Immunogenicity After Late Second or Third Dose of ChAdOx1 nCoV-19 Vaccine

Quick Takes

  • Immunity induced by the viral vectored vaccine ChAdOx1 nCoV-19 is maintained for long periods after a first dose, with greater boosting of effects after the second dose after a longer interval between doses than shorter intervals.
  • A single dose of ChAdOx1 nCoV-19 with a second dose after an extended period might be an effective strategy in locations where vaccine supplies are scarce in the short-term.
  • A third or booster dose results in a further increase in immune responses, including increased neutralization of variant SARS-CoV-2 viruses, and could be used to increase vaccine efficacy against variants in susceptible areas.

Study Questions:

What is the persistence of immunogenicity after a single dose of ChAdOx1 nCoV-19 (AZD1222), immunity after an extended interval (44–45 weeks) between the first and second dose, and response to a third dose as a booster given 28–38 weeks after the second dose?

Methods:

The investigators conducted a substudy of the COV001 trial, where volunteers aged 18–55 years enrolled in the phase 1/2 (COV001) controlled trial in the United Kingdom (UK) who received either a single dose or two doses of 5 × 1010 viral particles were invited back for vaccination. The authors report the reactogenicity and immunogenicity of a delayed second dose (44–45 weeks after first dose) or a third dose of the vaccine (28–38 weeks after second dose). Data from volunteers aged 18–55 years who were enrolled in either the phase 1/2 (COV001) or phase 2/3 (COV002), single-blinded, randomized controlled trials of ChAdOx1 nCoV-19 and who had previously received a single dose or two doses of 5 × 1010 viral particles were used for comparison purposes. COV001 is registered with ClinicalTrials.gov, NCT04324606, and ISRCTN, 15281137, and COV002 is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137, and both are continuing but not recruiting.

Results:

Between March 11–21, 2021, 90 participants were enrolled in the third-dose booster substudy, of whom 80 (89%) were assessable for reactogenicity, 75 (83%) were assessable for evaluation of antibodies, and 15 (17%) were assessable for T-cell responses. The two-dose cohort comprised 321 participants who had reactogenicity data (with prime-boost interval of 8–12 weeks: 267 [83%] of 321; 15–25 weeks: 24 [7%]; or 44–45 weeks: 30 [9%]) and 261 who had immunogenicity data (interval of 8–12 weeks: 115 [44%] of 261; 15–25 weeks: 116 [44%]; and 44–45 weeks: 30 [11%]). 480 participants from the single-dose cohort were assessable for immunogenicity up to 44–45 weeks after vaccination.

Antibody titers after a single dose measured approximately 320 days after vaccination remained higher than the titers measured at baseline (geometric mean titer of 66.00 ELISA units [EUs; 95% confidence interval, 47.83–91.08] vs. 1.75 EUs [1.60–1.93]). 32 participants received a late second dose of vaccine 44–45 weeks after the first dose, of whom 30 were included in immunogenicity and reactogenicity analyses. Antibody titers were higher 28 days after vaccination in those with a longer interval between first and second dose than for those with a short interval (median total immunoglobulin G [IgG] titer: 923 EUs [IQR, 525–1764] with an 8– to 12– week interval; 1860 EUs [917–4934] with a 15– to 25–week interval; and 3738 EUs [1824–6625] with a 44– to 45–week interval). Among participants who received a third dose of vaccine, antibody titers (measured in 73 [81%] participants for whom samples were available) were significantly higher 28 days after a third dose (median total IgG titer: 3746 EUs [IQR, 2047–6420]) than 28 days after a second dose (median 1792 EUs [IQR, 899–4634]; Wilcoxon signed rank test p = 0.0043).

T-cell responses were also boosted after a third dose (median response increased from 200 spot forming units [SFUs] per million peripheral blood mononuclear cells [PBMCs; IQR, 127–389] immediately before the third dose to 399 SFUs per million PBMCs [314–662] by day 28 after the third dose; Wilcoxon signed rank test p = 0.012). Reactogenicity after a late second dose or a third dose was lower than reactogenicity after a first dose.

Conclusions:

The authors concluded that an extended interval before the second dose of ChAdOx1 nCoV-19 leads to increased antibody titers and a third dose of ChAdOx1 nCoV-19 induces antibodies to a level that correlates with high efficacy after a second dose and boosts T-cell responses.

Perspective:

This substudy reports that immunity induced by the viral vectored vaccine ChAdOx1 nCoV-19 (AstraZeneca) is maintained for long periods after a first dose, with greater boosting of effects after the second dose after a longer interval between doses than shorter intervals. These data suggest that a single dose of ChAdOx1 nCoV-19 with a second dose given after an extended period might be an effective strategy in locations where vaccine supplies may be scarce in the short-term. Furthermore, this study shows for the first time that a third or booster dose resulted in a further increase in immune responses, including increased neutralization of variant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses, and could be used to increase vaccine efficacy against variants in susceptible areas.

Clinical Topics: Prevention

Keywords: Coronavirus, COVID-19, Enzyme-Linked Immunosorbent Assay, Immunoglobulin G, Immunity, Immunization, Secondary, Leukocytes, Mononuclear, Lymphocytes, Primary Prevention, SARS-CoV-2, Vaccination, Vaccine Potency, Viral Vaccines


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