A few days ago, the 9-valent HPV vaccine (9vHPV), which had become popular on the market, finally looked forward to the “Official Press Conference.” The Pharmacological Examination Center and the experts gave a professional and comprehensive interpretation of the “conditionally approved interpretation of the nine-valent human papilloma virus (HPV) vaccine in China”.
The article mentioned: “The 9vHPV vaccine is approved to be eligible for listing in China in accordance with global clinical research data (including the effectiveness of protection against persistent infections in some East Asian populations).”
The “East Asian population” here refers to the 7,099 women randomized to the 9vHPV vaccine group in the 5-year clinical phase III trial conducted by Merck in multiple centers in 18 countries, including 868 Asians, of which 776 were In the Asia Pacific region (Hong Kong, Japan, Korea, Thailand, Taiwan). It can be seen that its protective efficacy against Asian-American women (the end point of 6 months of continuous infection) is similar to that of other races (regions) (Table 1). Finally, the entire trial demonstrated that 9vHPV had a non-inferiority to HPV6/11/16/18 with a 4v HPV protection effect and also provided good protection for an additional 5 high-risk types HPV31/33/45/52/58.
Table 1 Comparison of effective ethnic subgroups of 9vHPV for HPV 31/33/45/52/58 persistent infection for 6 months
Despite this, the “Official Interpretation” mentions a regrettable fact: “International research data show that bivalent and tetravalent HPV vaccines can prevent about 70% of cervical cancer, and the nine-valent vaccine HPV type coverage is as high as 92%. The three vaccines were designed and validated based on the epidemiological background of Western populations, and the protection ratio for Asian populations is relatively lower than that of Western populations.”
So, is there a difference in the prevention effect of HPV vaccine? Does the results of vaccine trials in which Asians are involved directly “the bringing principle“? The “stupid approach” that “has foreign drugs must be re-doing clinical trials in China” has been criticized before.
Is the requirement for the applicant to further expand the clinical research and pharmacy research of Chinese population after listing a necessary risk control?
Therefore, it is necessary to review the global and regional HPV type prevalence studies to see if various high-risk carcinogenic HPVs are within the “effective range” of these vaccines.
From global to Asia, from Asia to China
Vaccine research and development must be supported by epidemiological data, otherwise it will be aimless.
Based on a large number of global research data, the International Cancer Institute identified 12 types of cancer related high risk HPV subtypes HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59. Among them, HPV16 (60.6%) and 18 (10.2%) had the highest prevalence in cervical cancer. The 7 HPV16, 18, 45, 31, 33, 52 and 58 accounted for 90% of HPV positive squamous cell carcinoma.
This is the basis for the development of three existing HPV vaccines: 2vHPV and 4vHPV against HPV16/18, covering 71% of the lesions caused by HPV infection and cervical cancer (4vHPV also protects two common non carcinogenic HPV6/11, preventing skin or genital warts, etc.); 9vHPV covers 7 high risk carcinogens, which can be preprotected from approximately 90% of the lesions and phases caused by HPV infection.
Correspondingly, in 2016, based on a global survey, 9vHPV had a protective rate of more than 86% for cervical cancer related HPV in different regions.
Asian HPV Type Prevalence Study
All Asian countries currently have only scattered, small-scale studies and reviews. From the available data, Thailand’s pre-2015 epidemiological data show that HPV16, 58 and 18 are the top three high-risk cancer types. The prevalence of HPV16 (38.5%) is far below the international level (60.6%), and the prevalence of HPV58 (20.0%) is much higher than the global 2.3%. Studies in Japan and South Korea in 2008 confirmed the prevalence of HPV16/18 in cervical cancer (>70%), followed by three types of 52/58/33, and global data 31/33/45 It is different, especially in South Korea HPV58 ranked third. Prior to 2004, studies in South Korea showed that HPV 33/58/31 prevalence was second only to HPV 16/18. The latest study (2014-2016) also confirmed the higher incidence of HPV52/58 in Korean women with precancerous lesions than HPV18.
HPV16 has the highest prevalence among Asian women. In cervical cancer and precancerous lesions, 16/18 is also the dominant type, consistent with the global. From the limited data, it seems that the prevalence of HPV58/52 in Asian women is higher than the global level in cervical cancer and high precancerous lesions. However, it should also be noted that the lack of data is a unified challenge for epidemiological studies in various countries, and it also brings uncertainties and risks to the effectiveness and strategies of vaccination for existing vaccines in various countries. The adverse reaction events in countries like Japan mentioned in the “Official Interpretation” –
“The collective occurrence of acute idiopathic polyneuritis such as muscle spasm, blurred vision, and movement and memory disorders in Japanese girls vaccinated in secondary schools led to class actions. The Japanese government also caused controversy because of adverse reactions and suspended media propaganda “encouraged inoculation”. ”
Study on prevalence of HPV type in China
The latest “cancer prevention vaccine” has been used over the world and more than three hundred million Chinese women have been waiting for years, and in the last two years, all three HPV vaccines have been landed in China. This is based on clinical trials of 2vHPV (6803 subjects) and 4vHPV (3006 subjects) in China, and 9vHPV’s global overseas clinical trials. Clinical trials are small-scale reverse validation, while large-scale epidemiological studies are clear guidelines.
Vaccination without supporting epidemiological data is tantamount to blindfolded targets.
The latest review of China in 2018 analyzed the previous 257 related articles and calculated that the top ten high-risk categories in Chinese cervical cancer patients were HPV 16 (62.5%), 18 (12.4%), 58 (8.6%), 52 ( 5.7%), 33 (4.6%), 31 (3.5%), 55 (2.4%), 68 (2.4%), 53 (2.2%) and 45 (2.0%). It can be seen that HPV16/18 is still the dominant type, the 58/52 ratio is slightly higher than the global level, and 45 is slightly lower.
Based on the cumulative percentage of prevalence of HPV types in cervical cancer in China (Figure 1), it is predicted that the current 2vHPV and 4vHPV protection effects on cervical cancer in Chinese women are approximately 55.4 and 57.4%, while the protective efficacy of 9vHPV is approximately 75.4%. Both are lower than the current globally accepted protection rates of 71% and 90%, and are also lower than the 9vHPV based on global data. The protection rate for Asian women can reach 87.7%.
Figure 1 Cumulative percentage of prevalence of HPV types in cervical cancer in China
Summary: All current literature confirms that regardless of region and population, type 16 is the most common infection type in all cervical disorders, and its infection rate increases with the degree of disease. Type 18 is the second most prevalent cervical cancer in the world. In Asia, including China, the prevalence of 58/52 is slightly higher than the global level. Some studies in China have listed 58/52 as a high-risk category after 16 and their pathogenicity may surpass that of type 18.
HPV vaccine R & D: Road blocked and long
Previous studies have shown that 2vHPV and 4vHPV have partial protection against 31/45 (2vHPV protection efficacy better than 4vHPV), in addition to providing effective protection for the 16/18 highest-risk types. However, the two do not cover the relatively high prevalence of 58/52 in Asia. 9vHPV covers these five types. The WHO did not make any propensity for the three vaccines and considered that “there is no difference in the efficacy and effectiveness of the prevention of HPV16/18-associated cervical cancer, which can prevent most cancers.” According to the epidemic situation described in the literature, it seems that the protective efficacy of 9vHPV in Asian population can only reach the global protection level (about 70%) of 2vHPV or 4vHPV. However, unfortunately, first, the Chinese clinical trials of the 9vHPV vaccine have not been fully carried out; secondly, its current listing price in China is 1298 yuan/injection
nearly doubled from the previous two vaccines, and it will take approximately 3,900 yuan to complete the entire process. Inoculation is hard to come by.
2-valent? 4-valent? 9-valent? The HPV vaccine may not yet be “enough.” However, the number of vaccines is not as good as possible, and targeted protection can provide targeted protection. It is noteworthy that almost all the studies or reviews on HPV type epidemiological surveys in China and other Asian countries, the authors have unanimously called for more systematic and large-scale epidemiological studies in the future. The challenges of this kind of research are also quite large, especially in a country where the development of an area such as China is unbalanced, the population is highly mobile, and society is changing rapidly. The distribution of HPV epidemic status may change over time, and may vary depending on the region and its economic development. Only with full support of popular data, the research and development of Chinese vaccine companies will be more targeted, and the cost-effectiveness of Chinese people’s vaccination will also increase.