Safety, Immunogenicity and Efficacy of Shigella Conjugate Vaccines in 1-4 Year Olds in Israel

Summary

Shigellosis remains a serious and frequent disease throughout the world. Development of vaccines has been difficult because shigellae are habitants of and pathogens for humans only and there is no consensus about the mechanism(s) of immunity to this pathogen. Incomplete, but compelling evidence, indicates that a critical level of serum IgG anti-LPS confers immunity to shigellosis. Important data come from our clinical trial in the Israel Defense Forces (IDF) recruits. A randomized, double-blind, vaccine-controlled study showed that the S. sonnei-rEPA elicited 74% protection against shigellosis occurring about 3 months after vaccination (p=0.001). This vaccine conferred 43% (p=0.04) protection in one company during an outbreak up to 14 days following vaccination suggesting that our Shigella conjugates might be of value in epidemics. The efficacy of S. sonnei-rEPA was correlated with the level of vaccine-induced IgG antibodies. The highest incidence, morbidity, and mortality of shigellosis is in young children. But serum antibody responsiveness to polysaccharide-based vaccines is age-dependent and infants and young children respond poorly or not at all to both disease and vaccination. The safety and immunogenicity of these Shigella conjugates in 4 to 6 years-old children in Israel was demonstrated. But although the fold rise in anti-LPS was similar in the children, the level of anti-LPS elicited by the conjugates was lower than in adults. We improved the immunogenicity of Shigella conjugates as shown in mice and then in adult humans. Now we apply to evaluate the safety, immunogenicity and efficacy of these improved conjugates in 1 to 4 years-old children in Israel. In Israel, shigellosis is common especially in children. S. sonnei (Group D) comprise about 60% of the isolates followed by S. flexneri (Group B): Shigella dysenteriae type 1 (Group A) is not found. We propose to administer 2 injections of either S. sonnei-CRM9 or S. flexneri type 2a-rEPAsucc 6 weeks apart in a random double-blind fashion to about 6,000 1 to 4 year-olds. Active surveillance of the vaccinees for enteric infections will be maintained for at least 2 years to evaluate the effect of vaccination.

Timeline

Start

2003-01

Primary completion

2008-01

Completion

2009-02

Publications

• Background Development of vaccines against shigellosis: memorandum from a WHO meeting. Bull World Health Organ. 1987;65(1):17-25.
• Background DuPont HL, Hornick RB, Snyder MJ, Libonati JP, Formal SB, Gangarosa EJ. Immunity in shigellosis. II. Protection induced by oral live vaccine or primary infection. J Infect Dis. 1972 Jan;125(1):12-6. doi: 10.1093/infdis/125.1.12. No abstract available.
• Background Taylor DN, Echeverria P, Blaser MJ, Pitarangsi C, Blacklow N, Cross J, Weniger BG. Polymicrobial aetiology of travellers' diarrhoea. Lancet. 1985 Feb 16;1(8425):381-3. doi: 10.1016/s0140-6736(85)91397-2.
• Background Hossain MA, Hasan KZ, Albert MJ. Shigella carriers among non-diarrhoeal children in an endemic area of shigellosis in Bangladesh. Trop Geogr Med. 1994;46(1):40-2.
• Background Huilan S, Zhen LG, Mathan MM, Mathew MM, Olarte J, Espejo R, Khin Maung U, Ghafoor MA, Khan MA, Sami Z, et al. Etiology of acute diarrhoea among children in developing countries: a multicentre study in five countries. Bull World Health Organ. 1991;69(5):549-55.
• Background Struelens MJ, Patte D, Kabir I, Salam A, Nath SK, Butler T. Shigella septicemia: prevalence, presentation, risk factors, and outcome. J Infect Dis. 1985 Oct;152(4):784-90. doi: 10.1093/infdis/152.4.784.
• Results Passwell JH, Ashkenazi S, Banet-Levi Y, Ramon-Saraf R, Farzam N, Lerner-Geva L, Even-Nir H, Yerushalmi B, Chu C, Shiloach J, Robbins JB, Schneerson R; Israeli Shigella Study Group. Age-related efficacy of Shigella O-specific polysaccharide conjugates in 1-4-year-old Israeli children. Vaccine. 2010 Mar 2;28(10):2231-2235. doi: 10.1016/j.vaccine.2009.12.050. Epub 2010 Jan 5.

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Indications