Guidelines for Adult Immunisation

Available Vaccines

Human Papillomavirus

Introduction

Human papillomaviruses (HPVs) are small, non-enveloped, double-stranded DNA viruses in the Papillomaviridae family. The genome is enclosed by an icosahedral capsid composed of major and minor structural proteins, L1 and L2 respectively. HPVs are highly tissue-specific and infect both cutaneous and mucosal epithelium. More than 200 HPV types have been identified and about 40 HPV types infect the anogenital tract. Some HPV types, including types 16, 18, 31, 33, 35, 45, 52 and 58, are ‘high-risk’, as they are causally associated with the development of cancer in humans.  The International Agency for Research on Cancer defines 12 HPV types as ‘high-risk’: types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59. Other HPV types, including types 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 73, 81 and 89, are classified as ‘low-risk’ and are predominantly associated with non-malignant lesions, such as genital warts. Infection with HPV is very common in both men and women, with initial infection related to the time of sexual debut.

HPV infection is often sub-clinical and transient, but low-risk HPV types may cause lesions that include cutaneous warts, genital warts and respiratory papillomatosis. The low-risk HPV types 6 and 11 cause 90% of anogenital warts and almost all recurrent respiratory papillomatosis. Anogenital HPV infection with low-risk types causes benign skin and mucosal tumours, including anogenital warts in both females and males (condylomata acuminata or venereal warts). In a systematic review of global estimates, the overall reported annual incidence of anogenital warts in both males and females, (including new and recurrent) ranged from 160 to 289 per 100 000. Prevalence ranged from 0.15% to 0.18% in the general population.

High-risk HPV types may cause dysplasias and cancers of the cervix, vulva, vagina, penis, anus, the oral cavity and oropharynx. Most genital HPV infections are self-limiting with complete recovery but in about 20% of infections, the virus persists. Persistent infections, within months or years, may progress towards premalignant glandular or squamous intra-epithelial lesions, classified histopathologically as cervical intra-epithelial neoplasia (CIN), and to HPV-associated cancers. CIN is further classified as: CIN 1: mild dysplasia; CIN 2: moderate to marked dysplasia; and CIN 3: severe dysplasia to carcinoma-in-situ. Most CIN lesions regress spontaneously, though over a number of years, the lesions can slowly become cancerous.

HPV-16 and HPV-18 are the most frequent types worldwide, with HPV-16 the most common type in all regions. Worldwide, high risk HPV types 16 and 18 cause about 70% of cases of cervical cancers. HPV-16 and 18 are associated with 85% of HPV-related head and neck cancers and 87% of anal cancers. HPV types 16, 18, 45, 31, 33, 52, and 58 account for approximately 90% of the squamous cell carcinomas which are positive for HPV DNA. It was estimated that 630 000 new HPV-related cancers occurred in females in 2012, of which 528 000 (84%) were cervical cancer and 266,000 female deaths, accounting for 8% of all female cancer deaths that year. The majority (around 85%) of the global burden occurs in the less developed regions, where it accounts for almost 12% of all female cancers. Most of these occur in females who are not screened or who do not receive early treatment. In Malaysia, statistics prior to 2007 and the National Cancer Registry data for 2007-2011 reported cervical cancer as the third most common cancer among women in Malaysia after breast and colorectal cancers.

Persons infected with one HPV type may be co-infected or subsequently infected with other types. HIV-positive men who have sex with men showed the highest HPV prevalence. Anal HPV infections are very common in men who have sex with men, and almost universal among people with HIV infection.

High risk HPV 16 and 18 which cause about 70% of cervical cancers, are covered by all three HPV vaccines. HPV 31, 33, 45 are the three high-risk types against which the bivalent vaccine (2vHPV) and quadrivalent vaccine (4vHPV) may afford cross-protection, which are associated with a further 13% of the cases. HPV 31, 33, 45, 52, 58 altogether (five high-risk types against which only 9vHPV affords direct protection) are associated with 18% of the cases, a further 5% compared with HPV 31, 33, 45.

WHO’s Strategic Advisory Group of Experts (SAGE), on vaccines and immunisation recommended the use of HPV vaccine in November 2008. The updated complete position paper published in April 2018 incorporates recent developments concerning HPV vaccines, including the licensure of a nonavalent (9-valent) vaccine (9vHPV). New recommendations are proposed regarding vaccination strategies targeting girls only or both girls and boys, and vaccination of multiple birth cohorts. Vaccination of older adolescents and adults should be based on assessments of the potential benefits, based on their risks of HPV exposure. Over 80 countries worldwide now have HPV vaccination programs. However, there are still barriers to HPV vaccine introduction, mostly in countries with the highest burden of cervical cancer and the greatest need for vaccination.

HPV vaccination form part of a coordinated and comprehensive strategy to prevent cervical cancer and other diseases caused by HPV. Regular cervical screening, which detects histopathological changes, remains an important preventive measure against cervical diseases. Both are recommended. Vaccination protects against most, but not all, HPV types that cause cervical cancer as well as the broader spectrum of cancers and other HPV-diseases. There are also other infections and risk factors associated with cervical cancer. Likewise, cervical screening is not an alternative to HPV vaccination and is recommended for both vaccinated and unvaccinated women. The vaccines have no therapeutic effect on existing HPV-related conditions or diseases, but may prevent future dysplasia due to different HPV types targeted by the vaccine. The vaccine does not prevent other sexually transmitted infections. Therefore, all vaccinated individuals should continue to practice safe sex, abstinence or protective sexual behaviours, such as condom use

Vaccines

 

Three highly efficacious HPV vaccines directed against high-risk HPV types are currently available and marketed in many countries worldwide. The vaccines are produced from non-infectious HPV virus-like particles (VLPs) developed through recombinant DNA technologies. The 4vHPV vaccine was first licensed in 2006, 2vHPV in 2007 and 9vHPV in 2014. Current evidence suggests that from the public health perspective, the three vaccines offer comparable immunogenicity, efficacy and effectiveness for the prevention of cervical cancer, which is mainly caused by HPV-16 and HPV-18. All three HPV vaccines have excellent safety profiles. The vaccines do not treat women with current HPV infection or related diseases. HPV vaccines are most efficacious in HPV-naive individuals, if administered before sexual debut. All three vaccines are registered for use in females, and the 4vHPV and 9vHPV vaccines are also registered for use in males.

1. Cervarix® – GlaxoSmithKline

  • Bivalent HPV vaccine (2vHPV)

  • Contains non-infectious major capsid (L1) protein of HPV types 16 and 18.

  • Produced using a baculovirus expression system in Trichoplusia ni insect cell line.

  • Volume of 0.5mL per dose, in vial or pre-filled syringe contains 20µg of HPV-16 L1 protein and 20 µg of HPV-18 L1 protein adsorbed onto a proprietary adjuvant system containing 500 µg of aluminum hydroxide and 50 µg of 3-O-desacyl-4-monophosphoryl lipid A (AS04). 

  • Indicated for use in females from the age of 10-45 years for the prevention of premalignant anogenital lesions affecting the cervix, vulva, vagina and anus, and cervical and anal cancers causally related to specific HPV types.

2. Gardasil® – Merck and Co., Inc

  • Quadrivalent HPV vaccine (4vHPV).

  • Contains non-infectious purified viral L1 capsid protein for HPV 6, 11, 16, and 18.

  • The vaccine is produced using Saccharomyces cerevisiae (Baker’s yeast), expressing L1 and includes amorphous aluminum hydroxyphosphate sulfate (AAHS) as adjuvant.

  • Volume of 0.5mL per dose, in vial or pre-filled syringe contains 20µg HPV-6 L1 protein, 40µg HPV-11 L1 protein, 40µg HPV-16 L1 protein and 20µg HPV-18 L1 protein, adsorbed onto 225µg of aluminium hydroxyphosphate sulphate; 780µg L-histidine; 50µg polysorbate 80; 35µg sodium borate adjuvant. It may also contain yeast proteins.

  • Gardasil is a vaccine indicated in girls and women 9-45 years of age for the prevention of cervical, vulvar, vaginal cancer; precancerous or dysplastic lesions and genital warts caused by HPV. Gardasil also provides protection in girls and women 9-26 years against anal cancer.

  • Gardasil is indicated to prevent the following diseases:

    >> Cervical, vulvar and vaginal, and anal cancer caused by HPV types 16 and 18.

    >> Genital warts (condyloma acuminata) caused by HPV types 6 and 11.

    >> Precancerous or dysplastic lesions caused by HPV types 6, 11, 16 and 18: Cervical intraepithelial neoplasia (CIN) grade 2/3 and Cervical adenocarcinoma in situ (AIS), cervical intraepithelial neoplasia (CIN) grade 1, vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3, vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3, anal intraepithelial neoplasia (AIN) grades 1, 2, and 3.

  • Gardasil is indicated in boys and men 9 through 26 years of age for the prevention of the following diseases caused by HPV types included in the vaccine:

    >> Anal cancer caused by HPV types 16 and 18.

    >> Genital warts (condyloma acuminata) caused by HPV types 6 and 11.

    >> Precancerous or dysplastic lesions caused by HPV types 6, 11, 16 and 18: anal intraepithelial neoplasia (AIN) grades 1, 2, and 3.

3. Gardasil 9® – Merck and Co., Inc

  • Nonavalent vaccine (9vHPV)

  • Contains non-infectious purified major capsid (L1) protein for HPV 6, 11, 16, 18, 31, 33, 45, 52 and 58.

  • The vaccine is produced using Saccharomyces cerevisiae (Baker’s yeast), expressing L1 and includes amorphous aluminum hydroxyphosphate sulfate (AAHS) as adjuvant.

  • Volume of 0.5mL per dose, in vials or prefilled syringes. Contains 30 µg of HPV-6 L1 protein, 40 µg of HPV-11 L1 protein, 60 µg of HPV-16 L1 protein, 40 µg of HPV-18 L1 protein, 20 µg of HPV-31 L1 protein, 20 µg of HPV-33 L1 protein, 20 µg of HPV-45 L1 protein, 20 µg of HPV-52 L1 protein and 20 µg of HPV-58 L1 protein adsorbed on 500 µg AAHS.

  • Gardasil 9 is a vaccine indicated in girls and women from 9 through 45 years of age for the prevention of cervical, vulvar, vaginal cancer, precancerous or dysplastic lesions and genital warts caused by HPV. Gardasil 9 also provides protection in girls and women 9- 26 years against anal cancer.

  • Gardasil 9 is indicated to prevent the following diseases:

    >> Cervical, vulvar, vaginal, and anal cancer caused by HPV types 16, 18, 31, 33, 45, 52, and 58.

    >> Genital warts (condyloma acuminata) caused by HPV types 6 and 11.

    >>Precancerous or dysplastic lesions caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58: Cervical intraepithelial neoplasia (CIN) grade 2/3 and cervical adenocarcinoma in situ (AIS), cervical intraepithelial neoplasia (CIN) grade 1, vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3, vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3, anal intraepithelial neoplasia (AIN) grades 1, 2, and 3.

  • Gardasil 9 is indicated in boys and men from 9 through 45 years of age for the prevention of anal cancer, anal precancerous or dysplastic lesions and external genital lesions (including genital warts) caused by HPV.

  • Gardasil 9 is indicated to prevent the following diseases:

    >> Anal cancer caused by HPV types 16, 18, 31, 33, 45, 52, and 58.

    >> Genital warts (condyloma acuminata) caused by HPV types 6 and 11.

    >> Precancerous or dysplastic lesions caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58: anal intraepithelial neoplasia (AIN) grades 1, 2, and 3.

 

Vaccines Available in Malaysia

 

  1. Cervarix® (Human papillomavirus vaccine types 16 & 18)
    GlaxoSmithKline Pharmaceuticals (M) Sdn Bhd/GlaxoSmithKline Biologicals S.A., Belgium

  2. Gardasil® (Human papillomavirus vaccine types 6, 11, 16 & 18)
    Merck Sharp & Dohme (M) Sdn Bhd/Merck Sharp & Dohme Corpe, USA

  3. Gardasil 9® (Human papillomavirus vaccine types 6, 11, 16, 18, 31, 33, 45, 52 and 58)
    Merck Sharp & Dohme (M) Sdn Bhd/Merck Sharp & Dohme B.V. Netherlands

Mode of Administration

 

The dose of HPV vaccines is 0.5mL, administered by intramuscular injections in the deltoid region, as a 2-dose schedule (0, 6-12 months). The 2nd dose should between 6 to 12 months after the first dose. In the year 2016, the two-dose schedule recommendation replaces the previous 3-dose schedule for persons starting HPV vaccination before the 15th birthday and for persons with certain immunocompromised conditions.

If the first dose of any HPV vaccine was given on or after the 15th birthday, vaccination should be completed according to a three-dose schedule. In a three-dose series, the second dose is recommended 1–2 months after the first dose, and the third dose is recommended six months after the first dose (0, 1–2, 6 month schedule).

If a vaccination schedule has been missed or interrupted, there is no need to repeat earlier doses. The number of recommended doses is based on age at administration of the first dose. The missed dose(s) should be given as soon as is practicable. The schedule should be completed for effective protection.

Co-administration with Other Vaccines

 
  • HPV vaccines can be co-administered with other non-live and live vaccines because the HPV vaccines are not live vaccines. HPV vaccines can be administered with other vaccines at the same visit, using separate syringes and different injection sites.

  • Co-administration of HPV vaccination with a booster dose of tetanus-diphtheria vaccination should be considered in vaccination programmes.

Contraindications and Adverse Effects

 
  • The only absolute contraindications to HPV vaccines are those with:

    >> A history of immediate hypersensitivity or anaphylaxis following a previous dose of either HPV vaccine.

    >> A history of immediate hypersensitivity or anaphylaxis to any vaccine component.

          • The 2vHPV vaccine in prefilled syringes is contraindicated for persons with anaphylactic latex allergy.

          • The 4vHPV and 9vHPV vaccines are contraindicated for persons with a history of anaphylaxis to yeast.

          • Adverse events following HPV vaccination are generally non-serious and of short duration.

  • HPV vaccines should not be given to:

    >> Those with moderate or severe acute illnesses. Wait until the illness improves before getting vaccinated.

    >> Pregnant women: data on the safety of HPV vaccination in pregnancy are limited, and HPV vaccination of  pregnant women should be avoided. However, the vaccine has not been causally associated with adverse  pregnancy outcomes or adverse effects on the developing foetus. If pregnancy occurs after initiating the  vaccination series, the remaining dose(s) should be delayed until after the pregnancy is completed. Termination of pregnancy is not indicated if vaccination was carried out inadvertently during pregnancy. Pregnancy testing is not indicated before giving the vaccine.

  • HPV vaccines can be given to:

    >> Lactating women: breastfeeding is not a contraindication for HPV vaccination. Available evidence does not indicate an increased risk of adverse events linked to the vaccine in the mothers or their babies after administration of HPV vaccine to lactating women.

    >>Those with minor acute illnesses, such as diarrhoea or mild upper respiratory tract infections, with or without fever.

    >> Women who have had an equivocal or abnormal Pap test, a positive HPV test, or genital warts. These patients should be advised that the vaccine will not have any therapeutic effect on existing Pap test abnormalities, HPV infection or genital warts.

    >> Patients who are immunocompromised by infection, disease or medication. It should be noted that the immune response to vaccination and vaccine efficacy might be less in immunocompromised persons. HPV vaccine can be administered safely to immunocompromised and/or HIV-infected. HIV testing not a prerequisite for vaccination.

  • Studies have shown HPV vaccines are safe and have no serious safety concerns. Studies showed that serious adverse effects following 2vHPV were similar in the vaccine and control groups. Post licensure data indicate that adverse events from 4vHPV are similar to those reported following other vaccines in adolescents.

  •  To date, the most frequently reported adverse events for HPV vaccines received by the National Pharmaceutical Regulatory Agency (NPRA) are consistent with other studies which include injection site pain and erythema, swelling of the injection site, dizziness and headache.

  • In 2013, The Global Advisory Committee on Vaccine Safety (GACVS) of the World Health Organization (WHO), reviewed the safety of HPV vaccination. The Committee continued to be reassured by the safety profile of the available products. More than 170 million doses had been distributed worldwide at the time of review, and with more countries offering the vaccine through national immunisation programmes.

  • Life-threatening allergic reactions from vaccines are very rare, which occur within a few minutes to a few hours after the vaccination. Syncope, brief fainting spells and related symptoms (such as jerking movements) can occur after any medical procedure, including vaccination. Recipients should be observed for 15 minutes after the vaccine is administered to avoid serious injury related to a syncopal episode.

Target Groups in Malaysia

  • HPV immunisation programmes should initially prioritise high coverage in the primary target population of girls aged 9-14 years before potential exposure to HPV through sexual activity. Such programmes should be part of a coordinated strategy that includes education about risk behaviours for HPV infection and screening programmes for cervical cancer.

  • The HPV vaccination programme was introduced in the Malaysian EPI in 2010, targeting girls aged 13 years. Vaccine is delivered through an on-going school based programme (Form 1, regardless of age) and to out-of-school girls aged 13 years.

  • The HPV immunisation programme has been extended in 2012 to the catch-up group, targeting 18-year old girls. This was initiated by the Population and Family Development Board Malaysia (LPPKN) under the provision of Ministry of Women, Family and Community Development (KPWKM).

  • For males aged 9-26 years: vaccination (4vHPV or 9vHPV vaccine series) is strongly recommended for men who have sex with men (MSM) and immunocompromised persons, including persons with HIV, who have not been previously vaccinated.

  • For immunocompromised individuals: vaccination is recommended for adult men and women who are immunocompromised (such as due to HIV, medications or other conditions) if they were not fully vaccinated when they were younger, following risk assessment.

Recommendations

 

WHO recommends that routine HPV vaccination should be included in national immunisation programmes. For the prevention of cervical cancer, WHO’s recommended primary target population is girls aged 9–14 years, prior to becoming sexually active. The initial vaccination of multiple cohorts of girls aged 9-14 is recommended when the vaccine is first introduced.

The current evidence supports the recommendation for a 2-dose schedule with adequate spacing between the first and second dose (0, 6-15 months) in females aged 9–14 years. Individuals ≥15 years and older should receive 3-dose schedule (0, 1–2, 6 months). Individuals known to be immunocompromised and/or HIV-infected (regardless of whether they are receiving ART) should also receive 3-dose schedule (0, 1–2, 6 months).

Interchangeability of the three vaccine types: currently, limited clinical data is available on safety, immunogenicity or efficacy of the vaccines when used interchangeably. Efforts should be made to administer the same vaccine for all doses. However, if the vaccine used for prior dose(s) is unknown or unavailable, either of the HPV vaccines can be administered to complete the recommended schedule.

Where the course includes a combination of the 2 HPV vaccines, the person is considered to be fully immunised against HPV-16 and HPV-18 if a complete dose schedule of HPV vaccines have been given and the minimum interval requirements between the doses are adhered to. The need for a booster dose has not been established.

9vHPV may be used to continue or complete a vaccination series started with 4vHPV or 2vHPV. For persons who completed vaccination with 2vHPV or 4vHPV, there is no recommendation regarding additional vaccination with 9vHPV. The benefit of protection against the five additional types targeted by 9vHPV would be mostly limited to females for prevention of cervical cancers and precancers. Only a small percentage of HPV-associated cancers in males is due to the five additional types prevented by 9vHPV.

In June 2019, the Advisory Committee on Immunisation Practices (ACIP) approved two new recommendations for HPV vaccine:

  1. “Catch-up” vaccination for males is recommended through age 26 years (previously through age 21 years). The catch-up recommendation for males is now the same with the recommendation for females.

  2. Vaccination of persons 27 through 45 years of age based on “shared clinical decision-making” between the patient and the clinician. This means that the decision to vaccinate persons 27 through 45 years of age should be based on a discussion of benefits and risks between the patient and the clinician.

Vaccination of secondary target populations, such as females aged ≥15 years or males, is recommended only if this is feasible, affordable, cost-effective, and does not divert resources from vaccination of the primary target population or from effective cervical cancer screening programmes.

The choice of HPV vaccine should be based on assessment of locally relevant data, particularly the extent of HPV-associated public health burden (cervical cancer, other anogenital cancers, or anogenital warts), the population for which the vaccines have been approved, and other characteristics, such as each vaccine features, price, supply, and other considerations.

For all three vaccines, the vaccination schedule depends on the age of the vaccine recipient.

  • Females <15 years at the time of the first dose: a 2-dose schedule with a 6-month interval between doses (0, 6-12 months) is recommended.

  • Those aged ≥15 years at the time of the second dose are also adequately covered by 2 doses.

  • Individuals ≥15 years at the time of first dose: a 3-dose schedule (0, 1-2, 6 months).

  • If the interval between doses is shorter than 5 months, then a third dose should be given at least 6 months after the first dose.

  • An interval no greater than 12–15 months is suggested in order to complete the schedule promptly and before becoming sexually active.

  • A 3-dose schedule remains necessary for those known to be immunocompromised and/or HIV-infected (regardless of whether they are receiving antiretroviral therapy). It is not necessary to screen for HPV infection or HIV infection prior to HPV vaccination.

  • HPV vaccines are not licenced for use in adults aged >45 years.

  • For females:

    >> Girls aged 11-12 years should receive the 2vHPV, 4vHPV or 9vHPV vaccine series.

    >> Girls as young as 9 years can receive the vaccine.

    >> Females aged 13-26 years:

        • Who have not received the HPV vaccine in the past should be given a series of 2 or 3 doses.

        • Who have not completed the full vaccine series should catch up on the missed doses.

  • For males:
    >> Boys aged 11-12 years should receive the 4vHPV or 9vHPV vaccine series.

    >> Boys as young as 9 years can receive the vaccine.

    >> Males aged 13-26 years:

        • Who have not received the HPV vaccine in the past may still be given the series of 2 or 3 doses.

        • Who have not completed the full vaccine series may catch up on the missed doses.

Vaccination is strongly recommended for men who have sex with men (MSM) and immunocompromised persons, including persons with HIV, who have not been previously vaccinated.

  • For immunocompromised individuals:

    Vaccination is recommended for adult men and women who are immunocompromised (such as due to HIV, medications or other conditions) if they were not fully vaccinated when they were younger. The decision should take into consideration their likelihood of previous exposure to HPV, future risks of exposure, the extent and duration of being immunocompromised. As HPV vaccines are not live viral vaccines, there are no specific safety concerns regarding administration to immunocompromised persons. It is not necessary to screen for HIV prior to HPV vaccination.

Implications for Healthcare Workers (HCWs)

 
  • No special recommendations for health care workers, and they should follow the vaccine recommendations for adults based on age or other individual risk factors.

Evidence for Effectiveness

 
  • Immunogenicity studies of both 2vHPV and 4vHPV vaccines have been conducted in girls aged 9-15 years. Very high antibody titres were demonstrated as compared to natural infection. Over 99% of the vaccinated girls in these studies developed antibodies after vaccination (high seropositivity rates). For 4vHPV vaccine, immunogenicity data in males also showed high seroconversion rates for all 4 HPV types.

  • Both 2vHPV and 4vHPV vaccine were shown earlier as safe and provide high efficacy against HPV 16-and 18-related cervical pre-cancer lesions. The 4vHPV vaccine also has high efficacy against HPV 6- and HPV 11-related genital warts and anal cancers, as well as HPV 16- and 18-related vaginal and vulvar pre-cancer lesions. The consistency of several years of observations strongly suggests that similar high rates of protection can be expected against cervical cancer.

  • The main efficacy study of 2vHPV vaccine was conducted in young women aged 15-25 years. The clinical trials demonstrated 93% vaccine efficacy in preventing cervical pre-cancers due to HPV 16 or 18, among the women who had not been previously exposed to a targeted HPV type. All studies of 2vHPV showed that more than 99% of females developed HPV-16 and HPV-18 antibody response 1 month after completing the 3-dose series.

  • The main efficacy studies of the 4vHPV vaccine were conducted in young women and men, aged 16-26 years. Among persons not previously exposed to a targeted HPV type, the trials demonstrated nearly 100% vaccine efficacy in preventing cervical pre-cancers, vulvar and vaginal cancers, and genital warts caused by the vaccine types in women, as well as 90% vaccine efficacy in preventing genital warts and 75% vaccine efficacy in preventing anal pre-cancers in men. Clinical efficacy against infection and cervical, vaginal and vulvar lesions of any grade has been demonstrated. Among the HPV-naïve MSM, vaccine efficacy was 95% against intra-anal HPV infection and 75% against high-grade anal intraepithelial neoplasia from vaccine HPV types. Efficacy of 2vHPV in males has not been assessed.

  • Evidence suggests that from the public health perspective, 2vHPV, 4vHPV and 9vHPV vaccines offer similar immunogenicity, efficacy and effectiveness for the prevention of cervical cancer (protection against selected cervical endpoints, such as cervical intraepithelial neoplasia grade 1 or more), which is mainly caused by HPV types 16 and 18. The serological response after vaccination is much stronger (1–4 logs higher) than the response after natural infection.

  • Studies indicate that the vaccines are effective and suggest that vaccine protection is long-lasting. No evidence of waning protection after a 3-dose series of HPV vaccine has been found, after 10 years of follow-up from clinical trials. Data from long-term population-based follow-up studies indicate that protective antibody levels are predicted to remain well above the natural infection level for at least 20 years.

  • For 9vHPV, a phase III efficacy trial comparing 9vHPV and 4vHPV among approximately 14,000 females aged 16 through 26 years showed non-inferior immunogenicity for the types shared by both vaccines and high efficacy for the five additional types. Non-inferior immunogenicity of 9vHPV compared to 4vHPV inferred efficacy for HPV 6, 11, 16 and 18. Other trials in the 9vHPV clinical development program included immunobridging studies that compared antibody responses across age groups and females and males and concomitant vaccination studies.

  • After a 3-dose schedule, 2vHPV, 4vHPV and 9vHPV vaccines are highly immunogenic with the highest immune responses observed in girls aged 9–15 years.  Antibody titres remain high for at least 10 years for 2vHPV with 100% seropositivity, for at least 9.9 years for 4vHPV, and for at least 5 years for 9vHPV in the currently available data.

  • The 9vHPV is approved for males and females aged 9 through 45 years. The US FDA based this expanded approval on a study of 3,200 women aged 27 to 45 years. With a mean follow-up of 3.5 years, the vaccine had an effectiveness of 88% against prevention of persistent infection, genital warts, vulvar and vaginal precancerous lesions, cervical precancerous lesions, and cervical cancer related to nine HPV types covered by the vaccine. The approval for men was based on inferences from the data in adult women, efficacy data from adolescents and men aged 16 to 26 years, as well as immunogenicity from 150 men aged 27 to 45 years who received a 3-dose regimen over 6 months.

  • Based on immunogenicity data, a 2-dose schedule was approved for all 3 vaccines. Results of a systematic review indicate that immunogenicity of 2 vaccine doses (0, 6–12 months) in girls aged 9–14 years are non-inferior to 3 doses (0, 1–2, 6 months) in women aged 15–24 years. The outcomes included seroconversion, geometric mean titers (GMTs), or antibody avidity. Immunogenicity was found to be non-inferior with 2 doses, in persons aged 9 through 14 years compared with 3 doses in a group in which clinical efficacy was demonstrated (women aged 15-24 years), if the HPV vaccination series is initiated before the 15th birthday.

  • Memory B cells elicited by the first vaccine dose require at least 4–6 months to mature and differentiate into high-affinity B cells. This implies that any vaccination schedule should include an interval of at least 4 months between the prime dose (first dose) and the prime-boost (last dose) to efficiently reactivate memory B cells and trigger their differentiation into antibody-secreting plasma cells. Two-dose schedules with shorter intervals might not allow this affinity maturation and could result in shorter duration of protection. Antibody kinetics similarity with 2-dose and 3-dose series implies that the duration of protection is expected to be long-lasting after a 2-dose series.

  • Data on whether a 1-dose schedule confers adequate levels of protection are contradictory. A recent study found that the response to a single dose of 2vHPV conferred 100% seroprotection against HPV-16 and HPV-18 up to 4 years. In contrast, another study reported that after 5 years of follow-up, women who received a single dose of 4vHPV had a higher cumulative incidence (4.3%) of high-grade cytology, CIN, adenocarcinoma in situ, and invasive cervical cancer than women who received 2 doses (3.0% (P=0.04)).

  • Studies on the immunogenicity of HPV vaccines in people who are immunocompromised and/or HIV-infected are limited. Data on the use of HPV vaccines in a 3-dose schedule are reassuring in terms of safety in HIV-infected females, males, and children (aged 7–12 years). No data are available on use of the 2-dose schedule for the three vaccines in persons infected with HIV. 

  • Regarding the impact of vaccination programmes at the population level, there is evidence of a reduction in high grade cervical abnormalities among young women and vaccination significantly reduces the prevalence of high-risk HPV types among young women. Achieving high vaccination coverage in girls (>80%) reduces the risk of HPV infection for boys.

  • HPV vaccination programmes are also effective in reducing the incidence of anogenital warts. The 4vHPV vaccine provides high-level protection against anogenital warts in men and women and anogenital precancerous lesions in susceptible men aged 16–26 years where introduction of this vaccine was followed by a rapid decline in the prevalence of genital warts.

  • Comparisons of the cost-effectiveness of switching from 2vHPV or 4vHPV to 9vHPV vaccine in adolescent females are not yet established. The 9vHPV price per dose and the cross-protection provided by HPV vaccine types would influence the outcomes of cost-effectiveness analyses. Further data are also needed on the longer-term clinical effectiveness and the duration of protection, particularly for the 9vHPV vaccine.

References

  1. Adult,& Schedule, I. (2020). Recommended Adult Immunization Schedule CDC 2019 guidelines. https://www.cdc.gov/vaccines/schedules/downloads/adult/adult-combined-schedule.pdf
  2. Aris, a. (2020). Cancer Registry Report. https://nci.moh.gov.my/index.php/ms/pengumuman/340-national-cancer-registry-report
  3. Azizah Ab M, (2015). Summary of Malaysian National Cancer Registry Report 2007-2011. 1, 1–73. https://www.crc.gov.my/wpcontent/uploads/documents/report/MNCRRrepor2007-2011.pdf
  4. Center for Biologics Evaluation and Research, (2019) . Gardasil. U.S. Food and Drug Administration website: https://www.fda.gov/vaccines-blood-biologics/vaccines/gardasil
  5. Center for Biologics Evaluation and Research, (2019). Gardasil 9 (human papillomavirus 9-valent vaccine,recombinant). Silver Spring, MD: US Department of Health and Human Services, Food andDrug Administration; 2018. https://www.fda.gov/media/90064/download
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