The cost-effectiveness of HPV vaccines: Global Evidence

When implementing vaccination strategies, health economic evaluation is an important indicator to consider alongside vaccine safety and efficacy. The economic evaluation of HPV vaccines is critical to improving the design of vaccination programs and optimizing resource allocation. The slow development of cervical cancer and other HPV-related diseases means the protective effect of the HPV vaccine can last for years. Researchers usually use mathematical models to estimate the long-term cost-effectiveness of vaccine interventions. One of the most commonly used health economics evaluation metrics is the incremental cost-effectiveness ratio (ICER), calculated as the ratio of incremental cost to incremental effect. The WHO recommends that an intervention strategy is not cost-effective if the ICER exceeds three times GDP per capita.

Table 1: HPV vaccine cost-effectiveness in selected high-income countries

Country	Year	Phase	Type of vaccine/ type of prevention	Fraction of coverage %	Age of inoculation	Price (USD) / dose	Vaccination dose	ICER/ QALY	GDP	ICER/ GDP	Cost-effectiveness level
United States	2015	dynamic	6/11/16/18	100	12			34.992	55.837	0.63	Very cost-effective
	2014	dynamic	16/18	100	12			37250		0.67	Very cost-effective
	2015	dynamic	16/18	100	12			73.483		1.32	Cost-effective
	2011	static	16/18	100	12	134	3	59.041		1.06	Cost-effective
	2015	static	16/18	100	35-45			166102		2.97	Cost-effective
	2004	dynamic	6/11/16/18	70	12	100	3	4.305		0.08	Very cost-effective
	2004	dynamic	16/18	70	12	100	3	13.087		0.23	Very cost-effective
	2003	mixing	6/11/16/18	70	12	300	3	14.226		0.25	Very cost-effective
	2003	mixing	16/18	70	12	300	3	20347		0.36	Very cost-effective
	2016	mixing	16/18	33	12-17			32.526		0.58	Very cost-effective
Canada	2008	static	6/11/16/18	100	12	120	3	23.351	44.310	0.53	Very cost-effective
	2008	static	16/18	100	12	120	3	35.358		0.80	Very cost-effective
	2009	dynamic	6/11/16/18	80	10	120	3	13.830		0.31	Very cost-effective
	2007	mixing	16/18	80	10	120	3	17.990		0.41	Very cost-effective
	2008	dynamic	16718	75	12	120	3	37.677		0.85	Very cost-effective
Britain	2013	dynamic	6/11/16/18	85	13	95	3	45760	41324	1.11	Cost-effective
	2004	static	6/11/16/18	80	12	100	3+1	47.602		1.15	Cost-effective
	2014	dynamic	6/11/16/18	80	12	95		12.483		0.30	Very cost-effective
	2014	dynamic	16/18	80	12	95		21504		0.52	Very cost-effective
Australia	2009	static	16/18	80	12	115	3	16710	45514	0.37	Cost-effective
Denmark	2014	dynamic	1618	85	12	20	3	14237	46.635	0.31	Very cost-effective
	2014	dynamic	6/11/16/18	85	12	20	3	5.748		0.12	Very cost-effective
Germany	2009	dynamic	16/18	50	12-17	110	3	15.434	47268	0.33	Very cost-effective
	2009	dynamic	6/11/16/18	50	12-17	110	3	7.835		0.17	Very cost-effective
Nether-land	2012	mixing	16/18	100	12-17	150.4	3	26865	48459	0,55	Very cost-effective
	2008	mixing	16/18	85	12	100	3	29.602		0.61	Very cost-effective
	2008	static	16/18	50	12	88.1	3	26199		0.54	Very cost-effective
	2008	static	6/11/16/18	50	12	88.1*	3	21459		0.44	Very cost-effective

Table 2: Cost-effectiveness of HPV vaccines in selected low- and middle-income countries and regions

Year	Country/region	Research perspective	Age of vaccination (years)	Cover rate (%)	CPD (dollar)	CYP ( dollar)	ICFR (USD / QALY)	ICER (Screen) (USD / QALY)	Core conclusion
2011	Thailand	SOC	12	80	2.3	11.5	Cost savings	–	ABCd
2012	Thailand	HCP	11	100	–	343.0	8.890	–	Abcd
2011	Thailand	SOC/ HCP	<12	100	430	1354.0	12642	16000	ABCd
2010	Malaysia	SOC	13	96	158.0	499.5	18603	–	ABCd
2010	Malaysia	SOC	15	96	52.4	183.7	4158	–	ABCd
2008	Vietnam	SOC	9	70	2.6	13.1	–	1554	ABCd
2008	India	SOC	<12	70	2.3	11.5	Cost savings	–	ABCd
2007	Brazil	SOC	9-12	70	6.5	32.7	Cost savings	–	ABCd
2012	Brazil	HCP	12	80	30.8	30.8	–	–	ABCd
2012	Brazil	HCP	12	85	15.2	–	–	–	Abcd
2007	Brazil	SOC	12	90	6.5	33.0	Cost savings	–	AbcD
2012	Brazil	HCP	12	90	5.0-120.0	25.0-556.0	–	–	abod
2008	Chile	HCP	12	100	70.0	355.0	–	33309	aBcd
	Poland				373.0	597.0	–	35602
2012	Peru	SOC	<12	82	70	34.9	11717	–	aBcd
2010	Lithuania	HCP	12	–	–	–	6172	–	Abcd
2008	Mexico	HCP	10	82	131.7	–	11927	11631	ABCd
2007	Mexico	HCP	12	80	–	–	–	4.502	aBcD
2012	East Africa	SOC	<12	70	0.6	5.8	2.926	–	ABCd
2009	South Africa	SOC/HCP	<12	80	120.0	804.0	–	1521	aBcd
2011	GAVI	SOC	12	70	2.0	11.5	230	–	Abcd
2008	GAVI	SOC	12	70	2.0	11.5	622	–	Abcd
2008	Latin America and the Caribbean region	SOC	9-12	70	5.0	28.8	–	392	aBcd
2008	Asian-Pacific region	SOC	<12	70	2.0	11.5	–	622	ABCd
2009	The whole world	HCP	12	100	–	4.7-10.9	131-408	–	ABCd

(Table 1&2 source: H.Q. Wang, F.F. Zhao, & Y. Zhao. (2019). Expert consensus on immunoprophylaxis for cervical cancer and other human papillomavirus-associated diseases. Chinese Journal of Preventive Medicine, 53 (8), 761-803. doi:10.3760/cma.j.issn.0253-9624.2019.08.001)

Tables 1 and 2 show the cost-effectiveness results of HPV vaccines in some high-income and low- and middle-income countries. Most of the studies found HPV vaccines cost-effective or very cost-effective, but due to differences in vaccine types, costs, target populations, model assumptions, parameters, and calculations, there are some differences in the incremental cost-effectiveness ratios observed in the studies. For future policy decision-making, it is necessary to consider the actual situation, particularly each country’s economic development level, vaccine types, and target population, to conduct specific analyses.

Incremental cost-effectiveness studies of HPV vaccination in high-income countries have shown that the bivalent and quadrivalent HPV vaccines are cost-effective for eligible women, even under different vaccination coverage conditions, whether in dynamic, static, or mixed studies. Although economic evaluation studies conducted in developing countries are limited compared with those in developed countries, growing evidence shows HPV vaccination is also cost-effective for eligible women in developing countries [1].

Health economics studies of HPV vaccination in China

Several studies have been conducted in China to develop dynamic and static models to measure the cost-effectiveness of HPV vaccination [2, 3]. Table 3 summarizes some of the economic evaluations of HPV vaccination conducted in China.

Table 3: Selected health economics studies of HPV vaccination in China

Author, year	Type of vaccine	vaccine price	site coverage	Vax age	Key findings
Mark, 2014 [4]	Three doses of bivalent vaccine	PAHO price is about $39 with an administered cost of $15	100%	12 years old	At a cost of approximately $3,210 per disability-adjusted life-year (DALY) reduction, vaccination is extremely cost-effective
Liu, 2016 [5]	Three doses of bivalent vaccine	Three doses cost 1900 CNY with an administered fee of 54 CNY	70%	12-55 years	Combined with cervical cancer screening, HPV vaccination is cost-effective before 23 years old for rural women and before 25 years old for urban women by age 25.
Zhang, 2016 [6]	Three doses of bivalent vaccine	247 CNY per dose	70%	12 years old	Very cost-effective when vaccine prices are 87-630 RMB (rural) and 87-750 RMB (urban)
Mo, 2017 [7]	Three vaccination schedules with 2/4/9-valent vaccines	Estimated at 2,000-3,000 CNY for three doses based on Hong Kong prices; Nine-valent vaccine price being 1.1 times of the 4-valent vaccine; Vaccination costs around US $4.84	20%	12 years old	Only when screening coverage increased to 60% ~ 70% did the HPV2 and screening combination strategy become economically feasible.   The combination of the HPV4/9 vaccine with current screening strategies for adolescent girls was highly cost-effective
Zou, 2020 [8]	Two doses of bivalent domestic vaccine	$99.80	70%	9-14 years	Using a willingness-to-pay threshold of 3 times China’s gross domestic product (GDP) per capita, vaccination combined with screening with rapid HPV testing every 5 years would be the most cost-effective intervention. When the total cost of vaccination is reduced to $50, the combination of vaccination and screening will be more cost-effective than screening alone, even at a willingness-to-pay threshold of 1x GDP per capita.

One study compared the cost-effectiveness of 61 intervention strategies, including a combination of various screening methods at different frequencies with and without vaccination and vaccination alone. The study found that HPV vaccination combined with HPV screening every five years was the most cost-effective compared to no intervention, with an ICER of $21,799 per quality-adjusted life year (QALY) (Figure 1).

Figure 1. Cost-effectiveness frontiers (Left) and cost-effectiveness acceptability curves (right) for all intervention strategies

The same study also evaluated the correlation between vaccine pricing and the cost-effectiveness of various interventions. The findings indicate that as vaccine prices decrease, cost-effectiveness improves (Figure 2). When the cost of vaccines is capped at less than $50 for two doses, any strategy integrating HPV vaccination for girls aged 9 to 14 with cervical cancer screening tends to be more cost-effective than screening alone at lower willingness-to-pay thresholds (around the per capita GDP). Furthermore, vaccination combined with a visual acetic acid screening method conducted every five years proved the most cost-effective approach. If the vaccine price is less than $10 for two doses, it becomes more cost-effective than screening alone at any willingness-to-pay threshold.

Figure 2. Cost-effectiveness acceptability curves for all strategies at various costs of vaccination

Key factors affecting HPV vaccines’ cost-effectiveness

Factors such as economic development level, vaccine type, the target population, and HPV infection prevalence could affect the vaccine’s cost-effectiveness outcomes. For example, a systematic review found that although there was heterogeneity in the methods used to measure cost-effectiveness, 10 of the 12 included studies concluded that the nine-valent HPV vaccine was cost-effective, and 2 studies did not [9]. Another systematic review indicated that it was unclear if the nine-valent vaccine was more cost-effective than the previously marketed bivalent and quadrivalent vaccines due to the unclear pricing of the nine-valent vaccine [10]. In these systematic reviews, researchers found that factors such as vaccine type, price, vaccination coverage, and target population are important parameters affecting the outcome of HPV vaccine cost-effectiveness analysis, with vaccine cost being the most important factor affecting the sensitivity analysis.

HPV vaccine types and price

The market-available vaccines target different HPV genotypes, and cost-effectiveness results vary due to differences in vaccine coverage and vaccine prices in different regions. For example, a Singapore study found that the ICER for bivalent vaccination was $10,392 Singapore dollar (SGD) SGD/QALY and that for quadrivalent vaccination was $9,071 SGD/QALY compared to no vaccination [11], while a UK study found that if the price per dose of the bivalent vaccine was 22-41% lower than that of the quadrivalent vaccine, the two could produce the same cost-effectiveness [12].

Age of vaccine recipients

Most studies concluded that HPV vaccination for girls aged 9-14 years and for women who are not yet sexually active are the most cost-effective interventions. In a systematic review of studies focusing on the cost-effectiveness of HPV vaccination for adult women aged 26 years and older, four of six studies found that HPV immunization was not cost-effective for adult women aged 26 years and older (ICER: $65,000-$192,000/QALY) [12]. One UK study showed that HPV vaccination in this population was only cost-effective vaccine price was below £20/dose and lifetime vaccine protection for women when no loss of immunity over time was considered [12]. A study from Lao PDR indicated that the vaccination could be cost-effective with a catch-up vaccination for women up to age 75 years, and the existing schoolgirls vaccination program was strongly subsidized [12].

Gender of vaccine recipients

HPV vaccination of males can indirectly reduce the rate of infection in the population with whom they have sex while reducing lesions such as genital warts. Some countries (e.g., the United States and Australia) have expanded the vaccination population to boys aged 9-14. However, evidence on the cost-effectiveness of expanding HPV vaccination to boys or conducting gender-neutral HPV vaccination programs is sparse and inconsistent.

A systematic review of articles published between 2005 and 2015 explored the economic evaluation of HPV vaccination for boys [13]. Among the 15 studies included, 53% showed that HPV vaccination among boys was cost-effective, and 7% found it was potentially cost-effective. In contrast, another systematic review covering 17 developed country studies came to the opposite conclusion, noting that there is little evidence that extending HPV vaccination programs to heterosexual men is cost-effective, but targeted vaccination of men having sex with men (MSM) is a cost-effective option (although the specific implementation of this strategy needs to be further explored) [14]. Similar conclusions were supported by another systematic review that included four studies that explored HPV vaccination in the MSM population, two of which found that HPV vaccination targeting the MSM group was cost-effective in preventing anal cancer-related disease [15]. Another recently published systematic review study included nine studies conducted in high-income countries (such as Spain, Germany, Italy, Belgium, the United Kingdom, and Canada), comparing the gender-neutral and female-only vaccination strategies. Four of the studies demonstrated a two-dose gender-neutral HPV vaccination strategy was more cost-effective compared to a female-only vaccination program [16].

Geographic Areas

Based on WHO recommendations, an intervention program is cost-effective when the cost per quality-adjusted life year (QALY) saved is less than three times the GDP per capita. Hence, the economic level of the geographic area targeted for vaccination impacts the cost-effectiveness calculation. A systematic review of 12 papers on the economic evaluation of HPV vaccines in low- and middle-income countries such as Laos, Malaysia, Iran, India, Thailand, South Africa, and Brazil shows that in 11 of the included studies, HPV vaccination among girls aged 9-14 years was cost-effective, Factors impacting cost-effectiveness include age, intervention coverage, and vaccine dose administered. Vaccination is cost-effective as a stand-alone intervention if coverage reaches 70-100% [1].

Implementation

A retrospective study focusing on HPV vaccination in low- and middle-income countries found that combining HPV vaccination with visual inspection with acetic acid (VIA) screening was the most cost-effective intervention compared to HPV vaccination or screening alone [17]. In addition, increasing evidence supports that the antibody titers produced after 2-dose bivalent vaccination were comparable to the 3-dose schedule, while a Malaysian study predicted a savings of nearly $57.29 million by applying a 2-dose schedule [18]. New evidence also suggests that HPV single-dose regimens are comparable to two- and three-dose regimens. Although there is a lack of evidence on the single-dose regimen’s long-term protection, the World Health Organization revised its HPV vaccine position paper in December 2022 to recommend a single-dose regimen for females between the ages of 9 and 20 years [19].

A modeling study showed that two doses of routine vaccination of 14-year-olds would be the best cost-saving strategy for future national immunization programs, compared with no vaccination, in a supply-constrained and on-label use scenario (NND:150-220, net cost savings: $15,164 million – $22,034 million, ROI: 7-14, depending on vaccine type). The study also found that if the WHO-recommended single-dose vaccination schedule were approved in China, redistributing the remaining second dose of vaccine in the routine vaccination cohort to add a catch-up vaccination for the 20-years-old would be the most efficient strategy (NNDs:73-107), and would be even more cost-saving compared to implementing routine single-dose vaccination for 14-year-olds only (Net Cost Savings: US$4,127 million-US$6,035 million, ROI:19-37) [20].

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