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Interim Results of a Phase 1–2a Trial of Ad26.COV2.S Covid-19 Vaccine
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Design
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Randomized, multicenter, double-blind, placebo-controlled, phase 1/2a clinical trial
N=805
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Objective
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To evaluate the safety, reactogenicity, and immunogenicity of Ad26.COV2.S, a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector encoding a full-length and stabilized SARS-CoV-2 spike (S) protein
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Study Groups
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Younger cohort (n=402)
Low-dose (n=162)
High-dose (n=158)
Placebo (n=82)
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Older cohort (n=403)
Low-dose (n=161)
High-dose (n=161)
Placebo (n=81)
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Inclusion Criteria
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healthy adults (considered to in good or stable health if underlying illness is present); aged 18-55 years or ≥65 years; body mass index <40 mg/k2; females with a negative pregnancy test |
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Exclusion Criteria
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Clinically significant acute illness or fever (≥38 °C) within 24 hours before first dose; history of malignancy within 5 years before screening; known allergy or history of anaphylaxis or other serious adverse reactions to vaccines or their excipients; abnormal immune system due to clinical conditions (e.g., autoimmune disease or immunodeficiency); Chronic (>10 days) or recurrent use of systemic corticosteroids within 6 months; administration of antineoplastic and immunomodulating agents or radiotherapy within 6 months; history of acute polyneuropathy; plans to receive a live vaccine within 28 days of planned administration or other vaccines within 14 days of planned administration; diagnosis of HIV infection
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Methods
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Participants were randomized to one of five vaccination groups: low dose followed by low dose, low dose followed by placebo, high dose followed by high dose, high dose followed by placebo, and placebo followed by placebo. Vaccinations were administered intramuscularly 56 days (2 months) apart. Data in the older population is only after the first vaccination.
The Ad26.COV2.S vaccine low-dose was 5×1010 viral particles/mL and the high-dose was 1×1011 viral particles/mL.
Immunogenicity was assessed using an enzyme-linked immunosorbent assay (ELISA) to measure SARS-CoV-2 S-specific binding antibodies. Seropositivity was defined as a titer above the lower limit of quantitation of the assay (50.3 EU[ELISA units]/mL). Seroconversion was measured from a random subgroup of participants in each group.
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Duration
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July 22 to October 30, 2020 (interim analysis); the study is still ongoing
Follow-up: 7, 28, and 71 days after vaccination
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Outcome Measures
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Primary: safety and reactogenicity of each dose schedule
Solicited local adverse events: erythema, pain, swelling
Solicited systemic adverse events: fatigue, headache, myalgia, nausea, pyrexia
Secondary: immunogenicity via humoral and cellular immunity to the SARS-CoV-2 S protein; seroconversion
Humoral immunity as reported as binding-antibody geometric mean concentration (GMC) against a full-length spike protein
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Baseline Characteristics
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Low-dose (n=323)
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High-dose (n=319)
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Placebo (n=163) |
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Age, years
Younger cohort
Older cohort
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36.1±10.1
69.6±4.0
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34.8±10.3
70.0±4.2
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35.4±10.0
69.9±3.7
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Female
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49.8% |
52.0% |
52.1% |
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White
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95.0% |
95.0% |
92.6% |
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Results
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Low-dose (n=323) |
High-dose (n=319) |
Placebo (n=163)
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Solicited local adverse events
Younger cohort
Older cohort
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64%
41%
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78%
42%
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9%
14%
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Solicited systemic adverse events
Younger cohort
Older cohort
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65%
46%
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84%
55%
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26%
23%
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Unsolicited adverse events
Younger cohort
Older cohort
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21%
17%
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35%
24%
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17%
16%
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The most solicited local adverse event was pain, and the most solicited systemic adverse events were fatigue, headache, and myalgia. Reactogenicity was lower after the second dose.
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Humoral immunogenicity, GMC (seroconversion): younger cohort
Day 1
Day 29
Day 57
Day 71
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<53
586 (99%)
754 (100%)
1677 (100%)
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<53
788 (100%)
1100 (100%)
2292 (100%)
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<53
<53
<53
<53
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Humoral immunogenicity, GMC (seroconversion): older cohort
Day 1
Day 15
Day 29
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<53
121 (75%)
312 (96%)
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<53
141 (77%)
350 (96%)
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<53
<53
<53
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A control of human convalescent plasma resulted in a GMC of 899 using the same ELISA.
The vaccine then placebo groups were similar to the two-dose vaccine groups, except the GMCs did not rise on day 71.
Neutralizing-antibody titers against wild-type virus were detected in 90% or more of all non-placebo participants on day 29. When compared to a wild-type virus neutralization assay, antibody levels were strongly correlated in both age groups; however, the older patients had a wider range, suggesting more variability in the relationship between the neutralizing-antibody titer and the binding-antibody titer in the older adults.
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Cellular immunity was seen via CD4+ T-cell responses were seen in 76-83% of younger patients and 60-67% of older patients by day 15. CD8+ T-cell responses were seen in 51-64% of younger patients and 24-36% (the low-dose group had 36%) of older patients by day 15.
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Adverse Events
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No grade 4 adverse events (solicited or unsolicited) were reported in any cohort. After the second dose among participants between the ages of 18 and 55 years, the incidence of grade 3 solicited systemic adverse events was much lower than that after the first immunization in both the low-dose and high-dose groups.
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Only one serious adverse event was deemed to be related to the vaccine: fever that resulted in hospitalization because of suspicion of Covid-19 (recovered within 12 hours). Other serious adverse events (deemed to be unrelated to vaccination) were: hypotension, bilateral nephrolithiasis, Legionella pneumonia, and worsening of multiple sclerosis.
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No participant discontinued the trial because of an adverse event.
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Study Author Conclusions
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The interim analysis of this phase 1/2a trial showed that the Ad26.COV2.S vaccine had an acceptable safety and reactogenicity profile and was immunogenic after a single vaccination with either the low or high dose.
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InpharmD Researcher Critique
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This is data from an interim analysis of a phase 1/2 study, as it is still ongoing. These results only represent the first dose for the older cohort. The participants of this study lack minority representation, which will likely be fulfilled in phase 3 studies.
This study only measured in vitro efficacy through the use of assays, so the clinical efficacy of this vaccine candidate cannot be established through this data. The ELISA used measured SARS-CoV-2 S protein-specific binding antibodies; however, there is no standard assay used. This means these results cannot be directly compared to studies using a different assay nor can the results be extrapolated to determine efficacy.
The comparison with a convalescent plasma sample is also arbitrary, since the reported titers have varied according to the composition of the panels (i.e., COVID-19 severity of the donors, time of sampling since disease onset, and other factors).
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