Safety, immunogenicity and dose ranging of a new Vi-CRM₁₉₇ conjugate vaccine against typhoid fever: randomized clinical testing in healthy adults

Pierre van Damme, Froukje Kafeja, Alessandra Anemona, Venere Basile, Anne Katrin Hilbert, Ilse De Coster, Simona Rondini, Francesca Micoli, Rana M Qasim Khan, Elisa Marchetti, Vito Di Cioccio, Allan Saul, Laura B Martin, Audino Podda, Pierre van Damme, Froukje Kafeja, Alessandra Anemona, Venere Basile, Anne Katrin Hilbert, Ilse De Coster, Simona Rondini, Francesca Micoli, Rana M Qasim Khan, Elisa Marchetti, Vito Di Cioccio, Allan Saul, Laura B Martin, Audino Podda

Abstract

Background: Typhoid fever causes more than 21 million cases of disease and 200,000 deaths yearly worldwide, with more than 90% of the disease burden being reported from Asia. Epidemiological data show high disease incidence in young children and suggest that immunization programs should target children below two years of age: this is not possible with available vaccines. The Novartis Vaccines Institute for Global Health developed a conjugate vaccine (Vi-CRM₁₉₇) for infant vaccination concomitantly with EPI vaccines, either starting at 6 weeks with DTP or at 9 months with measles vaccine. We report the results from a Phase 1 and a Phase 2 dose ranging trial with Vi-CRM₁₉₇ in European adults.

Methodology: Following randomized blinded comparison of single vaccination with either Vi-CRM₁₉₇ or licensed polysaccharide vaccines (both containing 25·0 µg of Vi antigen), a randomised observer blinded dose ranging trial was performed in the same center to compare three concentrations of Vi-CRM₁₉₇ (1·25 µg, 5·0 µg and 12·5 µg of Vi antigen) with the polysaccharide vaccine.

Principal findings: All vaccines were well tolerated. Compared to the polysaccharide vaccine, Vi-CRM₁₉₇ induced a higher incidence of mild to moderate short lasting local pain. All Vi-CRM₁₉₇ formulations induced higher Vi antibody levels compared to licensed control, with clear dose response relationship.

Conclusions: Vi-CRM₁₉₇ did not elicit safety concerns, was highly immunogenic and is therefore suitable for further clinical testing in endemic populations of South Asia.

Trial registration: ClinicalTrials.gov NCT01123941 NCT01193907.

Conflict of interest statement

Competing Interests: AA, VB, AKH, SR, FM, RMQK, EM, VDC, AS, LBM, AP are all Novartis employees. AS and AP receive stock options from Novartis. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. PvD, FK and IDC are all employees of Univeristy of Antwerp, Belgium.

Figures

Figure 1. Subject Completion Flow Chart.
Figure 1. Subject Completion Flow Chart.
Figure 2. Reverse Cumulative Curves of Anti-Vi…
Figure 2. Reverse Cumulative Curves of Anti-Vi ELISA Concentrations before (day 1) and four weeks (day 28) After Vaccination with Vi-CRM197 or Vi-PS.
Antibody concentrations are given in log scale. Values below the limit of detection of the assay were set to 1.0 U/mL.

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