Significant revisions since the last chapter update are highlighted in the CIG Table of Updates.
For additional information, refer to previously published National Advisory Committee on Immunization (NACI) Statements and Statement Updates.
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 (e.g., types 6 and 11) or high-risk for oncogenesis (e.g., types 16 and 18), based on whether they have an association with cervical cancer.
For further information about HPV refer to the Public Health Agency of Canada (PHAC) website.
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.
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.
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 and self-limiting, clearing within 24 months. 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; in some cases it can be fatal.
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. In the absence of vaccination, 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.
For complete prescribing information, consult the product leaflet or information contained within Health Canada's authorized product monographs available through the Drug Product Database. Refer to Table 1 in Contents of immunizing agents available for use in Canada in Part 1 for a list of all vaccines available for use in Canada and their contents.
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 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%. 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 15-26 years of age, vaccination with HPV4 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 24-45 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%.
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.
HPV vaccine is highly immunogenic. More than 99% of recipients develop an antibody response to vaccine HPV types after completing the three-dose series. In immunocompetent, non-HIV infected, individuals 9-14 years of age, a two-dose schedule is as equally immunogenic as a three-dose series in individuals 15-24 years of age. The immune correlates of protection against HPV infection are unknown.
9 to 26 years of age
HPV2 or HPV4 vaccine is recommended for prevention of cervical cancer and precursors in girls and women 9 to 26 years of age, including those who have had previous Pap test abnormalities, cervical cancer or genital warts. HPV4 vaccine is recommended for the prevention of vulvar, vaginal, anal cancers and their precursors and anogenital warts in girls and women 9 to 26 years of age.
While efficacy of HPV vaccine in girls 9 to 13 years of age has not been demonstrated, immunogenicity evidence implies that efficacy will be high; HPV vaccination between 9 and 13 years of age (prior to onset of sexual activity and exposure to HPV) maximizes 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 the vaccine does not have any therapeutic effect on pre-existing cervical disease.
Participation in cervical cancer screening programs should be recommended to women regardless of HPV immunization.
27 years of age and older
HPV2 or HPV4 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 five to ten years of the first sexual experience, a second peak in HPV DNA 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 for additional information. HPV4 vaccine's immunogenicity, safety, and efficacy have been demonstrated in women between 24 and 45 years of age. Efficacy of HPV2 vaccine has not been demonstrated in this age group, but immunogenicity data suggest that efficacy will be high.
Choice of vaccine
The choice of HPV vaccine (HPV2 or HPV4) for females is dependent upon the perceived value of additional protection against genital warts. If genital wart protection is desired, HPV4 vaccine should be used. If the goal of vaccination is prevention of HPV type 16 and 18-related cancers and their precursors, either HPV2 or HPV4 vaccine may be used.
9 to 26 years of age
HPV4 vaccine is recommended in boys and men 9 to 26 years of age for the prevention of anogenital warts, penile and anal cancer, perineal intraepithelial neoplasias and associated cancers. While efficacy of HPV vaccine in boys 9 to 15 years of age has not been demonstrated, immunogenicity evidence implies that efficacy will be high. Receipt of HPV4 vaccine between 9 and 13 years of age, 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 vaccine in men 27 years of age and older so no evidence-based recommendations can be made for the use of the vaccine in this age at this time. However, HPV4 vaccine may be considered for men 27 years of age and older who are at ongoing risk of exposure to HPV. Refer to Risk Factors for additional information.
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 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 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 vaccine in men 27 years and older who have sex with men, they should be strongly considered for HPV4 vaccine, regardless of their age, because of their increased risk of HPV related diseases.
Choice of vaccine
HPV2 vaccine is not approved for use in in boys or men at this time.
HPV vaccination after the onset of sexual activity is beneficial because the vaccinee is very unlikely to be infected with all HPV types in the vaccine. Vaccinees 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 (e.g. have a history of sexual abuse or have been diagnosed with a sexually transmitted infection).
Refer to Schedule.
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. If a vaccine dose has been administered during pregnancy, there is no indication for any intervention.
Vaccinees and health care providers are encouraged to report any exposure to HPV4 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 lactating women. Refer to Immunization in Pregnancy and Lactation in Part 3 for additional general information.
HPV vaccine may be administered to immunocompromised persons according to routine vaccination schedules. 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, immunodeficiency, or both 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 general information.
Each dose of HPV vaccine is 0.5 mL.
Route of administration
HPV vaccine should be administered intramuscularly. Refer to Vaccine Administration Practices in Part 1 for additional information.
Post-immunization observation period
Syncope can occur after any vaccination, most commonly among adolescents and young adults. HPV vaccine recipients should be observed for 15 minutes after vaccine administration to avoid serious injury in the event of syncope. Refer to Vaccine Administration Practices in Part 1 for additional information about post-vaccination counselling and observation.
Immunocompetent, non-HIV infected, adolescents 9-14 years of age: Administer at months 0 and 6-12 or months 0, 1 and 6. For incomplete or interrupted vaccine schedules refer to "Incomplete or interrupted vaccine schedules" below.
Immunocompromised individuals, immunocompetent HIV infected individuals, and people 15 years of age and older: Administer at months 0, 1 and 6.
NACI recommends that the interval between the first and last dose is 6 months, regardless of whether a two-dose or three-dose schedule is used. For a three-dose schedule, the minimum interval between the first and second dose is 4 weeks. The second and third dose should be separated by an interval of at least 20 weeks.
Immunocompetent, non-HIV infected, adolescents 9-14 years of age: Administer at months 0 and 6-12 or months 0, 2 and 6. For incomplete or interrupted vaccine schedules refer to "Incomplete or interrupted vaccine schedules" below.
Immunocompromised individuals, immunocompetent HIV infected individuals, and those 15 years of age and older: Administer at months 0, 2 and 6.
NACI recommends that the interval between the first and last dose is 6 months, regardless of whether a two-dose or three-dose schedule is used. For a three-dose schedule, the minimum interval between the first and second dose is 4 weeks. The second and third doses should be separated by an interval of at least 12 weeks.
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.
For a two-dose schedule, if the interval between doses is shorter than 5 months, a third dose should be given at least 6 months after the first dose. In individuals 15 years of age and older who received the first dose between 9-14 years of age, a two-dose schedule can be used with the second dose administered at least 6 months after the first dose.
For a three-dose schedule, if the series is interrupted after the first dose, the second dose should be given at the earliest convenience and the third dose given at the recommended interval from the second dose. If only the third dose is delayed, it should be administered at the earliest convenience.
Re-immunization with HPV vaccine is not indicated at this time, as protection lasts at least 7 years. If monitoring suggests that booster doses may be required, this matter will be reviewed by NACI.
Serologic testing is not indicated before or after receiving HPV vaccine. Testing methods are not routinely available.
HPV vaccine should be stored at +2°C to +8°C and should not be frozen. HPV vaccine should be protected from light. Refer to Storage and Handling of Immunizing Agents in Part 1 for additional general information.
HPV vaccine may be administered concomitantly with other age-appropriate vaccines at different injection sites, using separate needles and syringes. Refer to Timing of Vaccine Administration in Part 1 for additional general information.
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 vaccine were vaccination 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 (which included hepatitis A or hepatitis A/hepatitis B vaccine, aluminum phosphate or saline). 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.
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.
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.
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 US 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.
Vaccine providers are asked to report, through local public health officials, any serious or unexpected adverse event felt to be 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 Vaccine Safety in Part 2 and the PHAC website for additional information about AEFI reporting.
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. Refer to Contents of immunizing agents available for use in Canada in Part 1 for lists of all vaccines available for use in Canada and their contents. HPV4 vaccine contains yeast protein. Hypersensitivity to yeast is very rare and a personal history of yeast allergy is not generally reliable. In situations of suspected hypersensitivity or non-anaphylactic allergy to vaccine components, investigation is indicated, which may involve immunization in a controlled setting. Consultation with an allergist is advised.
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 lactation.
Refer to Contraindications and Precautions in Part 2 for additional general information.
All women should be screened for cervical cancer regardless of HPV immunization. While HPV vaccine has been shown to be highly effective against cervical cancer caused by HPV types 16 and 18, vaccinees remain susceptible to infection from other high-risk HPV types. In addition, sexually active women may have been infected with HPV type 16, 18 or both prior to receiving HPV vaccine.
Whenever possible, one manufacturer's brand of HPV vaccine should be used to complete the vaccine series. If the brand of the previously received doses is not known, either brand of HPV vaccine may be used to complete series. Because both HPV vaccines provide protection against HPV types 16 and 18, protective antibody concentrations against these types will likely be achieved if HPV2 and HPV4 vaccines are interchanged. If fewer than three-doses of HPV4 vaccine are administered, protection against HPV types 6 and 11 cannot be ensured. Refer to Principles of Vaccine Interchangeability in Part 1 for additional general information.