Human Papilloma Virus Vaccines

1. Introduction

It has been said that communities, countries, and ultimately the world are only as strong as the health of their women. Cervical cancer is a bane to women in their reproductive age. Addressing this dynamic issue will keep societies intact. Globally, cervical cancer is the fourth most common cancer in women, with nearly 6,04,000 new cases being reported in 2020. Almost 90% of Cervical cancer related deaths occur in low- and middle-income countries. Human papillomavirus (HPV) is the most common sexually transmitted infection globally [1, 2, 3]. Though majority of HPV infections are asymptomatic with spontaneous resolution, persistent infections pose the risk of developing into anogenital warts, precancerous lesions, and cervical, anogenital, or oropharyngeal cancers in both women and men. Over 200 identified HPV types exist, each with its own distinct tropism – a preference for specific tissues. Low-risk HPV strains like 6 and 11, often acquired through skin-to-skin contact, are the culprits behind familiar warts, whereas the high-risk HPV strains, like 16 and 18, promote uncontrolled proliferation, paving way for the development of various cancers [1, 2, 3].

The history and discovery of the human papillomavirus (HPV) cradles a fascinating journey through scientific theories, scientific investigations, virology, and medical breakthroughs. Despite being a radical breakthrough in preventing cancer, the evolution of HPV vaccines brought home some disregarded ethical issues. HPV, the human papilloma virus is a diverse group of DNA viruses, that was first identified and studied in the mid-20th century, paving way for understanding its implications in various medical conditions, particularly in the realm of oncology. Head start research began in the 1930s and 1940s with focus on causative agents behind genital warts and cervical cancer [1, 2].

The identification and isolation of HPV strains happened gradually over years. History was etched in 1976, with isolation of the first HPV types, HPV-1 and HPV-2, from plantar warts by Dr. F.M. Jablonska-Kaszewska and colleagues. It wasn’t until the use of techniques like DNA hybridization during the 1970s and early 1980s that identification of specific types of HPV associated with cervical cancer was made possible. Dr. Zur Hausen and his team in the early 1980s, identified HPV types 16 and 18 as the prominent culprits behind cervical cancer. Dr. Zur Hausen’s groundbreaking discoveries led to a paradigm shift in understanding the role of HPV in cervical cancer and thus initiating a cascade of research in this arena. He was later awarded the Nobel Prize in Physiology or Medicine in 2008.

Following these discoveries, the development of HPV vaccines became a significant stride in preventive medicine. The first HPV vaccine, Gardasil, targeting the most prevalent cancer-causing HPV types was introduced in 2006 [3, 4]. Subsequent advancements led to the development of more comprehensive vaccines with broader coverage against multiple high-risk HPV strains. Vaccination offers robust protection against HPV-associated cancers and precancerous lesions. Research into HPV’s implications in various cancers has propelled medical understanding and kickstarting of public health initiatives. Ongoing efforts tend to focus on improving vaccination accessibility, enhancing screening methods, and expanding knowledge of HPV-associated diseases, emphasizing its role in diverse malignancies.

For bringing this into action, the World Health Organization (WHO) evolved strategies for cervical cancer elimination. Achieving a global target of 90% vaccination coverage, providing 70% twice-lifetime screening, and enabling 90% treatment of preinvasive lesions and invasive cancer by 2030 was devised. Global statistics on HPV disease prevalence and the extent of vaccination coverage provided will help in achieving this global target by 2030.

2. Epidemiology

Global statistics reveal that this preventable disease had claimed the lives of over 310,000 women in 2018 [5]. Around 90% of the deaths reported occurred in the low-income and middle-income countries (LMICs). This same year saw approximately 570,000 new cases of cervical cancer being reported. Five major genera of HPV have been identified as alpha, beta, gamma, mu, and nu. The most common identifies variant is gamma with 99 known HPV types. A recent study has further identified 69 additional gamma variants. (VIDE Figure 1).

An alpha subgroup of human papillomavirus has been attributed to be a high-risk group (HR HPV). They are implicated in the progression of HPV infections to anogenital cancer and a subset of head and neck cancer. Though the beta and gamma genera are present on the skin surface in the general population, the etiological role of beta papillomaviruses (beta HPVs) in non-melanoma skin cancer (NMSC), is gaining importance. Studies have revealed that the oncoproteins E6 and E7 alter host immune response pathways, promote cellular transformation, and establish a persistent HPV infection thereby progressing to cervical cancer. E6 and E7 oncoproteins need to be expressed continuously for mucosal HR HPV type infection maintenance. But this is not required in case of cutaneous HPV types progressing to skin cancers. Beta HPV type act as facilitators of skin carcinogenesis especially NMSC by amassing UV radiation induced DNA breaks and mutations [6, 7].

3. Etiopathogenesis

Various factors influence the pathogenesis of HPV. Viral genotype, host susceptibility, immune response, and environmental factors contribute to the clinical manifestations associated with HPV infection. Anybody can contract HPV, but certain factors increase the likelihood like – multiple sexual partners, early age of sexual debut, weakened immune system as in patients with HIV/AIDS.

HPV is a diverse family of non-enveloped, double-stranded DNA viruses, with various genotypes exhibiting exquisite tropism for specific epithelial tissues. Low-risk strains, commonly HPV6 and 11 have a predilection for skin keratinocytes, leading to common and plantar warts. High-risk genotypes like HPV16 and 18, exhibit a predilection for mucosal epithelia, of anogenital and oropharyngeal regions, thus leading to development of various cancers associated with HPV [1] (VIDE Table 1).

An icosahedral capsid contains the HPV genome and is divided into three regions – the early (E) region, late (L) region and the Long Control Region (LCR). The early (E) region has different types of precursor proteins E1, E2, E4, E5, E6, and E7, which are essential in the early stages of infection and DNA replication. Among these, E6 and E7 have the major role in regulating the pathogenicity of the virus. The major and minor viral capsid structure is coded by the late (L) region proteins with two parts, L1 and L2. Viral replication and transcription are controlled by a non-coding region, the Long Control Region (LCR).

Proteins and specific functions

1. E1 Regulate viral DNA replication

2. E2 Regulatory factors of viral transcription

3. E4 Promote virus maturation and release

4. E5 Regulate growth factor signaling pathway

5. E6 Promotes the degradation of P53 and increases resistance to apoptosis

6. E7 Promotes retinoblastoma protein (pRb) degradation, affects the cell cycle and stimulates cell proliferation

7. L1 Major capsid protein is important for virus assembly and stability

8. L2 Secondary capsid protein is important for virus infection

Persistent HPV infections can lead to precancerous squamous intraepithelial lesions (SIL) or cervical intraepithelial lesions (CIN). SIL is further graded as LSIL / HSIL and CIN is further graded as CIN 1, CIN 2, and CIN 3. (VIDE Figures 2 and 3).

Microabrasions and hair follicles serve as entry points for the viral particles to invade the basal keratinocytes. HR HPV can directly invade the squamocolumnar junction of the cervix making it a prime target site for infection. Another similar direct breach of the epithelial lining is found to occur in the tonsillar crypts. E6 and E7 oncoproteins defy the cellular aging process and boost impromptu cell growth [5, 6, 7]. HPV mediated cellular transformation requires high expression of oncoproteins E6 and E7. This enhanced expression is favored by the loss of E2 repressive functions (VIDE Figure 4).

The pathogenesis of Human Papilloma Virus can lead to serious health consequences. Through vaccination, early detection, and targeted treatment, we can significantly reduce the disease burden of HPV-associated illnesses. Unraveling the mysteries of HPV pathogenesis equips us to break the cycle of infection and create a future free from its shadow.

4. History of vaccine development

The notoriety of HPV to cause malignancies has led to aggressive multi-modal therapies. This includes primary surgery coupled with radiation and chemotherapy. The consequences of these treatment methods are highly toxic with most patients experiencing adverse effects like xerostomia, dysphagia, and in the long run become dependent on gastrostomy tubes thus markedly compromising the quality of life [8, 9]. This led to the search for better and alternative methods of treatment. Experimental therapy for patients with HPV mediated malignancies led to the development of vaccines to combat HPV infections. It led to the development of vaccines which can be grouped as prophylactic vaccines and therapeutic vaccines. Vaccination curbs HPV infections proving beneficial for the vaccinated person as well their future sex partners by preventing the spread of transmission along with other barrier methods of protection (VIDE Table 2).

5. Vaccines currently in use

The Human Papilloma Virus vaccine was first developed by Professors Ian Frazer and Jian Zhou at the University of Queensland in Australia. They synthesized “virus-like particles” (VLPs), containing proteins like those from the outer layer of the HPV, in 1990. After 7 years, the first human trials for Gardasil, the first HPV vaccine was completed. This was followed by approval for Cervarix – a bivalent vaccine and Gardasil 9 – a nonavalent vaccine. Only HPV prophylactic vaccines have received approval for use. Considering the role of early proteins E6 and E7 in the pathogenesis of cancerous and precancerous lesions associated with HPV, therapeutic vaccines are under clinical research and development. There are various molecules under phase II and phase III trials. (VIDE Figure 5).

5.5 Alternative single dose schedule

In view of the decline in the first dose of HPV vaccination coverage from 25–15% between 2019 and 2021, the WHO’s independent expert advisory group, SAGE (Strategic Advisory Group of Experts) came up with an alternative single dose regimen (VIDE Figure 6). It was suggested as an off-label option to be used in girls and boys aged 9–20 years. Compared to the routine dosing schedule, this single dose schedule is deemed to offer better compliance and improved coverage. Single dose schedule is not recommended in immunocompromised individuals [4].

One dose efficacy with Cervavac has not yet been established [10].

6. Vaccines in the pipeline

7. Conclusion

The HPV vaccination program has markedly transformed the health status of women globally. It has helped in decreasing HPV infections and associated cancers. The hesitancy of individuals to opt for HPV vaccinations remains a hurdle in achieving the WHO goal of global cervical cancer elimination by 2030. The impact of HPV vaccination in males has been overlooked and one of the prime reasons cited is the lack of physician recommendation on it [14]. A systematic review published from Portugal in June 2023, has thrown light on the agonizing truth that only 4% of men worldwide were fully vaccinated against HPV as of 2019. Literatures imply evidence of HPV vaccine efficacy in men up to 26 years of age. Keeping increased vaccination coverage as a public health priority, the FASTER Strategy protocol was put forth to bridge the disconnect between HPV screening and vaccination and hasten reduction in HPV related infections and cervical cancer mortality [15]. Considering the role of early proteins other than E6 and E7 in the development of HPV related cancers, further exploration to encompass other antigens will widen the horizon to successfully generate more effective therapeutic vaccines.