A potential post-infection antibody treatment for yellow fever, named TY014, was devised by a multi-disciplinary research team at SMART. TY014 could complement vaccination efforts and reduce the risk and occurrence of yellow fever outbreaks worldwide.
Yellow fever is a haemorrhage-inducing viral disease transmitted by the Aedes aegypti mosquito. It infects about 200,000 people worldwide each year, with 10 percent case fatality rate. It is endemic in African and Central and South American countries. However, Southeast Asian countries are increasingly susceptible as the Aedes aegypti mosquito is very well adapted to the tropical climate and habitat.
Although there is an effective vaccine available, there are no approved treatments at hand. At present, global vaccine production facilities are unable to meet the increased demand should a yellow fever epidemic arise. Current vaccines for yellow fever are also unsuitable for young children, the elderly and for people with a weakened immune system due to the potential negative effects it could elicit. For these groups of patients, the infection is usually treated via supportive care only. All these point to a need for an effective yellow fever treatment, in complementation to the vaccines.
Collaborative efforts among researchers from the Antimicrobial Resistance (AMR) of the Singapore MIT Alliance for Research Technology (SMART), together with Singapore General Hospital, Duke-NUS Medical School and Tysana Pte Ltd have led to the development of a promising antibody treatment for yellow fever, named the TY014, which could answer this need.
Using a Rapid Response Strategy, they have considerably shortened the conventional time frame required for effective antibody therapeutics development. Their work detailing the methodology employed and outcomes of Phase 1 trials, titled “Phase 1 Trial of a Therapeutic Anti-Yellow Fever Virus Human Antibody” was published in the New England Journal of Medicine. They also reported that a combination of pre-infection vaccination and post-infection TY014 treatment resulted in a decreased inflammatory state, as compared to vaccination alone.
TY014 is a medically engineered, man-made IgG1 monoclonal antibody which specifically binds and detects the yellow fever virus. In the formulation of TY014, researchers were especially dedicated to the evaluation of its safety, toxicology, and pharmacokinetic properties through redundant orthogonal analytics. Many years are usually needed for the development and validation of monoclonal antibodies treatments. However, the development of TY014 was shortened from several years to just seven months because of simultaneous work on the multi-stage drug production and validation steps.
Initial clinical trials in Singapore show the high success rate of TY014 as a yellow fever treatment as there were no detectable traces of the yellow fever virus in healthy volunteers who underwent the TY014 treatment. Using the Rapid Response Strategy and specialised computational techniques pioneered by the SMART AMR team and MIT, researchers first established a potential antibody treatment for Zika within a similarly short time frame of nine months. Subsequently, the design of the TY014 antibody was done in a short time frame as well. A batch of TY014 antibody was ready for clinical trials in just five months after the first transfection step. Phase 1a and 1b trials were completed in the subsequent two months.
According to Professor Ram Sasisekharan, Principal Investigator at SMART AMR, Professor of Biological Engineering and Health Sciences & Technology at MIT, “Traditional drug development processes are very linear, and they take many years. If you’re going to get something to humans fast, you can’t do it linearly, because then the best-case scenario for testing in humans is a year to 18 months. If you need to develop a drug in six months or less, then a lot of these things need to happen in parallel.”
Antibodies treatments can also be devised for other diseases using the same Rapid Response Strategy. The shortened time frame comes in handy especially in times of urgent need, like the current COVID-19 pandemic. In fact, a new and effective COVID-19 antibody treatment named TY027 was formulated using the same method, taking only four months from conceptualisation to validation.
With continued improvements of the Rapid Response Strategy, an even shorter time frame of three months from the conceptualisation to the evaluation of a potential antibody treatment is very attainable in the future.
Dr Rahul Singhvi, the CEO of Nature Resilience Inc, a technology production firm in the US remarked, “This is a very important study that demonstrates the critical importance of innovation, process design, sophisticated analytics, and progressive regulatory thinking in the drug development process; bringing an antibody therapeutic to patients within months of a deadly disease. Thanks to the rigorous characterisation of the materials used at different stages of the programme, the reduction in timelines did not compromise any safety or efficacy requirements in clinical trials. This is not only transformational but essential to combat the increasing risks from current and emerging infectious disease threats.”
Overall, the TY014 treatment provides a potential post-infection treatment which complements the preventive method of vaccination available, to ultimately reduce the detrimental impact of yellow fever on human health and its strain on global health efforts.