The efficacy, safety and immunogenicity Nanocovax: results of a randomized, double-blind, placebo-controlled Phase 3 trial
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Abstract
Background
Nanocovax is a recombinant severe acute respiratory syndrome coronavirus 2 subunit vaccine composed of full-length prefusion stabilized recombinant SARS-CoV-2 spike glycoproteins (S-2P) and aluminum hydroxide adjuvant. In a Phase 1 and 2 studies, ( NCT04683484 ) the vaccine was found to be safe and induce a robust immune response in healthy adult participants.
Methods
We conducted a multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety, immunogenicity, and protective efficacy of the Nanocovax vaccine against Covid-19 in approximately 13,007 volunteers aged 18 years and over. The immunogenicity was assessed based on Anti-S IgG antibody response, surrogate virus neutralization, wild-type SARS-CoV-2 neutralization and the types of helper T-cell response by intracellular staining (ICS) for interferon gamma (IFNg) and interleukin-4 (IL-4). The vaccine efficacy (VE) was calculated basing on serologically confirmed cases of Covid-19.
Findings
Up to day 180, incidences of solicited and unsolicited adverse events (AE) were similar between vaccine and placebo groups. 100 serious adverse events (SAE) were observed in both vaccine and placebo groups (out of total 13007 participants). 96 out of these 100 SAEs were determined to be unrelated to the investigational products. 4 SAEs were possibly related, as determined by the Data and Safety Monitoring Board (DSMB) and investigators. Reactogenicity was absent or mild in the majority of participants and of short duration. These findings highlight the excellent safety profile of Nanocovax.
Regarding immunogenicity, Nanocovax induced robust IgG and neutralizing antibody responses. Importantly, Anti S-IgG levels and neutralizing antibody titers on day 42 were higher than those of natural infected cases. Nanocovax was found to induce Th2 polarization rather than Th1.
Post-hoc analysis showed that the VE against symptomatic disease was 51.5% (95% confidence interval [CI] was [34.4%-64.1%]. VE against severe illness and death were 93.3% [62.2-98.1]. Notably, the dominant strain during the period of this study was Delta variant.
Interpretation
Nanocovax 25 microgram (mcg) was found to be safe with the efficacy against symptomatic infection of Delta variant of 51.5%.
Funding
Research was funded by Nanogen Pharmaceutical Biotechnology JSC., and the Ministry of Science and Technology of Vietnam; ClinicalTrials.gov number, NCT04922788 .
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SciScore for 10.1101/2022.03.22.22272739: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: All participants signed a written consent before being enrolled in the trial.
Field Sample Permit: The trials were designed and funded by Nanogen Pharmaceutical Biotechnology JSC and the Ministry of Science and Technology (MOST) of Vietnam.
IRB: The trial protocol was approved by the Ethics Committee/Protocol Review Board of the Ministry of Health (Vietnam) and was performed in accordance with the ICH-GCP good clinical practice guidelines, with an ethical policy consistent with the “Declaration of Helsinki” and applicable Vietnamese laws and regulations.Sex as a biological variable Eligible participants were men and non-pregnant women, at least 18 years of age with a body mass index … SciScore for 10.1101/2022.03.22.22272739: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: All participants signed a written consent before being enrolled in the trial.
Field Sample Permit: The trials were designed and funded by Nanogen Pharmaceutical Biotechnology JSC and the Ministry of Science and Technology (MOST) of Vietnam.
IRB: The trial protocol was approved by the Ethics Committee/Protocol Review Board of the Ministry of Health (Vietnam) and was performed in accordance with the ICH-GCP good clinical practice guidelines, with an ethical policy consistent with the “Declaration of Helsinki” and applicable Vietnamese laws and regulations.Sex as a biological variable Eligible participants were men and non-pregnant women, at least 18 years of age with a body mass index (BMI) of 16 to 41 (kg/m2). Randomization This was a multicenter, randomized, double-blind, placebo-controlled clinical trial to evaluate the safety, immunogenicity, and protective efficacy of the Nanocovax vaccine on Vietnamese volunteers from 18 years of age and older. Blinding Trial staff responsible for the vaccine/placebo administration, as well as participants were unaware of vaccine/placebo assignment. Power Analysis The total number of research subjects selected in the study was expected to be 13,000 participants, with the statistical power 80% and 2 interim analysis (IA) at 35% and 70% of the total target cases using the one-sided O’Brien-Fleming boundary method, assuming the VE was 75%, and the alpha error in the one-sided test was 0.025 in the end-of-term analysis. Table 2: Resources
Antibodies Sentences Resources Neutralization Antibody Detection Kit, L00847-C) and the T cell response by intracellular cytokine-staining (ICS). L00847-Csuggested: NoneGeometric means (of anti-S IgG concentration and neutralizing antibody titer) and associated 95% confidence intervals (CI) were calculated based on log-transformed data. anti-S IgGsuggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:This Phase 3 trial has a number of limitations. As mentioned above, the VE analysis encountered multiple challenges: the emergence of Delta variant, the government polices (strict quarantine, vaccine mandate regardless of vaccine trial enrollment) and the difference in Covid-19 survaillance at different study sites. Other limitations are low ethnic diversity (all Vietnamese), small study sized and limited follow-up time. In fact, due to ethical concerns, especially the safety of all participants, the principal investigators, the sponsor, and Ethics Committee decided to terminate the study in December 2022 (1 year of ahead of the projected end date). All participants received emergency use authorized vaccines after this date. In conclusion, Nanocovax has excellent safety and immunogenicity profile and robust efficacy.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04683484 Recruiting A Clinical Trial to Assess the Safety and Immunogenicity of … NCT04922788 Recruiting Study to Evaluate the Safety, Immunogenicity, and Efficacy o… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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