Gender-Neutral HPV Vaccine in India; Requisite for a Healthy Community: A Review

Abstract

Human papillomavirus (HPV) affects approximately 80% of individuals, irrespective of gender, and is implicated in various cancers. Existing HPV vaccines, while safe and effective, do not sufficiently protect males when administered solely to females. This review, triggered by the urgent need to address this gap and reduce the associated stigma, aims to evaluate the introduction of a gender-neutral HPV vaccine, GARDASIL-9, in India. The primary objective is to assess the necessity and feasibility of incorporating the gender-neutral HPV vaccine into India’s national immunization program. This integration is crucial to ensure equitable access for all children and to mitigate the substantial burden of HPV. A literature search was conducted using databases such as Google Scholar, PubMed, government websites, and relevant publications. Keywords included “gender-neutral vaccine”, “HPV vaccine”, and “Indian population”. The central research question guiding this review is: How necessary and feasible is the inclusion of a gender-neutral HPV vaccine in India’s national immunization schedule to ensure equitable access for all children and reduce the HPV burden? The review inclusion criteria comprised studies addressing the prevalence of HPV infections, HPV vaccination awareness among both genders, the cost-effectiveness of gender-neutral vaccines, current HPV vaccination status, and future perspectives specific to India. Studies not meeting these criteria were excluded. The review highlights that introducing a gender-neutral HPV vaccine in India is imperative. Including males in vaccination efforts significantly reduces the overall disease burden and helps in reducing the stigma associated with HPV. A comprehensive vaccination program, bolstered by education and awareness campaigns, and its inclusion in the national immunization schedule is essential. This approach ensures equitable access to the vaccine for all children, fostering a healthier community, preventing HPV-related cancers, and enhancing public health outcomes in India.

Plain language summary

HPV is contracted by approximately 80% of people, regardless of gender, and is linked to various cancers. Existing HPV vaccines are safe and effective, but female vaccination alone is insufficient to protect men. The introduction of a gender-neutral HPV vaccine, GARDASIL-9, in India aims to protect both young women and boys from nine HPV serotypes. This study evaluates the urgency of including the vaccine in India's national immunization schedule to reduce the significant HPV burden. A literature search was conducted on Google Scholar, PubMed, government websites, and relevant publications using keywords like “gender-neutral vaccine,” “HPV vaccine,” and “Indian population.” The review focused on the HPV vaccine situation in India and related studies. Key findings were grouped into following themes: (1) Prevalence of HPV infections, (2) HPV vaccination knowledge among women and men, (3) Cost-effectiveness of gender-neutral HPV vaccines, (4) HPV vaccination status, and (5) Future perspective. A gender-neutral HPV vaccine in India is vital to combat HPV-related cancers. Including boys and men in vaccination efforts reduces disease burden. A comprehensive program with education and awareness campaigns fosters a healthier community, preventing HPV-related cancers and improving public health in India.

Introduction

Despite the multiplicity of cancer-related risk factors, infections with bacteria and viruses are known risk factors. Infections caused by viruses and bacteria are recognized as risk factors for cancer. ¹ The most common infections linked to cancer are H. pylori (36.3%), Human papillomavirus (HPV) (31.1%), hepatitis C (7.1%) and hepatitis B (16.3%). Of the over 200 types of HPV, 14 are considered high risk for cancer and 16 and 18 HPV types are responsible for the majority of HPV-related cancers, including 70% of cervical cancers and precancerous lesions. HPV can be transmitted through intimate or skin-to-skin contact. ² Approximately 80 percent of people, regardless of gender, will contract HPV in their lifetime. It is a common infection that is usually contracted shortly after beginning any kind of sexual activity. ³ It is important to note that HPV infection is responsible for nearly all cases of cervical cancer. HPV has been linked to a variety of cancers in men and women, such as vaginal, vulvar, anal, penial, and head and neck cancers, as well as genital warts.^4,5 Approximately 70% of vaginal and vulvar cancers, more than 90% of anal and cervical cancers, and more than 60% of penile cancers are thought to be caused by HPV. Additionally, around 70% of oropharynx cancers may also be caused by HPV, and the virus is estimated to be responsible for 5% of all cancer cases in the world. ³ Estimates show that each year there are 137 new cases of anogenital warts per 100,000 men and 121 per 100,000 women, with a prevalence of 0.18 percentage in women and 0.15-0.18 percentage in men.^4,5 High-risk HPVs are responsible for approximately 5% of all cancer cases worldwide. In 2018, it was estimated that there were around 570,000 women and 60,000 men infected with HPV and that 311,000 women died from cervical cancer that same year. ⁶ The highest incidence of HPV infection in males was identified among men who have sex with other men and are also infected with Human Immunodeficiency Virus (HIV). ⁷

Since their approval in 2006, the 9-valent, bivalent and quadrivalent HPV vaccines have been proven to be safe, highly effective in inducing immunity, and capable of providing direct and indirect protection against HPV and its related outcomes. ⁸ By the conclusion of 2008, approximately 25% of high- and upper-middle-income countries had established national HPV vaccination programs, compared to no such initiatives existing in low- and lower-middle-income countries. ⁹ According to the World Bank, 86 countries around the world had adopted an immunization schedule for the HPV vaccine as of October 2016. The majority of these countries, 74, were classified as upper middle-income countries, while the remaining 12 countries were classified as lower middle-income countries. This shows that the majority of HPV vaccine introductions were concentrated in high-income countries. ¹⁰ During the years 2013 to 2016, around 20 eligible countries were able to get help from Gavi, the Vaccine Alliance. The extent of coverage attained by national programs in different nations has varied greatly. ¹¹ Successful programs in high-income countries (HICs), such as those in Scotland and Australia, have covered more than 80% of the targeted girls with the whole immunization schedule. Although fewer national programs were implemented in lower-income countries (LICs) or lower-middle-income countries (LMICs) than in HICs/upper-middle-income countries (UMICs), the coverage achieved through their national programs has been relatively high. ¹²

It is evident that female vaccination is not enough to provide sufficient protection against HPV infection in men. Women who have not been vaccinated, either due to age or lack of access to the vaccine, are still at risk of contracting the virus and passing it on. Men are particularly vulnerable to infection, as even in countries with high rates of female vaccination, males are not protected. Additionally, men who engage in same-sex relationships are even more exposed, making immunization against HPV for both genders (“gender-neutral” or “universal” vaccination) a better option. Universal or gender-neutral vaccination leads to a higher degree of safety for all people, as it decreases the transmission of HPV between males and females, as well as among individuals in same-sex relationships, and results in “herd protection.” About half of the nations in the European region as defined by the World Health Organization (WHO) have implemented HPV vaccination initiatives for both men and women. ¹³ These countries include Finland, France, Hungary, the Netherlands, Poland, Portugal, Slovenia, and Sweden. Beyond Europe, nations such as Argentina, Australia, Barbados, Bermuda, Brazil, Canada, Guyana, New Zealand, Trinidad and Tobago, and the United States have implemented universal HPV vaccination programs as well. Certain countries, such as France and the United Kingdom, have also started targeted campaigns aimed at high-risk groups like male sexual partners and sex workers, as well as men who have sex with other men, to raise awareness about the benefits of HPV vaccination. ¹⁴

The first-ever gender-neutral HPV vaccine, GARDASIL-9, was introduced in India on September 20, 2021. The goal of this program is to safeguard both young women aged 9-26 and boys aged 9-15 years from nine different serotypes of the human papillomavirus (HPV), reducing the overall HPV burden among men and women who are susceptible to HPV-associated infections. Even though HPV-related infections among Indian women account for a significant proportion of the HPV burden among the Indian population, the proportion of Indian men infected with HPV and associated diseases also plays an important role in estimating overall prevalence and incidence of HPV within the Indian hemisphere. ¹⁵ This study aims to evaluate and discern the exigency of including gender-neutral HPV vaccine within the national immunization schedule of India so as to constrain and abate the substantial HPV burden.

Prevalence of HPV Related Infections in India

Human Papilloma Virus (HPV) accounts for 31% of worldwide cancer cases with HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68 types being classified as carcinogenic to humans.^16,17 HPV types 16 & 18 are known to have persistent HPV infections leading to cervical cancer and a substantial portion of anogenital, head and neck cancers. ¹⁸ As per 2020, 7% of global cancer incidence and 24% of global HPV related cancer incidence has been contributed by India ¹⁹ with HPV types 16 & 18 being the predominant cause.^20,21 Among the South Asian countries, India bears the second highest age-standardized incidence rate (ASR) of cervical cancer (18.7%) preceded by Maldives (24.5%) (highest ASR of cervical cancer in Asia as well) with Iran being the least (2.33%). ²² In comparison to the other regions of Asia, Mongolia (19.7%), Thailand (16.4%) and Nepal (16.4%) have comparable ASR of cervical cancer as that of India. On the global scale, developed countries such as United States of America (6.2%), Canada (5.5%) as well as Australia (5.6%) have much lower ASR of cervical cancer as compared to the Indian sub-continent. ²³

Approximately 5.0% of Indian women in the general population are estimated to have cervical HPV-16/18 infection at any given time, with 83.2% of invasive cervical cancers attributed to these HPV types. ²⁴ As per Ramamoorthy et al (2022), female incidence for all HPV related cancers was highest in North-eastern India (Papumpare district in Arunachal Pradesh) with the highest cumulative risk of 1 in 23 women and age-adjusted incidence rate (AAR) of 34.5 per 100,000 women. Among Indian men, Meghalaya had the maximum AAR for all HPV-related cancers (12.4 per 100,000 men), with 1 in 69 men developing HPV-associated cancers within the age of zero and 74 years bearing the highest cumulative risk. The most prevalent HPV-related malignancy in males (63.2%) was oropharyngeal carcinoma with highest AAR (11.4 per 100,000) in Meghalaya while female had the highest incidence in Arunachal Pradesh (3.6 per 100,000). Penile cancers accounts for one out of every four HPV-associated cancers in India. Oropharynx, anus & anal canal, vulva, and vaginal cancers collectively contribute to 12.4% of HPV-related malignancies among females. By 2025, estimated HPV-related malignancies is expected to be 121,302, accounting for 7.7% of total cancer cases in India (males: 3.3%, females: 12.0%). The oropharynx (60.6%) is projected to be the most common HPV-related infection site in men and the cervix uteri (88.4%) in females. ²⁵ Also, Indian (Men who have sex with men) MSM populace have high prevalence of anal (95%) ²⁶ and penile HPV infection (55%). ²⁷ However, there is dearth of studies depicting epidemiology of HPV infection in HIV-positive men as well as MSM Indian population. Determination of HPV prevalence for this high-risk group individual in India is the prime step in the formulation of preventive as well as interventional strategies for overall reduction of HPV burden.

Awareness towards HPV Vaccination among Women and Men in India

The World Health Organization (WHO) has provided guidelines to support countries in integrating the HPV vaccine into their national immunization programs. ²⁸ Despite these efforts, many South Asian countries struggle with inadequate vaccine coverage. ²⁹ Only a few countries in the region—Bhutan, Maldives, and Sri Lanka—have successfully included the vaccine in their routine national immunization schedules, as reported by PATH in 2022. ³⁰ The challenges in implementing the vaccine stem from various factors including socio-cultural norms, healthcare system complexities, and political considerations. ³¹ In India, HPV vaccination uptake is low, which might be connected to the media reports in 2010 due to the mortality cases in purported HPV vaccine-related accidents. This resulted in the suspension of two HPV vaccination programs and raised concerns about the vaccine’s safety. However, a subsequent government inquiry revealed that the fatalities were unrelated to the vaccine. ³² Furthermore, research conducted in India among 34,856 females aged 10 to 18 years found no significant side effects associated with the immunization. ³³

A study conducted among 1580 college going students in India reported that the knowledge as well as awareness regarding cancer-causing HPV strains or the names of the HPV vaccinations was very limited and despite from being educated and opulent households, the percentage of vaccinated females were relatively less (7%). Regardless of the fact that HPV vaccinations have been available in India since 2008, only few parents are interested in getting their girls vaccinated. Several variables, including cultural, religious, and prejudiced views, socioeconomic position, and dearth of information, attitude, and awareness, were the reason for poor coverage of HPV vaccine. Several studies have been undertaken in India to assess young women’s awareness of cervical cancer and HPV.^34–38 However, cervical cancer awareness and knowledge were reported to be very low among both young undergraduate and postgraduate students from rural and urban areas, which could be attributed due to lack of education and exposure to print/audio-visual media, as well as a variety of societal factors, social stigma, and ignorance.^39–41 Shetty et al.^42,43 found that HPV vaccination awareness was lower among male healthcare students in Mangalore than among females. Despite the fact that all females reported a willingness to be vaccinated, male participants tended to be hesitant even after the health education intervention. Also, Pandey et al reported a poor score (25.2%) among male medical students’ awareness regarding the need of HPV vaccination among men. There are scarcities of studies in India which have focused upon the knowledge as well as awareness of men towards HPV vaccination inclusive of both healthcare as well as general population. Hence, extensive studies inclusive of both Indian male as well as female at all the stratas towards HPV knowledge and vaccination awareness should be a prime focus for understanding the patterns of barriers associated with it.

Cost-Effectiveness of Gender-Neutral Vaccine and Associated Herd Immunity against HPV Virus

The primary goal of HPV vaccination for women was cervical cancer prevention, which is reported to be the most common malignancy linked to HPV. Men are also susceptible to HPV-related malignancies including oropharyngeal, anal, and penile cancer.^44,45 Unlike women, males experience >90% HPV-induced malignancies which are caused due to HPV-16 or HPV-18 and the HPV vaccinations have been demonstrated to be extremely immunogenic and efficacious. ⁴⁶ In terms of herd immunity, a systematic review of HPV post-vaccination surveillance data from 65 studies has demonstrated substantial reductions in anogenital warts in young men within the first four years following girls-only quadrivalent vaccination programs with high coverage (≥50%). ⁴⁷ In Australia, the number of anogenital warts consultations among heterosexual males had decreased by over 80% within the first five years of quadrivalent HPV vaccination coverage programme among girls. ⁴⁸ These findings indicate that HPV vaccination can generate substantial herd immunity effects for the anogenital warts-associated types (HPV 6 and 11). In Netherland, the gender-neutral vaccination program proved to be an effective strategy to provide protection against HPV associated cancers in both men and women. It has been shown that vaccinating 30,000 boys along with the girls’ vaccination programme in the Netherlands might possibly prevent 56 and 111 incidences of cancer in boys and girls, respectively, and save a total of 451 Quality-Adjusted Life-Year (QALYs). The extra costs per QALY gained were calculated to be €17,907 for boys and €7310 when the consequences of girls were also included. ⁴⁹ In Sweden, the base-case study estimates that the cost per QALY gained by implementing sex-neutral HPV vaccination would be around €40,000, taking into account the illnesses included in the model, the discount rate, and the vaccine price. Vaccinating preadolescent males as well as girls as part of Sweden’s national immunization policy is anticipated to be cost-effective, especially given current procurement. ⁵⁰ Some nations have addressed the high prevalence of HPV infection in MSM by adding male HPV vaccination programme to the existing girl’s program. As of 2016, six nations, including Australia, introduced a male’s HPV vaccination program to their school-based female programmes on the grounds that it was cost efficient and significantly reduced the incidences of anal, oropharyngeal cancer and anogenital warts. ⁵¹ Also, recent models have demonstrated that the cost-effectiveness of vaccinating males in an environment with female coverage below 50% may be cost-effective upon the prevalence of HPV-related disease and the availability of resources. ²⁰ Furthermore, a systematic review that predominantly comprised studies from high-income countries demonstrated that a gender-neutral vaccination program was cost-effective in the event of low coverage, provided that the price of the vaccine remained low.

The WHO Strategic Advisory Group of Experts on Immunization (Sage) have recommended updation in one or two doses of HPV vaccine for girls aged 9-14 years and women aged 15-20 years, stating that a single dosage is equivalent to two dose regime. ⁵² One-dose HPV vaccination could reduce program costs, increase ease of administration, promote multi-cohort vaccination delivery, and enhance HPV vaccine program adoption in populations with limited healthcare access and high cervical cancer rates. ⁵³ Additionally, simulation models implied that one-dose HPV vaccination has equivalent health benefits to a two-dose regime which not only simplifies vaccine administration, improve cost-effectiveness, it also alleviate vaccine supply restrictions.^54,55

In the United Kingdom, a study suggested that the cost-effectiveness of vaccinating 12- to 13-year-olds with a two-dose regimen is not as high as the single-dose option, which is assumed to be 90% effective for a 10-year period. Significantly surpassing the United Kingdom’s £20,000/QALY willingness-to-pay threshold, the incremental cost-effectiveness ratios for two dosages ranged from £230,903 to £1,082,916 per quality-adjusted life year (QALY). They reported that over the course of 70 years, the healthcare system could potentially save more than £1073 million by transitioning from a two-dose to a single-dose vaccination schedule. In addition, the incremental cost-effectiveness ratio of the single-dose regimen was less than £2040/QALY, in comparison to the absence of vaccination. ⁵⁶

Only few studies have estimated the cost-effectiveness of HPV vaccination in India^57,58 which has been recommended by the National Technical Advisory Group on Immunization. ⁵⁹ A study conducted in Punjab reported that the total cost of vaccinating girls (11 years old) was approximately 135 million INR (US$2 · 1 million) and the net cost, including the cervical cancer treatment cost in Punjab is around 38 million INR ($0 · 6 million) ⁵⁷ which depicts that HPV vaccination is highly cost-effective as well as economically sustainable in India. This forms the rationale for an extensive cost-effective analysis of gender-neutral HPV vaccination in the Indian sub-continent with effective modeling strategy based on the Indian socio-demographics. However, the lack of infrastructure and skilled labour in developing nations like India creates a financial obstacle for implementing a nation-wide vaccination policy especially in case of gender-neutral HPV vaccination. Hence, analysis of gender-neutral HPV vaccination cost-efficacy based on the compliance among population on all the strata is required given high price (10,850 INR per dose) of gender-neutral HPV vaccine (Gardasil-9) which has been recently launched in India. ⁶⁰ Also, mathematical models of HPV transmission can be a potential tool for examining the possible effects of HPV vaccination policies on the prevalence of HPV and its related co-morbidities in the Indian community which will be helpful in formulating gender-neutral vaccine programs. Given that herd effects from girls-only vaccination for non-HPV16 and non-HPV18 types are likely to be greater than for HPV 16 and HPV18, ⁶¹ the incremental benefit from prevention of HPV types under a sex neutral programme will be especially relevant for countries with low uptake among young population, such as India. ⁶²

HPV vaccination status in India

Indian authorities approved bivalent and quadrivalent HPV vaccinations for prescription use in 2008. The first large-scale introduction of HPV vaccination in a public health environment in India occurred in 2009, with demonstration projects focused at determining the optimum way to provide the vaccine. These initiatives were carried out in partnership with the Indian Council of Medical Research (ICMR) and the Programme for Appropriate Technology in Health (PATH) by the state governments of Andhra Pradesh and Gujarat. However, over the past eight years, the combination of press reporting and misinformation surrounding the deaths in the two demonstration projects, as well as the muted defence against this news, has proven to be an impediment to introducing and integrating HPV vaccination into India’s universal immunization program.^32,63 Although the National Technical Advisory Group on Immunisation has recommended its inclusion in the universal immunization programme, and professional societies such as the Federation of Obstetric and Gynecological Societies of India (FOGSI) and the Indian Academy of Pediatrics advocate its use, there is still significant resistance to HPV vaccination. ⁶⁴

In November 2016, the Government of the National Capital Territory of Delhi initiated an opportunistic HPV vaccination programme aimed at females aged 12 to 13 years. By 2018, 4741 girls had been vaccinated; 3263 of these girls had gotten the second dosage, and 8108 bivalent vaccine vials had been utilized. In this current opportunistic campaign, no significant adverse effects were recorded following immunization. The Punjab government in 2017, approved HPV vaccine to be incorporated as two-dose HPV vaccination using the quadrivalent vaccine as part of the state’s standard immunization campaign, targeting girls in class 6 (age 11-12 years) in schools. Punjab government started the vaccination program in the Bathinda and Mansa districts, which had high yearly occurrences of cervical cancer (175 cases per 100 000 women in Bathinda and 173 cases per 100 000 women in Mansa). ⁶⁵ Sikkim implemented HPV vaccination in 1166 schools using a two-dose schedule with a minimum interval of 6 months between doses (day 1 and day 180), targeting 25,284 girls aged 9-14 years. During a 2-week period in August 2018, 97% of the girls received their first dosage in school and health center. ⁶⁴ In September 2021, Merck Sharp & Dohme (MSD) pharmaceuticals India’s first gender-neutral HPV vaccine named Gardasil-9 in order to reduce the burden of HPV among women, girls as well as boys. The 9-valent HPV vaccine (Gardasil-9) has been reported to be effective against HPV serotypes 6, 11,16,18,31,33,45,52 and 58, which can be administered to women and girls in the age bracket of 9-26 years and boys within the age of 9-15 years. The nano-valent vaccine has to be administered in three doses across a period of 6 months (schedule 0, 2 & 6 months) (Figure 1). ⁶⁶ However, the vaccine is only available in the private sectors and not been included in the National Immunization Programme.

Figure 1.

Status of HPV vaccination in India.

Against the backdrop of unfavorable situations, the state-wide implementation of HPV vaccination in Sikkim, Punjab, and Delhi showed positive signs of Indian government engagement in delivering HPV vaccines to individuals seeking voluntary vaccination in India despite the fact that safety concerns have been a key hurdle to the country’s scale-up of HPV vaccination. The governments of Delhi, Punjab, and Sikkim showed a strong political commitment to the introduction of HPV vaccination, which was ably supported by strong state technical advisory groups that included experts from national and international organizations, agencies, and professional bodies. Other contributing factors included locally pertinent awareness campaigns aimed at parents, girls, teachers, and officials, as well as the provision of adequate funding for the purchase of vaccines. Such strategies should also be continued for the implementation of gender-neutral HPV vaccine. Although the overall incidence and mortality rates of cervical cancer in India decreased significantly between 1990 and 2019, ⁶⁷ the decreasing prevalence of the disease also presents an opportunity to potentially eliminate the disease through strategic combination of HPV gender neutral vaccination along with girls only vaccination and screening in order to meet the WHO cervical cancer elimination target. ⁶⁸ Furthermore, present trends of declining incidence do not ensure a future reduction in the HPV burden. This could be due to varied sociocultural norms influencing unsafe sexual practices among young populations including both men ⁶⁹ and women ⁷⁰ which necessitate the need of effective gender-neutral HPV vaccine.

Effective HPV Vaccination Strategies Based on Potential Mathematical Models at the Global Level

Mathematical models have been created to comprehend intricate network patterns in several domains, including epidemiology, social dynamics, signaling networks, and neuroscience. ⁷¹ Specifically, in the area of disease transmission, ⁷² several viable techniques based on mathematical models were offered to tackle the pandemics such as the current coronavirus 2019 pandemic.^73–75 In the case of HPV, various mathematical models have been developed to evaluate how well the HPV vaccination can prevent the transmission of the virus and the development of related diseases.

The primary focus of health authorities in low- and middle-income countries (LMICs), as well as the World Health Organization (WHO), is to address key policy questions related to HPV vaccination. These questions revolve around determining the appropriate age groups and the number of cohorts that should receive the vaccination. Should vaccination be limited to girls only or should both girls and boys be vaccinated? What is the recommended number and timing of doses for each vaccine recipient? ⁷⁶ Modelling studies have indicated that routine and multiple-age cohort HPV vaccination of girls is expected to be highly cost-effective in the majority of low- and middle-income countries (LMICs).^77,78

The utilization of mathematical models to assess the effects of HPV vaccines has been employed by Gavi and the Bill and Melinda Gates Foundation (BMGF) since 2011 to aid in program monitoring and prioritization. ⁷⁹ The VIMC (Vaccine Impact Modelling Consortium) includes two models for the HPV vaccine: the Papillomavirus Rapid Interface for Modelling and Economics (PRIME) and the Harvard model. PRIME was developed by a consortium of modelers led by the London School of Hygiene & Tropical Medicine, while the Harvard model was developed by a team of modelers at the Harvard T.H. Chan School of Public Health. Both models have been widely utilized to provide valuable insights for decision-making by Gavi,^77,80 BMGF, ⁸¹ and individual countries.^82,83 Portnoy et al ⁸⁴ projected the effects of HPV vaccination in four high HPV burden nations (Ethiopia, India, Nigeria, and Pakistan) using the PRIME and Harvard models. The range of cervical cancer cases averted by HPV vaccination between the PRIME and Harvard models was as follows: 262,000 to 270,000 in Ethiopia, 1,640,000 to 1,970,000 in India, 330,000 to 3,366,000 in Nigeria, and 111,000 to 1,333,000 in Pakistan. The statement emphasizes the importance of utilizing HPV vaccination as a crucial strategy to expedite progress towards the elimination of cervical cancer. This is especially significant in low-income and middle-income country settings where there is limited coverage and accessibility to cervical cancer screening.

Brisson et al ⁶⁰ also analyzed the impact of HPV vaccination and cervical screening on cervical cancer elimination through the use of three core models of Cervical Cancer Elimination Modelling Consortium (CCEMC) namely HPV-ADVISE,^85,86 Harvard, ⁸² and Policy1-Cervix ⁸⁷ in 78 low-income and LMICs. They concluded that girls-only HPV vaccination will eliminate cervical cancer in the majority of LMICs provided high coverage is achieved (>90%) and the vaccine would offer long-term protection. Countries with a high cervical cancer incidence (>25 incidences per 100,000 women-years), mostly in Sub-Saharan Africa, were unlikely to achieve eradication with immunization alone. To eliminate cervical cancer in all 78 LMICs, the authors suggested that girls-only HPV vaccination and twice-lifetime screening must be scaled up, with 90% HPV vaccine coverage, 90% screening uptake, and long-term protection against HPV strains 16, 18, 31, 33, 45, 52, and 58. They indicated that cervical cancer might be eliminated in all nations by 2100 provided the worldwide eradication plan of rigorous scale-up of HPV vaccine and cervical screening would be successful.

Additionally, Elfström et al ⁸⁸ using a population-based single-type HPV transmission model, based on data from Sweden indicated that implementing catch-up vaccination for males could result in a significant reduction of approximately 17% in the prevalence of HPV, in comparison to the scenario where only females are vaccinated. This has been supported by multiple studies where various models have indicated potential effect of vaccinating both men and women in reducing HPV infections than vaccinating just females, although male vaccination is less cost-effective than female vaccination.^88–92 This forms the rationale for conducting more assessments using robust mathematical models on the impact of HPV vaccination on HPV associated cancer specifically among men.

Challenges with HPV Vaccine Implementation

HPV vaccination is not widely used in India due to several aspects most notably its high cost, which puts a strain on parents, women, and healthcare professionals. Seven studies that were carried out in various parts of southern India provide similar evidences.^{42,61,93–97} Consequently, until immunization is included in India’s schedule for the Universal Immunization Program, most people believe it to be financially unaffordable. ⁹⁸ Three studies carried out in Bangalore, Mangalore, and Uttar Pradesh have shown that a further barrier to acceptance is women’s concerns about vaccinations possibly indicating a prior HPV infection.^99–101 Additionally, as shown by a study carried out in Patna, ¹⁰² the need for a three-dose schedule for the HPV vaccine has created a significant obstacle to its administration and acceptance owing to the accompanying exorbitant expenditures. The external environment presents several challenges for the HPV vaccination program, chief among them being the need for budgetary approval to carry out the immunization campaign. This was brought to light in research carried out in a few low-resource nations, such as India. ¹⁰³ It has also been highlighted that physicians are reluctant to recommend immunization due to the lack of a clear program plan or formal endorsement from reputable organizations. Doctors emphasized that unless the vaccine is provided in government settings or is advised by the Indian Academy of Pediatrics (IAP) Committee on Immunization, they are reluctant to promote it. ⁹⁴

Healthcare professionals often have misconceptions regarding the safety and efficacy of HPV vaccinations, which might impact their adoption in the internal environment due to a variety of sociocultural views. Six research, conducted in low-resource environments, including India, as well as in particular locations including Chennai, Manipal, Mangalore, and several regions in the country’s south, have published the findings. ^{61,93,95,97,103,104,109} Furthermore, research carried out in several Indian states, including West Bengal, Andhra Pradesh, Gujarat, and Uttar Pradesh, has shown that community members, parents, and women have voiced misunderstandings and worries about vaccinations.^{94,101,105–107} This misconception could have played a role in people’s hesitation to get the HPV vaccination, which might have been caused by a lack of knowledge about the subject. In addition, a lot of women have expressed the need for further research to support a greater degree of acceptance of this immunization, especially about potential side effects and overall efficacy. A research conducted in Mangalore, ¹⁰¹ which was undertaken, demonstrated this mindset. However, it’s crucial to recognize that older married women with more education and one or more kids were more likely to be open to giving their kids the HPV vaccine. ¹⁰⁸ Additionally, research carried out in Delhi and Mangalore has shown specific sociocultural ideas.^35,42,104 These ideas include the notion that certain cultural standards and sexual promiscuity are related. Furthermore, research carried out in certain low-resource environments ¹⁰⁶ discovered that family limitations are enforced since the father is the main decision-maker. According to two research projects carried out in Mysore, parents who don’t think about the potential of their girls having sex may prevent their daughters from receiving vaccinations. Moreover, research conducted in Bangalore, Mangalore, and other parts of South India has shown that certain beliefs, such as the notion that a regular menstrual cycle negates the need for HPV vaccination, and the perception of a low risk of developing cervical cancer, influence the uptake of HPV vaccination. Many variables about personal traits are impeding the HPV vaccine’s introduction in India. One of these concerns is that medical personnel do not know enough about the vaccination, as studies from Delhi, Mangalore, Mysore, the Andaman and Nicobar Islands, Chennai, and other parts of India have reported.^{35,61,93,98,104,109,110}

Future Perspective

There is a need to consider gender neutral approach to HPV vaccination to meet the WHO targets for the elimination of cervical cancer. Implementation of effective gender-neutral HPV vaccination programs in the Indian subcontinent has been predominantly influenced by potential challenges such as vaccine availability, financial constraints as well as cost-effectiveness. However, alternate approaches can also alter vaccine availability including promoting HPV vaccine awareness in both the genders, conducting nationwide HPV educational campaign by collaborating with potential stakeholders, reducing vaccine cost, increasing vaccine production, modifications in licensing policy and optimal resource allocation. These can yield potential opportunities for the transitioning of the existing HPV vaccine programs to alternative approaches which might pave a way for the inclusion of HPV vaccination programme in the National Immunization Schedule. Inclusion of HPV vaccination in the Universal Immunization Program will not only promote HPV vaccination, it will also reduce the economic burden and misconceptions associated with it among the Indian populace from various socio-economic strata. Although the HPV vaccine implementations are progressing in India at the district level, South-east Asian nations such as Bhutan, Sri Lanka, Thailand, and the Maldives have already implemented HPV vaccination in their national immunization programs. Also, HPV demonstration programs in Bangladesh and Nepal have been completed successfully, and national introduction preparations are under ongoing. ¹¹¹

Several countries that have successfully implemented HPV vaccination programs may serve as models for success. The HPV vaccination program in Geneva Canton, Switzerland has achieved impressive success in a relatively short amount of time with immunization coverage of 82%. The success in Geneva can be credited to effective planning, strong healthcare infrastructure, and community engagement strategies that helped to spread awareness and acceptance of the HPV vaccine. ¹¹² Rwanda’s national HPV vaccination program is highly regarded for its school-based rollout, which has contributed to its remarkable success. The program achieved an impressive 93% coverage among girls in grade six, which demonstrated a high level of completion for the three-dose series. The success in Rwanda highlighted the practicality and impact of incorporating HPV vaccination into school health programs. The success can be attributed to the collaboration between the health sector and educational institutions and the country’s dedication to comprehensive healthcare initiatives. ¹¹³ Uzbekistan has achieved remarkable success in attaining a high HPV vaccination coverage of 94% among girls aged 12-14 years. The success in Uzbekistan was attributed to the comprehensive strategy that involves educating important target groups, encouraging cooperation among stakeholders, and highlighting the wider societal advantages of safeguarding girls’ health for their future as mothers. This example underscores the significance of a comprehensive approach that goes beyond just vaccination, placing a strong emphasis on education and advocacy. ¹¹⁴

Several strategies can be implemented to address the current challenges pertaining to implementation of HPV vaccination in the Indian scenario.

• (i) Proactive HPV-Immunization and Awareness Programme:

• The development of a “Proactive HPV-immunization and screening program” for the rapid scale-up of HPV vaccination in India should be based on the COVID-19 vaccination model. ¹¹⁵ Structuring of inclusive community empowering ‘bottoms-up’ policies related to HPV vaccine implementation, along with automated allocation of the clinical resources is essential in a populace endowed with wide variation in genetic base inhabiting landscapes with unique geological relief structures contributing to segregated socio-cultural norms and practices. Furthermore, implementation of nuanced multifaceted approaches, such as Artificial Intelligence (AI)-enabled large-scale surveillance systems for now-casting and forecasting primary data, use of iterative and integrated dashboards with heuristic capabilities would be pivotal to address the diverse healthcare needs of the Indian populace. ¹¹⁶

• (ii) Vaccination programs at schools, colleges, and universities:

• Schools, colleges and universities are optimal locations for administering and advocating vaccines, as they facilitate the access of a significant number of adolescents, are convenient for families, foster peer support and social norms, promote high coverage, and help reduce inequitable access to vaccination.^117–119 School-based vaccination is believed to be the most effective and efficient method of guaranteeing high vaccine coverage for adolescents, particularly in light of the decrease in the frequency of visits to primary care practitioners during adolescence in comparison to childhood. ¹¹⁷ A diverse array of delivery strategies, including non-school and school-based initiatives, have been employed to introduce the HPV vaccine in numerous developing countries, including Rwanda, ¹¹² Botswana, ¹²⁰ Thailand ¹²¹ and South Africa. ¹²² Hence, in order to increase the prevalence of HPV vaccination among both boys and girls in India, it is necessary to implement a mandatory HPV immunization program at both schools and colleges for adolescents aged 9 to 19 years. It is pivotal that parents and educators provide assistance in the successful implementation of this program. Sikkim, a state in the north-eastern state of India, is a prime example of a school-based vaccination program that successfully accomplished a two-dose schedule and achieved an HPV vaccination coverage of over 95% in 9-13-year-old females. Additionally, no severe adverse effects were reported. ¹²³

• (iii) Promoting HPV vaccination by addressing socio-cultural barriers:

• It is imperative to recognize and comprehend the cultural and societal factors that influence vaccine adoption in order to customize interventions. Trust can be established and cultural barriers can be surmounted through community engagement initiatives that involve local leaders and influencers. The development of educational materials and campaigns that are culturally sensitive and resonate with diverse communities has the potential to alter perceptions and cultivate a positive perception of vaccination.^124,125 Community-based organizations, including Cancer Awareness, Prevention and Early Detection (CAPED), have been willing to initiate outreach initiatives in India regarding HPV vaccination. ¹²⁵ Additionally, authorities have conducted workshops on the vaccine for local media, which is essential in light of the HPV vaccine’s previous spread of misinformation. ¹²⁶ Healthcare providers and public health officials can be instrumental in addressing vaccine hesitancy and promoting HPV vaccination, in addition to community-based organizations. Healthcare clinicians are advised by the Centres for Disease Control and Prevention (CDC) to vigorously advocate for HPV vaccination among their patients and their guardians. The CDC also suggests that public health officials collaborate with healthcare providers, institutions, and community organizations to enhance the rate of HPV vaccination. ¹²⁶

• (iv) Advocacy and policy recommendations:

• The landscape of vaccination is significantly influenced by policy. The objective of advocacy efforts should be to influence policy decisions at the local, national, and international levels. This encompasses the promotion of HPV vaccination in national immunization programs, the guarantee of healthcare plan coverage, and the implementation of policies that encourage school-based vaccination programs. ¹²⁷ Engaging with policymakers, healthcare professionals, and advocacy groups can amplify the voice for HPV vaccination, promote policies that improve vaccine access, reduce financial barriers, and cultivate a supportive environment for vaccination efforts. ¹²⁸ Ultimately, the burden of cervical cancer can be reduced and women’s health can be advanced on a global scale by promoting HPV vaccination effectively through the implementation of a multifaceted approach that integrates education, enhanced access, cultural sensitivity, and policy advocacy. ¹²⁹

• (v) Gender-neutral HPV vaccination:

• Adopting a gender-neutral HPV vaccination strategy will mitigate HPV infections in the Indian sub-continent. Hence, it is substantial to promote HPV vaccination uptake, address misinformation, reducing vaccine-associated stigma, and advocate gender equity. ¹³⁰ HPV is not a virus that solely attacks female epithelium; rather, it is a gender-neutral infection. To minimize HPV infections and associated malignancies along with promoting gender equality, it is imperative to formulate programmatic research from a gender-neutral perspective. ¹³¹ Also, understanding the general community-based customs and sexual practices is the need of the hour which influences the acceptability and compliance of gender-neutral vaccination programs in India. This necessitates the conduction of large-scale HPV vaccine studies in Indian males in order to depict the effectiveness of gender-neutral HPV vaccination in the Indian demographics. The epidemiological and economic considerations regarding the vaccination of males should concentrate on the incremental marginal costs, feasibility, and benefits of increasing vaccination coverage among girls in comparison to implementing a gender-neutral program in terms of disease reduction.^60,132 It is crucial to note that the acceptability of the population^{55,70,133,134} and the political viability^134–137 will also have an impact on gender-neutral HPV vaccination programs.

Conclusion

The introduction of a gender-neutral HPV vaccine in India is crucial in combating the prevalence of HPV-related cancers. It is essential to expand vaccination efforts to include boys and men alongside girls and women. By doing so, we can ensure protection for both sexes and significantly reduce the burden of HPV-associated diseases. To maximize the impact, a comprehensive bottoms-up vaccination program needs to be implemented, complemented by effective education and awareness campaigns. By fostering a healthier community through widespread vaccination and knowledge dissemination, we have the potential to create a future in India with fewer cases of HPV-related cancers, ultimately saving lives and improving public health.

Ethical Statement

Ethical Approval

This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

ORCID iD

Neha Taneja https://orcid.org/0000-0003-3818-7993