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."
Nicole Gularte in Feb 2019 at her three-month follow up visit after her successful CAR T-cell therapy last fall at Penn.
[Editor's Note: This is the final video of a five-part series titled "The Future Is Now: The Revolutionary Power of Stem Cell Research." Produced in partnership with the Regenerative Medicine Foundation, and filmed at the annual 2019 World Stem Cell Summit, this series illustrates how stem cell research will profoundly impact human life.]
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.
The Troubling Reason I Obsessively Researched My Pregnancy
A pregnant woman in her third trimester.
At the end of my second trimester of pregnancy, I answered a call from an unknown number.
To be pregnant is to exist on a never-ending receiving line of advice, whether we want it or not.
"I know your due date is approaching," said a stranger at the other end of the line, completely freaking me out. She identified herself as being from Natera, a company that my doctor had used for genetic testing I had consented to months ago.
"Excuse me?" I said.
"Have you considered cord-blood banking?" she said.
"No, I'm not doing that," I said. I had read enough about cord-blood banking, the process of saving stem cell-containing blood from your baby's umbilical cord, to understand that my family was in the vast majority of those that would with extremely high likelihood derive no medical benefit from it. Of course, in the societally sanctioned spending spree that accompanies new parenthood, plenty of companies are happy to charge anyone hundreds if not thousands of dollars plus annual storage fees to collect and manage your cord blood.
"Why not? Have you considered all the bene—"
"I'm not doing it and I don't want to explain my decision," I said before hanging up. I would later learn I neglected to check a miniscule box on my testing consent forms at the doctor to opt out of solicitations. Still, I was angry that I was being telemarketed unnecessary and costly medical services by someone who had been trained to immediately call my judgment into question. I was annoyed that my doctor's office would allow such intrusions at all. When I asked my OB about it at my next visit, she told me there's no way Natera would have gotten my information from them. Apparently even she didn't realize what was on those forms.
The incident with Natera did nothing to heighten my trust of the medical establishment during my pregnancy. I was hardly alone. Almost every mom I knew had expressed a similar sentiment.
"I don't trust doctors," read the text of a loved one when I told her I would probably get an epidural after my doctor recommended getting one because, she said, it can help relax the pelvic muscles during labor. But this friend, a highly educated woman who had had done her research and had two unmedicated births, believed firmly otherwise. "Look it up," she said. Thus commenced more of the furious Googling I found myself doing multiple times a day since deciding I wanted to become pregnant.
To be pregnant is to exist on a never-ending receiving line of advice, whether we want it or not. Information presents to us from Google's never-out-of-reach search bar, friends and family eager to use our pregnancies as an excuse to recall their own, and the doctor's office, where the wisdom of medical professionals neatly comingles with brochures and free samples from myriad companies that would really, really like our business as new moms. Separating the "good" advice from the rest is a Herculean task that many pregnant women manage only with vigorous fact-finding missions of their own.
The medical community in America is poorly equipped to help women navigate the enormous pressures that come with birth and transitioning to motherhood.
Doing my research during pregnancy felt like a defense against the scary unknowns, overabundance of opinions, and disturbing marketing schemes that come with entering parenthood. The medical community in America is poorly equipped to help women navigate the enormous emotional and societal pressures that come with birth and transitioning to motherhood. Too much of what pregnant women experience at the doctor has to do with dated ideas about our care, mandated by tradition or a fear of being sued rather than medical necessity. These practices, like weigh-ins at every appointment or medically unnecessary C-sections (which are estimated to account, horrifically, for almost 50 percent of all C-sections performed in the U.S.), only heighten anxiety.
Meanwhile, things that might alleviate stress – like having thorough discussions about the kinds of interventions we might be asked to accept at the hospital during labor and delivery – are left to outside educators and doulas that insurance plans typically don't cover. The net effect isn't better health outcomes for mom and baby, but rather a normalized sense of distrust many American women feel toward their OBGYNs, and the burden of going to every appointment and the delivery room on the defensive. Instead of being wed to dated medical practices and tangled in America's new motherhood industrial complex, shouldn't our doctors, of all people, be our biggest advocates?
As soon as I found out I was pregnant, I devoured Expecting Better, by Emily Oster, an economist who embarked on her own fact-finding mission during her first pregnancy, predicated on the belief that the advice OBGYNs have been giving pregnant women for decades is out of date and unnecessarily restrictive. The book includes controversial stances, like that having small amounts of alcohol while pregnant is OK. (More recent research has called this view into question.) Oster writes that for the vast majority of pregnant women, it's perfectly fine to lie on your back, do sit-ups, and eat Brie — all things I was relieved to learn I wouldn't have to give up for nine months, despite the traditional advice, which my doctor also gave to me.
Oster recommends hiring a doula, based both on research and personal experience. It's a worthwhile investment for those who can afford it: according to one study, 20.4 percent of laboring women with doulas had C-sections compared with 34.2 percent of women without them. A doula can do many things for a pregnant client, including helping her write a birth plan, massaging her back in labor, and cheering her on, which is especially useful for women who plan to labor without pain medication. Use of doulas is on the rise; according to DONA International, the world's largest and oldest doula association, the number of doulas who have been certified to date is over 12,000, up from 2,000 in 2002.
But the most significant role a doula plays is that of patient advocate in the hospital. This is a profound commentary on the way the medical establishment handles childbirth, a medical event that 86 percent of women aged 40 to 44 had gone through as of 2016. Recognizing the maternal mortality crisis in the U.S., where women are far more likely to die as a result of childbirth than anywhere else in the developed world and black women are three times more likely to die in childbirth than white women, a few states now allow Medicaid to cover doulas. Can you imagine feeling the need to hire an independent non-medical care provider to help you run interference with your doctors and nurses for something like an appendectomy?
I wouldn't have been aware of all the imminent interventions during my labor if my doula hadn't told me about them. Things happen fast in the hospital and doctors and nurses may rush patients to consent before proceeding with things like breaking their water or hooking them up to an IV of Pitocin. Only because my husband and I had spent six hours in birth class — a suggestion by my doula — did I realize that I was empowered to say "no" to such procedures.
Expecting more trustworthy advice to come from my doctor than books or Google or even a doula hardly seems unreasonable.
Of course, we all feel immense pressure to become good parents, and questioning conventional medical wisdom is a natural response to that pressure. "Looking around at the world and saying, who am I as a parent? What is important to me? Who are the wise people? What do I think wisdom is? What is a good decision? If you're a certain type of introspective person, if you're really asking those questions, that's going to include like taking a second look at things that doctors, for example, say," says Koyuki Smith, a doula and birth educator.
Expecting more trustworthy advice to come from my doctor than books or Google or even a doula hardly seems unreasonable. Yet my doctor's office seemed more concerned with checking off a list of boxes rather than providing me with personalized care that might have relieved my understandable anxiety about my first birth. When I still hadn't gone into labor around the time of my due date, my doctor encouraged me to be induced because my baby appeared to be large. I declined but scheduled an induction to "hold my spot" around the 42-week mark.
When I asked what medication would be used for an induction if I had one and she said Cytotec, I told her I had read that drug could cause serious complications, but she dismissed my concerns after I told her they stemmed from a book I read on natural childbirth. The FDA's page on Cytotec isn't exactly reassuring.
The nurse who took me in triage after I went into labor a week past my due date practically scolded me for waiting to go into labor naturally instead of opting for induction sooner. My doula told her while I was struggling to speak through labor pains to get off my case about it. I hadn't even become a mom and I was already doing so many things "wrong." Because I had done my own reading, I felt confident that my choices weren't harming my baby or me.
Becoming a mom would be less daunting if the medical community found a way to help women navigate the pressures of motherhood instead of adding to them. "Our culture at large doesn't support women enough in the complicated emotions that are a part of this process," said Alexandra Saks, a reproductive psychologist and author of What No One Tells You: A Guide to Your Emotions From Pregnancy to Motherhood. "I hope that every practitioner that works with women around reproductive health prioritizes her emotions around her experience."
For many of us, that will mean doctors who help us understand the pros and cons of conventional advice, don't use their offices as marketing channels, and don't pressure women into medically unnecessary inductions. Moms should also receive more attention after delivery both in the hospital and after they get home; a single, quick postpartum visit at six weeks is not an adequate way to care for women recovering from the trauma of childbirth, nor is it an adequate way to ensure women are emotionally supported during the transition. While several people interrogated me about my mental health at the hospital and my doctor's office just before and after birth, if I had been concerned about postpartum depression, I can't imagine feeling comfortable enough in those moments to tell strangers filling out obligatory worksheets.
It also means figuring out how to talk to patients who are prone to Googling their pregnancies with gusto every single day. It would be impossible for many women to shun independent research during pregnancy altogether. But it would also be nice if our doctors didn't add to our impulse to do it.