Canadian Immunization Guide: Part 4 - Active Vaccines

Human Papillomavirus Vaccine

Updated: July 2016

Key Information (Refer to text for details)

What
  • Human papillomavirus (HPV) infections are the most common sexually transmitted infections. Most HPV infections occur without symptoms and resolve without treatment.
  • If not immunized, most sexually active Canadians will have an asymptomatic HPV infection at some time.
  • High-risk HPV types 16, 18, 31, 33, 45, 52, 58 and others can lead to cervical and anogenital cancers, as well as certain cancers of the head and neck.
  • Low-risk HPV types 6 and 11 can cause genital warts.
  • CERVARIX® (HPV2), GARDASIL® (HPV4), and GARDASIL® 9 (HPV9) vaccines protect against cervical cancer. HPV4 and HPV9 vaccines also protect against genital warts.
  • The most commonly reported adverse events following HPV vaccination are injection site pain, swelling or redness. As with other vaccines, syncope (fainting), sometimes associated with injury when falling, has occurred following HPV vaccination.
Who
  • HPV2, HPV4 or HPV9 vaccine is recommended for prevention of cervical cancer and precursors in girls and women 9 to less than 27 years of age, including those who have had previous Papanicolaou [Pap] test abnormalities, cervical cancer or genital warts.
  • HPV4 or HPV9 vaccine is recommended for the prevention of vulvar, vaginal, anal cancers and their precursors, and genital warts in girls and women, 9 to less than 27 years of age.
  • HPV2, HPV4 or HPV9 vaccine may be administered to women 27 years of age and older at ongoing risk of exposure.
  • HPV4 or HPV9 vaccine is recommended for prevention of anogenital cancer and genital warts in boys and men, 9 to less than 27 years of age.
  • HPV4 or HPV9 vaccine may be administered to men 27 years of age and older at ongoing risk of exposure.
  • HPV2 vaccine is not authorized for use in boys and men.
How
  • For immunocompetent, non-HIV infected, adolescents 9 to less than 15 years of age HPV2 or HPV4 vaccine can be administered using a 2- or 3-dose schedule:
    • HPV2 vaccine (females only) should be administered as 2 separate 0.5 mL doses at months 0 and 6; or
    • HPV4 vaccine should be administered as 2 separate 0.5 mL doses at months 0 and 6, or months 0 and 12; or
    • HPV2 (females only), HPV4 or HPV9 vaccine should be administered as 3 separate 0.5 mL doses - HPV2 vaccine at months 0, 1, and 6; or, HPV4 or HPV9 vaccine at months 0, 2, and 6.
  • For adolescents 9 to less than 15 years of age, HPV9 vaccine should be administered as 3 separate 0.5 mL doses.
  • For individuals 15 years of age and older (unless the first dose of HPV2 or HPV4 vaccine was given before 15 years of age), immunocompromised individuals and immunocompetent HIV-infected individuals, HPV vaccine should be administered as 3 separate 0.5 mL doses –
    • HPV2 vaccine (females only) at months 0, 1, and 6; or,
    • HPV4 or HPV9 vaccine at months 0, 2, and 6.
  • In healthy individuals 15 years of age and older who received the first dose of HPV2 or HPV4 vaccine between 9 to less than 15 years of age, a 2 dose schedule of HPV2 vaccine (females only) or HPV4 vaccine can be used.
  • Because syncope post-vaccination is more common in younger people, it is important to observe each vaccine recipient for 15 minutes after vaccine administration.
Why
  • If not immunized, it is estimated that 75% of sexually active Canadians will have a HPV infection at some time. Even if an individual is already infected with one or more vaccine HPV type(s), the vaccine will provide protection against the other HPV type(s) contained in the vaccine.
  • In Canada, immunization against HPV types 16 and 18 contained in HPV2, HPV4 and HPV9 vaccine can prevent approximately 70% of cervical cancers and 60% of high-risk precancerous cervical lesions. Immunization against HPV types 31, 33, 45, 52, and 58 contained in HPV9 vaccine could further prevent up to 17% of cervical cancers and 30% of high-risk precancerous cervical lesions. Immunization with either HPV4 or HPV9 vaccine can prevent approximately 90% of genital warts.

Significant revisions included in this chapter are highlighted in the Table of Updates to the Canadian Immunization Guide.

Epidemiology

Disease description

Infectious agent

Human papillomaviruses (HPV) are small, double-stranded DNA viruses that infect the epithelium. More than 100 HPV genotypes have been identified, including approximately 40 genotypes that affect the human anogenital area. These HPV genotypes are categorized as low-risk for oncogenesis (for example, types 6 and 11) or high-risk for oncogenesis (for example, types 16, 18, 31, 33, 45, 52, 58), based on whether they have an association with cervical cancer.

For additional information about HPV, refer to the Public Health Agency of Canada (PHAC) website.

Reservoir

Humans

Transmission

HPV infections are transmitted sexually by direct epithelial (skin or mucosa) to epithelial contact, and vertically to an infant exposed to the virus in the maternal genital tract.

Risk factors
Women

In women, risk factors for HPV infections include: number of sexual partners, previous sexually transmitted infection, history of sexual abuse, early age of first sexual intercourse, number of lifetime sex partners, tobacco or marijuana use, immune suppression, and HIV infection.

Men

The most consistent factor associated with increased risk of HPV infection among men is the lifetime number of sex partners, inconsistent condom use, and men who have sex with men (MSM). MSM are about 20 times more likely than heterosexual men to develop anal cancer. Rates of anal cancer among HIV-positive MSM are higher than rates of cervical cancer among women, even in countries with the highest cervical cancer rates. Lower incidence of HPV infection and penile cancer has been associated with circumcision.

Spectrum of clinical illness

Most HPV infections are asymptomatic, self-limiting, and resolve within 24 months without treatment. Infection with a given HPV type does not decrease the probability of being infected by other HPV types. Persistent infection with a high-risk HPV type is the major cause of cervical cancer and is implicated in cancers of the penis, anus, vulva, vagina, mouth and oropharynx. Infection with low-risk HPV types can cause non-cancerous lesions, such as genital warts. HPV infection can be transmitted to the fetus before and during birth. As a result, newborns can develop recurrent respiratory papillomatosis, which is associated with a high degree of morbidity and, in some cases, can be fatal.

Disease distribution

Incidence and prevalence
Global
  • Women: HPV prevalence estimates for women worldwide range from 2% to 44%. The peak risk for HPV infection is within 5 to 10 years of the first sexual experience. Among women less than 25 years of age, high-risk HPV types predominate, whereas in women over 55 years of age, low-risk and uncharacterized HPV types are the most common.
  • Men: A systematic review of studies identified HPV prevalence estimates of 1.3% to 72.9%, with 56% of studies reporting a prevalence of 20% or more in men. HPV type 16 is consistently among the most common HPV types reported. In men, no significant association between age and HPV prevalence, incidence or duration of infection has been found.
  • HPV-associated cancers: Worldwide, the total burden of HPV-associated cancers in both sexes is estimated at 5.2% of all cancers. Globally, cervical cancer is estimated to be the second most common malignancy affecting women. Almost all cervical cancers are associated with high-risk HPV types with types 16 and 18 being present in approximately 80% and types 31, 33, 45, 52, and 58 in approximately 17% of cervical cancers in North America. Among cancers affecting men, it is estimated that HPV infection is associated with 80% to 90% of anal cancers, 40% to 65% of penile cancers, 35% of oropharyngeal cancers and 25% of oral cavity cancers. Among HPV-associated cancers, approximately 90% of anal cancers, 60% of penile cancers and 90% of oral cavity and oropharyngeal cancers are attributable to HPV types 16 and 18.
  • Genital warts: In the United Kingdom, genital wart prevalence is estimated at 130 per 100,000. Estimates from the USA are slightly higher, between 150 and 205 per 100,000. Genital warts are associated with HPV types 6 and 11 in more than 90% of cases, with 20% to 50% of cases co-infected with high-risk HPV types.
National

In North America, the lifetime cumulative incidence of HPV infection is estimated at more than 70% for all HPV types combined, which makes HPV the most common sexually transmitted infection. If not immunized against HPV, it is estimated that 75% of sexually active Canadians will have a sexually transmitted HPV infection at some point in their lives. The highest prevalence is found in persons 20 to 24 years of age.

  • Women: A study of a Canadian population-based sample of women 13 to 86 years of age estimated overall HPV prevalence in women to be 16.8%. The prevalence of HPV types 6, 11, 16 and 18 was 4.0%, 0.2%, 10.7% and 3.5%, respectively. HPV positivity was most prevalent in women under 20 years of age with a significant trend of decreasing prevalence until 60 years of age.
  • Men: There are few published Canadian studies of HPV prevalence or incidence among men. Estimates of HPV infection among men are primarily based on prevalence and incidence studies in selected populations, many of which may have a bias towards higher rates of infection because of multiple sexual partners. One Canadian study reported a prevalence of any HPV type of 70% in a sexually transmitted infection clinic population of heterosexual men ranging in age from 16 to 69 years (median age, 29 years).
  • HPV-associated cancers: In 2011, the cervical cancer incidence rate was estimated to be 7 cases per 100,000. Cervical cancer is the 13th most common cancer among Canadian women of all ages and the third most common among those aged 20 to 44 years. Annually, there are approximately 1,300 cervical cancer cases and 350 deaths related to cervical cancer. Attribution of HPV infection to cancer in Canada is estimated to be similar to that observed internationally.
  • Genital warts: Canadian studies have reported incidence rates of genital warts between 131 to 154 per 100,000 in men and 120 to 121 per 100,000 in women. Prevalence was estimated at 146.4 to 148.0 per 100,000. Prevalence and incidence were consistently higher among men compared to women and incidence peaked between 20 and 24 years of age for women and 25 to 29 years of age for men.

Immunizing Agents Available for Use in Canada

HPV vaccines

  • CERVARIX® (bivalent human papillomavirus [types 16, 18], recombinant vaccine), GlaxoSmithKline Inc. (HPV2).
  • GARDASIL® (quadrivalent human papillomavirus [types 6, 11, 16, 18], recombinant vaccine), Merck Canada Inc. (HPV4).
  • GARDASIL®9 (nine-valent, human papillomavirus [types 6, 11, 16, 18, 31, 33, 45, 52, 58], recombinant vaccine), Merck Canada Inc. (HPV9)

For complete prescribing information, consult the product leaflet or information contained within the product monograph available through Health Canada's Drug Product Database.

Refer to Contents in Immunizing Agents Available for Use in Canada in Part 1 for a list of vaccines available for use in Canada and their contents.

Efficacy, Effectiveness and Immunogenicity

Efficacy and effectiveness

HPV vaccine is highly effective for the prevention of HPV vaccine type-related persistent infection and cervical cancer. In women 16 to 26 years of age, the efficacy of HPV4 and HPV9 vaccine against HPV types 16 and 18-related cervical disease is nearly 100%; efficacy against external genital lesions related to HPV types 6, 11, 16, or 18, including genital warts, is 95% to 99%; and efficacy against high grade disease related to HPV types 31, 33, 45, 52, and 58 contained in HPV9 vaccine is over 96%. In men 16 to 26 years of age, HPV4 vaccine efficacy against vaccine type-related external genital lesions is 84% to 100%; efficacy against persistent vaccine-type related infection is 70% to 96%. Among HPV-naïve women 15 to 26 years of age, vaccination with HPV4 vaccine resulted in an overall reduction in abnormal PAP smears of 17.5%, colposcopy by 19.8%, cervical biopsy by 22% and cervical definitive therapy of 42.3%. In women 24 to 45 years of age, efficacy of HPV4 vaccine against a composite end point of HPV 6, 11, 16 and 18 persistent infection and cervical or external genital disease was 91% and against HPV types 16 and 18 only was 83%. In women aged 15 to 25 years, efficacy of HPV2 vaccine against HPV types 16 and 18-related cervical disease is 95% to 99%. While efficacy of HPV vaccine in children less than 15 years of age has not been demonstrated, immunogenicity evidence implies that efficacy will be high.

In Canada, immunization against HPV types 16 and 18 contained in HPV2, HPV4 and HPV9 vaccine can prevent approximately 80% of cervical cancers and 60% of high-risk precancerous cervical lesions. Immunization against HPV types 31, 33, 45, 52, and 58 contained in HPV9 vaccine could further prevent up to 17% of cervical cancers and 30% of high-risk precancerous cervical lesions. Immunization with either HPV4 or HPV9 vaccine can prevent approximately 90% of genital warts.

HPV vaccine has no proven therapeutic effect on existing HPV infection. Prior infection with one or more vaccine HPV types does not diminish vaccine efficacy against other vaccine HPV types. The duration of protection following HPV vaccination is not known. Clinical trial subjects have been followed for more than 7 years with no evidence of waning protection.

Studies suggest that vaccination of women may prevent transmission of vaccine HPV types to men. While there are no studies that directly demonstrate that HPV vaccination of men will prevent transmission of vaccine HPV types from men to women with a reduction in incidence of cervical cancer, hypothetical models predict that addition of men to a routine HPV vaccination program will prevent additional cases of genital warts and cervical cancer among women to varying degrees.

Immunogenicity

HPV vaccine is highly immunogenic. More than 99% of vaccine recipients develop an antibody response to vaccine HPV types after completing a 3 dose series. In immunocompetent, non-HIV infected individuals 9 to 14 years of age, a 2 dose schedule of HPV 2 or HPV 4 vaccine is as equally immunogenic as a 3 dose series in individuals 15 to 24 years of age. The immune correlates of protection against HPV infection are unknown.

Recommendations For Use

Choice of vaccine will depend on the goal of immunization. If the goal of immunization is prevention of HPV type 16 and 18-related cancers and their precursors, then HPV2, HPV4 or HPV9 vaccine may be used. If the goal of immunization also includes prevention of cancers related to HPV types 31, 33, 45, 52, and 58, then HPV9 vaccine should be used. If genital wart protection is desired in addition to cancer prevention, then HPV4 or HPV9 vaccine should be used.

Girls and women

9 to less than 27 years of age

HPV2, HPV4 or HPV9 vaccine is recommended for prevention of cervical cancer and precursors in girls and women 9 to less than 27 years of age, including those who have had previous Pap test abnormalities, cervical cancer or genital warts. HPV4 or HPV9 vaccine is recommended for the prevention of vulvar, vaginal, anal cancers and their precursors, and genital warts in girls and women 9 to less than 27 years of age. HPV vaccination prior to onset of sexual activity and exposure to HPV is recommended to maximize the benefit of the vaccine.

Although women with previous Pap test abnormalities, cervical cancer or genital warts may have had prior infection with one or more vaccine HPV types, they will benefit from receiving HPV vaccine for the HPV types to which they have not been exposed. Women should be advised that HPV vaccine does not have any therapeutic effect on pre-existing cervical disease.

Refer to Other Considerations for additional information.

27 years of age and older

HPV2, HPV4 or HPV9 vaccine may be administered to women 27 years of age and older at ongoing risk of exposure to HPV. While peak risk for HPV infection is within 5 to 10 years of the first sexual experience, a second peak in HPV prevalence is observed in women 45 years and older. Although the second peak is not as high as the peak rates in younger women, it represents an increased risk. While the reason for this second peak is not yet fully understood, receipt of HPV vaccine by previously unimmunized adult women could reduce the risk of HPV infection occurring later in life.

Refer to Risk factors and Other Considerations for additional information.

Boys and men

9 to less than 27 years of age

HPV4 or HPV9 vaccine is recommended for the prevention of anogenital warts, penile and anal cancer, perineal intraepithelial neoplasias and associated cancers. Receipt of HPV4 or HPV9 vaccine prior to onset of sexual activity and exposure to HPV infection is recommended to maximize the benefit of the vaccine.

27 years of age and older

There are no data on the safety, immunogenicity, or efficacy of HPV4 or HPV9 vaccine in men 27 years of age and older and therefore, no evidence-based recommendations can be made for the use of the vaccine in this age. However, HPV4 or HPV9 vaccine may be administered to men 27 years of age and older who are at ongoing risk of exposure to HPV. Refer to Risk factors for additional information.

Men who have sex with men (MSM)

Compared to the general population, MSM have a disproportionately high burden of HPV infection, particularly high-risk HPV types 16 and 18. Infection with high-risk HPV types is associated with anal cancer and its precursor, particularly among MSM who are HIV-positive. Early receipt of HPV4 or HPV9 vaccine will confer maximum benefit, because MSM may become infected with HPV more rapidly, due to the high rate of infection in the MSM population. HPV4 or HPV9 vaccine is recommended for men less than 27 years of age who have sex with men. Although there are no data on the efficacy of HPV4 or HPV9 vaccine in men 27 years and older who have sex with men, immunization with HPV4 or HPV9 vaccine should be strongly considered because of their increased risk of HPV related diseases.

Immunization after onset of sexual activity

HPV vaccination after the onset of sexual activity is beneficial because the vaccine recipient is very unlikely to be infected with all HPV types in the vaccine. Vaccine recipients who have already had sexual activity should be advised that they may already be infected with a vaccine HPV type and should be informed that the vaccine will not have any therapeutic effect on pre-existing vaccine HPV type infections. There are no data on the use of HPV vaccine in children less than 9 years of age. HPV vaccine may be considered in children less than 9 years of age who are at risk of exposure to HPV (for example, have a history of sexual abuse or have been diagnosed with a sexually transmitted infection).

Schedule

Refer to Table 1 for a summary of recommended immunization schedules and HPV vaccines for groups of vaccine recipients. For incomplete or interrupted vaccine schedules refer to Incomplete or interrupted vaccine schedules.

HPV2 vaccine
  •  Immunocompetent and non-HIV infected, girls, 9 to less than 15 years of age: 2 doses (months 0 and 6), or 3 doses (months 0, 1 and 6).
  • Females 15 years of age and older, immunocompromised females, and immunocompetent HIV infected females: 3 doses (months 0, 1 and 6).
HPV4 vaccine
  • Immunocompetent and non-HIV infected adolescents 9 to less than 15 years of age: 2 doses (months 0 and 6), or 3 doses (months 0, 2 and 6).
  • Individuals 15 years of age and older, immunocompromised individuals, and immunocompetent HIV infected individuals: 3 doses (months 0, 2 and 6).
HPV9 vaccine
  • Immunocompetent and non-HIV infected adolescents, 9 to less than 15 years of age: 2 doses (months 0 and 6), or 3 doses (months 0, 2 and 6).
  • Individuals 15 years of age and older, immunocompromised individuals, and immunocompetent HIV infected individuals: 3 doses (months 0, 2 and 6).
Table 1: Recommended Immunization Schedule and HPV Vaccine, by Group
Groups Immunization Schedule Vaccine(s)

Table 1 - Abbreviations

HPV2 = bivalent human papillomavirus vaccine
HPV4 = quadrivalent human papillomavirus vaccine
HPV9 = 9-valent human papillomavirus vaccine

HealthyTable 1 - Footnote 1 girls (9 to less than 15 years of ageTable 1 - Footnote 2) 2 or 3 dose schedule HPV2 or HPV4
3 dose schedule HPV9
HealthyTable 1 - Footnote 1 girls and women (15 years of age and older) 3Table 1 - Footnote 2 dose schedule HPV2 or HPV4 or HPV9
HealthyTable 1 - Footnote 1 boys (9 to less than 15 years of ageTable 1 - Footnote 3) 2 or 3 dose schedule HPV4
3 dose schedule HPV9
HealthyTable 1 - Footnote 1 boys and men (15 years of age and older) 3Table 1 - Footnote 3 dose schedule HPV4 or HPV9
Immunocompromised individuals and immunocompetent HIV-infected individuals 3 dose schedule

Females: HPV2 or HPV4 or HPV9

Males: HPV4 or HPV9

Minimum intervals between doses of HPV vaccines

Efforts should be made to administer HPV vaccines at the recommended intervals. When an accelerated schedule is required, minimum intervals between vaccine doses should be met. For either 2 a dose or 3 dose HPV vaccines schedule, the first and last doses of vaccine should be separated by a minimum interval of 24 weeks (6 months). In a 3 dose schedule, the minimum interval between the first and second doses of vaccine is 4 weeks (1 month), the minimum interval between the second and third doses of vaccine is 12 weeks (3 months), and the minimum interval between the first and last doses is 24 weeks (6 months). Refer to Timing of Vaccine Administration in Part 1 for additional information about delayed immunization schedules and accelerated immunization schedules.

Incomplete or interrupted vaccine schedules

An HPV vaccine series should be initiated, even if the series may not be completed according to schedule. If the vaccine schedule is interrupted, the vaccine series does not need to be restarted.

In individuals 15 years of age and older who received the first dose between 9 to less than 15 years of age, a 2-dose schedule can be used, with the second dose administered at least 6 months after the first dose.

Refer to additional information contained within the product monographs available through Health Canada's Drug Product Database.

Booster doses and re-immunization

Re-immunization with HPV vaccine is not indicated at this time, as protection lasts at least 7 years.

Vaccination of Specific Populations

Pregnancy and breastfeeding

HPV vaccines are not recommended for use in pregnancy because data on HPV vaccination in pregnancy are limited. HPV vaccine, however, has not been causally associated with adverse outcomes of pregnancy or adverse events to the developing fetus. In the absence of data, it is recommended that initiation of the HPV vaccine series should be delayed until after completion of the pregnancy. If a woman is found to be pregnant after initiating the vaccination series, completion of the series should be delayed until after pregnancy. No intervention is required if vaccine has been administered during pregnancy.

Vaccine recipients and health care providers are encouraged to report any exposure to HPV4 or HPV9 vaccine during pregnancy to the vaccine manufacturer (Merck Canada Inc.) at 1-800-567-2594. Exposure to HPV2 vaccine during pregnancy should be reported to the vaccine manufacturer (GlaxoSmithKline Inc.) at 1-800-387-7374.

There are limited data on the effects on breastfed infants from HPV vaccination of their mothers; however, there have been no reported adverse events thought to be vaccine-related. Therefore, HPV vaccine may be administered to breastfeeding women.

Refer to Immunization in Pregnancy and Breastfeeding in Part 3 for additional information about vaccination of women who are pregnant or breastfeeding.

Immunocompromised persons

Immunization with HPV vaccine is recommended for immunocompromised individuals. However, the immune response and vaccine efficacy may be less than that in persons who are immunocompetent. For complex cases, referral to a physician with expertise in immunization or immunodeficiency is advised. For example, HPV vaccination may be considered prior to surgery in a 7 or 8 year old child who will be immunosuppressed following a renal transplant.

Refer to Immunization of Immunocompromised Persons in Part 3 for additional information about vaccination of people who are immunocompromised.

Serologic Testing

Serologic testing is not indicated before or after receiving HPV vaccine. Testing methods are not routinely available.

Administration Practices

Dose

Each dose of HPV vaccine is 0.5 mL.

Route of administration

HPV vaccine should be administered intramuscularly.

Post-immunization observation period

Vaccine recipients, particularly adolescents and young adults, should be observed for 15 minutes after immunization to prevent serious injury in the event of syncope.

Refer to Vaccine Administration Practices in Part 1 for additional information about pre-vaccination and post-vaccination counselling and observation. Refer to Early Vaccine Reactions Including Anaphylaxis in Part 2 for additional information about prevention and management of syncope.

Interchangeability of vaccines

Whenever possible, the same HPV vaccine should be used to complete a vaccine series. If the vaccine used for previously received doses is not known, any of the HPV vaccines authorized for use in Canada may be used to complete the vaccine series. Because all HPV vaccines provide protection against HPV types 16 and 18, protective antibody concentrations against these types will likely be achieved if HPV vaccines are interchanged. HPV2 vaccine is not authorized for use in boys and men.

If an individual has started an immunization series with HPV2 or HPV4 vaccine and wishes to complete the series with HPV9 vaccine, the person should be informed that there are no interchangeability data for HPV vaccines nor is there any published data regarding a 2 dose HPV9 vaccine schedule. However, based on expert opinion and studies of HPV2 and HPV4 vaccines among adolescents, there is a theoretical basis for advising immunocompetent, non-HIV infected, individuals less than 15 years of age to consider receiving 2 doses of HPV9 vaccine administered 6 months apart.

Refer to Principles of Vaccine Interchangeability in Part 1 for additional information about interchangeability of HPV vaccines.

Concurrent administration of vaccines

HPV vaccine may be administered concomitantly with other age appropriate vaccines at different injection sites, using separate needles and syringes. HPV vaccine should be administered after other vaccines because it is known to cause more injection pain.

Refer to Timing of Vaccine Administration in Part 1 for additional information about concurrent administration of vaccines.

Storage and Handling of Immunizing Agents

HPV vaccines should be stored at +2°C to +8°C and should not be frozen. HPV vaccines should be protected from light. Refer to Storage and Handling of Immunizing Agents in Part 1 for additional information and recommendations.

Safety and Adverse Events

Common and local adverse events

Based on pre-licensure clinical trials, involving more than 15,000 subjects given HPV4 vaccine and 12,000 given HPV2 vaccine, the most common adverse events in persons receiving HPV vaccines were: injection site pain (82% to 92%), swelling (24% to 44%) or redness (24% to 48%). These adverse events were observed significantly more often following HPV vaccine than following active vaccine or placebo controls. In over 94% of subjects who received HPV vaccine, the reactions were mild to moderate in intensity, resolved over a few days, and did not prevent completion of the immunization schedule. Systemic adverse events, such as fatigue, myalgia, headache, fever, and nausea, generally occurred with comparable frequency in vaccine and control groups. The safety profile of HPV9 vaccine is comparable to HPV4 vaccine, although mild to moderate intensity injection site reactions are more common following receipt of HPV9 vaccine.

Since vaccine licensure, tens of millions of doses of both vaccines have been distributed worldwide. Data from post-licensure safety surveillance reporting systems have consistently mirrored the pre-licensure data with the most frequently reported adverse events following immunization (AEFI) being vaccination site reactions and muscle pain.

Less common and serious or severe adverse events

Serious adverse events are rare following immunization and, in most cases, data are insufficient to determine a causal association. Clinical trials have found no increase in the number or type of serious adverse events in recipients of HPV vaccine compared with those who received placebo. Anaphylaxis following vaccination with HPV vaccine may occur but is exceedingly rare. Syncope can occur after immunization and is most common among adolescents and young adults. For information about post-vaccination observation and management of adverse events refer to Vaccine Administration Practices in Part 1 and Early Vaccine Reactions Including Anaphylaxis in Part 2.

Other reported adverse events and conditions

Studies of the AS04 adjuvant used in HPV2 vaccine have demonstrated no evidence of an increase in risk of autoimmune disorders associated with receipt of AS04 adjuvanted vaccine.

The vaccine safety profile of HPV vaccines has been reviewed by both the World Health Organization (WHO) Global Advisory Committee on Vaccine Safety and the USA National Academy of Sciences Institute of Medicine (IOM).

Based on the IOM review, to date there has been no published evidence to support an association between HPV vaccine and any of the following conditions: Guillain-Barre Syndrome, transverse myelitis, acute disseminated encephalomyelitis, multiple sclerosis, brachial neuritis, chronic inflammatory disseminated polyneuropathy, amyotrophic lateral sclerosis, neuromyelitis optica, pancreatitis, transient arthralgia or thromboembolic events.

Deaths following HPV vaccine that were observed in pre-licensure trials occurred no more frequently than in the placebo groups. While post-market AEFI reports have included deaths, the rate is not in excess of what could be expected to occur by chance alone.

Guidance on Reporting Adverse Events Following Immunization (AEFI)

Vaccine providers are asked to report, through local public health officials, any serious or unexpected adverse event temporally related to vaccination. An unexpected AEFI is an event that is not listed in available product information but may be due to the immunization, or a change in the frequency of a known AEFI.

Refer to Reporting Adverse Events Following Immunization (AEFI) in Canada and Vaccine Safety in Part 2 for additional information about AEFI reporting.

Contraindications and precautions

HPV vaccine is contraindicated in persons with a history of anaphylaxis after previous administration of the vaccine and in persons with proven immediate or anaphylactic hypersensitivity to any component of the vaccine or its container. Individuals who develop symptoms indicative of hypersensitivity after receiving a dose of HPV vaccine should not receive further doses. Refer to Contents of Immunizing Agents Available for Use in Canada in Part 1 for a list of vaccines available for use in Canada and their contents.

HPV vaccine is not recommended for use in pregnancy because data on HPV vaccination in pregnancy are limited. HPV vaccine, however, has not been causally associated with adverse outcomes of pregnancy or adverse events to the fetus. Refer to Pregnancy and breastfeeding.

Refer to Contraindications, Precautions and Concerns in Part 2 for additional information.

Other Considerations

Cervical cancer screening in women who have received HPV vaccine

All women should be routinely monitored and screened for cervical cancer regardless of HPV immunization. While HPV vaccine has been shown to be highly effective against cervical cancer caused by the HPV types contained within the vaccine, vaccine recipients remain susceptible to infection from other high-risk HPV types. In addition, sexually active women may have been infected with the HPV types contained within the HPV vaccine prior to receiving the vaccine. Appropriate precautions against sexually transmitted diseases should continue to be used.

Selected References

Canadian Immunization Committee. Recommendations on a Human Papillomavirus Immunization Program. Accessed August 2015.

Centers for Disease Control and Prevention. The Pink Book: Epidemiology and Prevention of Vaccine Preventable Diseases. 13th ed.; 2015. Accessed August 2015.

Dunne EF, Nielson CM, Stone KM et al. Prevalence of HPV infection among men: A systematic review of the literature. J Infect Dis. 2006 10/15;194(0022-1899;8):1044-57.

Giuliano AR, Lazcano-Ponce E, Villa LL, et al. The human papillomavirus infection in men study: Human papillomavirus prevalence and type distribution among men residing in Brazil, Mexico, and the United States. Cancer Epidemiol Biomarkers Prev. 2008 08;17(1055-9965;8):2036-43.

Giuliano AR, Lu B, Nielson CM, et al. Age-specific prevalence, incidence, and duration of human papillomavirus infections in a cohort of 290 US men. J Infect Dis. 2008 09/15;198 (0022-1899;6):827-35.

GlaxoSmithKline Inc. Product Monograph - CERVARIX®. February 2010.

Kliewer EV, Demers AA, Elliott L et al. Twenty-year trends in the incidence and prevalence of diagnosed anogenital warts in Canada. Sex Transm Dis. 2009 06;36(1537-4521; 6):380-6.

Marra F, Ogilvie G, Colley L et al. Epidemiology and costs associated with genital warts in Canada. Sex Transm Infect. 2009 04;85(1472-3263; 2):111-5.

Merck Frosst Canada Ltd. Product Monograph - GARDASIL®. September 2010.

Moore RA, Ogilvie G, Fornika D et al. Prevalence and type distribution of human papillomavirus in 5,000 British Columbia women-implications for vaccination. Cancer Causes Control. 2009 05/29(1573-7225).

National Advisory Committee on Immunization. Update on Human Papillomavirus (HPV) Vaccines. Can Commun Dis Rep 2012;37 (ACS-7):1-62.

National Advisory Committee on Immunization. Statement on Human Papillomavirus Vaccine. Can Commun Dis Rep 2007;33(ACS-2):1-32.

Newall AT, Brotherton JM, Quinn HE et al. Population seroprevalence of human papillomavirus types 6, 11, 16, and 18 in men, women, and children in Australia. Clin Infect Dis. 2008 06/01;46(1537-6591;11):1647-55.

Ogilvie GS, Taylor DL, Achen M et al. Self-collection of genital human papillomavirus specimens in heterosexual men. Sex Transm Infect. 2009 06;85(1472-3263; 1472-3263; 3):221-5.

Winer RL, Lee SK, Hughes JP et al. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol 2003;157:218-26.

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