Impact Evaluation of Typhoid Conjugate Vaccine Against Culture-Confirmed Typhoid in Extensively Drug-Resistant Outbreak Setting of Hyderabad, Pakistan

Background: We aim to report the effectiveness and impact evaluation of typhoid conjugate vaccine (TCV) against Salmonella Typhi (S.Typhi) among 6 months to 10 years old children in an outbreak setting of extensively drug resistant (XDR) Typhoid in Pakistan. Methods: A cohort and nested case-cohort studies conducted from March 01, 2018 to December 31, 2019. All households located in Qasimabad and Latifabad sub-districts were registered through electronic registry at baseline and age eligible children were offered free vaccination. Typhoid surveillance was established. 1058 randomly selected vaccinated cohort was followed till December 31, 2019 for additional S.Typhi cases. Besides, a case-cohort of 20,090 children were surveyed during Oct-Dec 2019 for any missed cases of S.Typhi. TCV vaccination status was available from baseline registry. Incidence rate ratio (IRR) and vaccine effectiveness (VE) against S.Typhi was calculated using 1-IRR. Findings: A total 23,407 children, 13436 (57·4%) were vaccinated, 12214 (52·2%) were male, and 10168 (43·4%) were 6-59 months old. 5378 (23%) children had suspected S.Typhi, among whom 775 (14·4%) were culture confirmed and 361/526 (68·6%) were XDR. The VE (95% CI) against suspected (regardless of cultures), culture confirmed and XDR S.Typhi, was 55% (52% to 57%), 95% (93% to 96%), and 97% (94% to 98%), respectively. The adjusted hazard ratio (aHR) of contracting culture confirmed S.Typhi among vaccinated children was 0·053; 95% CI 0·039 to 0·071; p <0·001). Interpretation: TCV is effective against culture confirmed S.Typhi among children aged 6 months to 10 years in an outbreak setting in Pakistan, and is able with only moderate deployment to curtail major  XDR typhoid outbreak in a dense populous setting. The vaccine is effective against typhoid irrespective of AMR.   Funding Statement: The study was funded through Bill & Melinda Gates Foundation with grant number OPP1176356. Declaration of Interests: Naor Bar-Zeev has obtained investigator-initiated research grants from Glaxo-Smith-Kline Biologicals, Takeda Pharmaceuticals, Merck Sharp & Dohme and the Serum Institute of India, all unrelated to this work. He has no other conflicts to declare. All other authors have nothing to declare. Ethics Approval Statement: This study was approved by the ethical review committee (ERC) of Aga Khan University Karachi and National Bioethics Committee (NBC) of Pakistan. Written informed consents were obtained from one of the parents/legal guardians.