Abstract
Enteric fever is a major global healthcare issue caused largely by Salmonella enterica serovars Typhi and Paratyphi A. The objective of this study was to develop a novel, bivalent oral vaccine capable of protecting against both serovars. Our approach centred on genetically engineering the attenuated S. Typhi ZH9 strain, which has an excellent safety record in clinical trials, to introduce two S. Paratyphi A immunogenic elements: flagellin H:a and lipopolysaccharide (LPS) O:2. We first replaced the native S. Typhi fliC gene encoding flagellin with the highly homologous fliC gene from S. Paratyphi A using Xer-cise technology. Next, we replaced the S. Typhi rfbE gene encoding tyvelose epimerase with a spacer sequence to enable the sustained expression of O:2 LPS and prevent its conversion to O:9 through tyvelose epimerase activity. The resulting new strain, ZH9PA, incorporated these two genetic changes and exhibited comparable growth kinetics to the parental ZH9 strain. A formulation containing both ZH9 and ZH9PA strains together constitutes a new bivalent vaccine candidate that targets both S. Typhi and S. Paratyphi A antigens to address a major global healthcare gap for enteric fever prophylaxis. This vaccine is now being tested in a Phase I clinical trial (NCT04349553).
Highlights
IntroductionTyphi ZH9 strain, which has an excellent safety record in clinical trials, to introduce two S
The widespread use of antibiotics in low- and middle-income countries (LMICs) has led to the emergence of extensively drug-resistant (XDR) Salmonella strains that are no longer susceptible to multiple lines of antibiotics
We have described a two-step process to genetically engineer a novel strain of Salmodescribed a of two-step process to genetically engineer a novel to strain of nella We thathave has the genotype attenuated
Summary
Typhi ZH9 strain, which has an excellent safety record in clinical trials, to introduce two S. The resulting new strain, ZH9PA, incorporated these two genetic changes and exhibited comparable growth kinetics to the parental. A formulation containing both ZH9 and ZH9PA strains together constitutes a new bivalent vaccine candidate that targets both S. Paratyphi A antigens to address a major global healthcare gap for enteric fever prophylaxis. This vaccine is being tested in a Phase I clinical trial (NCT04349553). Typhi, which is responsible for around 10.9 million cases per year, and S. Paratyphi A, which is responsible for around 3.4 million cases per year, based on 2017 data [2]. In a recent outbreak across three sites in Pakistan, over 90% of both
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