers versus the corresponding predose anti-ChAdOx1 nAb titers were assessed in the immunogenicity population. For (A), the bottom and top edges of the box indicate the first and third quartiles (the difference is the IQR), and the line inside the box is the median. Whiskers extend to the minimum and maximum values, excluding outliers. Any points with a log-transformed value of more than 1.5× IQR from the respective edges of the box were considered outliers. Boxplots werecreated based on the log-normal distribution. For (B,C), the dotted lines indicate the 95% prediction limits and the shaded areas the 95% confidence limits. CI, confidence interval; GMT, geometric mean titer; LLoQ, lower limit of quantification; nAb, neutralizing antibody; SARS -CoV, severe acute respiratory syndrome coronavirus; ULoQ, upper limit of quantification.
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