Review Article | Published:

Clinical trials of Shigella vaccines: two steps forward and one step back on a long, hard road

Nature Reviews Microbiology volume 5, pages 540553 (2007) | Download Citation

Abstract

More than 50 years of research has yielded numerous Shigella vaccine candidates that have exemplified both the promise of vaccine-induced prevention of shigellosis and the impediments to developing a safe and effective vaccine for widespread use, a goal that has yet to be attained. This Review discusses the most advanced strategies for Shigella vaccine development, the immune responses that are elicited following disease or vaccination, the factors that have accelerated or impeded Shigella vaccine development and our ideas for the way forward.

Key points

  • Evidence that clinical infection with Shigella, either following natural infection or volunteer challenge, confers serotype-specific homologous protection provides incentive for the development of an effective vaccine.

  • Shigella infection elicits a wide spectrum of immune responses to Shigella antigens, including antibodies to O-antigen polysaccharides, invasion plasmid antigens and other proteins, as well as cell-mediated immunity. Protective responses are largely thought to be targeted to the serotype-specific O-antigen. The role of the other immune responses to Shigella infection in protection remains undetermined.

  • Experimental models of shigellosis in volunteers and non-human primates have revealed details of the pathogenic process of Shigella infection and have provided a crucial tool for the evaluation of vaccine candidates.

  • Of the various vaccine platforms tested, live attenuated Shigella and lipopolysaccharide (LPS) conjugates have demonstrated efficacy in clinical trials. Multiple candidate live attenuated strains have been developed in attempts to achieve the correct balance of safety and immunogenicity.

  • Development of a broadly protective Shigella vaccine is complex due to the requirement for the inclusion of three species, Shigella sonnei, Shigella dysenteriae 1 and Shigella flexneri,and multiple S. flexneri serotypes. Identification of three S. flexneri serotypes that collectively express all of the group-specific antigens has allowed the pursuit of a manageable pentavalent strategy.

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Acknowledgements

This paper includes work funded, in part, by the National Institute of Allergy and Infectious disease (NIAID), National Institutes of Health (NIH), Department of Health and Human Services (DHHS) federal research grants and contracts N01 AI25461, R01 AI029471 and U54 AI57168 (to M.L.), R01 AI57927 and N01 AI30028 (to M.S.) and R01 AI059223 (to E.B.) and a grant from the Bill and Melinda Gates Foundation (to M.L.).

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Affiliations

  1. Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

    • Myron M. Levine
    • , Karen L. Kotloff
    • , Eileen M. Barry
    • , Marcela F. Pasetti
    •  & Marcelo B. Sztein

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The authors declare no competing financial interests.

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Correspondence to Myron M. Levine.

Glossary

T helper 1

(TH1 cell). A type of activated TH cell that promotes responses associated with the production of a particular set of cytokines, including interleukin-2 and interferon-γ, the main function of which is to stimulate phagocytosis-mediated defences against intracellular pathogens.

Parenteral

A vaccine administered by injection into the muscle, subcutaneous tissue or dermis (as opposed to mucosal immunization via an oral or nasal route).

Phase III trial

Refers to a large-scale field trial of rigorous epidemiological design to determine the efficacy of a vaccine. When feasible, the preferred design involves a randomized, controlled, adequately powered, double-blind study in which allocation of vaccine or control regimen takes place at the level of the individual subject. Phase III trials, which are usually designated as pivotal studies for licensure, use a final formulation of the vaccine.

Phase I trial

Initial evaluation of the safety and immunogenicity of a vaccine in small groups of healthy subjects who, in a step-wise manner, receive increasing dosage levels of the vaccine. For live vaccines, vaccine shedding is also monitored. If the Phase I study is conducted under physical containment (such as in a research isolation ward), one can preliminarily assess the propensity of the live vaccine to be transmitted by including several placebo recipients as contact controls.

Phase II trial

Expanded (usually placebo controlled) studies of the safety, clinical acceptability and immunogenicity of a vaccine in larger numbers (often tens or hundreds) of subjects who exemplify the target age and other characteristics for the use of the vaccine. Phase II trials aim to identify the optimal dosage level, formulation and immunization regimen of the vaccine to be used in the target groups, thereby paving the way for a pivotal Phase III efficacy trial.

Community volunteers

Community volunteers is a term commonly used to refer to volunteers in a defined population that participate in clinical trials.

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DOI

https://doi.org/10.1038/nrmicro1662

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