DOUBLE-BLIND VACCINE-CONTROLLED RANDOMIZED EFFICACY TRIAL OF AN INVESTIGATIONAL SHIGELLA-SONNEI CONJUGATE VACCINE IN YOUNG-ADULTS

Background The aim of this double-blind randomised vaccine-controlled trial was to assess the efficacy of a conjugate vaccine composed of Sh igella sonnei O-specific polysaccharide bound to Pseudomonas aeruginos a recombinant exoprotein A (S sonnei-rEPA) and of an oral, live-attenu ated Escherichia coli/S flexneri 2a (EcSf2a-2) hybrid vaccine among mi litary recruits in Israel at high risk of exposure to Shigella spp. We report here our preliminary findings on the efficacy of S sonnei-rEPA ; we have not documented sufficient cases to assess the efficacy of Ec Sf2a-2. Methods Between April, 1993, and August, 1994, male Israeli mi litary recruits aged 18-22 years were asked to take part in our study. We enrolled 1446 soldiers from seven separate field sites (groups A-G ). Soldiers were randomly allocated one injection of S sonnei-rEPA and four doses of oral placebo (n=576), four oral doses of EcSf2a-2 and o ne injection of saline placebo (n=580), or one injection of meningococ cal tetravalent control vaccine and four doses of oral placebo (n=290) . Because there were no cases of S flexneri 2a, the EcSf2a-2 and menin gococcal vaccines were the control group. We defined S sonnei shigello sis as diarrhoea with a positive faecal culture for S sonnei. Each gro up of soldiers was followed up for 2.5-7.0 months. The primary endpoin t was protective efficacy of S sonnei-rEPA against S sonnei shigellosi s. Findings Cases of culture-proven S sonnei shigellosis occurred in f our groups of soldiers (groups A-D), which comprised 787 volunteers (3 12 received S sonnei-rEPA, 316 received EcSf2a-2, and 159 received men ingococcal control vaccine). In groups A-C, cases of shigellosis occur red 70-155 days after vaccination, whereas in group D cases occurred a fter 1-17 days. In groups A-C, the attack rate of shigellosis was 2.2% in recipients of S sonnei-rEPA compared with 8.6% in controls (protec tive efficacy 74% [95% CI 28-100], p=0.006). S sonnei-rEPA also showed significant protection against shigellosis in group D (43% [4-82], p= 0.039). Prevaccination and postvaccination ELISA measurements of antib ody to S sonnei lipopolysaccharide among recipients of S sonnei-rEPA s howed that the vaccinees who developed S sonnei shigellosis had signif icantly lower serum IgG and IgA responses to the homologous lipopolysa ccharide than those who did not (p=<0.05). Interpretation One injectio n of S sonnei-rEPA confers type specific protection against S sonnei s higellosis. The high antibody concentration induced by the conjugate v accine in volunteers who did not develop shigellosis suggests that the re is an association between serum antibody titre and protection.