Cost-effectiveness analysis of rotavirus vaccination in China: Projected possibility of scale-up from the current domestic option

Diarrhea is the second leading cause of child mortality only after pneumonia in the world. Rotavirus is the most common cause of acute gastroenteritis (AGE) among children under 5 years of age and leads to substantial mortality and morbidities in both developing and developed countries [1]. Rotavirus causes approximately 111 million episodes of gastroenteritis requiring home care, leads to 25 million outpatients and 2 million hospitalizations [2]. Worldwide in 2008, diarrhea attributable to rotavirus infection resulted in 453,000 under-five deaths, accounting for 37 % of deaths attributable to diarrhea and 5 % of all deaths in children younger than 5 years [3]. In China, approximately 47.8 % of AGE hospitalization among under-five children attributed to rotavirus [4]. Although the overall annual number of deaths from rotavirus diarrhea decreased by 74 % during the past years, rural children suffer from rotavirus-related deaths 11 times greater than urban children (0.33 deaths vs. 0.03 deaths per live birth in 2012) [5]. There are annually 134,000 deaths of children under 5 years due to rotavirus infection and about 70 % of them living in the rural area [6]. Rotavirus diarrhea is currently no specific treatment. The main measures of oral rehydration salts (ORS) and intravenous fluids are to maintain electrolyte balance and to reduce the number of deaths caused by diarrheal dehydration. Therefore, vaccination against rotavirus serves as a principal strategy to reduce the disease burden.

There are two types in the world: Rotateq (a pentavalent vaccine manufactured by Merck, US) and Rotarix (a monovalent vaccine manufactured by GlaxoSmithKline, Belgium) and both have been approved in more than 100 countries, but not yet in China. Rather, a domestic Lanzhou Lamb Rotavirus vaccine (LLR) developed by Rotorway Lanzhou Institute of Biological Products has been licensed since 1998 and introduced into the second-category list of the national immunization program, which is not compulsory with free access and needs to charge a user-fee. The Rotarix vaccine is derived from a single human rotavirus strain (89–12; P[8] G1) that was attenuated by multiple passages in cell culture, divided into 2 doses of oral, interval 1 to 2 months [7]. The RotaTeq vaccine based on a parent bovine strain (WC3) is composed of 5 rotavirus strains that contains the types of rotavirus (G1–G4 and P1A) [7]. It need to take three doses of oral, each agent an interval of at least 1 month. The LLR vaccine is derived from a lamb rotavirus strain (P[12] G10),which induces generation the antigenic types of rotavirus (G1–G4), recommended to take one dose of oral annually [7]. The clinical research about 4000 infants and young children(aged 6 ~ 24 months), shows that the effectiveness of RV diarrhea protection was 78 % [8].

The World Health Organization (WHO) recommends introduction of the rotavirus vaccine into the routine immunization program, which can potentially bring health benefits including reduced hospitalization and mortality [9, 10]. Globally, rotavirus vaccination had been implemented in the national vaccination program of 75 countries at the moment. In China, a national routine immunization program is expected to reduce child mortality in rural areas and hospitalization in urban areas related to rotavirus. Although the national routine immunization program by RotaTeq and Rotarix have shown good cost-effectiveness in both developing and developed countries [11‐13], there was seldom economic evaluation to forecast the potential impacts of the two international vaccines with comparison to the domestic vaccine in China. Therefore, the aim of this study is to assess cost-effectiveness of possible options of rotavirus vaccination in China, in order to inform the decision making.

To best of our knowledge, this is the first economic evaluation to comprehensively compare all available options for rotavirus vaccination in China. In the hypothetical cohort of 100,000 infants, a national routine rotavirus vaccination by both Rotateq and Rotatrix showed high cost-effectiveness, and Rotateq reduced rotavirus disease burden most significantly, particularly among children aged between 6 months to 2 years and those living in the rural area. Considering the cost-effectiveness and the huge disease burden of rotavirus infection among children under 5 years, it is necessary to add vaccination against rotavirus into the current national routine immunization program.

Although LLR is the only approved vaccine in China and only Chinese-produced vaccines are regarded as a reliable supply for the national immunization program, the major problem of LLR is its complicated schedule, making it difficult to follow: one oral dose is given to the infant and children aged 2 to 35 months, followed by recommended yearly strengthening doses. Moreover, our study showed that compared to the two international vaccines, the effort of LLR to prevent and reduce rotavirus infection among children under 5-year is limited, particularly at children’s age between 0.5 to 2 years, at which 94 % of all episodes of rotavirus diarrhea occurred [4]. On the other hand, with the increase of age, the body's resistance gradually strengthens and the rate of rotavirus infection decreases [33]. Our findings is consistent with the report showing no significant protection among children vaccinated at 12–23 months of age [34]. For LLR, although earlier immunization and the administration of the full immunization regimen during infancy was recommended based on findings of a case-control study [28], the vague schedule makes confusion for parents and lead to difficulties in evaluation of the efficacy. Therefore, the current program is expected to scale up: based on the ICER shifting from LLR and health impacts on reduced disease burden of the two international vaccines, RotaTeq is dominating compared with Rotarix and expected to replace LLR. Besides the established safety and efficacy of the vaccine, the globally common rotavirus strains are the major cause of severe childhood diarrhea in China, suggesting that introduction of Rotateq vaccine would substantially reduce the disease burden [4]. In sensitivity analysis, infection rate affects the cost-effectiveness most significantly. After the introduction of rotavirus vaccines, rotavirus infection and hospitalizations among children has been reduced and in addition to such the direct effects, herd immunity also brings benefits to unvaccinated children [35]. However in China, due to relevantly low coverage, the impact of the vaccination on reduction of infection rate may be definitely limited, demonstrating that at the moment the national routine immunization against rotavirus with universal coverage would achieve good cost-effectiveness.

Without the national routine immunization program and public investment to reduce out-of-pocket payment to vaccination, it is extremely difficult to achieve universal coverage. The coverage of rotavirus vaccination is relevantly low, mainly attributable to the self-pay policy for the second-category vaccines, lack of knowledge of vaccination and rotavirus diseases among parents, and complicated and unclear schedule [36]. In China, vaccines are listed into two categories: the first category, freely and compulsorily provided, including bacillus Calmette-Guerin (BCG), hepatitis B vaccine, oral polio vaccine, measles vaccine and Diphtheria-Pertussis-Tetanus vaccine (DPT); and the second-category, which are totally self-paid. Under the current out-of-pocket payment policy for the second-category vaccines, the price for LLR is $24 per dose, and that for imported Rotateq or Rotatrix is uncertain and should be even higher, considering imported 7-valent pneumococcal vaccine costs as high as $140 per dose. Unlike most countries in the world, where financing for the immunization derived from either public funds or international donors and the user-fee is charged only a little, some vaccines addressing critical childhood diseases such as rotavirus infection and pneumonia are still self-paid and expensive, making profits for providers. As the results, the coverage of those vaccines is extremely low [36‐38], not comparable to that of DPT as well as other first-category vaccines, which is generally regarded as a principle indicator for universal coverage of the vaccination, more than 90 % of the target children in China [39].

Our study has several limitations. First, regarding efficacy, data were derived from other settings and not specific for Chinese population for the two international vaccines, because both have not been approved in China yet. As for LLR, a unique rotavirus vaccine only approved and applied in China so far, due to no randomized controlled trial (RCT), data were derived from meta-analysis of domestic observational studies. Second, we did not include herd immunity effect in the model due to low coverage of the vaccination, potentially underestimated the effectiveness when adding the rotavirus vaccine into the routine immunization program. Third, as a model for decision making at the national level, we did not specifically consider the epidemiological characteristics at different geographical regions within the country, as the incidence of rotavirus infection in low-latitude provinces tended to be higher and likely to be affected by living habits, living environments, education level and vaccine coverage [40], raising as a further issue after scale-up of the current program.

In China, rotavirus vaccination is highly cost-effective. To reduce disease burden of rotavirus infection, Rotateq is expected to replace LLR for the scale-up of the national routine immunization program, by increasing public investments and reducing costs of vaccines afforded by parents.