Durability of ChAdOx1 Ncov-19 (AZD1222) Vaccine and Hybrid Humoral Immunity Against Variants Including Omicron BA.1 and BA.4 Six Months after Vaccination: A Randomised, Phase 1b/2a Trial

Background: Covid-19 vaccine rollout is lagging in Africa, where there has been a high force of SARS-CoV-2 infection. We evaluated the effect of SARS-CoV-2 infection prior to vaccination with the ChAdOx-nCoV19 (AZD1222) vaccine on antibody responses through to 180 days (D180).Methods: We undertook a post-hoc immunogenicity analysis after two doses of AZD1222 in a randomised, placebo-controlled phase Ib/2a study undertaken in South Africa. Recipients were stratified by serological assessment of SARS-CoV-2 infection prior to 1st dose into baseline seropositive or baseline seronegative groups. Binding immunoglobulin G (IgG) to spike (anti-S) and receptor binding domain (anti-RBD) were measured prior to first dose (D0), 2nd dose (D28), and at D42 and D180. Neutralizing antibody (NAb) against SARS-CoV-2 variants D614G, Beta, Delta, Gamma, A.VOI.V2, Omicron BA1 and BA.4 variants and SARS-CoV-1, were measured by pseudovirus assay (D28, D42 and D180). Antibody dependent cellular cytoxicity against D614G and Delta was measured at D28 and D42.Findings: Anti-S (and anti-RBD) IgG geometric mean concentrations (GMCs) were higher throughout in the baseline seropositive than seronegative group, persisting to D180 (GMCs: 517.8 vs 82.1 BAU/ml). Similarly, the percentage who had anti-S IgG ≥264BAU/ml (i.e. putative 80% risk reduction threshold [PRRT] against wild type (WT)/Alpha symptomatic Covid-19) was 76.6% vs 13.8% at D180. Also D614G NAb geometric mean titres (GMT) were higher in the baseline seropositive than seronegative group, as was the percentage with titres ≥185 (80% PRRT against WT/Alpha Covid-19) even at D180 (92.0% vs 18.2%). Similar findings were observed for Beta, A.VOI.V2 and Gamma at D28, D42 and D180. NAb GMTS against BA.1 and BA.4 were higher in the baseline seropositive than seronegative group at D28 (499 vs. 14; and 436 vs. 25.0) and D42 (535 vs. 16; and 429 vs. 25.0), as was the percentage with NAb titres ≥185 for BA.1 and BA.4 at D28 (84.0% and 87.5% vs. 0%) and D42 (84.0% and 87.5% vs. 0%). Interpretation: A single dose of AZD1222 in the general African population, where Covid-19 vaccine coverage is low and SARS-CoV-2 seropositivity is 90%, could enhance the magnitude and quality of antibody responses to SARS-CoV-2.Trial Registration Details: The COV005 study is registered with ClinicalTrials.gov, NCT04444674, and the Pan African Clinical Trials Registry, ACTR202006922165132.Funding Information: Grants from The Bill & Melinda Gates Foundation and the South African Medical Research Council provided funding for the study and the funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. Vaccines used in the study were donated by the University of Oxford. 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 is 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 (GB2003670.3). TL is named as an inventor on a patent application covering ChAdOx1 nCoV-19 and was a consultant to Vaccitech. All other authors declare no competing interests.Ethical Approval Statement: The study was approved by the South African Health and Pharmaceutical Products Regulatory Authority (SAHPRA) and the Human Ethics Research Committees of the various sites. Signed informed consent was obtained from all study participants. The South African Health Products Regulatory Authority (SAHPRA, reference 20200407), the Ethics committees at the University of the Witwatersrand, (HREC:200501), University of Stellenbosch (Ref: M20/06/009_Covid-19), University of Cape Town (Ref: 350/2020) and Oxford Tropical Research Ethics Committee (OxTREC ref 35-20) at the University of Oxford provided Ethics approval.