Primary Prevention in Cervical Cancer—Current Status and Way Forward

Abstract

The effect of cancer in women has varied effects. Overall malignancies of the breast, cervix, and ovary account for over 43% of all cancer cases in India. Globally, cervical cancer is fourth cancer in terms of incidence among women, following breast, lung, and colorectal cancer. However, this illness primarily affects women in India, where it is the second most frequent malignancy after breast cancer. HPV-related cervical cancer is a serious public health issue that has a solution. In 2020, the World Health Organization (WHO) launched a global initiative to eliminate cervical cancer which set targets for three important strategies: HPV vaccination, cervical cancer screening, and treatment. The WHO’s “Best Buys” recommendations for cancer sub-set place vaccination of females between the ages of 9 and 14 at the top of the list. In India, efforts are underway to increase the number of teenage girls receiving the human papillomavirus (HPV) vaccine. The nation granted licenses for bivalent and quadrivalent HPV vaccinations in 2008, and in 2018, a nonavalent vaccine was approved. It is important to keep in mind that the cervical carcinoma vaccination is not a quick fix; thus, screening for the disease should continue. Any nation can potentially significantly lower the incidence of cervical cancer by carefully combining economical, high-coverage vaccinations with well-organized screening programs. Since 9–14 years is the ideal age range before sexual debut in today’s world, this is the key vaccine age range. Estimates of vaccine effectiveness for younger adolescents, those between the ages of 9 and 14 years, varied from roughly 74 to 93%. Let us envision an India of the future where girls grow up with one fewer cancer threatening their life and a place where cervical cancer has been eradicated.

Introduction

Interaction of women with cancer is a complex matter. In addition to being healthy people taking part in cancer prevention and screening programs, women deal with cancer in a variety of ways. These include caring for friends and family after receiving a cancer diagnosis, advocating for patients, working in the medical field, conducting research on the disease, and influencing policy [1]. All spheres of society must take action to end cancer-related suffering, including governments, business, education, healthcare facilities, nonprofit associations for professionals such as FOGSI, IAP, and IMA, and varied communities. Everyone in society can make a difference in the fight against cancer by following cancer prevention strategies, volunteering in their community, and holding executive positions in large corporations. In this setting, women contribute special and vital viewpoints to every conversation, across all societal strata.

The effect of cancer in women has varied effects. Overall malignancies of the breast, cervix, and ovary account for over 43% of all cancer cases in India [2]. Globally, cervical cancer is fourth cancer in terms of incidence among women, following breast, lung, and colorectal cancer [2]. However, this illness primarily affects women in India, where it is the second most frequent malignancy after breast cancer. HPV-related cervical cancer is a serious public health issue that has a solution.

We all know very well that women have the power to bring forth life as child bearers. In 2020, the World Health Organization (WHO) launched a global initiative to eliminate cervical cancer which set targets for three important strategies: HPV vaccination, cervical cancer screening, and treatment. Currently 193 countries, including India, are committed to eliminating cervical cancer. The World Health Organization’s strategy outlines a 90-70-90 triple pillar intervention to be implemented by 2030 with an additional focus on high-quality health care and equitable health care services [3]

• 90% of girls fully vaccinated with HPV vaccine by the age of 15 years;

• 70% of women screened using a high‐performance screening test at the age of 35 and 45 years;

• 90% of women detected with cervical precancer and cancer lesions receive treatment and care.

With HPV vaccination, we can prevent cervical cancers that can seriously affect woman’s health.

What Makes HPV Immunization a Top Priority?

Cervical cancers are preventable with HPV vaccination, and they can have a major negative impact on a woman’s health.

The World Health Organization (WHO) published a list of “Best Buys” in 2018 for treating non-communicable diseases (NCDs). These buy-effective, evidence-based public health initiatives can be implemented at the national, subnational, or local level by nations. The WHO’s “Best Buys” recommendations for cancer sub-set place vaccination of females between the ages of 9 and 14 at the top of the list. During India’s G20 chairmanship in September 2023, the nations pledged to advance fair access to vaccines, with a focus on low- and middle-income countries [4, 5].

Forty years ago, in 1983, German scientist Harald Zur Hausen proved that some papillomaviruses, often known as wart viruses, are the cause of cervical cancer in humans [6]. Researchers were therefore inspired to create a particular vaccination that would prevent HPV replication as a result of their increased understanding of HPV epidemiology. The development of a vaccine to prevent cervical cancer has increased optimism that the disease may eventually be eradicated. Currently, bivalent and quadrivalent vaccines, which were initially licensed in India in 2008 for HPV-naive women, are safe, effective, and accessible worldwide [7].

It is important to keep in mind that the cervical carcinoma vaccination is not a quick fix; thus, screening for the disease should continue. Any nation can potentially significantly lower the incidence of cervical cancer by carefully combining economical, high-coverage vaccinations with well-organized screening programs.

It is noteworthy that surgical excision is the standard treatment for neoplasia, which may lead to an increase in deaths and other complications, such as cesarean sections. However, in several cases, therapeutic vaccines could prevent invasive surgery; these vaccines would be most effective when administered to pre-neoplastic lesions when tumor-induced immunosuppression is less effective.

Therapeutic Vaccines may be the Answer?

HPV therapeutic vaccines can be broadly classified into four categories: live vector-based, peptide- and protein-based, nucleic acid-based, and whole-cell vaccines [8]. As a potential new tool to fill in the gaps in the cervical cancer program, therapeutic HPV vaccines are presently in the early stages of clinical research. Therapeutic vaccines would be created to cure or eradicate preexisting HPV infections, HPV-associated precancers, or aggressive cervical cancer, in contrast with current prophylactic HPV vaccinations, which shield against new infections. But for the time being at least, this path has a very long journey ahead of it.

Prophylactic Vaccines

There are now three licensed preventive HPV vaccinations available. All of them are meant to be taken, if at all feasible, prior to the start of sexual activity, or prior to being exposed to HPV. Utilizing recombinant DNA and cell culture techniques, all vaccines are made from the purified L1 structural protein, which self-assembles to create virus-like particles (VLPs), which are empty shells specific to HPV types. Since HPV vaccines don’t include viral DNA or live biological materials, they are not contagious. Use of HPV vaccinations Adjuvants are present along with distinct expression systems; neither antibiotics nor preservatives are present. The quadrivalent and nonavalent vaccines contain VLPs to protect against anogenital warts causally associated with HPV types 6 and 11, and all HPV vaccines have VLPs against high-risk HPV types 16 and 18. The nonavalent vaccine also contains VLPs against high-risk HPV types 31, 33, 45, 52, and 58 [9].

More than 140 nations have integrated the HPV preventive vaccines into their National Immunization programs (NIPs) after they have been available for more than 20 years. Neighboring countries in Southeast Asia, including Bangladesh, Bhutan, and Sri Lanka, have implemented the HPV vaccine, while Nepal is still in the planning stages. In India, efforts are underway to increase the number of teenage girls receiving the human papillomavirus (HPV) vaccine. The nation granted licenses for bivalent and quadrivalent HPV vaccinations in 2008, and in 2018 a nonavalent vaccine was approved. HPV vaccination was included to India’s public health services through demonstration programs that were started in 2009 in the states of Andhra Pradesh and Gujarat. The use of HPV vaccination in research projects was discontinued after a few deaths in these studies that were later determined to be unrelated to vaccination.

There is hope for the future widespread implementation and evaluation of HPV vaccination in India due to the successful introduction of the vaccine in immunization programs in Punjab and Sikkim. Since 2016, vaccines have been administered with high coverage and safety. The government-sponsored opportunistic vaccination in Delhi, the possibility that a single dose will provide protection, and the potential for an affordable Indian vaccine in the future have raised hopes of cancer prevention [10]. After being first announced by the Health Ministry in early 2023 and most recently by the finance minister in her interim budget statement, the HPV vaccination is still awaiting a national rollout [11, 12].

Prophylactic Vaccine Target Audience and Recommended Doses

The deltoid region is the recommended site of intramuscular administration. A 0.5 ml dosage is the standard. Compared to the reaction following a natural illness, the vaccination-induced serological response is significantly stronger (1–4 logs higher). Viral infections that occur naturally enter the mucosa and cause only mild inflammation. Antibodies produced by vaccination are believed to travel to the site of infection through active IgG transudation in the female vaginal canal and interstitial antibody exudation at trauma sites where infections first appear10. Six HPV malignancies, including cervical, vaginal, vulval, anal, penile, and oropharyngeal cancers, can be prevented with the use of this safe and efficient vaccination. For both boys and girls in different age groups, the FOGSI Good Clinical Practice Recommendations (FGCPR) [Table 1] have provided evidence-based recommendations for HPV vaccination [13].

Table 1.

FOGSI HPV vaccine recommendation [13]

Optimal dose	Schedule
Girls and boys	2 doses for 9 to 14 years (0 and 6 months)
Girls and boys	3 doses for 15–26 years (0, 1–2 and 6 months)
	3 doses for older women till 45 years of age
Reduced dose
A. 2 doses WHO SAGE recommendation	1 or 2 doses 9–14 years 1 or 2 doses 15–20 years 2 doses 21 years and above
B. Single dose (off label)

DGCI approval is awaited for reduced dose schedule

Since 9 to 14 years old is the ideal age range before a typical sexual debut in today’s world, this is the key vaccine age range. Estimates of vaccine effectiveness for younger adolescents, those between the ages of 9 and 14 years, varied from roughly 74 to 93%, and from 12 to 90% for those between the ages of 15 and 18 years [Table 2]. These findings highlight the need of timely immunization by showing that the HPV vaccine is most effective against HPV-related illness outcomes when administered at younger ages [14]. Numerous investigations have demonstrated the significance of receiving an HPV vaccination at a younger age. According to a 2021 longitudinal study, women who had at least one HPV vaccine before turning 14 years old saw an 87% reduction in the incidence of cervical cancer, demonstrating the effectiveness of England’s National Health Service (NHS) immunization program in preventing the disease [15]. When women between the ages of 14 and 16 received the HPV vaccine, the percentage of cervical cancer cases averted fell to 62%, whereas women between the ages of 16 and 18 only had a 34% reduction in cancer cases [16].

Table 2.

Age-wise efficacy of vaccine [14, 17]

Age at vaccination	Effectiveness against CIN3 + (%)	Effectiveness against cervical cancer (%)
12–13	97	87
14–16	75	62
16–18	39	34

According to their age category, all participants who are HIV positive and immunocompromised should receive an additional dosage

It is only advised to vaccinate secondary target populations such as boys, older men, or men who have sex with men (MSM), if it is both practical and economical to do so and does not take resources away from vaccinating the primary target population 14. For individuals aged 9–14, it is advised to administer two doses at intervals of 0 and 6 months, and three doses at intervals for 15–26 months.

15–26 years old is the secondary target age range for young women and adolescent girls. It is advisable to advise children about the vaccine’s restricted efficacy in this age range before presenting it to them. For the age group of women from 26 to 45 years, vaccine can be offered after explaining limited benefit of vaccine. Screening for cervical cancer should continue with frequent, age-appropriate cervical cancer screening methods, and a clear explanation of the minimal advantages of the HPV vaccine should be explained.

High-level protection against anogenital warts in both men and women, as well as anogenital precancerous lesions in susceptible men aged 16–26, is offered by the quadrivalent and nonavalent vaccinations [18]. High seroconversion rates and high levels of antibodies against HPV6 and HPV11 VLPs were seen in females aged 9–45 and in males aged 9–26 who were seronegative and had received the quadrivalent HPV vaccine. The single dosage of a bivalent, quadrivalent, or nonavalent vaccination is considered non-inferior, according to recommendations made by the WHO Strategic Advisory Group of Experts on Immunization (SAGE). Nevertheless, neither the Central Drugs Standards Control organization (CDSCO) nor the National Technical Advisory Group on Immunization (NTAGI) have approved this off-label suggestion.

Cross-Protection

The HPV bivalent and quadrivalent vaccines offer defense against HPV strains that they are not designed to target. Research has indicated that bivalent vaccine Cervarix offered protection against HPV-31 and HPV-33, which are closely linked to HPV-16 and HPV-45 which is closely related to HPV-18 [19]. For HPV-31, the effectiveness of the quadrivalent vaccine attained statistical significance (46.2% [15.3–66.4]; follow-up: 3.6 years) [20].

Even though the HPV vaccine has been around in India since 2008, vaccine coverage of target population has been low. Several obstacles exist, including:

1. All girls in India don’t have universal access to HPV immunization [21]

2. The private market currently offers it at a substantial out-of-pocket expense

3. Many doctors misjudge the prevalence and danger of HPV infection and cervical cancer.

4. Doctors also misjudge the efficacy and safety of HPV vaccinations.

5. Reluctance to advocate for the HPV vaccine to parents of age-eligible teenagers stems from a lack of confidence in the safety and efficacy of vaccinations [22].

6. Furthermore, because HPV infections are primarily spread by intimate skin-to-skin contact, doctors may be reluctant to recommend this cancer prevention vaccination.

7. Alternatively, they may believe it will take a lot of time to address the numerous questions by parents, many of which are related to myths and misinformation regarding the HPV vaccine

To facilitate the highly anticipated nationwide introduction of the HPV vaccine, the Federation of Obstetric and Gynecological Societies of India (FOGSI) in collaboration with American Cancer Society released a training module aimed at reacquainting member OB/Gyns with the facts surrounding HPV vaccination as a cancer prevention measure and disseminating best practices for communicating effectively with parents regarding this vaccine throughout. About 10,800 FOGSIans have received training under this program, covering a two-hour curriculum all throughout India. It is also anticipated that these trained individuals will educate their peers, the medical community, and the general public on the value of HPV vaccine in preventing cancer.

FOGSI is Currently Developing Resources and has Partnered with UNICEF once more for the Introduction of UNICEF HPV SAFE OBGYN

The first generation of Indian women free of cervical cancer can be ushered in by us, the FOGSIans! Girls between the ages of 9 and 14 can receive two doses of the HPV vaccination, which can prevent HPV infection and guard against the development of the majority of cervical cancers as well as four other cancers in women: vulvar, anal, vaginal, and throat. Let us pledge to make the HPV vaccine a top priority in our medical societies, clinics, and hospitals. Let us envision an India of the future where girls grow up with one fewer cancer threatening their life and a place where cervical cancer has been eradicated.

Conclusion

HPV vaccination is an effective strategy for lowering the incidence of illnesses and malignancies linked to HPV. Because of its well-established safety and efficacy, it is an essential part of public health programs all over the world. We can optimize HPV vaccination advantages and shield future generations from the devastation caused by HPV-related illnesses by removing obstacles to vaccination and raising public awareness. To improve global health and well-being, governments, healthcare providers, and communities must collaborate to make sure that everyone who can benefit from HPV vaccination receives it.