Ad26 vaccine protects against SARS-CoV-2 severe clinical disease in hamsters

Tostanoski, Lisa H.; Wegmann, Frank; Martinot, Amanda J.; Loos, Carolin; McMahan, Katherine; Mercado, Noe B.; Yu, Jingyou; Chan, Chi N.; Bondoc, Stephen; Starke, Carly E.; Nekorchuk, Michael; Busman‐Sahay, Kathleen; Piedra-Mora, César; Wrijil, Linda M.; Ducat, Sarah; Custers, Jerome; Atyeo, Caroline; Fischinger, Stephanie; Burke, John S.; Feldman, Jared; Hauser, Blake M.; Caradonna, Timothy M.; Bondzie, Esther A.; Dagotto, Gabriel; Gebre, Makda S.; Jacob-Dolan, Catherine; Lin, Zin; Mahrokhian, Shant H.; Nampanya, Felix; Nityanandam, Ramya; Pessaint, Laurent; Porto, Maciel; Ali, Vaneesha; Benetiene, Dalia; Tevi, Komlan; Andersen, Hanné; Lewis, Mark G.; Schmidt, Aaron; Lauffenburger, Douglas A.; Alter, Galit; Estes, Jacob D.; Schuitemaker, Hanneke; Zahn, Roland; Barouch, Dan H.

doi:10.1038/s41591-020-1070-6

Cited by 293 publications

(444 citation statements)

References 26 publications

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“…However, sVNT and pVNT reported in this study have well demonstrated a significant correlation with cVNT in NAb titers to SARS-CoV-2 ( P <0.0001, R =0.7678-0.8591) ( 28 ). This was also evidenced by close correlation between ELISA and pVNT or cVNT by other studies using adenovirus vectored COVID-19 vaccines in rhesus macaques ( P <0.0001, R =0.8314-0.8427) ( 12 ), hamsters ( P <0.0001; R =0.7849) ( 13 ) and human clinical phase II trial ( P <0.0001, R =0.72-0.75) ( 9 ). In addition, compared with a panel of convalescent serum samples from COVID-19 patients the level of binding or neutralizing antibodies observed in this study was favorable and in line with all other published data from COVID-19 vaccines.…”

Section: Discussionsupporting

confidence: 66%

“…In this study, we generated two novel adenovirus vectored COVID-19 vaccines encoding the full-length S gene of SARS-CoV-2. The intact S glycoprotein rather than the shorter S or RBD proteins was shown to be the most effective antigen eliciting protective immunity against SARS-CoV-2 infection in DNA vaccines and Ad26 vectored vaccines ( 12,13,26 ). The vectors Sad23L and Ad49L originated from simian adenovirus type 23 and human adenovirus type 49, respectively ( 22, 23 ), are novel adenoviral vector.…”

Section: Discussionmentioning

confidence: 99%

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Prime-boost vaccination of mice and Rhesus macaques with two novel adenovirus vectored COVID-19 vaccine candidates

Luo

Zhang

Liu

et al. 2020

Preprint

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COVID-19 vaccines are being developed urgently worldwide, among which single-shot adenovirus vectored vaccines represent a major approach. Here, we constructed two novel adenovirus vectored COVID-19 vaccine candidates on simian adenovirus serotype 23 (Sad23L) and human adenovirus serotype 49 vectors (Ad49L) carrying the full-length gene of SARS-CoV-2 spike protein (S), designated Sad23L-nCoV-S and Ad49L-nCoV-S vaccines, respectively. The immunogenicity elicited by these two vaccine strains was individually evaluated in mice. Specific humoral and cellular immune responses were proportionally observed in a dose-dependent manner, and stronger response was obtained by boosting. Furthermore, five rhesus macaques were intramuscularly injected with a dose of 5×109 PFU Sad23L-nCoV-S vaccine for prime vaccination, followed by boosting with 5×109 PFU of Ad49L-nCoV-S vaccine at 4-week interval. Three macaques were injected with Sad23L-GFP and Ad49L-GFP vectorial viruses as negative controls. Both mice and macaques tolerated well the vaccine inoculations without detectable clinical or pathologic changes. In macaques, prime-boost vaccination regimen induced high titers of 103.16 S-binding antibody (S-BAb), 102.75 cell receptor binding domain (RBD)-BAb and 102.38 neutralizing antibody (NAb) to pseudovirus a week after boosting injection, followed by sustained high levels over 10 weeks of observation. Robust IFN-γ secreting T-cell response (712.6 SFCs/106 cells), IL-2 secreting T-cell response (334 SFCs/106 cells) and intracellular IFN-γ expressing CD4+/CD8+ T cell response (0.39%/0.55%) to S peptides were detected in the vaccinated macaques. It was concluded that prime-boost immunization with Sad23L-nCoV-S and Ad49L-nCoV-S vaccines can safely elicit strong immunity in animals in preparation of clinical phase 1/2 trials.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Prime-boost vaccination of mice and Rhesus macaques with two novel adenovirus vectored COVID-19 vaccine candidates

Luo

Zhang

Liu

et al. 2020

Preprint

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“…The copyright holder for this this version posted September 25, 2020. ; https://doi.org/10.1101/2020.09.23.20199604 doi: medRxiv preprint 99% seroconversion in each dose group (Figure 2A). Of the cohort 1a participants who were seropositive at baseline, 7 out of 8 and 2 out of 3 demonstrated the preset criterion of a 4-fold 227 increase in binding antibody titer to be considered a vaccine responder, for the 5x10 10 and 1x10 11 vp dose level groups, respectively. The initial 15 enrolled participants in cohort 3 were seronegative at baseline and had seroconverted by Day 29 post vaccination with GMTs of 507 (95% CI: 181; 1418) and 248 (95% CI: 122; 506), for the 5x10 10 and 1x10 11 vp dose level group, 231…”

Section: Immunogenicity Of Ad26cov2s 220mentioning

confidence: 99%

“…We randomly assigned 405 eligible participants 18-55 years of age and 405 participants >65 years of age to receive one or two vaccinations with either a 5x10 10 or 1x10 11 vp dose level of vaccine, or placebo (1:1:1:1:1 per age group): 5x10 10 vp/5x10 10 vp; 5x10 10 vp/placebo; 1x10 11 vp /1x10 11 vp; 1x10 11 vp/placebo; or placebo/placebo for the first and second dose, respectively (Figure 1).…”

Section: Randomization and Blindingmentioning

confidence: 99%

“…In addition, we demonstrated that Ad26.COV2.S provided protective immunity in a Syrian golden hamster severe disease model. 11 These preclinical data supported the start of a Phase 1/2a randomized, double-blinded, placebocontrolled clinical study to assesses the safety, reactogenicity and immunogenicity of Ad26.COV2.S in one-or two-dose (8-week interval) schedules with 5x10 10 or 1x10 11 viral 66 particles (vp) per vaccination in adults 18-55 or >65 years of age. Here we report interim blinded safety and reactogenicity data as well as group unblinded immunogenicity data obtained during the first 4 weeks after the first vaccination.…”

mentioning

confidence: 93%

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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

Sadoff

Gars

Shukarev

et al. 2020

Preprint

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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

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Immunogenicity of the Ad26.COV2.S Vaccine for COVID-19

Stephenson

Gars

Sadoff

et al. 2021

JAMA

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IMPORTANCE Control of the global COVID-19 pandemic will require the development and deployment of safe and effective vaccines. OBJECTIVE To evaluate the immunogenicity of the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) in humans, including the kinetics, magnitude, and phenotype of SARS-CoV-2 spike-specific humoral and cellular immune responses. DESIGN, SETTING, AND PARTICIPANTS Twenty-five participants were enrolled from July 29, 2020, to August 7, 2020, and the follow-up for this day 71 interim analysis was completed on October 3, 2020; follow-up to assess durability will continue for 2 years. This study was conducted at a single clinical site in Boston, Massachusetts, as part of a randomized, double-blind, placebo-controlled phase 1 clinical trial of Ad26.COV2.S. INTERVENTIONS Participants were randomized to receive 1 or 2 intramuscular injections with 5 × 10 10 viral particles or 1 × 10 11 viral particles of Ad26.COV2.S vaccine or placebo administered on day 1 and day 57 (5 participants in each group). MAIN OUTCOMES AND MEASURES Humoral immune responses included binding and neutralizing antibody responses at multiple time points following immunization. Cellular immune responses included immunospot-based and intracellular cytokine staining assays to measure T-cell responses. RESULTS Twenty-five participants were randomized (median age, 42; age range, 22-52; 52% women, 44% male, 4% undifferentiated), and all completed the trial through the day 71 interim end point. Binding and neutralizing antibodies emerged rapidly by day 8 after initial immunization in 90% and 25% of vaccine recipients, respectively. By day 57, binding and neutralizing antibodies were detected in 100% of vaccine recipients after a single immunization. On day 71, the geometric mean titers of spike-specific binding antibodies were 2432 to 5729 and the geometric mean titers of neutralizing antibodies were 242 to 449 in the vaccinated groups. A variety of antibody subclasses, Fc receptor binding properties, and antiviral functions were induced. CD4+ and CD8+ T-cell responses were induced. CONCLUSION AND RELEVANCE In this phase 1 study, a single immunization with Ad26.COV2.S induced rapid binding and neutralization antibody responses as well as cellular immune responses. Two phase 3 clinical trials are currently underway to determine the efficacy of the Ad26.COV2.S vaccine.

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Ad26 vaccine protects against SARS-CoV-2 severe clinical disease in hamsters

Cited by 293 publications

References 26 publications

Prime-boost vaccination of mice and Rhesus macaques with two novel adenovirus vectored COVID-19 vaccine candidates

Prime-boost vaccination of mice and Rhesus macaques with two novel adenovirus vectored COVID-19 vaccine candidates

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

Immunogenicity of the Ad26.COV2.S Vaccine for COVID-19

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