For Mohommad Mustakim, the risk of diarrhea is everywhere. The 4-year-old and his family live in a crowded slum in Dhaka, Bangladesh, where open sewage and poor sanitation increase the spread of diarrhea-causing viruses and bacteria.
Rotavirus is the most common cause of severe diarrhea in young children worldwide, and in Bangladesh it kills nearly 6,000 children younger than 5 every year. In Pakistan, the infections kill an estimated 23,000 children a year. In India, the estimate is 78,000.
Although a rotavirus vaccine is one of the recommended childhood immunizations in countries like the United States, where the disease is responsible for only 20 to 60 deaths a year, it is not a routine immunization in many countries with a high burden of disease, including Bangladesh, Pakistan and India. Parents can pay for it themselves, but for many, it’s too expensive.
But Mohommad was supposed to have an advantage. When he was a baby, he was one of 350 infants who received the same highly effective rotavirus vaccine that’s standard in the United States. Researchers followed the children for five years to see how well it protected them. Nasima Begum, Mohommad’s mother, did not hesitate to take part in the study.
“The vaccine is not available in our community and there is diarrhea in our community,” she said.
How did it do for Mohommad? Not very well.
Before his first birthday, Mohommad had a rotavirus infection and suffered diarrhea at least 10 times in one day. He lost interest in eating and playing, Begum recalled. She took her baby back to the clinic where the study was being conducted and health workers there gave him oral rehydration solution, a sugary saltwater mix that has been a life-saving treatment for diarrhea in developing countries.
Mohommad recovered, and by now, the worst is probably over, as dehydration and serious complications from rotavirus infections usually only occur in the first two years of life. But for his mother, the fear still lingers that he will develop diarrhea again. He had another bad rotavirus infection about a year ago and had to go to the clinic again.
Mohommad’s story could be a common one in Bangladesh, as well as many low-income countries in Africa and South America where the rotavirus vaccine is already included in the routine immunization schedule. While the rotavirus vaccine protects about 98% of children in developed countries such as the United States and Finland, a study found the same vaccine protected only 43% of Bangladeshi children from getting severe diarrhea from rotavirus in their first two years of life.
India will soon add the vaccine to its routine immunization schedule, a move that is projected to save 27,000 of the 78,000 young lives that infections claim every a year. But that number could be higher if vaccine efficacy in India were greater than the 55% that studies have found.
There is hope that improvements are on the way, but they will probably come in small steps rather than big strides forward, said Dr. William A. Petri, a professor at University of Virginia School of Medicine and lead researcher of the study in Dhaka in which Mohommad and his family are participating.
Boosting the performance of the rotavirus vaccine “is more of an engineering problem than a scientific problem … to change several things so you incrementally improve it,” Petri said. “This vaccine is so ineffective that if we can just make a tiny improvement, that’s huge.”
The search is on among researchers to figure out why rotavirus vaccine doesn’t work better and to try to improve it in the countries that — because of poor sanitation, high population density and other factors — need it most.
A problem with the gut
The rotavirus vaccine isn’t the only one that fails to live up to its potential in developing countries. There’s also the cholera vaccine, which the World Health Organization recommends in areas at risk of outbreaks, as well as some vaccines that are being developed, such as shigella vaccine, which would protect against bacteria that cause diarrhea.
There’s a key similarity between the rotavirus, cholera and shigella vaccines: They are all given orally, as drops in the mouth or a solution to swallow. The viruses or bacteria in the vaccine, which are weakened or dead forms of what they are supposed to protect against, pass into the intestine, where they linger long enough to provoke an immune response in the gut and the development of antibodies.
The fact that the oral vaccines are the ones that don’t work as well in low-income countries tipped researchers off to study the guts of people in areas where they underperform.
Over the last few decades, researchers have realized that, compared with people in rich countries, people living in low-income countries harbor in their small intestines higher levels of bacteria associated with poor sanitation — bacteria transmitted in contaminated water and though exposure to feces in the environment. These bugs have been implicated in the lackluster immune response to the cholera vaccine, and Petri and his colleagues have linked inflammation in the gut with poor protection from the rotavirus vaccine. The thinking is that inflammation could prevent vaccines from lingering in the gut and could keep the immune system from reacting to them.
If inflammation in the gut is a root cause of the vaccine problem, it suggests a clear path forward: If you improve sanitation, you might prevent these harmful bugs from building up in the gut and triggering inflammation. Studies in Bangladesh and Africa are testing whether sanitation interventions such as installing hand-washing stations in rural homes and supplying families with chlorine to treat their drinking water could have that very effect. Experts are anxiously awaiting the results of these studies, which should start coming out this year.
In many ways, sanitation is already improving, as countries such as Bangladesh become richer. People are drinking more bottled water and have better access to clean drinking water in general; modern sewage systems are becoming more common. But the crux of the issue is, how long will it take for conditions to clean up enough to make oral vaccines work better?
“Bangladesh is not going to be a low-income country in 20 years. The health of the children will improve as sanitation improves, but the problem with this is, in the meantime, there’s going to be a lot of children that are going to die needlessly if we do nothing,” Petri said.
Speeding improvements in vaccine performance
Petri is not the only one who wants to make the vaccine problem go away faster. Other researchers are approaching the question from different angles.
“Our approach was trying to challenge the idea that this is all about the environment and we can’t do anything about it until we change the environment,” said Dr. Kelsey Jones, on the faculty of pediatrics at Imperial College London, who studies factors predisposing children to severe infections.
His strategy: Attack the inflammation head on with a drug called mesalazine, which is a treatment for inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis.
In a study by Jones and his colleagues of young children in a Kenyan slum who had severe malnutrition, there are hints that mesalazine might reduce intestinal inflammation, based on decreases in a marker of inflammation in the stool. But there were only 22 children in the study, too few to really say whether mesalazine was effective. Rather, the main point of the study was to address whether taking the drug for a month caused side effects, and at least for the small number of children in the study, there was no evidence that it did.
Despite the encouraging findings, experts do not seem to be “falling over themselves” to pursue this strategy, Jones said. Part of the reason is that many still hope to resolve the problem the natural way, by cleaning up the environment, he said. But there is also concern that anti-inflammatory drugs could still be harmful. Unlike the kinds of inflammatory diseases that tend to afflict those in high-income countries, such as Crohn’s disease, gut inflammation in places like the slums of Kenya and Bangladesh might actually be beneficial.
“It could be there because there are all these pathogens, and if you take away the (inflammatory) immune response, the pathogens run riot,” Jones said. If researchers decide to undertake more studies of anti-inflammatory drugs, they will need to proceed carefully, and as in Jones’ study, work with a small number of children and carefully monitor them for side effects as well as benefits.
Another angle that researchers are exploring is using probiotics, which has shown some promise in helping people with inflammatory bowel disease.
There are at least three ways that probiotics such as lactobacillus or bifidobacterium could help the vaccine problem, said Dr. Jacob John, a pediatrician at Christian Medical College in Vellore, India. It could control the level of inflammation in the gut, stimulate the immune response toward making antibodies and establish a gut microbiota that is “more conducive to a vaccine response,” said John, who studies the immune response to the rotavirus vaccine.
So far, John and his colleagues have found that giving infants a supplement of lactobacillus along with zinc, which also improves the health of the gut, in their breast milk starting one week before they got the rotavirus vaccine was associated with an increase in the number of children who developed protective antibodies to rotavirus. The rate jumped from 27% to 39%. Probiotics have also been shown to boost the already high immune response to rotavirus vaccine among babies in Finland.
Although probiotics could be part of the solution to the vaccine problem, more studies need to be done, John said. It remains to be seen whether the increase in immune response to the rotavirus vaccine translates to fewer children developing rotavirus diarrhea. There are also questions about how long babies would need to take supplements of probiotic and zinc and whether these supplements could improve the performance of other oral vaccines.
No ‘magic bullet’
Experts generally agree that gut disease is probably only one of several issues that contribute to the underperformance of oral vaccines. “I don’t think a single magic bullet will answer the problem,” said Dr. Umesh Parashar, who leads the Enteric Viruses Epidemiology Team at the Centers for Disease Control and Prevention.
Issues plaguing low-income countries, including malnutrition and deficiencies in zinc and other vitamins, may also thwart vaccine responses.
Another issue could be that newborn infants tend to already have antibodies to rotavirus passed on to them in the womb because their mothers have been exposed to rotavirus. The presence of these maternal antibodies could prevent the virus in the vaccine from taking hold in the baby’s gut and eliciting an immune response.
The study in which Mohommad and his family are participating tested the effect of giving children the two doses of rotavirus vaccine at 10 and 17 weeks of age instead of the recommended 6 and 10 weeks, when higher levels of maternal antibodies could remain and prevent infants’ immune systems from responding to the vaccine. Petri and his colleagues found that the vaccine prevented 70% of cases of severe diarrhea under these circumstances, compared with 43% in previous studies that followed the usual schedule. However, it could be hard to turn this improvement into policy because doctors may be reluctant to wait even a few weeks before vaccinating babies against this important disease, Petri said.
The idea of adjusting the rotavirus vaccine schedule to make it work better is reminiscent of a strategy used for oral polio vaccine. In the 1960s, doctors in India started seeing the oral vaccine problem for the first time when several children developed polio paralysis even though they had received the vaccine. The country overcame the problem, in part, by giving 10 extra doses of oral polio vaccine to children in their first five years of life. That many additional doses of rotavirus vaccine would be impractical because it’s really only a health threat in children up to age 2.
Another part of the solution for polio vaccine has been phasing in an injectable version of the vaccine, which is now used in the United States and many other countries. If an injectable version of rotavirus were developed, it could be part of the solution because, like the injectable polio vaccine, it would bypass the gut.
There is certainly a precedent for public health advances requiring the convergence of various strategies, said Dr. Rashidul Haque, who collaborates with Petri and studies infectious disease at the International Centre for Diarrhoeal Disease Research, Bangladesh.
In the 1980s, in the same slums in Dhaka where he and Petri now study rotavirus vaccination, nearly everybody was infected with a parasitic worm called ascaris, which can cause abdominal pain and growth delays in children. Today, the prevalence is between 10% and 20%, thanks to a combination of better sanitation, people wearing shoes more and clinics giving anti-parasitic medication when children come in for vaccinations, Haque said. He keeps a collection of the worms from back in their heyday, preserved in a jar at the entrance to his research laboratory, as a reminder of public health progress.
The greatest testament to the performance of the rotavirus vaccine is the lack of children showing up at the clinic where Petri, Haque and their team are carrying out the current study. Researchers ask the participating families to return to the clinic if their babies, after getting the rotavirus vaccine along with the routine immunizations, develop diarrhea.
On a mild, hazy day recently, several of the researchers in the study made the few minutes’ walk to the home of one of the families in the study that has been notably absent from the clinic. Three-year-old Munni had not had any bouts of bad diarrhea since she received her immunizations.
But her family has not exactly forgotten about the study. Her mother, Banu, lit up when she saw the clinic manager and research assistant at her door. As researchers explained, families in the study are generally grateful their children were able to get a vaccine they probably would not otherwise have received, even if, in some cases, it did not work the way it was supposed to. Families who participate also receive basic health care at the clinic during the period of the study.
Munni will hopefully become the norm, not the exception, for children in Bangladesh and other low-income countries. When the researchers arrived at her home, Munni wasn’t ill or struggling. She was nowhere to be found — she was too busy playing outside with her friends.
