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.

/pdf/clinical-trials-of-shigella-vaccines-two-steps-forward-and-5akba3c2vx.pdf

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

The protective efficacy of oral B subunit killed whole-cell (BS-WC) and killed whole-cell (WC) cholera vaccines was assessed in 63 498 Bangladeshi children aged 2-15 years and women aged over 15 years. Each received three doses of BS-WC, WC, or placebo in a randomised, double-blinded fashion. Surveillance for cases seeking medical care up to six months after the third dose revealed 26 cases of confirmed cholera in the placebo group, 4 cases in the BS-WC group (protective efficacy 85%; p less than 0.0001), and 11 cases in the WC group (protective efficacy 58%; p less than 0.01). For each vaccine protective efficacy was consistent in different age-groups (2-10 years versus greater than 10 years) and for different severities of cholera.

Field trial of oral cholera vaccines in Bangladesh

Results Of the 285 rotavirus cases, 265 (93%) required hospitalization; 251 (88%) received intravenous hydration. A single rotavirus strain (G2P(4)) was identified in 88% of the cases. Among cases and controls, respectively, 18% and 12% were unvacci- nated, 12% and 15% received 1 dose of RV5, 15% and 17% received 2 doses, and 55% and 57% received 3 doses. Vaccination with 3 doses was associated with a lower risk of rotavirus diarrhea requiring overnight admission or intravenous hydration (odds ratio (OR), 0.54; 95% confidence interval (CI), 0.36-0.82). Of the 285 rotavirus cases, 191 (67%) were severe and 54 (19%) were very severe. A progressively lower risk of severe (OR, 0.42; 95% CI, 0.26-0.70) and very severe rotavirus diarrhea (OR, 0.23; 95% CI, 0.08-0.61) was observed after RV5 vaccination. Thus, effectiveness of 3 doses of RV5 against rotavirus disease requiring admission or treatment with intravenous hydra- tion was 46% (95% CI, 18%-64%); against severe rotavirus diarrhea, 58% (95% CI, 30%-74%); and against very severe rotavirus diarrhea, 77% (95% CI, 39%-92%). Conclusion Vaccination with RV5 was associated with a lower risk of severe rota- virus diarrhea in children younger than 2 years in Nicaragua but to a lesser extent than that seen in clinical trials in industrialized countries.

https://jamanetwork.com/journals/jama/articlepdf/184013/joc90037_2243_2251.pdf

Association between pentavalent rotavirus vaccine and severe rotavirus diarrhea among children in Nicaragua.

Understanding the mechanisms underlying the induction of immunity in the gastrointestinal mucosa following oral immunization and the cross-talk between mucosal and systemic immunity should expedite the development of vaccines to diminish the global burden caused by enteric pathogens. Identifying an immunological correlate of protection in the course of field trials of efficacy, animal models (when available), or human challenge studies is also invaluable. In industrialized country populations, live attenuated vaccines (e.g. polio, typhoid, and rotavirus) mimic natural infection and generate robust protective immune responses. In contrast, a major challenge is to understand and overcome the barriers responsible for the diminished immunogenicity and efficacy of the same enteric vaccines in underprivileged populations in developing countries. Success in developing vaccines against some enteric pathogens has heretofore been elusive (e.g. Shigella). Different types of oral vaccines can selectively or inclusively elicit mucosal secretory immunoglobulin A and serum immunoglobulin G antibodies and a variety of cell-mediated immune responses. Areas of research that require acceleration include interaction between the gut innate immune system and the stimulation of adaptive immunity, development of safe yet effective mucosal adjuvants, better understanding of homing to the mucosa of immunologically relevant cells, and elicitation of mucosal immunologic memory. This review dissects the immune responses elicited in humans by enteric vaccines.

/pdf/immunology-of-gut-mucosal-vaccines-3rmto6ica9.pdf

Immunology of gut mucosal vaccines

The World Health Organization estimates that rotavirus diarrhea results in approximately half a million deaths and approximately 2.4 million hospitalizations in developing countries each year. Two live oral rotavirus vaccines, RotaTeq® (RV 5; Merck) and Rotarix® (RV 1; GlaxoSmithKline) with good efficacy against severe rotavirus disease and a reassuring safety profile could substantially impact the burden of rotavirus disease. In April 2009, WHO provided a recommendation for global introduction of these vaccines in national immunization programs of developing countries worldwide. In this article, we review published data on previous candidate rotavirus vaccines and vaccines in current use, with emphasis on their performance in developed versus developing countries. In developed countries, both first and second generation rotavirus vaccines have demonstrated high efficacy against severe rotavirus disease (pooled efficacy = 73% and 85%, respectively). In developing countries, small early trials for the first generation vaccines failed to provide protection against rotavirus disease (pooled efficacy = 20%), however, trials of the second generation vaccines yielded substantial improvements in efficacy in developing countries (pooled efficacy of 51%), leading to a global recommendation for rotavirus vaccine introduction by WHO. Future efforts for these vaccines should focus on optimizing the efficacy and delivery of these vaccines in challenging target populations of Asia and Africa with the greatest burden of severe rotavirus disease.

/pdf/performance-of-rotavirus-vaccines-in-developed-and-1zsskz10ae.pdf

Performance of rotavirus vaccines in developed and developing countries

Calibrated serological techniques demonstrate significant different serum response rates to an oral killed cholera vaccine between Swedish and Nicaraguan children

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Calibrated serological techniques demonstrate significant different serum response rates to an oral killed cholera vaccine between Swedish and Nicaraguan children