Risk assessment of S. Typhi ZH9 with regard to its use as a live vaccine

Salmonella enterica ssp. enterica serovar Typhi ( S. Typhi ) is a facultative intracellular human pathogenic bacterium from the family Enterobacteriaceae . The bacterium is distributed worldwide and causes the systemic infectious disease, especially in Southeast Asia, Africa, Central and South America Typhus . More than 10 million people are infected with typhus every year, and more than 100,000 people die from it each year. S. Typhi is classified by the ZKBS as Risk group 3 classified.

The current ZKBS statement from November 2022 includes the risk assessment of the attenuated strain S. Typhi ZH9 (2022) , whose use as Live vaccine (referred to as M01ZH09) is to be reviewed. Regarding the development of S. Typhi ZH9 was used as the starting strain S. Typhi Ty2 was chosen, which already has attenuation. S. Typhi ZH9 was generated by inserting two additional mutations into Ty2, which induce auxotrophy and prevent systematic replication of the bacterium. The tolerability and efficacy of S. Typhi ZH9 (2022) already presents the results of six clinical trials involving a total of 371 subjects. After a single oral administration, the vaccine strain was described as generally well-tolerated and safe. No adverse reactions occurred in the treated individuals. Bacteremia or other serious adverse events. Adverse events following oral administration included gastrointestinal side effects, headache, and fever in both the vaccine and placebo groups. However, these were mostly assessed as mild, occasionally as moderate, and in a few cases as severe. Attenuation by S. Typhi ZH9 compared to the wild type correlates not only with reduced pathogenicity but also with reduced Biodistribution and excretion. In clinical studies, no S. Typhi ZH9 bacteria were detected in blood or urine samples. Excretion of the vaccine strain in feces was primarily detected during the first seven days after administration.

According to Section 5 Paragraph 1 GenTSV in conjunction with the criteria in Annex 1 GenTSV, the ZKBS classifies Salmonella enterica ssp. enterica serovar Typhi ZH9 (2022) as a donor and recipient organism for genetic engineering work in the Risk group 1 This is justified by the good tolerability of the potential vaccine strain, which has been demonstrated in extensive clinical studies.

The ZKBS statement can be found under the reference number Ref. No. 45241.024 can be retrieved.