April 20, 2024

Shigella Vaccines: Empowering Immune Defenses

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Shigella bacteria are among the leading causes of diarrheal disease around the world. There are four types of Shigella—Shigella flexneri, Shigella sonnei, Shigella boydii, and Shigella dysenteriae—that can cause shigellosis in humans. The infection is usually contracted by ingesting contaminated food or water or through direct contact with an infected person. Symptoms of shigellosis usually appear 1-2 days after exposure and include diarrhea, fever, and stomach cramps. The diarrhea caused by Shigella is often bloody and can be severe. If left untreated, shigellosis can last from 4-7 days. In some cases, especially among young children and individuals with compromised immune systems, the infection may spread from the intestines to the bloodstream and cause a potentially fatal systemic infection.

An estimated 80-165 million cases of shigellosis occur globally each year, resulting in approximately 700,000 deaths. The highest disease burden is in developing countries with poor sanitation and limited access to clean water. Shigellosis is most severe in children under 5 years old. Recurrent infections are also common, as immunity after natural infection tends to wane over time. Due to its high transmissibility and disease morbidity, Shigella is a significant public health concern, especially in low-resource settings. The development of effective vaccines could help prevent infections and curb transmission globally.

Progress Towards an Affordable Shigella Conjugate Vaccine

Current treatment options for shigellosis mainly involve antibiotic therapy. However, Shigella resistance to commonly used drugs like ampicillin, trimethoprim-sulfamethoxazole, and fluoroquinolones is increasing worldwide. Preventive measures like access to safe drinking water, improved hygiene, and good sanitation remain challenging to implement in many parts of the developing world. As such, vaccination has emerged as a promising strategy to control Shigella disease.

Researchers have studied the potential of various vaccine candidates over the past few decades with some success. Non-live attenuated vaccines tested include a formalin-inactivated whole cell vaccine from the 1950s-1970s and more recent polysaccharide vaccines against S. flexneri 2a and S. sonnei. However, these early vaccines did not provide strong or long-lasting protection. Live attenuated candidate vaccines have shown greater effectiveness in clinical trials but manufacturing and safety issues have limited their feasibility, especially in resource-poor settings.

More recently, Shigella conjugate vaccines combining the polysaccharide antigens with protein carriers have shown strong promise. Conjugation aims to elicit higher and longer-term immune responses, similar to what is seen with childhood vaccines for diseases like Haemophilus influenzae type b and pneumococcal disease. A phase 3 efficacy trial of a bivalent S. flexneri 2a-S. sonnei conjugate vaccine found it provided 69% protection against shigellosis caused by the targeted serotypes for up to 2 years after vaccination in children aged 6 months-4 years.

Building on this success, the same vaccine is now included in WHO’s target product profiles for accelerated development. If licensed, it could offer a cost-effective public health tool for endemic countries. However, further investment is still required to bring down the projected cost per dose to meet affordability goals for widespread use in low-income settings most burdened by Shigella disease. Continued refinement of vaccine formulations and manufacturing methods hold promise to achieve lower prices in the coming years.

Expanding Coverage Through Multivalent Vaccine Formulations

While the bivalent vaccine in development targets the main global Shigella serotypes, broader multivalent coverage may be preferable from a public health perspective. Different serotypes can predominate in various geographic regions, so multivalent formulations could offer more comprehensive protection. Expanding to cover additional common serotypes like S. dysenteriae type 1 would be particularly valuable, as it accounts for the majority of epidemic shigellosis with often severe clinical outcomes in some regions.

Building on advances in conjugate vaccine technology and manufacturing know-how gained from licensed childhood vaccines, researchers are working to develop higher valence Shigella conjugate products. Preliminary studies report multivalent vaccine candidates including additional serotypes are immunogenic and well-tolerated in animal models and early-phase human trials. One candidate containing four serotypes—S. flexneri 2a, 3a, and 6 plus S. sonnei—is currently being tested for safety, reactogenicity and immune response in a phase 1/2 trial involving adults in Bangladesh. Multivalent Shigella conjugate vaccines represent an opportunity to further broaden disease protection across affected populations globally.

Continued Surveillance and Research Efforts Needed

Despite significant progress, major hurdles remain for widespread Shigella vaccination. Continuous epidemiological and microbiological studies will be important for anticipating how circulating strains may change over time, both regionally and potentially in response to vaccine selection pressure. Adjustments to vaccine serotype composition or formulations may need to be made periodically based on evolving disease dynamics. Surveillance of antimicrobial resistance profiles will also help guide treatment recommendations as resistance to commonly used drugs spreads.

Safety assessment and potential adverse event monitoring following broad implementation must continue. Results from ongoing and planned efficacy trials in young children will be key to establishing public health impact. Additional research areas like maternal immunization to provide protection to infants too young to be vaccinated directly also hold promise. Efficient, low-cost mass vaccine production and distribution particularly suited to low-resource settings also requires sustained efforts. With coordinated basic, applied and public health research advancement, effective Shigella vaccines could soon help curb the global burden of this important enteric infection.

In summary, while Shigella disease remains a major cause of morbidity and mortality worldwide, the development of effective conjugate vaccines offers hope for improved prevention and control. Continued progress across diverse research areas, supported by public and private partnerships, can help accelerate the availability and widespread use of new generation multivalent Shigella vaccines adapted to disease epidemiology in different regions. This in turn would advance progress toward global health goals of reducing diarrhea mortality in children under five.

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