Durable antibody responses elicited by 1 dose of Ad26.COV2.S and substantial increase after boosting: 2 randomized clinical trials

Jerald Sadoff, Mathieu Le Gars, Boerries Brandenburg, Vicky Cárdenas, Georgi Shukarev, Nathalie Vaissiere, Dirk Heerwegh, Carla Truyers, Anne Marit de Groot, Mandy Jongeneelen, Krisztian Kaszas, Jeroen Tolboom, Gert Scheper, Jenny Hendriks, Javier Ruiz-Guiñazú, Frank Struyf, Johan Van Hoof, Macaya Douoguih, Hanneke Schuitemaker, Jerald Sadoff, Mathieu Le Gars, Boerries Brandenburg, Vicky Cárdenas, Georgi Shukarev, Nathalie Vaissiere, Dirk Heerwegh, Carla Truyers, Anne Marit de Groot, Mandy Jongeneelen, Krisztian Kaszas, Jeroen Tolboom, Gert Scheper, Jenny Hendriks, Javier Ruiz-Guiñazú, Frank Struyf, Johan Van Hoof, Macaya Douoguih, Hanneke Schuitemaker

Abstract

Background: Ad26.COV2.S is a well-tolerated and effective vaccine against COVID-19. We evaluated durability of anti-SARS-CoV-2 antibodies elicited by single-dose Ad26.COV2.S and the impact of boosting.

Methods: In randomized, double-blind, placebo-controlled, phase 1/2a and phase 2 trials, participants received single-dose Ad26.COV2.S (5 × 1010 viral particles [vp]) followed by booster doses of 5 × 1010 vp or 1.25 × 1010 vp. Neutralizing antibody levels were determined by a virus neutralization assay (VNA) approximately 8-9 months after dose 1. Binding and neutralizing antibody levels were evaluated by an enzyme-linked immunosorbent assay and pseudotyped VNA 6 months after dose 1 and 7 and 28 days after boosting.

Results: Data were analyzed from phase 1/2a participants enrolled from 22 July-18 December 2020 (Cohort 1a, 18-55 years [y], N = 25; Cohort 2a, 18-55y, N = 17; Cohort 3, ≥65y, N = 22), and phase 2 participants from 14 to 22 September 2020 (18-55y and ≥ 65y, N = 73). Single-dose Ad26.COV2.S elicited stable neutralizing antibodies for at least 8-9 months and stable binding antibodies for at least 6 months, irrespective of age. A 5 × 1010 vp 2-month booster dose increased binding antibodies by 4.9- to 6.2-fold 14 days post-boost versus 28 days after initial immunization. A 6-month booster elicited a steep and robust 9-fold increase in binding antibody levels 7 days post-boost. A 5.0-fold increase in neutralizing antibodies was observed by 28 days post-boost for the Beta variant. A 1.25 × 1010 vp 6-month booster elicited a 3.6-fold increase in binding antibody levels at 7 days post-boost versus pre-boost, with a similar magnitude of post-boost responses in both age groups.

Conclusions: Single-dose Ad26.COV2.S elicited durable antibody responses for at least 8 months and elicited immune memory. Booster-elicited binding and neutralizing antibody responses were rapid and robust, even with a quarter vaccine dose, and stronger with a longer interval since primary vaccination.

Trial registration: ClinicalTrials.gov Identifier: NCT04436276, NCT04535453.

Keywords: Ad26.COV2.S; Antibody; COVID-19; Enzyme-linked immunosorbent assay; Vaccine; Virus neutralization assay.

Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors are employees of Janssen Pharmaceuticals, a Johnson & Johnson company, and may hold shares in Johnson & Johnson.

Copyright © 2022. Published by Elsevier Ltd.

Figures

Fig. 1
Fig. 1
CONSORT diagrams for participants who received Ad26.COV2.S (phase 1/2a and phase 2 trials). Participants in (A) Cohort 1a, (B) Cohort 2a, and (C) Cohort 3 of COV1001 received a single dose of Ad26.COV2.S 5 × 1010 vp; participants in Cohort 2a received a booster dose of 5 × 1010 vp 6 months after the first vaccination. (D) Participants in COV2001 received a single dose of Ad26.COV2.S 5 × 1010 vp and a booster of 5 × 1010 vp at 2 months post-dose 1 (Group 1), placebo at 2 months post-dose 1 (Group 5), 5 × 1010 vp 1 month post-dose 1 (Group 7), and 5 × 1010 vp 3 months post-dose 1 (Group 9); all groups received a lower-dose booster of 1.25 × 1010 vp 6 months after dose 1. N/E, not evaluated; psVNA, pseudotyped virus neutralization assay; S-ELISA, spike protein enzyme-linked immunosorbent assay; vp, viral particles; wtVNA, wild-type virus neutralization assay.
Fig. 2
Fig. 2
Summary of immunogenicity data according to cohort (phase 1/2a and phase 2 trials). The schematic shows available immune response durability data (neutralizing and/or binding antibody data) from each study cohort in COV1001 and COV2001. (A) For single-dose 5 × 1010 vp Ad26.COV2.S, neutralizing antibody response data were available from COV1001 Cohorts 1 and 3 and COV2001 participants aged 18–55 years and ≥ 65 years; spike-binding antibody response data were available for COV1001 Cohort 2a and both COV2001 age groups. (B) After a homologous boost with Ad26.COV2.S at the 5 × 1010 vp dose level, neutralizing antibody response data were available for COV1001 Cohort 2a; spike-binding data were available from COV1001 Cohort 2a and from both age groups of COV2001. (C) After a lower-dose boost with Ad26.COV2.S at the 1.25 × 1010 vp dose level, spike-binding antibody data were available from COV2001 participants in both age groups. The number of participants with available data (and corresponding time point) is shown above the line that indicates neutralizing or binding antibody data. psVNA, pseudotyped virus neutralization assay; S-ELISA, spike protein enzyme-linked immunosorbent assay; vp, viral particles; wtVNA, wild-type virus neutralization assay.
Fig. 3
Fig. 3
Durability of neutralizing antibody responses following a single dose of Ad26.COV2.S (5 × 1010 vp) (phase 1/2a and phase 2 trials). Phase 1/2a participants, aged 18–55 years (Cohort 1a) and aged ≥ 65 years (Cohort 3), were administered a single dose of Ad26.COV2.S (5 × 1010 vp) at Day 1. (A) Serum neutralizing antibody responses against SARS-CoV-2 were evaluated by wtVNA up to 8–9 months after the dose 1, in subsets of participants aged 18–55 years (N = 25; 22 with available data at Day 239; blue line) and ≥ 65 years (N = 24; 19 with available data at Day 268; black line). (B) Phase 2 participants, aged 18–55 years and ≥ 65 years, were administered a single dose of Ad26.COV2.S (5 × 1010 vp) at Day 1. Serum neutralizing antibody responses against SARS-CoV-2 were evaluated by wtVNA up to 6 months after dose 1 in subsets of participants aged 18–55 years (N = 22; blue line) and ≥ 65 years (N = 15; black line). GMTs are depicted above each time point, and response rates are illustrated at the bottom of each panel. In all panels, error bars represent 95% CIs. CI, confidence interval; GMT, geometric mean titer; LLOQ, lower limit of quantification; vp, viral particles; wtVNA, wild-type virus neutralization assay.
Fig. 4
Fig. 4
Durability of spike-binding antibody responses 6 months after first vaccination and impact of a 6-month booster dose on binding and neutralizing antibodies (phase 1/2a trial). Phase 1/2a participants aged 18–55 years (N = 27) were administered a single dose of Ad26.COV2.S (5 × 1010 vp) at Day 1, and 20 participants received a booster dose of Ad26.COV2.S (5 × 1010 vp) at approximately 6 months (Day 183) after the first vaccination; 17 participants had data available at Day 190. Only participants with booster data available were included in these analyses. (A) Serum spike-binding antibodies against SARS-CoV-2 were evaluated in a validated S-ELISA up to 28 days post-boost (Day 211). Participants aged 18–55 years are represented with a blue line. GMCs are depicted above each time point (error bars represent 95% CIs), and response rates are illustrated at the bottom of the panel. The asterisk denotes geometric mean increase. (B) Serum (N = 17) neutralizing antibody titers were evaluated via validated psVNA against the B.1 (D614G) reference strain and B.1.351 (Beta) variant at Days 1, 29, 183, 190, and 211. Arrows above the graph indicate GMI for Day 211 versus Day 183 and GMR for Day 211 versus Day 29. (C) Serum (N = 17) neutralizing antibody titers against the B.1 (D614G), B.1.617.2 (Delta), C.37 (Lambda), P.1 (Gamma), and Beta variants were evaluated via pre-qualified psVNA at Days 183, 190, and 211. The log10 GMTs per visit per strain were estimated in a Tobit model with subject, visit, strain, and interactions as factors. One participant who was missing data for Day 211 was excluded. With heavy censoring, the estimated GMT is below the LOD. Adjusting for censoring revealed good proportionality. The average GMT fold increase for all variants is indicated above the graph for Days 183–211 and Days 183–190. In all panels, error bars represent 95% CIs. CI, confidence interval; GMC, geometric mean concentration; GMT, geometric mean titer; ID50, serum dilution conferring 50% inhibition; LLOQ, lower limit of quantification; LOD, limit of detection; psVNA, pseudotyped virus neutralization assay; S-ELISA, spike protein enzyme-linked immunosorbent assay; vp, viral particles.
Fig. 5
Fig. 5
Durability of spike-binding antibody responses 6 months after first vaccination and responses 7 and 28 days after boosting (phase 2 trial). Phase 2 participants aged 18–55 years (N = 44; blue line) and ≥ 65 years (N = 29; black line) were administered a single dose of Ad26.COV2.S (5 × 1010 vp) at Day 1 and 73 received a booster dose of Ad26.COV2.S (1.25 × 1010 vp) at approximately 6 months (Day 169) after dose 1. Serum spike-binding antibody responses against SARS-CoV-2 were evaluated by validated S-ELISA up to 28 days after the booster dose (Day 197). GMCs are depicted above each time point (error bars represent 95% CIs), and response rates are illustrated at the bottom of each panel. CI, confidence interval; GMC, geometric mean concentration; LLOQ, lower limit of quantification; S-ELISA, spike protein enzyme-linked immunosorbent assay; vp, viral particles.

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