Scientists Are Growing an Edible Cholera Vaccine in Rice
The world's attention has been focused on the coronavirus crisis but Yemen, Bangladesh and many others countries in Asia and Africa are also in the grips of another pandemic: cholera. The current cholera pandemic first emerged in the 1970s and has devastated many communities in low-income countries. Each year, cholera is responsible for an estimated 1.3 million to 4 million cases and 21,000 to 143,000 deaths worldwide.
Immunologist Hiroshi Kiyono and his team at the University of Tokyo hope they can be part of the solution: They're making a cholera vaccine out of rice.
"It is much less expensive than a traditional vaccine, by a long shot."
Cholera is caused by eating food or drinking water that's contaminated by the feces of a person infected with the cholera bacteria, Vibrio cholerae. The bacteria produces the cholera toxin in the intestines, leading to vomiting, diarrhea and severe dehydration. Cholera can kill within hours of infection if it if's not treated quickly.
Current cholera vaccines are mainly oral. The most common oral are given in two doses and are made out of animal or insect cells that are infected with killed or weakened cholera bacteria. Dukoral also includes cells infected with CTB, a non-harmful part of the cholera toxin. Scientists grow cells containing the cholera bacteria and the CTB in bioreactors, large tanks in which conditions can be carefully controlled.
These cholera vaccines offer moderate protection but it wears off relatively quickly. Cold storage can also be an issue. The most common oral vaccines can be stored at room temperature but only for 14 days.
"Current vaccines confer around 60% efficacy over five years post-vaccination," says Lucy Breakwell, who leads the U.S. Centers for Disease Control and Prevention's cholera work within Global Immunization Division. Given the limited protection, refrigeration issue, and the fact that current oral vaccines require two disease, delivery of cholera vaccines in a campaign or emergency setting can be challenging. "There is a need to develop and test new vaccines to improve public health response to cholera outbreaks."
A New Kind of Vaccine
Kiyono and scientists at Tokyo University are creating a new, plant-based cholera vaccine dubbed MucoRice-CTB. The researchers genetically modify rice so that it contains CTB, a non-harmful part of the cholera toxin. The rice is crushed into a powder, mixed with saline solution and then drunk. The digestive tract is lined with mucosal membranes which contain the mucosal immune system. The mucosal immune system gets trained to recognize the cholera toxin as the rice passes through the intestines.
The cholera toxin has two main parts: the A subunit, which is harmful, and the B subunit, also known as CTB, which is nontoxic but allows the cholera bacteria to attach to gut cells. By inducing CTB-specific antibodies, "we might be able to block the binding of the vaccine toxin to gut cells, leading to the prevention of the toxin causing diarrhea," Kiyono says.
Kiyono studies the immune responses that occur at mucosal membranes across the body. He chose to focus on cholera because he wanted to replicate the way traditional vaccines work to get mucosal membranes in the digestive tract to produce an immune response. The difference is that his team is creating a food-based vaccine to induce this immune response. They are also solely focusing on getting the vaccine to induce antibodies for the cholera toxin. Since the cholera toxin is responsible for bacteria sticking to gut cells, the hope is that they can stop this process by producing antibodies for the cholera toxin. Current cholera vaccines target the cholera bacteria or both the bacteria and the toxin.
David Pascual, an expert in infectious diseases and immunology at the University of Florida, thinks that the MucoRice vaccine has huge promise. "I truly believe that the development of a food-based vaccine can be effective. CTB has a natural affinity for sampling cells in the gut to adhere, be processed, and then stimulate our immune system, he says. "In addition to vaccinating the gut, MucoRice has the potential to touch other mucosal surfaces in the mouth, which can help generate an immune response locally in the mouth and distally in the gut."
Cost Effectiveness
Kiyono says the MucoRice vaccine is much cheaper to produce than a traditional vaccine. Current vaccines need expensive bioreactors to grow cell cultures under very controlled, sterile conditions. This makes them expensive to manufacture, as different types of cell cultures need to be grown in separate buildings to avoid any chance of contamination. MucoRice doesn't require such an expensive manufacturing process because the rice plants themselves act as bioreactors.
The MucoRice vaccine also doesn't require the high cost of cold storage. It can be stored at room temperature for up to three years unlike traditional vaccines. "Plant-based vaccine development platforms present an exciting tool to reduce vaccine manufacturing costs, expand vaccine shelf life, and remove refrigeration requirements, all of which are factors that can limit vaccine supply and accessibility," Breakwell says.
Kathleen Hefferon, a microbiologist at Cornell University agrees. "It is much less expensive than a traditional vaccine, by a long shot," she says. "The fact that it is made in rice means the vaccine can be stored for long periods on the shelf, without losing its activity."
A plant-based vaccine may even be able to address vaccine hesitancy, which has become a growing problem in recent years. Hefferon suggests that "using well-known food plants may serve to reduce the anxiety of some vaccine hesitant people."
Challenges of Plant Vaccines
Despite their advantages, no plant-based vaccines have been commercialized for human use. There are a number of reasons for this, ranging from the potential for too much variation in plants to the lack of facilities large enough to grow crops that comply with good manufacturing practices. Several plant vaccines for diseases like HIV and COVID-19 are in development, but they're still in early stages.
In developing the MucoRice vaccine, scientists at the University of Tokyo have tried to overcome some of the problems with plant vaccines. They've created a closed facility where they can grow rice plants directly in nutrient-rich water rather than soil. This ensures they can grow crops all year round in a space that satisfies regulations. There's also less chance for variation since the environment is tightly controlled.
Clinical Trials and Beyond
After successfully growing rice plants containing the vaccine, the team carried out their first clinical trial. It was completed early this year. Thirty participants received a placebo and 30 received the vaccine. They were all Japanese men between the ages of 20 and 40 years old. 60 percent produced antibodies against the cholera toxin with no side effects. It was a promising result. However, there are still some issues Kiyono's team need to address.
The vaccine may not provide enough protection on its own. The antigen in any vaccine is the substance it contains to induce an immune response. For the MucoRice vaccine, the antigen is not the cholera bacteria itself but the cholera toxin the bacteria produces.
"The development of the antigen in rice is innovative," says David Sack, a professor at John Hopkins University and expert in cholera vaccine development. "But antibodies against only the toxin have not been very protective. The major protective antigen is thought to be the LPS." LPS, or lipopolysaccharide, is a component of the outer wall of the cholera bacteria that plays an important role in eliciting an immune response.
The Japanese team is considering getting the rice to also express the O antigen, a core part of the LPS. Further investigation and clinical trials will look into improving the vaccine's efficacy.
Beyond cholera, Kiyono hopes that the vaccine platform could one day be used to make cost-effective vaccines for other pathogens, such as norovirus or coronavirus.
"We believe the MucoRice system may become a new generation of vaccine production, storage, and delivery system."
Announcing "The Future of Science in America: The Election Issue"
As reviewed in The Washington Post, "Tomorrow's challenges in science and politics: Magazine offers in-depth takes on these U.S. issues":
"Is it time for a new way to help make adults more science-literate? What should the next president know about science? Could science help strengthen American democracy? "The Future of Science in America: The Election Issue" has answers. The free, online magazine is packed with interesting takes on how science can serve the common good. And just in time. This year has challenged leaders, researchers and the public with thorny scientific questions, from the coronavirus pandemic to widespread misinformation on scientific issues. The magazine is a collaboration of the Aspen Institute, a think tank that brings together a variety of public figures and private individuals to tackle thorny social issues, the digital science magazine Leapsmag and GOOD, a social impact company. It's packed with 15 in-depth articles about science with a view toward our campaign year."
The Future of Science in America: The Election Issue offers wide-ranging perspectives on challenges and opportunities for science as we elect our next national and local leaders. The fast-striking COVID-19 pandemic and the more slowly moving pandemic of climate change have brought into sharp focus how reliant we will be on science and public policy to work together to rescue us from crisis. Doing so will require cooperation between both political parties, as well as significant public trust in science as a beacon to light the path forward.
In spite of its unfortunate emergence as a flash point between two warring parties, we believe that science is the driving force for universal progress. No endeavor is more noble than the quest to rigorously understand our world and apply that knowledge to further human flourishing. This magazine aspires to promote roadmaps for science as a tool for health, a vehicle for progress, and a unifier of our nation.
This special issue is a collaboration among LeapsMag, the Aspen Institute Science & Society Program, and GOOD, with support from the Gordon and Betty Moore Foundation and the Rita Allen Foundation.
It is available as a free, beautifully designed digital magazine for both desktop and mobile.
TABLE OF CONTENTS:
- SCIENTISTS:
Award-Winning Scientists Offer Advice to the Next President of the United States - PUBLIC OPINION:
National Survey Reveals Americans' Most Important Scientific Priorities - GOVERNMENT:
The Nation's Science and Health Agencies Face a Credibility Crisis: Can Their Reputations Be Restored? - TELEVISION:
To Make Science Engaging, We Need a Sesame Street for Adults - IMMIGRATION:
Immigrant Scientists—and America's Edge—Face a Moment of Truth This Election - RACIAL JUSTICE:
Democratize the White Coat by Honoring Black, Indigenous, and People of Color in Science - EDUCATION:
I'm a Black, Genderqueer Medical Student: Here's My Hard-Won Wisdom for Students and Educational Institutions - TECHNOLOGY:
"Deep Fake" Video Technology Is Advancing Faster Than Our Policies Can Keep Up - VOTERS:
Mind the (Vote) Gap: Can We Get More STEM Students to the Polls? - EXPERTS:
Who Qualifies as an "Expert" and How Can We Decide Who Is Trustworthy? - SOCIAL MEDIA:
Why Your Brain Falls for Misinformation—And How to Avoid It - YOUTH:
Youth Climate Activists Expand Their Focus and Collaborate to Get Out the Vote - SUPREME COURT:
Abortions Before Fetal Viability Are Legal: Might Science and a Change on the Supreme Court Undermine That? - NAVAJO NATION:
An Environmental Scientist and an Educator Highlight Navajo Efforts to Balance Tradition with Scientific Priorities - CIVIC SCIENCE:
Want to Strengthen American Democracy? The Science of Collaboration Can Help
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.
Scientists Envision a Universal Coronavirus Vaccine
With several companies progressing through Phase III clinical trials, the much-awaited coronavirus vaccines may finally become reality within a few months.
But some scientists question whether these vaccines will produce a strong and long-lasting immunity, especially if they aren't efficient at mobilizing T-cells, the body's defense soldiers.
"When I look at those vaccines there are pitfalls in every one of them," says Deborah Fuller, professor of microbiology at the Washington University School of Medicine. "Some may induce only transient antibodies, some may not be very good at inducing T-cell responses, and others may not immunize the elderly very well."
Generally, vaccines work by introducing an antigen into the body—either a dead or attenuated pathogen that can't replicate, or parts of the pathogen or its proteins, which the body will recognize as foreign. The pathogens or its parts are usually discovered by cells that chew up the intruders and present them to the immune system fighters, B- and T-cells—like a trespasser's mug shot to the police. In response, B-cells make antibodies to neutralize the virus, and a specialized "crew" called memory B-cells will remember the antigen. Meanwhile, an army of various T-cells attacks the pathogens as well as the cells these pathogens already infected. Special helper T-cells help stimulate B-cells to secrete antibodies and activate cytotoxic T-cells that release chemicals called inflammatory cytokines that kill pathogens and cells they infected.
"Each of these components of the immune system are important and orchestrated to talk to each other," says professor Larry Corey, who studies vaccines and infectious disease at Fred Hutch, a non-profit scientific research organization. "They optimize the assault of the human immune system on the complexity of the viral, bacterial, fungal and parasitic infections that live on our planet, to which we get exposed."
Despite their variety, coronaviruses share certain common proteins and other structural elements, Fuller explains, which the immune system can be trained to identify.
The current frontrunner vaccines aim to train our body to generate a sufficient amount of antibodies to neutralize the virus by shutting off its spike proteins before it enters our cells and begins to replicate. But a truly robust vaccine should also engender a strong response from T-cells, Fuller believes.
"Everyone focuses on the antibodies which block the virus, but it's not always 100 percent effective," she explains. "For example, if there are not enough titers or the antibody starts to wane, and the virus does get into the cells, the cells will become infected. At that point, the body needs to mount a robust T-cytotoxic response. The T-cells should find and recognize cells infected with the virus and eliminate these cells, and the virus with them."
Some of the frontrunner vaccine makers including Moderna, AstraZeneca and CanSino reported that they observed T-cell responses in their trials. Another company, BioNTech, based in Germany, also reported that their vaccine produced T-cell responses.
Fuller and her team are working on their own version of a coronavirus vaccine. In their recent study, the team managed to trigger a strong antibody and T-cell response in mice and primates. Moreover, the aging animals also produced a robust response, which would be important for the human elderly population.
But Fuller's team wants to engage T-cells further. She wants to try training T-cells to recognize not only SARV-CoV-2, but a range of different coronaviruses. Wild hosts, such as bats, carry many different types of coronaviruses, which may spill over onto humans, just like SARS, MERS and SARV-CoV-2 have. There are also four coronaviruses already endemic to humans. Cryptically named 229E, NL63, OC43, and HKU1, they were identified in the 1960s. And while they cause common colds and aren't considered particularly dangerous, the next coronavirus that jumps species may prove deadlier than the previous ones.
Despite their variety, coronaviruses share certain common proteins and other structural elements, Fuller explains, which the immune system can be trained to identify. "T-cells can recognize these shared sequences across multiple different types of coronaviruses," she explains, "so we have this vision for a universal coronavirus vaccine."
Paul Offit at Children's Hospitals in Philadelphia, who specializes in infectious diseases and vaccines, thinks it's a far shot at the moment. "I don't see that as something that is likely to happen, certainly not very soon," he says, adding that a universal flu vaccine has been tried for decades but is not available yet. We still don't know how the current frontrunner vaccines will perform. And until we know how efficient they are, wearing masks and keeping social distance are still important, he notes.
Corey says that while the universal coronavirus vaccine is not impossible, it is certainly not an easy feat. "It is a reasonably scientific hypothesis," he says, but one big challenge is that there are still many unknown coronaviruses so anticipating their structural elements is difficult. The structure of new viruses, particularly the recombinant ones that leap from wild hosts and carry bits and pieces of animal and human genetic material, can be hard to predict. "So whether you can make a vaccine that has universal T-cells to every coronavirus is also difficult to predict," Corey says. But, he adds, "I'm not being negative. I'm just saying that it's a formidable task."
Fuller is certainly up to the task and thinks it's worth the effort. "T-cells can cross-recognize different viruses within the same family," she says, so increasing their abilities to home in on a broader range of coronaviruses would help prevent future pandemics. "If that works, you're just going to take one [vaccine] and you'll have lifetime immunity," she says. "Not just against this coronavirus, but any future pandemic by a coronavirus."
Lina Zeldovich has written about science, medicine and technology for Popular Science, Smithsonian, National Geographic, Scientific American, Reader’s Digest, the New York Times and other major national and international publications. A Columbia J-School alumna, she has won several awards for her stories, including the ASJA Crisis Coverage Award for Covid reporting, and has been a contributing editor at Nautilus Magazine. In 2021, Zeldovich released her first book, The Other Dark Matter, published by the University of Chicago Press, about the science and business of turning waste into wealth and health. You can find her on http://linazeldovich.com/ and @linazeldovich.