Efficacy, safety, and immunogenicity of the DNA SARS-CoV-2 vaccine (ZyCoV-D): the interim efficacy results of a phase 3, randomised, double-blind, placebo-controlled study in India.

BACKGROUND: ZyCoV-D, a DNA-based vaccine, showed promising safety and immunogenicity in a phase 1/2 trial. We now report the interim efficacy results of phase 3 clinical trial with ZyCoV-D vaccine in India. METHODS: We conducted an interim analysis of a multicentre, double-blind, randomised, placebo-controlled phase 3 trial at 49 centres in India. Healthy participants aged at least 12 years were enrolled and randomly assigned (1:1) to receive either ZyCov-D vaccine (Cadila Healthcare; 2 mg per dose) or placebo. An interactive web response system was used for randomisation (blocks of four) of participants as well as to enrol those aged 60 years and older with or without comorbid conditions, and those aged 12-17 years. It was also used to identify 600 participants for immunogenicity (blocks of six). Participants, investigators, and outcome assessors were masked to treatment assignment. Three doses of vaccine or placebo were administered intradermally via a needle-free injection system 28 days apart. The primary outcome was the number of participants with first occurrence of symptomatic RT-PCR-positive COVID-19 28 days after the third dose, until the targeted number of cases (interim analysis n=79, full analysis n=158) have been achieved. The analysis was done in the per-protocol population, which consisted of all participants with negative baseline SARS-CoV-2 status who received three doses of vaccine or placebo. Assessment of safety and tolerability was based on the safety population, which consisted of all enrolled participants who were known to have received at least one dose of study vaccine or placebo. This trial is registered with Clinical Trial Registry India, CTRI/2021/01/030416, and is ongoing. FINDINGS: Between Jan 16, and June 23, 2021 (data cutoff), 33 194 individuals were screened, of whom 5241 did not meet screening criteria and 27 703 were enrolled and randomly assigned to receive ZyCoV-D (n=13 851) or placebo (n=13 852). Per-protocol, 81 cases were eligible and included in efficacy analysis (20 of 12 350 in the ZyCoV-D group and 61 of 12 320 in placebo group). The ZyCoV-D vaccine efficacy was found to be 66·6% (95% CI 47·6-80·7). The occurrence of solicited adverse events was similar between the treatment groups (623 [4·49%] in the ZyCoV-D group vs 620 [4·47%] in the placebo group). There were two deaths (one in each group) reported at the data cutoff, neither of which was considered related to the study treatments. INTERPRETATION: In this interim analysis, ZyCoV-D vaccine was found to be efficacious, safe, and immunogenic in a phase 3 trial. FUNDING: National Biopharma Mission, Department of Biotechnology, Government of India and Cadila Healthcare, Ahmedabad, Gujarat India.

Immunogenicity and safety of two quadrivalent influenza vaccines in healthy adult and elderly participants in India - A phase III, active-controlled, randomized clinical study.

BACKGROUND: This study was conducted to compare the immunogenicity and safety profile of two quadrivalent influenza vaccines (QIVs) in healthy adults (18-60 years) and elderly (>61 years) participants. METHOD: This phase III study was conducted from March 2018 to April 2018 across 12 sites in India. In this randomized, observer-blind, active-controlled study, 480 participants were randomized to receive a single dose of test vaccine (subunit, inactivated influenza vaccine; Influvac® Tetra, Abbott) (n = 240) or reference vaccine (split virion, inactivated influenza vaccine; VaxiFlu-4, Zydus Cadilla Healthcare) (n = 240). The primary objective was to describe and compare the immunogenicity of each vaccination group based on hemagglutination inhibition (HI) assay seroprotection and seroconversion rates, and geometric mean fold increase (GMFI) against four vaccine strains in two age groups. Safety and reactogenicity were also compared for the vaccines in both the age groups. RESULTS: The pre- and post-vaccination HI titers for both the vaccines were comparable. The GMFI varied from 4.3 - 22.7 in the test and 3.7-21.6 in the reference vaccine group. The seroprotection rates were >90% for the A-strains and ranged between >43% and <60% for B-strains for both the vaccines. Seroconversion rates varied between 41.4% and 78.8%. Overall, the reported adverse events (AEs) for both the vaccines were <1% and comparable. Reported local and systemic reactions were comparable. CONCLUSION: Influvac® Tetra elicited an adequate immune response with a favorable safety profile which was comparable with the reference vaccine. (Clinical trial registry number: CTRI/2018/02/012222).

A Randomized Trial of Mycobacterium w in Severe Presumed Gram-Negative Sepsis.

BACKGROUND: Mycobacterium w (Mw), an immunomodulator, has been shown to resolve early organ failure in severe sepsis. RESEARCH QUESTION: Does Mw improve survival in patients with severe presumed gram-negative sepsis? STUDY DESIGN AND METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group study conducted in ICUs of five tertiary care centers in India. We included consecutive patients (age ≥ 18 years) with presumed gram-negative sepsis in the study within 48 h of the first organ dysfunction. Patients in the treatment arm received 0.3 mL/d of Mw intradermally for 3 consecutive days, whereas the control arm received matching placebo. The primary outcome was 28-day all-cause mortality. The secondary outcomes were ventilator-free days, days receiving vasopressor therapy, ICU and hospital length of stay, nosocomial infection rate, antibiotic use duration, and delta Sequential Organ Failure Assessment (SOFA) score. RESULTS: We included 202 patients with severe sepsis (101 Mw, 101 placebo). The use of Mw significantly reduced the mortality (9/101 vs 20/101; estimate difference, 0.11 [95% CI, 0.01-0.21]; P = .04). We found no difference in ventilator-free days, days receiving vasopressor drugs, ICU length of stay, and the hospital length of stay. The time to mortality (median, 13 days vs 8.5 days) was significantly longer in the Mw than in the placebo arm. The delta SOFA score, rate of nosocomial infections, and antibiotic use duration were similar in the two arms. We found Mw to reduce significantly the odds (OR, 0.37 [95% CI, 0.15-0.9]) of mortality after adjusting for culture-positive sepsis, baseline SOFA score, age, and sex. INTERPRETATION: The use of Mw was associated with a significant reduction in mortality in patients with severe presumed gram-negative sepsis. Further studies are required to confirm our findings. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02330432; URL: www.clinicaltrials.gov.

Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine in adults 50 to 65 years of age in India: An open-label trial.

Streptococcus pneumoniae infection is a major global public health concern in older adults, especially as life expectancy continues to increase in most countries, including India. Recently, a 13-valent pneumococcal conjugate vaccine (PCV13) with the ability to enhance immunity (immunologic memory) on natural exposure or revaccination has been shown to protect against community-acquired pneumonia and invasive pneumococcal disease in adults 65 years of age and older. An unconjugated 23-valent pneumococcal polysaccharide vaccine has been available for decades; however, data on protection against pneumonia are inconsistent. For the first time, a multicenter study has been conducted in India to assess the safety and immunogenicity of a single dose of PCV13 in adults aged 50 to 65 years. In this study, PCV13 elicited robust immune responses against all 13 pneumococcal serotypes as reflected by the magnitude of geometric mean fold rises (range, 6.6-102.7) in functional antibody levels from before to 1 month after vaccination. No serious adverse events occurred. These clinical trial findings support the safety and immunogenicity of PCV13 when administered to adults in India and indicate that a single dose of PCV13 has the potential to protect against vaccine-type pneumococcal disease in adults aged 50 to 65 years. ClinicalTrials.gov identifier: NCT02034877.