title: A cluster randomized non-inferiority field trial on the immunogenicity and safety of tetanus toxoid vaccine kept in controlled temperature chain compared to cold chain.
abstract: BACKGROUND
  In resource-poor settings, cold chain requirements present barriers for vaccine delivery. We evaluated the immunogenicity and safety of tetanus toxoid (TT) vaccine in "Controlled Temperature Chain" (CTC; up to 40 °C for <30 days before administration), compared to standard cold chain (SCC; 2-8 °C). Prior to the study, stability parameters of TT-CTC were shown to meet international requirements.
  
  
  METHODS
  A cluster randomized, non-inferiority trial was conducted in Moïssala district, Chad, December 2012-March 2013. Thirty-four included clusters were randomized to CTC or SCC. Women aged 14-49 years, eligible for TT vaccination and with a history of ≤1 TT dose, received two TT doses 4 weeks apart. Participants were blinded to allocation strategy. Tetanus antibody titers were measured using standard ELISA at inclusion and 4 weeks post-TT2. Primary outcome measures were post-vaccination seroconversion and fold-increase in geometric mean concentrations (GMC). Non-inferiority was by seroconversion difference (TTSCC-TTCTC) <5% and ratio of GMCs (TTSCC/TTCTC) <1.5. Adverse events were monitored at health centers and at next contact with participants.
  
  
  RESULTS
  A total of 2128 women (CTC=1068; SCC=1060) were recruited. Primary intention to vaccinate analysis included 1830 participants; 272 of these were included in the seroconversion analysis. Seroconversion was reached by >95% of participants; upper 95%CI of the difference was 5.6%. Increases in GMC were over 4-fold; upper 95%CI of GMC ratio was 1.36 in the adjusted analysis. Few adverse events were recorded.
  
  
  CONCLUSIONS
  This study demonstrates the immunogenicity and safety of TT in CTC at <40 °C for <30 days. The high proportion of participants protected at baseline results in a reduction of power to detect a 5% non-inferiority margin. However, results at a 10% non-inferiority margin, the comparable GMC increases and vaccine's stability demonstrated in the preliminary phase indicate that CTC can be an alternative strategy for TT delivery in situations where cold chain cannot be maintained.
authors.affiliation: Epicentre, 8 rue Saint Sabin, 75011 Paris, France. Electronic address: aitana.juan@epicentre.msf.org.
authors.forename: Aitana
authors.initials: A
authors.lastname: Juan-Giner
authors.affiliation: Institut Scientifique de Santé Publique, Brussels, Belgium.
authors.forename: Camille
authors.initials: C
authors.lastname: Domicent
authors.affiliation: Epicentre, 8 rue Saint Sabin, 75011 Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Langendorf
authors.affiliation: Consultant, New Haven, CT, USA.
authors.forename: Martha H
authors.initials: MH
authors.lastname: Roper
authors.affiliation: Médecins Sans Frontières, N'Djamena, Chad.
authors.forename: Paul
authors.initials: P
authors.lastname: Baoundoh
authors.affiliation: Médecins Sans Frontières, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Fermon
authors.affiliation: Médecins Sans Frontières, N'Djamena, Chad.
authors.forename: Primitive
authors.initials: P
authors.lastname: Gakima
authors.affiliation: World Health Organization, Geneva, Switzerland.
authors.forename: Simona
authors.initials: S
authors.lastname: Zipursky
authors.affiliation: Expanded Program of Immunization, Ministry of Health, N'Djamena, Chad.
authors.forename: Mbaihol
authors.initials: M
authors.lastname: Tamadji
authors.affiliation: Epicentre, 8 rue Saint Sabin, 75011 Paris, France.
authors.forename: Rebecca F
authors.initials: RF
authors.lastname: Grais
mesh_terms: D000293:Adolescent; D000328:Adult; D000907:Antibodies, Bacterial / Q000097:blood; D002596:Chad; D004356:Drug Storage / Q000379:methods*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D008875:Middle Aged; D012034:Refrigeration; D016037:Single-Blind Method; D013696:Temperature; D013742:Tetanus / Q000517:prevention & control; D013745:Tetanus Toxoid / Q000276:immunology*; D064166:Vaccine Potency; D055815:Young Adult
chemical_list: D000907:Antibodies, Bacterial; D007074:Immunoglobulin G; D013745:Tetanus Toxoid
keywords: Cold chain; Controlled temperature chain; Immunogenicity; Maternal and neonatal tetanus elimination; NCT01559597; Tetanus toxoid