Reactogenicity and immunogenicity after a late second dose or a third dose of ChAdOx1 nCoV-19 in the UK: a substudy of two randomised controlled trials (COV001 and COV002)

Abstract

Background: COVID-19 vaccine supply shortages are causing concerns about compromised immunity in some countries as the interval between the first and second dose becomes longer. Conversely, countries with no supply constraints are considering administering a third dose. We assessed 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: In this substudy, volunteers aged 18-55 years who were enrolled in the phase 1/2 (COV001) controlled trial in the UK and had received either a single dose or two doses of 5 × 10¹⁰ viral particles were invited back for vaccination. Here we 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, randomised controlled trials of ChAdOx1 nCoV-19 and who had previously received a single dose or two doses of 5 × 10¹⁰ viral particles are 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.

Findings: Between March 11 and 21, 2021, 90 participants were enrolled in the third-dose boost substudy, of whom 80 (89%) were assessable for reactogenicity, 75 (83%) were assessable for evaluation of antibodies, and 15 (17%) were assessable for T-cells 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 titres after a single dose measured approximately 320 days after vaccination remained higher than the titres measured at baseline (geometric mean titre of 66·00 ELISA units [EUs; 95% CI 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 titres 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 IgG titre: 923 EUs [IQR 525-1764] with an 8-12 week interval; 1860 EUs [917-4934] with a 15-25 week interval; and 3738 EUs [1824-6625] with a 44-45 week interval). Among participants who received a third dose of vaccine, antibody titres (measured in 73 [81%] participants for whom samples were available) were significantly higher 28 days after a third dose (median total IgG titre: 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 milion 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.

Interpretation: An extended interval before the second dose of ChAdOx1 nCoV-19 leads to increased antibody titres. A third dose of ChAdOx1 nCoV-19 induces antibodies to a level that correlates with high efficacy after second dose and boosts T-cell responses.

Funding: UK Research and Innovation, Engineering and Physical Sciences Research Council, National Institute for Health Research, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research Oxford Biomedical Research Centre, Chinese Academy of Medical Sciences Innovation Fund for Medical Science, Thames Valley and South Midlands NIHR Clinical Research Network, AstraZeneca, and Wellcome.

Figure 1

Trial profile for three-dose cohort

Figure 2

Solicited adverse reactions up to 7 days after ChAdOx1 nCoV-19 vaccination by interval between first and second doses (A) and after the first, second, and third dose for participants who received a third dose of vaccine (B) Figure shows maximum severity of respective solicited adverse event recorded for each participant during days 0–7 after vaccination. In panel A, reactogenicity data after the second dose are shown for 263 participants for fever (≥38°C) and 267 participants for all other symptoms for the 8–12 week interval, for 23 participants for fever (≥38°C) and 24 participants for all other symptoms for the 15–25 week interval, and 28 participants for fever (≥38°C) and 30 participants for all other symptoms for the 44–45 week interval. In panel B, reactogenicity data are from after each dose recorded by participants who received a third dose of vaccine, with data available for 80 participants for all symptoms after dose 1; 15 participants for all symptoms after dose 2; and 77 participants for fever and 80 participants for all symptoms after dose 3. Participants included in panel B received their third dose 20–38 weeks after the second dose (median of 30 weeks [IQR 30–30]).

Figure 3

Antibody (A) and T-cell (B) persistence after one dose of ChAdOx1 nCoV-19 vaccine Datapoints represent individual participants and the solid line represents estimates from a linear regression model, with shaded areas showing the 95% CI. Antibody levels to SARS-CoV-2 Victoria/01/2020 spike measured by total IgG ELISA over 1 year after a single dose. Data are from 480 participants across COV001 and COV002 who received a standard dose of ChAdOx1 nCoV-19. Vaccine-induced T-cell responses against the SARS-CoV-2 spike insert were monitored up to day 182 in a cohort of 44 participants who received a single dose of ChAdOx1 nCoV-19. For participants who were excluded from these analyses due to positive PCR test result, second dose on trial, or external COVID-19 vaccination, no ELISA results or ELISpot results beyond the date of censoring were used. PBMCs=peripheral blood mononuclear cells. SFUs=spot-forming units

Figure 4

Antibody response by interval between first and second vaccination Datapoints are medians for each group, with error bars showing IQRs. Antibody levels to SARS-CoV-2 Victoria/01/2020 spike measured by total IgG ELISA. Data are shown for 115 participants for the 8–12 week interval; 116 participants for the 15–25 week interval, and 30 participants for the 44–45 week interval. Unadjusted and age-adjusted geometric mean ratios are shown in appendix 3 (p 16).

Figure 5

Antibody responses in participants who received a third dose of ChAdOx1 nCoV-19 (A) Antibody levels to SARS-CoV-2 Victoria/01/2020 spike protein measured by total IgG ELISA (n=75). Datapoints in lighter colours represent individual participants and darker datapoints show median values with error bars showing the IQRs and with solid lines connecting these median values. (B) Neutralisation titres from a randomly selected subset of participants (45 of 75 participants who received a third dose of vaccine and who had an interval of 8–16 weeks between their first and second dose). Datapoints represent individual participants for the three variants of concern investigated. FRNT50=focus reduction neutralisation titres with 50% neutralisation cutoff.

Figure 6

IFN-γ ELISpot responses in participants who received a third dose of ChAdOx1 nCoV-19 15 participants with an interval of 8 weeks between their first and second doses were assessed for ELISpot responses. These participants received their third dose 37–38 weeks after the second dose (median 38 weeks [IQR 38–38]). Datapoints in lighter colours represent individual participants and darker datapoints show median values with error bars showing the IQRs and with solid lines connecting these median values. The dotted horizontal line represents the lower limit of detection of the assay (48 SFU per million PBMCs). SFU=spot-forming unit. PBMC=peripheral blood mononuclear cells.