Breaking the Import Monopoly: Multinational Giants Pivot as Domestic HPV Vaccine Makers Risk Missing the Market Window

Source丨Healthnews21 Original Work

Author/Ji Yuanyuan

As the only vaccine in the world currently capable of preventing cancer, the HPV vaccine has become a highly sought-after vaccine product among women globally. However, under the promotion of the World Health Organization (WHO),The trend of reducing HPV vaccine doses from three to one will deal a heavy blow to companies globally that are actively deploying HPV vaccines.

Recently, MSD announced plans to launch a clinical trial for a novel multivalent human papillomavirus (HPV) vaccine at the 2024 European Research Organization on Genital Infection and Neoplasia (EUROGIN) Congress. Additionally, MSD plans to conduct other clinical trials to evaluate the efficacy and safety of a single-dose vaccination regimen of Gardasil®9 [Nine-valent Human Papillomavirus Vaccine (Saccharomyces cerevisiae)] compared to the currently approved three-dose regimen.

On January 9, MSD announced that the two-dose vaccination schedule (0.6–12 months) for females aged 9–14 using its nine-valent HPV vaccine (trade name: Gardasil 9) had been approved by the China National Medical Products Administration. This approval means that, in addition to the previously approved three-dose schedule for ages 9–45, Gardasil 9 will now include a two-dose schedule for females aged 9–14.

As the world's only supplier of the nine-valent HPV vaccine, MSD has taken the lead in adjusting the number of vaccination doses, which will impact numerous domestically produced nine-valent HPV vaccines in China that are about to enter the application phase for market approval.

Currently, several companies in China are in Phase III clinical trials for the domestically produced 9-valent HPV vaccine, including WANTAI BioPharm, Shanghai Bovax Biotechnology Co., Ltd., Beijing Health Guard Biotechnology, Inc., Jiangsu Ruike Biotech Co., Ltd., and Walvax. Among them, WANTAI BioPharm and Walvax are leading in progress. On March 17, Walvax announced that the overall data from the head-to-head clinical trial of its 9-valent HPV vaccine compared with similar vaccines is currently under statistical analysis.

Currently, the HPV vaccines approved in China are divided into 2-valent, 4-valent, and 9-valent. Among them, domestically produced approved products are mainly 2-valent, including "Cervicare" by WANTAI BioPharm and "Vaucervix" by Walvax. Additionally, there is an imported 2-valent HPV vaccine, "Cervarix" by GSK. The market for 4-valent and 9-valent HPV vaccines in China is exclusively dominated by Merck & Co., Inc.

Previously, when the supply of the 9-valent HPV vaccine was insufficient, most people opted for the 2-valent or 4-valent HPV vaccines. However, currently, the market supply of the 9-valent HPV vaccine has improved significantly. MSD publicly stated that, in order to meet the increasing global demand for Gardasil® and Gardasil®9 and to support broader and fairer vaccine distribution, MSD has invested heavily in vaccine manufacturing. Starting from 2019, MSD committed to expanding its production capacity by increasing output at existing facilities and building new ones. Between 2017 and 2020, vaccine supply nearly doubled under these new initiatives, and then doubled again between 2020 and 2024. MSD expects to supply sufficient quantities of the HPV vaccine to meet anticipated demand in 2025, while continuing to focus on expanding its vaccine production capabilities in the future.

According to Frost & Sullivan, since the approval of China's first HPV vaccine in 2016, the market size of HPV vaccines increased to 13.5 billion yuan in 2020 and is expected to reach 69 billion yuan by 2030, with the 9-valent HPV vaccine anticipated to hold the largest market share in the HPV vaccine market by 2030.

Previously, industry experts noted: "The continuous growth in 9-valent HPV vaccine imports will put some pressure on the market for domestically produced 2-valent HPV vaccines among the over-30 age group. After the age range for the 9-valent HPV vaccine is expanded to 45, more people will opt to receive the 9-valent vaccine."

As the exclusive agent of MSD's quadrivalent and nonavalent HPV vaccines in China, Zhifei Biological Products achieved revenue of 23.583 billion yuan from its agency products in the first half of 2023, representing a year-on-year increase of 41.35%. In the same period, the batch release of the quadrivalent HPV vaccine reached 6.2667 million doses, up by 28.5% year-on-year, while the batch release of the nonavalent HPV vaccine amounted to 14.6782 million doses, marking a year-on-year increase of 57.85%. Additionally, according to MSD's financial report, the sales of the nonavalent HPV vaccine Gardasil/Gardasil 9 reached 8.886 billion US dollars, reflecting a year-on-year growth of 29%.

Driven by the huge market demand, many Chinese pharmaceutical companies are also accelerating the layout of HPV vaccines. According to publicly available information, more than 10 companies in China that are currently working on HPV vaccines include Jiangsu Ruike Biotech Co., Ltd., Health Guard, Shanghai Bovax Biotechnology Co., Ltd., and Sino Biological, among others. A research report by CITIC Securities pointed out,Currently, the 9-valent HPV vaccines of five Chinese manufacturers (WANTAI BioPharm, Jiangsu Ruike Biotech Co., Ltd., Walvax, Health Guard, Shanghai Bovax Biotechnology Co., Ltd.) have entered Phase III clinical trials. In addition, the 11-valent vaccine developed by China National Biotec Group/Chengdu Institute/Beijing Institute is in Phase III clinical trials, the 14-valent vaccine of Sino Biological has entered Phase III clinical trials, and the 15-valent vaccine jointly developed by Chengda Biological and Health Guard has also entered the clinical stage.

So, what are the differences between the 2-valent, 4-valent, and 9-valent vaccines? How should the public choose? In this regard, a clinical expert from East China told the 21st Century Business Herald that there are currently 2-valent, 4-valent, and 9-valent HPV vaccines available. Although the numerical difference seems significant, the actual difference in virus protection coverage is not substantial. For instance, both the 2-valent and 4-valent vaccines primarily cover two types for cervical cancer: HPV16 and HPV18. Over 70% of cervical cancers globally and about 84% of cervical squamous cell carcinomas in China are caused by HPV16 and HPV18. When it comes to vaccine selection, getting the 2-valent HPV vaccine can already prevent most cervical cancers and precancerous lesions, making it "sufficient" for cancer prevention.

Despite the fact that the bivalent HPV vaccine can already prevent the majority of cervical cancer and precancerous lesions, the imported nonavalent vaccine remains the first choice for the public. This also continuously puts pressure on domestically produced HPV vaccines.

On January 23 this year, WANTAI BioPharm announced that its net profit for 2023 is expected to be RMB 1.2 billion to 1.35 billion, a decrease of approximately RMB 3.536 billion to 3.386 billion compared to approximately RMB 4.736 billion in the same period last year, representing a year-on-year decrease of 71.49% to 74.66%.Behind the over 70% drop in WANTAI BioPharm's net profit, an important reason is that the company’s revenue from its main 2-valent HPV vaccine plummeted by 4.2 billion yuan.

However, in 2020, WANTAI BioPharm's 2-valent HPV vaccine "Cervicare" became the first domestically produced 2-valent HPV vaccine in China, breaking the long-term monopoly of this market by foreign enterprises. Compared with imported HPV vaccines at the time, "Cervicare" had a wider target population, for females aged 9-45. Due to the severe shortage of imported HPV vaccines and the market's supply failing to meet demand, WANTAI BioPharm's HPV vaccine quickly filled the market gap.

Subsequently, the HPV vaccine business gradually became the company's primary source of income. From 2020 to 2022, vaccine segment revenues of WANTAI BioPharm reached 865 million yuan, 3.363 billion yuan, and 8.493 billion yuan respectively, increasing nearly ninefold in two years. In 2022, the company’s vaccine revenue accounted for over 75% of total revenue with a gross margin of nearly 94%.

Market analysis believes that the main reasons for the decline in sales of WANTAI BioPharm's 2-valent HPV vaccine "Cervavax" are increased market supply, intensified competition, and reduced prices.

In this regard, a securities analyst also told the 21st Century Economic Report,After the introduction of single-dose vaccination for the 9-valent vaccine, it will only bring greater market pressure and challenges to domestically produced vaccine companies. In addition, domestically produced HPV vaccines are generally expected to enter the market successively after 2025. As more companies enter the market, vaccine pricing will also become one of the core factors in competition between Chinese and foreign pharmaceutical enterprises. Whether companies can respond still needs to be verified by the market.

To counter the impact of domestically produced vaccines, a single-dose strategy has become MSD's choice. Regarding the influence of dosage differences, Professor Zhao Fanghui, Director of the Epidemiology Department at the National Cancer Center and the Cancer Hospital of the Chinese Academy of Medical Sciences, previously told the 21st Century Business Herald that the earliest HPV vaccine research and development in Europe and the U.S. took place during 2006-2007, with clinical registration trials for the developed products primarily based on a three-dose regimen. Therefore, when other countries initially included the HPV vaccine in their immunization programs, it was administered in three doses. However, as evidence accumulated, it was found that two doses in younger age groups were as effective as three doses in adult women. Consequently, the WHO issued a recommendation a few years ago that girls aged 9-14 should receive two doses.

Moreover, when China first began clinical registration trials for vaccines, three doses were used. Later, evidence showed that two doses were completely effective for younger age groups. Additionally, the WHO officially updated its position paper last year, advocating for a single-dose vaccination schedule. Some countries, including the UK and Australia, are now revising their procedures accordingly. However, a single-dose HPV vaccine has not yet been approved in China.

"At present, reducing the three doses to two doses, the question everyone is most concerned about is how long the protection will last and how effective the protection will be? This depends on the accumulation of long-term scientific evidence. In fact, reducing the number of doses would have a significant impact on China. Given China's large population and limited resources, switching from three doses to two doses could save substantial costs," said Professor Zhao Fanghui.

“However, whether the efficacy of a single dose can meet clinical needs and truly achieve comprehensive protection against cervical cancer still requires confirmation from real-world research data."The aforementioned clinical expert from East China also emphasized to the 21st Century Economic Report journalist."

Chief Physician Bi Hui from the Department of Obstetrics and Gynecology at Peking University First Hospital also pointed out in a media interview that, based on current research progress, it can be seen that even with just one dose, the antibody titer generated is very high, and the effectiveness three years after a single dose of HPV vaccination remains ideal. However, how long it will last and its overall protective effect against cervical cancer still require an extended period of clinical research to verify. "For the 9-valent vaccine, China currently follows the 2-dose and 3-dose immunization schedules, with completely different intervals between the two vaccination programs. Single-dose vaccination has not yet been approved by the state, so people must not arbitrarily 'reduce doses' when getting vaccinated."