title: A randomised trial evaluating the safety and immunogenicity of the novel single oral dose typhoid vaccine M01ZH09 in healthy Vietnamese children.
abstract: BACKGROUND
  The emergence of drug resistant typhoid fever is a major public health problem, especially in Asia. An oral single dose typhoid vaccine would have major advantages. M01ZH09 is a live oral single dose candidate typhoid vaccine containing Salmonella enterica serovar Typhi (Ty2 aroC(-)ssaV(-)) ZH9 with two independently attenuating deletions. Studies in healthy adults demonstrated immunogenicity and an acceptable safety profile.
  
  
  OBJECTIVE
  We conducted a randomised placebo controlled, single-blind trial to evaluate the safety and immunogenicity of M01ZH09 in healthy Vietnamese children aged 5 to 14 years.
  
  
  METHODS
  Subjects were randomly assigned to receive either a nominal dose of 5x10(9) CFU of M01ZH09 or placebo and were followed up for 28 days. The primary safety outcome was the proportion of subjects with any adverse event attributed to M01ZH09. The primary immunogenicity endpoint was the proportion of subjects who showed a positive immune response to M01ZH09 in the Salmonella Typhi lipopolysaccharide (LPS) specific serum IgA and IgG ELISA.
  
  
  RESULTS
  One hundred and fifty-one children were enrolled, 101 subjects received M01ZH09 and 50 subjects received placebo. An intention to treat analysis was conducted. There were no serious adverse events and no bacteraemias. In the M01ZH09 group, 26 (26%; 95% CI, 18-5%) of 101 subjects experienced adverse events compared to 11 (22%; 95% CI, 12-36%) of 50 subjects in the placebo group (odds ratio (OR) [95%CI] = 1.23 [0.550-2.747]; p = 0.691). Faecal shedding of S. Typhi (Ty2 aroC(-)ssaV(-)) ZH9 was detected in 51 (51%; 95% CI, 41-61%) of 100 M01ZH09 subjects. No shedding was detected beyond day 3. A positive immune response, defined as 70% increase (1.7 fold change) in LPS specific serum IgG (day 14 or 28) and/or 50% increase (1.5 fold change) in LPS specific serum IgA (day 7 or 14) from baseline was detected in 98 (97%; 95% CI, 92-99%) of 101 M01ZH09 recipients and 8 (16%; 95% CI, 7-29%) of 50 placebo recipients. Twenty-eight (100%; 95% CI, 88-100%) of 28 vaccine recipients who were evaluated in the LPS specific IgA ELISPOT assay showed a positive response compared to none of the 14 placebo recipients tested.
  
  
  CONCLUSIONS
  This was the first phase II trial of a novel oral candidate typhoid vaccine in children in an endemic country. M01ZH09 had an appropriate safety profile and was immunogenic in children.
  
  
  BACKGROUND
  Controlled-trials.com ISRCTN91111837.
authors.affiliation: The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Tinh Hien
authors.initials: TH
authors.lastname: Tran
authors.forename: Thi Dung
authors.initials: TD
authors.lastname: Nguyen
authors.forename: Thanh Truong
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Thi Thanh Van
authors.initials: TT
authors.lastname: Ninh
authors.forename: Nguyen Bich Chau
authors.initials: NB
authors.lastname: Tran
authors.forename: Van Minh Hoang
authors.initials: VM
authors.lastname: Nguyen
authors.forename: Thi Thu Nga
authors.initials: TT
authors.lastname: Tran
authors.forename: Thu Thuy
authors.initials: TT
authors.lastname: Cao
authors.forename: Van Minh
authors.initials: VM
authors.lastname: Pham
authors.forename: Thi Cam Binh
authors.initials: TC
authors.lastname: Nguyen
authors.forename: Thi Diem Ha
authors.initials: TD
authors.lastname: Tran
authors.forename: Van Toi
authors.initials: VT
authors.lastname: Pham
authors.forename: Song Diep
authors.initials: SD
authors.lastname: To
authors.forename: James I
authors.initials: JI
authors.lastname: Campbell
authors.forename: Elaine
authors.initials: E
authors.lastname: Stockwell
authors.forename: Constance
authors.initials: C
authors.lastname: Schultsz
authors.forename: Cameron P
authors.initials: CP
authors.lastname: Simmons
authors.forename: Clare
authors.initials: C
authors.lastname: Glover
authors.forename: Winnie
authors.initials: W
authors.lastname: Lam
authors.forename: Filipe
authors.initials: F
authors.lastname: Marques
authors.forename: James P
authors.initials: JP
authors.lastname: May
authors.forename: Anthony
authors.initials: A
authors.lastname: Upton
authors.forename: Ronald
authors.initials: R
authors.lastname: Budhram
authors.forename: Gordon
authors.initials: G
authors.lastname: Dougan
authors.forename: Jeremy
authors.initials: J
authors.lastname: Farrar
authors.forename: Van Vinh Chau
authors.initials: VV
authors.lastname: Nguyen
authors.forename: Christiane
authors.initials: C
authors.lastname: Dolecek
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000907:Antibodies, Bacterial / Q000097:blood; D044466:Asian People; D002648:Child; D002675:Child, Preschool; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D012485:Salmonella typhi / Q000276:immunology*; D014436:Typhoid-Paratyphoid Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D014744:Vietnam
chemical_list: D000907:Antibodies, Bacterial; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D014436:Typhoid-Paratyphoid Vaccines; C503988:typhoid vaccine M01ZH09