Immunogenicity and safety of a multi-human dose formulation of Biological E’s 14-valent pneumococcal polysaccharide conjugate vaccine (PNEUBEVAX 14®) administered to 6–8-week-old healthy infants: a phase 3, single-blind, randomized, active-controlled study

BackgroundPneumococcal conjugate vaccines (PCVs) have considerably reduced the burden of invasive pneumococcal disease (PD) worldwide. Consequently, though, there has been an increase in non-vaccine serotype-induced PD particularly at both the extremes of age. Biological E has developed a 14-valent PCV (PNEUBEVAX 14®) that includes additional serotypes 22F and 33F. PNEUBEVAX 14® was shown to be safe, immunogenic, and non-inferior to Prevenar-13® (PCV-13) when administered to infants in a pivotal phase 3 trial. In this study, the multi-dose presentation of PNEUBEVAX 14® with 2-phenoxyethanol as a preservative was assessed for safety and immunogenicity in infants.MethodsThis was a phase 3, single-blind, randomized, active-controlled study in 6–8-week-old healthy infants, conducted at three sites across India. The safety and immunogenicity of multi-dose presentation of PNEUBEVAX 14® were assessed in a 6–10–14-week dosing schedule, with 300 infants randomized to receive either PNEUBEVAX 14® or PCV-13. Safety-wise solicited local reactions and systemic events, unsolicited adverse events (AEs), serious AEs, and medically attended AEs (MAAEs) were recorded and analyzed. Immunogenicity was assessed by measuring anti-pneumococcal capsular polysaccharide (anti-PnCPS) immunoglobulin G (IgG) antibodies for all 14 serotypes, as well as cross-reactivity to serotype 6A.FindingsThe safety aspects of the multi-dose presentation of PNEUBEVAX 14® and PCV-13 were comparable with 23.3% of subjects having AEs in each of the two arms. There were no serious AEs, medically attended AEs, or deaths in either of the two study arms. Reported AEs were mild and solicited in nature, with injection site swelling and injection site pain being the most common AEs in both arms. The multi-dose presentation of PNEUBEVAX 14® was found to induce a robust immune response, including the new serotypes 22F and 33F. Importantly, PNEUBEVAX 14® also induced cross-reactive antibodies against serotype 6A.InterpretationThe multi-dose presentation of PNEUBEVAX 14® is both safe and immunogenic when administered to 6–8-week-old infants in a 6–10–14-week dosing schedule. These results extend the findings of a pivotal phase 3 study of the single-dose presentation of PNEUBEVAX 14® that showed that it was safe, robustly immunogenic, and non-inferior to PCV-13 in the same age group and dosing schedule. Taken together, these data suggest that both the single-dose and multi-dose presentations of PNEUBEVAX 14® can be safely administered to infants to prevent pneumococcal disease caused by Streptococcus pneumoniae.Clinical Trial Registrationhttps://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=NTk0MzA=&Enc=&userName=, identifier CTRI/2021/10/037067

A multi-centre, single arm, Phase 3 study to assess the safety and reactogenicity of biological Es Vi-capsular polysaccharide-CRM197 conjugate typhoid vaccine in ≥6 months old infants to ≤45 years old adults.

Background: Typhoid fever is a serious bacterial infection caused by Salmonella Typhi, with a significant burden in low- and middle-income countries, particularly in Sub-Saharan Africa and South/Southeast Asia. To mitigate its spread, the World Health Organization (WHO) advocates for typhoid vaccination programs that particularly target high-risk populations. However, unconjugated polysaccharide vaccines have shown limited efficacy in children under two years of age.Biological E has developed a typhoid conjugate vaccine, TYPHIBEV®, which incorporates the Vi-polysaccharide conjugated to the CRM197 carrier protein. TYPHIBEV®’s safety and immunogenicity were evaluated in Phase 1 and Phase 2/3 clinical trials involving infants, children, adolescents, and adults, compared to an established licensed vaccine. This Phase 3 study was specifically designed to assess the safety profile of TYPHIBEV® in the target population aged ≥6 months to ≤45 years. Methods: A multi-centre, single-arm, non-comparative Phase 3 study was conducted to evaluate the safety, tolerability and reactogenicity of a single intramuscular dose of Biological E's Vi-capsular Polysaccharide-CRM197 Conjugate Typhoid Vaccine. A total of 1770 subjects were enrolled into three age subsets; infants and toddlers, ≥6 months to <2 years of age; children and adolescents, ≥2 years to <18 years of age; and adults, ≥18 years to ≤45 years of age (n = 590 in each age group). A single dose of THPHIBEV® was administered, and all the subjects were followed up for a period of 42 days. Solicited local and systemic AEs were recorded up until 7 days post-vaccination. Unsolicited AEs, serious AEs (SAEs), and medically attended AEs (MAAEs) were recorded throughout the study duration. Findings: A total of 114 AEs were recorded in 101 (5.71 %) participants. A majority of these AEs were solicited in nature with general disorders and administration site conditions reported in 5.42 % of participants. The most commonly reported AEs were injection site pain and pyrexia. All MAAEs (1.30 % subjects) were solicited and pyrexia (0.85 % of subjects) was the most common reason for medical attention. No severe or serious AEs and/or deaths were reported throughout the study. None of the subjects discontinued the study due to an AE. Conclusions: TYPHIBEV® was found to be safe and well tolerated across different age groups and the safety profile was comparable to other TCVs in terms of reported solicited and unsolicited AEs. No severe or serious AEs were reported during the entire study period

Selection of optimum formulation of RBD-based protein sub-unit covid19 vaccine (Corbevax) based on safety and immunogenicity in an open-label, randomized Phase-1 and 2 clinical studies

ABSTRACTBackgroundWe present the data from an open-label study involved in the selection of optimum formulation of RBD-based protein sub-unit COVID-19 vaccine.MethodsThe randomized Phase-1/2 trial followed by a Phase-2 trial was carried out to assess safety and immunogenicity of different formulation of COVID-19 vaccine (Corbevax) and select an optimum formulation for a phase 3 study. Healthy adults without a history of Covid-19 vaccination or SARS-CoV-2 infection, were enrolled.FindingsLow incidence of adverse events were reported post-vaccination of different Corbevax formulations and majority were mild in nature and no Grade-3 or serious adverse events were observed. All formulations in Phase-1/2 study showed similar profile of humoral and cellular immune-response with higher response associated with increasing CpG1018 adjuvant content at same RBD protein content. Hence, high concentration of CpG1018 was tested in phase-2 study, which showed significant improvement in immune-responses in terms of anti-RBD-IgG concentrations, anti-RBD-IgG1 titers, nAb-titers and cellular immune-responses while maintaining the safety profile. Interestingly, binding and neutralizing antibody titers were persisted consistently till 6 months post second vaccine dose.InterpretationsCorbevax was well tolerated with no observed safety concerns. Neutralizing antibody titers were suggestive of high vaccine effectiveness compared with human convalescent plasma or protective thresholds observed during vaccine efficacy trials of other COVID-19 vaccines. The study was prospectively registered with clinical trial registry of India-CTRI/2021/06/034014 and CTRI/2020/11/029032.FundingBill &amp; Melinda Gates Foundation, BIRAC-division of Department of Biotechnology, Govt of India, and the Coalition for Epidemic Preparedness Innovations funded the study.</jats:sec

Immunogenicity and safety of Biological E’s CORBEVAX™ vaccine as a heterologous booster dose in adult volunteers previously vaccinated with two doses of either COVISHIELD™ or COVAXIN: A Prospective double-blind randomised phase III clinical study

ABSTRACTBackgroundVaccines developed against Covid-19 infection were effective in controlling symptomatic infections and hospitalizations. However, waning immunity was reported within 6 months of primary vaccination series. Due to waning of SARS-CoV-2 specific primary immunity, protection towards emerging variants of concern (VoC) was low. To rejuvenate the immunogenicity of vaccines, a third or booster dose was highly recommended by many state governments. In this regard, several clinical studies were conducted to evaluate the homologous or heterologous booster dose effectiveness against VoCs and showed that heterologous immune boosting more effective in controlling breakthrough infections. In this study, we studied the safety and immunogenicity of Biological-E’s CORBEVAX™ vaccine in adult population as a heterologous booster dose.MethodsThis is a prospective phase-3, randomised, double-blind, placebo-controlled, study evaluating safety, reactogenicity, tolerability and immunogenicity of CORBEVAX™ vaccine as a heterologous booster dose administered to adult volunteers previously vaccinated with two doses of either COVISHIELD™ or COVAXIN at least 6 months ago. Subjects were RT-PCR negative to SARS-CoV-2 prior to enrolment. A total of 416 subjects between 18 to 80 years of age, were enrolled in to one of the two treatment (COVISHIELD™ or COVAXIN primed subjects) groups (n=208/group) for safety and immunogenicity assessment. Within each group (n=208), subjects were randomized to receive CORBEVAX™ vaccine or placebo in a 3:1 ratio.FindingsThe safety profile of CORBEVAX™ vaccine administered as booster dose is comparable to the placebo-control group. All the reported adverse events (AEs) were mild to moderate in their intensity. There was no grade 3 or serious or AEs of special interest (AESI) reported during the study period and all the reported AEs resolved without any sequelae. CORBEVAX™ booster dose administration resulted in significant increase in humoral immune response (nAb titers and Anti-RBD IgG concentration) that was much superior to the placebo in both COVISHIELD™ and COVAXIN recipient arms. Significant increase in nAb titers against Omicron VOC as well as cellular immune response was also observed post CORBEVAX™ booster dose administration.InterpretationsEnhancement of immune response coupled with excellent safety profile of the CORBEVAX™ booster dose demonstrates significant benefit of giving CORBEVAX™ heterologous booster dose to subjects that have received COVISHIELD™ or COVAXIN primary vaccination; as early as 6 months post second dose of primary vaccination.The study was prospectively registered with clinical trial registry of India-CTRI/2022/01/039366</jats:sec

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

ABSTRACTBackgroundAfter 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.MethodsThis 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 &lt;18 to ≥12 years of age in Phase-II and &lt;18 to ≥5 years of age in Phase-III with placebo as a control. This study has two age sub groups; age subgroup-1 with subjects &lt;18 to ≥12 years of age and age subgroup-2 with subjects &lt;12 to ≥5 years of age. In both age 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.FindingsThe 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 the 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.InterpretationsThe safety profile of CORBEVAX™ vaccine in &lt;18 to ≥5 years’ children and adolescents was found to be safe and tolerable. The adverse event profile was also found to be acceptable. Significant increase in anti-RBD IgG and nAb titers and IFN-gamma immune responses were observed post vaccination in both pediatric age sub groups. Both humoral and cellular immune responses were found to be non-inferior to the immune responses induced by CORBEVAX™ vaccine in adult population. 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</jats:sec

Immunogenic superiority and safety of Biological E CORBEVAX vaccine compared to COVISHIELD (ChAdOx1 nCoV-19) vaccine studied in a phase III, single blind, multicenter, randomized clinical trial

Background: Optimum formulation of Biological Es CORBEVAX vaccine that contains protein sub unit of Receptor Binding Domain (RBD) from the spike protein of SARS-COV-2 formulated with aluminum hydroxide (Al3+) and CpG1018 as adjuvants was selected in phase-1 and 2 studies and proven to be safe, well tolerated and immunogenic in healthy adult population. In the current study, additional data was generated to determine immunogenic superiority of CORBEVAX vaccine over COVISHIELD vaccine and safety in larger and older population. Methods: This is a phase III prospective, single blinded, randomized, active controlled study (CTRI/2021/08/036074) conducted at 18 sites across India in healthy adults aged between 18-80 years. This study has two arms; immunogenicity arm and safety arm. Participants in immunogenicity arm were randomized equally to either CORBEVAX or COVISHIELD vaccination groups to determine the immunogenic superiority. Healthy adults without a history of Covid-19 vaccination or SARS-CoV-2 infection, were enrolled. Findings: The safety profile of CORBEVAX vaccine was comparable to the comparator vaccine COVISHIELD in terms of overall AE rates, related AE rates and medically attended AEs. Majority of reported AEs were mild in nature, and overall CORBEVAX appeared to cause fewer local and systemic adverse reactions/events. Overall, two grade-3 serious AEs (Dengue fever and femur fracture) were reported and they are unrelated to study vaccine. Neutralizing Antibody titers, against both Ancestral and Delta strain, induced post two-dose vaccination regimen were higher in the CORBEVAX arm as compared to COVISHIELD and the analysis of GMT ratios demonstrated immunogenic superiority of CORBEVAX in comparison with COVISHIELD. Both CORBEVAX and COVISHIELD vaccines showed comparable seroconversion post vaccination when assessed against anti-RBD IgG response. The subjects in CORBEVAX cohort also exhibited higher Interferon-gamma secreting PBMCs post stimulation with SARS-COV-2 RBD peptides than the subjects in COVISHIELD cohort. Interpretations: Neutralizing antibody titers induced by CORBEVAX vaccine against Delta and Ancestral strains were protective, indicative of vaccine effectiveness of &gt;90% for prevention of symptomatic infections based on the Correlates of Protection assessment performed during Moderna and Astra-Zeneca vaccine Phase III studies. Safety findings revealed that CORBEVAX vaccine has excellent safety profile when tested in larger and older population.</jats:p

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.</p