The safety and immunogenicity of a bivalent conjugate vaccine against Salmonella enterica Typhi and Paratyphi A in healthy Indian adults: a phase 1, randomised, active-controlled, double-blind trial
Kulkarni PS., Potey AV., Bharati S., Kunhihitlu A., Narasimha B., Yallapa S., Dharmadhikari A., Gavade V., Kamat CD., Mallya A., Sarma AD., Goel S., Pisal SS., Poonawalla CS., Venkatesan R., Jones E., Flaxman A., Kim YC., Pollard AJ., McLean F., Pantazi E., Dinesh T., Atherton R., Day N., Park J., Sahoo S.
Background: Enteric fever caused by Salmonella enterica Typhi and Salmonella Paratyphi A is an important public health problem, especially in low-income and middle-income countries with limited access to safe water and sanitation. We present results from, to our knowledge, the first ever human study of a bivalent paratyphoid A-typhoid conjugate vaccine (Sii-PTCV). Methods: In this double-blind phase 1 study, 60 healthy Indian adults were randomly assigned (1:1) to receive a single intramuscular dose of either Sii-PTCV or typhoid conjugate vaccine (Typbar-TCV). Safety was assessed by observing solicited adverse events for 1 week, unsolicited events for 1 month, and serious adverse events (SAEs) over 6 months. Immunogenicity at 1 month and 6 months was assessed by measuring anti-capsular polysaccharide antigen Vi (anti-Vi) IgG and IgA against Salmonella Typhi and anti-lipopolysaccharide (LPS) IgG against Salmonella Paratyphi A by ELISA, and functional antibodies using serum bactericidal assay (SBA) against Salmonella Paratyphi A. This study is registered with Clinical Trial Registry–India (CTRI/2022/06/043608) and is completed. Findings: 60 participants were enrolled. Of these 60 participants, 57 (95%) participants were male and three (5%) participants were female. Solicited adverse events were observed in 27 (90%) of 30 participants who received Sii-PTCV and 26 (87%) of 30 participants who received Typbar-TCV. The most common local solicited event was pain in 27 (90%) participants who received Sii-PTCV and in 23 (77%) participants who received Typbar-TCV. The most common solicited systemic event was myalgia in five (17%) participants who received Sii-PTCV, whereas four (13%) participants who received Typbar-TCV had myalgia and four (13%) had headache. No vaccine-related unsolicited adverse events or SAEs were reported. The seroconversion rates on day 29 were 96·7% (95% CI 82·8–99·9) with Sii-PTCV and 100·0% (88·4–100·0) with Typbar-TCV for anti-Vi IgG; 93·3% (77·9–99·2) with Sii-PTCV and 100·0% (88·4–100·0) with Typbar-TCV for anti-Vi IgA; 100·0% (88·4–100·0) with Sii-PTCV and 3·3% (0·1–17·2) with Typbar-TCV for anti-LPS (paratyphoid); and 93·3% (77·9–99·2) with Sii-PTCV and 0% (0·0–11·6) with Typbar-TCV for SBA titres (paratyphoid). Paratyphoid anti-LPS immune responses were sustained at day 181. Interpretation: Sii-PTCV was safe and immunogenic for both typhoid and paratyphoid antigens indicating its potential for providing comprehensive protection against enteric fever. Funding: Serum Institute of India.