Comparison of the immunogenicity and safety of Euvichol-Plus with Shanchol in healthy Indian adults and children: an open-label, randomised, multicentre, non-inferiority, parallel-group, phase 3 trial.

Background: Considering the cholera menace in India and to seek licensure of the oral cholera vaccine (OCV), Euvichol-Plus, we conducted a clinical trial to compare the immunogenicity and safety of Euvichol-Plus with Shanchol in healthy Indian adults and children. Methods: This phase 3, open-label, multicentre, randomised, non-inferiority, parallel-group, comparative study was conducted at seven sites across India involving 416 healthy adults (aged ≥18-60 years) and children (aged ≥1 to <18 years). Healthy individuals who agreed to participate through a voluntary written informed consent form along with oral or written assent (for children aged 7-18 years) were included. No assent was required for those <7 years, as consent was given by the legally acceptable representatives (LAR). Participants were randomised 1:1 to receive two doses of either Euvichol-Plus or Shanchol orally, 14 days apart. The first dose (1.5 ml) was administered on visit 1, and the second dose at 2 weeks after the first dose during visit 2. Participants were followed up telephonically for 3 consecutive days after each visit and returned for final assessment at 2 weeks after the second dose (visit 3). Blood samples were collected for immunogenicity assessment, and safety analyses were done during all the visits. The primary immunogenicity endpoint was the percentage of participants with ≥4-fold increase in anti-Vibrio cholerae (V. cholerae) O1 Ogawa and O1 Inaba (vibriocidal) antibody titres at 2 weeks after the second dose as compared to baseline titres prior to dosing. The secondary immunogenicity endpoints included the percentage of participants with ≥4-fold increase in anti-V. cholerae O139 antibody titres at 2 weeks after the second dose as compared to baseline titres, and geometric mean titres (GMT) and geometric mean ratios (GMR) as measured by anti-V. cholerae O1 Ogawa, O1 Inaba, and O139 antibody titres at 2 weeks after the second dose as compared to baseline titres. The safety endpoints included assessment of solicited, unsolicited adverse events (AEs), and serious adverse events (SAEs). The clinical trial was registered with the Clinical Trials Registry of India (CTRI/2021/08/035344). Findings: The study was performed in two age cohorts: cohort 1 (aged ≥18-60 years, 208 participants [104 in Euvichol-Plus group and 104 in Shanchol group]), and cohort 2 (aged ≥1 to <18 years, 208 participants [104 in Euvichol-Plus group and 104 in Shanchol group]). A total of 414 participants (Euvichol-Plus: 206 and Shanchol: 208) who completed the study (intention-to-treat and per-protocol set) were analysed to compare the vibriocidal titre as an index for immunogenicity. At 2 weeks after the second dose, the percentage of participants in the Euvichol-Plus group who reported a ≥4-fold increase in anti-V. cholerae antibody titres were 68.93% (O1 Ogawa) [95% CI 62.13%-75.18%], 66.02% (O1 Inaba) [95% CI 59.11%-72.46%], and 59.71% (O139) [95% CI 52.67%-66.47%] as compared to 63.94% (O1 Ogawa) [95% CI 57.01%-70.47%], 65.87% (O1 Inaba) [95% CI 58.99%-72.28%], and 56.25% (O139) [95% CI 49.22%-63.10%] in the Shanchol group. The lower limit of 95% CI for treatment difference for all the antibody titres was ≥10% (non-inferiority margin), demonstrating that Euvichol-Plus was non-inferior to Shanchol. The post-vaccination GMT (Day 14 and 28) were more than the pre-vaccination GMT for all three serotypes in both groups. The GMR obtained for Euvichol-Plus over Shanchol for O1 Ogawa, O1 Inaba, and O139 serotypes was >1, indicating non-inferiority of Euvichol-Plus to Shanchol. The safety cohort included 416 participants. Headache was the most common solicited AE, whereas cold and cough were the most common unsolicited AEs in both groups. Interpretation: Euvichol-Plus appears to be non-inferior to Shanchol in terms of immunogenicity and safety in healthy Indian adults and children. Funding: Techinvention Lifecare Private Limited, Mumbai, India.

A randomized, open label trial to evaluate and compare the immunogenicity and safety of a novel liquid hexavalent DTwP-Hib/Hep B-IPV (EasySix™) to licensed combination vaccines in healthy infants.

Immunogenicity and safety of a newly developed liquid DTwP-Hib/HepB-IPV hexavalent vaccine (EasySix™) was evaluated and compared with administration of commercially licensed Pentavac SD® (DTwP-HepB/Hib) and Imovax Polio® vaccine in an open-label, randomized multi-centric trial. 284 participants, aged 6-10weeks, randomized in a 1:1 allocation, received three doses of test or comparator vaccines, administered 4weeks apart. Immunogenicity of the vaccines was determined by measuring the baseline and post-vaccination antibody responses and comparing the proportions of subjects achieving seroprotection against the vaccine antigens; safety was evaluated in terms of solicited (local and systemic) and unsolicited incidences in the follow up phase. Post-vaccination, seroprotection was achieved against all six vaccine antigens in both vaccine groups. The seroresponse rate as well as geometric mean titers of antibody for all vaccine components were comparable between EasySix™ and Pentavac SD®-Imovax Polio® group. Both vaccines had similar reactogenicity profiles and were well tolerated; all adverse events resolved completely without any sequelae. Only one serious adverse event was reported that completely resolved; it was regarded unconnected to the vaccine administered. This study demonstrated that immunogenicity and safety profiles of EasySix™ vaccine, manufactured by Panacea Biotec Ltd, are non-inferior to the commercially available vaccines. CLINICAL TRIAL REGISTRATION: CTRI/2015/02/005578.

A randomized, open-label clinical trial to evaluate immunogenicity and safety of an indigenously developed DTwP-Hib tetravalent combination vaccine (Easyfour®-TT) with Quadrovax® in Indian infants.

An open-label, randomized, multi-center trial was conducted to compare the immunogenicity and safety of an indigenously developed tetravalent DTwP-Hib vaccine, Easyfour®-TT with a commercially available vaccine, Quadrovax®. A total of 244 infants in good health, aged 6-10 weeks, were randomized in a 1:1 allocation to receive three doses of the test or comparator vaccine. Immunogenicity of the vaccines was determined by measuring the baseline and post-vaccination antibody response against the vaccine antigens; safety was evaluated in terms of local and systemic reactions (solicited and unsolicited) reported during the trial. Similar levels of seroprotection/seroresponse were achieved, 4 weeks after receiving 3 doses of Easyfour®-TT and Quadrovax®, and the antibody response of Easyfour®-TT was found non-inferior to Quadrovax®, against all four vaccine antigens. Both vaccines were well tolerated and had similar reactogenicity profiles, with a significantly lower occurrence of local (redness at injection site) and systemic reactions (irritability post-vaccination) with Easyfour®-TT vaccine as compared to Quadrovax® (p < 0.05). All adverse events resolved completely with no sequelae. All through the study, only one serious adverse event was observed that completely resolved upon treatment and was deemed unrelated to the vaccine administered. This study demonstrated that Easyfour®-TT vaccine was safe and immunogenic. CLINICAL TRIAL REGISTRATION NUMBER: CTRI/2014/12/005326 (registered with the Clinical Trial Registry of India (CTRI)).

Safety and immunogenicity of a Vi polysaccharide-tetanus toxoid conjugate vaccine (Typbar-TCV) in healthy infants, children, and adults in typhoid endemic areas: a multicenter, 2-cohort, open-label, double-blind, randomized controlled phase 3 study.

BACKGROUND: Enteric fever caused by Salmonella Typhi remains a major public health problem in developing countries. Typbar-TCV is a single-dose typhoid Vi polysaccharide-tetanus toxoid conjugate vaccine for persons ≥6 months of age. METHODS: Six hundred fifty-four healthy subjects aged 2-45 years enrolled in a double-blind, randomized controlled trial (RCT) received a single dose of Typbar-TCV or comparator "Vi polysaccharide" (Typbar), and 327 healthy subjects aged 6-23 months received a single dose of Typbar-TCV in an open-label trial (OLT); both received single- or multidose presentations from different lots. After 2 years, subsets in each group received a booster dose. The primary objective included analysis of geometric mean titer (GMTs) and 4-fold rise of anti-Vi serum immunoglobulin G (IgG) enzyme-linked immunosorbent assay titers over baseline (seroconversion [SCN]) 42 days after immunization. RESULTS: Typbar-TCV recipients in the RCT attained higher anti-Vi IgG GMTs 42 days after immunization (SCN, 97%; GMT, 1293 [95% confidence interval {CI}, 1153-1449]) than recipients of Typbar (SCN, 93%; GMT, 411 [95% CI, 359-471]) (P < .001). Typbar-TCV was highly immunogenic in the OLT (SCN, 98%; GMT, 1937 [95% CI, 1785-2103]). Two years after vaccination, anti-Vi titers remained higher in Typbar-TCV subjects (GMT, 82 [95% CI, 73-92]); and exhibited higher avidity (geometric mean avidity index [GMAI], 60%) than in Typbar recipients (GMT, 46 [95% CI, 40-53]; GMAI 46%) in the RCT (P < .001). OLT Typbar-TCV recipients achieved GMT of 48 (95% CI, 42-55) and GMAI of 57%. Typbar-TCV induced multiple IgG subclasses and strong booster responses in all ages. No serious vaccine-attributable adverse events were observed. CONCLUSIONS: Single-dose Typbar-TCV is well tolerated and induces robust and long-lasting serum anti-Vi IgG across age groups. CLINICAL TRIALS REGISTRATION: CTRI/2011/08/001957, CTRI/2014/01/004341.

A Japanese Encephalitis Vaccine From India Induces Durable and Cross-protective Immunity Against Temporally and Spatially Wide-ranging Global Field Strains.

BACKGROUND: Japanese encephalitis (JE) is a vaccine-preventable acute disease. We report the results of a phase 2/3 trial of JENVAC, a Vero cell-derived vaccine developed using an Indian strain of JE virus (JEV). METHODS: JENVAC was administered in 2 doses 28 days apart, and immunogenicity was compared to that from a single dose of SA-14-14-2, the only approved JE vaccine and regimen at the time in India. RESULTS: After both the doses, seroconversion and seroprotection were >90% for JENVAC. For SA-14-14-2, seroconversion and seroprotection were 57.69% and 77.56%, respectively, on day 28 and 39.74% and 60.26%, respectively, on day 56. The geometric mean titers at day 28 and day 56 were 145.04 and 460.53, respectively, for JENVAC and 38.56 and 25.29, respectively, for SA-14-14-2. With a single dose of JENVAC, seroprotection titers lasted at least 12 months in >80% of the subjects. Following receipt of 2 doses, 61.17% of subjects retained seroprotection titers at 24 months, and immunogenicity criteria were higher than that for SA-14-14-2 at 12, 18, and 24 months each. Sera from JENVAC subjects neutralized JEV genotypes I, II, III, and IV equally well. Adverse events were not significantly different between the 2 vaccines. CONCLUSIONS: JENVAC elicits long-lasting, broadly protective immunity. CLINICAL TRIALS REGISTRATION: CTRI/2011/07/001855.

A clinical study to determine the pattern of occlusal contacts in lateral positions and its validity in classifying guidance patterns.

The existing classification systems like canine-guided and group function are insufficient to classify all clinical conditions and chances of subjective variations are always there, as there is no standardization in examination method. Hence a study was planned to find out the frequency of tooth contacts in different lateral positions and to assess whether existing occlusal schemes like canine protection and group function can classify all occlusal guidance in the natural dentition. 100 systematically healthy undergraduate students between the age group of 18 to 25 years were selected. Occlusal contacts were examined with shim stock in lateral positions, 0.5, 1, 2, and 3 mm from the maximum intercuspation. Frequency of tooth contacts in different lateral positions was examined. The SPSS version 15.0 statistical software and Chi- Square test were used for statistical analysis. Out of all the four lateral positions, 0.5 mm position showed maximum contacts which progressively decreases for further positions. Out of all teeth, canine showed consistent contact frequency throughout all four positions. Most contact patterns belonged to group function, and a few to canine protection. Majority of the contact patterns were those other than canine protection and group function and were unclassifiable. On the basis of the results of this study, it does not seem appropriate to describe and classify the patterns of occlusal contact using only existing classification system. A clear description regarding the position of mandible should be included in definition for research as well as clinical situations. Here an attempt is made to classify eccentric occlusal contact at different lateral positions so as to get consistent result for future studies.