Association of Nonavalent Human Papillomavirus Vaccine with Abdominal Pain Symptoms: A Post-Marketing Drug Safety Study

1. INTRODUCTION

The World Health Organization launched, in 2020, a global strategy to eliminate cervical cancer, centered on three key targets: ensuring that 90% of girls are fully vaccinated against HPV by age 15; screening 70% of women by age 35 and again by age 45; and providing appropriate treatment for 90% of women with precancerous lesions, as well as effective management for 90% of those with invasive cervical cancer [1].

The human papillomavirus vaccination (HPV) is currently the cornerstone of long-term cervical cancer control [2]. However, as with any other drug, vaccines may be associated with the occurrence of adverse reactions, although they must have a higher level of safety than the pharmaceuticals used for treatment because they are usually given to people who are healthy and used in large groups of the population. Before vaccines are licensed, their efficacy has to be shown in clinical trials, and any adverse effects should be detected. However, these studies may lack the statistical power to detect rare but potentially serious adverse effects [3]. As a result, when a new vaccine comes to market, there is some uncertainty about its safety profile, specifically about rare events or those occurring a longer time after vaccination. Their administration may occasionally be linked to adverse effects that cannot be detected until the vaccine is administered within large populations [4].

The Vaccine Adverse Event Reporting System database (VAERS, U.S.A) is a spontaneous reporting system for adverse events following vaccination. It serves as the national early warning system for detecting possible safety problems with U.S.-licensed vaccines. Their data are intended to detect signals indicating adverse events that may require further assessment [5].

A signal refers to information (whether from a single source or multiple sources) that indicates a new and potentially causal relationship, or a novel aspect of an existing relationship, between an intervention and an event or group of related events, which may be either adverse or beneficial. This information is considered sufficiently credible to warrant further verification, regardless of its origin. Signals must be investigated, beginning with validation and, if confirmed, followed by hypothesis testing [3, 6].

The HPV vaccine protects against the types of HPV that most often cause cervical cancer. It is expected that with the nonavalent vaccine (9-valent), the prevention of cervical cancer will increase to up to 90% [7]. As of late 2016, the HPV 9-valent vaccine has been the only available vaccine in the United States [8].

The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) recommends the HPV vaccine for routine vaccination at age 11 or 12 years (vaccination can be started at age 9). ACIP also recommends vaccination for everyone through the age of 26 years if not adequately vaccinated when younger [9].

Abdominal pain represents a spectrum of conditions. It is a common presentation in the outpatient setting and is challenging to diagnose [10, 11]. Analyses of VAERS reports from 2006 to 2017 identified abdominal pain as one of the most frequently reported gastrointestinal symptoms following quadrivalent HPV vaccination, with 202 serious reports of abdominal pain [12]. These symptoms have also been reported to VAERS with the 9-valent HPV vaccine. However, the existing literature has not focused on signal detection thresholds for abdominal pain in relation to this vaccine.

The objective of this study is to analyze the relationship between the human papillomavirus nonavalent vaccine and abdominal pain symptoms, with procedures that are easy to apply by the clinician, also in other symptoms or drugs, by using the Proportional Reporting Rate (PRR) to measure the proportion of notifications in VAERS of abdominal pain with the 9-valent HPV vaccine. In the same database, this ratio is compared with notifications of the same symptoms but with the other vaccines. If the PRR vaccine-abdominal pain is significantly high, it may represent a sign [13]. Research question: Is abdominal pain more frequently reported after 9-valent HPV vaccination than after other vaccines?

The study hypothesis is that the PRR for abdominal pain following 9-valent HPV vaccination is significantly elevated compared to other vaccines, potentially indicating a safety signal that warrants further investigation.

2. METHODS

This is a post-marketing descriptive pharmacoepidemiologic study based on spontaneous adverse event reports. The VAERS database was searched for reports submitted from January 1, 2016, to November 29, 2024. Various filters were applied to extract information related to the 9-valent HPV vaccine and its association with abdominal pain and other reported symptoms. Similarly, data for all other vaccines were retrieved using the same symptom classification approach to allow for comparative analysis. The analysis focused on individuals aged 6–17 and 18–29 years, which include the recommended vaccination age groups, according to the age intervals in the database.

To evaluate whether abdominal pain was disproportionately reported following HPV vaccination compared to other vaccines, a 2 × 2 contingency table was constructed. From this, the following measures were calculated:

Proportional Reporting Ratio (PRR): to identify whether abdominal pain occurred at a higher-than-expected frequency among HPV vaccine reports.

Odds Ratio (OR): to estimate the strength of association between the 9-valent HPV vaccine and reports of abdominal pain.

Yates’ Chi-Squared Test: to adjust for continuity and minimize overestimation of statistical significance in small samples.

These statistical methods were selected for their established role in signal detection within spontaneous reporting systems such as VAERS.

3. RESULTS

A total of 15,005 adverse event reports were associated with the 9-valent HPV vaccine in individuals aged 6 to 29 years from January 1, 2016, to November 29, 2024. Of these, 127 reports (0.85%) involved abdominal pain. In contrast, for all other vaccines, 1,229,411 adverse events were reported, among which 9,970 (0.81%) included abdominal pain. Table 1 summarizes the distribution of abdominal pain and other reported adverse events across vaccine types.

To evaluate whether abdominal pain was disproportionately reported following the 9-valent HPV vaccine, a 2 × 2 contingency table was constructed. The results of the disproportionality analysis were as follows:

PRR= (a/a+c)/ (b/b+d) = 0.00845/0.00812= 1.04

odds ratio (OR)= ad/bc = 154867007/148288600= 1.04

Yates’ chi-squared test =0.204 (p = 0.651)

The test produced a value of 0.204 with 1 degree of freedom, indicating no statistically significant difference in the reporting of abdominal pain between the 9-valent HPV vaccine and other vaccines.

These findings suggest no evidence of disproportionate reporting of abdominal pain following HPV vaccination compared to other vaccines. The PRR and OR values are both close to 1, indicating a nearly identical frequency of abdominal pain reports between the two groups. Clinically, this suggests that abdominal pain is not more commonly associated with the HPV vaccine than with other routine immunizations.

Table 2 shows the general characteristics by age group of reported cases of abdominal pain in the 9-valent HPV vaccine. The majority of cases were reported in the 6–17-year age group (n = 104; 73.2%), which corresponds to the primary target population for HPV vaccination. A smaller number of cases occurred in older age groups, with a few reports lacking specific age data.

In terms of sex distribution, females accounted for 102 of the 142 cases (71.8%), consistent with higher vaccination rates historically seen among females in HPV immunization programs. Among females, 80 events (78.4%) were classified as non-serious, and 20 (19.6%) as serious but non-fatal. No deaths were reported.

When comparing abdominal pain to other reported adverse events following immunization (AEFIs), abdominal pain represented a very small proportion of total reports: 0.85% for the 9-valent HPV vaccine and 0.81% for all other vaccines. The minimal difference resulted in PRR and OR values of 1.04, with no statistically significant signal identified.

Furthermore, the majority of abdominal pain cases were non-serious and self-limiting, with no deaths and few serious reports. This supports the conclusion that abdominal pain, although occasionally reported, is not uniquely or disproportionately associated with the 9-valent HPV vaccine and does not represent a distinct safety concern based on current data.

4. DISCUSSION

The 9-valent HPV vaccine safety profile has been evaluated in several studies and is generally considered favorable. A study found three percent more local adverse reactions were observed in women who received the 9-valent HPV vaccine versus the quadrivalent vaccine: RR = 1.03 (95% CI 1.02 to 1.04). However, no significant differences in systemic serious adverse events were noted [14]. The results of this study are in line with this safety profile, particularly in relation to abdominal pain, which appears to be infrequent and generally non-serious.

All vaccines can have some side effects. Abdominal pain and other gastrointestinal symptoms, such as nausea, vomiting, constipation, diarrhea, and distention, are reported with most vaccines [15].

A retrospective study compared the risk of emergency department visits and hospitalizations during the interval shortly after vaccination with the risk during a later interval of a poorly defined category, which included abdominal pain, allergic reactions, syncope, etc., obtaining an OR of 1.36, 95% CI: 1.13-1.64. The timing of all of these outcomes was not significant, except for syncope episodes, which were much more likely to occur on the day of vaccination [16].

A randomized, double-blind study was conducted on girls aged 9 to 15 years to evaluate the safety profile of the quadrivalent (4vHPV) and 9-valent human papillomavirus vaccine. Participants were randomly assigned to two groups, each receiving a three-dose regimen of either vaccine. Adverse effects were common in both groups, with 93.3% of participants in the 9-valent human papillomavirus vaccine group and 90.3% in the 4vHPV group reporting at least one adverse event. In the 9-valent human papillomavirus vaccine group, the most frequently reported systemic adverse effects included: Headache (11.4%), fever (5%), nausea (3%), oropharyngeal and upper abdominal pain (2.7 and 1.7%, respectively) [17]. In this study, data from the VAERS database were analyzed to evaluate the frequency and characteristics of abdominal pain reports associated with the 9-valent human papillomavirus vaccine among individuals aged 6 to 29 years and to compare these with all other vaccines. The findings indicated that the 9-valent human papillomavirus vaccine does not significantly increase the risk of abdominal pain when compared to other vaccines, with a proportional reporting ratio (PRR) of 1.04 and an odds ratio of 1.04. Yates’ chi-squared test yielded a value of 0.204 (p= 0.651), indicating no evidence of a significant association.

Data mining methods have been proposed as screening tools for improving the efficiency of adverse event reporting. The PRR is a statistic that is used to generate a signal about the potential hazard of drugs (a value close to or less than one may prevent unnecessary additional evaluation) [18]. A signal can be determined with the methods presented above based on simple mathematical procedures, which can be calculated with a basic calculator. However, the number of PRR signals for singleton reports can result in many false alarms and divert resources from more consequential relationships. The screening proportional reporting ratio, which considers the number of reports for a given vaccine ≥3, PRR ≥2, and Yates-corrected chi-square ≥4, eliminates the overweighting of singleton reports [19].

The results obtained from this study found that the 9-valent HPV vaccine is safe regarding the risk of abdominal pain symptoms. However, its presence could stem from anxiety, vagal reactions, coincidental illness, or inflammatory responses.

This study also contributes to understanding demographic patterns in reported cases. Table 2 shows that the majority of abdominal pain reports were in females aged 6 to 17 years, and most were non-serious. No deaths were reported, which aligns with global post-licensure surveillance data indicating a strong safety profile for the HPV vaccine. However, our analysis also highlights the importance of continued monitoring, particularly in specific subpopulations.

Despite its strengths, our study has several limitations. First, VAERS is a passive surveillance system and is subject to underreporting and reporting biases, especially for non-serious events, which may be underrepresented. Second, VAERS reports are not medically verified, and symptom causality or timing is not always clearly documented. Third, we could not account for confounding factors such as concomitant vaccine administration, preexisting health conditions, or psychosomatic reactions. Additionally, the cross-sectional nature of the data and the lack of unvaccinated controls limit our ability to draw causal inferences. Finally, the proportional reporting ratio (PRR), while useful for signal detection, is a hypothesis-generating tool and not a definitive measure of risk.

CONCLUSION

No statistically significant differences in abdominal pain symptoms, when evaluated using epidemiological methods of alert, were observed with the injection of the 9-valent HPV vaccine in relation to the other vaccines. The data available on VAERS do not recommend further research on this association. However, these findings must be interpreted with caution due to the inherent limitations of passive surveillance data. The VAERS system is subject to underreporting, reporting biases, and lacks clinical verification, which restricts its capacity to establish causality. From a public health and clinical perspective, these findings support the favorable safety profile of the 9-valent HPV vaccine and should reinforce confidence in its continued use within recommended age groups. However, healthcare professionals and policy-makers should remain vigilant and support systems that encourage comprehensive and timely adverse event reporting to ensure early detection of any emerging safety concerns.

REFERENCES