Persistence of immune responses after heterologous and homologous third COVID-19 vaccine dose schedules in the UK: eight-month analyses of the COV-BOOST trial

Abstract

Background: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of seven COVID-19 vaccines used as a third booster dose in June 2021. Monovalent messenger RNA (mRNA) COVID-19 vaccines were subsequently widely used for the third and fourth-dose vaccination campaigns in high-income countries. Real-world vaccine effectiveness against symptomatic infections following third doses declined during the Omicron wave. This report compares the immunogenicity and kinetics of responses to third doses of vaccines from day (D) 28 to D242 following third doses in seven study arms.

Methods: The trial initially included ten experimental vaccine arms (seven full-dose, three half-dose) delivered at three groups of six sites. Participants in each site group were randomised to three or four experimental vaccines, or MenACWY control. The trial was stratified such that half of participants had previously received two primary doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd) and half had received two doses of BNT162b2 (Pfizer-BioNtech, hereafter referred to as BNT). The D242 follow-up was done in seven arms (five full-dose, two half-dose). The BNT vaccine was used as the reference as it was the most commonly deployed third-dose vaccine in clinical practice in high-income countries. The primary analysis was conducted using all randomised and baseline seronegative participants who were SARS-CoV-2 naïve during the study and who had not received a further COVID-19 vaccine for any reason since third dose randomisation.

Results: Among the 817 participants included in this report, the median age was 72 years (IQR: 55-78) with 50.7% being female. The decay rates of anti-spike IgG between vaccines are different among both populations who received initial doses of ChAd/ChAd and BNT/BNT. In the population that previously received ChAd/ChAd, mRNA vaccines had the highest titre at D242 following their vaccine dose although Ad26. COV2. S (Janssen; hereafter referred to as Ad26) showed slower decay. For people who received BNT/BNT as their initial doses, a slower decay was also seen in the Ad26 and ChAd arms. The anti-spike IgG became significantly higher in the Ad26 arm compared to the BNT arm as early as 3 months following vaccination. Similar decay rates were seen between BNT and half-BNT; the geometric mean ratios ranged from 0.76 to 0.94 at different time points. The difference in decay rates between vaccines was similar for wild-type live virus-neutralising antibodies and that seen for anti-spike IgG. For cellular responses, the persistence was similar between study arms.

Conclusions: Heterologous third doses with viral vector vaccines following two doses of mRNA achieve more durable humoral responses compared with three doses of mRNA vaccines. Lower doses of mRNA vaccines could be considered for future booster campaigns.

Keywords: Antibodies; Boosters; COVID-19; Immunisation; Immunogenicity; SARS-CoV-2; T-Cells; Vaccination.

Fig. 1

CONSORT diagram.

Fig. 2

Kinetics of anti-spike IgG (ELU/mL) for A) ChAD/ ChAD; B) BNT/BNT and kinetics of cellular response (SFC/10⁶ PBMCs) for C) ChAD/ ChAD; D) BNT/BNT among the SARS-CoV-2 naïve population. Data presented are predicted geometric mean concentrations(or counts) and 95% confidence intervals estimated by repeated measurements mixed effects models, adjusting for immunogenicity at D0, age group (<70 years, ≥70 years), the interval between the first and second dose and the interval between the second and the third dose as fixed effects, and study sites and participants as random effects; for A) and B), the immunogenicity at D0 is D0 anti-spike IgG; for C) and D), the immunogenicity at D0 is D0 cellular response against wild type. The number of participants contributed to the models is presented in Fig. 3A for A); Fig. 4A for B); Fig. 3C for C); and Fig. 4C for D).

Fig. 3

Immunogenicity at D28, D84, and D242, and D242-to-D28 ratio for A) Anti-spike IgG (ELU/mL); B) Live virus neutralising antibody against wild type (NT₈₀); C) Cellular response (SFC per million PBMCs) among the SARS-CoV-2 naïve population primed with ChAD/ ChAD. GM: geometric mean; GMR: geometric mean ratio; One model was fitted for each time point; model adjusted for immunogenicity at D0, age group (<70 years, ≥70 years), the interval between the first and second dose and the interval between the second and the third dose as fixed effects, and study sites as a random effect for D24 and D84 analyses; The visit time as days post third dose vaccination was further adjusted in the D242 and D242-to-D28 ratio analysis; For A) and B), the immunogenicity at D0 is D0 anti-spike IgG; For C), the immunogenicity at D0 is D0 cellular response against wild type.

Fig. 4

Immunogenicity at D28, D84, and D242, and D242-to-D28 ratio for A) Anti-spike IgG (ELU/mL); B) Live virus neutralising antibody against wild type (NT₈₀); C) Cellular response (SFC per million PBMCs) among the SARS-CoV-2 naïve population primed with BNT/BNT. GM: geometric mean; GMR: geometric mean ratio; One model was fitted for each time point; Model adjusted for immunogenicity at D0, age group (<70 years, ≥70 years), the interval between the first and second dose and the interval between the second and the third dose as fixed effects, and study sites as a random effect for D24 and D84 analyses; The visit time as days post third dose vaccination was further adjusted in the D242 and D242-to-D28 ratio analysis; For A) and B), the immunogenicity at D0 is D0 anti-spike IgG; For C), the immunogenicity at D0 is D0 cellular response against wild type. There was only one participant with D242 live virus neutralising antibody data available in the NVX-half arm and removed in B).