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

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.