Key Challenges in Clinical Trials for Innovative Vaccines: RSV and Norovirus

With the arrival of the autumn and winter seasons, the number of outpatient and emergency visits in multiple hospitals has surged to varying degrees. In addition to various types of respiratory infectious diseases such as mycoplasma pneumonia, RSV (Respiratory Syncytial Virus), influenza, and the novel coronavirus, this also includes enteric infectious diseases like norovirus, which has entered its epidemic season.

Since the COVID-19 pandemic began in 2019, vaccines, being the fastest and most effective means to combat infectious diseases, have quickly become a focal point in both primary and secondary markets. With the potential demand population continuously rising, progress on urgently needed vaccine products such as those for Norovirus and RSV has also been particularly noteworthy.

In May this year, GSK and Pfizer's two RSV preventive vaccines for adults aged 60 and above were successively approved for marketing, breaking the market void in this billion-dollar track. Recently, GSK and Pfizer also released their financial reports respectively, showing that the two RSV vaccines generated a total of $1.26 billion in sales in the first quarter, officially kicking off the battle for the RSV vaccine market. In addition to GSK and Pfizer, other multinational players such as Moderna, AstraZeneca/Sanofi have joined this track. Similar to the RSV vaccine, the preventive vaccine for norovirus is also a blue ocean. To date, there are no globally approved drugs or preventive products available for the treatment of norovirus.

According to Anqiu Release, the cause of "74 middle school students in Shandong experiencing nausea and vomiting" was precisely Norovirus infection. As one of the leading pathogens responsible for acute gastroenteritis outbreaks and epidemics across all age groups globally, it is highly contagious and spreads rapidly, potentially leading to chronic illness or death in children, the elderly, and immunocompromised individuals. Outbreaks can occur in both developing and developed countries.

Although the development of norovirus vaccines has achieved considerable progress, it still faces enormous challenges. NoVs mutate rapidly, possess viral genetic diversity, and exhibit significant antigenic differences among genotypes. Their binding patterns with highly polymorphic HBGAs (histo-blood group antigens) in the population are also constantly changing. Additionally, the current in vitro culture system for noroviruses is not well-established, and there are issues such as difficulties in sourcing animal models, non-obvious clinical symptoms, and high research and development costs.

RSV: A Race That Has Attracted Numerous MNCs and Taken Nearly 70 Years to Conquer

In addition to the RSV vaccines already marketed by GSK and Pfizer, among the R&D pipelines, the mRNA vaccine from Moderna is currently progressing rapidly and has submitted marketing applications in multiple countries. On the other hand, infant and toddler vaccines led by Sanofi's SP0125 pipeline are also under continuous exploration. In terms of passive immunity for RSV, the FDA has approved MedImmune's humanized lgG1K monoclonal antibody Synagis, as well as Nirsevimab (Beyfortus), co-developed by AstraZeneca and Sanofi, for market release.

According to incomplete statistics, so far, there are nearly 70 RSV prevention pipelines under research and development globally. Although China currently has no approved vaccines or antibody products for the prevention of RSV infection, there are also many domestic players. Those with relatively rapid progress include Tanox BioPharma and Advaccine, which have entered the late stages of clinical trials. Meanwhile, companies such as AIM Vaccine, CSPC Pharmaceutical Group, Zhifei Biological Products, Jiamen West Sea Biotech, BCHT Biotech, Bluebird Bio/Walvax Biotech, and Clover Biopharmaceuticals are also striving to catch up.

In contrast, China is at the forefront of the world in the research and development of norovirus vaccines. In July this year, China National Biotec Group (CNBG) announced that the Phase III clinical trial of the recombinant bivalent norovirus vaccine jointly developed by the CNBG Research Institute and Lanzhou Institute of Biological Products, both under the China National Pharmaceutical Group (Sinopharm), had completed the enrollment and vaccination of the first batch of subjects. This marks that the world's first norovirus vaccine may be successfully developed in China. Additionally, ZF Bio's quadrivalent recombinant norovirus vaccine using Pichia pastoris is currently undergoing Phase II clinical trials, while the hexavalent norovirus vaccine developed by Kanghua Bio has also initiated Phase I clinical trials overseas.

RSV vaccines and norovirus vaccines, as innovative vaccines, face different challenges in the early research and development, preclinical studies, and clinical trial phases. It should be emphasized thatDue to the particularity of seasonal infectious diseases, large-sample efficacy clinical trials can only be conducted during the epidemic season and within the epidemic region. Any slight oversight in site selection could lead to the risk of failure or delay.It is precisely because of the particularity of such clinical trials that the human and material costs involved in these trials are also higher.

Therefore, unlike drug development, the first tough challenge for preventive products in clinical research is usually not patient recruitment but rather professional, comprehensive, and authoritative epidemiological studies. Such studies present significant challenges in terms of survey methods, data processing, and expertise, and pharmaceutical companies generally entrust professional vaccine clinical trial CROs to carry them out.

What are the methodologies for conducting epidemiological research? What are the key difficulties and challenges that need special attention? On this basis, how should clinical trials be carried out? What is the duration? What are the challenges in each phase? How to monitor endpoint cases? At this critical moment in the development of innovative vaccines such as RSV vaccines and norovirus vaccines, with various questions about the clinical trials of innovative vaccines,VCBeat had the privilege of interviewing Beijing Simuray Pharmaceutical Technology Co., Ltd. (hereinafter referred to as Simuray), a leading CRO company in China for vaccine clinical trials.

According to a survey by VCBeat, Chinese companies such as China Biologic, Zhifei Biological, and Tainuo Magpie, which have entered the late-stage clinical trials for RSV and norovirus pipelines, have all chosen the same vaccine clinical trial CRO company—Simurek. To date, Simurek has undertaken hundreds of operational projects for vaccine clinical trials in Phases I-IV, along with clinical data management and statistical analysis services. The preventive products involved exceed 25 types, including innovative vaccines such as the COVID-19 vaccine, intranasal flu vaccine, 13-valent/15-valent pneumococcal conjugate vaccine, norovirus vaccine, EV71 enterovirus vaccine, RSV vaccine, HPV vaccine, and more, as well as RSV monoclonal antibodies.

During the clinical development process of vaccines, vaccine clinical trial CRO companies face healthy populations in disease-prevalent areas. This means that the first step in vaccine pipeline clinical trials is not to find diseased populations but to gather epidemiological data such as disease-prone areas, epidemic seasons, prevalent strains, transmission methods, and susceptible populations. The corresponding executing units are not large hospitals or specialized clinical trial institutions, but rather provincial CDCs (Centers for Disease Control) which delegate the tasks to municipal and county-level CDCs under their jurisdiction. According to Simuric, there are currently over 200 trial sites across 20 provinces in China capable of conducting vaccine clinical trials, covering major regions in both southern and northern parts of the country.

Focusing on the research of innovative preventive products such as RSV and norovirus, the study design and implementation will face significant challenges. Complex procedures, unclear safety, prominent adverse reactions, and insufficient evidence of effectiveness can all contribute to pipeline failures. Additionally, the difficulty in vaccine development lies in the fact that neither has a clear serological surrogate endpoint, and their effectiveness must be verified through large-scale protective efficacy trials. In this context, the design of clinical trial protocols is not only a crucial step in implementing GCP but also an important basis for conducting research, monitoring, and auditing. It is also a key guarantee for evaluating the effectiveness and safety of vaccines.

According to Simcere, to evaluate the effectiveness of a vaccine, the design of the protocol needs to consider two key aspects: epidemiology and medical evaluation. Epidemiology defines the vaccinated population, sample size, enrollment time, observation period, and enrollment regions, while medical evaluation involves case visits, collection, testing, and confirmation of endpoint cases.

"Faced with such complex efficacy evaluation indicators, a qualified clinical trial protocol needs to balance scientific rigor, feasibility, and research costs. Creating such a protocol requires comprehensive epidemiological investigation work (epidemiological survey) in the early stages," emphasized Lin Yuan, Medical Director of Simurek.

"China's vast territory, along with varying climates and population living habits, results in different epidemic seasons and transmission patterns for the same infectious disease across regions. The incidence rates and prevalent genotypes differ significantly. For many vaccines, the protective efficacy trials fail to detect enough target cases in the later stages, mostly due to inadequate epidemiological investigations conducted earlier," Lin Yuan added.

What Constitutes a Well-Conducted Epidemiological Investigation?

Taking the epidemiological investigation in the RSV field as an example, Wei Pengchong, chairman of Simuric, introduced that two years before the clinical development of RSV preventive products, they had already sampled children with lower respiratory tract infections in multiple provinces in southern and northern China, conducting cross-sectional surveys at different times. After combining the analysis with literature, they confirmed the time when different regions in China enter the RSV epidemic season, based on which they formulated clinical enrollment plans for different centers. "At this point, the initiation of centers is not limited to a specific time or sequence. It is optimal if the trial centers are located in epidemic areas and can complete enrollment just before the start of the epidemic season. This is very different from traditional drug trial center selection and determines the success or failure of registration studies." It should also be noted that most clinical trials previously conducted in hospitals were for therapeutic drugs, mostly observing individual patient efficacy as the endpoint. However, clinical trials evaluating the protective efficacy of preventive products in populations are relatively rare in hospitals. This requires principal investigators, sponsors, or CROs to be familiar with national trends in relevant viral epidemics and to establish active and passive disease surveillance networks in advance, which is a massive systematic project.

In addition, Simcere is drawing on its past experience in completing efficacy trials for respiratory virus vaccines and is currently conducting epidemiological research on RSV in adults to lay the groundwork for clinical trial design and implementation.

"For diarrheal infectious diseases such as norovirus and rotavirus, the incidence rates vary significantly across different experimental centers. 'We conducted surveys at different trial centers within the same province, and the difference in diarrhea incidence rates can be more than 10 times,' said Wei Pengchong. Fortunately, although the prevalence of strains within the same virus may slightly differ across provinces and cities, the proportion of each bacterium or virus in diarrheal diseases remains relatively stable. When selecting trial centers for vaccines like norovirus and rotavirus, 'we generally need to investigate dozens or even hundreds of trial centers before making a final decision.'"

"To evaluate whether a diarrhea clinical trial is well-conducted, it is necessary to compare the proportion of suspected diarrhea cases collected among the total observed participants across similar clinical trials. Trials with failed case monitoring often encounter issues in epidemiological investigation or management," noted Wei Pengchong. For preventive vaccines against infectious diseases, multi-center clinical trials are essential. "They not only allow for the observation of as many genotypes as possible but also enable each region to vaccinate at a lower proportion, preventing the formation of an immune barrier."

In this regard, vaccine CROs participating in clinical trials need to have sufficient capabilities to handle large samples and multi-center situations. They must screen out as many suitable centers for conducting clinical trials as possible from a wide range of epidemic disease data.The workload is enormous, and without a sufficient team size, professional expertise, and experience, it would undoubtedly be difficult to complete.

According to Simcere, it usually takes 6 to 8 years for a newly developed vaccine from obtaining clinical trial approval to the end of Phase III clinical trials and application for marketing. Each phase of the clinical trials (Phase I to Phase III) typically lasts around 2 years on average. Therefore, for Contract Research Organizations (CROs), completing the design of clinical trials is often just the first step; long-term management and continuous improvement are also required throughout the entire clinical trial process.

"In particular, innovative vaccines like the RSV vaccine and the norovirus vaccine are frontier vaccines in China and even globally. The methods for case diagnosis, case monitoring, and sample testing require continuous improvement over long-term management to reach the 'optimal solution' and obtain objective and scientific clinical trial evaluation results," emphasized Wei Pengchong.

He also mentioned several details. First, it is necessary to frequently verify the SOP of each trial operation to determine whether the expected results of the trial design can be achieved. Pharmaceutical companies, CRO medical teams, external medical expert teams, and researchers need to make timely adjustments based on specific situations. "Especially for innovative vaccines undergoing clinical trials in China for the first time, it is important to integrate the latest clinical practices and guidelines in China. Avoid blindly copying past experiences or foreign clinical operations. Generally speaking, by the time a product completes its first clinical trial in China, its operational steps and ideas have usually changed significantly from the initial setup. Blindly following old plans is not advisable," said Wei Pengchong.

In view of various characteristics of epidemiology, the diagnosis of cases must comply with the patterns of disease diagnosis and treatment in China. Wei Pengchong explained, "Due to differences in medication habits and medical scenarios, we need to be particularly mindful to distinguish our standards from those of overseas clinical trials when evaluating disease severity or collecting samples." He also suggested completing methodological validation of sample testing using epidemiological survey sampling before initiating Phase III clinical trials.

In addition,In the clinical trials of preventive vaccines, the collection of endpoint cases is a key element. Wei Pengchong pointed out that being able to follow up on more suspected cases can increase the number of endpoint cases.. Restricted by the characteristics of large samples, multi-center, and long duration in efficacy trials, researchers need to conduct long-term follow-up on vaccinated participants. "Participant mobility may reduce compliance, so the stability of researchers and CRO project managers is extremely important. The CRO and sponsor teams must work together to supervise and manage the case collection process, not only evaluating partners but also providing regular training for grassroots health centers and higher-level investigators. Any data anomalies must be promptly addressed," said Wei Pengchong.

Currently, vaccine CROs represented by Simcere have achieved certain results in entirely new vaccine fields such as RSV and norovirus. However, due to the relatively short development time of the industry and the many unknown factors faced in innovative vaccine research, accelerating progress requires not only the sponsor pharmaceutical companies but also CROs and researchers to work together with a strong sense of ownership to drive clinical development. With the joint efforts of all parties, the design and implementation level of clinical trials in China's vaccine field will continue to improve, accelerating the process of domestic vaccine substitution.