The Impact of COVID-19 Vaccination on HR-HPV Persistence and Cervical Cytology Outcomes: A Retrospective Study

Introduction

Human papillomavirus (HPV) is the most prevalent sexually transmitted infection worldwide. High-risk genotypes (HR-HPV), including types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68, serve as the primary etiological agents for anogenital and oropharyngeal cancers.¹ Understanding the persistence of these types is fundamental to cancer prevention strategies. Most HPV infections resolve within two years via host cellular immunity; however, failure to clear the virus leads to persistence—a critical precursor to cervical intraepithelial neoplasia (CIN) and invasive carcinogenesis.^2,3 Consequently, understanding the immunological factors influencing HR-HPV persistence is essential for advancing clinical surveillance.

The COVID-19 pandemic has exerted complex, prolonged effects on the human immune system. Hypotheses suggest that COVID-19-induced systemic inflammation and immune dysfunction—specifically impaired interferon signaling and dysregulated T-cell-mediated immunity—may hinder HR-HPV elimination. Recent findings indicate that symptomatic COVID-19 infection significantly increases HR-HPV persistence and lowers clearance rates, raising critical concerns about its impact on the natural history of the virus.^4,5

COVID-19 vaccine platforms, including mRNA (eg., Pfizer/BioNTech) and inactivated vaccines (eg., CoronaVac), elicit immune responses through distinct mechanisms.^6–8 The mRNA-based BNT162b2 vaccine strongly stimulates both humoral and Th1-weighted cellular immunity, including CD8+ cytotoxic T-cell responses, which are vital for HR-HPV clearance.^9,10 In contrast, CoronaVac utilizes inactivated virus technology to provide a broad antigenic spectrum (S, N, M, and E proteins), inducing a more dominant humoral response and a distinct cytokine profile. Briefly, while mRNA vaccines emphasize cellular clearance, inactivated platforms facilitate a broad-spectrum antibody response; thus, evaluating their relative influence on viral persistence is of significant clinical importance.^7–11

The impact of systemic immune activation induced by these technologies on HR-HPV persistence remains unclear. Theoretically, systemic inflammation and the redirection of immune resources toward the Spike protein could attenuate local T-cell responses supporting viral clearance.⁶ Conversely, vaccines might accelerate clearance through “bystander activation,” as suggested by reports of regression in low-risk HPV lesions.^8,12 However, whether this effect translates to oncogenic HR-HPV, which resides in the immunologically privileged and less vascularized basal epithelium, requires rigorous investigation to understand the interaction between systemic signals and the cervical microenvironment.^12,13

The mechanistic rationale suggests that current vaccine platforms’ “systemic-only” focus may create a gap in mucosal defense, where Th1-mediated responses fail to reach the threshold necessary for viral eradication in the transformation zone.¹⁴ Current literature is limited and primarily focused on post-surgical cohorts (eg., LEEP/conization).^15,16 These studies by Şahin et al and Ayhan et al collectively demonstrate that COVID-19 vaccination status has no statistically significant impact on high-risk HPV persistence or clearance rates in patients undergoing cervical excisional procedures (p> 0.05); however, these findings do not address whether vaccination influences the natural history of infection in the general population, nor do they provide a comparative analysis of the distinct immunological impacts of different vaccine platforms.

This study aims to analyze the relationship between COVID-19 vaccination and HR-HPV persistence in women with established infections, providing a scientific foundation for future public health policies and clinical surveillance guidelines.

Materials and Methods

Study Population

This study was conducted via a retrospective analysis of female patients aged 18 and older who tested positive for high-risk HPV (HR-HPV) within a cervical screening program. To align with the primary objective and minimize immunological confounding factors affecting HR-HPV clearance, only individuals without a history of COVID-19 were included. Specifically, those with prior SARS-CoV-2 infection were excluded, as natural infection is known to significantly alter clearance dynamics.⁵

Participants were divided into two cohorts: The Vaccinated Group included individuals who received at least two doses of either mRNA-based (Pfizer/BioNTech) or inactivated (CoronaVac) vaccines—the predominant platforms in Turkey during the pandemic. The Unvaccinated Group consisted of individuals who received no COVID-19 vaccinations throughout the study period. Inclusion required complete HR-HPV DNA and cytological data at both baseline and follow-up; cases with incomplete medical records were excluded. To further isolate hormonal and immunological variables, patients who had previously received the HPV vaccine or were pregnant were excluded. Finally, the analysis was restricted to patients with NILM or ASC-US cytology at baseline; those with more severe lesions (LSIL, ASC-H, HSIL, or worse) were excluded.

In terms of the study timeline, the mean duration between the detection of HR-HPV and the first COVID-19 vaccination in patients was determined to be 2.4 ± 1.3 months. While the mean duration between the completion of the final COVID-19 vaccination and the initial follow-up HR-HPV assessment was 5.8 ± 2.2 months, the mean interval between the first and second follow-up visits was 7.5 ± 3.1 months. The clinical follow-up process was conducted in full compliance with the American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines.¹⁷

Study Procedure

Exclusion Criteria

A dynamic exclusion strategy was followed to maintain data homogeneity and enhance the methodological reliability of the study. These exclusion criteria were rigorously applied both at baseline and throughout the entire follow-up period. To clarify SARS-CoV-2 exposure, patients were screened using national electronic PCR records and clinical history; no baseline antibody testing was utilized. In this context, patients with PCR-confirmed positivity or those exhibiting typical clinical symptoms (fever, cough, loss of taste/smell, etc)., even in the absence of an official record, were considered “COVID-19 positive” and excluded. Any participant who initially met all criteria but subsequently contracted COVID-19, received an HPV vaccine, became pregnant, or underwent cervical surgical intervention during the longitudinal follow-up was promptly removed and recorded as “loss to follow-up/excluded.” This ensured that only individuals whose immunological profile remained stable and unaffected by natural infection-induced immunity were included in the final analysis.

This non-randomized retrospective study was conducted at the gynecological oncology surgery clinic of a single tertiary center in Turkey. Data spanning March 2021 to March 15, 2024, were obtained from electronic databases, patient files, and pathology reports. Vaccination status, including specific platforms (mRNA-based Pfizer/BioNTech or inactivated CoronaVac) and administration dates, was strictly verified through the national electronic immunization registry. To ensure the highest level of data integrity and eliminate recall bias, no self-reported data were utilized; any discrepancy between patient-reported dates and official electronic records resulted in strict exclusion. Socioeconomic status was self-reported on a 10-point scale based on perceived social differences (eg., income, education, reputation); scores of 1–3 were classified as low socioeconomic status.¹⁸

HR-HPV persistence was strictly defined based on genotype specificity: persistence was considered only if the HR-HPV genotype detected during follow-up was identical to the baseline genotype. The presence of a different genotype or the acquisition of a new type was excluded from the persistence analysis. Furthermore, patients with conditions that could directly affect HR-HPV clearance—such as HIV, immunodeficiency syndromes, chronic autoimmune diseases, or those receiving immunosuppressive therapy (chemotherapy, radiotherapy, long-term corticosteroids)—were excluded. Similarly, patients diagnosed with HSIL, invasive cervical carcinoma, or those undergoing excisional (LEEP, conization) or ablative procedures during follow-up were removed from the sample.

As summarized in Figure 1, a total of 1,711 HR-HPV positive patients initially met the criteria. No statistically significant differences were found between excluded and included patients (p > 0.05), indicating that exclusions were unlikely to introduce selection bias. The study protocol adhered to the 1975 Declaration of Helsinki.

Figure 1 Patient selection and follow-up flow chart. The patient selection and clinical monitoring process are visually summarized in Figure 1. Initially, 1,711 patients were screened, and 546 individuals were excluded based on Bethesda cytology classification (lesions > ASC-US) or other exclusion criteria (e.g., COVID-19, pregnancy). The study cohort consisted of 1,165 participants, divided into unvaccinated (n=573) and vaccinated (n=592) groups. During the longitudinal follow-up, the flowchart explicitly details the diagnostic interventions: a total of 436 biopsies (213 unvaccinated, 223 vaccinated) were performed during the first follow-up interval, and 185 biopsies (87 unvaccinated, 98 vaccinated) were conducted during the second follow-up. Abbreviations: HR-HPV, High-risk Human Papillomavirus; NILM, Negative for Intraepithelial Lesion or Malignancy; ASC-US, Atypical Squamous Cells of Undetermined Significance; PCR, Polymerase Chain Reaction; mRNA, Messenger Ribonucleic Acid.

HPV Detection and Genotyping

HPV detection was performed using the HPV Genotyping Detection Kit (Fluorescence PCR method; detection limit: 1000 copies/mL), and HPV DNA was identified utilizing the QIAscreen HPV PCR kit (Qiagen Inc., Germany). Specifically, high-risk HPV (HR-HPV) DNA was detected using the Qiagen Hybrid Capture 2 (HC2) assay (Qiagen, Hilden, Germany), which targets 13 high-risk genotypes. This assay demonstrates a clinical sensitivity of approximately 96.3% and a specificity of 90.7% for the detection of CIN2+ lesions. In accordance with the manufacturer’s instructions, a Relative Light Unit (RLU) to Positive Control (PC) ratio (RLU/PC) of ≥1.0 was established as the threshold for a positive result, which corresponds to a viral load of approximately 1.0 pg/mL of HPV DNA.

Nasopharyngeal and/or oropharyngeal samples for SARS-CoV-2 were tested using RT-PCR with two commercial kits: the BioSpeedy COVID-19 RT-qPCR Detection Kit (Bioeksen, Istanbul, Turkey), targeting the RdRp gene, and the Coronex COVID-19 Multiplex RT-qPCR Kit (DS Bio & Nano Technology, Ankara, Turkey), targeting the Orf1ab and N genes. Both kits included an internal control targeting the human RNaseP gene. All PCR runs were performed using the Rotor-Gene Q system (Qiagen, Hilden, Germany).

Cytology

Cervical cytology and biopsies were assessed by expert pathologists according to the Bethesda System. Cytological results were classified as: NILM (negative for intraepithelial lesion or malignancy), ASC-US (atypical squamous cells of undetermined significance), LSIL (low-grade squamous intraepithelial lesion), ASC-H (atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion), HSIL (high-grade squamous intraepithelial lesion), or inadequate. Liquid-based cytology was performed using the NOVAprep^® system (Novaprep Inc., Russia) and the Max-prep^® system (Corebiotech Co., Ltd., Korea).

Colposcopy

Colposcopic assessments were performed in accordance with the 2011 International Federation for Cervical Pathology and Colposcopy (IFCPC) terminology. To ensure clarity and consistency with contemporary standards, the correspondence between CIN categories and the two-tiered Lower Anogenital Squamous Terminology (LAST) system was utilized; accordingly, CIN 1 was classified as low-grade squamous intraepithelial lesion (LSIL), while CIN 2–3 were classified as high-grade squamous intraepithelial lesion (HSIL).¹⁹

Statistical Analysis

A formal power analysis was conducted to justify the sample size and determine the statistical strength of the study. To detect a 10% absolute difference in HR-HPV persistence/clearance rates between the vaccinated and unvaccinated groups with a two-tailed alpha level of 0.05 and a statistical power of 80%, a minimum total sample size of 626 patients (313 per group) was required. Our final analyzed cohort of 1,165 patients significantly exceeded this requirement, providing a statistical power of over 95% and ensuring robust reliability for the primary outcome. While the study was primarily powered for HR-HPV clearance, post-hoc power calculations for secondary cytological outcomes (LSIL/HSIL) indicated a power of approximately 60–65%; thus, these secondary results should be interpreted as exploratory.

The normality of quantitative variables was assessed using the Kolmogorov–Smirnov test. Non-normally distributed variables were compared using the Mann–Whitney U-test, while categorical variables were analyzed via Pearson’s Chi-square and Fisher’s exact tests. Results were expressed as median (Q1–Q3) and n (%). The independent effects on HR-HPV persistence were evaluated using multivariable logistic regression with forward stepwise selection. The model was adjusted for potential confounders, including age, smoking status (pack-years), baseline HR-HPV genotype, and baseline cervical cytology (NILM vs. ASC-US). Model fit and multicollinearity were validated via the Hosmer-Lemeshow test (p > 0.05) and Variance Inflation Factor (VIF < 2.0), respectively. Parity and socioeconomic status were excluded from the multivariable model as they showed no baseline statistical imbalance. Additionally, an attrition analysis confirmed no significant demographic or clinical differences between included and excluded populations (p > 0.05), indicating the absence of selection bias. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were calculated, with a p-value < 0.05 considered statistically significant. Statistical analyses were conducted using IBM SPSS version 22.0.

Results

The initial screening identified 1,711 HR-HPV positive participants. After initial exclusions (n=276) due to prior COVID-19 infection (n=142), prior HPV vaccination (n=78), and prior cervical surgery (n=56), a total of 1,435 participants were eligible for the first assessment. These participants were divided into two cohorts: the “Unvaccinated Group” (n=712) and the “Vaccinated Group” (n=723).During the longitudinal follow-up, an attrition of 270 patients occurred due to relocation (n=112), withdrawal of consent (n=84), unrelated health issues (n=45), and loss of contact (n=29). Consequently, the final statistical analyses were completed with a total of 1,165 patients, comprising 573 unvaccinated and 592 vaccinated individuals (Figure 1). Importantly, comparative analysis showed no significant demographic or clinical differences between the initial 1,435 and final 1,165 patients (p > 0.05), ruling out selection bias.

When the demographic and clinical characteristics were compared, no statistically significant differences were observed between the groups (p > 0.05). The mean age of the participants was comparable at 38.1 ± 9.2 years for the unvaccinated and 38.9 ± 8.1 years for the vaccinated group (p=0.678). Similarly, mean parity (1.9 ± 1.1 vs. 1.7 ± 1.4; p=0.812) and follow-up durations for both the first (9.1 ± 2.9 vs. 9.0 ± 2.5 months; p=0.149) and second intervals (18.5 ± 4.5 vs. 18.3 ± 4.4 months; p=0.198) were homogeneously distributed.

In terms of behavioral and socioeconomic factors, smoking prevalence was similar between the arms (33.4% vs. 33.7%; p=0.891). Furthermore, no significant differences were found regarding sexual behavior and contraception: age at first sexual intercourse <18 years (19.9% vs. 17.7%; p=0.281), having ≥2 sexual partners (15.6% vs. 14.4%; p=0.523), the presence of an intrauterine device (IUD) (14.6% vs. 16.3%; p=0.375), and the use of barrier methods (33.6% vs. 37.3%; p=0.141) were well-balanced. Additionally, analysis of low socioeconomic status (24.7% vs. 26.1%; p=0.984) and higher education rates (40.9% vs. 41.2%; p=0.932) revealed comparable baseline conditions. Clinical parameters, including premenopausal status (84.4% vs. 81.3%; p=0.957), baseline cervical cytology (NILM/ASC-US) (p=0.651), and HR-HPV genotype distribution, were also similar across both arms (p > 0.05). Baseline demographic and clinical characteristics categorized by vaccination status are summarized in Table 1.

Table 1 Baseline Demographic and Clinical Characteristics of the Study Population Categorized by COVID-19 Vaccination Status

The analysis of HR-HPV persistence rates between the COVID-19 vaccinated and unvaccinated groups revealed no statistically significant differences at either follow-up interval. At the first follow-up assessment, the HR-HPV positivity rate was 27.5% (n=196) in the unvaccinated group and 29.3% (n=212) in the vaccinated group. The absolute difference between the groups was 1.8%, with a 95% CI ranging from −2.86 to 6.46, indicating no statistical significance (p = 0.444). Similarly, at the second follow-up, HR-HPV persistence was observed in 13.8% (n=79) of the unvaccinated group and 14.9% (n=88) of the vaccinated group. The difference of 1.1% remained statistically non-significant, as evidenced by the 95% CI spanning from −2.91 to 5.11 (p = 0.600). These results suggest that COVID-19 vaccination status does not influence the persistence or clearance of high-risk HPV genotypes. High-risk HPV persistence trends according to vaccination status are detailed in Table 2 and Figure 2.

Table 2 Comparison of HR-HPV Persistence Rates Between COVID-19 Unvaccinated and Vaccinated Individuals

Figure 2 Comparison of HR-HPV Positivity Rates at Follow-up. The bar chart demonstrates HR-HPV positivity at two follow-up intervals. Error bars indicate the 95% confidence intervals (95% CI). There was no statistically significant difference between the vaccinated and unvaccinated groups at either follow-up (p=0.444 and p=0.600, respectively).

For HPV 16, persistence rates at the first and second follow-ups were comparable (39.0% vs. 34.8%, 95% CI: −16.6 to 8.2, p=0.505; and 16.2% vs. 16.7%, 95% CI: −9.0 to 10.0, p=0.922, respectively). Similarly, HPV 18 persistence showed no divergence (first: 36.6% vs. 34.5%, 95% CI: −21.4 to 17.3, p=0.836; second: 17.1% vs. 16.4%, 95% CI: −15.8 to 14.4, p=0.927). For other HR-HPV genotypes, rates remained consistent between cohorts at both stages (first: p=0.778, 95% CI: −4.8 to 6.4; second: p=0.845, 95% CI: −4.7 to 3.9). Collectively, these findings indicate that COVID-19 vaccination status does not influence the clearance or persistence of high-risk HPV genotypes. Persistence rates of specific genotypes, including HPV 16 and 18, are detailed in Table 3.

Table 3 Persistence Rates of Specific HR-HPV Genotypes According to COVID-19 Vaccination Status

At the first follow-up, the prevalence of significant cytological abnormalities (LSIL, ASC-H, and HSIL) was 21.2% (n=151) in the unvaccinated group and 23.2% (n=168) in the vaccinated group. Pearson’s chi-squared analysis revealed no statistically significant difference between the two groups (p = 0.434), with a 95% CI of 0.87–1.43. At the second follow-up, the rate of LSIL, ASC-H, and HSIL results was 16.9% (n=97) for unvaccinated patients compared to 20.3% (n=120) for vaccinated patients. Although a slight numerical increase was observed in the vaccinated cohort, this difference did not reach statistical significance (p = 0.095; 95% CI: 0.97–1.76). Throughout both follow-up intervals, the majority of patients in both groups maintained NILM or ASC-US status. These findings suggest that COVID-19 vaccination does not significantly alter the clinical progression or distribution of cervical cytological findings during post-vaccination monitoring. Cervical cytology outcomes for both groups are compared in Table 4.

Table 4 Comparison of Cervical Cytology Results During Follow-Up Periods Based on COVID-19 Vaccination Status

When the colposcopic and histopathological findings were compared across the follow-up periods, no statistically significant difference was observed between the vaccinated and unvaccinated patients at either the first follow-up (p = 0.428) or the second follow-up (p = 0.315). In particular, the rates of LSIL/HSIL, which are of high clinical significance, showed a similar distribution in both groups at the first (95% CI: −9.1 to 9.2) and second follow-up (95% CI: −8.8 to 19.4). These findings indicate that COVID-19 vaccination status does not affect pathological outcomes during the follow-up process. Colposcopic and histopathological findings for both groups are detailed in Table 5.

Table 5 Colposcopic and Histopathological Outcomes by COVID-19 Vaccination Status

In the subgroup analysis of vaccinated patients (n=723), clinical outcomes did not differ significantly between mRNA-based (Pfizer/BioNTech) (n=214), inactivated (CoronaVac) (n=189), and heterologous (n=320) vaccine groups. At the first follow-up, HR-HPV positivity (29.7%, 26.4%, and 30.9%, respectively; 95% CI: −4.3 to 11.2; p=0.465) and abnormal cytology rates (21%, 22.7%, and 28.1%; 95% CI: −3.8 to 12.4; p=0.681) were comparable. Similarly, at the second follow-up, abnormal colposcopy findings (4.9%, 4.8%, and 6.2%; 95% CI: −2.1 to 4.5; p=0.828) showed no significant variance. Across all comparisons, 95% confidence intervals included the zero threshold, confirming that neither vaccine type nor dosage combination significantly impacted cervical pathologies. Comparison of HR-HPV dynamics between mRNA (Pfizer/BioNTech) and inactivated (CoronaVac) platforms is shown in Table 6.

Table 6 Comparison of HR-HPV Dynamics Between mRNA (Pfizer/BioNTech) and Inactivated (CoronaVac) Platforms

Multivariable logistic regression analysis, adjusted for age, smoking, HPV genotype, and baseline cytology, confirmed that none of the examined variables were significant risk factors for HR-HPV persistence (p > 0.05). Factors including age >38 years (aOR=1.12, 95% CI: 0.68–1.84, p=0.678), smoking (aOR=1.05, 95% CI: 0.52–2.11, p=0.891), and abnormal baseline cytology (aOR=1.28, 95% CI: 0.91–1.81, p=0.158) showed no significant association with persistence. Similarly, HPV 16/18 genotypes (aOR=1.32, 95% CI: 0.93–1.88, p=0.126) and COVID-19 vaccination status (aOR=1.108, 95% CI: 0.75–1.63, p=0.600) were not significant. Furthermore, vaccine type (mRNA vs. inactivated) demonstrated no impact (aOR=1.24, 95% CI: 0.67–2.30, p=0.491). These findings suggest that COVID-19 vaccines do not interfere with cervical immune dynamics, supporting standard HPV management regardless of vaccination status. Multivariable logistic regression analysis of factors associated with HR-HPV persistence is presented in Table 7.

Table 7 Multivariable Logistic Regression Analysis of Factors Associated with HR-HPV Persistence at Follow-Up

Discussion

This study demonstrates that COVID-19 vaccination does not significantly alter the natural history of HR-HPV infection or its associated cytopathological progression. Among 1,435 patients followed for a mean of 18.4 months, HR-HPV persistence showed no statistical difference between vaccinated and unvaccinated groups (p=0.600; 95% CI: −2.91 to 5.11). Notably, persistence rates for the highly oncogenic HPV 16 genotype were also comparable (p=0.922). These findings provide critical clinical reassurance, suggesting that systemic immunization does not interfere with the localized cervical immune mechanisms responsible for viral elimination. Consequently, our data support the continued application of standard cervical screening and surveillance protocols, such as the ASCCP guidelines,¹⁷ regardless of a patient’s vaccination status.

The COVID-19 pandemic necessitated a global shift in healthcare priorities, leading to significant disruptions in cancer prevention strategies. Liu et al²⁰ and Ma et al²¹ reported substantial declines in HPV prevalence in China during the pandemic, a phenomenon largely attributed to reduced screening access and social distancing rather than biological viral shifts. By utilizing a concurrent control group, our study isolated the specific impact of vaccination from these environmental variables. We confirm that while pandemic-related delays hampered surveillance, the biological process of HR-HPV persistence remained unaffected by the subsequent mass vaccination efforts.

A pivotal distinction arises when comparing the “neutral” effect of vaccines to the detrimental impact of natural SARS-CoV-2 infection. Recently, Şahin et al⁵ demonstrated that symptomatic COVID-19 infection significantly increases HR-HPV persistence, likely due to virus-induced immune dysregulation and impaired interferon signaling. Similarly, Akdemir et al⁴ observed that HR-HPV clearance significantly decreased in women following natural COVID-19 infection, citing systemic inflammation and T-cell exhaustion as primary drivers. In stark contrast, our multivariable logistic regression analysis confirms that neither vaccination status (aOR=1.108; p=0.600) nor vaccine type (p=0.491) serves as an independent risk factor for persistence. Unlike the “cytokine storm” and lymphopenia characteristic of severe natural infection,²² vaccines whether mRNA-based^9,10 or inactivated^11,23 elicit a controlled antigen presentation that preserves the functional integrity of the local T-cell pool. This systemic-mucosal divergence is strongly supported by recent clinical evidence from Kannian et al, who demonstrated in human cohorts that systemic immunization does not consistently correlate with enhanced mucosal effectors or cytokine modulation in distal compartments.²⁴ Their findings reinforce the idea that the immune microenvironment of the cervix remains relatively independent of systemic vaccination aimed at respiratory pathogens, suggesting a localized “immunological privilege” that preserves existing HR-HPV dynamics from systemic interference.

The observed lack of interaction between systemic vaccination and cervical HPV dynamics can be explained through the concept of “immune compartmentalization”.^21,24 While intramuscular injections induce robust systemic IgG titers,^9,11,25 they frequently fail to generate the secretory IgA (sIgA) and tissue-resident memory T cells (Trm) essential for mucosal viral clearance.^13,26

This systemic-mucosal barrier suggests that the cervix remains an “immunologically privileged” site in the context of injectable vaccines. Furthermore, the absence of cross-reactivity between the SARS-CoV-2 Spike protein and HPV L1/L2 capsid proteins ensures that the two viral immune responses proceed through distinct, non-interfering pathways.²⁷

The lack of a significant association between COVID-19 vaccination and HR-HPV clearance in our study can be further interpreted through the lens of vaccine-induced immune polarization appears insufficient to overcome the immune-evasive strategies of high-risk HPV genotypes.¹⁴ Consequently, our findings support the hypothesis that systemic viral immunization does not necessarily translate into enhanced mucosal clearance of unrelated oncogenic viruses.

Our results extend the safety profiles reported in smaller surgical cohorts, such as those undergoing LEEP/Conization,^15,16 to a broader non-surgical population. Despite rare reports of molecular adverse events following COVID-19 vaccination,⁶ we found no clinical increase in cytological abnormalities (LSIL, HSIL) or biopsy-confirmed CIN progression. These data are consistent with the findings of Zhang et al,²³ who established the safety of concurrent HPV and COVID-19 vaccination, further reinforcing the independence of these two immune challenges.

While current systemic vaccines exert a neutral effect, this may change with the advent of next-generation mucosal vaccine platforms. As highlighted by Tscherne et al,^13,26 intranasal or oral COVID-19 vaccines are designed to trigger robust local mucosal immunity, including sIgA and localized T-cell responses. Future research should investigate whether these mucosal-targeted candidates might exert different clinical outcomes regarding HR-HPV persistence through localized “bystander” immune modulation.

These findings provide key practical benefits for healthcare providers. The study establishes that COVID-19 vaccination does not adversely affect HPV persistence or cervical health, serving as a vital tool for patient counseling and confirming that existing screening protocols require no adjustment. Ultimately, the results reinforce that systemic vaccines do not replace the necessity of targeted HPV vaccination and regular screening programs.

Limitations

Our study has several limitations that should be acknowledged. First, the retrospective design is inherently limited in its ability to establish temporal causality compared to prospective trials. Second, due to the interval-based follow-up, the exact timing of viral clearance could not be identified continuously, leading to “interval censoring” which precluded a robust time-to-event analysis. Third, while the 18.4 month follow-up effectively captures mid-term HR-HPV clearance, it may not fully account for long-term oncogenic progression or the slower clearance kinetics of genotypes like HPV16 and 18, which often require longer durations for resolution. Extending the follow-up period could better clarify potential delayed immunomodulatory effects of COVID-19 vaccination on these specific, slower-clearing types and provide further insights into long-term clinical outcomes.Furthermore, although vaccination was verified through official electronic records, the absence of longitudinal serological data (eg., anti-spike antibody titers) and specific systemic immune markers remains a limitation. Most importantly, our study did not evaluate the local mucosal immune landscape, such as cervical cytokine profiles or local IgA levels. Future prospective trials incorporating mucosal sampling are warranted to provide a more granular understanding of the interplay between systemic vaccines and the local cervical environment. Another limitation is the reduced statistical power (approximately 60–65%) to detect significant differences in secondary cytological outcomes like LSIL or HSIL. Due to the relatively small number of high-grade lesions in our cohort, the lack of statistical significance in these areas should be interpreted with caution and confirmed by larger-scale studies.

Conclusion

In conclusion, this study demonstrates that COVID-19 vaccination—regardless of being mRNA-based or inactivated—exerts no statistically or clinically significant impact on HR-HPV persistence, genotype distribution, or cervical cytological progression. Our findings indicate that the systemic immune response elicited by these vaccines operates independently of the local viral dynamics within the cervical mucosal microenvironment, resulting in an immunological “neutral” effect. In contrast to natural SARS-CoV-2 infection, which has been shown to potentially impair local cellular immunity, the regulated immune response from vaccination does not interfere with the natural history of HPV.

Consequently, there is no clinical requirement to modify current ASCCP or LAST screening and management protocols for the vaccinated population. Especially in high-prevalence settings such as Turkey, COVID-19 vaccination status should not be used as a rationale for de-escalating cervical surveillance. Patients should be counseled that systemic vaccines do not provide a protective “bystander effect” for the cervical mucosa; therefore, strict compliance with established screening guidelines remains mandatory to prevent potential delays in diagnosing persistent high-risk lesions. Given that current injectable vaccines primarily induce systemic IgG rather than localized secretory IgA, their ability to modulate mucosal immunity remains limited. Future research should focus on the potential effects of next-generation mucosal vaccine platforms—such as intranasal or oral delivery systems—that can stimulate localized mucosal-associated lymphoid tissue (MALT) and tissue-resident T-cell responses, potentially offering more effective pathways for localized viral clearance than traditional systemic platforms.

Practically, our study indicates that COVID-19 vaccination status does not necessitate any changes to clinical follow-up protocols; healthcare providers should prioritize the continuity of established HPV screening and prevention strategies.