Getting low-priced vaccines as soon as possible is more realistic than waiting for nine-valent vaccines
Several nine-valent HPV vaccines are already in Phase III clinical trials, and the industry predicts that supply and demand will tend to balance in the next two to three years
Since the launch of the quadrivalent and nine-valent HPV vaccines, the contradiction between supply and demand has become very prominent, and the nine-valent HPV vaccine is even more difficult to obtain.
In order to solve this problem, some companies have expanded production capacity, some companies have accelerated research and development, and some have changed the quadrivalent and nine-valent HPV vaccines to bivalent vaccines.
In fact, the domestic bivalent HPV vaccine has been pre-certified by the World Health Organization, and the quality is not inferior to similar foreign products. It is more realistic and cost-effective to vaccinate bivalent and quadrivalent vaccines as soon as possible.
In addition, the National Health and Health Commission stated that it will actively promote the inclusion of HPV vaccination into local policies to benefit the people in places where conditions permit, and focus on promoting the introduction of free HPV vaccination policies in regions with mature conditions, and continuously improve the HPV vaccination rate of school-age girls.
The industry predicts that in the next two to three years, the contradiction between supply and demand of HPV vaccine will be alleviated.
Timely vaccination of high-priced vaccines to low-priced vaccines
"I asked the 5 surrounding community hospitals, but neither the tetravalent nor the 9-valent vaccine was available. Two of them said that the bivalent HPV can be administered without an appointment." Zhu Jun, who lives in Huilongguan, Changping, is a full-time wife. Knowing the HPV vaccine, I first heard about it when I was chatting with a friend a month ago.
This friend made an appointment for a whole year, and it took another year to complete the three-shot quadrivalent HPV vaccine.
Zhu Jun said that she had undergone surgery for breast disease and learned that the incidence of cervical cancer is also high. She decided to get vaccinated because she was very resistant to vaccines.
On July 11, Zhu Jun specially went to the hospital for an HPV test. The doctor who received him at that time emphasized that he must be vaccinated against HPV.
On July 14, Zhu Jun completed the first injection of domestic bivalent HPV vaccine at the Huoying Community Health Service Center in Changping District.
"Huoying Community Hospital said that nine prices have been out of stock since the epidemic, and it is expected to wait 1-2 years to queue up." Zhu Jun said.
Up to now, there are three bivalent HPV vaccines on the market in my country.
In March this year, the bivalent human papillomavirus vaccine (Pichia pastoris) of Yuxi Zerun, a subsidiary of Watson Bio, was approved, which is also the second domestic bivalent HPV vaccine.
Previously, my country's approved HPV vaccines include GSK's bivalent HPV vaccine and Wantai Bio's bivalent HPV vaccine.
Li Wei, general manager of Yuxi Zerun, a wholly-owned subsidiary of Watson Bio, told the Beijing News that the length of the vaccine production cycle is related to the industrial design, but in principle, the lower the price, the shorter the production cycle.
Watson's bivalent HPV vaccine takes up to ten days to produce, but the subsequent inspection cycle is longer, including animal in vivo titer tests, etc. It takes more than one month for internal testing alone, and then it can be sent for batch issuance. The batch issuance time is generally 3 months.
"Currently, the supply of quadrivalent and 9-valent HPV vaccines is mainly in short supply, and there is no shortage of bivalent vaccines." Du Heng, senior project officer of the Bill & Melinda Gates Foundation, introduced that the world's quadrivalent and 9-valent vaccines are only produced by Merck & Co. Vaccine production is very planned and planned, and the production volume needs to be planned in advance, often several years in advance. Enterprises estimate the output by predicting the future market demand, carry out capacity construction and arrange production.
Du Heng further explained that when vaccine companies do market analysis, they need to predict how many people usually know about the vaccine, believe it is safe and effective, and finally complete the vaccination.
In the absence of more marketing and government procurement, the proportion of groups who can do these three points is not high.
After this part of the population is vaccinated, the stock market accumulated in a few years will become less and less.
However, there will be a small increment every year, that is, new people entering the vaccination age group every year.
"If the HPV vaccine is not included in the immunization plan, the vaccination rate may be only about 10%, and the vaccination rate of the adolescent population is even lower. Once it is included, the vaccination rate may increase to 80% or even 90%." Du Heng used the original HPV vaccine in the United States For example, the sales of HPV vaccines have peaked after the initial launch. This is because the previous stock market, when the stock market is exhausted, the sales peak begins to decline and maintains a relatively stable level, because every year there are New demand market.
However, Du Heng believes that the duration of the peak sales in China will be longer because of the large stock.
After the vaccine production plan is done, the production cycle of the vaccine is also long. It needs to be produced one by one before mixing and preparation. The more the price, the more difficult the production line deployment management and the longer the production cycle.
After the production cycle of vaccines is over, batch issuance needs to be done, including the quality control batch issuance within the enterprise and the batch issuance by the regulatory department. The round cycle is often several months or even a year. It is not ruled out that if there are problems during the production and issuance process, The cycle will be longer.
"It's not that the shortfall of millions of doses of vaccines is suddenly discovered today and can be filled the next day. If the market demand far exceeds the company's production capacity and production schedule, there will be a shortage of vaccines." Du Heng explained.
Accelerate the deployment of multiple vaccines into Phase III clinical trials
With the continuous introduction of relevant support policies, coupled with good market prospects and the current situation of short supply, many domestic vaccine companies have been attracted to deploy HPV vaccines and seize the unmet market.
In terms of types, the types of HPV vaccines under development in the world include bivalent, trivalent, quadrivalent, hexavalent, 9valent, 11valent, 14valent, and 15valent, and the expression systems include Hansenula yeast, Pichia pastoris , Escherichia coli, insect cells and other different technical paths.
The preventive effect of high-priced HPV vaccine should be higher, but due to the need to increase the types of virus-like particles, and the interference between different HPV types that affect immunogenicity, the increase in the content of antigens and adjuvants may lead to increased safety risks, etc. , the development difficulty is also higher.
In terms of HPV vaccine research and development, in addition to the two approved domestic bivalent HPV vaccines, many vaccines in my country have entered or are about to enter phase III clinical trials.
The rapid development of research and development is the nine-valent HPV vaccine that is most in short supply on the market, and production capacity construction is also advancing simultaneously.
Among them, the nine-valent HPV vaccine under development by Wantai Bio, Shanghai Bowei, Recreation Guard and Ruike Bio is undergoing Phase III clinical trials; the nine-valent HPV vaccine of Watson Bio Holdings subsidiary Shanghai Zerun is undergoing Phase III clinical trials of preparatory work.
In addition, the trivalent HPV vaccine (Escherichia coli) of Recreation Guard, the quadrivalent HPV vaccine of Chengdu Institute, and the quadrivalent HPV vaccine of Shanghai Bowei are all in the phase III clinical trial stage; in March this year, Sinopharm Zhongsheng and Chengdu Institute , The 11-valent HPV vaccine jointly developed by Beijing Institute has also started phase III clinical trials.
In addition to the above-mentioned vaccines with the fastest progress, the two bivalent HPV vaccines of Ruike Biotech are in the phase I clinical trial stage; the quadrivalent HPV vaccine of the Shanghai Institute has completed the phase II clinical trial.
The recombinant 14-valent HPV vaccine (insect cells) independently developed by Shenzhou Cell is the first 14-valent HPV vaccine variety approved for clinical research in the world, and clinical phase I/II research is being carried out at the Jiangsu Provincial Center for Disease Control and Prevention.
In the investor relations activity record sheet released by China Cell on July 8, China Cell stated that if it progresses smoothly, it is expected to carry out Phase III clinical trials before the end of this year.
The 15-valent HPV vaccine (Escherichia coli) jointly developed by Chengda Biology and Recreation Guard is currently the most expensive HPV vaccine under development in the world. It was approved for clinical trials in March this year.
The accelerated deployment of enterprises will inevitably lead to increasingly fierce competition in the market, especially in the competition of the nine-valent HPV vaccine, there are many companies with layout, and the competition will be extremely fierce. Merck, which still dominates the four-valent and nine-valent HPV market, will face a lot in the future. pressure.
However, with the increasing number of approved HPV vaccines and the expansion of production by enterprises, the shortage of quadrivalent and nine-valent HPV vaccines in China will be alleviated, and more Chinese consumers will benefit.
"If these HPV vaccines in phase III clinical trials are approved for marketing in the next 2-3 years, the current situation of 'one vaccine is hard to find' will be reversed, and the supply of nine-valent HPV vaccines will eventually exceed the demand." Du Heng predicted.
All HPV serotypes that can infect women can also infect men and cause serious diseases in men, including cancers of the penis, anus, and head and neck.
Therefore, clinical trials of HPV vaccines for male indications are also being gradually advanced in China.
According to the Lilac Garden Insight database, in October 2021, Merck announced the launch of a Phase 3 clinical trial for the first time in China to evaluate the protective efficacy and immunogenicity of the nine-valent human papillomavirus vaccine (Jia Daxiu 9) in Chinese men. and safety, the study intends to enroll 8,100 people.
The immunogenicity surrogate endpoint data provided by the international multicenter clinical trial showed that the vaccine can also be used to vaccinate girls aged 9-15 years, and in the United States, the vaccine has been approved for women and men aged 9-45 years.
The domestic clinical study of the vaccine for people aged 9-15 is still in progress.
In June this year, the two-dose vaccination program of GlaxoSmithKline HPV bivalent vaccine Cervarix for girls aged 9-14 was approved by the State Food and Drug Administration. The first imported product for the two-dose vaccination program for girls.
"In terms of vaccination program adjustment, GSK has recently approved a two-dose vaccination program. Du Heng pointed out that the two-dose vaccination program for people aged 9-15 has been used globally for more than 10 years, and hundreds of millions of women have used this vaccination. Procedures, numerous real-world clinical research data show that two doses of 9-15-year-old girls can establish effective protection.
Du Heng analyzed that the domestic bivalent HPV vaccine has been included in the immunization plan in some areas and entered the public market mainly because of its price advantage, and the 9-15-year-old group is a two-dose vaccination program, and the entire vaccination program can cost more than 600 yuan. From a health economics standpoint, the cost-effectiveness is high.
By reducing the number of doses and costs, it may be possible for more local governments to consider including HPV vaccines in their immunization plans, so that domestic HPV vaccines can enter a broader public market.
Pilot free multi-site vaccines included in immunization programs
In November 2020, WHO officially released the global strategy to eliminate cervical cancer, and 194 countries around the world, including China, made a joint commitment to achieve the goal of eliminating cervical cancer by 2030.
To promote the realization of this goal, China is taking action.
As a primary preventive measure to prevent HPV infection-related diseases, HPV vaccination can block the occurrence and development of cervical precancerous lesions by preventing primary HPV infection and reducing persistent HPV infection.
According to the World Health Organization, 9-14 years old is the optimal age for HPV vaccination.
At the national policy level, in February 2021, the National Health and Health Commission mentioned in its "Reply to Recommendation No. 8996 of the Third Session of the Thirteenth National People's Congress" that HPV vaccination will be included in the national immunization plan to conduct overall research and gradually promote it HPV vaccination for age-appropriate populations.
In May 2021, the National Health and Medical Commission launched the pilot work of "Healthy City Construction Promotes Healthy China Action Innovation Model" in 15 cities across the country to explore strategies and measures to eliminate comprehensive cervical cancer prevention and treatment.
Recently, the National Health and Medical Commission stated that it will actively promote the inclusion of HPV vaccination in local policies to benefit the people where conditions permit, will vigorously promote the experience of Guangdong, Hainan, Fujian and other provinces, and summarize the use of government livelihood projects and medical insurance funds to raise funds through multiple channels. Based on experience and practice, local governments are encouraged to take the lead in the first trial, focusing on promoting regions with mature conditions to take the lead in introducing a policy of free HPV vaccination, and continuously improve the HPV vaccination rate of school-age girls.
At the local level, the pilot has already begun.
On August 1, 2020, Ordos, Inner Mongolia Autonomous Region, began to vaccinate HPV vaccines for middle school students aged 13-18 and above for free, becoming the first city in China to explore free HPV vaccine vaccination for school-aged people.
In addition to Ordos, as of now, my country has piloted free HPV vaccination programs for school-age girls in Fujian, Guangdong, Hainan, Chengdu, Sichuan, Jinan, Shandong; Wuxi, Lianyungang, Nanjing and Yangzhou in Jiangsu; Shijiazhuang and Tangshan in Hebei. .
Among them, Guangdong Province, Hainan Province, and Fujian Province have implemented the province's free vaccination of domestic bivalent HPV vaccine for school-age girls, which has been included in the 2022 provincial party committee and provincial government's practical projects for the private sector.
Chengdu, Sichuan, based on the unified procurement of bivalent HPV vaccines in other pilot cities and the unified arrangement of vaccinations, has made a pilot model innovation. It provides a subsidy of 600 yuan for school-age girls to receive HPV vaccines, and they can go to community clinics to receive different types of HPV vaccines. The excess part will be paid at your own expense.
On June 6 this year, Nanjing began to "vaccinate the domestic bivalent HPV vaccine purchased by centralized bidding for free, and subsidize the vaccination of other similar imported bivalent or quadrivalent vaccines" for first-year girls.
Judging from the vaccine procurement results announced by the Jiangsu Provincial Public Resource Trading Center on June 2, Watson Bio won 70% of the government procurement at the price of 246 yuan per piece, while Wantai Bio got it at the price of 329 yuan per piece. 30% of the purchase volume.
As more and more local governments purchase HPV vaccines, the competition for domestic bivalent HPV vaccines will become more intense.
"There are more products and supply markets, and the price of vaccines can be reduced, and the price reduction of vaccines will allow more local governments to consider including them into immunization plans. There will also be a larger public market for HPV vaccines, and the market's plate will expand. If The HPV vaccine has not entered the regional immunization plan, and the domestic bivalent HPV vaccine market is far from the current situation.” Du Heng said that the difficulty in promoting the inclusion of the HPV vaccine in the immunization plan nationwide is mainly due to price.
One of Du Heng's important jobs at the Gates Foundation is to help HPV vaccine companies increase production capacity, reduce costs, and improve quality, and at the same time support Chinese partners to carry out health economics research on cervical cancer vaccines, research on multiple financing and payment mechanisms, Regional pilot project to provide scientific basis and practical exploration for incorporating cervical cancer vaccine into national immunization program.
When in contact with local experts and government officials, Du Heng could feel the willingness of various places to push forward, but the cheapest domestic HPV currently costs 246 yuan per stick.
If there is no new HPV vaccine listed to compete in the short term and increase the supply, some local governments have concerns about including the HPV vaccine into the immunization program due to the consideration of limited supply and higher prices.
On May 30 this year, the Shanghai Municipal Health Commission mentioned in its reply to the proposal No. 0153 of the Fifth Session of the 13th CPPCC that the main problem in HPV vaccination in Shanghai is still the price of the vaccine. The population of older age groups has a higher willingness to be vaccinated. The vaccination rate of people aged 9-14 is less than 1%, and they have a high willingness to choose quadrivalent and 9-valent vaccines. It accounted for 89% of the total number of vaccinations, and the overall vaccination rate was low.
The inclusion of the HPV vaccine in the Shanghai Municipal Immunization Program still needs to be fully demonstrated.
【sample】
Ordos
Free vaccinations for school-age girls
Ordos is a prefecture-level city with Mongolians as the main body and Han people in the majority. It is located in the southwest of Inner Mongolia Autonomous Region and has 2 districts and 7 banners under its jurisdiction.
In terms of cervical cancer disease burden, the city of Ordos faces high incidence of cervical cancer, weak health awareness, low screening accessibility and screening rate, lack of appropriate local screening, diagnosis and treatment standards, introduction and popularization of cervical cancer screening technology difficulties, etc.
A survey in 2020 showed that there are 113 million ethnic minorities in my country, most of whom live in areas with underdeveloped health resources.
Qiao Youlin, professor/doctoral supervisor of Peking Union Medical College/Qunming School of Medicine and Public Health, and member of the WHO Global Cervical Cancer Elimination Group, pointed out that the urban cervical cancer burden in Inner Mongolia, Ordos and Hohhot is relatively serious.
Things have turned around in 2020.
According to statistics from the Banner Education and Sports Bureau, in 2020, there are 9,892 middle school girls over the age of 13 in the 39 primary and secondary schools in the banner.
On August 1 of that year, Zhungeer Banner, Ordos, implemented the "Caring for Girls Entering Campus" project, and began to vaccinate the above-mentioned 9,892 middle school students aged 13-18 and above with HPV bivalent vaccine free of charge.
From August 1, 2020 to March 15, 2021, the vaccination clinics in the pilot areas have vaccinated 8,355 women of school age with the first dose of cervical cancer vaccine free of charge, accounting for 84.46% of the total number of school-age girls; 8,056 girls have been vaccinated The second dose of cervical cancer vaccine was given, accounting for about 96.42% of the total number of vaccinations.
Shenzhen
Who can be vaccinated by lottery
In Shenzhen, the scarce nine-valent HPV vaccine is determined by lottery.
On November 19, 2018, Shenzhen City adopted the lottery method to reserve the nine-valent HPV vaccine for the first time. The first lottery has a total of 1305 number sources. The winners need to complete the appointment within two days.
According to reports, since the approved vaccination scope of the nine-valent HPV vaccine in China is for women aged 16-26, the lottery system has set a registration "threshold": the birthday displayed on the ID card shall prevail, and the age shall not exceed 26 years and 6 months. Only women of 100,000 are eligible for lottery, to ensure that applicants have more than 6 months to complete the three-shot vaccination.
Every month, the system will clear out the applicants who are over-aged in the current month in the "Number Source Pool".
In addition, the lottery does not have Shenzhen household registration restrictions.
However, a WeChat ID can only be bound to one ID card, and the applicant must fill in the ID card and related information in real name when registering.
The Shenzhen Center for Disease Control and Prevention stated that those who fail to make an appointment within the specified time after winning the lottery, or who cannot be vaccinated on time due to objective reasons after the appointment is successful, but who do not contact the vaccination clinic one day in advance to cancel the appointment will be included in the "blacklist", 3 You cannot participate in the lottery within one month.
In 2021, the winning rate of Shenzhen's nine-valent HPV vaccine lottery will basically remain between 2% and 4%. The number of valid applicants for each lottery is about 400,000 to 600,000, but the number of winners is only 10,000 or 20,000.
This year, Shenzhen has released 5 lottery results. The winning rates are 3.08%, 2.97%, 4.02%, 5.11%, and 7.26%, respectively. The winning rate has increased significantly.
Written by version B02-B08/Beijing News reporter Wang Kara, Zhang Xiulan, Liu Xu