ABSTRACT
It is of interest to pinpoint SARS-CoV-2 sequence features defining vaccine resistance. In the ENSEMBLE randomized, placebo-controlled phase 3 trial, estimated single-dose Ad26.COV2.S vaccine efficacy (VE) was 56% against moderate to severe–critical COVID-19. SARS-CoV-2 Spike sequences were measured from 484 vaccine and 1,067 placebo recipients who acquired COVID-19 during the trial. In Latin America, where Spike diversity was greatest, VE was significantly lower against Lambda than against Reference and against all non-Lambda variants [family-wise error rate (FWER) p < 0.05]. VE also differed by residue match vs. mismatch to the vaccine-strain residue at 16 amino acid positions (4 FWER p < 0.05; 12 q-value ≤ 0.20). VE significantly decreased with physicochemical-weighted Hamming distance to the vaccine-strain sequence for Spike, receptor-binding domain, N-terminal domain, and S1 (FWER p < 0.001); differed (FWER ≤ 0.05) by distance to the vaccine strain measured by 9 different antibody-epitope escape scores and by 4 NTD neutralization-impacting features; and decreased (p = 0.011) with neutralization resistance level to vaccine recipient sera. VE against severe–critical COVID-19 was stable across most sequence features but lower against viruses with greatest distances. These results help map antigenic specificity of in vivo vaccine protection.
Subject(s)
COVID-19 , Encephalomyelitis, Acute DisseminatedABSTRACT
Anti-spike IgG binding antibody, anti-receptor binding domain IgG antibody, and pseudovirus neutralizing antibody measurements four weeks post-vaccination were assessed as correlates of risk of moderate to severe-critical COVID-19 outcomes through 83 days post-vaccination and as correlates of protection following a single dose of Ad26.COV2.S COVID-19 vaccine in the placebo-controlled phase of ENSEMBLE, an international, randomized efficacy trial. Each marker had evidence as a correlate of risk and of protection, with strongest evidence for 50% inhibitory dilution (ID50) neutralizing antibody titer. The outcome hazard ratio was 0.49 (95% confidence interval 0.29, 0.81; p=0.006) per 10-fold increase in ID50; vaccine efficacy was 60% (43, 72%) at nonquantifiable ID50 (< 2.7 IU50/ml) and rose to 89% (78, 96%) at ID50 = 96.3 IU50/ml. Comparison of the vaccine efficacy by ID50 titer curves for ENSEMBLE-US, the COVE trial of the mRNA-1273 vaccine, and the COV002-UK trial of the AZD1222 vaccine supported consistency of the ID50 titer correlate of protection across trials and vaccine types.
Subject(s)
COVID-19ABSTRACT
BackgroundDespite the availability of effective vaccines against coronavirus disease 2019 (Covid-19), the emergence of variant strains and breakthrough infections pose a challenging new reality. Booster vaccinations are needed to maintain vaccine-induced protection. MethodsENSEMBLE2 is an ongoing, randomized, double-blind, placebo-controlled, phase 3 pivotal trial including crossover vaccination after emergency authorization of Covid-19 vaccines. Adults aged [≥]18 years were randomized to receive Ad26.COV2.S or placebo as a primary dose plus a booster dose at two months. The primary endpoint was vaccine efficacy against the first occurrence of molecularly-confirmed moderate to severe-critical Covid-19 with onset [≥]14 days after booster vaccination in the per-protocol population. Key efficacy, safety, and immunogenicity endpoints were also assessed. ResultsThe double-blind phase enrolled 31,300 participants, 14,492 of whom received 2 doses and were evaluable for efficacy (per-protocol set, Ad26.COV2.S n=7484; placebo n=7008). Baseline demographics and characteristics were balanced. Vaccine efficacy was 75.2% (adjusted 95% CI, 54.6-87.3) against moderate to severe-critical Covid-19 and was similar against symptomatic infection (75.6% [55.5-99.9]). Efficacy was consistent across participants with and without comorbidities, and reached 93.7% (58.5-99.9) in the US. Vaccine efficacy against severe-critical Covid-19 was 100% (32.6-100.0; 0 vs 8 cases). The booster vaccine induced robust humoral responses and exhibited an acceptable safety profile. ConclusionsA homologous Ad26.COV2.S booster administered 2 months after primary single-dose vaccination in adults led to high vaccine efficacy, including against any symptomatic infection and SARS-CoV-2 variants prevalent during the study. (Funding: Janssen Research and Development and others; ENSEMBLE2 ClinicalTrials.gov number, NCT04614948.)
Subject(s)
COVID-19 , Breakthrough Pain , Protein S DeficiencyABSTRACT
BackgroundWe evaluated the durability of SARS-CoV-2 antibody levels elicited by the single dose Janssen COVID-19 vaccine, Ad26.COV2.S, and the impact on antibody responses of boosting with Ad26.COV2.S after 6 months in clinical trial participants. MethodsSpike-binding antibody and SARS-CoV-2 neutralizing antibody levels elicited by a single-dose Ad26.COV2.S (5x1010 viral particles [vp]) primary regimen and booster doses (5x1010 vp and 1.25x1010 vp) were assessed by ELISA and wild-type VNA in sera from participants in a Phase 1/2a clinical trial (Cohort 1a, 18-55 years old, N=25; Cohort 2a, 18-55 years old boosted at 6 months, N=17; Cohort 3, [≥]65 years old, N=22) and a Phase 2 clinical trial (18-55 and [≥]65-year old participants boosted at 6 months, total N=73). Neutralizing antibody levels were determined approximately 8 months after the primary vaccination in participants aged 18-55 years and approximately 9 months in participants aged [≥]65 years. Binding antibody levels were evaluated 6 months after primary vaccination and 7- and 28-days after booster doses in both age groups. ResultsA single dose of Ad26.COV2.S elicited neutralizing antibodies that remained largely stable for approximately 8-9 months and binding antibodies that remained stable for at least 6 months irrespective of age group. A 5x1010 vp booster dose at 6 months post prime vaccination in 18-55-year-old adults elicited a steep and robust 9-fold increase at Day 7 post boost compared to Day 29 levels following the initial immunization. A lower booster dose of 1.25x1010 vp at 6 months in adults 18-55 and [≥]65 years of age also elicited a rapid and high increase of 6-7.7 fold at Day 28 post boost compared to Day 29 levels following the initial immunization, with similar magnitude of post-boost responses in both age groups. ConclusionsA single dose of Ad26.COV2.S, which demonstrated protection in a Phase 3 efficacy trial, elicited durable neutralizing and binding antibodies for at least 8 and 6 months, respectively, in adults >18 years of age at levels similar to Day 29 responses. A 5x1010 vp or 1.25x1010 vp booster dose at 6 months elicited rapid and robust increases in spike binding antibody levels. The anamnestic responses after booster immunization imply robust immune memory elicited by single-dose Ad26.COV2.S.
Subject(s)
COVID-19 , Protein S DeficiencyABSTRACT
Interim immunogenicity and efficacy data for the Ad26.COV2.S vaccine for COVID-19 have recently been reported. We describe here the 8-month durability of humoral and cellular immune responses in 20 individuals who received one or two doses of 5x10^10 vp or 10^11 vp Ad26.COV2.S and in 5 participants who received placebo. We evaluated antibody and T cell responses on day 239, which was 8 months after the single-shot vaccine regimen (N=10) or 6 months after the two-shot vaccine regimen (N=10), although the present study was not powered to compare these regimens. We also report neutralizing antibody responses against the parental SARS-CoV-2 WA1/2020 strain as well as against the SARS-CoV-2 variants D614G, B.1.1.7 (alpha), B.1.617.1 (kappa), B.1.617.2 (delta), P.1 (gamma), B.1.429 (epsilon), and B.1.351 (beta).
Subject(s)
COVID-19ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve and recently emerging variants with substitutions in the Spike protein have led to growing concerns over increased transmissibility and decreased vaccine coverage due to immune evasion. Here, sera from recipients of a single dose of our Ad26.COV2.S COVID-19 vaccine were tested for neutralizing activity against several SARS-CoV-2 variants of concern. All tested variants demonstrated susceptibility to Ad26.COV2.S-induced serum neutralization albeit mainly reduced as compared to the B.1 strain. Most pronounced reduction was observed for the B.1.351 (Beta; 3.6-fold) and P.1 (Gamma; 3.4-fold) variants that contain similar mutations in the receptor-binding domain (RBD) while only a 1.6-fold reduction was observed for the widely spreading B.1.617.2 (Delta) variant.
Subject(s)
Coronavirus Infections , COVID-19ABSTRACT
The emergence of SARS-CoV-2 variants, such as 501Y.V2, with immune evasion mutations in the spike has resulted in reduced efficacy of several COVID-19 vaccines. However, the efficacy of the Ad26.COV2.S vaccine, when tested in South Africa after the emergence of 501Y.V2, was not adversely impacted. We therefore assessed the binding and neutralization capacity of n=120 South African sera (from Day 29, post-vaccination) from the Janssen phase 3 study, Ensemble. Spike binding assays using both the Wuhan-1 D614G and 501Y.V2 Spikes showed high levels of cross-reactivity. In contrast, in a subset of 27 sera, we observed significantly reduced neutralization of 501Y.V2 compared to Wuhan-1 D614G, with 22/27 (82%) of sera showing no detectable neutralization of 501Y.V2 at Day 29. These data suggest that even low levels of neutralizing antibodies may contribute to protection from moderate/severe disease. In addition, Fc effector function and T cells may play an important role in protection by this vaccine against 501Y.V2.
Subject(s)
COVID-19ABSTRACT
The first COVID-19 vaccines have recently gained authorization for emergency use.1,2 At this moment, limited knowledge on duration of immunity and efficacy of these vaccines is available. Data on other coronaviruses after natural infection suggest that immunity to SARS-CoV-2 might be short lived,3,4 and preliminary evidence indicates waning antibody titers following SARS-CoV-2 infection.5 Here we model the relationship between immunogenicity and protective efficacy of a series of Ad26 vectors encoding stabilized variants of the SARS-CoV-2 Spike (S) protein in rhesus macaques6,7,8 and validate the analyses by challenging macaques 6 months after immunization with the Ad26.COV2.S vaccine candidate that has been selected for clinical development. We find that Ad26.COV2.S confers durable protection against replication of SARS-CoV-2 in the lungs that is predicted by the levels of S-binding and neutralizing antibodies. These results suggest that Ad26.COV2.S could confer durable protection in humans and that immunological correlates of protection may enable the prediction of durability of protection.
Subject(s)
COVID-19 , Severe Acute Respiratory SyndromeABSTRACT
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