HPV Vaccination




© Springer Science+Business Media Singapore 2017
Sumita Mehta and Poonam Sachdeva (eds.)Colposcopy of Female Genital Tract10.1007/978-981-10-1705-6_7


7. HPV Vaccination



Saritha Shamsunder  and Deepika Pannu1


(1)
Department of Obstetrics and Gynecology, Vardhman Mahavir Medical College and Safdarjung Hospital, Delhi, India

 



 

Saritha Shamsunder




7.1 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.


7.2 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).


7.3 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.


7.4 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 [68].

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).


7.5 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].


7.6 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.

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Aug 25, 2017 | Posted by in GYNECOLOGY | Comments Off on HPV Vaccination

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