Flexibility of Oral Cholera Vaccine Dosing—A Randomized Controlled Trial Measuring Immune Responses Following Alternative Vaccination Schedules in a Cholera Hyper-Endemic Zone

<div><p>Background</p><p>A bivalent killed whole cell oral cholera vaccine has been found to be safe and efficacious for five years in the cholera endemic setting of Kolkata, India, when given in a two dose schedule, two weeks apart. A randomized controlled trial revealed that the immune response was not significantly increased following the second dose compared to that after the first dose. We aimed to evaluate the impact of an extended four week dosing schedule on vibriocidal response.</p><p>Methodology/Principal Findings</p><p>In this double blind randomized controlled non-inferiority trial, 356 Indian, non-pregnant residents aged 1 year or older were randomized to receive two doses of oral cholera vaccine at 14 and 28 day intervals. We compared vibriocidal immune responses between these schedules. Among adults, no significant differences were noted when comparing the rates of seroconversion for <i>V</i>. <i>cholerae O1 Inaba</i> following two dose regimens administered at a 14 day interval (55%) vs the 28 day interval (58%). Similarly, no differences in seroconversion were demonstrated in children comparing the 14 (80%) and 28 day intervals (77%). Following 14 and 28 day dosing intervals, vibriocidal response rates against <i>V</i>. <i>cholerae</i> O1 Ogawa were 45% and 49% in adults and 73% and 72% in children respectively. Responses were lower for <i>V</i>. <i>cholerae</i> O139, but similar between dosing schedules for adults (20%, 20%) and children (28%, 20%).</p><p>Conclusions/Significance</p><p>Comparable immune responses and safety profiles between the two dosing schedules support the option for increased flexibility of current OCV dosing. Further operational research using a longer dosing regimen will provide answers to improve implementation and delivery of cholera vaccination in endemic and epidemic outbreak scenarios.</p></div

Vibriocidal antibody titers and proportion of ≥ 4 fold rise from baseline GMT in children.

<p>^aGeometric mean reciprocal titers</p><p>^bGeometric mean-fold rise from baseline to 14 days after first dose or from baseline to 14 days after second dose</p><p>^c # with ≥4 fold rise in titers from baseline to 14 days after first dose or from baseline to 14 days after second dose</p><p>^d 95% confidence intervals using Wilson Score method</p><p>^e Primary endpoint. Difference in seroconversion rates after second dose were calculated by subtracting 14 day interval from 28 day interval. The 28 days interval group is non-inferior to the 14 day interval group as the lower limit of the proportion difference is greater than pre-defined cut-off (-20%)</p><p>Vibriocidal antibody titers and proportion of ≥ 4 fold rise from baseline GMT in children.</p

Flowchart of adult and children participants in the study.

<p>Flowchart of adult and children participants in the study.</p

Demographic characteristics of study participants.

<p>Demographic characteristics of study participants.</p

Solicited adverse events among adults and children following 14 and 28 day dosing intervals.

<p>^a mild fever (n = 1) and mild headache (n = 1)</p><p>^b mild diarrhea (n = 1), mild nausea (n = 1), mild general ill feeling (n = 1), mild fever (n = 2), mild vomiting (n = 1)</p><p>^c moderate diarrhea (n = 1), mild general ill feeling (n = 1)</p><p>Solicited adverse events among adults and children following 14 and 28 day dosing intervals.</p

Vibriocidal antibody titers and proportion of ≥ 4 fold rise from baseline GMT in adults.

<p>^bGeometric mean-fold rise from baseline to 14 days after first dose or from baseline to 14 days after second dose</p><p>^c # with ≥4 fold rise in titers from baseline to 14 days after first dose or from baseline to 14 days after second dose</p><p>^d 95% confidence intervals using Wilson Score method</p><p>^e Primary endpoint. Difference in seroconversion rates after second dose were calculated by subtracting 14 day interval from 28 day interval. The 28 days interval group is non-inferior to the 14 day interval group as the lower limit of the proportion difference is greater than pre-defined cut-off (-20%)</p><p>Vibriocidal antibody titers and proportion of ≥ 4 fold rise from baseline GMT in adults.</p

Comparison of solicited adverse events following the first and second doses of vaccine (n = 44) and placebo group (n = 43).

<p>Comparison of solicited adverse events following the first and second doses of vaccine (n = 44) and placebo group (n = 43).</p

Dosing schedule for participants.

<p>Dose 1 of vaccine was given on day 0 in both groups, whereas dose 2 was given either on day 14 or day 28</p><p>Dosing schedule for participants.</p

Serum vibriocidal antibody titres to Vibrio Cholerae 01 at baseline, day 7 and day21.

a<p>GMT: geometric mean reciprocal titre.</p>b<p>GMF: geometric mean reciprocal titre: folds rise over baseline.</p

Flow chart for the recruitment of volunteers in the study.

<p>Flow chart for the recruitment of volunteers in the study.</p