title: Immunogenicity and safety of the Vi-CRM197 conjugate vaccine against typhoid fever in adults, children, and infants in south and southeast Asia: results from two randomised, observer-blind, age de-escalation, phase 2 trials.
abstract: BACKGROUND
  Typhoid vaccination is a public health priority in developing countries where young children are greatly affected by typhoid fever. Because present vaccines are not recommended for children younger than 2 years, the Novartis Vaccines Institute for Global Health developed a conjugate vaccine (Vi-CRM197) for infant immunisation. We aimed to assess the immunogenicity and safety of Vi-CRM197 in participants of various ages in endemic countries in south and southeast Asia.
  
  
  METHODS
  We did two randomised, observer-blind, age de-escalation, phase 2 trials at two sites in Pakistan and India (study A), and at one site in the Philippines (study B), between March 2, 2011, and Aug 9, 2012. Adults aged 18-45 years, children aged 24-59 months, older infants aged 9-12 months, and infants aged 6-8 weeks were randomly assigned (1:1) with a computer-generated randomisation list (block size of four) to receive either 5 μg Vi-CRM197 or 25 μg Vi-polysaccharide vaccine (or 13-valent pneumococcal conjugate vaccine in children younger than 2 years). Both infant populations received Vi-CRM197 concomitantly with vaccines of the Expanded Programme on Immunization (EPI), according to WHO schedule. With the exception of designated study site personnel responsible for vaccine preparation, study investigators, those assessing outcomes, and data analysts were masked to treatment allocation. We specified no a-priori null hypothesis for the immunogenicity or safety objectives and all analyses were descriptive. Analyses were by modified intention-to-treat. These studies are registered with ClinicalTrials.gov, numbers NCT01229176 and NCT01437267.
  
  
  RESULTS
  320 participants were enrolled and vaccinated in the two trials: 200 in study A (all age groups) and 120 in study B (children and infants only), of whom 317 (99%) were included in the modified intention-to-treat analysis. One dose of Vi-CRM197 significantly increased concentrations of anti-Vi antibody in adults (from 113 U/mL [95% CI 67-190] to 208 U/mL [117-369]), children (201 U/mL [138-294] to 368 U/mL [234-580]), and older infants (179 U/mL [129-250] to 249 U/mL [130-477]). However, in children and older infants, a second dose of conjugate vaccine had no incremental effect on antibody titres and, at all ages, concentrations of antibodies increased substantially 6 months after vaccination (from 55 U/mL [33-94] to 63 U/mL [35-114] in adults, from 23 U/mL [15-34] to 51 U/mL [34-76] in children, and from 21 U/mL [14-31] to 22 U/mL [14-33] in older infants). Immune response in infants aged 6-8 weeks was lower than that in older participants and, 6 months after third vaccination, antibody concentrations were significantly higher than pre-vaccination concentrations in Filipino (21 U/mL [16-28] vs 2.88 U/mL [1.95-4.25]), but not Pakistani (3.76 U/mL [2.77-5.08] vs 2.77 U/mL [2.1-3.66]), infants. Vi-CRM197 was safe and well tolerated and did not induce any significant interference with EPI vaccines. No deaths or vaccine-related serious adverse events were reported throughout the studies.
  
  
  CONCLUSIONS
  Vi-CRM197 is safe and immunogenic in endemic populations of all ages. Given at 9 months of age, concomitantly with measles vaccine, Vi-CRM197 shows a promise for potential inclusion in EPI schedules of countries endemic for typhoid. An apparent absence of booster response and a reduction in antibody titres 6 months after immunisation should be further investigated, but data show that an immunogenic typhoid vaccine can be safely delivered to infants during EPI visits recommended by WHO.
  
  
  BACKGROUND
  Sclavo Vaccines Association and Regione Toscana.
authors.affiliation: Department of Pediatrics and Child Health, Division of Women and Child Health, Aga Khan University, Karachi, Pakistan.
authors.forename: Zulfiqar A
authors.initials: ZA
authors.lastname: Bhutta
authors.affiliation: Research Institute for Tropical Medicine, Manila, Philippines.
authors.forename: Maria Rosario
authors.initials: MR
authors.lastname: Capeding
authors.affiliation: King Edward Memorial Hospital Research Centre, Rasta Peth, Pune, India.
authors.forename: Ashish
authors.initials: A
authors.lastname: Bavdekar
authors.affiliation: Novartis Vaccines Institute for Global Health, Siena, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Marchetti
authors.affiliation: Novartis Vaccines Institute for Global Health, Siena, Italy.
authors.forename: Shabina
authors.initials: S
authors.lastname: Ariff
authors.affiliation: Department of Pediatrics and Child Health, Division of Women and Child Health, Aga Khan University, Karachi, Pakistan.
authors.forename: Sajid B
authors.initials: SB
authors.lastname: Soofi
authors.affiliation: Novartis Vaccines Institute for Global Health, Siena, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Anemona
authors.affiliation: Department of Pediatrics and Child Health, Division of Women and Child Health, Aga Khan University, Karachi, Pakistan.
authors.forename: Muhammad A
authors.initials: MA
authors.lastname: Habib
authors.affiliation: Research Institute for Tropical Medicine, Manila, Philippines.
authors.forename: Edison
authors.initials: E
authors.lastname: Alberto
authors.affiliation: King Edward Memorial Hospital Research Centre, Rasta Peth, Pune, India.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Juvekar
authors.affiliation: Novartis Vaccines Institute for Global Health, Siena, Italy.
authors.forename: Rana M Qasim
authors.initials: RM
authors.lastname: Khan
authors.affiliation: Novartis Vaccines and Diagnostics Human Serology Laboratories, Marburg, Germany.
authors.forename: Rachid
authors.initials: R
authors.lastname: Marhaba
authors.affiliation: Department of Pediatrics and Child Health, Division of Women and Child Health, Aga Khan University, Karachi, Pakistan.
authors.forename: Noshad
authors.initials: N
authors.lastname: Ali
authors.affiliation: Research Institute for Tropical Medicine, Manila, Philippines.
authors.forename: Nelia
authors.initials: N
authors.lastname: Malubay
authors.affiliation: King Edward Memorial Hospital Research Centre, Rasta Peth, Pune, India.
authors.forename: Anand
authors.initials: A
authors.lastname: Kawade
authors.affiliation: Novartis Vaccines Institute for Global Health, Siena, Italy.
authors.forename: Allan
authors.initials: A
authors.lastname: Saul
authors.affiliation: Novartis Vaccines Institute for Global Health, Siena, Italy.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Martin
authors.affiliation: Novartis Vaccines Institute for Global Health, Siena, Italy. Electronic address: audino.podda@novartis.com.
authors.forename: Audino
authors.initials: A
authors.lastname: Podda
mesh_terms: D000293:Adolescent; D000328:Adult; D000907:Antibodies, Bacterial / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D002675:Child, Preschool; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007194:India; D007223:Infant; D057194:Intention to Treat Analysis; D008297:Male; D008875:Middle Aged; D010154:Pakistan; D010679:Philippines; D012485:Salmonella typhi / Q000276:immunology*; D016037:Single-Blind Method; D014435:Typhoid Fever / Q000276:immunology*; D014436:Typhoid-Paratyphoid Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D018074:Vaccines, Conjugate / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D055815:Young Adult
chemical_list: D000907:Antibodies, Bacterial; D015415:Biomarkers; D014436:Typhoid-Paratyphoid Vaccines; D018074:Vaccines, Conjugate