A new vaccine has been made to protect against deadly cholera by crushing genetically modified rice grains. The first human trial showed no obvious side effects and a good immune response. Researchers at the University of Tokyo and the University of Chiba have published peer-reviewed results of the phase 1 clinical trial of the vaccine, called MucoRice-CTB, in The Microbe Lancet.
Vaccine manufacturing has made tremendous progress in 2020, driven by COVID-19. However, the complexity of mRNA-based SARS-CoV-2 vaccines has highlighted the value of inoculations that can be made, transported, and stored at an economical price and without refrigeration.
The MucoRice-CTB vaccine it is stable at room temperature from beginning to end.
“I am very optimistic about the future of our MucoRice-CTB vaccine, especially due to the results of dose escalation. Participants responded to the vaccine at low, medium and high doses, with the greatest immune response to the highest dose, ”he said. Professor Hiroshi Kiyono, DDS, PhD, from the Institute of Medical Sciences at the University of Tokyo, who directs the MucoRice project. Kiyono is also a faculty member at Chiba University in Japan and the University of California, San Diego in the United States.
Thirty volunteers received a placebo and groups of 10 volunteers received a total of four doses spaced every two weeks of 3 milligrams (mg), 6 mg, or 18 mg each of the vaccines. Tests two to four months after receiving the last dose revealed that volunteers who responded to the vaccine had IgA and IgG antibodies, two types of proteins that the immune system produces to fight infections, specific to cholera toxin. B (CTB). Participants who received a higher dose of vaccine were more likely to have CTB-specific antibodies.
An independent review committee found no evidence of significant side effects.
Growing a new type of vaccine Vibrio cholerae bacteria are most often spread by drinking water contaminated with wastewater. Without medical attention, cholera can kill in a few hours due to diarrhea with severe dehydration. According to the World Health Organization, cholera infects between 1.3 and 4 million people and causes 21,000 to 143,000 deaths each year.
There are four modern needleless cholera vaccines, all administered in the form of drops on the tongue, but which require cold storage and are made from whole or attenuated (weakened) deaths. cholera cells; https://www.fda.gov/media/98688/download).
The new cholera vaccine is grown in Japanese genetically modified short-grain rice plants that produce a non-toxic portion of CTB that can be recognized by the immune system. CTB has a toxin-like structure produced by some types of disease-causing E. coli bacteria, so cholera vaccines often provide cross-protection against travelers ’diarrhea.
Researchers grow rice plants on a specifically built indoor hydroponic farm that meets WHO standards of good drug manufacturing practices, ensuring that the vaccine is not contaminated and that the plants are isolated from the wild. .
Plants produce the CTB subunit in their seeds, the edible grains of rice, and store the antigens in droplets called protein bodies with membranes made of fat.
“The protein bodies of rice behave like a natural capsule to administer the antigen to the intestinal immune system,” Dr. Kiyono.
Other drugs have been grown on plants, most often on the leaves, including treatments for Ebola, lymphoma, and the flu, but the drugs must be extracted and purified before they can be used. The grain-based aspect of the MucoRice system avoids these additional steps, the need for cold storage, and protects antigens as they travel through the hard acid in the stomach.
When the plants are ripe, the rice is harvested and ground into fine powder and sealed in aluminum packets for storage. When people are ready to be vaccinated, the powder is mixed with about 90 milliliters (1/3 of an American cup) of liquid and then drunk. Researchers have only tested the saline vaccine (a saline solution equivalent to body fluids), but expect it to work just as well with normal water.
Immunity through the gut is strong, but complicated by the microbiome
“The most beautiful part of our vaccine is that it intelligently uses the body’s immune system through the gut for the induction of antigen-specific antibodies,” said Dr. Kiyono.
MucoRice-CTB enters the body through the intestinal mucous membranes, mimicking a natural way of finding and responding to germs. Stimulation of the mucosal immune system produces two classes of antibodies that identify germs and target them for elimination, IgG and IgA. Vaccines that are injected under the skin or into a muscle usually increase only IgG antibodies, not IgA.
Volunteers who responded to MucoRice-CTB had the highest levels of antigen-specific IgG and IgA after eight to 16 weeks.
However, 11 of the 30 volunteers who received the vaccine showed a measurable low or no immune response. All study volunteers reported that they never traveled outside of Japan, so they were unlikely to have any prior exposure or natural immunity to pathogenic V. cholerae or E. coli.
“When we saw this data on the eleven low and unanswered people, we thought maybe intestinal microflora they have an influence on the outcome of the immune response, ”Dr. Kiyono recalled.
The microflora or microbiome is the community of microorganisms that live in our bodies and that also benefit us or are harmless. It is well accepted that the microflora of the digestive system influences health and immunity, but scientists are just beginning to understand the precise mechanisms of the relationship.
Extensive genetic analysis of all volunteer fecal samples identified the thousands of bacterial species that lived in the volunteers ’gut.
“In simplified terms, higher-response users had a more diversified microflora, and in the low-response group, diversity was much narrower,” Drs. Kiyono.
The researchers warned that the small size of the phase 1 study (administering the vaccine to only 30 healthy Japanese men volunteering) means that the relevance and prevalence of those who do not respond is still unclear and that the total difference in diversity of the microflora was subtle. However, the results suggest the most important role of microflora in vaccine efficacy.
“Now it’s all speculation, but perhaps a greater diversity of microflora creates a better situation for a strong immune response against the oral vaccine,” Dr. Kiyono said.
The link between the intestinal microbiome and vaccine efficacy has been previously revealed by the unfortunate fact that most vaccines are developed in industrialized nations and that some are less effective when delivered to developing countries. Mucosal vaccines, including oral polio and cholera vaccines, appear to be especially prone to this disparity. Most scientific theories to explain the phenomenon focus on chronic intestinal inflammation related to poor sanitation. (https://doi.org/10.1186/1741-7007-8-129)
“Probably for all vaccines at this time, even injected vaccines, we should think about the individual’s immune status based on the status of their microflora,” Dr. Kiyono.
It remains to be seen how the diversity of the microflora will affect the global effectiveness of MucoRice’s new edible vaccine system compared to the records of other oral vaccines.
For now, researchers plan to work with partners in the pharmaceutical industry to bring MucoRice-CTB to the next phase of clinical trials in Japan and abroad.
University of Tokyo
Citation: Edible Cholera Vaccine Made with Rice Powder Shows Safe in Phase 1 Human Trials (2021, June 25), Retrieved June 25, 2021 at https://medicalxpress.com/news/2021-06 -edible-cholera-vaccine-powdered-rice. html
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