HPV vaccine snapped up

  Author: Zhou Xinyu

  Published in the 1050th issue of "China News Weekly" magazine in 2022.7.4

  Wang Han, a 24-year-old girl from Shanghai, did not expect that the grand event of grabbing concert tickets would be repeated when she made an appointment for the HPV nine-valent vaccine.

  At noon on April 19, the staff of the private hospital United Family sent a link to snap up the vaccine in the vaccine reservation group. The quantity of about 50 doses will be scrambled at 13:30.

Wang Han opened the purchase page 5 minutes in advance and purchased a nine-price package of 5,000 yuan.

When the time came, the payment page immediately became a blank while loading, and a few seconds later, the word "out of stock" popped up.

Wang Han didn't give up and continued to refresh the page. After more than ten minutes, she picked up a "leak".

At the moment of payment, Wang Han felt that "a major event in life has been completed".

  In April last year, Ordos, Inner Mongolia became the first city in the mainland to vaccinate girls aged 13 to 18 with HPV vaccine free of charge.

Today, more than 12 provincial and municipal governments in China have tendered and purchased the bivalent HPV vaccine for free.

  On May 30, the National Health Commission held a press conference.

Wang Linhong, chairman of the Women's Health Branch of the Chinese Preventive Medicine Association and chief expert on chronic diseases of the Chinese Center for Disease Control and Prevention, mentioned, "The state will promote the policy of free HPV vaccination to cover more people. At the same time, increase multi-departmental collaboration to gradually solve the shortage of HPV vaccines, etc. problems, and strive to meet vaccination needs.”

  Behind the insufficient supply of vaccines, there are many problems involving the business of manufacturers, revision of vaccination norms, and changes in the concept of prevention.

The 3-dose rule is being revised

  In early April, the WHO Strategic Advisory Group of Experts on Immunization (SAGE) announced the results of a meeting that said: "A single dose of HPV vaccine provides reliable protection, comparable to a 2-dose or 3-dose vaccination regimen." At the same time, SAGE recommended that countries 1-dose or 2-dose regimens are available for girls 9-14 years old and women 15-20 years old.

  HPV vaccine is an important measure to prevent cervical cancer caused by persistent infection of high-risk human papillomavirus (HPV).

The valence of HPV vaccine refers to the types of HPV virus subtypes that the vaccine can prevent.

There are three types of HPV vaccines currently available in the market: bivalent, quadrivalent and 9-valent.

Typically, HPV vaccines are given in 3 doses.

  The bivalent vaccine can prevent nearly 70% of cervical cancers caused by HPV types 16 and 18. On this basis, the quadrivalent vaccine increases the protection against HPV types 6 and 11.

On the basis of the quadrivalent vaccine, the nine-valent vaccine adds the prevention of five subtypes of cervical cancer that can cause 20% of cervical cancer.

  The domestic HPV vaccine market has long been monopolized by British GlaxoSmithKline and American Merck & Co.

In March of this year, Watson's Pichia recombinant protein cervical cancer bivalent vaccine "Wo Zehui" was approved for marketing.

Prior to this, on New Year's Day 2020, the E. coli recombinant protein cervical cancer bivalent vaccine "Xin Ke Ning" jointly developed by Wantai and Xiamen University was approved for marketing by the State Food and Drug Administration, with a single issue price of 329 yuan.

  Shares in Wantai fell 20% from April 14 to April 25 after the WHO announced a one- or two-dose vaccination regimen, while shares in Merck's Chinese agent, Zhifei Bio, fell 31%.

Watson was also implicated. From April 19 to 25, the stock price continued to fall for five trading days.

  Judging from clinical trials, the claim that a single dose of vaccination has the same protective effect is well documented.

Zhang Jun, dean of the School of Public Health of Xiamen University and a member of the "Xin Ke Ning" research and development team, said in an interview with China News Weekly: "The current experimental results largely show that the protective effect of a single dose of vaccination is comparable to that of two in a short period of time. Three doses are equivalent."

  In June 2018, an NIH-funded, University of Washington professor in Seattle led a two-and-a-half-year study that followed 2,275 women who received a single dose of the HPV vaccine.

The results of the study showed that after two and a half years, the HPV antibody retention rate was 98 percent.

Another follow-up study, published in the Journal of the National Cancer Institute in February 2020, showed that after a single dose of GlaxoSmithKline's bivalent vaccine Cervarix, the preventive effect of HPV infection was comparable to that of vaccination in 134 people. 2 or 3 doses are equivalent and last for at least 7 years.

When vaccinating the HPV vaccine, there is usually a gap of 1 to 2 months between the first and second doses, and 6 months between the second and third doses.

  However, the ideal duration of HPV vaccine effect is not less than 40 years.

Zhang Jun made an assumption: "If the vaccine is vaccinated at the age of 10, it must be guaranteed that it will still have a protective effect from the first sexual life to the frequent HPV infection period around the age of 50." The current research cannot prove a single dose. The long-term effective protection period of vaccination is comparable to that of multiple doses.

Aimée Kreimer, a senior researcher in the epidemiology of infection and immunity at the National Cancer Institute, also pointed out that more research is needed to support the duration of the single-dose vaccination effect.

  As far as mainland China is concerned, domestic vaccines can partially alleviate the tight supply situation, but the "Guangdong Expert Consensus on the Application of HPV Vaccines to Eliminate Cervical Cancer" released in September 2021 mentioned that the current domestic HPV vaccine immunization coverage rate is low, and adolescents The population vaccination rate is less than 3%, and the whole population vaccination rate is less than 6%.

Due to the shortage of supply, the situation that Wang Han needs to rely on snatch and luck to get the vaccine often occurs.

Last year, 420,000 people participated in the second 9-valent HPV vaccine lottery in Shenzhen, and only 7,093 people won the lottery, with a probability of less than 1.7%.

 Behind the "26-year-old panic"

  "If you don't pay nine prices before the age of 26, you will have no chance after that." Liu Si, a Shanghai girl who will turn 26 in November, keeps brushing similar messages on social media.

However, due to the epidemic, her community has been closed for nearly two months since March 24.

"If I don't get 9-price vaccination, I will have regrets in my life." In those two months, she was often surrounded by the anxiety of vaccination when she was approaching 26 years old.

  On June 1, Shanghai officially resumed work and production.

Liu Si immediately made an appointment to Wusong Hospital, Zhongshan Hospital Affiliated to Fudan University.

But the other party told her that she would have to queue for 1-2 years to get a nine-price deal.

  For women in China, the panic of vaccination of the nine-valent vaccine mostly occurs when they are close to the age of 26.

Merck is the exclusive global manufacturer of the nine-valent HPV vaccine.

In 2018, Merck's nine-valent HPV vaccine was approved in mainland China, and the vaccination range is for women aged 16-26.

  The approved population of the HPV vaccine in mainland China is not exactly the same as in other countries.

In the U.S., the Food and Drug Administration extended the nine-valence coverage to men and women between the ages of 9 and 45.

Many other countries allow men and women over the age of 26 and even over 45 to receive the 9-valent vaccine in private hospitals.

Zhang Jun analyzed that due to the late development and launch, and the lack of research data, the scope of application of the nine-valent vaccine in the mainland is subject to stricter control.

  Zhang Jun explained that the previous clinical data of the East Asian population of Merck's nine-valent vaccine was concentrated in 16-26 years old, which is why people beyond this age group have not been approved to be vaccinated in the mainland, "but this does not mean that in other age groups Inoculation with nine valence has no protective effect."

Wei Lihui, director of the Colposcopy and Cervical Cancer Pathology Branch (CSCCP) of the Chinese Eugenics Association, said that my country is currently conducting clinical trials of HPV preventive vaccines in diverse populations, including the marketed nine-valent vaccine to expand the age group and clinical trials for young men. , Some domestic HPV vaccines are also entering the stage of clinical trials.

Zhang Jun added that as long as the sexual life after vaccination and attention to protection are maintained, postponing the follow-up injections will not have much impact on the protective effect.

  However, many studies have shown that the earlier the vaccination, the better the protective effect of the HPV vaccine.

In March 2022, a study published in the journal "Vaccine" under the Nature Publishing Group pointed out that the performance of related antibodies in 10- to 14-year-old adolescents after HPV vaccine is generally better than that of 18- to 53-year-old adults, which means that HPV vaccine It can produce better protective effect in young people.

The study also found that juvenile vaccine recipients had stronger persistence of binding antibodies than adults.

WHO also recommends that girls aged 9 to 14 should be vaccinated as a priority.

"Don't postpone the vaccination just to wait for the nine-valent, the two-valent and four-valent protective power is enough." Wei Lihui told "China News Weekly".

  The difference between the approved groups at home and abroad makes many groups over 26 years old willing to pay high prices to go abroad to receive the nine-valent vaccine.

Last year, Xiao Lin, who was doing market analysis at the Japanese headquarters of a cross-border trading company, had waited for more than two months and finally got a number in a private hospital in Tokyo.

She thought that the vaccinated people were all Japanese, but she and "more than a dozen vaccinated people chatted in Chinese" - the opponents for the nine-valent vaccine are still the Chinese who can't get the vaccine.

  But even overseas, hospitals are still cautious about the 9-valent vaccine.

Merck mentioned in the "HPV Vaccination Recommendations" published on its official website: "All adults 27 to 45 years old should have a joint decision-making discussion with a clinician to determine whether they should receive the 9-valent vaccine." US Centers for Disease Control and Prevention (CDC) Explain that most adults in this age group have been infected with HPV, and the protection provided by the vaccine is more limited than that of people aged 9-26. "HPV vaccine can only prevent new infections, but cannot treat existing infections." .

Before the vaccination, Xiao Lin was also told many times by Japanese doctors that due to the late launch, the test results of the nine-valent vaccine can only guarantee an effective protection period of more than 7 years.


  Not only for women, but also studies have confirmed that the HPV quadrivalent vaccine and the nine-valent vaccine also have protective effects on men.

An earlier CDC study in the United States found that HPV types 6 and 11, which are covered by the quadrivalent vaccine, are the main culprits in causing 90% of condyloma acuminatum in men and women.

However, the "Recommendations for the Use of HPV Vaccines in Children and Adolescents" updated in 2018 by the Canadian Association of Pediatrics and the Committee on Infectious Diseases and Immunization pointed out that compared with the quadrivalent, men would not benefit much from the other five serotypes of the nine-valent vaccine. After all, These five viruses cause less than 1 percent of oropharyngeal cancers.

  In 2015, the Advisory Committee on Immunization Implementation under the CDC recommended that the nine-valent HPV vaccine be included in the national immunization plan.

A year later, the CDC removed the bivalent and quadrivalent vaccines from its purchase list.

The CDC explained that this is because the incidence of condyloma acuminatum in the United States is higher than that of cervical cancer. Purchasing the nine-valent vaccine is a choice in line with national conditions.

Moreover, this is also related to the degree of economic development of the United States itself.

  In addition to several existing HPV vaccines, domestic 11-valent, 14-valent and 15-valent HPV vaccines are currently under development.

As one of the developers of the 15-valent HPV vaccine in China, Liaoning Chengda Biological Co., Ltd. introduced that the 15-valent vaccine can prevent all high-risk types and HPV viruses related to condyloma acuminatum on the basis of nine-valent.

Zhang Jun revealed: "It is expected that in the next 2 to 4 years, we may see the domestic nine-valent cervical cancer vaccine on the market. Within 10 years, higher-priced vaccines are also likely to be available."

  Vaccination does not mean the end of prevention

  In July 2020, Emily Hamburg, a scholar at Harvard School of Public Health, and others analyzed 48 countries assisted by the Global Alliance for Vaccines and Immunization (Gavi) and found that the bivalent HPV vaccine with cross-protective effect was in 63%~ 83% of low- and middle-income countries are more cost-effective than nine prices.

  The study by Hamburg et al. deduced such a set of data: by 2100, when the vaccination rate of 48 Gavi donor countries reaches 70%, the bivalent vaccine with cross-protection effect can avoid 17.2 million cases of cervical cancer, compared with 17.2 million cases of cervical cancer. Nine prices avoided a comparable number of 18.5 million cases.

  "Most countries with centralized procurement and public immunization programs will not spend more than $30 per dose of HPV vaccine." Eduardo Franco, chair of the Department of Cancer Epidemiology and Department of Oncology at McGill University School of Medicine in Montreal, Canada, distributes the vaccine Considered as an economy of scale, as long as the coverage rate is higher, the unit cost can be reduced through centralized procurement.

  However, under the current situation of short supply, the sharp price reduction may only wait for the arrival of the "patent cliff".

Lin Yuancheng, deputy director of the Domestic Patent Office of the Patent and Trademark Office of the China Council for the Promotion of International Trade, told China News Weekly that the so-called "patent cliff" refers to the sales of pharmaceutical factories and related commercial institutions after the technology and products are copied in large quantities once the patent expires. and profits will plummet.

  From 2006 to 2008, this was the first blowout period for different institutions and manufacturers to apply for HPV vaccine-related patents in China.

The study found that 43% of the world's HPV vaccine-related patents were applied for in China, and the United States ranked second, accounting for 28%.

The Patent Law of the People's Republic of China stipulates that the term of a patent right for invention is 20 years.

This also means that a large number of HPV vaccine-related patents will expire between 2026 and 2028.

  But getting the HPV vaccine does not mean the end of prevention.

A patient who develops cervical cancer due to HPV infection will live as a healthy person for the first ten or even twenty years.

In 2003, the Cervical Cancer Prevention Alliance jointly established by eight public health international organizations published a "Cervical Cancer Prevention Fact Sheet", which pointed out that the cervical precursor lesions caused by persistent infection with high-risk HPV usually take 7 years to develop into cancer. ~20 years.

Once the diseased stage is over, the patient may one day find that his vagina begins to bleed in contact, and there is often pain in the lumbosacral region.

  But few people care about the changes in their bodies at this stage.

Most HPV is transmitted through sexually transmitted infections, so many women miss the best time for cervical cancer screening because of the "sex" secret.

  "Women who have sex have an 80% chance of being infected with HPV in their lifetime. This is not a matter of style, but a normal and common phenomenon." Wei Lihui told China News Weekly, "Cervical cancer is not like most other cancers. Precancerous lesions can be detected through regular screening and can be effectively prevented through active treatment. Therefore, it is also necessary to eliminate stigma and build people’s awareness of regular screening.”

  In Italy, all women between the ages of 25 and 64 receive an email from the National Health Service every three years.

It states the procedure for cervical cancer smear test, when it should be tested, and where.

Similarly, the American Cancer Society's "Guidelines for Prevention and Early Detection of Cervical Cancer," revised on April 22, 2021, recommend that cervical cancer screening should begin at age 25 and be performed every 5 years.

The National Cancer Center in Japan moved the age of cervical cancer screening to 20 years old and increased the frequency to every 2 years.

  By the end of 2025, 50% of women of school age will be screened for cervical cancer, which is a short-term goal set by the National Health Commission.

In 2021, the "Cervical Cancer Screening Work Plan" issued by the National Health and Medical Commission shows that the objects of domestic cervical cancer screening will cover women aged 35-64.

  This is not an easy goal to achieve.

Wei Lihui believes that the first priority is to ensure the screening of women who are in the peak period of cancer between the ages of 35 and 45.

But for individuals, as soon as they start having sex, it is best to do regular screenings on their own.

Even if adult women are vaccinated against HPV, screening is still important, after all, there is a possibility of contracting the virus before vaccination.

  According to WHO recommendations, by 2030, the global coverage of cervical cancer screening among adult women should reach 70%.

This figure was mentioned again in the implementation plan of the 2021-2030 Program for the Development of Chinese Women and Children issued by the National Health Commission in April this year.

Qiao Youlin, director of the Cancer Epidemiology Research Office of the Cancer Institute of the Cancer Hospital of the Chinese Academy of Medical Sciences and Peking Union Medical College, mentioned in an interview with the media that "if this number cannot be reached, the control of the disease is insignificant."

  (At the request of the interviewee, Wang Han, Liu Si and Xiao Lin are all pseudonyms in the article)

  "China News Weekly" Issue 24, 2022

  Statement: The publication of "China News Weekly" manuscripts is authorized in writing