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

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.

Figure 1

Pandemics of Shiga dysentery. The first member of the genus Shigella to be isolated, Shigella dysenteriae 1, was isolated by Kiyoshi Shiga during epidemics that occurred in Japan in the 1890s. Beginning in Central America in the late 1960s, pandemics of S. dysenteriae 1 caused severe disease with many complications and high case-fatality rates in all age groups. Subsequent pandemics occurred in Asia and Africa over the following 3 decades.

Figure 2

The distribution of Shigella species and Shigella flexneri serotypes from selected studies in Latin America, Asia and Africa. Several population-based surveillance studies lasting at least 2 years used extensive serotyping methods (including either commercial absorbed animal sera or monoclonal antibodies for Shigella flexneri typing)^–,–. In all countries, S. flexneri 2a is the single most important S. flexneri subserotype. The most developed of the countries, Chile and Thailand, show a notable proportion of cases due to Shigella sonnei. In any individual country, 3–4 serotypes constitute ∼75% of all cases. However, the other important S. flexneri serotypes, in addition to S. flexneri 2a, differ from country to country. Serotype 1c described in some studies is a provisional serotype. If the CVD pentavalent vaccine strategy that incorporates S. flexneri 2a, S. flexneri 3a and S. flexneri 6 (along with Shigella dysenteriae 1 and S. sonnei) succeeds in conferring cross-protection against the other 11 classical S. flexneri serotypes in future field trials, it should be possible to achieve a broad-spectrum global vaccine against shigellosis.

Figure 3

Immunity to Shigella. a | Immune responses to wild-type Shigella infection. The specific immune responses that mediate protection against shigellosis remain controversial. The strong serum IgG and IgA antibody responses to Shigella O-antigen induced by wild-type infection correlate with protection data from epidemiological and seroepidemiological studies^, as well as non-human primate challenges. Gut-derived IgA anti-O-antigen antibody-secreting cell (ASC) responses are also thought to have a significant role in protection. By contrast, the role of antibody responses to Shigella protein antigens (such as invasion plasmid antigen (Ipa) proteins, VirG and others) and of cell-mediated immunity (CMI) in contributing to protection remain a matter of speculation. b | Immune responses to vaccines. The immune responses generated by types of Shigella vaccines (live oral and parenteral conjugate) that have been shown to confer protection are shown. Responses elicited by live oral vaccines include IgA and IgG anti-O-antigen and anti-Ipa ASC detected among peripheral blood mononuclear cells (PBMC), serum IgA and IgG anti-O-antigen and anti-Ipa, as well as IgA anti-O-antigen in stool, intestinal fluid and urine^,,,,. Interferon-γ(IFN-γ) responses to Shigella antigens have also been observed in volunteers immunized with Shigella flexneri 2a strain CVD 1207 (REF. 87), Shigella sonnei strain WRSS1 (REF 94) and SFL1070 (REF 85). The contribution of CMI and of antibodies to Shigella proteins (for example, Ipa and VirG) elicited by live oral vaccines in preventing clinical Shigella infection remains uncertain. In contrast to the broad immune responses elicited by live oral vaccines, parenteral conjugate vaccines elicit a narrower response, characterized predominantly by serum IgG antibodies to Shigella O-antigen. Wild-type Shigella or live oral vaccines are likely to generate long- and short-lived plasma cells (PC) and memory B cells (Bμ) that reside in the bone marrow, spleen and gut-associated lymphoid tissue (GALT). By contrast, PC and Bμ elicited by conjugate vaccines are likely to be confined to the bone marrow and spleen. The relative magnitudes of immune responses are depicted by gradients of colour at the various effector sites. IL, interleukin; ND, no data; TNF-α, tumour-necrosis factor-α.