Domestic HPV Vaccines Surge: China's Biotech Firms Accelerate Innovation and Market Expansion

The HPV vaccine sector has recently seen a wave of good news, with new clinical advances in nine-valent and trivalent prophylactic vaccines as well as therapeutic vaccines.

In the HPV vaccine market, previously dominated by overseas manufacturers, Chinese manufacturers are rapidly rising.

The bivalent HPV vaccine market was the first to feel the impact from domestic manufacturers.

According to the procurement award announcement for bivalent HPV vaccines for girls of eligible age entering school in Shandong Province in 2024, disclosed on the Shandong Provincial Public Resources Electronic Trading Platform, Zerun Biotechnology, a subsidiary of Walvax Biotechnology, won the bid for 1.0162 million doses at a total price of RMB 27.9465 million. This means the winning bid price per dose of the bivalent HPV vaccine has dropped to RMB 27.5.

Historically, the bivalent HPV vaccine market was dominated solely by GSK. In 2017, GSK’s winning bid price across 17 provinces was RMB 580 per dose. After May 2020, with the market entry of domestically produced bivalent HPV vaccines from Wantai Bio and Walvax Biotechnology, the price dropped to RMB 329 per dose. Currently, at a price of RMB 27.5 per dose, the price of domestically produced bivalent HPV vaccines has fallen by more than 90%.

Why Has the Price of the Bivalent HPV Vaccine Dropped to Such a Low Level?

Walvax Biotechnology stated in its response: “Regarding pricing, the Company takes into account both profits and costs. The Company remains focused on key procurement programs designed to benefit the public, continuously improving product accessibility and striving to reach more eligible women. The winning bid price for this tender was determined comprehensively based on the total procurement volume and related conditions of the local government’s public-benefit program.”

In short, the recent bottoming out of vaccine prices may be attributed to procurement mechanisms. The centralized procurement conducted by provincial governments to provide free HPV vaccination to school-aged girls involves clear demand assessments and unified fiscal payments. Coupled with the competition between Walvax Biotechnology and Wantai Biological Pharmacy in this procurement round, these factors ultimately drove prices to their lowest point.

It should be noted that the price of 27.5 yuan per dose does not reflect the overall market situation. The price of bivalent HPV vaccines in the out-of-pocket market still fluctuates at over 300 yuan per dose. Moreover, the share of HPV vaccines in China’s publicly funded market lags far behind that of the out-of-pocket market, accounting for less than 10% of the total domestic HPV vaccine market.

Excluding price bottoms driven by special circumstances, the intensifying competition in the bivalent vaccine market is an indisputable fact.

First, the launch of domestically produced bivalent HPV vaccines has further eroded the market share of imported vaccines. In 2023, only 13 batches of GSK’s imported bivalent HPV vaccine were approved for release in China, whereas Wantai BioPharma had 328 batches and Walvax Biotechnology had 27 batches of their respective bivalent HPV vaccines approved during the same year. Domestic manufacturers achieved an overwhelming victory.

Secondly, with the imminent launch of domestically produced trivalent and quadrivalent HPV vaccines, competition in the low-valent HPV vaccine market is intensifying. Currently, Kangleshengwei’s trivalent HPV vaccine is expected to submit a Biologics License Application (BLA) within the year. Compared with GSK’s bivalent vaccine, it provides additional coverage against HPV type 58. This genotype is the third most common HPV type detected in cervical cancer cases and high-grade lesions in China and East Asia, surpassed only by HPV types 16 and 18. Meanwhile, quadrivalent HPV vaccines are also on the horizon. On July 4 this year, the National Medical Products Administration (NMPA) accepted the marketing authorization application for the quadrivalent recombinant human papillomavirus vaccine (types 6, 11, 16, and 18) (Hansenula polymorpha yeast), jointly submitted by Chengdu Institute of Biological Products, China National Biotec Group (CNBG), and the National Engineering Research Center for New Vaccines under CNBG.

In response to this situation, GlaxoSmithKline (GSK) has recently decided to halt the development of its Phase II HPV vaccine, citing that “the asset lacks best-in-class potential.”

In this increasingly competitive “bivalent” market, domestic companies are also seeking new directions for development.

GSK may have provided a replicable pathway for domestic manufacturers: entering developing countries with low HPV vaccine penetration. As acceptance of quadrivalent and nonavalent HPV vaccines continues to rise, and the nonavalent HPV vaccine is included in the U.S. immunization schedule recommendations, the market development for bivalent HPV vaccines has been severely constrained. This directly led to GSK’s exit from the U.S. market in October 2016, accompanied by a sharp decline in sales growth. Almost simultaneously (in July), GSK entered the Chinese market. In 2023, GSK still generated £120 million ($154 million) in global revenue from its bivalent HPV vaccine.

Chinese HPV vaccine manufacturers have designed an annual production capacity of tens of millions of doses and are accelerating their global expansion. Currently, the three main pathways for vaccine export include obtaining WHO Prequalification (PQ) certification to access international procurement; conducting overseas clinical trials to achieve localized registration and manufacturing; and submitting marketing authorization applications in other countries based on Chinese clinical trial data. For instance, the bivalent HPV vaccines from Wantai Bio and Walvax Biotechnology have successively obtained WHO PQ certification. Wantai Bio has sequentially received marketing approvals in multiple countries, including Morocco, Nepal, Thailand, the Democratic Republic of the Congo, Cambodia, and Ethiopia. In March 2023, its bivalent HPV vaccine was exported to Thailand.

The nine-valent HPV vaccine market is bracing for a new “battle.”

In the domestic market for high-priced multivalent vaccines, Merck’s GARDASIL 9 remains the only nine-valent HPV vaccine available. As patents near expiration, the nine-valent HPV vaccine distributed by Zhifei Biological has seen a gradual increase in volume in recent years (Note: Zhifei Biological distributes both Merck’s quadrivalent and nine-valent HPV vaccines; the ramp-up of the nine-valent vaccine has, to some extent, impacted sales of the quadrivalent vaccine. Only two batches of the quadrivalent HPV vaccine were approved and released in the first half of 2024). Recently, Merck announced its latest quarterly financial results, which showed that HPV vaccine sales grew by only single digits year-on-year. The report indicated that declining sales in the Chinese domestic market offset growth in the United States and other regions. This has led to speculation that the domestic nine-valent HPV vaccine market has become saturated, resulting in sluggish sales.

However, during the subsequent conference call, Merck pointed out that the timing of HPV vaccine shipments to the Chinese market was related to the ongoing anti-corruption campaign in the healthcare sector in recent years. Industry insiders also noted that “the sales revenue reported for a given quarter does not accurately reflect the actual sales performance of vaccines during that period. Given that Merck’s HPV vaccine sales in the first quarter of 2024 were still primarily driven by the Chinese market, it is premature to conclude that the market is contracting.”

Whether the market is contracting remains to be seen, but potential market competition is evident. Several nine-valent HPV vaccines on the market have already entered Phase III clinical trials, leaving limited time for the former star product, Merck’s Gardasil 9.

In August 2023, in its response to Proposal No. 4359 submitted to the First Session of the 14th National People’s Congress, the National Medical Products Administration (NMPA) stated that “to date, 19 HPV vaccines developed by 10 domestic companies have been approved for clinical trials, including 10 high-valent vaccines covering nine or more HPV types, with at least eight already in Phase III clinical trials.” Just one year later, this number has only increased. According to incomplete media statistics, there are currently 17 nine-valent HPV vaccines undergoing clinical trials in China, among which the pipelines of Recbio, Kanglerweishi, Walvax Biotechnology, and Bowei Biologics are all in Phase III clinical trials. The nine-valent HPV vaccines from Recbio and Kanglerweishi are expected to submit Biologics License Applications (BLA) in 2025.

On August 12 this year, the “Recombinant Human Papillomavirus (HPV) Types 6/11/16/18/31/33/45/52/58 Nonavalent Vaccine (Escherichia coli),” jointly developed by Xiamen Wantai Canghai Biotechnology Co., Ltd., a wholly-owned subsidiary of Wantai BioPharma, and Xiamen University, was included in the list of drugs proposed for priority review by the Center for Drug Evaluation (CDE).

Domestic Nine-Valent HPV Vaccine Is One Step Away from Market Launch.

To better prepare for the impending changes in China’s nine-valent HPV vaccine market, Merck & Co. has implemented a series of measures—

First, further expanding the eligible age groups for indications in China will drive additional growth in the nine-valent HPV vaccine market. On August 23, 2022, the National Medical Products Administration (NMPA) approved the expansion of the indicated population for Merck’s GARDASIL 9 from females aged 16–26 years to females aged 9–45 years.

Second, the economic burden of vaccination for eligible populations has been further reduced through changes in the vaccination schedule. Although the price per dose of the 9-valent HPV vaccine has not changed significantly, beneficiaries have clearly perceived a decrease in the overall cost, thanks to the reduction of the 9-valent HPV vaccination regimen from three doses to two. On January 5, 2024, Gardasil 9 received approval from the National Medical Products Administration (NMPA) to include a two-dose immunization schedule for females aged 9–14 years.

Third, the target population for vaccines is being further expanded. In the domestic market, males have long been excluded from the target population for HPV vaccines. However, HPV infection not only leads to cervical, vulvar, and vaginal cancers in women, but also causes penile, anal, and head and neck cancers in men. Companies such as Kangleshishiwei (CanSino Biologics’ competitor, often referred to as Kelun-Biotech or simply by its Chinese name in industry reports) and Wantai BioPharma have recognized the importance of the male market and have strategically positioned their nine-valent HPV vaccines for male indications. Under competitive pressure from domestic vaccine manufacturers, Merck & Co. submitted a marketing application in China for the male indication of its nine-valent HPV vaccine. In September 2023, this new indication application was accepted for review. The expansion to include male indications will undoubtedly further enlarge the potential market space for HPV vaccines and alleviate concerns regarding the product lifecycle of HPV vaccines.

However, it must be emphasized that the fiercely competitive market for the 9-valent HPV vaccine still needs to face competition from higher-valency HPV vaccines.Domestic 11-valent, 14-valent, and 15-valent HPV vaccines are currently undergoing clinical trials. For instance, the recombinant 15-valent human papillomavirus vaccine (Escherichia coli) (“15-valent HPV vaccine”), jointly developed by KangLeWeiShi and Liaoning Chengda Biotechnology Co., Ltd., has completed preparations for Phase I clinical trials and officially launched its Phase I clinical trial on March 28, 2024. Furthermore, according to data from the Center for Drug Evaluation (CDE), Shanghai Bowei Biotechnology Co., Ltd. is also conducting clinical trials for a 15-valent HPV vaccine.

Source: CDE

The high-valent HPV vaccine market is poised for intense competition.

HPV Vaccines: Beyond the widely recognized prophylactic vaccines, therapeutic vaccines are also involved. The latter primarily target patients with established cervical cancer or precancerous lesions, aiming to treat or prevent disease progression by inducing cell-mediated immune responses.

Currently, therapeutic HPV vaccines are mainly categorized into DNA vaccines, mRNA vaccines, viral vector vaccines, recombinant protein vaccines, and peptide vaccines.However, no HPV therapeutic vaccines have been approved to date, indicating that this remains an untapped blue-ocean market.

A large number of therapeutic HPV vaccines are currently undergoing clinical trials, with companies such as Walvax Biotechnology, Dongfanglue, Auro Biopharma, Nuowei Technology, Renjing Biotechnology, and Pukang Biotechnology active in this field.

For instance, while Walvax Biotechnology is positioning itself in the preventive HPV vaccine market, it is also developing therapeutic vaccines. In a 2013 announcement, the company stated that its HPV therapeutic vaccine had successively received patent approvals in the United States and Australia.

Another example is Oriental Strategy, which began laying out its therapeutic vaccine portfolio in 2017 by acquiring the product rights, patents, and know-how licenses for Inovio’s HPV therapeutic vaccine, VGX-3100. In 2018, it further secured exclusive rights to develop and commercialize VGX-3100 within China. Currently, the multi-center Phase III clinical trial of Oriental Strategy’s ABC-3100 (i.e., Inovio’s VGX-3100) is underway in China.

The latest news is that Luye Pharma Group announced that the Investigational New Drug (IND) application for “LY01620,” an mRNA therapeutic vaccine independently developed by its controlled subsidiary, Jimai Biopharma, has been approved by the Center for Drug Evaluation (CDE). The vaccine is intended for the treatment of HPV16-associated high-grade squamous intraepithelial lesions of the cervix.

This highly enticing market for therapeutic HPV vaccines is attracting a surge of industry participants. In this global landscape, where no products have yet received approval, it remains to be seen whether Chinese manufacturers can accelerate their emergence as frontrunners.

Undoubtedly, in the field of HPV vaccines, domestic manufacturers are gradually capturing a larger market share, altering the landscape previously dominated absolutely by GSK and Merck & Co. Whether in preventive or therapeutic vaccines, Chinese enterprises are accelerating their rise.