Human papillomavirus vaccination at the national and provincial levels in China: a cost-effectiveness analysis using the PRIME model

Human papillomaviruses (HPV) are a large family of epitheliotropic DNA tumor viruses [1]. Approximately 80% of sexually active women are infected with at least one HPV subtype at some point in their lifetimes [2]. Continuous infection with a high-risk HPV subtype is the main cause of cervical cancer [3]. The HPV high-risk subtypes include HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68. Among them, HPV 16 and 18 are highly associated with cervical cancer, and cause about 75% of cervical cancers worldwide [4]. Cervical cancer has become a global public health problem. It is the fourth most common cancer in women. In 2020, an estimated 604,000 women worldwide were diagnosed with cervical cancer, and an estimated 342,000 women died. In China, 110,000 new cases of cervical cancer and 59,000 deaths were reported, therefore having the second-largest burden of cervical cancer in the world [5]. Cervical cancer in China accounts for 18% of the worldwide cervical cancer incidence and 17% of cervical cancer deaths.

As the only cancer that has clear causes, and can be prevented and treated, it is expected to be fully eradicated. Therefore, promoting cervical cancer prevention is of great importance. Vaccination is an effective measure against HPV infection and to reduce cervical cancer incidence. Three prophylactic HPV vaccines are currently available worldwide, including the bivalent, quadrivalent, and 9-valent HPV vaccines [6]. The World Health Organization (WHO) recommends using HPV vaccination as part of routine vaccination in all countries [7]. HPV vaccines are currently used in 129 countries worldwide to prevent HPV-related diseases [8] and have been introduced into the national immunization plans (NIP) of 74 countries [9]. However, the HPV vaccination is not included in China’s NIP.

China has approved HPV vaccines since 2016 [10], including the Cervarix® (GlaxoSmithKline Inc.), Cecolin® (Wantai BioPharm), and Gardasil® and Gardasil® 9 (Merck & Co., Inc.) vaccines. It has a large population and unbalanced economic development among regions. The payment methods for obtaining HPV vaccination services are different among various provinces. Currently, there are three main payment methods for HPV vaccines in China: 1) residents are vaccinated against HPV at their own expense, 2) target populations get free HPV vaccination, such as in Ordos, Inner Mongolia, and Xiamen [11, 12], and 3) medical insurance does a co-payment with residents for the vaccine. However, in Guizhou Province, HPV vaccination is paid through the balance of the employee’s personal medical insurance account [13]. The local government-led free HPV vaccination program is rare in China. Most provinces still need residents to get vaccinated at their own expense, and residents experience a heavy burden of paying for the HPV vaccine. In 2019, China’s Vaccine Management Law authorized provincial governments to increase the types of vaccines available for immunization programs in accordance with the needs of disease prevention and control in their administrative regions [14]. However, China still lacks the economic evidence for HPV vaccine cost-effectiveness at the national and provincial levels. To provide information that could affect policy-making decisions to expand the use of HPV vaccines, we evaluated the economics of all valent HPV vaccines available in the Chinese market at the national and provincial levels.

Cost-effectiveness analysis was used to assess the economics of HPV vaccination at a national level and in 31 provinces in Mainland China. From the perspective of the health system, we compared the final cost and health effects of the two strategies of vaccinating and not vaccinating HPV vaccine for women of the target age. The HPV vaccines available in the Chinese market include the domestic bivalent, imported bivalent, imported quadrivalent, and imported 9-valent HPV vaccines. Lifetime effects after vaccination were estimated using the Papillomavirus Rapid Interface for Modeling and Economics (PRIME) model. The results of the economic evaluation were expressed by incremental cost-effectiveness ratios (ICER), and ICER indicators that were constructed based on the disability-adjusted life years (DALYs) were reported. The evaluation assumed that the target population had not been infected with HPV prior to vaccination. Stata15.0 was used to draw a map of China to show the cost-effectiveness results. Sensitivity analysis was conducted to test the impact of six parameters, including target age, discounted rate, vaccine efficacy, procurement, transportation and management cost, and cervical cancer treatment cost, on the robustness of the model results; the results are shown in a tornado diagram. The cost parameters used in the model have been adjusted to 2019 according to the average exchange rate of the RMB against the US dollar and the consumer price index [15]. To eliminate the effect of the time value of money, costs were discounted at a rate of 3%, as recommended by the WHO Guidelines on Health Economics [16]. This study is reported as per the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) guideline (Additional file 1: Table S1) [17].

This study evaluated the cost-effectiveness of HPV vaccination at the national and provincial levels in China compared with no HPV vaccination. Compared with not vaccinating with the HPV vaccine, vaccinating with the HPV vaccine can reduce the incidence of cervical cancer cases in women of all ages. When HPV vaccine coverage reached 80%, for the target population in 2019, introducing bivalent, quadrivalent or 9-valent HPV vaccines into the immunization program could have averted more than 12,545–28,140 cervical cancer cases and approximately 5109–11,459 deaths. Once the HPV vaccine is included in the immunization program, 80% vaccine coverage can be expected. In 2020, Erdos, China, implemented a program for free HPV vaccination for girls aged 13–18 years, and the vaccination rate of the target population reached 85% [28]. The incremental cost of using the domestic bivalent, imported bivalent, imported quadrivalent, and imported 9-valent HPV vaccines for each DALY saved is US$ 7213, US$ 13,074, US$ 18,165, and US$ 16,939, respectively. With 3 times GDP per capita as the threshold, HPV vaccination is cost-effective nationwide. This result is consistent with the research results of HPV vaccination in Vietnam, Australia, South Africa, and other countries [29‐31].

With the 3 times per capita GDP as the threshold, the usage of the domestic and imported bivalent HPV vaccines in 31 provinces is cost-effective. Among them, the domestic bivalent vaccine is very cost-effective in 22 of the 31 provinces due to its price advantage. The imported bivalent HPV vaccine is very cost-effective in six economically developed regions (per capita GDP in 2019 > US$ 13,655). Except for Heilongjiang and Gansu, usage of the imported quadrivalent and 9-valent HPV vaccines in other provinces was cost-effective. In the deterministic sensitivity analysis, when the most model parameters were changed, HPV vaccination was still cost-effective.

The net cost of the 9-valent HPV vaccine was higher. However, the 9-valent HPV vaccine protects against more HPV subtypes, prevents more morbidity, and saves more treatment costs than the other vaccines. The reduction in the cost of the 9-valent HPV vaccine can further reduce its net cost. For cervical cancer, bivalent and quadrivalent HPV vaccines have the same protective effect. Currently, the net cost depends on the vaccine price. The bivalent HPV vaccines, especially the domestic bivalent HPV vaccine, have the greatest price advantage and the lowest net cost.

There are provincial differences in the economics of HPV vaccination. The increased cost is either completely worth it, or it is accepted that it is affected by the ICER value and threshold. The ICER values for the domestic bivalent HPV vaccine in Gansu and Beijing were 7138 (US$/DALY gained) and 7254 (US$/DALY gained), respectively; the per capita GDP was US$ 4784 and US$ 23,811, respectively. In Beijing, even if the 9-valent HPV vaccine was used at its highest price, its ICER value was still less than double the per capita GDP. In Gansu, even if the domestically made bivalent HPV vaccine was used at its lowest price, its ICER value was only less than 3 times the per capita GDP. The level of economic development in each province will affect its ability to pay for HPV vaccines. Including the HPV vaccine in the scope of medical insurance payments or state subsidies can increase the availability of HPV vaccines in economically disadvantaged areas.

This study had some limitations. First, our study only considered the protective effect of HPV vaccines on cervical cancer and did not consider the protective effect of HPV vaccines on genital warts, oral cancer, and other diseases, which may have caused the ICER to be overestimated. Second, we assumed that the target age population had not been infected with HPV when entering the model, but there may have been people who were infected with HPV. Third, the impact of cervical cancer screening and HPV transmission on the incidence of cervical cancer was not considered, and the herd immune response was also not considered. Fourth, the vaccine dropout rate, due to side effects after vaccination, was not considered.

The HPV vaccine being included in the immunization program can reduce the burden of cervical cancer. As a country with a large population, to help accelerate the elimination of cervical cancer, China should include the HPV vaccine in its immunization program as soon as possible. From a provincial perspective, Guangdong, Shandong, Henan, Sichuan, and Jiangsu have benefited from the preventable cervical cancer incidence and avoidable cervical cancer deaths after HPV vaccination, and consideration should be given to including the HPV vaccine in their immunization programs as soon as possible. In various provinces, there is a large gap in the ability to pay for HPV vaccines. To improve the accessibility of HPV vaccines, more attention should be given to economically disadvantaged areas.