A lifetime of malaria research begins in the United States
Horii began his research in 1984 at 32 years old. At that time, he was conducting cutting-edge research in molecular biology, but he knew little about malaria; in fact, his first education about the disease came from an encyclopedia. What, then, prompted him to shift to malaria research in his 30s? Interestingly, it was not because of a strong desire to study malaria. He was looking for a new research topic, one that could become his life’s work, when an associate outside Japan made the intriguing suggestion that he consider integrating molecular biology into malaria research. Horii decided to study at Dartmouth College in the United States, which had a strong malaria research program.
After returning to Japan, he resumed his original post and conducted research unrelated to malaria. However, Horii, still young and with few accomplishments to his name, was offered a position that had the potential to lead to a professorship. Upon accepting the position as manager of a laboratory and eventually an associate professor, he focused on malaria and the improvement of the science of parasitology in Japan, as at that time the country has fallen behind the rest of the world in this aspect.
“Why would a Japanese person do research on malaria?”
When Horii began his malaria research, it was a struggle for him to convince other people of the value of his work. Even the Ministry of Education, Culture, Sports, Science and Technology questioned why he would conduct research on malaria in Japan –when the disease has long been eradicated in the country and thus, was not a priority. At that time (around 2000), most medical research with global application was conducted in United States, and the rest of the world expected little from Japan (and from Dr. Horii’s his research), since countries tend to focuse more on their domestic priorities. However, Horii persisted in his belief that research on malaria from within Japan could be at par with and valuable to global efforts.
At that time, Horii began to simultaneously conduct basic research on malaria, drug target discovery, and vaccine development activities. “Maintaining the laboratory required funding,” he reflected, “and I was willing to do anything to keep it going—I was on the lookout for the best avenue.”
Drawing insights from observations over an extended period of time
In the early 2000s, the malaria vaccine candidate antigen known as MSP-1 was garnering positive attention in the United States. Nevertheless, Horii continued the research that he started at Dartmouth, focusing on the serine repeat antigen (SERA) protein, another vaccine candidate antigen. His analysis led him to believe that MSP-1 could not overcome the innumerable hurdles to vaccine development.
A researcher in Uganda who had read Horii’s paper on SERA contacted him and offered to “compare the antibodies of affected and unaffected people in malaria endemic areas and measure SERA alongside MSP-1.” Horii immediately sent SERA protein to the researcher, who told him, six months later, “Only SERA showed a strong correlation with protective immunity against malaria.” Horii could hardly contain his excitement.
Belief in success ensures the team does not lose hope
Before the vaccine can be licensed and used by the general population, it is necessary to conduct a number of challenging clinical trials to test for safety and measure effectiveness. During a clinical study conducted in Uganda in April 2010, discouraging news was obtained: adults over the age of 21 did not show any significant immune response in contrast to earlier successful induction/positive data obtained in Japanese adults. Horii’s team was devastated. Horii reviewed and pondered the data repeatedly as he was flying to Uganda and came to the realization that the lack of response must be attributable to immunological tolerance (where an immunoreaction toward a specific antigen is not demonstrated).
As soon as the plane landed, he gathered his team and announced, “[This finding] was due to immunological tolerance. With the next stage in our study, involving younger children, the levels of antibodies will go up!” His team members’ faces brightened immediately. Looking back, Horii explains, “As a leader, you have to show the way so that people can keep moving forward.”
Joy upon learning that the vaccine was effective against malaria
In 2011, the vaccine showed efficacy in younger Ugandan vaccinees. Upon completion of the one year follow-up for children aged six to twenty years who received the vaccine, Horii and associate professor Nirianne Palacpac reviewed the follow-up results at an Ugandan restaurant. With excitement and anticipation, they recorded the results by hand as if counting ballots in an election: “Number 192 was infected once…this one was not vaccinated. The next one was infected…not vaccinated. The next person wasn’t infected either…this one had the vaccine”.. and so on. The results gave them proof that the vaccine was effective; it prevented infection in 72% of the cases and had no safety concerns. Horii recalls, “The level of excitement at that moment was extraordinary. It was the happiest moment I have ever had while working on research.”
Motivated by an unflagging sense of responsibility, with approval close at hand
May 2015: Phase I clinical trial kick-off meeting in Burkina Faso
Still a few steps remain before the BK-SE36 vaccine is approved. There must be clinical studies to determine whether the vaccine can be effective on children under age five in malaria-endemic areas as well as on people in countries where malaria is not endemic. The team expects that the vaccine will have 80% and 90% efficacy, respectively, in these populations. After the completion of clinical studies, the data will be sent to the Pharmaceuticals and Medical Devices Agency (PMDA). Once PMDA approves its license, the vaccine can then be used. Horii’s aim is to obtain PDMA approval by 2020.
People residing in malaria-endemic areas are not the only ones looking forward to availability of this vaccine. Many others, including tourists, the army, and visiting workers, expatiates, missionaries and aid workers eagerly await the vaccine. Although it may still be some time before this becomes a reality, Horii cheers us on, saying, “The sense of responsibility I gained from my discovery makes me want to keep going forward, even if I feel on the verge of tears.” His efforts continue.
Note: Quotes are from a June 4, 2015, interview conducted with Horii.
What type of vaccine is being developed?
The BK-SE36 malaria vaccine
Tropical malaria is transmitted through the bite of mosquitoes carrying the malaria parasite, which serves as the disease vector, transmitting the pathogen to the next host. On entering the body, these parasites consume red blood cells, digesting hemoglobin and multiplying several fold. Symptoms of infection mainly include high fever, headache, and nausea; and if left untreated can lead to debilitating illness and death. The BK-SE36 malaria vaccine developed by Horii is aimed at reducing parasite growth and multiplication in red blood cells, thus impeding the disease at an early stage. This is achieved by manipulating the SERA antigen gene in the parasite genome and using it as a vaccine antigen (the SE36 protein). The vaccine is a freeze-dried agent composed of a mixture of the SE36 protein and an aluminum-hydroxide gel.
Malaria Vaccine Development
Toshihiro Horii was born in Osaka in 1953 and graduated from the Osaka University School of Science in 1976. In 1984, he became an associate professor at Dartmouth College in United States, where he his research on malaria began. He was an assistant professor at the Osaka University Research Institute for Microbial Diseases from 1991 until 1999, and in 2005, he became the Director of both the Research Center for Infectious Disease Control and the International Research Center for Infectious Diseases at Osaka University.