Currently in the third quarter financial reporting season, the performance of the Chinese vaccine industry is under pressure due to economic fluctuations, and major vaccine types that used to sell well are facing further price competition challenges in the domestic market. For the domestically produced innovative vaccine industry in the biopharmaceutical sector, how to find a breakthrough and stable path, and unveil the core strategic considerations that will determine the future commercial life and death of domestic vaccine manufacturers, under the current economic cycle fluctuations.

At the same time, in recent times, in other sub-segments of innovative biopharmaceuticals, such as bispecific antibodies, innovative small molecule drugs, and nuclear drugs, there are potential best-in-class (Best-in-Class) bio assets independently developed by domestic enterprises, which have been acquired by international major pharmaceutical companies (MNC) for tens of millions or even hundreds of millions of dollars. This indicates that in the Chinese biopharmaceutical innovation track incubated by the capital boom from 2018 to 2021, domestically developed biopharmaceutical companies with real independent research and development innovation strength are leading the way for Chinese innovative biological assets to go global. With this industry mega-trend, we look forward to domestic innovative vaccine companies with the ability to independently research and develop innovative vaccines to ride the wave as soon as possible. It is highly likely that entering the vast international market with self-developed and strong innovative vaccine products is the only feasible path to break through the current domestic operational challenges in the domestic vaccine industry. With this in mind, Clover Biopharmaceuticals (02197), which went public in Hong Kong at the end of 2021, has caught our attention.

Clover Biopharmaceuticals has a self-developed Trimer-Tag (protein trimerization) vaccine development technology platform, which has been fully validated: Its self-developed SCB-2019 COVID-19 vaccine based on this technology platform has nearly 0.04 million people enrolled in multiple Phase III clinical trials in eight countries across five continents, and subsequently obtained Emergency Use Authorization (EUA) in China. Starting from the middle of 2023, Clover Biopharmaceuticals, with the rich experience and resources accumulated from its self-developed COVID-19 vaccine, combined with the characteristics of its own technology platform, has strategically focused on the rapid advancement of its self-developed respiratory syncytial virus (RSV) candidate vaccine SCB-1019 with the aim of maximizing potential commercial value. In early December 2023, Clover Biopharmaceuticals announced the initiation of Phase I clinical trials for its RSV candidate vaccine, becoming the first Chinese vaccine company to develop an RSV PreF (based on pre-fusion conformation of the F protein) vaccine and enter the human clinical trial stage, solidifying Clover Biopharmaceuticals' leading position in the RSV field in China.

Soon after, in April and June 2024, Clover Biopharmaceuticals disclosed the positive preliminary data from Phase I clinical trials of its bivalent RSV candidate vaccine SCB-1019 in young adults and elderly populations. Just four months later, Clover Biopharmaceuticals became the first company globally to release the head-to-head clinical trial results of its RSV candidate vaccine against the internationally leading commercialized RSV vaccine products, garnering high attention from global peers and the capital markets. Currently, three major pharmaceutical giants globally have approved RSV vaccine products for the elderly. What high degree of differentiated advantages does Clover Biopharmaceuticals' self-developed RSV candidate vaccine have to achieve overtaking on the curve and ultimately achieve the strategic goal of going global, is worth further research and attention!

Potential best-in-class, SCB-1019 stands out

On October 29, Clover Biopharmaceuticals announced in a statement that in its Phase I clinical trial, the two-valent RSV PreF trimer subunit candidate vaccine SCB-1019 evaluated without adjuvant obtained more positive immunogenicity and safety data in elderly subjects compared to the RSV vaccine AREXVY from GSK using the AS01E adjuvant.

In terms of immunogenicity, on day 28, the geometric mean titers (GMTs) of neutralizing antibodies induced by RSV-A and RSV-B with SCB-1019 without adjuvant were approximately 30,500 IU/mL and 32,000 IU/mL, respectively; while those induced by AREXVY were approximately 26,700 IU/mL and 37,700 IU/mL for RSV-A and RSV-B, respectively; the placebo group was approximately 3,300 IU/mL and 2,900 IU/mL, respectively.

In terms of safety, compared to GSK's RSV vaccine AREXVY (76.7%) using the AS01E adjuvant, the incidence of local adverse events (AEs) was significantly lower with SCB-1019 without adjuvant (16.7%).

It indicates that SCB-1019 has good overall tolerability, with both local and systemic adverse events (AEs) being generally milder compared to the saline placebo group.

It is worth noting that in the global commercialized RSV vaccine market, based on sales data, GSK's AREXVY can be said to be a leader in the RSV vaccine field. Therefore, Tri-Leaf Biologics released the head-to-head clinical trial results of SCB-1019, their adjuvant-free RSV candidate vaccine, against GSK's AREXVY with AS01E adjuvant, and the data is quite positive: comparable efficacy with better safety profile, highlighting Tri-Leaf Biologics' SCB-1019 as having the potential to be the best in its class.

According to the Wise News Finance APP, RSV is a common respiratory virus, for which there are currently no specific drugs on the market, only symptomatic treatment for complications caused by RSV infection. Therefore, vaccination for proactive prevention is a key effective measure to avoid severe RSV infections and reduce mortality.

In fact, since the 1960s, the development of an RSV vaccine has been a priority for the WHO. Due to the complex pathogenic mechanism of RSV, many large pharmaceutical companies have faced challenges in RSV vaccine development over the years.

It was not until last year, in 2023, that GSK announced the approval of its respiratory syncytial virus (RSV) vaccine Arexvy by the Food and Drug Administration (FDA) in the USA for the prevention of lower respiratory diseases caused by RSV infections in the elderly, successfully achieving a breakthrough in RSV infection prevention.

Currently, there are four RSV vaccines and preventive medications approved for marketing globally, developed by GlaxoSmithKline (GSK) Arexvy, Pfizer ABRYSVO, Sanofi and AstraZeneca Nirsevimab (Nirsevimab monoclonal antibody), and Moderna mRNA-1345.

From the perspective of technical pathways and protective efficacy, the RSV vaccines of GlaxoSmithKline (GSK) and Pfizer both belong to the recombinant protein route. GSK's AREXVY is a monovalent RSV vaccine that uses an adjuvant. It offers higher protection compared to other RSV vaccines, reaching 82.6%. The protective efficacy against severe RSV-related lower respiratory diseases is as high as 94.1%. The bivalent RSV vaccine from Pfizer has a protection level of around 60%. Moderna's monovalent RSV vaccine only entered the market in May this year, using mRNA technology with a protective efficacy of over 80%. However, the CDC disclosed in mid-year that the protective efficacy of this monovalent RSV vaccine using mRNA technology is not sufficient to cover a complete flu season, dropping to below 50% after 8 months of vaccination. The commercial prospects of mRNA technology-based RSV vaccines are worrying, as reflected by Moderna's stock price dropping by nearly 50% from the end of June till now. In contrast, the RSV vaccines from GSK and Pfizer based on the recombinant protein route, both show a lasting protective efficacy of around 2 years. Therefore, at present, from the perspectives of protective efficacy and durability, the recombinant protein route RSV vaccines are superior to the mRNA route RSV vaccines.

Based on current commercial sales results, GSK's RSV vaccine has the advantage. In 2023, GSK's RSV vaccine sales reached $1.564 billion, while Pfizer achieved sales of $0.89 billion, only half of GSK. GSK CEO Emma Walmsley once stated that their RSV vaccine already holds two-thirds of the US market.

Although the first-time sales of RSV vaccines set a near $1.3 billion quarterly record, the global RSV vaccine's potential to become the next multi-billion dollar product depends on future opportunities for repeat vaccinations. The two commercially approved recombinant protein route RSV vaccines face challenges regarding effective repeat vaccinations based on previous and latest clinical data. Both GSK and Pfizer, irrespective of their III-phase clinical data, show that 12 or 24 months after the first dose, repeat vaccinations only induce neutralizing antibody titers reaching around 45-60% of the peak levels after the first dose. GSK has disclosed III-phase clinical protection efficacy data, showing that repeated vaccinations 12 months after the first dose do not reach the protection efficacy corresponding to the neutralizing antibody titer peak of 55% after the first dose, equivalent to no protective efficacy in the placebo group. From a scientific perspective, although the RSV vaccine antigens of both companies differ, they employ the T4-Foldon technology in their trimer labels. Considering this technology itself is an antigen, it may cause immune interference in the body, leading to poor effects of repeat vaccinations.

Currently, GSK and Pfizer announced conducting III-phase clinical trials for repeat vaccinations at intervals of 3 and 4 years, but the data on the durability of protective efficacy for both RSV vaccines show the need for repeat vaccinations approximately every 2 years. So, who can fill the gap?

Among the three commercially approved RSV vaccines for the elderly by international pharmaceutical giants, two face challenges with effective repeat vaccinations, while the protective efficacy of the third one cannot even cover a complete disease epidemic season. The current product deficiencies of global industry leaders present potential opportunities for Trimer Bio and various global biotech innovative vaccine companies to advance by overcoming these challenges.

Looking at Trimer Bio, their adjuvant-free bivalent recombinant protein RSV candidate vaccine SCB-1019 is developed based on their in-house Trimer-Tag technology platform. Trimer-Tag is the only global recombinant protein vaccine technology utilizing a human covalent trimerized label, maintaining the stable natural trimer antigen structure, thereby inducing strong and precise neutralizing immune responses. Based on previous clinical trial experiences, no immune interference or pre-existing immunities were observed. In the ongoing Phase I clinical trial in Australia, SCB-1019 demonstrates positive data in comparison with the GSK's AREXVY, securing a potential best-in-class protective efficacy among RSV vaccines. It is reported that Trimer Bio plans to commence clinical trial evaluations of SCB-1019 for repeat vaccinations in RSV vaccines in 2025, a development worth anticipating and paying attention to.

Based on the Trimer-Tag platform, RSV vaccines and other respiratory combination vaccines are expected to be rapidly developed.

In the respiratory vaccine field, developing efficient combination vaccines is the industry's development trend. Similarly, for the RSV vaccine market, the long-term pipeline planning of various companies also involves developing related respiratory combination vaccines to tap into larger commercial market opportunities. It is worth mentioning that seasonal influenza, respiratory syncytial virus (RSV), and SARS-CoV-2 have become major global public health challenges. Seasonal influenza affects 5% to 10% of adults and 20% to 30% of children globally each year, resulting in 3 to 5 million severe cases and causing approximately 0.29 to 0.65 million deaths.

In 2019, the COVID-19 pandemic caused by SARS-CoV-2 has exacerbated the situation, with at least 0.775 billion reported cases globally, resulting in approximately 7 million deaths.

Following COVID-19, studies have confirmed the co-infection of influenza and viruses like SARS-CoV-2, with infection rates ranging from 0.2% to 48%. Such co-infections typically lead to worsened conditions and extended illness.

Therefore, the development of combined respiratory vaccines has gradually become a new focus in vaccine research. The core of this trend lies in providing protection against multiple respiratory viruses through a single vaccine, reducing the number of doses, increasing vaccination rates, and expanding the immunization coverage.

Trimer-Tag (trimerization of protein) vaccine development technology platform by Trefoil Bio is particularly suitable for combining multiple respiratory virus antigens with similar structures. This platform enhances the stability and immunogenicity of vaccine antigens, providing a solid foundation for the development of multivalent or combination vaccines. Importantly, Trefoil Bio's valuable experience in RSV vaccine development based on this platform has paved the way for the development of respiratory combination vaccines.

Currently, Trefoil's RSV candidate vaccine SCB-1019 is being used to develop a respiratory combination vaccine for RSV+hMPV±PIV3, with plans to initiate clinical trials evaluating SCB-1019's application in respiratory combination vaccines in 2025. If the efficacy of its respiratory combination vaccine is clinically validated, its candidate vaccine product is poised to make significant strides in international markets.

Global outlook on the commercialization and market competition of RSV vaccines.

Due to the near $2.5 billion in sales recorded for RSV vaccines starting in the second half of 2023, the successful ventures of GSK and Pfizer further confirm the significant demand in the RSV market, providing assurance to subsequent research companies. According to data from Torch Insight, the overall global market size of RSV drugs (including therapeutic and preventive drugs) is projected to increase from $1.8 billion in 2020 to $12.8 billion in 2030, with a compound annual growth rate of 21.4%.

According to the ClinicalTrials database, as of September 2023, over 20 different technical pathways of RSV vaccines and antibody drugs have entered various stages of clinical research globally.

Although there are many companies involved in the development of RSV vaccines, the barriers to RSV vaccine research and development are extremely high, making it difficult to successfully develop a safe and effective RSV vaccine. With its original and mature Trimer-Tag technology platform, Trimer Bio's RSV candidate vaccine SCB-1019 is expected to become the best in the industry, leading the way in domestic RSV vaccine development, and has a great opportunity to become a representative of successful domestic bio-innovative vaccine going global.

Conclusion

With the rapid development of the RSV vaccine market, Trimer Bio has shown great potential in this field with its unique Trimer-Tag technology platform and RSV candidate vaccine SCB-1019. According to clinical trial data, Trimer Bio's bivalent RSV PreF-Trimer subunit candidate vaccine not only performs excellently in terms of immunogenicity and safety, but also has the potential to address the issue of poor repeat vaccination efficacy of existing commercialized RSV vaccines. The clinical evaluation of its application in respiratory combination vaccines is also promising.

Although the RSV vaccine market is currently dominated by international pharmaceutical giants such as GSK, Trimer Bio is gradually establishing its leading position in domestic and even global RSV vaccine research and development based on its unique advantages. In the future, with the advancement of more clinical trials and the development of potential respiratory combination vaccines, Trimer Bio is expected to provide more effective and long-lasting solutions for resisting RSV infections, and further expand its influence in the global biotech health field.