Third Booster Half Dose of ChAdOx1-nCov-19 Is Effective, Safe, and Induces Long-Duration Humoral and Cellular Immune Response to Omicron: 1-Year Follow-Up of Viana Study

Background: Dose-sparing approaches can be effective in maintaining immunogenicity and safety while expanding vaccine coverage. We previously demonstrated that a half dose of ChAdOx1 nCoV-19 is as effective and immunogenic for primary vaccination. Methods: This non-inferiority, non-randomized controlled trial evaluated the effectiveness, humoral, and cellular immune responses of a third booster dose—comparing half-dose and full-dose regimens—in individuals aged 18–49 years, with a 1-year follow-up. Results: A total of 2801 participants were enrolled: 2352 received half doses and 449 received full doses. The incidence rate of COVID-19 was 225.0 per 1000 person-years in the half-dose group and 173.8 in the full-dose group, with no significant difference in effectiveness (β = −0.05; 95% CrI: −0.24 to 0.15). No deaths occurred, and hospitalization rates were similar. In a subsample (n = 558), anti-S IgG levels peaked 28 days post-dose and declined by day 180 after the primary series [175 (121–252) vs. 121 (71–208) GMT, p < 0.001], but remained elevated after the booster [192.1 (124–297) vs. 550 (380–797) GMT, p < 0.001]. Booster antibody levels were similar between groups [592.4 (318–1140) vs. 550 (380–797) GMT]. The half-dose group showed high titers against Omicron and robust T/B-cell responses (e.g., EMCD4, EMCD8, IFN+CD4+, CD19+TNF+). Conclusions: Fractional half dose of ChAdOx nCov-19 was effective and non-inferior to a full booster dose. Homologous regimen with 3 half doses or 3 full doses induced a similar increase in antibody titers and robust cellular response. ClinicalTrials.gov (NCT05059106).