Continuing Education Activity

The 9-valent human papillomavirus (HPV) vaccine (9vHPV) is a second-generation, noninfectious, recombinant vaccine available in the United States and indicated for the management and prevention of infections, diseases, or cancers caused by both low-risk and high-risk HPV types, including 6, 11, 16, 18, 31, 33, 45, 52, and 58. HPVs are the leading sexually transmitted viruses responsible for precancerous and cancerous lesions. The 9vHPV has been licensed by the US Food and Drug Administration (FDA) since 2014 and is classified as a preventive immunization.

The exact mechanism of action of 9vHPV remains unclear, as HPV only affects humans, which poses challenges for research. However, researchers hypothesize that the vaccine operates by triggering the humoral response. This activity comprehensively examines the indications, actions, and contraindications of the 9vHPV vaccine as a crucial tool in managing and preventing HPV infection and associated diseases. Furthermore, this activity underscores the mechanism of action, adverse event profile, and other essential considerations regarding administering the 9vHPV vaccine, which is crucial for clinicians in delivering HPV immunization to patients effectively.

Objectives:

• Identify individuals eligible for the human papillomavirus vaccine (9vHPV) based on current guidelines, considering age, gender, and other relevant factors.

• Differentiate between the various human papillomavirus vaccines (HPV) available, including the bivalent, quadrivalent, and 9-valent formulations, based on their indications, dosing schedules, and target HPV types.

• Implement evidence-based protocols for administering the human papillomavirus vaccine, ensuring adherence to recommended dosing schedules and administration routes.

• Collaborate with other healthcare providers, such as pharmacists, nurses, and public health officials, to promote human papillomavirus vaccination initiatives and ensure comprehensive vaccination coverage within the community.

Indications

The 9-valent human papillomavirus (HPV) vaccine (9vHPV) is a second-generation, noninfectious, recombinant vaccine available in the United States and indicated for the management and prevention of infections, diseases, or cancers caused by both low-risk and high-risk HPV types, including 6, 11, 16, 18, 31, 33, 45, 52, and 58. HPVs are the leading sexually transmitted viruses responsible for precancerous and cancerous lesions. The 9vHPV has been licensed by the US Food and Drug Administration (FDA) since 2014 and is classified as a preventive immunization. The exact mechanism of action of 9vHPV remains unclear, as HPV only affects humans, which poses challenges for research. However, researchers hypothesize that the vaccine operates by triggering the humoral response.

FDA-Approved Indications

The 3 different FDA-approved vaccines designed to protect against infection from different numbers of HPV types are mentioned below.

• 2vHPV (bivalent vaccine): Protects against HPV types 16 and 18. Although this vaccine is unavailable in the United States, it is still used in other countries.

• 4vHPV (quadrivalent vaccine): Protects against HPV types 6, 11, 16, and 18.

• 9vHPV (9-valent vaccine): Protects against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. This is the only HPV vaccine available in the United States that confers protection against these specific HPV types.

The 9vHPV vaccine is routinely recommended for males and females aged 9 to 45 to prevent various diseases and dysplastic lesions caused by HPV,[1] which include the following:

• 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, and vaginal intraepithelial neoplasias caused by HPV types 16, 18, 31, 33, 45, 52, and 58.

Routine vaccination with 9vHPV is recommended for several patient populations,[2] which include the following:

• Males and females aged 9 through 45 who have not previously received a vaccination or who did not complete the currently recommended 3-dose regimen.

• Men who have sex with men (MSM) aged 26 and older.

• 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/.

Vaccination with 9vHPV does not replace the need for regular screening for cervical, vulvar, vaginal, anal, oropharyngeal, and other head and neck cancers.

Mechanism of Action

The exact mechanism of action of 9vHPV is unknown. Nevertheless, researchers believe that the vaccine works by activating the humoral response. 9vHPV is a noninfectious recombinant vaccine containing purified virus-like particles (VLPs) obtained from the major capsid (L1) protein of HPV serotypes 6, 11, 16, 18, 31, 33, 45, 52, and 58. The L1 proteins are separated using recombinant Saccharomyces cerevisiae and self-assembled into VLPs. Each 0.5 mL dose of the vaccine contains aluminum, sodium chloride, L-histidine, polysorbate, sodium borate, yeast protein less than 7 mcg, and water. The product does not contain preservatives or antibiotics.[3][4]

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 dysplastic lesions caused by HPV. The same study reported that antibody titers for 9vHPV are 10- to 100-fold more significant than those produced by natural infection. Thus, the vaccine's efficacy is mediated via humoral response mechanisms.[5]

Administration

Available Dosage Forms and Strengths

9vHPV administration is an intramuscular (IM) injection in the deltoid region or anterolateral thigh area. A single dose for adults and pediatric patients consists of a 0.5-mL suspension. 9vHPV is administered in a 2- or 3-dose schedule depending on the patient's age at initial vaccination.[6]

Dosages

• Two-dose schedule for patients aged 9 through 14 at initial vaccination:
  • 0, 6 to 12 months: A minimum of 5 months 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 4 months after the second dose, at the latest.[6]

• Three-dose schedule for patients aged 15 through 45 at initial vaccination according to manufacturer's labeling (may not reflect current clinical practice):
  • 0, 2, 6 months[6]

The series can continue as previously scheduled and does not need to be restarted if the schedule is interrupted.[2] Lastly, 9vHPV can be administered 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 the effect; however, the recommendation is to administer in different body sites.[7]

Current vaccination recommendations are based on the guidelines provided by the Centers for Disease Control and Prevention (CDC) and the Advisory Committee on Immunization Practices (ACIP).[8]

• Routine vaccination is recommended for all individuals aged 11 to 12, with the option to begin vaccination as early as age 9. The American Academy of Pediatrics (AAP) suggests initiating the HPV vaccine series for patients aged 9 through 12. According to the AAP guidelines, parents or adolescents who avoid 3 or more concomitant vaccines at age 11 or 12 may prefer to initiate the vaccine at age 9 or 10. The American Academy of Pediatrics (AAP) policy aims to promote the introduction of the HPV vaccine at an earlier age to achieve higher vaccine initiation and completion rates.[9]

• ACIP also recommends vaccination for everyone through age 26 if not adequately vaccinated when younger. 

• ACIP recommended shared clinical decision-making for patients aged 27 to 45.

Patients aged 9 to 15:

• 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 2 doses less than 5 months apart require a third dose of the HPV vaccine.

Patients aged 15 to 26:

• Three doses of the HPV vaccine are recommended for teens and young adults who start the series at ages 15 through 26.

• The recommended three-dose schedule is 0, 1 to 2, and 6 months.

• Three doses are recommended for a patient with immunocompromised conditions (eg, HIV infection, immunosuppressive therapy)

Patients aged 27 to 45:

• ACIP (2019) recommended shared clinical decision-making for patients aged 27 to 45, as most adults in this age group have minimal benefits from vaccination.

• Individuals who are not already immunized to HPV (eg, a previously unvaccinated person who has never had sex) and the person at risk for acquiring a newer HPV infection soon (eg, who plans to have sex with a new partner) might get benefit from vaccination.[10]

HPV vaccines are not licensed in adults aged 45 and older.

Specific Patient Populations

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 the pregnancy is completed.[11]

Breastfeeding considerations: According to the CDC, vaccines given to a nursing mother do not impact breastfeeding safety for mothers or infants. For instance, a slightly higher percentage of breastfed infants with the active quadrivalent HPV 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.[12] According to ACOG 2020 guidelines, the HPV vaccine should be administered to breastfeeding women aged 26 and younger who have not been previously vaccinated.[11]

Adverse Effects

The most common adverse effects recorded with 9vHPV are injection-site events, systemic events, and syncope.[13][14] Injection-site events were recorded within 5 days after vaccination, including pain, swelling, erythema, and tenderness.[14][15] Systemic events were recorded within 15 days following vaccination, including headaches, pyrexia, fatigue, and nausea.[15] Syncope after administration of 9vHPV is reported, occurring post-administration of the vaccine and posing a significant risk of severe secondary injury to patients.

A 2016 study concluded that incidences of adverse effects were comparable in all age groups.[6] This study also concluded that the safety profile of 9vHPV is comparable to its quadrivalent counterpart, 4vHPV. Injection site effects are common with 9vHPV, given more HPV virus-like antigens and aluminum hydroxyphosphate sulfate adjuvants, which help potentiate the immunological response.[16]

Postmarketing surveillance of the HPV vaccine has identified multiple adverse events following immunization, such as abdominal pain, syncope, dizziness, loss of consciousness, alopecia, amenorrhea, anemia, dyskinesia, migraine, pallor, and seizures.[17]

According to a comprehensive surveillance study conducted over 5 years involving the administration of more than 1.8 million doses of the 9vHPV vaccine to individuals aged 9 to 26, no statistically significant increases in the risk of Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, or stroke were observed following vaccination with the 9vHPV vaccine. These longer-term findings endorse the safety of the 9vHPV vaccine.[18]

Drug-Vaccine Interactions

Immunosuppressive therapies, such as irradiation, alkylating agents, antimetabolites, cytotoxic medications, and corticosteroids, attenuate immune responses to the HPV vaccine.

Contraindications

Vaccine-related anaphylactic reactions are uncommon; however, anaphylaxis to a known vaccine ingredient is an absolute contraindication to immunization.[13] As a result, 9vHPV is contraindicated in individuals with a history of hypersensitivity reactions to yeast since 9vHPV is a recombinant vaccine expressed in S cerevisiae (brewer’s yeast).[2]

Contraindications include persons with previous hypersensitivity reactions to a dose of 9vHPV or 4vHPV (quadrivalent vaccine).[2] According to the CDC, moderate or severe acute illness is a precaution to vaccination, and clinicians should postpone vaccination until symptoms of the critical illness improve.

The safety of 9vHPV has not been studied 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.[19] 

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 patient is pregnant, the vaccination series should be halted and resumed after pregnancy.[20]

Monitoring

Syncope, occasionally accompanied by tonic-clonic movements and other seizure-like activity, is documented as a potential adverse effect following HPV vaccination. Patients should receive monitoring for syncopal events to prevent severe secondary injury to the patient.

Clinicians should monitor patients for presyncope signs and symptoms for 15 minutes when administering 9vHPV. Additionally, standard operating procedures should be in place to avoid severe secondary injuries resulting from the patient's collapse; these include keeping the patient in a Trendelenburg or supine position to maintain adequate cerebral perfusion. Patients should be monitored for acute onset of signs and symptoms of anaphylactic reactions such as hypotension, tachycardia, urticaria, and respiratory compromise.[21]

Toxicity

9vHPV is a generally well-tolerated vaccine with a robust safety profile. The most common adverse effects are minor issues such as injection-site pain, swelling, erythema, and tenderness.[14] Minor systemic effects have been reported, such as headaches, pyrexia, fatigue, and nausea.[15] 

Toxic effects are attributable to anaphylaxis and hypersensitivity reactions. In the case of an anaphylactic reaction, clinicians should immediately administer 1.0 mg/mL of epinephrine via the IM route in the anterolateral vastus lateralis muscle. Administration of IM epinephrine should be repeated every 5 to 15 minutes until the desired response is achieved.[22]

Enhancing Healthcare Team Outcomes

According to the 2019 ACIP report, HPV is responsible for an estimated 33,700 cancer cases annually in the United States. This includes 12,900 cases of oropharyngeal cancers among both men and women, 10,800 cases of cervical cancer among women, and 6,000 cases of anal cancer among both men and women. Although vaginal, vulvar, and penile cancers are relatively less frequent, they are also associated with HPV infection.[8] 

Clinicians should recognize that the burden of HPV-related mortality is significantly greater than the combined mortality caused by tetanus, diphtheria, pertussis, and meningococcal disease.[9] To support widespread vaccination efforts and increase the global prevention of diseases and dysplastic lesions caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58, clinicians must increase patient awareness during wellness visits regarding the importance of HPV vaccination. Interprofessional team members should also educate their patients on the different cancers and avoidable precancerous lesions when immunized with 9vHPV. Patients must be urged to complete the recommended three-dose sequence of 9vHPV. 

Clinicians can increase vaccine compliance by scheduling follow-up visits in person. Further, clinics, pharmacies, and hospitals should implement standard operating procedures to prevent severe injury, such as safe vaccine administration spaces. 

Interventions that include healthcare education, tailored systems changes, feedback, and early initiation of the HPV vaccine may improve patient adherence and completion of vaccination schedules.[23] 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. Clinicians should prescribe the HPV vaccine according to the latest ACIP and CDC recommendations. Nurses should administer and monitor for adverse reactions. Pharmacists should report adverse events following immunization by the Vaccine Adverse Event Reporting System (VAERS), which would enhance patient safety.[24] Interprofessional collaboration between clinicians and pharmacists facilitates improved outcomes with reduced adverse reactions, along with higher vaccination rates and increased public awareness regarding the significance of the 9vHPV vaccination.