A randomised trial evaluating the safety and immunogenicity of the novel single oral dose typhoid vaccine M01ZH09 in healthy Vietnamese children.
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.
Tran
Tinh Hien
TH
The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
Nguyen
Thi Dung
TD
Nguyen
Thanh Truong
TT
Ninh
Thi Thanh Van
TT
Tran
Nguyen Bich Chau
NB
Nguyen
Van Minh Hoang
VM
Tran
Thi Thu Nga
TT
Cao
Thu Thuy
TT
Pham
Van Minh
VM
Nguyen
Thi Cam Binh
TC
Tran
Thi Diem Ha
TD
Pham
Van Toi
VT
To
Song Diep
SD
Campbell
James I
JI
Stockwell
Elaine
E
Schultsz
Constance
C
Simmons
Cameron P
CP
Glover
Clare
C
Lam
Winnie
W
Marques
Filipe
F
May
James P
JP
Upton
Anthony
A
Budhram
Ronald
R
Dougan
Gordon
G
Farrar
Jeremy
J
Nguyen
Van Vinh Chau
VV
Dolecek
Christiane
C
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
D000907:Antibodies, Bacterial; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D014436:Typhoid-Paratyphoid Vaccines; C503988:typhoid vaccine M01ZH09