|
 
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| REVIEW ARTICLE |
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| Year : 2020 | Volume
: 7
| Issue : 1 | Page : 3-8 |
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Human papillomavirus vaccination: An important tool in cervical cancer elimination
Veena Pampapati, Arpitha Anantharaju
Department of Obstetrics and Gynecology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| Date of Submission | 17-May-2020 |
| Date of Acceptance | 12-Jun-2020 |
| Date of Web Publication | 18-Aug-2020 |
Correspondence Address:
Dr. Veena Pampapati
Department of Obstetrics and Gynecology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/IJAMR.IJAMR_56_20
The World Health Organization (WHO) has called for global elimination of cervical cancer, which essentially means achieving age-standardized incidence rates of <4/100,000 women worldwide, so that it ceases to be a public health issue. Vaccination against the human papillomavirus (HPV), screening for cervical cancer, and the treatment of precancerous lesions are effective tools for achieving this goal. HPV vaccination is recommended as a primary prevention measure in young girls before their sexual debut, and screening for cervical cancer is recommended for sexually active women. Three types of HPV vaccines are available-bivalent, quadrivalent, and 9-valent vaccines. Standard dosing recommended is the 3-dose regimen, whereas, in young girls between 9 and 15 years, 2-dose schedule is found to be as immunogenic as the 3-dose schedule. Countries like Australia have implemented vaccination using the quadrivalent HPV vaccine, and a large impact on HPV-related disease has been noted in Australia. Screening for cervical cancer can be done by cervical cytology, visual inspection after application of acetic acid (VIA), or HPV DNA testing. Low-cost screening techniques like VIA are useful in our country for large scale screening. Challenges in achieving elimination of cervical cancer are manifold and include vaccine manufacture and delivery, vaccine hesitancy, setting up of cervical screening and effective treatment of precursors, and, most importantly, availability of resources to fund screening and vaccination to a huge population. In developing countries like ours, the WHO goal can be achieved only by the commitment of state and central governments and nongovernment organizations. Keywords: 9-valent human papillomavirus vaccine, bivalent human papillomavirus vaccine, cervical cancer, cervical screening, elimination, quadrivalent human papillomavirus vaccine
How to cite this article:
Pampapati V, Anantharaju A. Human papillomavirus vaccination: An important tool in cervical cancer elimination. Int J Adv Med Health Res 2020;7:3-8 |
| Introduction | |  |
The World Health Organization (WHO) has called for global elimination of cervical cancer[1] as it is a preventable cancer with a known etiological factor. Different levels of prevention are available to prevent this cancer – primary prevention by human papillomavirus (HPV) vaccination and sexual education, secondary prevention by screening and treatment of preinvasive lesions with 100% cure rate, and tertiary prevention using early diagnosis and treatment of invasive cervical cancer. Primary prevention with vaccines is applicable to young adolescent girls before their sexual debut, and secondary prevention with screening is applicable for sexually active women.
The elimination of cervical cancer essentially means achieving age-standardized incidence rates of <4/100,000 women worldwide.[1] It is important to understand here that it is “elimination,” not “eradication” we are talking about. The purpose of this target is to control cervical cancer as a “public health issue.” The strategy to achieve this target is by achieving full vaccination of 90% of girls with HPV vaccine by 15 years of age, screening of 70% of women using a high-performance test by 35 and 45 years of age and treatment of 90% of women identified with the cervical disease by 2030.[2]
| Burden of Cervical Cancer | | |
If the target is to achieve an age-standardized incidence rate of <4/100,000 women worldwide, let's have a peek at the burden of this disease in different countries and how it is “unequally” distributed in the world. The age-standardized incidence rates are as high as 75 per 100,000 women in the highest-risk countries to as low as <10/100,000 women in the developed world where screening for cervical cancer is well developed.[3] In the United States of America (USA), the age-standardized incidence rate in 2016 was 8/100,000 women.[4] In another success story of the fight against cervical cancer, Australia reported an incidence of 7.4/100,000 women in 2014.[5] The highest incidence rates of cervical cancer are seen in sub-Saharan Africa (>50 per 100,000 women).[6] In India, the estimated age-standardized incidence rate of cervical cancer was 22.9/100,000 women in 2012[7], and it varies between urban and rural areas. It was noticed by researchers that even though we lack a robust screening program in India, the incidence of cervical cancer is decreasing, especially in urban areas. In Chennai, age-adjusted incidence rate declined from 42.3 (1982–1983) to 16.7 (2010) per 100,000 women and in Barshi a slow decline was noted (23.5 [1988–1989] to 19.5 per 100,000 women [2010]).[8] The main reasons for the increased burden of cervical cancer in poorly developed nations are poverty, illiteracy, poor awareness about possible prevention, and lack of political commitment for mass vaccination and screening.[9]
| Etio-Pathogenesis of Cervical Cancer | | |
As of today, we are clear about HPV infection's natural history and its oncogenic potential as the main etiology of invasive cervical cancer
Human papillomavirus is epitheliotropic. It infects epithelial cells of the skin and mucous membranes and causes epithelial proliferation at the site of infection. There are 120 genotypes of HPV currently, among which 40 are known to infect the anogenital tract.[10] Classification of HPV into high risk and low risk is based on their potential to cause preinvasive and invasive cervical disease. International Agency for Research on Cancer has described 12 α-1 HPV types as high risk, which include HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59. HPV 68, in the group α-2A, is categorized as “probably carcinogenic.”[11] HPV is a nonenveloped virus with a proteinaceous coat, which encases and protects the viral DNA. The proteinaceous coat is composed of 72 capsomeres made of major and minor capsid proteins, L1 and L2, respectively. These capsid proteins provide protection to the viral DNA and serve as the initial interaction site of the viral particle with the host cell. The HPV genome is a circular, double-stranded DNA, and contains nearly 8000 base pairs. The genome contains eight open reading frames, which are transcribed as a single mRNA and this mRNA is translated into the eight proteins E1, E2, E4, E5, E006, E7, L1, and L2. Six early genes, which encode nonstructural proteins (E1, E2, E4, E5, E6, and E7) are responsible for viral replication and transcription, and two late genes (L1 and L2), encode the structural components of the viral capsid. HPV-related cancers arise because of the integration of viral DNA into cellular DNA, and subsequently, E6/E7 interacts with p53 and RB (retinoblastoma), which prolongs the cell cycle, inhibits apoptosis, and can result in malignant transformation [Figure 1].[12]
| Human Papillomavirus Vaccines | | |
The epidemiologic association between HPV infection and cervical cancer fulfills all the established epidemiologic criteria for causality. As a result, HPV is now accepted to be the central, necessary causal factor for virtually all cases of cervical cancer.[13] With the established causality, prevention requires decreasing the risk factors for HPV infection and avoidance of factors that enhance the persistence of HPV infection. These measures might not be a good public health strategy in terms of implementation and adherence to prevent cervical cancer. So, having a vaccine that stimulates immunity against HPV is the best option for cervical cancer prevention.
L1 protein expressed in recombinant vectors, self-assembled into virus-like particles (VLPs), closely resemble the antigenic characteristics of the wild-type virions. When these VLPs are formulated on aluminum adjuvants, they were shown to induce a strong immune response in nonhuman primates, and this led to their development for humans.[14],[15] A large number of trials in humans tested the immunogenicity and safety of monovalent VLP-based vaccines and found that they were immunogenic and antibodies produced far exceeded those seen in natural infections and were sustained at long-term follow-up and the predominant antibody responses are of the immunoglobulin G1 subclass.[16] It was observed in these human trials these were 100% vaccine efficacy against HPV 16 and 18 and against CIN 2+ at 6.4 years of follow-up.[17] Subsequently, two vaccines have been developed for use in humans, Gardasil (Merck), a quadrivalent vaccine that includes HPV-16, -18, -6, and -11, and a bivalent vaccine Cervarix (GlaxoSmithKline), which includes HPV-16 and -18 which has demonstrated cross-protection to nonvaccine HPV types. Bivalent and quadrivalent vaccines are known to prevent 70% of HPV-related cancers.
The US Food and Drug Administration in 2014 approved Gardasil 9 – a nonavalent vaccine for the prevention of diseases caused by nine types of HPV. Gardasil 9 has the potential to prevent approximately 90%–96% of cervical, vulvar, vaginal, and anal cancers. Five additional HPV types covered by Gardasil-9 are HPV 31, 33, 45, 52, and 58-which cause approximately 20% of cervical cancers. Gardasil 9 is a vaccine approved for use in females aged 9 through 26 and males aged 9 through 15. This is recommended by the US Advisory Committee on Immunization Practices in February 2015 and by the American Academy of Paediatrics HPV vaccine recommendations in 2015.[18] 9-valent vaccine will give only the complementary coverage for the remaining (20%) part of the etiological agent.
| Implementation of Preventive Measures | | |
Developed countries have conquered invasive cervical cancer to a large extent by a comprehensive approach to cervical screening, and this is the reason why 85% of cervical cancer is now seen in under developed nations.[19] To achieve the WHO goal of elimination of cervical cancer, it is important to concentrate on these under developed nations by improving the screening and vaccination facilities and by the treatment of preinvasive and invasive cancers appropriately. As of now, high coverage with HPV vaccination alone is not enough to decrease mortality due to invasive cervical cancer. If implemented seriously today, vaccination will take another 3–4 decades to show a significant decrease in the burden of cervical cancer.[19] If we need to achieve WHO goal of elimination of cervical cancer, it is very important to screen the older population who will not be candidates for vaccination, for preinvasive and invasive disease and treat them accordingly.
| Screening for Cervical Cancer | | |
Many modalities are available to screen for cervical cancer among women. Cytology (either conventional Pap test or by liquid-based cytology), HPV DNA testing, and visual inspection after application of acetic acid (VIA) are available for the same. According to the WHO strategy for elimination, it is advised to screen women at least two times in their reproductive age. In our country, we are not able to screen all women with cytology at least once in their lifetime due to a lack of resources and competing health needs of the population. Mass screening using cytology or HPV DNA test requires financial support and is not feasible in our country. A trial conducted in south India regarding screening using different modalities concluded that VIA is as good as cytology and HPV DNA test for detecting high-grade dysplasia.[20] So, using cost-effective screening tests like VIA will be more judicious in resource-constrained countries like ours. Similarly, the WHO in 2013 recommended either VIA or HPV testing for screening of cervical cancer in resource-constrained countries.[8] However, recent evidence has shown that VIA has only a downstaging effect rather than the prevention of cervical cancer. The 2016 American Society of Clinical Oncology (ASCO) guidelines for resource-stratified cervical screening recommend HPV-based screening.[7] According to ASCO, HPV test performed once 15–20 years after the onset of sexual activity will detect many precancers while limiting overtreatment.[7] The need to continue screening in those women vaccinated before their sexual debut with 9-valent vaccine is unclear, but it is preferable to continue screening until new screening guidelines are issued.
| Implementation of Human Papillomavirus Vaccination | | |
The inclusion of the vaccine in national vaccination programs is the best way to implement HPV vaccination. Several countries such as Australia, the United Kingdom, and Denmark have done this with relative success.[21],[22],[23] Vaccine acceptance in the USA has been suboptimal when compared to other developed countries.[24],[25] This shows the importance of proper information and health education of the parents regarding the safety and efficacy of HPV vaccination. School-based vaccination programs are optimal as the target population can be easily approached in schools.
Australia is an important example for a very successful fight in the prevention of invasive cervical cancer. Their screening program for cervical cancer prevention has been well established since 1991. The burden of cervical cancer over a decade between 1991 and 2002 reduced from 18 to 6–7/100,000. HPV vaccination with the quadrivalent vaccine was introduced in 2007 for girls and extended to boys in 2013 (gender-neutral approach). The prevalence of 4 vaccine-type HPV declined from 28.7% to 2.3% in vaccinated women from 2010 to 2012.[26],[27] Further, they have switched to a 2-dose course of the nonavalent HPV vaccine Gardasil 9 (9vHPV vaccine), from January 2018.[26] With the above measures and the recent move of the Australian government to shift to primary HPV screening, it is estimated that its likely to achieve rates of less than 4 per 1000,000 women by 2035 if current rates of screening and vaccination coverage can be maintained.[28] The recently created “HPV FASTER” protocols aim to offer a combined approach of HPV vaccine between 25 and 45 years, with concomitant HPV-DNA test for women 30 years and above, followed by the assessment of women who screen HPV positive.[29]
| Human Papillomavirus Vaccination in India | | |
In India, HPV vaccines were introduced in 2008 (bivalent and quadrivalent), and 9-valent vaccine was approved a decade later. For the first time, HPV vaccination was introduced in large scale in 2009 as a demonstration project to test the feasibility, acceptability, and implementation of vaccination through the existing public health services by the joint efforts of Gujarat and Andhra Pradesh governments in collaboration with the Indian Council of Medical Research and the Program for Appropriate Technology in Health, a nongovernmental organization. This demonstration project was stopped due to the alleged death of 5 girls in Andhra Pradesh and two deaths in Gujarat following vaccination, which were later investigated and found to be due to other causes unrelated to HPV vaccination.[30],[31] This incident also led to the suspension of another Indian multi-center cluster-randomized study started in 2009 to compare the efficacy of two doses against 3 doses of quadrivalent HPV vaccine for preventing persistent HPV infection and cervical neoplasia.[32] The suspension led to another default group of girls who had received only one dose of vaccine. Despite the suspension of vaccination, follow-up of the study participants was continued, and the researchers have shown that two doses of HPV vaccination was as immunogenic as three doses and even one dose of vaccine led to sustained antibody levels against HPV 16 and 18, even though slightly inferior when compared to 2-dose or 3-dose schedule. The main result of the study was that for girls aged 9–15 years, two doses were as effective as three doses in increasing the antibody levels, and this finding will substantially reduce the cost of mass vaccination in resource-constrained countries. They also reported the absence of any serious adverse events associated with HPV vaccination. Further follow-up of this study is continuing to assess the reduction in preinvasive lesions with fewer than standard 3-dose schedule.[33],[34]
After a gap of 7 years, the first state to introduce HPV vaccination in India was Punjab in 2016, when the state health department of Punjab included two-dose HPV vaccination as a part of the immunization program, in which school-going girls between the age 11–12 years were vaccinated.[35] Health education of parents about the benefits of the vaccine was done through the “Punjab Edusat network.”[36] They were able to cover 98% of the target population with two doses indicating high acceptability and compliance with the intervention.[30]
Following Punjab, two-dose schedule was introduced in Sikkim in 2018, where again 97% coverage was noted.[30] Opportunistic HPV vaccination was used in Delhi, and 4741 girls have been vaccinated by 2018 December.[30]
| Challenges | | |
Vaccine hesitancy is a big issue in the implementation of vaccines, not only in India but also in developed countries such as Japan, the USA, Denmark, and Ireland.[37] In a survey done in the USA, top five reasons quoted by parents who did not intend to have their daughters vaccinated were: “the vaccine was not needed, the vaccine was not recommended, concern about vaccine safety, lack of knowledge about the vaccine or disease, and lack of sexual activity by their daughter.”[38] Health education and sensitizing parents of the target population is very important for implementing HPV vaccination in a large scale.
Numerous studies have reported that awareness about preventive measures available for cervical cancer is poor among women in India.[39],[40],[41] Moreover, there are a multitude of challenges due to initial problems that occurred during the demonstration project of 2009, such as poor media publicity, controversy, and confusion surrounding the safety in our country, along with moral and cultural issues. Furthermore, there are certain unanswered questions regarding how long the immunity will last? Are the endpoints used in trials valid? How effective are these vaccines in decreasing mortality due to invasive cervical cancer? What about the cost-effectiveness of HPV vaccines? Added to this, experts have also questioned the need to introduce HPV vaccines as part of the National Immunization Program when the incidence of cervical cancer is already on a decline.[42],[43],[44]
Although important bodies like the National Technical Advisory Group on Immunization have advised its inclusion in the universal immunization program and professional societies such as Federation of Obstetrics and Gynaecology Societies of India and the Indian Academy of Paediatrics recommend its use, it is yet to be implemented.[30]
| Cost-Effectiveness | | |
Diaz et al. did a cost-effectiveness study for three modalities to reduce the incidence of cervical cancer in India-implementation of preadolescent vaccination of girls before age 12, screening of women over age 30, and combined vaccination and screening. They reported that if we assume coverage of 70%, HPV-16, -18 vaccination alone will reduce the lifetime cancer risk by 44% compared to 21%–33% with screening three times per lifetime. The risk reduction was 56%–63% if both the modalities were used. They concluded that vaccination followed by screening three times per lifetime would reduce cancer deaths by half and be cost-effective in India.[44]
| Conclusions | | |
Three effective tools available for us to prevent invasive cervical cancer are HPV vaccine, screening for cervical cancer followed by treatment of preinvasive cervical lesions. The WHO has called for the elimination of cervical cancer globally using the same effective tools, especially in countries with a high burden of cervical cancer. It is estimated that HPV vaccination before sexual debut and cervical screening at least twice in a lifetime will help prevent around 13 million cervical cancer cases worldwide, and most of the countries will be able to achieve the incidence of <4/100,000 women by 2100.[1] Challenges in achieving these numbers are manifold and include vaccine manufacture and delivery, vaccine hesitancy, setting up of cervical screening and effective treatment of precursors, and most importantly, committed financial support for both HPV vaccination and cervical screening on a large scale. WHO's call for the elimination of cervical cancer is expected to act as a catalyst in developing countries for influencing a policy change. In developing countries like India, elimination goal can be achieved only by the commitment of state and central governments and nongovernment organizations.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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