Off-Label HPV Vaccination in a 67-Year-Old Woman with Recurrent HPV Infection

Abstract

Human Papillomavirus (HPV) is a highly prevalent sexually transmitted infection associated with malignancies of the cervix, vulva, and vagina. While prophylactic vaccination with Gardasil^®9 is FDA-approved through age 45, no clinical trials have evaluated its use in older adults who remain sexually active and at risk for HPV-related cancers. We describe the case of a woman who presented with recurrent high-risk HPV and received the three-dose Gardasil^®9 series off-label at the age of 67. Following vaccination, her cervical cytology was negative for HPV and subsequent colposcopy did not demonstrate any evidence of intraepithelial lesion or malignancy. As this is a single case report, this temporal association cannot establish that vaccination caused viral clearance. Nonetheless, this case raises important questions regarding age-based HPV vaccination limits. Immunosenescence in older populations may impair viral clearance and could increase cumulative risk of progression from dysplasia to malignancy. Vaccination may therefore serve both prophylactic and potentially therapeutic roles; however, this must be evaluated in further controlled studies. This case highlights the need for further research into HPV vaccination in patients over the age of 45 years with or without history of HPV infection.

1. Introduction

Human Papillomavirus (HPV) is a widely prevalent sexually transmitted infection, and it is estimated that more than 80% of people acquire HPV by the age of 45 [1]. Although most HPV infections are asymptomatic and resolve spontaneously, the virus remains a significant public health concern. More than 150 HPV strains have been identified, of which at least 12 are classified as high-risk due to their oncogenic potential [2]. These high-risk strains are associated with several cancers, including cervical, anal, penile, vaginal, vulvar, and oropharyngeal cancers [3]. In the United States alone, HPV is responsible for approximately 33,700 cancer cases each year [1]. In addition, several lower-risk strains, including types 6 and 11, can cause genital warts and recurrent respiratory papillomatosis [4].

Beyond its physical manifestations, HPV infection carries a substantial psychosocial burden. Receiving an HPV diagnosis often triggers profound feelings of shame, embarrassment, and self-blame, with many people internalizing the stigma that society attaches to sexually transmitted infections despite HPV being remarkably common [5]. This emotional weight frequently translates into substantial changes in intimate behavior and relationship dynamics. Feelings of being “damaged” or “unclean” can erode self-esteem and body image, while the uncertainty surrounding the virus’s persistence, recurrence, and long-term health implications can generate chronic anxiety and hypervigilance about one’s body [6].

Since 2006, two safe and highly immunogenic prophylactic HPV vaccines have been recommended to reduce the likelihood of new HPV infections and HPV-associated diseases and cancers. Gardasil^®9, which provides active immunity against HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 infections, is the vaccine most widely distributed in the United States. HPV vaccination for adolescents has been routinely recommended for females since 2006 and for males since 2011 [7]. Over time, the recommended patient population for the vaccine has expanded. In 2018, the FDA expanded approval of Gardasil^®9 to ages 27–45 years, based on clinical trials of the quadrivalent vaccine in women aged 24–45 [1]. Currently, no clinical trials have investigated Gardasil^®9 in populations older than 45 years, and regulatory agencies have not pursued licensure beyond this age. It remains unknown whether patients above the age of 45, who remain at risk for HPV-related cancers, may benefit from vaccination.

Time between exposure to high-risk (hr) HPV strains and development of high-grade dysplasia is typically 5–10 years, with progression to invasive carcinoma occurring over the span of another approximately 10–15 years [8,9]. If a patient is expected to have greater than 10–20 years of life expectancy—for example, an otherwise healthy 46-year-old—then possibly decreasing the likelihood of contracting high-risk HPV via vaccination may be beneficial. Furthermore, over 20% of cervical cancer cases are diagnosed in women over the age of 65, representing a potential gap in cervical cancer prevention [10]. The present case report describes a 67-year-old female with active HPV infection who received the Gardasil^®9 vaccine. Written informed consent was obtained from the patient for this report.

2. Case Presentation

In February 2020, a 62-year-old woman with a history of irritable bowel syndrome and chronic gastroesophageal reflux disease tested positive for high-risk (hr) HPV infection (non-16/18). The assay utilized detects HPV16 and HPV18 individually and reports the remaining high-risk genotypes as a pooled “other-high-risk” category. This was the first time HPV was detected in her screening. Her follow-up pap smear in February 2021 revealed no intraepithelial lesion and was hr-HPV-negative. Of note, the patient had no personal or family history of breast, ovarian, or cervical cancers and no history of immunocompromise.

Her repeat pap smear in February 2023 revealed Atypical Squamous Cells of Undetermined Significance (ASC-US) and HPV18 was detected. In August 2023, her pap smear revealed Low-Grade Squamous Intraepithelial Lesion (LSIL) and non-16/18 HPV was detected. Colposcopic evaluation was performed in September 2024 and showed atrophic changes without dysplasia. HPV evaluation was positive for a non-16/18 strain, and her biopsies were negative for intraepithelial lesion or malignancy at this time. She denied any gynecologic symptoms during this timeframe. At the end of 2024, her care team recommended consideration of HPV vaccination to enhance mucosal immunity.

Following an informed discussion between the care team and the patient, the patient’s internist agreed to prescribe the three-dose series of Gardasil^®9 (administered in January 2025, March 2025, and July 2025) for the off-label indication of recurrent high-risk HPV. All three vaccine doses were administered without reported adverse events or tolerability concerns. In September 2025, her pap smear was negative for intraepithelial lesion or malignancy and HPV was not detected. Follow-up colposcopy in May 2026 revealed benign squamous epithelium, with a clinical recommendation to repeat pap smear and colposcopy in March 2027. The timeline of the patient’s clinical course is summarized in

Table 1. Chronological summary of gynecologic findings, HPV genotype results, and vaccination timing.

Date	Approx. Age (Yrs)	Cervical Cytology	HPV Result	Colposcopy/Biopsy	Notes/Vaccination Events
Feb 2020	~62	Not specified	hr-HPV-positive (non-16/18, pooled)	—	First HPV detection on screening
Feb 2021	~63	No intraepithelial lesion	hr-HPV-negative	—	—
Feb 2023	65	ASC-US	HPV18 detected	—	—
Aug 2023	65	LSIL	Non-16/18 h-HPV detected	—	—
Sept 2024	~66	—	Non-16/18 h-HPV-positive	Atrophic changes; no dysplasia; biopsy negative	—
Jan/Mar/Jul 2025	~67	—	—	—	Gardasil®9, doses 1–3
Sept 2025	~67	Negative for intraepithelial lesion/malignancy	HPV not detected	—	~8 months after dose 1
May 2026	~68	—	—	Benign squamous epithelium	~16 months after dose 1

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3. Discussion

We present the case of a 67-year-old patient with a history of hrHPV with low-grade dysplasia of the cervix who received the three-dose Gardasil^®9 series. She has had one year of subsequent pap smears and colposcopies without detection of hrHPV. While the purpose of this report is not to imply causation, this case raises important questions about the current age-based limitations of HPV vaccination guidelines and highlights a potentially underserved population that may benefit from expanded access.

Older adults remain sexually active, may enter new partnerships, and can be infected with HPV multiple times across the lifespan [11]. Despite this, sexual health discussions are less likely to occur between geriatric patients and their providers compared to younger populations [12]. Furthermore, immunosenescence in older populations impairs viral clearance, prolonging the duration of active infection and increasing the cumulative risk of progression to dysplasia or malignancy [13]. In addition, prophylactic HPV vaccination did not improve viral clearance in studies of younger individuals, potentially because their immune system is already robust enough to augment a response [14,15]. As the older population experiences immunosenescence, the immune system might need additional support in the form of active immunization to assist clearance. Together, these potential mechanisms should motivate future research into whether HPV vaccination is safe and effective in older populations [16]. We propose that future research should examine the safety of the HPV vaccine, with subsequent measurement of HPV antibody titers, among older patients who have received vaccination versus those who have not to determine vaccine safety and assess for a serological response. Assuming adequate safety, it would also be important to perform dose-finding studies for efficacy against HPV infection.

Spontaneous regression of HPV infection—reflecting immune control—occurs in almost 90% of younger women but only about 50% of older women [17]. Given the patient’s older age, spontaneous regression of the HPV infection is considered less likely. It is therefore possible that the vaccination may have helped enhance her immune response, leading to HPV not being detected at the September 2025 assessment. This further highlights the need for more investigation into the potential benefit of HPV vaccination among older adults. Despite this biological and epidemiological rationale, no clinical trials of Gardasil^®9 have enrolled participants over 45 years of age [18,19,20]. Our case underscores the need to revisit this gap. Vaccination in older adults may serve dual roles: prophylactically, by reducing the likelihood of infection with new HPV strains, and potentially therapeutically, by augmenting immune responses against existing infections.

While our case report emphasizes the important issue of consideration of older populations in relation to HPV vaccination, we do not mean to imply that the HPV vaccination caused regression of the virus. Other possible explanations include the spontaneous regression of infection, potential error in biopsy or cytology sampling, intermittent detectability of HPV DNA below assay thresholds, inherent variability in the clinical hr-HPV assay between testing rounds, and natural fluctuation in viral load over time.

Lastly, an HPV diagnosis is frequently accompanied by stigma, shame, and assumptions about sexual behavior that can deter patients from seeking care from their providers or from engaging in sexual activity. If proven safe and effective, vaccination to older patients may provide an opportunity to destigmatize conversations around HPV. Therefore, the potential psychosocial impact should also be further investigated.

4. Conclusions

This case demonstrates the feasibility and short-term tolerability of off-label three-dose Gardasil^®9 vaccination in a woman older than the currently approved age range. While Gardasil^®9 is currently FDA-approved through the age of 45, whether vaccination confers benefit past this threshold remains untested and should not be inferred from this single case. This case highlights the need for observational cohorts and controlled studies evaluating the immunogenicity, safety, and clinical outcomes associated with HPV vaccination in older adults.