The domestic nine-valent HPV vaccine is difficult to find, where is the difficulty?

Written by / Yang Qian

Editor / Yang Jie

Domestically, women's "HPV vaccine anxiety" may be alleviated.

Recently, many places in Xi'an City, Shaanxi Province, launched reservations for quadrivalent and nine-valent HPV vaccines, and this topic quickly rushed to the hot search. Prior to this, the health commissions of Haikou, Tangshan and other places have successively announced that they will receive HPV vaccines free of charge for women of appropriate age from April. Since 2020, many places in China have successively carried out or announced that they will soon carry out free HPV vaccination.

For some time, some young women in China have been caught in "HPV vaccine anxiety". In particular, the nine-valent HPV vaccine, which has long been only a manufacturer of multinational pharmaceutical giant Merck, has long been the norm for a whole year without being able to make an appointment. Even many people have begun to turn to the so-called "vaccine intermediary" to increase the price, but it is still "difficult to find a shot".

(Source: Visual China)

Driven by strong market demand, the HPV vaccine track continues to heat up. On March 31, Ruike Bio officially landed on the Hong Kong Stock Exchange, closing up 1.81% on the first day of listing, with a total market value of more than HK$12.1 billion on the same day. Its core product, recombinant HPV heptagonal vaccine REC603, is already in phase III clinical trials and is expected to become the first domestic HPV heptagon vaccine approved for marketing.

On March 24, Watson Bio's bivalent HPV vaccine was approved for listing, becoming the second local enterprise in China to produce a bivalent HPV vaccine. Prior to this, Wantai Biotech's bivalent HPV vaccine was approved for marketing in 2009 and has occupied 65% of the domestic market share by the end of 2021.

Domestic HPV vaccines have formed a "siege" trend for pharmaceutical giants such as Merck. In the future, can they achieve "HPV vaccine freedom" for domestic women?

Deng Zhidong, general manager of Hainan Boao Medical Technology Co., Ltd., told Caijing Weekly that vaccine research and development requires huge investment in funds, personnel and time, and the development of the HPV vaccine industry also needs capital injection to help in research and development, production, sales, circulation and other links. Judging from the research and development history of existing marketed HPV vaccines, it usually takes nearly 10 years for an HPV vaccine to go from phase I clinical trials to the final launch of the product. The real large-scale listing of the domestic nine-valent HPV vaccine may take more time.

Who is making HPV vaccine anxiety?

On Women's Day on March 8 this year, Nanjing University of Science and Technology introduced 3,000 doses of the nine-valent HPV vaccine, which is open to all female teachers and students (16-26 years old) to make vaccination appointments. A day earlier, Zhejiang University also issued a document saying that it would open 500 nine-valent HPV vaccination places to all full-time female students. These two special "holiday gifts" for women have rushed to the weibo hot search.

In the Little Red Book, there have been more than 320,000 notes related to the nine-valent HPV vaccine. On Weibo, the topic related to "playing the nine prices" has also been constantly being hyped up... Being able to get vaccinated and successfully "ashore" has become the wish of countless young girls. Since the advent of the nine-valent HPV vaccine, it has been in a state of short supply, which can be described as "difficult to find a seedling".

This has also led to HPV vaccine anxiety, which has spread in women's circle of friends and social media.

Wu Sanjin, a 25-year-old graduate student based in Shijiazhuang, Hebei Province, has been caught in "HPV vaccine anxiety" for three years. Previously, the first-tier city where she was located could be described as "a seedling is difficult to find". Because of her age and the limited supply of vaccines, she was very worried that she would not be able to get the nine-valent HPV vaccine at the right age. When she learned that her hometown Shijiazhuang could also make an appointment, since 2019, she began to "grab" the vaccine appointment every day through a small program.

After the first successful appointment, Wu Sanjin and his sister set off for the local epidemic prevention station before 6 o'clock in the morning. But when she arrived, she found that the crowd waiting for vaccination at the epidemic prevention station in the early morning was a long queue, and the queue in front of her was already 10 meters long. "At that time, a doctor wrote the number with a note, sent it one by one, and stopped sending it to a certain number." Wu Sanjin recalled: "If the people in the back queue did not get the number, they would also come in vain."

After the first injection, Wu Sanjin joined a WeChat group of the "Cervical Cancer Protection Plan" formed by the staff of the epidemic prevention station, and she was in the fifth WeChat group, but the upper limit of 500 people in the group was soon full. The staff in the group will regularly notify the time of the vaccine release number, and until now, someone in the group will ask about the situation every day.

Due to the shortage of needle sources and the epidemic situation, Wu Sanjin spent two years on three doses of vaccines, and finally finished before the age of 26, becoming a "lucky" one in the circle of friends. She constantly informs her friends around her, urging everyone to seize the time and finish the vaccine as soon as possible before the age of 26.

(Photo/Courtesy of respondent)

Cervical cancer is one of the most common malignancies in women worldwide. According to the data in the prospectus of Ruike Bio, in 2020, there were 604,100 confirmed cases of cervical cancer and 431,800 deaths worldwide. China is home to a high incidence of cervical cancer, with the world's second-highest number of deaths each year, and 59,000 people die of cervical cancer in China.

Most cervical cancers are caused by HPV infection. HPV, also known as human papillomavirus, is a virus that can be contracted by both men and women after sexual transmission and skin-to-skin contact. Studies have shown that about 70% of cervical cancer in Asian women is caused by two viruses, high-risk HPV16 and high-risk HPV18. Therefore, people are accustomed to calling the HPV vaccine a cervical cancer vaccine.

According to the appropriate age and prevention range, HPV vaccines can be divided into three categories: bivalent HPV vaccine, quadrivalent HPV vaccine, and nine-valent HPV vaccine. Among them, the nine-valent HPV vaccine is currently the most widely protected against HPV and is suitable for women aged 16-26 years.

At present, the nine-valent HPV vaccine can only be produced by a Merck company in the United States. But Merck's nine-valent HPV vaccine capacity is far from meeting the needs of the global market. Merck has previously said that its supply of HPV vaccines will not be able to keep pace with global demand growth until at least 2023.

The shortage of nine-valent HPV vaccine, the improvement of women's awareness of self-protection in China, and the age limit of vaccination have all spawned "HPV vaccine anxiety".

In 2016, the nine-valent vaccine was officially launched in Hong Kong, China, and there is not much age limit for nine-valent vaccination in Hong Kong, China. In the period since then, there has been a wave of "grouping" to go to Hong Kong, China, to get a nine-valent vaccine in the domestic female consumer group. Statistics show that in 2016, the number of "vaccine groups going to Hong Kong" even exceeded the number of tour groups that traveled to Hong Kong that year.

According to the biological product batch issuance column on the website of the China Institute of Food and Drug Control, in 2018, the batch issuance of nine-valent HPV vaccines was 1.216 million, which increased to 3.324 million in 2019 and reached 5.0664 million in 2020. However, compared with the huge number of domestic demand groups, it is still far from enough.

To this end, some regions have also opened a "lottery appointment system" for the nine-valent HPV vaccine, and set a "threshold", and only women of the right age between 16 and 26 can participate in the lottery. In Shenzhen, on the day the nine-valent HPV vaccine lottery system was opened, the total number of appointment visits reached 3.6 million, which once paralyzed the system.

However, the winning rate of the nine-valent HPV vaccine is not high. In August 2020, the Shenzhen CDC's phase I vaccine appointment reached the highest number of 5761 places in history, but the number of applicants exceeded 220,000, and the winning rate was only 2.58%.

Under the "one seedling is difficult to find", some areas even have the phenomenon of rushing to buy HPV vaccines.

On second-hand trading platforms and social platforms, searching for "nine-valent vaccine", in addition to obtaining relevant knowledge popularization, experienced users will always find a hidden "proxy robbery", which has also become a channel for "scalpers" to profit.

A young woman living in Zhengzhou, Henan Province, told Caijing Tianxia that she was born in 1997 and was anxious to get a nine-valent HPV vaccine before the age of 26, but she couldn't make it on her own. So, she had the idea of "looking for scalpers". However, the local "snatching" scalper requires an intermediary fee of at least 1,000 yuan.

A vaccine intermediary in Chengdu, Sichuan Province, told Caijing Tianxia Weekly that the number of people who looked for him to grab the nine-valent vaccine was still "innumerable", and users in Chengdu had to pay an intermediary fee of 1600 yuan, while users in Beijing were 2000 yuan. Moreover, even if the appointment is successful, it will take a few months to a year for the user to get the shot.

The scam of "snatching the nine-valent HPV vaccine" also came into being. Previously, the police in Anhui, Shandong and other provinces have prompted that some intermediaries have borrowed the name of being able to make an appointment for HPV vaccines, collecting deposits and appointment fees from consumers and disappearing, and the amount involved is as high as tens of thousands of yuan.

Break down anxiety when proceeding

According to the Frost & Sullivan report, the market size of HPV vaccines in China will increase to 13.5 billion yuan in 2020 and is expected to reach 69 billion yuan by 2030, with a compound annual growth rate of 17.7% from 2020 to 2030.

Under the long-term publicity of social media, in the minds of countless people, "HPV vaccine" is the default and "nine-valent vaccine" is equated. Coupled with the psychological effects of the high price and scarcity of the nine-valent HPV vaccine, the nine-valent vaccine is more sought after than the bivalent and quadrivalent among domestic female consumers.

A director of obstetrics and gynecology at a hospital once told Caijing Weekly that bivalent and quadrivalent vaccines are both protective against two carcinogenic viruses, high-risk HPV16 and high-risk HPV18, which can prevent most cervical cancers and precancerous lesions. Especially for the domestic low- and middle-income women, the domestic low-cost HPV vaccine is of great significance.

On 17 November 2020, the World Health Organization (WHO) released the Global Strategy to Accelerate the Elimination of Cervical Cancer, in which 194 member states jointly committed to eliminating cervical cancer, including China.

In order to break the "HPV vaccine anxiety", many provinces and cities in China have reported domestic free HPV vaccination programs. From the second half of 2020, including Ordos in Inner Mongolia, Xiamen in Fujian, Jinan in Shandong, Wuxi in Jiangsu and other places, began to promote the free vaccination of HPV vaccine (mainly bivalent vaccines) for women of appropriate age. Among them, Guangdong said that it will give free HPV vaccine to girls in more than 90% of counties and districts in the province who have newly entered the first grade of junior high school in Guangdong Province and have not been vaccinated against HPV under 14 years old, becoming the first province to announce free HPV vaccination.

Local financial subsidies and advocacy have further accelerated vaccination rates among target populations and the prevalence of HPV vaccines. Huaxi Securities analysts believe that the current domestic HPV vaccine is still in a state of imbalance between supply and demand, and some local governments pay for domestic HPV vaccines, which will further promote the popularization of HPV vaccination.

The "nine-valent vaccine anxiety" is gradually being alleviated.

Since 2019, Xiao Song, a post-90s person working in Hangzhou, has been trying to make an appointment for the nine-valent HPV vaccine on WeChat every day. In order to grab a shot, she and her 3 roommates got up at 6 a.m. to queue up in the community to "grab the vaccine."

But until her 26th birthday in 2020, she couldn't make an appointment. Now, she has given up the idea of a nine-valent vaccine and decided to make an appointment for a quadrivalent or bivalent vaccine on Hangzhou's local treasure.

The aforementioned vaccine intermediary said that the current supply of domestic bivalent and quadrivalent vaccines is increasing, and users do not need to pass through them, "as long as they have their own snacks", they can also make an appointment.

However, some analysts believe that the current gap between supply and demand of domestic HPV vaccines is still very large, and the current "best-selling" of domestic bivalent HPV vaccines is mainly due to the spillover of nine-valent vaccines. Many vaccinators still start to make an appointment for a bivalent or quadrivalent vaccine when there is no result in making an appointment for a nine-valent vaccine.

How far is "HPV vaccine freedom"?

Domestic vaccine manufacturers are also actively entering the game.

In the field of HPV vaccines, due to the high technical threshold and long research and development cycle, it has been a monopoly situation of multinational pharmaceutical giants for many years. Before 2019, the domestic bivalent HPV vaccine was basically controlled by GlaxoSmithKline (GSK), and the quadrivalent and nine-valent HPV vaccines were exclusively supplied by Merck.

In 2017, Merck's quadrivalent HPV vaccine was officially approved in China. On April 20, 2018, Merck submitted an application for the domestic marketing of its nine-valent vaccine, and it took only 8 days for the approval to be published on the official website of the State Food and Drug Administration.

In May of that year, Zhifei Bio became the exclusive agent of Merck's nine-valent HPV vaccine in China. As soon as the vaccine was launched, it became a "sought-after commodity" in various parts of the country. Zhifei Bio also ushered in a take-off in performance, and its agency revenue soared from 7.1806 million yuan in 2016 to 13.955 billion yuan in 2020, an increase of 1942 times in 5 years.

The entry of Wantai Bio has broken the monopoly of domestic HPV vaccines by multinational pharmaceutical giants. On December 30, 2019, Wantai Biotech's bivalent vaccine Xinkoning was approved for marketing by the State Drug Administration. According to the batch issuance data released by the China Institute of Food and Drug Control, the batch issuance volume of Wantai Biological Divalent HPV Vaccine in 2020 is 2.46 million, far exceeding the 690,000 bottles of GSK divalent HPV vaccine; its batch issuance volume is expected to reach about 10 million in 2021.

In April 2020, Wantai Bio landed on the main board of the Shanghai Stock Exchange, and the stock price rose by 44% on the first day of listing, and then recorded 26 consecutive limit increases. As of now, the stock price of Wantai Bio has increased by more than 200 times compared with the issue price, and the market value has exceeded 160 billion yuan. According to the latest financial report of Wantai Biology, the company achieved revenue of 5.75 billion yuan in 2021, of which the vaccine sector achieved revenue of 3.36 billion yuan, contributing more than 60% of revenue, and the gross profit margin was as high as 92.55%.

Now, the "second oldest" of the domestic divalent HPV vaccine is also officially launched. On March 24, the official website of the State Food and Drug Administration showed that the HPV bivalent vaccine of Yuxi Zerun Biology, a wholly-owned subsidiary of Watson Biologics, was officially approved for listing, and the number of HPV vaccines approved for use in the domestic market has increased to 5.

Domestic Ruike Biological, Kangle Guardian, Bowei Biological and other enterprises are laying out HPV vaccines. Bowei Biotech's quadrivalent HPV vaccine is already in phase III clinical trials. Ruike Bio has two bivalent HPV vaccines and a nine-valent HPV vaccine under development, of which the bivalent vaccine is in phase I clinical trials.

At the same time, the research and development of domestic nine-valent HPV vaccines is also in full swing.

According to the Lilac Garden insight database, there are 5 companies in the domestic nine-valent HPV vaccine under research. At present, Ruike Bio's nine-valent HPV vaccine is in the phase III clinical trial stage.

Wantai Biology told Caijing Tianxia Weekly that users can also receive the nine-valent HPV vaccine after receiving the bivalent HPV vaccine, and there is no conflict between the two. Wantai Bio's nine-valent HPV vaccine is now in the phase III clinical trial stage and is expected to be approved for marketing at the end of 2024 or early 2025, becoming the first domestic nine-valent HPV vaccine product.