Human Papillomavirus (HPV) Vaccine


The 9-valent human papillomavirus (HPV) vaccine (9vHPV) is a second-generation, non-infectious, recombinant, 9-valent vaccine indicated to prevent diseases and cancers caused by both low-risk and high-risk human papillomavirus (HPV) types 6, 11, 16, 18, 31, 33, 45, 52, 58. HPVs are the number one sexually transmitted viruses causing precancerous and cancerous lesions. The 9-valent human papillomavirus (HPV) vaccine (9vHPV) has been licensed by the US Food and Drug Administration (FDA) since 2014, and it is the only HPV vaccine available in the United States that confers protection against specific HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58.

Three different FDA-approved vaccines protect against infection with a varying number of HPV types:

  • 2vHPV (bivalent vaccine): protects against HPV types 16 and 18 (not available in the US, but it is still in use in other countries)
  • 4vHPV (quadrivalent vaccine): protects against HPV types 6, 11, 16, and 18
  • 9vHPV (nine-valent vaccine): protects against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 

9vHPV is routinely recommended to both males and females from ages 9 to 45 years of age to help prevent the following diseases and dysplastic lesions caused by human papillomavirus:

  • Anal, oropharyngeal, cervical, vulvar, vaginal, and other head-and-neck cancers caused by HPV types 16, 18, 31, 33, 45, 52, and 58
  • Condyloma acuminata (genital warts) caused by HPV types 6 and 11
  • Cervical adenocarcinoma in situ, anal, cervical, vulvar, vaginal intraepithelial neoplasias caused by HPV types 16, 18, 31, 33, 45, 52, and 58

Routine vaccination with 9vHPV is a recommendation for:

  • Males and females from age 9 through 45 who have not previously received a vaccination or who did not complete the 3-dose regimen currently recommended
  • Bisexual and men who have sex with men (MSM) through the age of 26
  • Patients with the immunocompromised state who have no prior vaccination or who did not complete the 3-dose regimen
  • Victims of sexual abuse or assault
  • Transgender individuals

Mechanism of Action

The exact mechanism of action of 9vHPV is unknown since HPV only affects humans, which makes it challenging to study. Nevertheless, the belief is that the vaccine works by activating the humoral response. 9vHPV is synthetically manufactured from the oncogenic protein subunit component L1 virus-like particles (VLP) of the HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58.

A 2016 immunogenicity study reports that the inactive HPV L1 VLPs in the vaccine produce neutralizing antibodies against HPV types eliciting a strong humoral immune response to protect against the diseases and dysplastic lesions caused by HPV. The same study reported that antibody titers for 9vHPV are 10 to 100-fold greater than antibody titers produced by natural infection. Thus, the vaccine’s efficacy appears to be mediated via humoral response mechanisms.


9vHPV administration is an intramuscular (IM) injection in the deltoid region or anterolateral thigh area. A single dose for both adults and pediatric patients consists of a 0.5 mL suspension. 9vHPV is administered in a two- or three-dose schedule depending on patient age at initial vaccination.

Two-dose schedule for ages 9 through 14 years at initial vaccination:

  • 0, 6 to 12 months – a minimum of five months in between doses.
  • 0, 2, 6 months – if administration of the second suspension occurs before the 5-month mark, then a third suspension should be administered four months after the second dose, at the latest.

Three-dose schedule for ages 15 through 45 years at initial vaccination according to manufacturer’s labeling (may not reflect current clinical practice):

  • 0, 2, 6 months

It is important to know that the series can continue as previously scheduled and does not need to be restarted if the schedule is interrupted. Lastly, 9vHPV administration can occur simultaneously with other routine vaccinations such as the meningococcal (groups A, C, Y, and W-135), polysaccharide diphtheria toxoid conjugate vaccine, tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine adsorbed (Tdap). Coadministration of 9vHPV with either of these vaccinations is well tolerated and does not interfere with either effect; however, the recommendation is to administer in different body sites.

Current vaccination recommendations are based on CDC (Centers for Disease Control and Prevention) and ACIP (Advisory Committee on Immunization Practices).

  • Routine vaccination is advised at 11 to 12 years of age for all individuals (vaccination can start at age 9.)
  • ACIP also recommends vaccination for everyone through the age of 26 years if not adequately vaccinated when younger. 
  • ACIP recommended shared clinical decision-making for patients aged 27 to 45 years. 

Age 9 to 15 years

  • Two doses of the HPV vaccine are recommended for most patients.
  • The second dose of the HPV vaccine is administered 6 to 12 months after the first dose.
  • Adolescents who have received two doses less than five months apart require a third dose of the HPV vaccine.

Age 15 to 26 years

  • Three doses of the HPV vaccine are recommended for teens and young adults who start the series at 15 through 26 years.
  • The recommended three-dose schedule is 0, 1 to 2, and 6 months.
  • Three doses are recommended for a patient with immunocompromised conditions (e.g., HIV infection, immunosuppressive therapy).

Age 27 to 45 years

  • ACIP(2019) recommended shared clinical decision-making for patients aged 27 to 45 years, as most adults in this age group would have very minimal benefits from vaccination.
  • Individuals who are not already immunized to HPV (e.g., a previously unvaccinated person who has never had sex) and the person at risk for acquiring a newer HPV infection in the near future (e.g., who plans to have sex with a new partner) might benefit from vaccination.

Use in Specific Patient Population

Hepatic Impairment: The manufacturer’s product labeling provides no information regarding dose adjustment in patients with hepatic impairment.

Renal Impairment: The manufacturer’s product labeling provides no information regarding dose adjustment in patients with renal impairment.

Pregnancy Considerations: According to the CDC and the American College of Obstetricians and Gynecologists (ACOG), the HPV vaccine is not recommended during pregnancy. However, if the vaccine is accidentally administered to a pregnant woman, the patient should be informed that available safety data are reassuring. In addition, if a vaccine series is initiated and a patient becomes pregnant, the clinician should postpone the vaccine series until that pregnancy is completed.

Breastfeeding Considerations:  According to CDC, vaccines given to a nursing mother do not impact breastfeeding safety for mothers or infants. For example, a slightly higher percentage of breastfed infants with the active quadrivalent human papillomavirus vaccine had pneumonia 30 days after maternal vaccination. Still, these effects were not attributable to the vaccine. Maternal vaccination is not a contraindication to breastfeeding; clinicians may administer the HPV to breastfeeding patients. Additionally, according to ACOG 2020 guidelines, the HPV vaccine should be administered to breastfeeding women aged 26 years and younger who have not been vaccinated previously.

Adverse Effects

The most common adverse effects recorded with 9vHPV are injection-site events, systemic events, and syncope. Injection-site events were recorded within five days after vaccination and included: pain, swelling, erythema, and tenderness. Systemic events were recorded within fifteen days after vaccination and included: headaches, pyrexia, fatigue, and nausea. Also, syncope after administration of 9vHPV has been reported, occurring post administration of the vaccine and posing a significant risk of serious secondary injury to patients.

A 2016 study concluded that incidences of adverse effects were comparable throughout all the age groups. Additionally, this study also concluded that the safety profile of 9vHPV is comparable to its quadrivalent counterpart, 4vHPV. Injection site effects were more common with 9vHPV, given more HPV virus-like antigens and aluminum hydroxyphosphate sulfate adjuvants, which help potentiate the immunological response.

Postmarketing surveillance of the human papillomavirus vaccine has identified multiple AEFI (adverse events following immunization) such as abdominal pain, syncope, dizziness, loss of consciousness, alopecia, amenorrhea, anemia, dyskinesia, migraine, pallor, and seizures.


Vaccine-related anaphylactic reactions are uncommon; however, anaphylaxis to a known ingredient of any vaccine is an absolute contraindication to immunization. As a result, 9vHPV is contraindicated in individuals with a history of hypersensitivity reactions to yeast since 9vHPV is a recombinant vaccine expressed in Saccharomyces cerevisiae (brewer’s yeast).

Contraindications also include persons who have had hypersensitivity reactions to a previous dose of 9vHPV or 4vHPV (quadrivalent vaccine). According to the CDC, moderate or severe acute illness is a precaution to vaccination, and clinicians should postpone vaccination until symptoms of the acute illness improve.

The safety of 9vHPV has not been a topic of study in pregnant human subjects; thus, 9vHPV is not currently recommended in pregnancy. A 2018 animal study assessed the general, reproductive, and developmental toxicity of 9vHPV in Sprague-Dawley rats. The study followed a 3-month repeat-dose toxicity study on rats reporting no effects on the reproductive ability of rats, no effects on offspring development, no vaccine-related fetal abnormalities, and no effect on male rat fertility.

These results add to the available data that 9vHPV does not increase the risk of adverse pregnancy outcomes in rats; however, more studies need to evaluate the safety profile in pregnant human subjects. Currently, standard protocol dictates that if a woman is found to be pregnant, the vaccination series should be halted and resumed after pregnancy.


Patients should receive monitoring for occurrences of syncope to prevent serious secondary injury to the patient. Health care professionals should monitor patients for presyncope signs and symptoms for 15 minutes when administering 9vHPV. Additionally, standard operating procedures should be in place to avoid serious secondary injuries that could result from the collapse of the patient, such as keeping the patient in a Trendelenburg or supine position to maintain adequate cerebral perfusion. Patients should have monitoring for acute onset of signs and symptoms of anaphylactic reactions such as hypotension, tachycardia, urticaria, and respiratory compromise.


9vHPV is a generally well-tolerated vaccine with a high safety profile. The most common side effects are minor issues such as injection-site pain, swelling, erythema, and tenderness. Minor systemic effects have also been reported, such as headaches, pyrexia, fatigue, and nausea. More dangerous toxic effects are attributable to anaphylaxis and hypersensitivity reactions. In the case of an anaphylactic reaction, health care providers should be ready to immediately administer 1.0 mg/mL of epinephrine intramuscularly (IM) in the anterolateral vastus lateralis muscle. Administration of IM epinephrine should be repeated every 5 to 15 minutes until achieving the desired response.

Additional Information

To support widespread vaccination efforts and increase the global prevention of diseases and dysplastic lesions caused by human papillomavirus (HPV) types 6, 11, 16, 18, 31, 33, 45, 52, and 58, clinicians must increase patient awareness during wellness visits on the importance of obtaining HPV vaccination. Physicians should also educate their patients on the different cancers and avoidable precancerous lesions when immunized with 9vHPV. Also, it is imperative to urge patients to complete the recommended three-dose sequence of 9vHPV. Clinicians can increase vaccine completion rates by the in-person scheduling of the next follow-up visits.

Furthermore, to increase patient safety and avoid syncope-related injuries, healthcare professionals should monitor patients for 15 minutes when administering 9vHPV. Further, clinics, pharmacies, and hospitals should implement standard operating procedures to avoid serious injury, such as safe vaccine administration space. Similarly, all healthcare providers should report Adverse Events Following Immunization (AEFI) by VAERS (Vaccine Adverse Event Reporting System), which would enhance patient safety.

Interventions that include healthcare education, tailored systems changes, feedback, and early initiation of the human papillomavirus vaccine administration may improve patient adherence and completion of vaccination schedules. Moreover, healthcare professionals should be aware of and attentive to the acute onset of symptoms of an anaphylactic reaction. All healthcare team members should receive training in the administration of epinephrine auto-injectors. Interprofessional strategies can help achieve better outcomes with fewer adverse reactions while increasing vaccine-completion rates and increasing public awareness of the importance of HPV vaccination with 9vHPV.


Soca Gallego L, Dominguez A, Parmar M. Human Papilloma Virus Vaccine. [Updated 2023 Jan 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from:

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