Currently during the third quarter financial reporting season, the Chinese vaccine industry is under pressure in the current economic cycle fluctuations. Major vaccine varieties that used to sell well are also facing challenges of further price competition in the domestic market. As a domestically innovative vaccine industry in the biomedical sector, how to find a breakthrough and stabilize the situation, and find a path out of the predicament, is a core strategic consideration that will determine the future life or death of domestic vaccine manufacturers in each country.

At the same time, in recent innovative biopharmaceuticals and other sub-competitive sectors, such as bispecific antibodies, innovative small molecule drugs, and nuclear drugs, domestic companies have autonomously developed potential best-in-class biomedical assets, which have been purchased by international pharmaceutical giants for tens of millions or even hundreds of millions of dollars for their overseas rights. This indicates that in the Chinese biomedical innovative drug sector nurtured by the capital frenzy from 2018 to 2021, domestically innovative pharmaceutical companies with truly independent research and development innovation capabilities are leading Chinese innovative biomedical assets to "go global". Under such a major industry trend, we look forward to domestically innovative vaccine companies with the capability to independently develop innovative vaccines to seize the opportunity as soon as possible. It is very likely that the ability to export independently developed innovative vaccine products to the vast international market may be the only feasible path to break the current domestic operational challenges in the domestic vaccine industry. With this mindset, Clover Biopharmaceuticals (02197), which went public on the Hong Kong Stock Exchange at the end of 2021, has attracted our attention.

Clover Biopharmaceuticals has its own Trimer-Tag vaccine development technology platform, and this technology platform has been fully validated: Based on this technology platform, the self-developed SCB-2019 COVID-19 vaccine has been involved in multiple Phase III clinical trials with nearly 0.04 million participants in eight countries and five continents globally, and subsequently obtained Emergency Use Authorization (EUA) in China. Starting from mid-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 been focusing on rapidly advancing the self-developed respiratory syncytial virus (RSV) candidate vaccine SCB-1019, guided by maximizing the potential commercial value. In early December 2023, Clover Biopharmaceuticals announced the initiation of the Phase I clinical trial of the RSV candidate vaccine, becoming the first vaccine company in China to develop an RSV PreF (based on the pre-fusion conformation of the F protein) vaccine and enter the human clinical trial phase, firmly establishing Clover Biopharmaceuticals' leading position in the RSV field in China.

Soon after, in April and June 2024, Clover Biopharmaceuticals successively disclosed positive preliminary data from the 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 in the world to announce the head-to-head clinical trial results of its RSV candidate vaccine with the internationally leading commercialized RSV vaccine products for elderly individuals, attracting high attention from global peers and capital markets. At present, there are already three major pharmaceutical giants globally that have approved RSV vaccine products for the elderly. What high degree of differentiated advantages can Clover Biopharmaceuticals' self-developed RSV candidate vaccine possess to achieve overtaking on the curve, thereby realizing the strategic objective of going global, is worth in-depth investigation and attention!

Potential best-in-class, SCB-1019 shines

On October 29, Clover Biopharmaceuticals announced that in the Phase I clinical trial, its unadjuvanted bivalent RSV PreF trimer subunit candidate vaccine SCB-1019, when compared head-to-head with GSK's AS01E-adjuvanted RSV vaccine AREXVY, obtained more positive immunogenicity and safety data in elderly participants.

In terms of immunogenicity, on day 28, the geometric mean titers (GMTs) of neutralizing antibodies induced by SCB-1019 without adjuvant for RSV-A and RSV-B were approximately 30500IU/mL and 32000IU/mL, respectively; while the GMTs of neutralizing antibodies induced by AREXVY for RSV-A and RSV-B were approximately 26700IU/mL and 37700IU/mL, respectively; and the placebo group was approximately 3300IU/mL and 2900IU/mL, respectively.

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

It is indicated 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 mentioning that among the globally commercialized RSV vaccines, from sales data, GSK's AREXVY can be regarded as a leader in RSV vaccine field. Therefore, Trimer Biopharma released the head-to-head clinical trial results of SCB-1019, its RSV candidate vaccine without adjuvant, and GSK's AREXVY with AS01E adjuvant, with quite positive data: comparable efficacy with better safety, showing the potential for Trimer Biopharma's SCB-1019 to become a top contender in the same category.

According to the Wise News Finance app, RSV is a common respiratory virus, currently there are no specific drugs on the market, only symptomatic treatment for complications caused by RSV infection, so 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 RSV vaccines has been a priority for the WHO. Due to the complex pathogenesis of RSV, many major 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 US Food and Drug Administration (FDA) for market launch, aimed at preventing lower respiratory tract diseases caused by RSV infections in the elderly population, successfully achieving a breakthrough in zero prevention of RSV infections.

Currently, there are four RSV vaccines and preventative medications approved for marketing globally, including Arexvy developed by GlaxoSmithKline (GSK), ABRYSVO by Pfizer, Nirsevimab (Nirsevimab) by Sanofi and astrazeneca, and mRNA-1345 by moderna.

From the perspective of technical paths and protective efficacy, both GlaxoSmithKline and Pfizer's RSV vaccines belong to the recombinant protein route. GSK's AREXVY is a single-dose RSV vaccine that uses an adjuvant, with a protection rate higher than other RSV vaccines, reaching 82.6%. The protective efficacy against severe RSV-related lower respiratory tract diseases reaches 94.1%. Pfizer's bivalent RSV vaccine has a protection rate of around 60%. Moderna's single-dose RSV vaccine was only launched in May of this year, with a mRNA technology route, and a protective efficacy of over 80%. However, the CDC disclosed in mid-year that the effective protective efficacy of this single-dose RSV vaccine based on mRNA technology is insufficient to cover a complete epidemic season, dropping to less than 50% protection after 8 months of administration. The commercial prospects of mRNA technology route RSV vaccines are worrying, with Moderna's stock prices dropping by nearly 50% since the end of June. Meanwhile, the recombinant protein-based RSV vaccines from GSK and Pfizer, which were released around the same time, have a durability of protection lasting around 2 years. Therefore, currently, in terms of efficacy and durability of protection, the recombinant protein route RSV vaccines are superior to mRNA technology route RSV vaccines.

From the current commercial sales results, GSK's RSV vaccine has the advantage. In 2023, GSK's RSV vaccine sales reached $1.564 billion, while Pfizer's sales were $0.89 billion, only half of GSK's. GSK CEO Emma Walmsley has stated that their RSV vaccine has captured two-thirds of the U.S. market.

Although the initial sales of RSV vaccines set an industry record of nearly $1.3 billion in a quarter, the global potential for RSV vaccines to become the next multi-billion-dollar asset depends on future market opportunities for repeat vaccinations. Both approved commercially available recombinant protein-based RSV vaccines face challenges in effective repeat vaccinations, as shown by their previous and latest clinical data. Both GSK and Pfizer's Phase III clinical data show that 12 to 24 months after the initial dose, repeated vaccinations induced neutralizing antibody titers can only return to about 45-60% of the peak levels achieved by the initial dose. GSK has disclosed Phase III clinical protection data showing that repeat vaccinations 12 months after the initial dose do not achieve the protective efficacy corresponding to the peak neutralizing antibody titers of 55% induced by the initial dose, equivalent to no protective efficacy as the placebo group. From a scientific perspective, while the RSV vaccine antigens of these two companies differ, they both use T4-Foldon technology on trimer labels. Considering that this technology is an antigen itself, it may cause immune interference once introduced into the body, potentially leading to poor outcomes in repeat vaccinations.

Currently, GSK and Pfizer have announced Phase III clinical trials for repeat vaccinations at intervals of 3 and 4 years. However, data on the durability of protective efficacy for both RSV vaccines show that they need to be repeated approximately every 2 years. So who can fill the gap?

Three international major pharmaceutical companies have launched commercially available RSV vaccines targeting the elderly, with two facing challenges in effective repeat vaccinations, and one whose protective efficacy may not cover a complete seasonal epidemic. The current product deficiencies of international giants represent a potential opportunity for Trimer-Tag Bio and other global biomedical innovative vaccine companies to make breakthroughs.

Looking at Trimer-Tag Bio, their bivalent recombinant protein RSV candidate vaccine SCB-1019, developed based on their self-developed Trimer-Tag technology platform, is without an adjuvant. Trimer-Tag is the only globally used recombinant protein vaccine technology utilizing a human covalent trimerized tag, maintaining the stable structure of a natural trimer antigen. This can induce a strong and precise neutralizing immune response, with no observed immune interference or pre-existing immunity according to past clinical trial experience. In the Phase I clinical trials currently being conducted in Australia, SCB-1019 has displayed positive data compared to GSK's AREXVY, potentially offering the best protective efficacy among similar RSV vaccines. It is reported that Trimer-Tag Bio plans to initiate clinical trials in 2025 to evaluate SCB-1019 for repeat vaccinations in RSV vaccines, promising and worth attention.

Based on the Trimer-Tag platform, RSV vaccines and other respiratory tract combination vaccines have the potential for rapid development.

In the respiratory vaccine field, developing efficient combination vaccines is the industry's development trend as a whole. Similarly, for the RSV vaccine market, the long-term pipeline planning of various companies also includes the development of related respiratory combination vaccines to tap into bigger commercial market opportunities. It is worth mentioning that influenza virus, respiratory syncytial virus (RSV), and SARS CoV-2 virus 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 290,000 to 650,000 deaths.

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

Following COVID-19, studies have confirmed the co-infection of influenza and SARS-CoV-2 viruses, with an incidence ranging from 0.2% to 48%. Such combined infections often worsen the condition and prolong the course of the disease.

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

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

Currently, Clover's RSV candidate vaccine SCB-1019 is being used in the development of a respiratory combination vaccine for RSV+hMPV±PIV3 viruses, with plans to start clinical trials evaluating SCB-1019's application in respiratory combination vaccines in 2025. If the effectiveness of its respiratory combination vaccine is clinically validated, its candidate vaccine product will gain even more strength in international markets.

Global prospects and market competition of RSV vaccines have witnessed significant commercial success, with sales nearing 2.5 billion USD starting in the second half of 2023, which further validates the immense potential demand in the RSV market for both GSK and Pfizer, providing reassurance to subsequent research enterprises. According to the Acute Insight research data, the global overall market size of RSV drugs (including therapeutic and preventive drugs) is expected to grow from 1.8 billion USD in 2020 to 12.8 billion USD in 2030, with a compound annual growth rate of 21.4%.

As RSV vaccines generated close to 2.5 billion USD in sales in the second half of 2023, the success of GSK and Pfizer further confirming the significant potential demand in the RSV market has provided confidence to subsequent research enterprises. According to Acute Insight research data, the global overall market size of RSV drugs (including therapeutic and preventive drugs) is projected to increase from 1.8 billion USD in 2020 to 12.8 billion USD by 2030, with a CAGR of 21.4%.

According to the ClinicalTrials database, as of September 2023, over 20 different technology pathways of RSV vaccines and antibody drugs have entered clinical research stages 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 innovative and mature Trimer-Tag technology platform, Trimer-Tag Technology, Three Leaves Bio's RSV candidate vaccine SCB-1019 is expected to become a potential industry leader, taking the lead in domestic RSV vaccine development and having a great opportunity to represent successful innovation of domestic vaccines in the international market.

Conclusion

With the rapid development of the RSV vaccine market, Three Leaves Bio has shown great potential in this area with its unique Trimer-Tag technology platform and RSV candidate vaccine SCB-1019. According to clinical trial data, Three Leaves Bio's bivalent RSV PreF-Trimer subunit candidate vaccine not only performs well in terms of immunogenicity and safety, but also has the potential to address the issue of poor effectiveness of repeated vaccinations with existing commercial RSV vaccines. The clinical application of this vaccine in respiratory combined vaccines is also promising.

Despite the dominance of international pharmaceutical giants like GSK in the current RSV vaccine market, Three Leaves Bio is gradually establishing its leading position in domestic and even global RSV vaccine research and development due to its unique advantages. In the future, with the advancement of more clinical trials and the development of potential respiratory combined vaccines, Three Leaves Bio is expected to provide a more effective and long-lasting solution to combat RSV infections and further expand its influence in the global biopharmaceutical sector.