Safety and immunogenicity of the Ad26.COV2.S COVID-19 vaccine candidate: interim results of a phase 1/2a, double-blind, randomized, placebo-controlled trial

Abstract

BACKGROUND The ongoing coronavirus disease (COVID)-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be controlled by an efficacious vaccine. Multiple vaccines are in development, but no efficacious vaccine is currently available. METHODS We designed a multi-center phase 1/2a randomized, double-blinded, placebo-controlled clinical study to assesses the safety, reactogenicity and immunogenicity of Ad26.COV2.S, a non-replicating adenovirus 26 based vector expressing the stabilized pre-fusion spike (S) protein of SARS-CoV-2. Ad26.COV2.S was administered at a dose level of 5x1010 or 1x1011 viral particles (vp) per vaccination, either as a single dose or as a two-dose schedule spaced by 56 days in healthy adults (18-55 years old; cohort 1a & 1b; n= 402 and healthy elderly >65 years old; cohort 3; n=394). Vaccine elicited S specific antibody levels were measured by ELISA and neutralizing titers were measured in a wild-type virus neutralization assay (wtVNA). CD4+ T-helper (Th)1 and Th2, and CD8+ immune responses were assessed by intracellular cytokine staining (ICS). RESULTS We here report interim analyses after the first dose of blinded safety data from cohorts 1a, 1b and 3 and group unblinded immunogenicity data from cohort 1a and 3. In cohorts 1 and 3 solicited local adverse events were observed in 58% and 27% of participants, respectively. Solicited systemic adverse events were reported in 64% and 36% of participants, respectively. Fevers occurred in both cohorts 1 and 3 in 19% (5% grade 3) and 4% (0% grade 3), respectively, were mostly mild or moderate, and resolved within 1 to 2 days after vaccination. The most frequent local adverse event (AE) was injection site pain and the most frequent solicited AEs were fatigue, headache and myalgia. After only a single dose, seroconversion rate in wtVNA (50% inhibitory concentration - IC50) at day 29 after immunization in cohort 1a already reached 92% with GMTs of 214 (95% CI: 177; 259) and 92% with GMTs of 243 (95% CI: 200; 295) for the 5x1010 and 1x1011vp dose levels, respectively. A similar immunogenicity profile was observed in the first 15 participants in cohort 3, where 100% seroconversion (6/6) (GMTs of 196 [95%CI: 69; 560]) and 83% seroconversion (5/6) (GMTs of 127 [95% CI: <58; 327]) were observed for the 5x1010 or 1x1011 vp dose level, respectively. Seroconversion for S antibodies as measured by ELISA (ELISA Units/mL) was observed in 99% of cohort 1a participants (GMTs of 528 [95% CI: 442; 630) and 695 (95% CI: 596; 810]), for the 5x1010 or 1x1011 vp dose level, respectively, and in 100% (6/6 for both dose levels) of cohort 3 with GMTs of 507 (95% CI: 181; 1418) and 248 (95% CI: 122; 506), respectively. On day 14 post immunization, Th1 cytokine producing S-specific CD4+ T cell responses were measured in 80% and 83% of a subset of participants in cohort 1a and 3, respectively, with no or very low Th2 responses, indicative of a Th1-skewed phenotype in both cohorts. CD8+ T cell responses were also robust in both cohort 1a and 3, for both dose levels. CONCLUSIONS The safety profile and immunogenicity after only a single dose are supportive for further clinical development of Ad26.COV2.S at a dose level of 5x1010 vp, as a potentially protective vaccine against COVID-19. Trial registration number: NCT04436276

Immunogenicity and protective efficacy of one- and two-dose regimens of the Ad26.COV2.S COVID-19 vaccine candidate in adult and aged rhesus macaques

“…Although humoral immune responses were significantly higher in NHP that received the 1x10 11 vp dose as compared to recipients of the 5x10 10 vp vaccine dose, differences in neutralizing antibody levels decreased over time and do not suggest a clear benefit of the higher dose, in agreement with interim Phase 1/2a clinical data (Sadoff et al, 2020).…”

Phase 1/2 trial of SARS-CoV-2 vaccine ChAdOx1 nCoV-19 with a booster dose induces multifunctional antibody responses

“…Antibodies against the ChAdOx1 vector are induced by the first vaccination but do not prevent boosting and are not further increased by the second vaccination with either a 4-week or 8-week interval. These observations are also important for further development of viral vectors in general, particularly as multiple vaccines are being developed that use the same viral vectors as those in development for SARS-CoV-2 vaccines, including Ad26, Ad5 and ChAdOx1 2,3,[25][26][27] . T cell responses, here measured by IFN-γ ELISpot, were induced rapidly after vaccination and are well maintained in all dosing regimens and intervals between vaccinations.…”

Efficacy and safety of COVID-19 vaccines in older people

“…Use of genetically modified organisms as vaccines dates back to the early 1980s [ 6 ] and has the advantage that the safety of the adenovirus vector at low doses is well established and likely to be transferable to new vaccines, although the vector has never been used in large numbers of older people with frailty. Janssen’s phase II trial included just 15 participants aged 65 and over, with rates of adverse events lower (36%) than in younger people (64%) [ 7 ]. More robust Phase II safety data have been published for the AstraZeneca vaccine, including 200 people aged 70 or over without severe comorbidities or frailty [ 8 ].…”