Immunogenicity and Reactogenicity of Vaccine Boosters after Ad26.COV2.S Priming

Abstract

Background: The Ad26.COV2.S vaccine, which was approved as a single-shot immunization regimen, has been shown to be effective against severe coronavirus disease 2019. However, this vaccine induces lower severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (S)-specific antibody levels than those induced by messenger RNA (mRNA)-based vaccines. The immunogenicity and reactogenicity of a homologous or heterologous booster in persons who have received an Ad26.COV2.S priming dose are unclear.

Methods: In this single-blind, multicenter, randomized, controlled trial involving health care workers who had received a priming dose of Ad26.COV2.S vaccine, we assessed immunogenicity and reactogenicity 28 days after a homologous or heterologous booster vaccination. The participants were assigned to receive no booster, an Ad26.COV2.S booster, an mRNA-1273 booster, or a BNT162b2 booster. The primary end point was the level of S-specific binding antibodies, and the secondary end points were the levels of neutralizing antibodies, S-specific T-cell responses, and reactogenicity. A post hoc analysis was performed to compare mRNA-1273 boosting with BNT162b2 boosting.

Results: Homologous or heterologous booster vaccination resulted in higher levels of S-specific binding antibodies, neutralizing antibodies, and T-cell responses than a single Ad26.COV2.S vaccination. The increase in binding antibodies was significantly larger with heterologous regimens that included mRNA-based vaccines than with the homologous booster. The mRNA-1273 booster was most immunogenic and was associated with higher reactogenicity than the BNT162b2 and Ad26.COV2.S boosters. Local and systemic reactions were generally mild to moderate in the first 2 days after booster administration.

Conclusions: The Ad26.COV2.S and mRNA boosters had an acceptable safety profile and were immunogenic in health care workers who had received a priming dose of Ad26.COV2.S vaccine. The strongest responses occurred after boosting with mRNA-based vaccines. Boosting with any available vaccine was better than not boosting. (Funded by the Netherlands Organization for Health Research and Development ZonMw; SWITCH ClinicalTrials.gov number, NCT04927936.).

Figure 1. Screening, Randomization, and Analysis.

Between trial enrollment and randomization, 236 health care workers were excluded, including 78 who did not meet the inclusion criteria, 18 who declined to participate after reading the patient information form, and 140 who could not adhere to the strict schedule of the trial or did not reply to the screening questionnaire. After randomization, the numbers of participants who were lost to follow-up did not differ significantly among the groups. SARS-CoV-2 denotes severe acute respiratory syndrome coronavirus 2.

Figure 2. SARS-CoV-2 S–Specific Immune Responses.

Panel A shows levels of SARS-CoV-2 spike protein (S)–specific IgG antibodies at baseline (before booster vaccination) and after booster vaccination in the four groups. The lower limit of detection (LLoD) was 4.81 binding antibody units (BAU) per milliliter. The cutoff value for response was 33.8 BAU per milliliter (horizontal line). Panel B shows the per-participant factor changes that were calculated by dividing the after-booster response by the before-booster response for S-specific binding antibodies. The dashed line indicates a factor change of 1 (no increase or decrease). Panel C shows the levels of neutralizing antibodies at baseline (before booster vaccination) and after booster vaccination, as assessed with a plaque reduction neutralization test with a 50% cutoff (PRNT₅₀) in the four groups. The LLoD was 7.7 IU per milliliter. The cutoff value for response was 28.6 IU per milliliter (corresponding to a serum dilution of 1:40; horizontal line). Panel D shows the per-participant factor changes that were calculated by dividing the after-booster response by the before-booster response for neutralizing antibodies. The dashed line indicates a factor change of 1 (no increase or decrease). Panel E shows interferon-γ levels in plasma after stimulation of whole blood with a peptide pool spanning the S protein at baseline (before booster) and after booster vaccination in the four groups. The LLoD was 0.01 IU per milliliter. The cutoff value for response was 0.15 IU per milliliter (horizontal line). Panel F shows per-participant factor changes calculated by dividing the after-booster response by the before-booster response for interferon-γ levels in plasma. The dashed line indicates a factor change of 1 (no increase or decrease). All data are presented in box-and-whisker plots. The whiskers indicate the range, the top and bottom of the boxes indicate the interquartile range, and the horizontal line within each box indicates the median. P values are reported for prespecified primary and secondary end points only (on the basis of Mann–Whitney tests). Comparisons between mRNA-1273 and BNT162b2 boosters (Panels A, C, and E, right panel) and comparisons among the groups on the basis of factor changes (Panels B, D, and F) were performed as post hoc analyses, and estimated effect sizes are reported in Table S4. Each dot in the figure represents an individual participant.

Figure 3. Correlation between S-Specific IgG Antibodies and Neutralizing Antibodies.

Panel A shows the correlation between S-specific IgG antibody levels and neutralizing antibody levels for the before-booster data, as assessed with PRNT₅₀ (Spearman’s rank correlation coefficient, 0.82). Linear regression (diagonal lines) on log-transformed data was performed (beta coefficient, 0.90; 95% CI, 0.82 to 0.98). The gray shaded areas indicate the 95% CI of the best-fit line. Panel B shows the correlation between S-specific IgG antibody levels and neutralizing antibody levels for the after-booster data (Spearman’s rank correlation coefficient, 0.93). Linear regression (diagonal lines) on log-transformed data was performed (beta coefficient, 0.72; 95% CI, 0.68 to 0.76). The gray shaded areas indicate the 95% CI of the best-fit line. Each dot in the figure represents an individual participant.

Figure 4. Severity of Systemic and Local Reactions after Booster Vaccination.

Panel A shows the percentage of participants with systemic reactions (fatigue, chills, fever, nausea, headache, muscle aches, or joint pain), and Panel B shows the percentage of participants with local reactions (redness, swelling, or pain at the injection site) after booster vaccination. These reactions were monitored in the 7 days after the administration of the booster. P values for the between-group differences in the distribution of adverse events are shown in Table S7.