Participants
From July 22 to August 7, 2020, a total of 593 persons underwent screening for enrollment in cohort 1 (including 1a and 1b combined) (Fig. S1). Of these persons, 405 were enrolled and 402 received the first dose of Ad26.COV2.S; these participants had received the second dose by November 7, 2020. From August 3 to August 24, 2020, a total of 660 persons underwent screening for cohort 3. Of these participants, 405 were enrolled and 403 received the first dose of Ad26.COV2.S. (Details regarding age distribution are provided in Table S2.) Analyses of data obtained from participants in cohort 3 after the administration of the second dose, as well as durability and longer-term safety data, are ongoing.
Characteristics of the Participants at Baseline.
At baseline, the percentage of participants who were seropositive for SARS-CoV-2 S-specific antibodies was 2% in cohort 1a and 1% in cohort 3. The baseline characteristics of the participants were broadly similar across the groups (Table 1).
Vaccine Safety and Reactogenicity
Solicited Adverse Events in Cohorts 1 and 3 after the First Vaccine Dose.
Shown are solicited adverse events in participants who received the Ad26.COV2.S vaccine at a dose of 5×1010 viral particles (low dose) or 1×1011 viral particles (high dose) per milliliter or placebo. Healthy adults between the ages of 18 and 55 years were included in cohort 1 (Panel A), and those 65 years of age or older were included in cohort 3 (Panel B). The younger group was divided into cohorts 1a and 1b, with the latter designated as an exploratory cohort for in-depth analysis of immunogenicity. As shown here, data for cohorts 1a and 1b have been pooled. Data for patients in cohort 1a who received a second dose of vaccine are provided in Figure S2 in the Supplementary Appendix.
Data regarding both solicited and unsolicited adverse events and serious adverse events were available for more than 99% of the participants who returned diary cards. The investigator’s assessment of reactogenicity after the administration of the first dose of vaccine was available for 402 participants in cohort 1 and for 403 participants in cohort 3. In the two cohorts, solicited local adverse events were mostly of grade 1 or 2; the most frequent event was injection-site pain. In cohort 1, solicited local adverse events were reported in 103 of 162 low-dose recipients (64%), in 123 of 158 high-dose recipients (78%), and in 7 of 82 placebo recipients (9%) (Figure 1A and Table S3). In cohort 3, solicited local adverse events were reported in 66 of 161 low-dose recipients (41%), in 68 of 161 high-dose recipients (42%), and in 11 of 81 placebo recipients (14%) (Figure 1B).
In the two cohorts, most solicited systemic adverse events were of grade 1 or 2; the most frequent events were fatigue, headache, and myalgia. In cohort 1, solicited systemic adverse events were reported in 105 low-dose recipients (65%), in 133 high-dose recipients (84%), and in 21 placebo recipients (26%). In cohort 3, solicited systemic adverse events were reported in 74 low-dose recipients (46%), in 88 high-dose recipients (55%), and in 19 placebo recipients (23%).
In cohort 1, solicited grade 3 systemic adverse events were reported in 15 low-dose recipients (9%) and in 32 high-dose recipients (20%); no placebo recipients reported such events. In cohort 1a, among the participants between the ages of 18 and 30 years who had one or more solicited grade 3 adverse events, 24% had received the low dose and 26% had received the high dose; in those between the ages of 31 and 45 years, the corresponding percentages were 43% and 14%; and in those between the ages of 46 and 55 years, the corresponding percentages were 3% and 11%. In cohort 3, grade 3 solicited systemic adverse events were reported in 1 low-dose recipient (1%) and in 4 high-dose recipients (2%); no placebo recipients reported having such events.
In cohort 1, fever was reported in 25 low-dose recipients (15%) and in 62 high-dose recipients (39%); grade 3 fever (temperature range, 39.0 to 40.0°C) was reported in 8 low-dose recipients (5%) and in 15 high-dose recipients (9%). In cohort 3, fever was reported in 7 low-dose recipients (4%) and in 14 high-dose recipients (9%); grade 3 fever was reported in no low-dose recipients and in 2 high-dose recipients (1%). No participants in the placebo group in either cohort reported having fever. All cases of fever occurred within 2 days after immunization and resolved within 1 or 2 days; more than 80% of the participants with fever received an antipyretic drug at the onset of symptoms.
In cohort 1, unsolicited adverse events were reported in 34 low-dose recipients (21%), in 56 high-dose recipients (35%), and in 14 placebo recipients (17%). In cohort 3, unsolicited adverse events were reported in 27 low-dose recipients (17%), in 38 high-dose recipients (24%), and in 13 placebo recipients (16%) (Table S4). No grade 4 adverse events (solicited or unsolicited) were reported in any cohort.
In cohort 1a, safety data after the administration of the second dose of vaccine were available for 363 participants (Fig. S2). One or more solicited adverse events were noted in 77% and 80% of the participants in the low-dose and high-dose groups, respectively, as compared with 34% and 31% of those who received placebo as a second dose after a first dose of vaccine and in 22% of those who received placebo for both doses. Solicited adverse events of grade 3 or higher were noted in 1% of low-dose recipients and in 7% of high-dose recipients; the corresponding percentages were 1% and 2% among participants in the placebo group who received a first dose of vaccine and in no participants who received placebo for both doses. No grade 3 fevers were reported in any group after a second dose of vaccine.
No participant discontinued the trial because of an adverse event. Five serious adverse events occurred: one case of hypotension that was deemed by the investigator to be unrelated to the vaccine because of a history of recurrent hypotension; one case of bilateral nephrolithiasis in a participant with a history of kidney stones (not related); one case of legionella pneumonia (not related); one worsening of multiple sclerosis, which had remained undiagnosed for approximately 8 to 10 years on the basis of findings on magnetic resonance imaging (not related); and one case of fever that resulted in hospitalization because of suspicion of Covid-19. In the last case, the participant recovered within 12 hours, and the fever was subsequently deemed by the investigator to be related to the vaccine. Details regarding all safety data are provided in the Supplementary Appendix.
Immunogenicity and Seroconversion
Humoral Immunogenicity.
Shown are measures of humoral immunogenicity in serum samples obtained from the participants in cohort 1a (left side) and cohort 3 (right side), according to the receipt of the low or high dose of Ad26.COV2.S or placebo. In cohort 1a, the participants received two injections of high-dose or low-dose vaccine or placebo, as indicated with slashes (e.g., placebo/placebo if they received two injections of placebo). The samples were measured on enzyme-linked immunosorbent assay (ELISA) in ELISA units (EU) per milliliter (Panel A) and on wild-type virus neutralization assay, with seropositivity defined as a half maximal inhibitory concentration (IC50) titer of more than 58 at the lower limit of quantitation (Panel B). Logarithmic values are reported as the geometric mean concentration (GMC) in the ELISA analyses and as the geometric mean titer (GMT) in the neutralizing-antibody analyses. The values were measured at baseline and at day 29 after vaccination in all the participants and on days 57 and 71 in those in cohort 1a. The two horizontal dotted lines in each panel indicate the lower and upper limits of quantitation of the respective assay; values below the lower line have been imputed to half the lower limit of quantitation. 𝙸 bars indicate 95% confidence intervals. HCS denotes human convalescent serum.
Immunogenicity data for this interim analysis were unblinded according to dose level. In all five groups in cohort 1a, the binding-antibody geometric mean concentration (GMC), as reported in ELISA units per milliliter, was measured against a stabilized SARS-CoV-2 full-length spike protein. At baseline, the GMC values in all the participants were lower than the lower limit of quantitation. By day 29 after vaccination, the values had increased to 478 (95% confidence interval [CI], 379 to 603) in the low-dose/placebo group, 586 (95% CI, 445 to 771) in the low-dose/low-dose group, 625 (95% CI, 505 to 773) in the high-dose/placebo group, and 788 (95% CI, 628 to 988) in the high-dose/high-dose group, with an incidence of seroconversion of 99% or more in all the groups (Figure 2A and Fig. S3A). By day 57, the corresponding GMC values had further increased to 660 (95% CI, 513 to 849), 754 (95% CI, 592 to 961), 873 (95% CI, 701 to 1087), and 1100 (95% CI, 908 to 1332). After the first dose, the incidence of seroconversion was 100% in all but the high-dose/placebo group (97%). Fourteen days after the second dose, the GMC was 1677 (95% CI, 1334 to 2109) in the low-dose/low-dose group and 2292 (95% CI, 1846 to 2845) in the high-dose/high-dose group, with 100% seroconversion in each group. On day 71, in the low-dose/placebo and high-dose/placebo groups, the GMC was 600 (95% CI, 443 to 814) and 951 (95% CI, 696 to 1,300), respectively, values that were similar to those on day 57.
In cohort 3, the GMCs in all the participants were also below the lower limit of quantitation at baseline. By day 15 after vaccination, the GMC had increased to 122 (95% CI, 97 to 152) in the low-dose group and to 141 (95% CI, 114 to 175) in the high-dose group, with a seroconversion incidence of 75% and 77%, respectively. By day 29, the GMC was 312 (95% CI, 246 to 396) in the low-dose group and 350 (95% CI, 281 to 429) in the high-dose group, with 96% seroconversion.
The SARS-CoV-2 neutralizing-antibody titer (IC50) was measured in a random subgroup of participants in cohorts 1a and 3. In cohort 1a, the geometric mean titer (GMT) was below the lower limit of quantitation at baseline and by day 29 after vaccination had increased to 224 (95% CI, 158 to 318) in the low-dose/placebo group, 224 (95% CI, 168 to 298) in the low-dose/low-dose group, 215 (95% CI, 169 to 273) in the high-dose/placebo group, and 354 (95% CI, 220 to 571) in the high-dose/high-dose group, with an incidence of seroconversion of 96%, 88%, 96%, and 92%, respectively (Figure 2B and Fig. S3B). By day 57, the GMT had further increased to 310 (95% CI, 228 to 422), 288 (95% CI, 221 to 376), 370 (95% CI, 268 to 511), and 488 (95% CI, 334 to 714), respectively, with a 100% incidence of seroconversion in the low-dose/placebo group and 96% seroconversion in the other groups.
In cohort 1a, 14 days after the second dose, the GMT was 827 (95% CI, 508 to 1183) in the low-dose/low-dose group and 1266 (95% CI, 746 to 2169) in the high-dose/high-dose group, with 100% seroconversion in the two dose groups. On day 71, the GMT was 321 (95% CI, 227 to 438) in the low-dose/placebo group and 388 (95% CI, 290 to 509) in the high-dose/placebo group, values that were similar to those on day 57; the incidence of seroconversion was 100% in both groups.
In cohort 3, the GMTs in all the participants were below the lower limit of quantitation at baseline and had increased to 212 (95% CI, 137 to 284) in the low-dose group and 172 (95% CI, 119 to 269) in the high-dose group on day 15 and to 277 (95% CI, 193 to 307) and 212 (95% CI, 163 to 266), respectively, on day 29. The incidence of seroconversion was 91% and 84%, respectively, on day 15 and 96% and 88%, respectively, on day 29. These data were confirmed on IC80 analysis (Fig. S4).
Antibody levels as measured on wild-type virus neutralization assay and ELISA were strongly correlated in the two cohorts (Fig. S5). However, the correlation had a wider elliptical shape in cohort 3, which suggested more variability in the relationship between the neutralizing-antibody titer and the binding-antibody titer in the older adults. Antibody levels in the different human convalescent serum panels that were included in assays for humoral-immunity assessment that were performed in different laboratories and in serum samples that were obtained from vaccine recipients were in the same range. Details regarding differences in values according to demographic characteristics are provided in Tables S5 and S6 in the Supplementary Appendix. Levels of Ad26 neutralizing antibodies at baseline or after the first dose of vaccine did not correlate with the levels of SARS-CoV-2 neutralizing antibodies on either day 29 or day 71 (Fig. S6).
S-Specific T-Cell Responses
Cellular Immunogenicity of Ad26.COV2.S.
In CD4+ T cells, the response to low-dose or high-dose vaccine or placebo in type 1 helper T (Th1) cells was characterized by the expression of interferon-γ, interleukin-2, or both, without cytokines expressed by type 2 helper T (Th2) cells (Panel A). The response in CD4+ Th2 cells was characterized by the expression of interleukin-4, interleukin-5, or interleukin-13 (or all three cytokines) plus CD40L (Panel B). In CD8+ T cells, the response was measured by the expression of interferon-γ, interleukin-2, or both (Panel C). In all three panels, the horizontal bars indicate median values on intracellular cytokine staining for individual responses to a SARS-CoV-2 S protein peptide pool in peripheral-blood mononuclear cells at baseline and 15 days after vaccination in a subgroup of participants in cohort 1a (left side) and cohort 3 (right side), according to the receipt of the low or high dose of Ad26.COV2.S or placebo. The horizontal dotted line in each panel indicates the lower limit of quantitation (LLOQ); values below the line have been imputed to half the LLOQ.
The vaccine-elicited responses in S-specific CD4+ Th1 and Th2 cells and in CD8+ T cells were assessed in a subgroup of participants at baseline and 15 days after the first dose. In cohort 1a, a Th1 response to S peptides was detected in 76% (95% CI, 65 to 86) of low-dose recipients and in 83% (95% CI, 73 to 91) of high-dose recipients; the corresponding values in cohort 3 were 60% (95% CI, 46 to 74) and 67% (95% CI, 53 to 79), respectively (Figure 3A). In cohort 1a, the median CD4+ Th1 response to S peptides increased from an undetectable level at baseline to a median of 0.08% (interquartile range [IQR], 0.05 to 0.16) in low-dose recipients and 0.11% (IQR, 0.07 to 0.16) in high-dose recipients on day 15; in cohort 3, the corresponding values were 0.09% (IQR, 0.04 to 0.17) and 0.11% (IQR, 0.04 to 0.15), respectively. A low-dose recipient in cohort 1a and a high-dose recipient in cohort 3 had a measurable Th2 response (Figure 3B). However, all the participants who had a measurable Th1 or Th2 response had a Th1:Th2 ratio that was well above 1, which indicated a vaccine-induced Th1-skewed response.
S-specific CD8+ T-cell responses, as identified by the expression of interferon-γ or interleukin-2 cytokines on S-peptide stimulation, were absent at baseline in the two cohorts (Figure 3C). On day 15 in cohort 1a, a CD8+ T-cell response was detected in 51% of participants (95% CI, 39 to 63) in the low-dose group and in 64% (95% CI, 52 to 75) in the high-dose group, with a median S-specific CD8+ T-cell response of 0.07% (IQR, 0.03 to 0.19) and 0.09% (IQR, 0.05 to 0.19), respectively. In cohort 3, CD8+ T-cell responses were lower, with an incidence of 36% (95% CI, 23 to 51) in the low-dose group and 24% (95% CI, 13 to 37) in the high-dose group, with a median response of 0.06% (IQR, 0.02 to 0.12) and 0.02% (IQR, 0.01 to 0.08), respectively. The correlation between CD4+ Th1 and CD8+ T-cell response was poor in the two cohorts (Fig. S7).
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