Be it from tap water on a vacation, some dodgy chicken, or something the kids have brought home from school, we've almost all been flattened by an awful stomach bug at some point in our lives. For moderately healthy people, symptoms clear up after a day or two, but during that time it's absolute hell.
So now imagine a world in which we could be saved the vast unpleasantries that come with contracting a stomach bug, be it from a pathogen in the Salmonella species or a norovirus. That might not be too far off, with scientists at the University of Florida making inroads into developing a vaccine for Salmonella infection, and at the same time Moderna is at Phase 3 trial stage with its jab for norovirus.
The researchers have made a breakthrough using small extracellular vesicles (sEVs) that are produced by macrophages infected with Salmonella typhimurium – a leading cause of gastroenteritis. Among their many important roles in maintaining human health on a microbiological level, macrophages, which are white blood cells critical to the immune system, seek out pathogens and then engulf and digest them.
The team also wanted to test this process using Florida wastewater, rather than lab-grown samples, to reflect a real-world approach. Some 120 strains of Salmonella were identified in the wastewater collected, identified through whole genome sequencing. Then, two strains were selected – S. enterica serovar Enteritidis (SE), a common trigger of food-poisoning, and the S. enterica subspecies diarizonae, which is behind more severe infections.
"By integrating wastewater-based epidemiology with vaccine development, we can identify relevant Salmonella strains in the community and test immune responses against them," the researchers noted in the study. "Traditional vaccine development often focuses on laboratory strains, which fail to represent the genetic diversity of real-world infections. This study helps bridge that gap."
So, macrophoages were infected with S. typhimurium to produce the sEVs, which were extracted and purified to become the rudimentary 'vaccine' that was then delivered to mice via their noses. The mice received three doses of this novel treatment. (It's worth noting the mice were not infected with any Salmonella strains; the process was to test whether these macrophages could trigger an effective antibody response that would essentially 'prime' the immune system to be better prepared to fight a potential pathogenic invasion.)
What the scientists found was that when they analyzed the animals' antibody production (IgG and SIgA) and tested blood samples against S. typhimurium, S. enteritidis, and S. diarizonae, they found that the sEV immune response was robust against all three strains even though the sEVs had come from macrophages that had only been infected with the one type, S. typhimurium.
"sEV-based immunization resulted in significant IgG and SIgA responses, key indicators of both systemic and mucosal immunity, which are critical for fighting enteric infections," the scientists wrote. "The presence of antibody responses up to four weeks post-vaccination aligns with the establishment of a memory response, an essential feature of long-term protection."
This demonstrated that the potential vaccine had broad-spectrum protection, being able to recognize foreign strains and wipe them out, even though the immune system had no experience fighting those two other specific bugs. The scientists believe these sEVs may have latent antigens ('conserved' antigens) that will switch on, which is a fascinating area of genetic evolution that we're only just beginning to unravel.
While this is an exciting result, it's worth noting that it will still need to be studied on the animals, not just samples, to see how vaccinated mice would be able to fend off infection, compared to unvaccinated rodents. The researchers will also need to look at viral load in living animals, to see just how well their immune system could eradicate Salmonella bugs.
Ideally, a rapid immune response and a significant reduction in viral load would be a game-changer if replicated in a human model. While the vaccine wouldn't shield someone against infection altogether, much like the COVID-19 jabs, it would dial down the body's chaotic panic-mode immune response, so symptoms would be mild. Say, for example, just feeing a bit 'off' rather than violently ill. But unlike the COVID-19 vaccines, which were biologic, this one is free of live pathogens – it just has those nano-sized cell-free sEVs, which mean risk of adverse reactions or complications are greatly reduced.
"Unlike traditional live-attenuated vaccines, sEVs eliminate the risk of potential reversion to virulence, making them a safer alternative for immunization," the researchers noted. "Further studies are needed to determine whether sEVs provide long-term protection and if they can be optimized for human use."
Each year in the US, nearly 30,000 people are hospitalized as a result of Salmonella, and around 400 people die as a result, according to the US Centers for Disease Control and Protection (CDC). Overall, an estimated 1.35 million infections occur annually. Despite much research, there is currently no human vaccine for these bugs; the two existing types largely for poultry also don't work on the kind of infections that are usually responsible for food-borne illness. On top of this, the scientists identified antibiotic-resistant strains during their testing of the wastewater, which underpins the urgency to have new ways of fighting infections.
"Our research demonstrates that sEVs from infected macrophages can serve as a potent cell-free vaccine platform, generating robust antigen-specific immune responses," the scientists concluded. "This study establishes a foundation for developing an sEV-based vaccine that could one day mitigate the global burden of non-typhoidal Salmonella infections."
Meanwhile, Moderna has a novel norovirus vaccine – mRNA-1403 – currently at Phase 3 trial, and the results could be out as early as later this year. Like Salmonella, we're yet to develop therapeutic intervention for the highly contagious virus that has hit the US hard this winter. While different, both are often symptomatically hard to tell apart. Noroviruses – which can be contracted through contaminated water and food, and passed on easily through avenues such as surface contact and food handling – can cause illness similar to a Salmonella infection.
Moderna's vaccine candidate is now at potentially the final – and most critical – hurdle, with the research ahead of schedule due to public interest and the number of cases that the trial required to meet robust data requirements. As such, the study has recruited a massive 25,000 adults.
Like influenza, noroviruses have a lot of diversity, which has so far been the barrier to the development of an effective vaccine. Moderna's candidate focuses on three virus genotypes that do the most harm in humans. The treatment doesn't infect the recipient but, again, sends an instruction kit to the immune system to be able to respond to the real thing if presented with an infection.
However, this year's norovirus outbreak in the US has a different genotype to the main offenders – but the company's researchers are hopeful, given that while the vaccine candidate doesn't target this specific virus, mRNA technology allows scientists to quickly and quite easily tweak the 'recipe' to account for those genetic changes.
Again, this vaccine – much like Moderna's COVID-19 mRNA one – won't protect against infection, but train up the immune system to quickly deal with the norovirus, resulting in milder symptoms and quicker recovery. This is particularly important for older people and other vulnerable individuals who are at higher risk of hospitalization from illness.
The CDC reports that around 900 Americans die as a result of their norovirus infection each year, with those aged 65 and older overrepresented in the fatalities.
The Salmonella vaccine study was published in the journal Infection and Immunity.
Source: University of Florida