June 17, 2024

Shigella Vaccines: The Need for an Effective Prevention Strategy

Shigella bacteria are one of the leading causes of diarrhea globally, responsible for millions of cases and deaths each year, especially among young children in developing countries. With the risks Shigella poses to public health, scientists have been working on developing effective vaccines against the infection. In this article, we review the progress made so far in Shigella vaccine research and development.

The Shigella Disease Burden
Shigella bacteria are spread through the fecal-oral route and can cause shigellosis, also known as bacillary dysentery. The disease begins with diarrhea, fever, and stomach cramps, which can become bloody if left untreated. While Shigella infections are usually self-limiting in healthy adults, they can be life-threatening for young children and individuals with compromised immunity. It is estimated that Shigella causes 99 million cases of diarrhea and over 100,000 deaths annually worldwide, with over 80% of cases occurring in developing countries with poor sanitation and limited access to clean water. Young children are especially vulnerable, as the disease can lead to malnutrition, impaired cognitive development, and even death in severe cases. Given its high disease burden and socioeconomic impact, developing an effective Shigella vaccine has been identified as a global public health priority.

Challenges in Shigella Vaccine Development
Despite extensive research efforts, developing a shigella vaccine has proven challenging for several reasons. First, there are four different serogroups of Shigella – S. flexneri, S. sonnei, S. dysenteriae and S. boydii -each of which can cause disease. An ideal vaccine would need to provide broad, serogroup-independent protection against all four. Second, a suitable animal challenge model to adequately test vaccine efficacy and immunogenicity is lacking. Third, the immunological mechanisms underlying protective immunity against shigellosis are not fully understood. Both antibodies and cell-mediated responses are thought to be important for protection, but their relative contributions remain unclear. This knowledge gap has made it difficult for scientists to rationally design correlates of protection against shigellosis. Finally, as a self-limiting diarrheal disease, shigellosis does not always present an attractive commercial market for pharmaceutical companies to justify costly product development efforts. These challenges have slowed the clinical progress of shigella vaccine candidates over the past few decades.

Promising Candidates in the Pipeline
Despite the complexities, researchers have made considerable headway in developing shigella vaccine candidates that have advanced to clinical trials in recent years. Some of the most promising candidates currently in development include:

– Live Attenuated Oral Vaccines: These utilize genetically modified shigella strains that have been rendered safe but still able to induce robust mucosal and systemic immune responses. Some leading examples include S. sonnei and S. flexneri 2a strains currently in Phase 2 trials.

– Conjugate Vaccines: By conjugating inactivated shigella polysaccharides to immunogenic carrier proteins, these vaccines aim to induce strong T-cell dependent antibody responses offering wider cross-reactivity. A S. sonnei conjugate vaccine developed by the University of Maryland is now in Phase 1 trials.

– Combination Live-Attenuated/Subunit Vaccines: Seeking to combine the benefits of live and subunit approaches, researchers are exploring formulations using attenuated shigella strains co-administered with purified polysaccharide antigens. Preclinical studies show this strategy induces both antibodies and cellular immunity.

These new vaccines represent rational designs backed by in-depth research on immunology and pathogenesis. Though more clinical evaluation is still needed, they offer hope that an effective shigella vaccine protecting all age groups may be available within the next 5-10 years.

Regulatory Pathways and Global Access
For any shigella vaccine to achieve widespread use and public health impact, it must first receive licensure from stringent regulatory bodies and prequalification from the World Health Organization (WHO). Currently two main pathways are envisioned:

– Traditional Regulatory Licensure: Through Phase 1-3 clinical trials in developed country sites demonstrating safety, immunogenicity and efficacy, followed by registration with agencies like the US FDA or European Medicines Agency (EMA). This pathway is suited for high-income country or traveler markets.

– Alternative Licensure Pathway: For candidates unlikely to pursue traditional licensure due to commercial viability concerns, the WHO may grant a “prequalification” based on more limited but supportive data from Phase 1-2 efficacy studies in endemic countries. National regulatory agencies in low-income countries can then consider granting approval. Multilateral financing organizations would also be able to procurement vaccine for national programs.

This dual regulatory model can help bring forward shigella vaccines tailored for both high-income and developing country contexts, crucially expanding global access if efficacy is demonstrated. Coordination among WHO prequalification, regulatory harmonization via Stringent Regulatory Authorities and financing agencies will be important to realizing this goal.

Conclusion – Commitment Needed
While progress has been promising, developing a shigella vaccine still requires overcoming scientific and programmatic obstacles. Sustained commitment from funders, manufacturers, researchers and public health agencies will be critical to eventually realizing this important public good. Only by turning promising candidates into licensed products that are broadly accessible where needed most can we hope to control the health and socioeconomic burden posed by shigellosis worldwide. With new tools on the horizon but still more work ahead, the global health community must maintain focus and collaboration toward the shared goal of a shigella-free future.

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  1. Source: Coherent Market Insights, Public sources, Desk research
  2. We have leveraged AI tools to mine information and compile it