Integrative literature review on human papillomavirus vaccination recommendations in national immunization programs in select areas in the Asia-Pacific region

ABSTRACT

There is limited literature on current human papillomavirus (HPV) vaccination in the Asia-Pacific region. This integrative literature review was conducted to describe HPV vaccination programs in Hong Kong, Indonesia, Japan, South Korea, Malaysia, the Philippines, Singapore, Taiwan, Thailand, and Vietnam. Program descriptions, recommendations, f unding, and coverage data were extracted. Twenty-five citations were included. As of 2022, eight of the 10 areas of interest include HPV in their national immunization program (NIP) for school-aged girls; full implementation in Indonesia is expected in 2023 whereas Vietnam’s NIP does not include HPV. Singapore also includes HPV vaccination for women (18–26 years). None of the HPV vaccination programs include males. In most areas (n = 7), programs include only one vaccine option. While female HPV NIPs are present in the Asia-Pacific region, opportunities remain to strengthen NIPs in broader populations (e.g., males, catch-up cohorts) to expand public health impact and provide gender equity in HPV vaccination.

KEYWORDS:

• Asia
• human papillomavirus
• immunization
• papillomavirus vaccines
• integrative review

Introduction

Human papillomavirus (HPV) is one of the most common sexually transmitted infections.^1–3 There are more than 100 types of HPV, including low-risk types (HPV 6 and 11) that are associated with benign genital warts and recurrent respiratory papillomatosis and high-risk types (HPV 16, 18, 31, 33, 45, 52, and 58) that account for most cases of cervical, head and neck, penile, and anal cancers.⁴

Three types of HPV vaccines are available worldwide.⁵ The bivalent (2vHPV) vaccine protects against HPV types 16 and 18, which are responsible for approximately 70% of cervical cancer cases globally. The quadrivalent (4vHPV) vaccine protects against HPV types 16 and 18 as well as HPV 6 and 11, which are responsible for 90% of genital warts cases worldwide. The nonavalent (9vHPV) vaccine protects against the types in the 4vHPV vaccine and five additional oncogenic HPV types (HPV 31/33/45/52/58), allowing for direct protection against nine HPV types responsible for 90% of genital warts and an additional 20% of HPV-related cervical cancers.⁵

While a declining trend in the incidence/prevalence of HPV infection and HPV-related diseases has been observed since the introduction of HPV vaccinations for girls in many countries,^6,7 the burden of HPV-related diseases among men remains.⁸ Direct protection against HPV infection and associated diseases in males may further reduce HPV-related diseases in females.⁹ In recent years, several countries have introduced gender-neutral vaccination programs into their national immunization schedule to provide greater and more equitable prevention of HPV-related diseases in their populations.^10–14

Although the Asia-Pacific (AP) region contributes more than half of the global burden of HPV-related disease,¹⁵ literature on current HPV vaccination programs in the region is limited. The objective of this integrative literature review was to provide data on the current status of HPV vaccination programs (recommendations, funding, coverage) in select areas in the AP region.

Methods

Search strategy and data sources

An integrative literature review was conducted to identify publications regarding HPV vaccination programs in select AP areas (Hong Kong, Indonesia, Japan, South Korea, Malaysia, Philippines, Singapore, Taiwan, Thailand, and Vietnam). Journal articles and conference abstracts published from January 1, 2000, to February 25, 2022, in MEDLINE and Embase were searched via ProQuest (Supplemental Table S1) using a search strategy created by the study authors. Additional searches were conducted within national government/ministry of health websites and gray literature sources for each of the countries of interest.

Study selection and data extraction

Literature reporting vaccination programs from Hong Kong, Indonesia, Japan, South Korea, Malaysia, the Philippines, Singapore, Taiwan, Thailand, and Vietnam was included. Mainland China was not included in this review as literature from this area will be summarized in a separate publication by the study authors. Studies were eligible for inclusion if they included data on the current HPV vaccination programs in each area (including national immunization program [NIP] start year, f und ing body, vaccinations, recommendations, dosing schedule, and coverage). Publications in non-English languages were translated using native speakers or Google. Two reviewers independently screened the titles and abstracts of identified citations and selected full-text articles for potential inclusion. Reviewers extracted relevant data from each included publication; data were reconciled to assure accuracy. Relevant data were extracted into a Microsoft Excel database.

Results

No data were identified from 3050 publications from MEDLINE and Embase. Of the 32 publications identified in the gray literature, 25 citations regarding NIPs and HPV vaccine recommendations available in the selected AP areas were included (Figure 1).

Figure 1. PRISMA diagram.

Table 1 outlines the NIP programs among the select AP areas. Vaccinations for HPV are included in the NIPs for school-aged girls (primarily 9–14 years of age) without catch-up in 80% (8/10) of the included AP areas: Hong Kong, Japan, Malaysia, the Philippines, Singapore, South Korea, Taiwan, and Thailand. Vaccinations for HPV are currently not part of the NIP in Vietnam. Indonesia is in an introductory phase of adding the HPV vaccine to the NIP, with implementation planned in all provinces and districts/cities in 2023.⁴¹ Additionally, Singapore has a National Adult Immunization Schedule that includes women between 18 and 26 years old. Japan and South Korea have catch-up cohorts for some adult women as well (Table 1). Males were not included in HPV vaccination programs in any of the 10 included areas.

Table 1. National immunization programs for HPV.

Area/Country	NIP Start Year	F und ing Body	Vaccines	Recommendation	Dosing Schedule
Hong Kong^Citation16,Citation17	2019/2020 school year^a	DH	Gardasil 9 (9vHPV)	2 doses for female students in Primary 5 and 6	First dose: Primary 5 Second dose: Primary 6
Indonesia^Citation18,Citation19	2023^b	MOH	Gardasil (4vHPV)^b	2 doses for female students in grade 5 (11 years old) and 6 (12 years old)^b	First dose: Grade 5^b Second dose: Grade 6^b
Japan^Citation20,Citation21	2013^c	MHLW	Gardasil (4vHPV)	3 doses for female students equivalent to 6th grade of elementary school to 1st grade of high school Among women whose birthdays are from April 2, 1997, to April 1, 2006, those who missed the vaccination during the target age for regular HPV vaccine vaccination	3 doses 2 inoculations with 1-month interval, and the third inoculation with an interval of 6 months from the first inoculation
Malaysia^Citation22,Citation23	2010	MOH	Cervarix (2vHPV)	2 doses for female students at 13 years old	Dose 1 and dose 2 at 13 years old
The Philippines^Citation24,Citation25	2015	DOH	Gardasil (4vHPV)	2 doses for females aged 9–14 years old, grade 4 school-based program	Dose 2 given 6 months after first dose
Singapore^Citation26–31	2010 (NCIS), 2017 (NAIS)	MOH	Cervarix (2vHPV)	School-based program 2 doses for female students between 12 and 14 years old	School-based program First dose at 12–13 years and second dose at 13–14 years
				Outside of school-based program Age-appropriate doses for females between 9 and 26 years	Outside of school-based program Females aged 9–14 years: 2-dose series Females aged 15–26 years: 3-dose series
South Korea^Citation32–35	2016^d	KDCA	Cervarix (2vHPV), Gardasil (4vHPV)	2 doses for female students at 12 years old Catch-up cohort: Females aged 13–17 years and underprivileged women aged 18–26 years	Females aged 12–14 years: 2 doses (6 months apart between first and second dose) Females aged 15–26 years: 3 doses (2vHPV: 0, 1, 5 months; 4vHPV: 0, 2, 6 months)
Taiwan^Citation36,Citation37	2011 (pilot program)^e	HPA	Cervarix (2vHPV); Gardasil 9 (9vHPV) from September 2022	2 doses for females aged 9–14 years old 3 doses for females aged 15 years and above	School-based program: Females aged 13–14 years: 2 doses (second dose given 6 months after first dose)
Thailand^Citation38–40	2017	NHSO	Gardasil (4vHPV)	2 doses for female students in grade 5	First dose: 11 years old Second dose: 6 months after first dose
Vietnam	NA	NA	NA	NA	NA

Abbreviations: 4vHPV, quadrivalent HPV vaccine; 9vHPV, nonavalent HPV vaccine; 2vHPV, bivalent HPV vaccine; DH, Department of Health; DOH, Department of Health; HPA, Health Promotion Administration; KDCA, Korea Disease Control and Prevention Agency; MHLW: Ministry of Health, Labour and Welfare; MOH, Ministry of Health; NA, not available; NAIS, National Adult Immunization Schedule; NCIS, National Child Immunization Schedule; NHSO, National Health Security Office.

^aChildhood Immunization Program.

^bThe HPV vaccine was not introduced in the full National Immunization Program of Indonesia until the end of 2022.

^cThe HPV vaccine was temporarily withheld from being actively recommended in Japan from June 2013 until April 2022.

^dThe HPV vaccine NIP in South Korea started with 12-year-old females in 2016 and was expanded in 2022 to include the catch-up cohort (females aged 13–17 years and underprivileged women aged 18–26 years).

^eThe HPV vaccine NIP in Taiwan started with 2vHPV in specific selected cities.

As of 2022, of the nine AP areas with HPV vaccines as part of their NIPs (Hong Kong, Indonesia, Japan, Malaysia, the Philippines, Singapore, South Korea, Taiwan, and Thailand), bivalent and quadrivalent vaccines were utilized in 4/9 AP areas and 5/9 AP areas, respectively, while nonavalent vaccine was included in 2/9 areas. Moreover, one vaccine option is included in the NIP for seven areas: 9vHPV in Hong Kong and Taiwan (for Taiwan, this replaced 2vHPV in September 2022); 4vHPV in Japan, the Philippines, and Thailand; and 2vHPV in Singapore and Malaysia. The NIP in South Korea includes 2vHPV and 4vHPV. In 5/9 areas, the NIP dosing schedule mentioned girls receiving the second dose 6 months after the initial dose.

Discussion

Our review adds to the currently available literature by providing more recent data on NIPs for HPV in the AP region. The global burden of cervical cancer, as measured by the number of cases and deaths, is highest in Asia.⁴² HPV vaccination is recognized as one of the most effective strategies for control of HPV-related cancers.⁴² As of 2022, the available HPV vaccination programs in the AP region are often for a single sex (females) and single cohort (without multiple year catch-up programs), and few have existed for more than 10 years.

The impact of HPV vaccination on cervical cancer rates is already being seen in high-income European countries with early adoption of HPV vaccination programs, such as Sweden (2007), Denmark (2008), and the United Kingdom (2008).^43–45 In Malaysia, which was one of the earliest AP countries to introduce an NIP for HPV (2010), there are early indications that the HPV NIP may be reducing the burden of cervical cancer as well. In a cross-sectional study comparing HPV prevalence rates in women, there was a 91% decline in bivalent vaccine–targeted HPV prevalence (HPV16/18) and 87% reduction in quadrivalent vaccine–targeted HPV prevalence (HPV6/11/16/18) among young women aged 18 to 24 years from 2019 to 2020 compared to those aged 18 to 24 years from 2013 to 2015.⁴⁶

In contrast, suspension of proactive recommendations for HPV vaccination in Japan from June 2013 through November 2021 caused vaccination rates to plummet to less than 1%, which has led to a significant increase in HPV infection rates in young Japanese women.^47,48 The HPV vaccine crisis has been estimated to increase the future incidence and death from cervical cancer in Japan, including an estimated 5000 to 5700 additional deaths, and recent studies have shown catch-up vaccination is unlikely to be able to redress the full impact of the vaccination gap.^49–51

These data highlight the beneficial impact HPV vaccination could have on the burden of HPV-related disease in the region. Future research should continue to compare results before and after the introduction of HPV vaccinations in NIPs in the AP region. However, such comparisons would require registry and surveillance systems to see the impact of the HPV NIPs. Moreover, this review provides a snapshot of HPV NIP programs in the AP region, especially among middle-income countries (MICs). However, many HPV programs are renewed annually, and despite achieving targets of HPV vaccine availability to adolescent girls, lower MICs in particular face many challenges in implementing and sustaining these programs, including vaccine supply constraints, confusion on eligibility, access issues, the political climate, and rumors/misinformation.⁵¹

Limitations of this review must also be noted. First, this review was conducted in February 2022; government vaccination recommendations may have changed since the review was conducted. Second, this review looked at specific AP areas, which may not align across the entire AP region. Future reviews could focus on other countries not included in this review, including Mainland China. The literature search in MEDLINE and Embase did not yield any eligible articles, and relevant data were identified through the gray literature search of government websites. As the objective of this review was to summarize the most current recommendations, f und ing, coverage, and dosing schedules in NIPs, the data in the identified MEDLINE/Embase studies were largely outdated compared with those found on national/global health websites. Future research on this topic could potentially incorporate additional databases (e.g., Global Health) that may provide additional literature not captured in MEDLINE or Embase.

The epidemiologic and economic burdens of HPV are well described in women, but the full burden may be underestimated due to the limited availability of data in men. Most of the AP areas included in our analysis have female NIPs, but none include males in HPV vaccination programs. Reduction of HPV-related disease in men with HPV vaccination has been seen in real-world studies and clinical trials.^52–54 Countries in the AP region should therefore consider strengthening their NIPs by introducing male vaccination to further reduce female HPV-related disease burden and provide direct protection against HPV to males who are vulnerable to HPV infection and associated diseases.^8,9 Across all genders, there is also a need to increase awareness of HPV vaccination among young adults. In a 2021 systematic literature review on vaccine attitudes among adolescents in Asia, HPV and vaccine awareness was generally low across 20 publications, and included publications demonstrated high variability in the percentage of respondents who intended to be vaccinated against HPV (range: 38% to 95%).⁵⁵

The ongoing COVID-19 pandemic has caused a sustained drop in childhood immunizations worldwide, including HPV.⁵⁶ It has highlighted the fragility of the current immunization programs: According to the World Health Organization, over one-quarter of the HPV vaccine coverage that was achieved globally in 2019 had been lost by 2022, and 3.5 million more children missed the first dose of the HPV vaccine compared to 2019.⁵⁶ More effort is needed to increase the resilience of HPV vaccination programs. In addition to addressing pandemic-related disruptions, such as the effect of school closures on school-based NIPs, countries must intensify catch-up vaccination efforts to reach missed children. Gender-neutral vaccination programs could also increase the resilience of HPV vaccination programs and accelerate HPV prevalence reduction.⁵⁷ All these approaches will require political commitment from national governments and increased domestic resource allocation to strengthen and sustain NIPs.⁵⁶

In 2020, the World Health Organization started a global initiative to eliminate cervical cancer. The goal is to reduce cervical cancer incidence to below four cases per 100,000 women-years in every country.⁵⁸ Results of a recent modeling study suggest that high HPV vaccination coverage is the most powerful intervention to reduce the burden of HPV and could lead to cervical cancer elimination in most low-income and lower MICs by the end of the century.⁵⁹ Strong political commitment to primary HPV cancer prevention could make elimination an achievable goal in the AP region.

Conclusions

While HPV NIPs are present in females in the AP region, opportunities remain to strengthen NIPs in broader populations (e.g., males, catch-up cohorts) to expand public health impact and provide gender equity in HPV vaccination. Highly populous countries with high disease burden within the region, such as Indonesia and Vietnam, have not yet introduced full NIPs for HPV. A multi-stakeholder effort and political will are required to reduce the disease burden in these countries. As HPV vaccination programs in the AP region continue to grow, government commitment is also required to start planning how to track the real-world impact of vaccination.

Author contributions

Conception and design of the study: PJL, WP, YHW, IS

Acquisition of data: OZ, AS, FD, MB

Analysis and interpretation of data: OZ, AS, FD, MB, YHW, IS

Drafting the manuscript: OZ, MB

Revising critically for important intellectual content: PJL, WP, YHW, IS

Final approval of version to be submitted: All authors

Acknowledgments

Medical writing and editorial support were provided by Catherine Mirvis from OPEN Health, Bethesda, MD, and funded by the study sponsor.

Disclosure statement

PJL: Received study f und ing from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. WP: Received study f und ing from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and from GSK. IS: Employee of MSD Thailand. YHW: Employee of MSD Taiwan. OZ, FD, AS, MB: Employees of OPEN Health.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2024.2362449

Additional information

Funding

This study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.