Cholera is a lethal infection of the small intestine that affects around 3–5 million people worldwide and kills 28,800–130,000 people per year. A person can get cholera by drinking dirty water or eating food contaminated with cholera bacteria, most of which include shellfish and plankton.
Japanese scientists from Chiba University and the University of Tokyo have developed a new type of cholera vaccine by genetically modifying rice to carry a non-toxic cholera antigen. The vaccine doesn’t need to be refrigerated with the rice ground into a powder, stirred with water, and consumed.
To make the new vaccine, called MucoRice-CTB, the scientists first genetically engineered short-grain rice to yield cholera toxin subunit B (CTB). This part of the cholera toxin is frequently used for conventional cholera vaccines because it’s non-toxic and can induce potent immunity against the symptoms of a cholera infection. The engineered rice is then ground up into a powder, which is mixed into a liquid.
Since rice naturally stores its proteins in miniature membranes known as protein bodies, the cholera antigens are protected from digestive enzymes that would typically destroy other orally delivered vaccines. “The rice protein bodies behave like a natural capsule to deliver the antigen to the gut immune system,” explained Dr. Hiroshi Kiyono, a researcher working on the study.
The team published the first phase 1 human clinical trial of MucoRice-CTB in the journal The Lancet Microbe. Four groups of ten volunteers were recruited for the dose-response safety trial. Each group, except for the placebo control, received a different dose of the vaccine. Overall, four doses over eight weeks were given to each volunteer.
The results showed MucoRice-CTB caused no significant side effects, and the cohort displayed positive dose-dependent immune responses with the most prominent response at the highest dose. However, approximately one-third of the total cohort receiving the vaccine showed minimal immune reactions.
According to Dr. Kiyono, this led the team to hypothesize whether the composition of each gut microbiome plays a role in the vaccine’s efficacy. “When we saw those data about the 11 low and non-responders, we thought maybe gut microflora has an influence on the outcome of the immune response,” recalled Dr. Kiyono.
However, studying the volunteers’ microbial flora didn’t reveal any specific bacterial species common to the vaccine non-responders. Therefore, the only factor the team could use to distinguish vaccine efficacy was overall microbial diversity. “In simplified terms, high responders had more diversified microflora, and in the low-responder group, diversity was much narrower. It’s all speculation right now, but maybe, higher microflora diversity creates a better situation for a strong immune response against the oral vaccine,” explained Dr. Kiyono.
It is important to note that this small phase 1 trial only recruited young, healthy Japanese men.
If this vaccine is to be deployed globally, it will be crucial to understand how gut flora influences its efficacy. Microbiome differences could be drastic in low-income regions where cholera is endemic, such as Africa and Southeast Asia. The researchers are planning a similar phase 1 trial, which will focus on safety and efficacy in other ethnicities.
Other oral cholera vaccines are available, but MucoRice-CTB is the only one that doesn’t require refrigeration. Eliminating cold storage from a supply route would make distribution significantly easier in remote countries and lower emissions. In addition, MucoRice-CTB can be manufactured at low cost, making it a promising new tool to fight a disease that still kills hundreds of thousands of people each year.
