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1 Introduction

Human papilloma viruses are small non-enveloped DNA viruses that belong to the Papovaviridae family. The viral capsid is composed of two proteins: L1 and L2. Of more than 100 different HPV types identified, 40 of these infect the genital tract [1]. These mucosal HPV types are classified as low-risk and high-risk types based on the prevalence ratio in cervical cancer and its precursors. HPV infections are highly transient and mostly clear within 2 years. The small proportion of HPV infection that persists can cause neoplastic change. Various modes of transmission of HPV are documented, viz. physical contact via autoinoculation or fomites, sexual contact and vertically from the HPV-positive mother to her newborn, causing subclinical or clinical infections.

Oncogenic types of HPV are known to cause 100 % of cervical cancer, 90 % of anal cancer, 40 % of cancers of the vulva, vagina and penis and 12 % of head and neck cancers [2]. Approximately, 70 % of all cases of cervical cancer are associated with HPV genotypes 16 and 18, and 90 % of cases of genital warts are associated with HPV genotypes 6 and 11 [2].

India has the highest incidence of cervical cancer in the world with an age-standardised incidence of 22 per 10,000 females and 67,477 deaths reported in 2013 due to cervical cancer, falling just behind breast cancer [3]. It has been estimated that there will be around 2,05,496 new cases and 1,19,097 deaths due to cervical carcinoma by 2020 in India [4]. Primary prevention by HPV vaccination can prevent most cases of cervical cancer in females, if given before exposure to the virus prior to first sexual debut. In addition, it can prevent vaginal and vulvar cancer in females, and genital warts and anal cancer in both males and females.

2 Development

The vaccine development was initiated in parallel, by researchers at Georgetown University Medical Center and the University of Rochester in the USA, the University of Queensland in Australia and the US National Cancer Institute.

The US Food and Drug Administration approved Gardasil (HPV4) manufactured by Merck against four types of HPV, in 2006, and Cervarix (HPV2) manufactured by GlaxoSmithKline against two high-risk types of HPV in 2009 [5], both of which are commercially available in India and approved by the Drug Controller General of India (DCGI).

3 HPV Vaccine

Recombinant DNA technology is used to express the L1 major capsid protein of HPV in yeasts, which self-assemble to form empty shells resembling a virus, called virus-like particles (VLPs). The VLPs have the same outer L1 protein coat as HPV but contain no genetic material. The vaccine uses these VLPs as antigens to induce a strong protective immune response [6, 7].

If an exposure occurs, the vaccinated person’s IgG antibodies against the L1 protein coat of the virus prevent it from releasing its genetic material.

4 Types of Vaccine

Two prophylactic HPV vaccines are being marketed.

Gardasil® the quadrivalent vaccine is manufactured by Merck. It contains VLP antigens for HPV6, 11, 16 and 18, reassembled from L1 proteins of HPV6 (20 μg), 11 (20 μg), 16 (40 μg) and 18 (40 μg), and is designed to protect against infection and disease due to these types. It is produced using yeast substrate, and contains the adjuvant amorphous aluminium hydroxyl phosphate sulphate [6–8].

Cervarix®, the bivalent vaccine, is manufactured by GlaxoSmithKline (GSK). It contains VLP antigens for HPV16 and 18 reassembled from L1 proteins of HPV16 (20 μg) and HPV18 (20 μg) and is designed to protect against infection and disease due to these types. It is produced using a novel recombinant baculovirus expression system and a cell line derived from Trichoplusia ni cells. It contains the adjuvant AS04, which includes monophosphoryl lipid A (MPL).

5 Immunogenicity

Natural immune response: HPV infections are cleared from the body by the action of two different pathways of immune response.

Firstly, the humoral response leads to the production of neutralising antibodies, which will prevent the virus from entering the epithelial cell. These antibodies, although useful in the prevention of primary infection of basal keratinocytes, are insufficient to prevent new infections [9].

Secondly, the HPV enters the cell through contact with the basal membrane and gets internalised. After internalisation, the epithelial cell sheds the capsid, losing L1 and L2. The cytotoxic T cells then react with infected cells through the recognition of expressed viral proteins for the cellular clearance of HPV [9]. This mechanism is less understood.

Immune response by vaccination: Protection against infection by vaccines is believed to be achieved from neutralising serum immunoglobulin (IgG) antibody, which transudates from capillaries to the genital epithelial mucosa, and binds to viral particles. This serological response is much stronger than the response towards a natural infection, which is likely due to the use of specific adjuvants, the strong immunogenicity of the VLPs themselves as well as the route of administration.

Both vaccines induce serum antibodies for all vaccine-related types in more than 99 % of females after three doses (month 7), and antibody levels for all vaccine-related types are several times higher than those seen after natural infection in all ages [10].

Titres peak after the third dose, gradually decline and level off by 24 months after the first dose; they then remain stable at levels as high as, or higher than, levels seen after natural infection.

The quality of the antibody response is best for HPV16 for both vaccines. The quality of the antibody response to HPV6/11/18 for Gardasil is much poorer than its response to HPV16. Cervarix induces an equally high and sustained antibody response to HPV16/18 [1].

There is some evidence from clinical trials that vaccination might result in some cross protection against other HPV types not included in the vaccine possibly explained by phylogenetic similarities between L1 genes from vaccine and non-vaccine types. It is still not known how long cross protection lasts [1].

HPV16 is most closely related to HPV31 and HPV18 is most closely related to HPV45. The bivalent vaccine gives cross protection against both of them in addition to HPV16 and 18. The quadrivalent vaccine gives 40.3 % cross protection against HPV31 and 45 and 32 % cross protection against HPV31, 33, 45 and 52 [6].

HPV4 vaccine has also demonstrated, together with the protection against cervical cancer, high efficacy against genital warts due to HPV types 6 and 11, vaginal and vulvar precancerous lesions, re-infection, persistent infection and anal precancerous lesions [6].

The bivalent and quadrivalent vaccines available are prophylactic, not therapeutic. Participants who were already positive to any vaccine HPV types before vaccination acquired protection against disease caused by other vaccine types [11].

The immune response may be less robust in the immune-compromised patients like those with HIV-positive or patients with organ transplantation. In a phase I/II study in South Africa, the bivalent HPV vaccine was shown to be immunogenic and well tolerated in HIV-infected women up to 12 months after vaccination [12].

6 Efficacy

Both vaccines are highly immunogenic with the highest immune responses being observed in young girls aged 9–15 years. Two phase III studies, FUTURE I and FUTURE II, have evaluated the efficacy of quadrivalent vaccine. The bivalent vaccine also has been evaluated in two phase III studies, PATRICIA and the Costa Rica HPV vaccine trial. Clinical efficacy against infection and cervical lesions associated with HPV16 and HPV18 has been demonstrated up to 8.4 years with the bivalent vaccine, and up to 5 years with the quadrivalent vaccine [1, 13].

Studies of the quadrivalent HPV vaccine have shown that in participants naive to the vaccine genotypes who followed protocol, the vaccine was almost 100 % effective in preventing high-grade cervical intraepithelial neoplasia CIN 2 and CIN 3 and condylomatous vulvar disease related to the HPV genotypes covered by the vaccine [1, 10]. It was shown to have nearly 100 % protection against genital warts associated with HPV6 and 11, and an efficacy of about 83 % for all genital warts.

For the bivalent vaccine, the efficacy shown by the PATRICIA trial is 95 % for CIN 2 and 100 % for AIS [1, 10]. Results of the studies of this bivalent vaccine indicate that it offers protection similar to the quadrivalent vaccine against HPV infections caused by genotypes 16 and 18 [6–8]. The bivalent vaccine does not protect against lower genital tract condyloma caused by low-risk HPV types 6 and 11 [1].

One study reported that in men who have sex with men, the quadrivalent vaccine was 77.5 % effective in preventing anal intraepithelial neoplasia related to HPV genotypes 6, 11, 16 and 18 [14]. US FDA has approved the quadrivalent vaccine for the prevention of anal cancer and associated precancerous lesions that are caused by these genotypes [15].

The need for booster doses remains to be demonstrated.

7 Dosage and Administration

They are available as 0.5-mL suspension for intramuscular injection.

Both of the vaccines are currently marketed as single-dose vials or prefilled syringes which require storage and transport in a cold-chain system [14].

8 Method of Administration

The vaccines are for intramuscular use only. Thorough shaking immediately before administration is necessary to maintain suspension of the vaccine. After thorough agitation, this vaccine is a white, cloudy liquid. Vaccine should not be diluted or mixed with other vaccines.

The vaccine should be administered intramuscularly in the deltoid region of the upper arm or in the higher anterolateral area of the thigh.

Observation for 15 min after administration is recommended. Syncope has been reported following vaccination.

9 Storage

Both formulations should be stored at 2–8 °C and should not be frozen.

10 Schedule

Cervarix: It is given as three intramuscular injections at 0, 1 and 6 months.

Gardasil: It is given as three intramuscular injections at 0, 2 and 6 months.

Minimum interval between first and second dose is 4 weeks. Between second and third dose is 12 weeks. Interval between first and third dose is 24 weeks. If the vaccine schedule is interrupted, the series does not need to be restarted, regardless of the length of time between the doses [15].

At present, there is no data to support the use of boosters.

In March 2014, the Joint Committee on Vaccination and Immunisation (JCVI) of the United Kingdom revised its existing recommendation to change from a three- to a two-dose schedule [16]. Recent research shows that antibody response to two doses in adolescent girls is as good as a three dose course in this age group. Two doses schedule of HPV vaccine has also been recommended by Indian academy of Pediatrics.

Testing for HPV DNA is currently not recommended for adolescents or adults before vaccination. However if the patient is tested and the results are positive, vaccination is still recommended [15].

11 Recommended Target Population

Target age: The Advisory Committee on Immunisation Practices has recommended that HPV vaccination should routinely be given to girls when they are 11 or 12 years old. The vaccine can be given to individuals as young as 9 years; catch-up vaccination is recommended in females aged 13 years through 26 years. ACOG also endorses the same [15, 17].

The Indian Academy of Pediatrics Committee on Immunisation (IAPCOI) recommends offering HPV vaccine to all females who can afford the vaccine (Category 2 of IAP categorisation of vaccines) [14].

Women aged 19–26 years are more likely to have been exposed to HPV; the American Cancer Society therefore suggests that the decision to vaccinate women in this age range should be made on an individual basis.

Data available are insufficient to make recommendations for women older than 26 years.

12 Specific Issues

Sexually active adolescent: Sexually active adolescents and young women can receive either of the vaccine. However, they need to be counselled that the vaccine may be less effective if they have been exposed to HPV before vaccination [15].

Young women with previous CIN or warts: Vaccination can be given to patients with previous CIN or genital warts. This need to be emphasised to the patients that benefits may be limited and cervical cytology screening should continue afterwards as per protocols [15].

Women older than 26 years: HPV vaccines are currently not licensed for women older than 26 years [15].

Vaccination of pregnant and lactating women: Both the quadrivalent and bivalent HPV vaccines have been classified by the FDA as pregnancy category B. However, HPV vaccination in pregnancy is not recommended. Getting the HPV vaccine when pregnant is not a reason to consider terminating a pregnancy [15].

Lactating women can receive either HPV vaccine because these are inactivated vaccines and do not affect the safety of breastfeeding for mothers or infants.

Vaccination in males: US FDA has approved the quadrivalent vaccine for boys and men aged 9 years through 26 years for the prevention of genital warts. Bivalent vaccine is not recommended for use in males [15].

13 Screening After Vaccination

The vaccines do not protect against all HPV types; hence, they will not prevent all cases of cervical cancer. About 30 % of cervical cancers will not be prevented by the vaccines, so it will be important that women continue to get screened for cervical cancer [1, 15].

14 Safety

WHO Global Advisory Committee on Vaccine, FIGO Committee on Gynecologic Oncology and the FIGO sub-committee for Cervical Cancer Prevention reviewed all the data available on the safety of vaccine and concluded that both HPV vaccines are generally safe and well tolerated [18]. This conclusion was based on 4 or more years of trial data and 1 year of passive, post-marketing surveillance data on the quadrivalent vaccine in the United States. No safety concerns were reported in a study on bivalent vaccine for up to 9.4 years and with quadrivalent vaccine up to 5 years of follow-up post vaccination. Safety of the vaccines has not been established in pregnant women [6, 19].

15 Contraindications

Hypersensitivity, including severe allergic reactions to yeast (a vaccine component), or after a previous dose of vaccine, has been reported [15].

16 Adverse Reactions

Headache, fever, nausea, and dizziness and local injection site reactions (pain, swelling, erythema, pruritus and bruising) have occurred after administration of vaccine [15, 17].

Syncope, sometimes associated with tonic-clonic movements and other seizure-like activities, has been reported following vaccination and may result in a fall leading to injury; observation for 15 min after administration is recommended.

Anaphylaxis has also been reported (0.1 %). Reported rates of anaphylaxis following HPV vaccination have been consistent in both national passive surveillance and population-based studies and found to be 1–10 cases per million doses, which compares favourably with other vaccines [18].

Guillain-Barre syndrome (GBS): Population based studies have not provided any evidence that GBS is significantly greater than that expected in the adolescent and young females [18].

Venous thromboembolism (VTE): Studies reported this to be unlikely due to vaccination [18].

17 New Developments

17.1 Nine-Valent Vaccine

The currently registered vaccines cover only HPV6, HPV11, HPV16 and HPV18. It is estimated that this would protect against 70 % of all squamous cell cancers. To increase the protection, studies are on-going to increase the number of HPV types to nine by adding HPV31/33/45/52 and 58 to the quadrivalent vaccine.

This vaccine, code named V503, is tested in eight trials registered at clinicaltrials.gov. The results of the trials are still unpublished. From mathematical modelling, it was calculated however that this vaccine could raise the protection to 90 % of all SCC cases worldwide [1, 20].

17.2 Prophylactic L2 Vaccines

Recently, success has been reported in mice by the use of bacteriophage VLPs and orally administered Lactobacillus casei expressing L2 on their surface. The latter induced a significant vaginal mucosal immunity with production of broadly protective IgA, which could be effective in early phases of the viral infection, suggesting that this type of oral immunisation may be a promising strategy for prophylactic vaccination of humans [1].

17.3 Therapeutic Vaccines

A lot of trials have been conducted to develop therapeutic vaccines against HPV infection. Most HPV therapeutic vaccines target carcinoma-associated HPV proteins, particularly E6 and E7, to generate the T cell-mediated response. Various forms of HPV vaccines, such as peptide-based vaccines, protein based vaccines, DNA-based vaccines, live vector-based vaccines, chimeric VLP-based vaccines and cell-based vaccines have been tested targeting HPV16 E6 and/or E7 proteins. Recently, phase 1 trial using recombinant E7 protein of HPV16 and 18 concluded it to be safe [1].

18 Summary

Two types of prophylactic vaccines have been approved. Both vaccines are based on VLPs of the L1 capsid protein, and are highly immunogenic and efficacious. The vaccine if given before exposure can protect against 70 % of the cervical cancers. HPV vaccine should be routinely targeted to females aged 11–12 years. Vaccine is given as three doses of intramuscular injections. Safety data for both of the vaccines is reassuring. Cervical cytology screening should continue as per protocol. Quadrivalent vaccine has also been recently approved for use in males.

Key Points

  • Two prophylactic vaccines Cervarix which is bivalent and Gardasil which is quadrivalent are approved.

  • Screening should continue as per recommendations after immunisation.

  • Recommendations are to give vaccination routinely to girls 11–12 years (can be started as early as 9 years).

  • Catch-up vaccination can be given from age 13 through 26 years.

  • Nine-valent and prophylactic L2 vaccine are newer developments.

  • Clinical efficacy is demonstrated up to 8.4 years with the bivalent vaccine, and up to 5 years with the quadrivalent vaccine.

  • Cross protection is demonstrated with HPV types 31, 33, 45 and 52.