Recently, news in the field of respiratory syncytial virus (RSV) vaccine research and development has emerged intensively, becoming a hot topic of concern for new drug research and development. First, the FDA awarded the breakthrough therapy for RSV vaccine to Janssen. Second, large pharmaceutical companies around the world (such as Sanofi, GSK, Pfizer, Janssen, etc.) and biotechnology companies (such as Novavax, Bavarian Nordic) have launched a number of clinical trials. In addition, many emerging startups have also completed large-scale financing, such as Icosavax ($51 million) and Meissa ($30 million). Chinese biotechnology company Advaccine also announced the successful completion of Phase I clinical trials. Everyone is trying to be the first to achieve breakthroughs in the field of RSV, the most important respiratory vaccine, and seize the billions of dollars in the market.
RSV infection with vaccine requirements
Respiratory syncytial virus (RSV) can lead to upper respiratory tract infections (such as cold-like symptoms) and lower respiratory tract infections (such as bronchioles and pneumonia), which is the most common cause of bronchioles and pneumonia in babies under 1 year old. According to WHO's epidemiological data, more than 33 million acute lower respiratory tract infections, more than 3 million visits and more than 110,000 deaths are related to RSV infection every year.
In addition to children, RSV infection also creates a huge disease burden in the elderly population. According to an epidemiological survey in the United States, the annual mortality rate of people over 65 years old is 7.2 cases per 100,000, and the global direct economic burden caused by RSV exceeds US$80 billion every year.
Therefore, RSV has always been the crown jewel in the field of new vaccine research and development. EvaluatePharma, a professional consulting agency for the pharmaceutical market, released a market research report "World Preview 2018, Outlook to 2024" in 2018, predicting the five most commercially promising vaccines, two of which are RSV vaccines. If successfully listed, its sales in 2024 will total US$2.5 billion.
Source: EvaluatePharma
However, the difficulty and challenges of developing RSV vaccines are also very high. In 2007, Professor Stanley A. Plotkin, an expert at the World Health Organization, made a prediction on the progress of the world's most important vaccine product research and development. More than a decade later, most of the vaccine products on the list have been successfully launched, but the RSV vaccine is absent.
Figure 2. World Health Organization expert Professor Stanley A. Plotkin on the progress of vaccine research and development forecast (2007) and achievement results (2017)
RSV vaccine difficult development process
Since the RSV virus was first discovered in 1957, the development of vaccines has started quickly. Unfortunately, there was a major setback in the clinical trial of Pfizer's formaldehyde-inactivated RSV vaccine (FI-RSV) in the 1960s. More than 80% of the young children in the subject had severe pneumonia after being infected with RSV, and two of them eventually died. This incident led to a long period of silence in the development of RSV vaccines.
In the following 60 years, only two products were approved for the prevention of RSV infection, RSV immunoglobulin and palivizumab for intravenous injection, but the population of both is very narrow, especially the latter is only used in children with multiple risk factors for severe lower respiratory infection and premature children, and the high price further limits their use population.
In the past decade, the research and development of RSV vaccines has made rapid progress, and products developed based on various technical means such as viral particles, vectors, virus subunits and attenuated vaccines have entered the clinical research and development stage. However, RSV vaccines have always been known for their high clinical development failure rate: data from the clinical trial public registration platform show that more than 40% of RSV vaccines and antibody research and development projects have been terminated since 2015. PATH organizations that continue to track the progress of RSV vaccine research and development regularly publish statistics, and projects in the clinical development stage will increase and decrease.
Figure 3. Currently under development of RSV vaccine varieties (from PATH organization)
According to the current consensus in the academic and industrial circles, the design and development of RSV vaccines need to overcome two major problems. First, how to make the vaccinated person produce sufficient levels of antibodies against the RSV virus and provide continuous protection; second, how to avoid severe lung pathological damage (i.e., VED) when the vaccinated person is reinfected with RSV virus.For the first problem, with the deepening of research on RSV virology, the optimization and structural transformation of vaccine antigens, as well as the application of new adjuvants, it is no longer a big challenge to stimulate sufficient amounts of neutralizing antibodies; but the second problem VED has covered many dark clouds for clinical projects of each RSV. The RSV F vaccine (ResVax), the most popular Novavax company, has not met the main endpoint indicators in the phase III trial of clinical trials. MedImmune's new RSV F adjuvant vaccine and BBG2Na G polypeptide vaccine have all terminated clinical trials due to VED phenomenon.
Treg cell regulation technology and RSV vaccine Dawn
In recent years, with the continuous deepening of cell immunology research, it has been found that regulatory T cells (i.e. Tregs) play a key inhibitory role in the occurrence and development of many autoimmune diseases and inflammations. Related diseases can be explained by the insufficient level of Treg cell subpopulations, that is, excessive cell immune activity will lead to self-attack, and Treg cells are required to play a crucial negative feedback balance. Because the VED phenomenon is a vaccine-induced over-activation of cellular immunity, the latest vaccine development idea based on immunology believes that an ideal RSV vaccine needs to induce Treg to inhibit the cellular immune response while activating antibodies, in order to fundamentally solve the VED problem that has plagued the development of RSV vaccine for nearly 60 years.
Aidiweixin Biopharma, a Chinese company focusing on the research of Treg cell regulation technology, took the lead in using Treg regulation technology to independently design and develop the RSV vaccine BARS13 for VED, successfully induced Treg cells with negative regulatory capabilities, effectively controlled VED pneumonia in RSV, and at the same time, its adjuvant design greatly improved the antibody level.
Recently, BARS13 successfully completed the Phase I clinical trial in Australia. The trial used a randomized, double-blind design to evaluate the safety and tolerance of BARS13 in healthy adult subjects (FIH), and explored the specific antibody responses of BARS13 and the cellular immunology changes. The trial successfully reached the phase I clinical endpoint and laid a solid foundation for the subsequent RSV vaccine target population (elderly and infants) to explore the dose, optimize the immune procedure, and international multicenter confirmatory clinical practice.
We see that with the continuous deepening of immunology research, the development of RSV vaccines has seen the dawn. China's biotechnology companies have also begun to occupy the first echelon of the international vaccine research and development landscape, leading the global R&D trend.
