In the global fight against foodborne illness, few pathogens are as pervasive or as problematic as Salmonella. This bacterium causes an estimated 1.35 million infections, 26,500 hospitalizations, and 420 deaths each year in the United States alone, with an economic burden exceeding $3.7 billion. Globally, the picture is even grimmer, with approximately 93 million non-typhoidal Salmonella infections and 155,000 deaths annually. For decades, the primary defenses have been food safety measures and antibiotic treatments, but the relentless rise of antimicrobial resistance is forcing a strategic shift. Scientists are now racing to develop a new generation of vaccines, aiming to protect both humans from illness and poultry flocks from becoming reservoirs of infection in the first place. This two-pronged approach represents a modern frontier in public health, where immunization is increasingly seen as a critical tool to outsmart a wily and adaptable foe.
The challenge is as complex as the pathogen itself. Salmonella isn’t a single entity but a family with over 2,600 different serovars, broadly categorized into those that cause typhoidal fever and those that cause non-typhoidal gastroenteritis. Typhoidal serovars, like Salmonella Typhi, are human-restricted and cause a severe, often invasive illness. Non-typhoidal serovars, such as Typhimurium and Enteritidis, have a wide range of animal hosts and are a leading cause of food poisoning worldwide. This biological diversity means that a one-size-fits-all vaccine is not feasible. Instead, researchers are creating a sophisticated arsenal of vaccines, each designed with a specific target and mechanism of action, for both people and the poultry that represents a major source of human infection.
The Human Front: Conquering Typhoid and Beyond
For humans, the most significant recent progress has been against typhoidal Salmonella. Typhoid fever is a major global health challenge, affecting more than 12 million people annually and posing a particular threat in areas with limited access to clean water and sanitation. For years, vaccine development was hampered by the fact that Salmonella Typhi only naturally infects humans, making animal testing difficult. To overcome this, researchers have turned to Controlled Human Infection Models (CHIMs), where healthy volunteers are intentionally exposed to the pathogen in a carefully controlled clinical setting to test potential vaccines.
This approach has paid dividends. The leading typhoid conjugate vaccine (TCV), Typbar TCV®, demonstrated an efficacy of at least 55% in CHIM studies, data that helped contribute to the World Health Organization’s recommendation for its programmatic use. A subsequent field study in Malawi found that a single dose of this vaccine provided lasting efficacy in preventing typhoid fever in children aged 9 months to 12 years. This was a critical finding, as children are among the most vulnerable to the disease. The success of TCVs has marked a turning point, showing that conjugate technology, which links a Salmonella polysaccharide to a carrier protein to boost the immune response, is a potent strategy.
The next logical step, and one of the most exciting recent developments, is the creation of a vaccine that can protect against both typhoidal and invasive non-typhoidal Salmonella. This is the goal of a new trivalent Salmonella conjugate vaccine (TSVC) that produced a strong immune response and was found to be safe and well-tolerated in a phase 1 trial with healthy U.S. adults, as reported in early October 2025. This single vaccine targets Salmonella Typhi, the cause of typhoid fever, as well as Salmonella Typhimurium and Enteritidis, the two serovars responsible for roughly 90% of invasive non-typhoidal Salmonella infections in young children in Africa.
“This single vaccine that protects against both could be a game-changer for global pediatric health,” said Dr. Wilbur Chen, chief of the adult clinical studies section within the Center for Vaccine Development and Global Health at the University of Maryland School of Medicine, a lead investigator on the project. The potential impact is massive. Typhoid fever caused an estimated 8,751 deaths in sub-Saharan Africa in 2017, while invasive non-typhoidal Salmonella caused approximately 66,000 deaths, primarily among children. A trial to assess this trivalent vaccine in young infants and toddlers in sub-Saharan Africa is now planned.
Simultaneously, research continues for vaccines against the non-typhoidal Salmonella that cause common foodborne illnesses. At the University of Florida, researchers are testing an innovative approach that uses small extracellular vesicles (sEVs) as a delivery method for a vaccine against non-typhoidal strains. These tiny particles, created by cells, are used to carry bacterial proteins, triggering a long-lasting immune response without introducing any live bacteria. In a promising step, the researchers tested this vaccine not just on lab-derived strains but on environmental Salmonella from a local wastewater system, and found it successfully created antibodies in mice. This method represents the kind of novel, next-generation technology that could one day lead to a vaccine for the common forms of salmonellosis.
The Poultry Front: Building a Barrier at the Source
While human vaccines aim to protect the individual from disease, poultry vaccines are primarily designed to prevent the bacteria from colonizing the birds’ guts, thereby reducing the contamination of meat and eggs and creating a barrier for human infection. This is a crucial part of the “farm-to-fork” strategy. In many parts of the world, the non-therapeutic use of antibiotics in animal production has been banned due to the alarming rise of antimicrobial resistance, making vaccination an even more essential tool for flock health and food safety.
The most common types of vaccines used in poultry are live-attenuated vaccines and killed inactivated vaccines. Live-attenuated vaccines use a weakened form of the Salmonella bacterium that can no longer cause serious disease but can still stimulate a robust immune response. Brands like Poulvac ST, AviPro Salmonella Vac E, and AviPro Salmonella DUO are used commercially to protect against key serovars like Enteritidis and Typhimurium. These vaccines have a key advantage: because they mimic a natural infection, they can trigger both cellular and humoral immunity, offering broader protection. Killed vaccines, which contain bacteria inactivated by heat or chemicals, are also available and are often seen in autogenous formulations tailored to specific farms.
However, the use of live vaccines is not without its complexities. A 2023 study highlighted that different commercial live vaccines can have distinct effects on the chickens’ cecal microbiota, the community of microbes in the gut that plays a vital role in health and disease resistance. The study found that vaccination with AviPro Salmonella Vac T and AviPro Salmonella DUO significantly altered the microbiota composition, while AviPro Salmonella Vac E did not. This suggests that the choice of vaccine can influence the gut environment in ways that might impact the bird’s overall health and its resistance to other pathogens, a factor farmers and veterinarians must now consider.
A more unexpected challenge has also emerged: the persistence of vaccine-origin strains in the food chain. Analyses of over 26,000 database isolates indicated that strains from live-attenuated vaccines can sometimes persist through the entire commercial production cycle, making their way onto retail meat products and, occasionally, even into human patients. While these vaccine strains are attenuated and not intended to cause illness, their presence complicates disease surveillance and diagnostics. In response, researchers have developed a novel PCR test that can quickly differentiate between wild-type Salmonella Typhimurium and the attenuated strains used in common vaccines, helping poultry producers monitor their flocks more effectively.
Table: Vaccine Platforms for Salmonella and Their Characteristics
| Vaccine Platform | How It Works | Key Advantages | Key Considerations |
| Live-Attenuated (Poultry & Human Research) | Uses a weakened form of the bacterium to stimulate a comprehensive immune response | Induces strong cellular and humoral immunity; can be administered easily in water | Potential for microbiota alteration; rare persistence in the food chain |
| Killed/Inactivated (Poultry) | Uses bacteria inactivated by heat or chemicals to stimulate an immune response | Stable and safe; cannot cause disease or revert to virulence | Primarily induces humoral immunity; may require adjuvants |
| Conjugate (Human) | Links a polysaccharide from the bacteria to a carrier protein to boost immune recognition | Creates a strong, long-lasting antibody response; effective in young children | Complex and costly to manufacture; targets specific serovars |
| Subunit & Reverse Vaccinology | Uses only specific, identified pieces of the bacterium (proteins) as the vaccine antigen | High safety profile; no live components | May require strong adjuvants and multiple doses to be effective |
| Novel Platforms (sEVs, Bacterial Ghosts) | Uses innovative delivery systems like extracellular vesicles or empty bacterial membranes | Can be safer than live vaccines and elicit a robust, targeted immune response | Largely in experimental stages; long-term efficacy in humans not yet known |
Analysis and Next Steps
The landscape of Salmonella vaccine development is undergoing a significant transformation, moving from traditional one-dimensional approaches to integrated, high-tech strategies. What is new is the concerted push for combination vaccines, like the promising trivalent TSVC, which aim to tackle multiple disease threats with a single shot. Furthermore, the pipeline is now filled with innovative platforms, from bacterial ghosts to sEV delivery systems, that seek to provoke a strong immune response without the risks associated with live bacteria. These advances are paralleled in the poultry industry by a more nuanced understanding of how live vaccines interact with the gut microbiome, revealing that immunization is not just about provoking an immune response but about shaping an entire internal ecosystem.
These developments are relevant because the stakes are immense, both in terms of human life and economic stability. The burden of Salmonella falls most heavily on the most vulnerable. In sub-Saharan Africa, invasive non-typhoidal Salmonella can have a mortality rate as high as 25% in children under five, and even in the United States, the very young, the elderly, and the immunocompromised face the greatest risk of severe outcomes. For the global poultry industry, Salmonella contamination leads to devastating economic losses from recalls, lost productivity, and reputational damage. Consumers everywhere are affected, facing the constant, low-level risk of foodborne illness from common foods like chicken, eggs, and produce. The rise of multidrug-resistant strains, with some regions reporting resistance rates to key antibiotics like ciprofloxacin as high as 30%, makes effective vaccines not just a convenience but a critical necessity for preserving the utility of our modern medicine cabinet.
Moving forward, the path is both clear and challenging. The immediate next step for the most advanced human vaccine, the trivalent TSVC, is to move from successful phase 1 trials in adults to larger studies in infants and children in endemic regions of sub-Saharan Africa. This will be the true test of its potential to become a “game-changer” for pediatric health. For poultry producers, the task is to continue refining vaccination programs, potentially using new diagnostic tools to monitor for vaccine strains and selecting vaccines based on a holistic understanding of their impact on gut health and immunity. Across the board, continued investment in research is paramount to overcome the hurdle of Salmonella’s incredible serovar diversity. The ultimate goal is a coordinated defense, where vaccination in poultry reduces the pathogen’s pressure from the start, and vaccination in humans, particularly in high-risk populations and regions, provides a final, unbreachable line of protection. It is a complex quest, but one that promises to save millions of lives and reshape our relationship with a persistent microscopic adversary.
