Safety, immunogenicity and non-interference of concomitant Typhoid Vi capsular polysaccharide-tetanus toxoid conjugate vaccine (Typbar-TCV®) and measles or measles-mumps-rubella vaccines in 8-9 months-old Indian children.

We evaluated safety, reactogenicity, and immunogenicity when the WHO-prequalified single-dose Typhoid Vi-polysaccharide conjugate vaccine, Typbar-TCV®, was administered concomitantly with measles (MV) or measles-mumps-rubella (MMR) vaccines in 8- or 9-month-old children. We enrolled 493 children who were randomized 2:1:1:1 to four groups to receive either TCV (0.5 mL intramuscularly) and MV (0.5 ml subcutaneously) concomitantly at 9 months of age (Group 1) with two subgroups given TCV booster 28 days (Group 1A) or 180 days (Group 1B) later, or MV on Day 0 and TCV on Day 28 (Group 2); or TCV at 8 months of age and MV 28 days later (Group 3), or MV only at 9 months of age (Group 4). All children received MMR at 15 months of age. We observed no statistically significant differences between group rates of solicited or unsolicited adverse events assessed throughout the study. Seroconversion rates for measles, mumps, and rubella antibodies were unaffected by concomitant administration with TCV, being similar in Groups 1, 2, and 3 and comparable to Group 4 (Control). IgG anti-Vi antibody titers were similar in all groups after primary Typbar-TCV® vaccination and were not increased by a second dose 28 days later. A small response to a booster dose of Typbar-TCV® given at 180 days did not achieve the high titers observed after the first dose, suggesting that booster vaccination may be more effective after a longer interval than 6 months. Typbar-TCV® can be safely co-administered with measles and MMR vaccines in children aged ≥9 months.Clinical trial registration number: CTRI/2014/04/004532.

Safety and immunogenicity clinical trial of an inactivated SARS-CoV-2 vaccine, BBV152 (a phase 2, double-blind, randomised controlled trial) and the persistence of immune responses from a phase 1 follow-up report

BackgroundBBV152 is a whole-virion inactivated SARS-CoV-2 vaccine (3 {micro}g or 6 {micro}g) formulated with a Toll-like receptor 7/8 agonist molecule adsorbed to alum (Algel-IMDG). Earlier, we reported findings from a phase 1 (vaccination regimen on days 0 and 14) randomised, double-blind trial on the safety and immunogenicity of three different formulations of BBV152 and one control arm containing Algel (without antigen). Two formulations were selected for the phase 2 (days 0 and 28) study. Here, we report interim findings of a controlled, randomised, double-blind trial on the immunogenicity and safety of BBV152: 3 {micro}g and 6 {micro}g with Algel-IMDG. MethodsWe conducted a double-blind, randomised, multicentre, phase 2 clinical trial to evaluate the immunogenicity and safety of BBV152. A total of 380 healthy children and adults were randomised to receive two vaccine formulations (n=190 each) with 3 {micro}g with Algel-IMDG and 6 {micro}g with Algel-IMDG. Two intramuscular doses of vaccines were administered (four weeks apart). Participants, investigators, and laboratory staff were blinded to the treatment allocation. The primary outcome was seroconversion ([≥]4-fold above baseline) based on wild-type virus neutralisation (PRNT50). Secondary outcomes were reactogenicity and safety. Cell-mediated responses were evaluated. A follow-up blood draw was collected from phase 1 participants at day 104 (three months after the second dose). FindingsAmong 921 participants screened between Sep 7-13, 2020, 380 participants were randomised to the safety and immunogenicity population. The PRNT50 seroconversion rates of neutralising antibodies on day 56 were 92{middle dot}9% (88{middle dot}2, 96{middle dot}2) and 98{middle dot}3% (95{middle dot}1, 99{middle dot}6) in the 3 {micro}g and 6 {micro}g with Algel-IMDG groups, respectively. Higher neutralising titres (2-fold) were observed in the phase 2 study than in the phase 1 study (p<0.05). Both vaccine groups elicited more Th1 cytokines than Th2 cytokines. After two doses, the proportion (95% CI) of solicited local and systemic adverse reactions were 9.7% (6{middle dot}9, 13{middle dot}2) and 10.3% (7{middle dot}4, 13{middle dot}8) in the 3 {micro}g and 6 {micro}g with Algel-IMDG groups, respectively. No significant difference was observed between the groups. No serious adverse events were reported in this study. Phase 1 follow-up immunological samples at day 104 showed seroconversion in 73{middle dot}5% (63{middle dot}6, 81{middle dot}9), 81{middle dot}1% (71{middle dot}4, 88{middle dot}1), and 73{middle dot}1% (62{middle dot}9, 81{middle dot}8) of individuals in the 3 {micro}g with Algel-IMDG, 6 {micro}g with Algel-IMDG, and 6 {micro}g with Algel groups, respectively. InterpretationIn the phase 1 trial, BBV152 produced high levels of neutralising antibodies that remained elevated in all participants three months after the second vaccination. In the phase 2 trial, BBV152 led to tolerable safety outcomes and enhanced humoral and cell-mediated immune responses. The safety profile of BBV152 is noticeably lower than the rates for other SARS-CoV-2 vaccine platform candidates. The 6 {micro}g Algel-IMDG formulation was selected for the phase 3 efficacy trial. FundingThis work was supported and funded by Bharat Biotech International Limited. Clinicaltrials.gov: NCT04471519

Evaluation of a standardised Vi poly-l-lysine ELISA for serology of Vi capsular polysaccharide antibodies.

Typhoid vaccines based on protein-conjugated capsular Vi polysaccharide (TCVs) prevent typhoid in infants and young children. Analysis of the serum anti-Vi IgG response following immunisation against typhoid confirms the immunogenicity of TCVs and forms an important part of the pathway to licensing. Comparative studies could expedite the licencing process, and the availability of a standardised ELISA method alongside the 1st International Standard (IS) 16/138 for anti-typhoid capsular Vi polysaccharide IgG (human) will facilitate this process. To this end, a non-commercial ELISA based on a coat of Vi and poly-l-lysine (Vi-PLL ELISA) was evaluated by 10 laboratories. Eight serum samples, including IS 16/138, were tested in the standardised Vi-PLL ELISA (n = 10), a commercial Vi ELISA (n = 3) and a biotinylated Vi ELISA (n = 1). Valid estimates of potencies relative to IS 16/138 were obtained for all samples in the Vi-PLL ELISA and the commercial ELISA, with good repeatability and reproducibility evident from the study results and concordant estimates obtained by the two ELISA methods. The study demonstrates that the Vi-PLL ELISA can be used in clinical trial studies to determine the immunogenicity of TCVs.