Vaccine profiles: Shigella

In 1897, a massive outbreak of Sekiri, or “red diarrhoea”, in Japan killed more than 20,000 people within six months.

Epidemics of dysentery were common in 19th Century Japan and elsewhere, but had been documented since biblical times, with the Ancient Greek physician Hippocrates coining the term dysentery (bowel trouble) to describe the cramping rectal pain and bloody, mucus-containing diarrhoea it provoked.

Shigella still causes between 28,000 and 64,000 deaths among children in lower-income countries every year.

With a fatality rate of more than 20%, the fear provoked by such outbreaks was palpable. The Japanese bacteriologist Dr Kiyoshi Shiga described dysentery as “the most dreaded disease of children” due to its sudden and severe onset and high risk of death.

But the 1897 outbreak marked a turning point in the centuries-old battle against this scourge. Drawing on the latest scientific techniques, Shiga managed to isolate and identify the causative micro-organism from the faeces of affected patients – bacteria we now know as Shigella.

Today, antibiotics and improved sanitation have dramatically reduced the frequency of such bacillary (bacterial) dysentery, but Shigella still causes between 28,000 and 64,000 deaths among children in lower-income countries every year.

In places where clean water and sanitation are lacking, repeated infections can also lead to stunted growth and impaired brain development, which could have a lasting impact on children’s long-term health and productivity.

Scientists have been trying to develop vaccines against Shigella for more than 100 years. But with several candidates now in phase 2 and 3 trials, hope is mounting that an effective vaccine may finally be within reach.

What is Shigellosis?

Shigella belongs to a large family of bacteria called Enterobacteriaceae and is closely related to Escherichia coli. There are four main types: S. dysenteriae, S. boydii, S. flexneri and S. sonnei, each of which have multiple strains. They are spread through dirty hands, food or water contaminated by human faeces, or contaminated flies landing on food.

Fewer than a hundred bacteria are needed to trigger an infection, which makes shigellosis – a variety of dysentery – extremely contagious, and people can continue to spread the bacteria for several weeks after they have recovered.

Shigella is a major cause of moderate to severe diarrhoea worldwide, responsible for an estimated 80–165 million cases each year, mostly in low or middle-income countries (LMICs). It is also a major cause of diarrhoea among travellers and military personnel visiting these countries.

Symptoms can be mild, but include watery and/or bloody diarrhoea, fever, stomach pain and the urge to pass stool even when the bowels are empty. These typically start one to three days after infection and last for around seven days.

Although many people get better with fluids and rest, severe infections are treated with antibiotics, making antimicrobial resistance (AMR) a growing problem. This could make treatment increasingly complex and expensive: a systematic review of travel-associated Shigella infections found that the percentage of drug resistant infections increased from 19% in 1990–1999 to 65% in 2000–2009. A Shigella vaccine would help to counter this problem by reducing countries’ reliance on antibiotics to treat such infections; overuse of antibiotics is a major driver of AMR.

We also have growing amounts of evidence linking Shigella to stunting and long-term disability, meaning a vaccine could bring potentially considerable economic and societal benefits in the long-term.

Vaccine development

The World Health Organization (WHO) has listed Shigella as a priority pathogen for the development of new vaccines, but despite decades of research, there is currently no widely licensed vaccine available.

One issue has been the lack of a commercial incentive to develop such vaccines, as shigellosis predominantly affects LMICs that don’t necessarily have the money to fund the necessary research and development, or to commit to purchasing doses in advance. This market failure is a key reason why Gavi, the Vaccine Alliance, was established.

Another challenge has been that with approximately 50 different strains of Shigella in circulation, a vaccine against just one of them is unlikely to solve the problem, because people can be reinfected with a different strain. The development of multivalent vaccines – ones targeting multiple types and strains of Shigella – is therefore a priority.

Researchers have estimated that a vaccine with antigens from S. sonnei, plus three strains of S. flexneri, could cover up to 75% of global strains – and perhaps as many as 93% – due to cross-reactivity between vaccine-generated antibodies and antigens from other related strains of Shigella.

Vaccine candidates

There are currently nine Shigella vaccine candidates in clinical trials. These include five protein or polysaccharide-based vaccines, which are designed to be injected into muscle, plus four oral vaccines that are based on either live attenuated (weakened) or inactivated (killed) bacteria.

Some of these vaccines are designed to prevent other infections, such as enterotoxigenic E. Coli (ETEC) – a major cause of diarrhoeal disease and travellers’ diarrhoea in lower-income countries – as well as shigellosis. Such combination vaccines could be particularly attractive in the context of increasingly crowded and expensive immunisation schedules, as countries seek to weigh competing health priorities.

Of particular interest are vaccine candidates being developed by GSK and a Swiss company called LimmaTech Biologics, both of which are currently in Phase 2 trials, and contain antigens from S. sonnei and plus three strains of S. flexneri. They are designed to be given as two or three doses.

Otherwise the pipeline of vaccines is still very young, and a vaccine against Shigella is unlikely to be widely available until the early 2030s.

However after almost a century of research, an effective vaccine against a leading cause of diarrhoeal deaths in children is within reach. Not only could such vaccines save millions of lives, but they could also help to counter the growing problem of antimicrobial resistance and a major cause of stunting in young children.