Immunogenicity and safety of a 14-valent pneumococcal polysaccharide conjugate vaccine (PNEUBEVAX 14™) administered to 6-8 weeks old healthy Indian Infants: A single blind, randomized, active-controlled, Phase-III study.

BACKGROUND: Introduction of pneumococcal conjugate vaccines (PCVs) reduced the number of cases of pneumococcal disease (PD). However, there is an increase in clinical and economic burden of PD from serotypes that are not part of the existing pneumococcal vaccines, particularly impacting pediatric and elder population. In addition, the regions where the PCV is not available, the disease burden remains high. In this study, immunogenicity and safety of the BE's 14-valent PCV (PNEUBEVAX 14™; BE-PCV-14) containing two additional epidemiologically important serotypes (22F and 33F) was evaluated in infants in comparison to licensed vaccine, Prevenar-13 (PCV-13). METHODS: This is a pivotal phase-3 single blind randomized active-controlled study conducted at 12 sites across India in 6-8 weeks old healthy infants at 6-10-14 weeks dosing schedule to assess immunogenic non-inferiority and safety of a candidate BE-PCV-14. In total, 1290 infants were equally randomized to receive either BE-PCV-14 or PCV-13. Solicited local reactions and systemic events, adverse events (AEs), serious AEs (SAEs), and medically attended AEs (MAAEs) were recorded. Immunogenicity was assessed by measuring anti-PnCPS (anti-pneumococcal capsular polysaccharide) IgG concentration and functional antibody titers through opsonophagocytic activity (OPA), one month after completing three dose schedule. Cross protection to serotype 6A offered by serotype 6B was also assessed in this study. FINDINGS: The safety profile of BE-PCV-14 was comparable to PCV-13 vaccine. Majority of reported AEs were mild in nature. No severe or serious AEs were reported in both the treatment groups. For the twelve common serotypes and for the additional serotypes (22F and 33F) in BE-PCV-14, NI criteria was demonstrated as defined by WHO TRS-977. Primary immunogenicity endpoint was met in terms of IgG immune responses for all 14 serotypesof BE-PCV-14. Moreover, a significant proportion of subjects (69%) seroconverted against serotype 6A, even though this antigen was not present in BE-PCV-14. This indicates that serotype 6B of BE-PCV-14 cross protects serotype 6A. BE-PCV-14 also elicited comparable serotype specific functional OPA immune responses to all the serotypes common to PCV-13. INTERPRETATIONS: BE-PCV-14 was found to be safe and induced robust and functional serotype specific immune responses to all 14 serotypes. It also elicited cross protective immune response against serotype 6B.These findings suggest that BE-PCV-14 can be safely administered to infants and achieve protection against pneumococcal disease caused by serotypes covered in the vaccine. The study was prospectively registered with clinical trial registry of India - CTRI/2020/02/023129.

A phase II/III randomised, comparative study evaluating the safety and immunogenicity of Biological E's live, attenuated Measles-Rubella vaccine in 9-12 month old healthy infants.

Measles is a major cause of childhood mortality and one-third of the world's Measles deaths occur in India. Rubella causes lifelong birth defects (Congenital Rubella Syndrome). Although neither condition has a cure, the MR vaccination can successfully prevent both diseases. The safety of Biological E's live attenuated MR vaccine (BE-MR) was established in 4-5-year-old healthy children. This phase-2/3 study was conducted to assess the safety and immunogenicity of BE-MR in 9-12 month old healthy infants. Overall, 600 subjects were enrolled and equally randomized to receive either BE-MR (n = 300) or the comparator vaccine, SII MR-Vac™ (n = 300). Safety profile of BE-MR vaccine was comparable to SII MR-Vac™ with no severe or serious adverse events (AEs) reported across the study groups. The primary objective of demonstrating non inferiority by BE-MR vaccine compared to SIIL's-MR Vac™ was met. The proportion of subjects with ≥ 2-fold and ≥ 4-fold increase in antibody titre against Measles and Rubella in both the study groups was comparable. Overall, BE-MR vaccine elicited robust and protective immune response as demonstrated by high proportion of sero-protected subjects and a large increase in anti-Measles and anti-Rubella antibodies at day 42 and can be administered safely to infants below one-year of age. This study was prospectively registered with the clinical trial registry of India- CTRI/2016/07/007109.

Immunogenicity and safety of Biological E's CORBEVAX™ vaccine compared to COVISHIELD™ (ChAdOx1 nCoV-19) vaccine studied in a phase-3, single blind, multicentre, randomized clinical trial.

Optimum formulation of Biological-E's protein subunit CORBEVAX™ vaccine was selected in phase-1 and -2 studies and found to be safe and immunogenic in healthy adult population. This is a phase-3 prospective, single-blinded, randomized, active controlled study conducted at 18 sites across India in 18-80 year-old subjects. This study has two groups; (i) immunogenicity-group, participants randomized either to CORBEVAX™ (n = 319) or COVISHIELD™ arms (n = 320). (ii) Safety-group containing single CORBEVAX™ arm (n = 1500) and randomization is not applicable. Healthy adults without a history of COVID-19 vaccination or SARS-CoV-2 infection were enrolled into immunogenicity arm and subjects seronegative to SARS-CoV-2 infection were enrolled into the safety arm. The safety profile of CORBEVAX™ vaccine was comparable to the comparator vaccine COVISHIELD™. Majority of reported AEs were mild in nature in both arms. The CORBEVAX™ to COVISHIELD™ GMT-ratios at day-42 time-point were 1·15 and 1·56 and the lower limit of the 95% confidence interval for the GMT-ratios was determined as 1·02 and 1·27 against Ancestral and Delta strains of SARS-COV-2 respectively. Both COVISHIELD™ and CORBEVAX™ vaccines showed comparable seroconversion post-vaccination against anti-RBD-IgG response. The subjects in CORBEVAX™ cohort also exhibited higher interferon-gamma secreting PBMC's post-stimulation with SARS-COV-2 RBD-peptides than subjects in COVISHIELD™ cohort.

Safety, tolerability and immunogenicity of Biological E's CORBEVAX™ vaccine in children and adolescents: A prospective, randomised, double-blind, placebo controlled, phase-2/3 study.

BACKGROUND: After establishing safety and immunogenicity of Biological-E's CORBEVAX™ vaccine in adult population (18-80 years) in Phase 1-3 studies, vaccine is further tested in children and adolescents in this study. METHODS: This is a phase-2/3 prospective, randomised, double-blind, placebo-controlled study evaluating safety, reactogenicity, tolerability and immunogenicity of CORBEVAX™ vaccine in children and adolescents of either gender between <18 to ≥12 years of age in Phase-2 and <18 to ≥5 years of age in Phase-Phase-2/Phase-3 with placebo as a control. This study has two age sub-groups; subgroup-1 with subjects <18 to ≥12 years of age and subgroup-2 with subjects <12 to ≥5 years of age. In both sub groups, eligible subjects (SARS-CoV-2 RT-PCR negative and seronegative at baseline) were randomized to receive either CORBEVAX™ vaccine or Placebo in 3:1 ratio. FINDINGS: The safety profile of CORBEVAX™ vaccine in both pediatric cohorts was comparable to the placebo-control group. Majority of reported adverse events (AEs) were mild in nature. No severe or serious-AEs, medically attended AEs (MAAEs) or AEs of special interest (AESI) were reported during the study period and all reported AEs resolved without any sequelae. In both pediatric age groups, CORBEVAX™ vaccinated subjects showed significant improvement in humoral immune-responses in terms of anti-RBD-IgG concentrations, anti-RBD-IgG1 titers, neutralizing-antibody (nAb)-titers against Ancestral-Wuhan and Delta-strains. Significantly high interferon-gamma immune- response (cellular) was elicited by CORBEVAX™ vaccinated subjects with minimal effect on IL-4 cytokine secretion. INTERPRETATIONS: The safety profile of CORBEVAX™ vaccine in <18 to ≥5 years' children and adolescents was found to be safe and tolerable. Significant increase in anti-RBD-IgG and nAb-titers and IFN-gamma immune-responses were observed post-vaccination in both pediatric age sub-groups. The nAb titers observed in both the pediatric age cohorts were non-inferior to the adult cohort (BECT069 study) in terms of ratio of the GMT's of both the cohorts. This study shows that CORBEVAX™ vaccine is highly immunogenic and can be safely administered to pediatric population as young as 5 years old. The study was prospectively registered with clinical trial registry of India- CTRI/2021/10/037066.

Evaluation of safety and immunogenicity of receptor-binding domain-based COVID-19 vaccine (Corbevax) to select the optimum formulation in open-label, multicentre, and randomised phase-1/2 and phase-2 clinical trials.

BACKGROUND: We assessed the efficacy of a receptor-binding domain (RBD)-based protein subunit COVID-19 vaccine. METHODS: A randomised Phase-1/2 trial followed by a Phase-2 trial were conducted to assess the safety and immunogenicity of the COVID-19 vaccine Corbevax and select to an optimum formulation. Healthy adults (n=460) without COVID-19 vaccination or SARS-CoV-2 infection in the Phase-1/2 study were randomly divided into four vaccine formulation groups. FINDINGS: A low incidence of adverse events was reported post-vaccination. All formulations showed similar profiles of humoral and cellular immune responses that were associated with the content of CpG1018 adjuvant in the vaccine. In the Phase-2 study, 750 µg of CpG1018 showed significant improvement (> 4-fold increase from baseline) in immune responses, including the titres of anti-RBD IgG and neutralising antibody (nAb), and cellular immune responses, while maintaining the safety profile. Antibodies persisted consistently for 12 months after the second dose of vaccine. INTERPRETATIONS: Corbevax (two-dose schedule with 28 days of interval between doses) was well tolerated with no observed safety concerns. Previous observations from efficacy studies by Moderna and AstraZeneca and the correlation between nAb titres post-vaccination and a human convalescent serum panel showed that Corbevax induced significantly high nAb titres. These studies were prospectively registered with the Clinical Trial Registry of India (CTRI/2021/06/034014 and CTRI/2020/11/029032). FUNDING: Bill & Melinda Gates Foundation, BIRAC-Division of Department of Biotechnology, Govt of India, and the Coalition for Epidemic Preparedness Innovations funded this study.

A multicenter, single-blind, randomized, phase-2/3 study to evaluate immunogenicity and safety of a single intramuscular dose of biological E's Vi-capsular polysaccharide-CRM197 conjugate typhoid vaccine (TyphiBEVTM) in healthy infants, children, and adults in comparison with a licensed comparator.

The current scenario of typhoid fever warrants early prevention with typhoid conjugate vaccines in susceptible populations to provide lifelong protection. We conducted a multicenter, single-blind, randomized, Phase 2/3 study to assess the immunogenicity and safety of Biological E's Typhoid Vi-CRM197 conjugate vaccine (TyphiBEVTM) compared to Vi-TT conjugate vaccine manufactured by Bharat Biotech International Limited (Typbar-TCV; licensed comparator) in healthy infants, children, and adults from India. The study's primary objective was to assess the non-inferiority of TyphiBEVTM in terms of the difference in the proportion of subjects seroconverted with a seroconversion threshold value of ≥2.0 µg/mL against Typbar-TCV. A total of 622 healthy subjects (311 each in both vaccine groups) were randomized and received the single dose of the study vaccine. The TyphiBEVTM group demonstrated noninferiority compared to the Typbar-TCV group at Day 42. The lower 2-sided 95% confidence interval limit of the group difference was -.34%, which met the non-inferiority criteria of ≥10.0%. The geometric mean concentration (24.79 µg/mL vs. 26.58 µg/mL) and proportion of subjects who achieved ≥4-fold increase in antiVi IgG antibody concentrations (96.95% vs. 97.64%) at Day 42 were comparable between the TyphiBEVTM and Typbar-TCV vaccine groups. No apparent difference was observed in the safety profile between both vaccine groups. All adverse events reported were mild or moderate in intensity in all age subsets. This data demonstrates that TyphiBEVTM is non-inferior to TypbarTCV in terms of immunogenicity, and the overall safety and reactogenicity in healthy infants, children, and adults studied from India was comparable.

A single blind randomized phase 3 study to evaluate safety and immunogenicity of inactivated hepatitis A vaccine (HAPIBEVTM) in 1-15 years-old healthy hepatitis A vaccine-naïve children.

The Biological E inactivated hepatitis A (HAPIBEV™) vaccine was developed by importing the Healive® vaccine bulk from China and fill-finish it in India. Healive® vaccine is approved in China for both children and adults. This study assessed the safety and immunogenicity of HAPIBEV™ vaccine as compared to the Havrix 720® vaccine of GlaxoSmithKline (GSK) pharmaceuticals when administered intramuscularly (IM) 6 months apart in 1-15 years old hepatitis A virus (HAV) vaccine naive children in India. This Phase 3, single blind, parallel, randomized, active-controlled, two-arm study was conducted at 8 centers in India in healthy HAV vaccine-naive children. Subjects were stratified into 2 age subsets (1-7 and 8-15 years) and randomly assigned to either BE-HAPIBEV™ or GSK's Havrix® vaccine and administered 2 IM injections 6 months apart. The immunogenicity evaluations included: (1) proportion of subjects who achieved the following at Day 210 from baseline: (a) seroconversion (≥20 mIU/mL) with anti-HAV immunoglobulin G (IgG) antibodies, (b) ≥4-fold increase in anti-HAV IgG antibodies, and (c) ≥2-fold increase in anti-HAV IgG antibodies concentration who were already seroconverted at baseline and (2) geometric mean concentrations (GMC) of anti-HAV IgG antibodies at baseline and Day 210. Safety was evaluated throughout the study. A total of 467 (89.8%) subjects completed the study. The non-inferiority criterion was met by HAPIBEV™ vaccine as seroconversion rates in both vaccine groups were 100%. Overall, other immunogenicity evaluations were either similar in both vaccine groups or higher in the HAPIBEV™ group compared with the Havrix® group. The safety profile was also comparable between HAPIBEV™ and Havrix® groups. The most common adverse event (AE) was injection site pain, and the majority of AEs were mild in severity. The HAPIBEV™ vaccine demonstrated an immunological and safety profile on par with Havrix® in 1-15 years old healthy HAV vaccine-naive Indian children. This study is registered with clinical trial registry of India bearing no: CTRI/2019/04/018384 on 02 Apr 2019.