Kanghua Bio: From China's First to World's First – Leading Domestic Vaccine Innovation with Global Ambition

In 2024, it marked the 10th anniversary of the market launch and sales of China’s first human diploid cell rabies vaccine, as well as the 20th anniversary of the establishment of Kanghua Biologics, a local enterprise in Chengdu.

On the occasion of its 20th anniversary, Kangh held the “Vaccine Innovation and Disease Prevention” Forum in Chengdu on February 27, inviting experts from R&D, disease control, and other fields to participate. Notably, Adam Ingber, Senior Manager of Business Development at HilleVax, Inc. (hereinafter referred to as “HilleVax”), traveled specially from the United States to Chengdu to attend the event and deliver a keynote speech.

At the beginning of this year, Kanghua Biological signed an Exclusive License Agreement with HilleVax. Under the agreement, Kanghua Biological granted HilleVax the rights to develop, manufacture, and commercialize its recombinant hexavalent norovirus vaccine and derivatives in all regions outside China (including Hong Kong, Macao, and Taiwan). In return, HilleVax will pay a $15 million upfront payment, up to $255.5 million in milestone payments, and single-digit percentage royalties on sales.

This transaction not only marks the first outbound licensing of a domestically developed innovative vaccine, but also signifies that Kangh has used innovation as the “key” to unlock a new chapter on its 20th anniversary.

One of the prerequisites for the collaboration between Kanghua Biological and HilleVax lies in the significant unmet clinical needs and market gaps for norovirus vaccines. This is also one of the reasons why Kanghua Biological initially initiated the project for recombinant norovirus vaccine.

As a highly contagious disease with rapid transmission capabilities, norovirus is one of the primary pathogens causing epidemics and outbreaks of acute gastroenteritis across all age groups worldwide. In extreme cases, it can lead to chronic conditions or death in children, the elderly, and immunocompromised individuals. Although significant progress has been made in the global development of norovirus vaccines, their研制 still faces substantial challenges.As of now, no norovirus vaccine has been approved for marketing worldwide.

Based on genetic characteristics, noroviruses are classified into 10 genogroups (GI–GX), each of which is further divided into multiple genotypes. For instance, genogroup GII comprises at least 21 genotypes. Noroviruses evolve rapidly through the accumulation of regular genetic recombination or point mutations, leading to the emergence of new strains every 2–3 years that can cause global pandemics. Since 1995, several GII.4 variants have been associated with global outbreaks of acute gastroenteritis, including the 95/96 US strain (1996), Farmington Hills strain (2002), Hunter strain (2004), Den Haag strain (2006), New Orleans strain (2009), and Sydney 2012 strain (2012). Over the past decade, China has witnessed a substantial increase in outbreaks caused by the GII.17 variant.

Kanghua Biologics’ recombinant hexavalent norovirus vaccine (HilleVax product code HIL-216) is currently one of the multivalent norovirus vaccines with the highest valency under development, and it is also the world’s first hexavalent norovirus vaccine to receive clinical trial approval.It covers six major prevalent genotypes of norovirus (GI.1, GII.2, GII.3, GII.4, GII.6, and GII.17) and can theoretically prevent more than 90% of norovirus infections and the associated acute gastroenteritis.

Currently, HIL-216 has obtained clinical trial approvals in Australia and the United States. According to Kanghua Biological, the company has initiated the application for clinical trial approval in China, with an Investigational New Drug (IND) application expected as early as this year, and will expedite the advancement of clinical research in China. Under the terms of the agreement between Kanghua Biological and HilleVax, Kanghua Biological will supply HIL-216 to HilleVax for use in upcoming clinical trials, with HilleVax planning to initiate Phase I clinical trials in 2024.

According to Dr. Xie, Head of R&D for HIL-216 at Kanghua Biologicals, another key factor enabling this collaboration lies in the design and manufacturing of “internationalized products.” “From the very inception of the project, our considerations extended beyond clinical needs in China to encompass global clinical demands. Following comprehensive preliminary epidemiological investigations, weHIL-216 was designed and manufactured with a global product strategy in mind, adhering to and meeting the international standards of the FDA, EMA, and NMPA throughout process development, quality system establishment, and final clinical drug production.“Dr. Xie said.”

From Dr. Xie’s perspective, the collaboration with HilleVax is a clear win-win partnership. “HilleVax boasts a world-class clinical trial team for norovirus vaccines, while we possess internationally competitive capabilities in product design, CMC, and manufacturing. Moving forward, we will leverage our complementary strengths through close collaboration, harnessing the synergy of ‘a superior product plus a top-tier team’ to jointly accelerate the global launch of HIL-216.”

For two decades, “innovation” has been the unwavering commitment ingrained in Kanghua Biologics’ DNA. From launching China’s first commercially available human diploid cell rabies vaccine to introducing the world’s first recombinant hexavalent norovirus vaccine and achieving the first overseas licensing deal for a domestically developed innovative vaccine, Kanghua Biologics has consistently upheld “innovation” as its core guiding principle and action plan.

Dr. Wei, R&D Director at Kanghua Biologicals, stated, “Over the past 20 years, Kanghua Biologicals has been dedicated to the research, development, and promotion of innovative vaccines, achieving remarkable accomplishments in technology, manufacturing processes, and original innovation, and launching several pioneering innovative products.” Among these, Kanghua Biologicals’ flagship product is the freeze-dried human rabies vaccine (human diploid cell rabies vaccine, HDCV)^®) The outstanding achievements may serve as a case study or a mirror, reflecting, from a micro perspective, the 20-year journey of Kanghua Biologics and the accelerated development of China’s vaccine industry.

Rabies is the disease with the highest case fatality rate in recorded history, reaching 100%. Rabies vaccines are the sole agents used to control and prevent rabies and are classified as Category II vaccines in China. Based on the substrate cells used, human rabies vaccines are categorized into three generations: primary cell culture rabies vaccines, Vero cell rabies vaccines, and human diploid cell rabies vaccines. Among these, only the human diploid cell rabies vaccine is produced using human-derived cell substrates and was designated by the WHO in 2002 as the “gold standard” vaccine for rabies.

Compared with previous generations of products, human diploid cell rabies vaccines offer advantages such as high safety, good immunogenicity, and long-lasting protection, without the potential risks associated with residual heterologous cell DNA and proteins. They are particularly suitable for individuals with lower immunity, including those with allergic constitutions, the elderly, and children. Human diploid cell rabies vaccines were first successfully launched by Sanofi in 1980. However, due to low yield and high technical barriers to scale-up, they have been widely used mainly in Europe and the United States. At that time, the mainstream rabies vaccines used in China were Vero cell rabies vaccines and hamster kidney cell vaccines.

Since its establishment, Kanghua Biological has made the research, development, and production of human diploid cell rabies vaccine one of its core missions. According to Dr. Wei, Kanghua Biological began establishing its R&D team and conducting preclinical studies on the human diploid cell rabies vaccine in 2005. Seven years later, the vaccine obtained a New Drug Certificate and Drug Registration Approval, and received its GMP Certificate in April of the following year.By 2014, Kanghua Biologics’ independently developed human diploid cell rabies vaccine (HDCV) was officially launched on the market after batch release by the National Institutes for Food and Drug Control (NIFDC), breaking the long-standing limitation of using animal cells for rabies vaccine production in China and becoming the first human diploid cell rabies vaccine marketed in the country. Since then, as the “barrier-breaker” in the domestic R&D of human diploid cell rabies vaccines, Kanghua Biologics’ HDCV^®It has been exclusively promoted and sold in China for nearly a decade.

As the primary raw material, the quality of cell substrates directly affects the quality and yield of vaccines, particularly their safety.According to Kanghua Biologics' HDCV^®Dr. Liu, R&D Manager for the rabies vaccine, introduced that HDCV® employs China’s leading “100-L large-volume bioreactor microcarrier-based scalable culture and expansion technology for human diploid cells,” and is purified using ultrafiltration concentration combined with size-exclusion chromatography.Impurity removal rate can reach 99%, with a higher safety profile.

In 2016, the dog bite outpatient clinic of Shijiazhuang Center for Disease Control and Prevention used Kanghua HDCV^®A total of 1,040 vaccine recipients were enrolled as study subjects for a safety statistical analysis. The results showed that adverse reactions occurred in 9 individuals, with no Grade 1 or higher adverse reactions reported, yielding an adverse reaction rate as low as 0.87%. In contrast, the adverse reaction rate for domestically produced Vero cell rabies vaccines is 18.1%, and for imported Vero cell vaccines, it is 14.6%.^【1】

In addition, Kanghua Biologics' HDCV^®Excellent immunogenicity and rapid onset of action: the mean Geometric Mean Titer (GMT) at day 42 reached 75 times the seroconversion threshold; the seroconversion rate achieved 100% by day 14. Eight years post-vaccination, the mean GMT remained as high as 1.31 IU/mL, making it suitable for the general population.

According to Dr. Liu,HDCV^®Currently covering all provinces in China, with 10 years of clinical follow-up data and over 20 million doses administered cumulatively.

“Innovation is the core competitiveness that enables enterprises to gain a firm foothold amid the waves of development. Since its inception, Kanghua Biological has adhered to an innovation-driven R&D strategy, overcoming challenges and continuously increasing R&D investment. This commitment has led to the launch of several pioneering innovative products, progressing from China’s first to the world’s first. Indeed, innovation is the lifeblood of biopharmaceutical enterprises and the key to Kanghua Biological’s sustainable development.“Dr. Wei said.

The Source of Kangh’s Sustainable Innovation Relies on Two Key Drivers: Talent and R&D Model。

In terms of talent, Kanghua Bio’s R&D team comprises nearly 120 members, with over 40% holding master’s or doctoral degrees. The team possesses extensive experience in the biologics industry and comprehensive capabilities across the entire R&D value chain. “We adhere to the talent selection principle of ‘integrity as the foundation, combining virtue and competence.’ We have assembled a multidisciplinary team spanning R&D, quality control, industrial translation, regulatory affairs, and clinical development. Our team includes both senior technical experts and technical management professionals. Beyond rich experience, we emphasize breadth of vision, seeking individuals with holistic thinking and a global perspective,” said Dr. Wei.

From the perspective of R&D models, Kangh adheres toGuided by innovation in R&D, we have adopted a hybrid model combining independent and collaborative research and development, establishing an efficient management framework for R&D innovation.. Leveraging its corporate R&D center, Kanghua Biological has successively been designated as a Sichuan Provincial Enterprise Technology Center and Postdoctoral Innovation Practice Base, as well as a Chengdu Academician Innovation Workstation. It has also become a graduate student practice base for Sichuan University and the University of Electronic Science and Technology of China, thereby achieving a closed loop of talent development and innovation through university-enterprise collaboration. Currently, Kanghua Biological has established multiple high-level vaccine technology platforms, including a recombinant protein VLP platform, a polysaccharide-protein conjugate vaccine platform, an inactivated vaccine platform, and a novel adjuvant platform.

According to Dr. Liu, while Kanghua Biologics strongly supports and strengthens its independent R&D capabilities, it has launched a project on immobilized culture of human diploid cells, leveraging the advantages of its existing product platform. In terms of external collaborations, Kanghua Biologics has established partnerships with universities such as The University of Hong Kong, Sichuan University, and the University of Electronic Science and Technology of China, as well as biopharmaceutical companies like WuXi Biologics, seeking further enhancement and breakthroughs in R&D capabilities to drive the company’s overall research and development progress.

Furthermore, to further enhance its R&D and production capabilities, Kanghua Biologics officially signed an agreement with the Wenjiang District Government of Chengdu in 2018 to construct the Wenjiang Medical Research Center, covering an area of 108 mu, with planned facilities for R&D, quality control, administration, and animal experimentation. Currently, the first phase of construction, comprising the Vaccine R&D Center and the Animal Experimentation Center, was completed and put into operation in 2021.

Standing at the 20-year milestone and looking ahead to the next two decades, Zhou Yongdong, Head of R&D at Kangh, offers this outlook:Innovation and differentiation are in Kanghua Biology’s DNA. With the emergence of our first licensed overseas pipeline, global expansion has become a key direction for our future development. In addition to our human diploid cell rabies vaccine, another mature product, our ACYW135 meningococcal polysaccharide vaccine, is already marketed and sold abroad. Therefore, amid intense domestic competition, we must step up as a vital force in China’s biologics sector, working alongside the biopharmaceutical industry to break into overseas markets and collectively advance Chinese biologics to the next level.

References:

Cao Qing, Huang Guihua, Wen Shuying, Pan Huai, Zhang Daming. Clinical Safety Observation of 2430 Cases of Chengda and Verorab Rabies Vaccines [J]. Journal of Tropical Medicine, 2007(07):693-694.