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In this study, investigators measured immune responses in 20 participants who had received either one or two doses of the Ad26.COV2.S vaccine and in 5 who had received placebo. A high level of neutralizing antibodies against SARS-CoV-2 was maintained for at least 8 months after single-dose injection, with a median decrease by a factor of 1.8 in the titer.

In this interim phase 1–2a trial of an adenovirus-based vaccine (Ad26.COV2.S), participants were divided into two age groups and received one or two injections of either a low-dose or high-dose vaccine or placebo. The vaccine elicited a local injection response in most patients and high titers of neutralizing antibodies in all vaccinated groups. In addition, T-cell responses were noted.

Ad26.COV2.S vaccine is a replication-incompetent human adenovirus type 26 vector containing the gene sequence that produces SARS-CoV-2 spike protein in a prefusion-stabilized conformation. In a randomized trial involving nearly 40,000 persons, vaccine efficacy was 66% against moderate to severe–critical Covid-19 and 85% against severe–critical Covid-19. Efficacy against the variant first identified in South Africa was 64% against moderate disease and 82% against severe–critical disease.

The Ad26.COV2.S vaccine 1 – 3 has demonstrated clinical efficacy against symptomatic COVID-19, including against the B.1.351 variant that is partially resistant to neutralizing antibodies 1 . However, the immunogenicity of this vaccine in humans against SARS-CoV-2 variants of concern remains unclear. Here we report humoral and cellular immune responses from 20 Ad26.COV2.S vaccinated individuals from the COV1001 phase I–IIa clinical trial 2 against the original SARS-CoV-2 strain WA1/2020 as well as against the B.1.1.7, CAL.20C, P.1 and B.1.351 variants of concern. Ad26.COV2.S induced median pseudovirus neutralizing antibody titres that were 5.0-fold and 3.3-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020 on day 71 after vaccination. Median binding antibody titres were 2.9-fold and 2.7-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020. Antibody-dependent cellular phagocytosis, complement deposition and natural killer cell activation responses were largely preserved against the B.1.351 variant. CD8 and CD4 T cell responses, including central and effector memory responses, were comparable among the WA1/2020, B.1.1.7, B.1.351, P.1 and CAL.20C variants. These data show that neutralizing antibody responses induced by Ad26.COV2.S were reduced against the B.1.351 and P.1 variants, but functional non-neutralizing antibody responses and T cell responses were largely preserved against SARS-CoV-2 variants. These findings have implications for vaccine protection against SARS-CoV-2 variants of concern. Analysis of the immunogenicity of the Ad26.COV2.S vaccine against the B1.351 and P.1 SARS-CoV-2 variants of concern shows reduced neutralization antibody titres, but comparable T cell responses and antibody-dependent effector functions.

•One dose of Ad26.COV2.S elicited high neutralizing and binding antibody levels.•Antibody levels persisted through 8 months (neutralizing) and 6 months (binding).•A homologous 6-month booster led to a rapid and robust increase in antibody titers.•Ad26.COV2.S elicited immune memory supporting anamnestic responses after boosting.•Ad26.COV2.S may provide sustained efficacy against reference and variant strains. 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. 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. 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. 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.

Without clinical efficacy data, vaccine protective effect may be extrapolated from animals to humans using an immunologic marker that correlates with protection in animals. This immunobridging approach was used for the two-dose Ebola vaccine regimen Ad26.ZEBOV, MVA-BN-Filo. Ebola virus (EBOV) glycoprotein binding antibody data obtained from 764 vaccinated healthy adults in five clinical studies (NCT02416453, NCT02564523, NCT02509494, NCT02543567, NCT02543268) were used to calculate mean predicted survival probability (with preplanned 95% confidence interval [CI]). We used a logistic regression model based on EBOV glycoprotein binding antibody responses in vaccinated non-human primates (NHPs) and NHP survival after EBOV challenge. While the protective effect of the vaccine regimen in humans can be inferred in this fashion, the extrapolated survival probability cannot be directly translated into vaccine efficacy. The primary immunobridging analysis evaluated the lower limit of the CI against predefined success criterion of 20% and passed with mean predicted survival probability of 53.4% (95% CI: 36.7–67.4).

A safe and effective vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be required to end the coronavirus disease 2019 (COVID-19) pandemic 1 – 8 . For global deployment and pandemic control, a vaccine that requires only a single immunization would be optimal. Here we show the immunogenicity and protective efficacy of a single dose of adenovirus serotype 26 (Ad26) vector-based vaccines expressing the SARS-CoV-2 spike (S) protein in non-human primates. Fifty-two rhesus macaques ( Macaca mulatta ) were immunized with Ad26 vectors that encoded S variants or sham control, and then challenged with SARS-CoV-2 by the intranasal and intratracheal routes 9 , 10 . The optimal Ad26 vaccine induced robust neutralizing antibody responses and provided complete or near-complete protection in bronchoalveolar lavage and nasal swabs after SARS-CoV-2 challenge. Titres of vaccine-elicited neutralizing antibodies correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate robust single-shot vaccine protection against SARS-CoV-2 in non-human primates. The optimal Ad26 vector-based vaccine for SARS-CoV-2, termed Ad26.COV2.S, is currently being evaluated in clinical trials. The protective efficacy of a single dose of adenovirus serotype 26 (Ad26) vector-based vaccine expressing the SARS-CoV-2 spike protein in non-human primates is demonstrated.

The randomized trial assessing the efficacy of a single injection of the Ad26.COV2.S showed 56.3% vaccine efficacy beginning 14 days after injection and 52.9% efficacy more than 28 days after injection against moderate to severe–critical Covid-19. Protection lasted at least 6 months without an added boost. Vaccination was associated with mild-to-moderate adverse effects.

We investigated safety, tolerability, and immunogenicity of the heterologous 2-dose Ebola vaccination regimen in healthy and HIV-infected adults with different intervals between Ebola vaccinations. In this randomised, observer-blind, placebo-controlled Phase II trial, 668 healthy 18- to 70-year-olds and 142 HIV-infected 18- to 50-year-olds were enrolled from 1 site in Kenya and 2 sites each in Burkina Faso, Cote d'Ivoire, and Uganda. Participants received intramuscular Ad26.ZEBOV followed by MVA-BN-Filo at 28-, 56-, or 84-day intervals, or saline. Females represented 31.4% of the healthy adult cohort in contrast to 69.7% of the HIV-infected cohort. A subset of healthy adults received booster vaccination with Ad26.ZEBOV or saline at Day 365. Following vaccinations, adverse events (AEs) were collected until 42 days post last vaccination and serious AEs (SAEs) were recorded from signing of the ICF until the end of the study. The primary endpoint was safety, and the secondary endpoint was immunogenicity. Anti-Ebola virus glycoprotein (EBOV GP) binding and neutralising antibodies were measured at baseline and at predefined time points throughout the study. The first participant was enrolled on 9 November 2015, and the date of last participant's last visit was 12 February 2019. No vaccine-related SAEs and mainly mild-to-moderate AEs were observed among the participants. The most frequent solicited AEs were injection-site pain (local), and fatigue, headache, and myalgia (systemic), respectively. Twenty-one days post-MVA-BN-Filo vaccination, geometric mean concentrations (GMCs) with 95% confidence intervals (CIs) of EBOV GP binding antibodies in healthy adults in 28-, 56-, and 84-day interval groups were 3,085 EU/mL (2,648 to 3,594), 7,518 EU/mL (6,468 to 8,740), and 7,300 EU/mL (5,116 to 10,417), respectively. In HIV-infected adults in 28- and 56-day interval groups, GMCs were 4,207 EU/mL (3,233 to 5,474) and 5,283 EU/mL (4,094 to 6,817), respectively. Antibody responses were observed until Day 365. Ad26.ZEBOV booster vaccination after 1 year induced an anamnestic response. Study limitations include that some healthy adult participants either did not receive dose 2 or received dose 2 outside of their protocol-defined interval and that the follow-up period was limited to 365 days for most participants. Ad26.ZEBOV, MVA-BN-Filo vaccination was well tolerated and immunogenic in healthy and HIV-infected African adults. Increasing the interval between vaccinations from 28 to 56 days improved the magnitude of humoral immune responses. Antibody levels persisted to at least 1 year, and Ad26.ZEBOV booster vaccination demonstrated the presence of vaccination-induced immune memory. These data supported the approval by the European Union for prophylaxis against EBOV disease in adults and children ≥1 year of age. ClinicalTrials.gov NCT02564523.

HIV type 1 (HIV-1) remains a global health concern, with the greatest burden in sub-Saharan Africa. Despite 40 years of research, no vaccine candidate has shown durable and protective efficacy against HIV-1 acquisition. Although pre-exposure prophylaxis in groups with high vulnerability can be very effective, barriers to its use, such as perceived low acquisition risk, fear of stigma, and concerns about side-effects, remain. Thus, a population-based approach, such as an HIV-1 vaccine, is needed. The current study aimed to evaluate the efficacy and safety of a heterologous HIV-1 vaccine regimen, consisting of a tetravalent mosaic adenovirus 26-based vaccine (Ad26.Mos4.HIV) and aluminium phosphate-adjuvanted clade C glycoprotein (gp) 140, in young women at risk of acquiring HIV-1 in southern Africa. This randomised, double-blind, phase 2b study enrolled sexually active women without HIV-1 or HIV-2 aged 18–35 years at 23 clinical research sites in Malawi, Mozambique, South Africa, Zambia, and Zimbabwe. Participants were centrally randomly assigned (1:1) to receive intramuscular injections of vaccine or saline placebo in stratified permuted blocks via an interactive web response system. Study participants, study site personnel (except those with primary responsibility for study vaccine preparation and dispensing), and investigators were masked to treatment group allocation. The vaccine regimen consisted of Ad26.Mos4.HIV administered at months 0 and 3 followed by Ad26.Mos4.HIV administered concurrently with aluminium phosphate-adjuvanted clade C gp140 at months 6 and 12. The primary efficacy outcome was vaccine efficacy in preventing laboratory-confirmed HIV-1 acquisition diagnosed between visits at month 7 and month 24 after the first vaccination (VE[7–24]) in the per-protocol population, which included participants who had not acquired HIV-1 4 weeks after the third vaccination, received all planned vaccinations at the first three vaccination visits within the protocol-specified windows, and had no major protocol deviations that could affect vaccine efficacy. Primary safety outcomes were assessed in randomly assigned participants who received one study injection or more based on the actual injection received. The primary safety endpoints were the incidences of unsolicited adverse events (AEs), solicited local and systemic AEs, serious AEs, AEs of special interest, and AEs leading to discontinuation of vaccination. This trial is registered with ClinicalTrials.gov, NCT03060629, and is complete. Between Nov 3, 2017, and June 30, 2019, 2654 women were randomly assigned, of whom 2636 women (median age of 23 years [IQR 20–25]) were enrolled and received at least one study injection (1313 assigned vaccine, 1323 placebo; 1317 received vaccine, 1319 placebo). Analysis of the primary efficacy outcome in the per-protocol cohort included 1080 women in the vaccine group and 1108 women in the placebo group; the incidence of HIV-1 acquisition per 100 person-years over months 7–24 after the first vaccination was 3·38 (95% CI 2·54–4·41) in the vaccine group and 3·94 (3·04–5·03) in the placebo group, with an estimated VE(7–24) of 14·10% (95% CI –22·00 to 39·51; p=0·40). There were no serious unsolicited AEs, AEs of special interest, or deaths related to the study vaccine. In the vaccine group, 663 (50·3%) of 1317 participants had grade 1 or 2 solicited local AEs and ten (0·8%) of 1317 participants had grade 3 or 4 solicited local AEs. In the placebo group, 305 (23·1%) of 1319 participants had grade 1 or 2 solicited local AEs and three (0·2%) of 1319 participants had grade 3 or 4 solicited local AEs. 863 (65·5%) of 1317 participants in the vaccine group had grade 1 or 2 solicited systemic AEs and 34 (2·6%) of 1317 participants had grade 3 or 4 solicited systemic AEs. 763 (57·8%) of 1319 participants in the placebo group had grade 1 or 2 solicited systemic AEs and 20 (1·5%) of 1319 participants had grade 3 or 4 solicited systemic AEs. Overall, three (0·2%) of 1317 participants in the vaccine group and three (0·2%) of 1319 participants in the placebo group discontinued vaccination due to an unsolicited AE, and three (0·2%) of 1317 participants in the vaccine group and one (0·1%) of 1319 participants in the placebo group discontinued vaccination due to a solicited AE. The heterologous Ad26.Mos4.HIV and clade C gp140 vaccine regimen was safe and well tolerated but did not show efficacy in preventing HIV-1 acquisition in a population of young women in southern Africa at risk of HIV-1. Division of AIDS at the National Institute of Allergy and Infectious Diseases through the HIV Vaccine Trials Network, Bill & Melinda Gates Foundation, Janssen Vaccines & Prevention, US Army Medical Materiel Development Activity, and Ragon Institute.