Wataru Akahata, CEO of VLP Therapeutics Japan LLC, thinks he can help provide a solution to the challenge of securing COVID-19 vaccines for billions of people — the development of a second-generation messenger RNA (mRNA) vaccine that requires only a fraction of the dosage of those currently available.
The biotech startup will file an application for a clinical trial in June, with the initial stage, which involves dozens of volunteers at the Oita University Hospital in Kyushu and is used to evaluate safety, expected to start in the summer. Unlike the mRNA vaccines made by U.S.-based Pfizer Inc. and Moderna Inc., VLP’s proprietary “replicon” RNA in the vaccine will self-amplify inside the body before producing antigen proteins, which would induce immune responses against the coronavirus.
The key benefit of self-replicating vaccines is their efficiency, because they would require only a fraction of the dosage of conventional vaccines to trigger a strong immune response. Scientists have calculated that self-replicating mRNA vaccines would require as little as 1 to 10 micrograms to induce an effective immune response. Compared with mRNA COVID-19 vaccines that have so far been commercialized, the dosage would in theory be a tenth or less. If it’s proven efficacious and safe, as little as 126 grams would be needed to vaccinate all of Japan’s 126 million residents, according to VLP’s calculations.
Major Western mRNA COVID-19 vaccine manufacturers plan to produce anywhere from 800 million to 3 billion doses this year, but self-replacing mRNA vaccines might enable vaccine production of unparalleled speed, some scientists say.
Because of the strong immune response, a single shot of a replicon vaccine might be enough to trigger effective protection, though that is still to be determined in clinical trials. Second-generation mRNA COVID-19 vaccine candidates have begun clinical trials around the world but have not been commercialized yet.
“We’re aiming for a significant reduction in dosage, so we expect to vastly speed up production compared with other vaccine platforms,” Akahata said. “We are also hoping that the lower dosage will reduce side-effects in people.
“I often hear of people vaccinated with a COVID-19 vaccine having a high fever and calling in sick, especially after the second shot. Japanese people are considered more sensitive to side-effects in general, so I hope to develop a vaccine with fewer side-effects.”
Before co-founding VLP Therapeutics in 2013, Akahata researched a mosquito-borne RNA virus called alphavirus, which has been afflicting people in Africa and other regions, for over 10 years at the U.S. National Institutes of Health. While there, he invented a vaccine for the disease using a “virus-like particle,” which like viruses has viral proteins that can elicit a strong immune response but is safe because it contains no genetic information.
At VLP Therapeutics, he took up research on self-amplifying mRNA technology, which he thought could be applied to the development a highly effective vaccine for COVID-19. If the initial clinical trial confirms safety, the company is considering conducting follow-up clinical trials in Japan.
But the lower number of COVID-19 cases compared with other countries makes it difficult to secure trial candidates, so the company is likely to seek conditional approval from the regulator without conducting a final phase trial involving tens of thousands of volunteers, on the assumption that the vaccine is safe and efficacious, Akahata said.
“We will focus all our efforts on Japan, as there’s a heightened need for domestic vaccines,” he said. “We previously aimed to supply the vaccine between 2022 and 2023, but we are now aiming for 2022.”
Akahata says that its animal experiments have confirmed its vaccine candidate’s efficacy against the more contagious coronavirus variants first identified in the U.K., South Africa and India. When a need emerges to develop an updated vaccine to more specifically target new mutations of COVID-19, the development could be done “very quickly,” he added.
“Once this platform is established, we will be able to quickly deal with cases when there’s a new variant that calls for a new vaccine or a new illness emerges,” he said. “That’s why I wish with all my heart that this vaccine will take hold in Japan.”
VLP has been working with Oita University, the National Center for Global Health and Medicine, the National Institute of Biomedical Innovation, Health and Nutrition, Osaka City University, the Nagoya Medical Center and Hokkaido University on the vaccine candidate. The project has been awarded a grant of up to ¥10 billion by the Japan Agency for Medical Research and Development. The company also signed a manufacturing contract with Fujifilm Corp. for its COVID-19 vaccine formulation last October.
Akahata says that his firm’s mRNA vaccine is different from those of its rivals in that it encodes only the signature part of the spike protein that the immune system recognizes and attacks, which he says makes it possible to kill the coronavirus more efficiently.
Akahata says that once self-amplified, the mRNA is designed to produce proteins that would then be immediately attacked by the immune system.
“Scientifically, it would be impossible for the mRNA to continue self-replicating for long,” he says.
Still, some experts have expressed concerns about the unfettered self-replication of RNA.
“I’m worried that the mRNA, which is mass produced by self-replication, would give a strong stimulus to humans’ natural immunity,” which might lead to unintended side reactions, said Tetsuo Nakayama, a project professor at Kitasato Institute for Life Sciences and director of the Japanese Society of Clinical Virology.
Globally, several companies have been developing self-replicating mRNA vaccines. San Diego-based Arcturus Therapeutics Holdings Inc. has conducted a randomized clinical trial involving 580 participants of its single-dose vaccine in the U.S. and Singapore and is preparing to begin a large-scale trial. A clinical trial also began in Japan in May, with Elixirgen Therapeutics Inc. conducting a trial of 60 participants in cooperation with Fujita Health University in Aichi Prefecture.
Despite intense competition over the commercialization of replicon mRNA vaccines, VLP aims to be the first company to commercialize the shots in Japan. Though the first products may need to be stored in a special freezer like other mRNA vaccines, the company may be able to offer a freeze-drying vaccine in a powder form in the future, which would help with storage, handling and deliveries for developing countries that do not have an ultracold supply chain, Akahata said.
“This technology has so much room for improvement, so I’d like to nurture it with great care,” he said.
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