Industry Frontiers

Respiratory syncytial virus (RSV), as an RNA virus, belongs to the pulmonary virus genus of the Paramyxoviridae family. It is mainly transmitted through droplets and contact, posing a serious threat to the health of infants, children, the elderly, and immunocompromised populations. The clinical manifestations after infection are diverse, ranging from mild upper respiratory symptoms to severe lower respiratory tract infections such as high fever, severe coughing and sputum production, difficulty breathing, etc. In severe cases, it can affect other systems of the body and even develop into respiratory failure, leading to higher hospitalization and mortality rates. The prevention and control of RSV has always been an important issue in the field of public health worldwide, which has also attracted much attention to the RSV vaccine track. Many pharmaceutical companies have invested in research and development, hoping to occupy a place in this potential billion dollar market.

1、 Performance and challenges of RSV vaccines already on the market

In 2023, significant breakthroughs were made in the development of RSV vaccines, with GSK's Arexvy and Pfizer's Abrysvo both receiving FDA approval for marketing in May. The initial performance of these two vaccines was impressive, bringing substantial returns to both companies. Arexvy brought in over $1.5 billion in revenue for GSK in 2023, while Abrysvo contributed $890 million in revenue to Pfizer, becoming Pfizer's sixth largest product of the year, and the overall RSV market size also skyrocketed.

However, as we enter 2024, the situation has changed. The mass production of the two vaccines failed to maintain their high performance at the beginning, with sales of only around 550 million US dollars in the first three quarters, and even in Q2 2024, sales in a single quarter did not exceed 100 million US dollars. The reasons for the decline in sales are multifaceted, among which seasonal demand changes are one factor. The popularity of RSV shows seasonality, generally occurring in winter and early spring. The Q2 sales bottoming out may be related to this to some extent. But more importantly, there are "guideline restrictions". In June of this year, the CDC in the United States adjusted the vaccination guidelines for RSV vaccines, recommending that all adults aged 75 and above, as well as high-risk individuals aged 60-74, receive a single dose of RSV vaccine. Prior to this, it was recommended that adults aged 60 and above receive the vaccine through shared clinical decision-making (SCDM). This adjustment has changed market expectations, resulting in a shift in the scope of eligible populations for vaccination, directly affecting vaccine sales.

2、 Commercialization opportunities in the RSV vaccine market

Despite the current challenges in vaccine sales, the repeat vaccination market for the elderly is considered one of the biggest commercialization opportunities for RSV vaccines. In the first year of commercialization last year, the penetration rate of RSV vaccine among the elderly population for the first time exceeded 25%, and this year it is close to 40%. Given that the penetration rate of influenza vaccine among the elderly population in the United States is about 50-60%, the penetration rate of RSV vaccine for the first time may have approached its peak level. This means that the opportunities and scale of the RSV vaccine market among the elderly population in the United States in the future will mainly depend on the development and approval of RSV vaccines for repeat administration.

At present, the CDC emphasizes that the RSV vaccine is not an annual vaccine and eligible adults do not need to receive one dose every RSV season. However, research has shown that the protective efficacy of Arexvy's vaccine can cover three RSV epidemic seasons, but its protection rate has been declining over time. To address this pain point, GSK and Pfizer are conducting more clinical trials to investigate whether a second dose is needed and to clarify the time interval for re administration. If a vaccine regimen suitable for repeated administration can be successfully developed, it is expected to reignite the growth of the elderly population market.

Expanding the infant and toddler population is also an important commercialization direction, especially for "2-4 year old children". Most children in this age group have been exposed to RSV infection, but there is still a need for vaccination, and trials targeting this population are not within the clinical shelving scope recently disclosed by the FDA.

Previously, the development of RSV vaccines in infants and young children faced many difficulties. The FDA suspended research on Moderna's two mRNA vaccines for infants and young children due to "imbalanced severe RSV infections". Pfizer's Abrysvo achieved indirect coverage of infants and young children through vaccination in pregnant women, but GSK abandoned the RSV maternal vaccine GSK3888550A due to observing a higher incidence of premature birth. However, there is still an opportunity for vaccine development for the 2-4 year old child population. If a safe and effective vaccine can be successfully developed, it will bring new growth points to the market.

At present, the sales of RSV vaccines are mainly concentrated in the US market, with approximately 90% of Arexvy and Abrysvo's global sales in the first three quarters of this year contributed by the US region. With regulatory approval, markets in other regions are gradually opening up as well. The disease burden of RSV is heavy globally, especially in developing countries where there is a huge demand for RSV vaccines. Once approved for market in more countries and regions, the global sales of RSV vaccine are expected to achieve significant growth, which will bring broad market space for pharmaceutical companies.

Developing differentiated vaccines is also one of the ways to leverage a larger market share. One approach is to iteratively optimize RSV vaccines with higher effectiveness and safety. The potential of the bivalent RSV vaccine SCB-1019 from Trifolium repens in China has begun to emerge, and positive results have been obtained in the phase I study of Arexvy head to head. Another approach is to develop a combination vaccine to extend the potential product lifecycle of RSV vaccine monomers, such as mRNA-1365, which belongs to this type of combination vaccine. From the perspective of disease burden, vaccination procedures, national policies, and industry trends, respiratory combination vaccines will gradually become a seasonal protection trend, which can meet the market's demand for more efficient and convenient vaccines and stand out in the fiercely competitive market.

3、 The setbacks and inspirations of mRNA RSV vaccine

Moderna represents the mRNA technology roadmap for RSV vaccine development and has successfully developed the first mRNA RSV vaccine, mRNA-1345. However, its development has not been smooth sailing. The FDA delayed the approval of the vaccine and the company's stock price fell on the day of approval. From the perspective of immune duration, the protective efficacy of mRNA-1345 significantly decreased with prolonged follow-up time. For RSV-LRTD defined by two or more symptoms, its protective efficacy increased from 78.7% at 3.7 months of follow-up, to 62.5% at 8.6 months, and then to 50.3% at 18.8 months.

In July of this year, security issues followed one after another. Evaluate the triggering pause criteria for the Phase I study of mRNA-1345 and mRNA-1365 for immunization in infants and young children aged 5 months to 2 years, i.e., two or more subjects with severe lower respiratory tract infections accompanied by positive RSV detection. In August, Moderna determined that mRNA-1345 and mRNA-1365 may cause RSV VAERD (vaccine associated enhanced respiratory disease) in infants aged 5 to 8 months.

In the same month, the FDA partially shelved research on other non attenuated live vaccines for infants and young children. In September, Moderna promptly cut losses, stating that the clinical development of mRNA-1345 for infants and young children under 2 years old will stop at Phase I. This series of events has dealt a heavy blow to the mRNA RSV vaccine track and has prompted the entire industry to re-examine the safety issues of mRNA technology in RSV vaccine development.

This situation is similar to the Pfizer inactivated vaccine FI-RSV incident in the 1960s, when FI-RSV not only failed to provide the necessary protective effect, but also caused VAERD, resulting in the death of two young children and causing the entire RSV vaccine development track to stagnate for a long time. This indicates that safety is always the primary factor that companies planning RSV vaccines need to consider, and the higher safety needs of infants and young children must be fully taken into account at the beginning of vaccine design.

There are currently two main design approaches to address this issue. One is through adjuvant control, such as GSK's Arexvy incorporating its proprietary liposome adjuvant AS01E, and domestically leading ADV110 from Edivixin also containing the novel adjuvant AE011; The second is through antigen design, such as sequence design for mRNA vaccines. Different sequences will produce different antigens, and some antigens perform better in safety.

Although the development of mRNA-1345 in the infant and toddler population has been hindered, mRNA-1365 may still have opportunities for expansion. Because Moderna has not explicitly stated its abandonment of its research and development in the infant and toddler population, and the mechanisms of action of mRNA-1365 and mRNA-1345 are different. The former encodes the fusion pre F glycoprotein (pre-F) of RSV and the human metapneumovirus (hMPV) F protein, while the latter only encodes RSV pre-F. In addition, the FDA also stated in the briefing that attention should be paid to the differences between mRNA candidate vaccines and FI-RSV vaccines, as well as the non clinical data showing that mRNA candidate vaccines can reduce the risk of VAERD in infants, which leaves a glimmer of hope for further exploration of mRNA 1365 in the infant and toddler population.

From the trajectory of track development, it is reasonable for mRNA RSV vaccines to face setbacks now. Although the COVID-19 has accelerated the development of mRNA technology, the technical route has not gone through the process of full failure, trial and error, redesign, and validation, and the precipitation is insufficient. In addition, the development of RSV vaccines itself has significant difficulties, involving the complexity of the virus, differences in immune responses among special populations such as infants, young children, and the elderly, which makes mRNA RSV vaccines encounter numerous challenges in the development process. This also sounds the alarm for domestic mRNA companies, who need to be more cautious in considering factors such as technological maturity, safety, and market demand when developing RSV vaccines or other mRNA vaccine projects.

4、 Layout and response strategies of domestic enterprises

At present, there are about 70 RSV vaccine research and development pipelines in progress worldwide, and there are also several domestic companies with layouts, such as Zhongxin Biology, Hualan Biology, Aibo Biology, etc. However, only a few have entered clinical trials. There are 14 RSV mRNA research pipelines that have been disclosed, of which 7 products have been approved for clinical trials and 3 clinical trial applications have been accepted. In the research and development process, domestic enterprises not only face common problems in the global RSV vaccine development, such as the complex pathogenic mechanism of the virus and the difficulty in balancing the safety and efficacy of vaccines, but also have their own advantages and challenges.

The advantage of domestic enterprises is that they can learn from the R&D experience of foreign enterprises, avoid some known technological traps, and at the same time, the huge population base and potential market demand in China provide strong impetus for enterprises. However, domestic enterprises also face challenges such as relatively weak technological strength, limited research and development funds, and fierce international market competition. In the field of mRNA technology, although domestic enterprises have accumulated some experience in the research and development of COVID-19 vaccine, there is still a gap compared with international leading enterprises such as Moderna. In addition, domestic enterprises also face many obstacles in promoting and certifying in the international market, and need to continuously improve their research and development level and market competitiveness in order to make breakthroughs in the RSV vaccine track.

In response to these situations, domestic enterprises can adopt various coping strategies. Firstly, strengthen industry university research cooperation, integrate resources from all parties, and improve research and development efficiency and technological level. For example, collaborating with universities and research institutions to conduct basic research and gain a deeper understanding of the pathogenic mechanisms and immune response principles of RSV, providing a more solid theoretical foundation for vaccine development. Secondly, actively expanding international cooperation, introducing advanced foreign technology and experience, and enhancing our own research and development capabilities.

We can accelerate the research and development process of domestic RSV vaccines by collaborating with international pharmaceutical companies on research and development projects, technology transfer, and other means. In addition, domestic enterprises should also pay attention to the differentiated research and development of vaccines, and develop distinctive RSV vaccine products based on the characteristics of domestic disease epidemics and population needs, such as vaccines targeting specific age groups and regional epidemic strains, in order to improve product competitiveness and market adaptability.

5、 Future prospects

Although the RSV vaccine track currently faces many challenges, such as declining sales of marketed vaccines and setbacks in mRNA vaccine development, in the long run, the track still has enormous potential. With the acceleration of global aging and the increasing attention to the health of infants and young children, the demand for RSV vaccines will continue to grow. In terms of technology, pharmaceutical companies will continuously explore and optimize vaccine research and development technology, improve the safety and effectiveness of vaccines, and develop vaccine products that are more suitable for different populations. At the same time, regulatory policies worldwide will gradually improve, providing a more favorable environment for the research, approval, and marketing of RSV vaccines.

Although the application of mRNA technology in the field of RSV vaccines has encountered setbacks, it has prompted enterprises and research institutions to further study the advantages and disadvantages of mRNA technology. Through continuous improvement of technology, mRNA vaccines are expected to play an important role in RSV prevention and control in the future. Domestic enterprises will gradually accumulate experience and enhance their technological strength in the research and development of RSV vaccines, and are expected to make a name for themselves in the international market, contributing to the global RSV prevention and control cause.

In summary, although the RSV vaccine track is shrouded in fog, as long as companies can seize commercial opportunities, overcome technical challenges, and focus on safety and effectiveness, they may still achieve significant achievements in this field in the future, bringing positive impacts to global public health, protecting high-risk populations such as infants, young children, and the elderly from RSV, reducing the burden of disease, and improving human health.

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Source: Xianji.com

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