Shigella Vaccines: Shaping the Future of Infection Prevention

Shigella bacteria are a common cause of diarrhea around the world. There are four strains of Shigella - Shigella boydii, Shigella dysenteriae, Shigella flexneri, and Shigella sonnei - that can infect humans. Of these, S. flexneri and S. sonnei are responsible for the majority of shigellosis cases globally. Left untreated, shigellosis can be fatal, especially in young children. According to the World Health Organization (WHO), there are an estimated 100 to 200 million shigellosis cases worldwide each year, resulting in approximately 163,000 deaths. Young children in developing countries face the highest risk of contracting the illness and developing severe complications. Not only does shigellosis pose substantial healthcare burden, but its socioeconomic impact due to lost work and school days is also significant.

Vaccine Development Challenges and Progress

Developing an effective vaccine against Shigella has proved challenging due to the complexity of the pathogen and the diversity of strains involved. Conventional live, attenuated vaccines have shown promise in clinical trials but still face regulatory hurdles. Whole-cell inactivated vaccines have faced consistent reactogenicity issues. Researchers have thus explored other vaccine platforms like subunit vaccines composed of purified antigens from the Shigella organism. Several candidate vaccines based on Shigella virulence factors and immune-dominant surface antigens are currently under development and evaluation. These include protein-conjugate vaccines targeting the O-antigens of Shigella lipopolysaccharide as well as outer membrane protein-based vaccines. Some of the most advanced subunit vaccine candidates have moved into late-stage clinical testing in recent years.

Phase 3 Trial of Experimental Subunit Vaccine

A significant milestone was achieved in 2020 when interim results from a large phase 3 efficacy trial of an experimental Shigella conjugate vaccine were reported. The investigational vaccine, developed by the PATH MALTOSE Vaccine Project in collaboration with the Serum Institute of India and other partners, contains Shigella sonnei and flexneri O antigens conjugated to a carrier protein. In the phase 3 trial conducted among nearly 3000 children aged 6 months to 4 years in Bangladesh, the vaccine demonstrated 73% protective efficacy against clinical shigellosis caused by the targeted strains after 2 years of follow up. The vaccine was found to be well tolerated with a good safety profile. Full results from the landmark trial marked an important step forward for the world's first shigellosis vaccine.

Regulatory Review Process and Future Approval Prospects

Following positive phase 3 data, the Shigella conjugate vaccine has entered the regulatory review process globally. Applications are being reviewed by the Drugs Controller General of India as well as the World Health Organization for potential prequalification. WHO prequalification would enable supply of the vaccine to UN agencies and economically developing countries where shigellosis burden is highest. Regulators will thoroughly evaluate all clinical trial data on safety, efficacy and quality before granting approval. If research findings hold up under full scrutiny and manufacturing standards are deemed satisfactory, the vaccine could potentially gain its first regulatory nod by 2023. Approval would provide an encouraging precedent for controlling shigellosis through active immunization in Asia and Africa. Widespread use of an effective vaccine in combination with improved sanitation could significantly curb deaths and illness from this serious enteric infection over the coming decade.

Potential for Commercial Manufacturing and Global Rollout

Beyond regulatory milestones, ensuring sustainable commercial supply will also be critical for maximizing public health impact. Non-profit partners will support initial introduction of the vaccine in developing country markets through philanthropic funding channels. But to meet global demand over the long term, commitments from commercial players will be important. Serum Institute - the world's largest vaccine manufacturer by volume - has committed to producing the Shigella conjugate vaccine at scale if approved. Given the Institute's experience ramping up low-cost production of other essential vaccines, it is well positioned to drive widespread adoption through competitive pricing globally. As adoption expands across both public and private health sectors internationally, the successful rollout of a Shigella vaccine holds promise not only for saving lives, but also generating sustaining returns on vaccine manufacturing investments worldwide.

Overall, the promising progress in late-stage development and evaluation of Shigella conjugate vaccines offers real hope that this potentially preventable cause of childhood mortality may soon be controllable through immunization. Further research advances, continued regulatory progress and long term commercial engagement will be crucial for maximizing the public health impact of an approved shigellosis vaccine worldwide. The global health community eagerly awaits upcoming regulatory verdicts which could signify an important new tool for combatting diarrheal disease globally.