Expert Opinion on Drug Safety

ISSN: 1474-0338 (Print) 1744-764X (Online) Journal homepage: https://www.tandfonline.com/loi/ieds20

Surveillance of adverse events following

immunization related to human papillomavirus
vaccines: 12 years of vaccinovigilance in Southern
Italy

Cristina Scavone, Cristina Di Mauro, Simona Brusco, Michele Bertini,

Gabriella di Mauro, Concetta Rafaniello, Liberata Sportiello, Francesco Rossi
& Annalisa Capuano

To cite this article: Cristina Scavone, Cristina Di Mauro, Simona Brusco, Michele Bertini,
Gabriella di Mauro, Concetta Rafaniello, Liberata Sportiello, Francesco Rossi & Annalisa Capuano
(2019): Surveillance of adverse events following immunization related to human papillomavirus
vaccines: 12 years of vaccinovigilance in Southern Italy, Expert Opinion on Drug Safety, DOI:
10.1080/14740338.2019.1598969

To link to this article: https://doi.org/10.1080/14740338.2019.1598969

Accepted author version posted online: 23

Mar 2019.

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Publisher: Taylor & Francis

Journal: Expert Opinion on Drug Safety

DOI: 10.1080/14740338.2019.1598969
Surveillance of adverse events following immunization related to human
papillomavirus vaccines: 12 years of vaccinovigilance in Southern Italy

Cristina Scavone, Cristina Di Mauro, Simona Brusco, Michele Bertini, Gabriella di Mauro,

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Concetta Rafaniello, Liberata Sportiello, Francesco Rossi and Annalisa Capuano

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Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology,
Department of Experimental Medicine, Section of Pharmacology “L. Donatelli”, University

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of Campania “Luigi Vanvitelli”, Naples, Italy
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Corresponding author:
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Cristina Scavone
Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology
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Department of Experimental Medicine

Section of Pharmacology “L. Donatelli”
University of Campania “Luigi Vanvitelli”
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Via Costantinopoli 16, 80138 Naples

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Italy

Phone: +390815665805
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Email: cristina.scavone@unicampania.it
Abstract

Objectives: Human papillomavirus (HPV) vaccines have proved to be effective in

preventing cervical carcinoma. Although their safety profile resembled those of any other
vaccine, few clinical studies showed that HPV vaccines might also induce severe adverse
events.
Methods: The authors aimed to investigate the safety profile of HPV vaccines, by
analyzing the individual case safety reports (ICSRs) of suspected adverse event following

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immunization (AEFI) concerning HPV vaccines that were sent to the Italian
Pharmacovigilance Spontaneous Reporting System (RNF) in the Campania Region from

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January 2007 to September 2018.
Results: During the study period, 82 ICSRs, covering 181 AEFIs, related to HPV vaccines

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were sent to the RNF in the Campania Region. The mean age of patients who
experienced an AEFI after HPV vaccinations was 13 ± 4.5 years. The majority of ICSRs
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reported AEFIs that were considered as not serious (82%) and that had a favorable
outcome (93%).
Conclusion: The overall results of the study demonstrated that, except for few cases,
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AEFIs related to HPV vaccines reflect those already reported in the summary of product
characteristics. The authors did not identify any new safety issues or serious, rare or
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unexpected AEFIs that were medically confirmed to be related to HPV vaccines.

Key words: HPV, AEFIs, safety, Italy, pharmacovigilance

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1. Introduction
Human Papillomavirus (HPV) vaccines have been extensively introduced in several
medium- and high-income countries as part of the respective national immunization
programs. HPV vaccines have proved to be effective in preventing cervical carcinoma, the
second most common cancer in women, especially when they are administered before the

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beginning of sexual activity [1].
Currently, three types of HPV vaccines are available in Europe: a quadrivalent vaccine

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(4vHPV), covering serotypes 6, 11, 16, 18 and licensed in 2006; a bivalent vaccine
(2vHPV), covering serotypes 16, 18 and licensed in 2007; a nonavalent vaccine (9vHPV),

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covering serotypes 6, 11, 16, 18, 31, 33, 45, 52, 58 and licensed in 2015. These serotypes
are responsible for more than 70% of all cervical cancers but they are also associated with
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penis, vagina, anus, mouth cancers and genital warts [2]. HPV vaccines are administered
intramuscularly in different doses, depending on age. In particular, for all HPV vaccines a
two-dose schedule is recommended in girls in the age range 9 to 14 years, while a three-
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dose schedule is recommended for 2vHPV and 4vHPV vaccines in girls aged 14 years
and over and for 9vHPV in girls aged 15 years and over. Starting from February 2007,
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these vaccines become gradually available in Italy, where they are currently recommended
in boys and girls according to the Italian National Vaccination Prevention Plan (PNPV)
2017-2019 [3,4]. The coverage for HPV vaccines in Italy (updated to December 2017;
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2005 cohort) was 64.3% for the first dose and 49.9% for the full cycle in girls. A negative
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trend was confirmed, although with a wide variability between the Italian Regions and the
Autonomous Provinces; for instance, in Campania Region the coverage stood at 43.30%
for the full cycle, compared to 75.54% in Umbria Region [5].
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The safety profile of HPV vaccines resembled those of any other vaccines [6,7]. Indeed,
data shared by the Centers for Disease Control and Prevention (CDC) in 2014 revealed
that HPV vaccines might commonly cause the occurrence of syncope, dizziness, nausea,
headache, pyrexia, injection site reactions, and autoimmune disorders [8]. However, few
clinical studies and case reports showed that HPV vaccines can also induce severe
adverse events, including complex regional pain syndrome (CRPS), postural orthostatic
tachycardia syndrome (POTS), and chronic fatigue syndrome (CFS) [9-11]. At the present,
as stated by the European Medicines Agency (EMA), there is no evidence supporting a
possible association between those adverse events and HPV vaccines [12].
Considering that HPV vaccines have been used for a long period of time among Italian
regions and that new safety issues have emerged in recent years, we have examined the
individual case safety reports (ICSRs) of suspected adverse event following immunization
(AEFI) concerning HPV vaccines sent to the Italian Pharmacovigilance Spontaneous
Reporting System (Rete Nazionale Farmacovigilanza - RNF) in Campania Region (South
of Italy; about 6,000,000 inhabitants) from January 2007 to September 2018. The aim of

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this study was to evaluate the safety profile of HPV vaccines, comparing the number of
ICSRs received in Campania Region with the total number of ICSRs received in all Italian

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Regions, and to eventually detect the presence of CRPS, POTS, or CFS among ICSRs
sent to the Campania Pharmacovigilance Regional Center.

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2. Methods
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2.1. Data source
The Italian Medicines Agency (AIFA) shall coordinate all pharmacovigilance activities
performed on Italian territory. In order to collect and analyze data from ICSRs, the AIFA
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established in 2001 the RNF. The AIFA has also established the Pharmacovigilance
Regional Centers, which are fully involved in the evaluation of ICSRs coming from each
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respective region, in terms of quality of data, evaluation of the causality assessment for
each drug or vaccine/event couple, and contribution to signal detection in collaboration
with AIFA. The Campania Regional Center of Pharmacovigilance was established with the
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implementation of the Legislative Decree 95/2003. National data, exclusively related to the
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number of ICSRs reporting AEFIs to HPV vaccines, were obtained from the RAM, a
database that allows the access to ICSRs recorded into the RNF in all Italian Regional
centers.
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2.2. Descriptive analysis and case series

All ICSRs that reported HPV vaccines (2vHPV, 4vHPV and 9vHPV) as suspected and that
were validated by the Campania Pharmacovigilance Regional Center from January 1st,
2007 to September 30th, 2018 were selected. In order to obtain the number of ICSRs
related to HPV vaccines on all Italian territory, we used the RAM database.
We performed a descriptive analysis of ICSRs sent to Campania Pharmacovigilance
Regional Center, stratifying by year, mean age (± Standard Deviation - SD), gender,
suspected HPV vaccine, seriousness (serious – death; serious – hospitalization or its
prolongation; serious – severe or permanent disability; serious – life-threat; serious –
congenital abnormalities/birth deficits; serious – medically significant; not serious),
outcome (favorable: completely resolved or improved; unfavorable: resolved with sequelae
or unchanged), System Organ Class (SOC), Preferred Term (PT), source of report, and
causality assessment. We have also searched for PTs related to cases of CRPS, POTS,
or CFS only among serious ICSRs. In order to detect any relevant clinical information,
serious ICSRs were individually screened. For the vaccine causality assessment,

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Pharmacovigilance Regional Centers use a standardized algorithm, that defines the
relationship between vaccine and AEFI as “consistent causal association to immunization”,

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“indeterminate”, “inconsistent causal association to immunization” or “not classifiable” [13-
15]. Given the clinical impact of serious AEFIs and considering that all not serious ones

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were already expected, we decided to show the results of the vaccine causality
assessment results exclusively for serious AEFIs.
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Safety data deriving from the Italian spontaneous reporting system are anonymous and in
compliance with the ethical standard. Therefore, no further ethical measures were
required.
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3. Results
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From January 1st, 2007 to September 30th, 2018, 82 ICSRs, covering 181 AEFIs, related to
HPV vaccines were sent to the Campania Pharmacovigilance Regional Center, compared
to 5,402 ICSRs across Italian territory. The first ICSRs related to HPV vaccines in
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Campania Region were reported in 2008; in line with the Italian situation, after achieving a
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peak in years 2009 and 2011, the reporting of AEFIs showed a fluctuating trend until 2014
and then it gradually decreased (Figure 1).
The 91% of all ICSRs reported as suspected the 4vHPV, 9% the 9vHPV, while no ICSRs
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were related to the 2vHPV. The mean age (± SD) of patients who experienced an AEFI
after HPV vaccinations was 13 ± 4.5 and 98% of these were female (Table 1). Out of 76
ICSRs for which seriousness degree was reported, 82% reported AEFIs that were
considered as not serious. Out of 60 ICSRs for which outcome was reported, 93%
reported AEFIs that had a favorable outcome, while the remaining 7% had an unfavorable
outcome. Among serious ICSRs (n=14), we didn’t find any diagnosis of CRPS, POTS or
CFS, although some of their signs/symptoms were reported (Table 2). Except for serious
cases n. 3 and 4, which reported AEFIs not listed in the summary of product characteristic
of HPV vaccines (tachycardia and a suspicious case of Guillain Barre' syndrome - GBS),
all serious AEFIs were already known. Out of 14 serious ICSRs, 9 had a favorable
outcome (Table 2). Except for serious case n. 12, all AEFIs occurred the same day of HPV
vaccines administration (data not shown). Finally, the causality assessment resulted in
“consistent causal association to immunization” for 12 out of 14 ICSRs.
ICSRs were mainly reported by healthcare professional (96%) (Table 1). Out of 181
AEFIs, more than 80% referred to the SOCs “Nervous system disorders” (31.49%),

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“General disorders and administration site conditions” (21.55%), “Skin and subcutaneous
tissue disorders” (14.36%), “Gastrointestinal disorders” (9.94%), and “Musculoskeletal and

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connective tissue disorders” (6.08%). For those SOCs the most commonly reported PTs
are shown in Table 1.

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4. Discussion
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Starting from 2007, when the first HPV vaccine became available for the use in clinical
practice in Italy, until September 2018, 82 ICSRs were sent to the Campania
Pharmacovigilance Regional Center. Those ICSRs account for a mere 1.5% (82/5,402) of
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all ICSRs related to HPV vaccines sent in all Italian regions. In our opinion, such low
numbers could be a consequence of the low vaccination coverage for HPV vaccines in
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Campania Region. Indeed, data shared by the National Institute of Health (Istituto
Superiore di Sanità – ISS) revealed that the HPV coverage in Campania for the full cycle
has declined from 55.59% for patients born in 1997 to 43.30% for those born in 2005.
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Those percentages were considerably lower compared to other Italian regions, such as
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Umbria, Emilia Romagna or Piemonte, suggesting the need of targeted interventions in

Campania [5]. In line with our results, a recent pharmacovigilance study carried out in
Apulia (another region of Southern Italy) from 2008 to 2016 found a limited number of
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ICSRs related to HPV vaccinations [16].

Looking at the trend in AEFIs’ reporting, two peaks were observed both in Campania and
in Italy. The first detected in 2009 was probably related to the pandemic influenza H1N1,
which was followed by an increase in AEFIs’ reporting for all vaccines, while the second
and third in 2011 and 2014, respectively, could be attributed to the activation of national
and regional vaccinovigilance programs [17].
In our study AEFIs occurred in patients aged 13 ± 4.5. This is not surprising considering
that patients aged 9-17 years are the major target population for HPV vaccines, according
to the PNPV 2017-2019 [4]. The majority of AEFIs was reported in female patients, which
was expected considering that the recommendation for HPV vaccination in male patients
was recently introduced [5]. The 91% of all ICSRs reported as suspected the 4vHPV.
That's to be expected considering that the 9vHPV was recently authorized as well as that
in Campania the 4vHPV was more used than other HPV vaccines [18-20].
The majority of ICSRs reported AEFIs that were considered as not serious and that had a

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favorable outcome. This is in line with further pharmacovigilance studies [21-26], including
the aforementioned one performed in Apulia Region [16]. Similarly, the results of a study

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performed in Canada revealed that out of 195,270 females who received one or more
doses of HPV vaccine, less than 0.1% (n=192) reported one or more AEFIs and among

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those women only 5 experienced a serious AEFI [21]. Additional studies demonstrated
that HPV vaccines rarely induce serious AEFIs [22-24]. Indeed, AEFIs related to HPV
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vaccines are generally mild-to-moderate and tend to resolve within few days from their
occurrence, without affecting the completion of the immunization schedule [25,26].
We did not find any ICSR related to cases of CRPS, POTS or CFS, although few
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signs/symptoms of those conditions [27-29] were found (Table 2). Examples are the case
n. 2 that described the occurrence of headache (symptom of CFS) and the case n. 3 that
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reported sweating, tachycardia and respiratory distress (signs and symptoms of POTS).
Although signs/symptoms of CRPS, POTS and CFS were reported, it should be
emphasized that all serious AEFIs occurred the same day of vaccine administration. In our
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opinion, all serious AEFIs could be related to infusion reactions. Indeed, according to a
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recent meta-analysis on the immunogenicity and safety profile of HPV vaccination,

infusion-related reactions, which are usually reported within 5-7 days after the vaccine
administration, may have both local (pain, redness and swelling) and systemic (arthralgia,
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asthenia, pyrexia, gastrointestinal symptoms, headache and myalgia) symptoms [30-32].

Furthermore, generally infusion-related reaction may include other symptoms, such as
tachycardia, hypotension, rash and respiratory distress [33]. Therefore, according to
literature data as well as with the results of the safety review of HPV vaccines started in
2015 by the EMA [11,34], there is currently no evidence supporting a causal association
between HPV vaccines and development of CRPS, POTS or CFS; at the same time, our
results do not show a correlation between HPV vaccines and these syndromes. Lastly,
among our serious cases we found 2 AEFIs not reported in the summary of product
characteristics, tachycardia (serious case n. 3) – that could be a sign of an infusion
reaction - and a suspicious case of GBS not medically confirmed (serious case n. 4).
Considering that this last event occurred the same day of vaccine administration, which is
not consistent with the normal time to event referred to drug-induced GBS [35], that there
was not a confirmed diagnosis of GBS neither results of clinical, instrumental, and
laboratory parameters, and that the causality assessment resulted in “inconsistent causal
association to immunization”, this case cannot be considered as relevant. Furthermore,

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according to recent literature data, there is no evidence supporting the correlation between
GBS and HPV vaccines [36-39].

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In our study, the causality resulted in “consistent causal association to immunization” for
the majority of ICSRs because AEFIs reported were already known for HPV vaccines but

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also because ICSRs were very complete and full of clinical data.
With regard to the source of reports, we have found that the highest percentage of ICSRs
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came from healthcare professionals. In this regard it should be emphasized that the
involvement and empowerment of patients and citizens in the spontaneous reporting
systems in European countries was reinforced with the recent update of the
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pharmacovigilance legislation [40]. Therefore, considering that the highest number of

ICSRs in our study was sent until 2014 and that the increase in AEFIs’ reporting by
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patients/citizens in all Italian regions began in 2015 [41,42], our findings were expected.
Concerning the distribution by SOCs, we found that AEFIs generally referred to nervous,
gastrointestinal, musculoskeletal, cutaneous and general disorders.
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This is in line with findings reported by the AIFA [17,43]. The results of a systematic review
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and meta-analysis revealed that cutaneous and general disorders were the most common
AEFIs observed in patients who received HPV vaccines, while among serious AEFIs,
gastrointestinal, musculoskeletal, nervous system, and skin and subcutaneous tissue
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disorders were frequently reported [44]. Finally, in our study, PTs most commonly reported
were fainting, syncope, headache, seizure, pyrexia, asthenia, injections site reactions,
urticarial rashes, vomiting and abdominal pain. This is in line with the findings from
previous studies. Indeed, these PTs were commonly reported in a study of Arana JL et al.,
who analyzed 19,760 ICSRs sent to the Vaccine Adverse Event Reporting System and
related to the 4vHPV [45]. The same PTs were also confirmed by the results of a
systematic review, which involved 29,540 patients who received HPV vaccines [46].
4.1. Strengths and limitations
This study is founded on the spontaneous reporting system and it is well known that it is
affected by limitations, including the under-reporting and the incomplete clinical
information. Given these intrinsic boundaries, we cannot rule out the presence of
information that were not listed in AEFIs’ reports and that might have influenced both the
occurrence of the AEFIs and the proper evaluation of the causality assessment. Lastly,
since we have performed an analysis of pharmacovigilance data in a single region (which
is the third-most-populous region of Italy, by the way), we have extracted a limited number

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of AEFIs’ reports, which should not be considered representative of other Italian regions.
While recognizing these limitations, this is the second comprehensive evaluation of safety

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data related to HPV vaccines, using the Italian spontaneous reporting system (after the
one performed in Apulia). It is widely recognized that the spontaneous reporting system is

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an inexpensive and simple tool that covers large population, including pediatrics that are
usually excluded by the premarketing clinical trials, and all medicines and vaccines.
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Furthermore, the spontaneous reporting system allows detecting unexpected, rare and
serious ADRs/AEFIs [47] and its importance lies in the early identification of signals and
formulation of hypotheses, leading to further confirmatory investigations [48].
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5. Conclusion
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In conclusion, the overall results of our study demonstrated that, except for a few cases,
AEFIs related to HPV vaccines in the Campania Region reflect those already reported in
the summary of product characteristics. We did not identify any new safety issues or
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serious, rare or unexpected AEFIs that were medically confirmed to be related to HPV
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vaccines; thus, we believe that our results provide reassuring data on the safety profile of
HPV vaccines. Moreover, these results should be put into perspective by the huge
beneficial effects deriving from HPV vaccination. Being a long-term disease, all benefits
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deriving from these vaccines will be visible when vaccinated groups have a lower
frequency of pre-cancerous lesions due to HPV viruses.
According to the ISS, the HPV vaccination coverage in Italy is better than that registered in
other European countries, but remains below the limit value set by the PNPV 2017-2019
(95% for girls and 60-95% for boys) [5].
In this context, the continuous monitoring of the safety profile of medicines and vaccines in
real life settings [49-52], as well as the implementation of vaccine-vigilance programs, will
help in achieving higher confidence in immunization programs and improve knowledge
about the safety profile of vaccines.

Authors’ contributions
Drafting the work and revising it for important intellectual content: CS, CDM, SM, MB,
GdM, CR, LS, FR and AC. Substantial contributions to the acquisition, analysis, or
interpretation of data for the work: CS, CDM, SM, MB, GdM, CR, LS, FR and AC. Final
approval of the version to be published: CS, CDM, SM, MB, GdM, CR, LS, FR and AC.

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Developed the concept: CS, FR and AC. Wrote the paper: CS, CDM, SM, MB, GdM, CR,
LS, FR and AC.

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Funding

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This paper was not funded.
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Declaration of interests
The authors have no relevant affiliations or financial involvement with any organization or
entity with a financial interest in or financial conflict with the subject matter or materials
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discussed in the manuscript. This includes employment, consultancies, honoraria, stock

ownership or options, expert testimony, grants or patents received or pending, or royalties.
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Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to
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disclose.
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Papers of special note have been highlighted as:
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Figure 1. Trend in AEFIs’ reporting for HPV vaccines in Campania Region and in Italy.

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Table 1. Main features of ICSRs related to HPV vaccines in Campania Region

Total ICSRs
N. 82
Mean age (±SD) 13 ± 4.5
Gender (% female) 98
Suspected vaccine N. 82 (100)
4vHPV 75 (91)
9vHPV 7 (9)
Seriousness N. 76 (100)
Not serious 62 (82)
Serious 14 (18)
Outcome N. 60 (100)

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Favorable outcome a 56 (93)

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Unfavorable outcome a 4 (7)
Source N. 81 (100)
Healthcare professional 78 (96)

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Patient 3 (4)
System Organ Class N. 181 (100)
Nervous system disorders 57 (31.49)

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Fainting and Syncope 22
Headache 11
Seizure 5
General disorders and administration site conditions 39 (21.55)
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Pyrexia 12
Asthenia 11
Injection site reactions 9
Skin and subcutaneous tissue disorders 26 (14.36)
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Urticarial rashes and pruritus 20
Gastrointestinal disorders 18 (9.94)
Vomiting, nausea and abdominal pain 15
Musculoskeletal and connective tissue disorders 11 (6.08)
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Arthralgia and myalgia 9

Vascular disorders 7 (3.87)
Respiratory, thoracic and mediastinal disorders 6 (3.31)
Ear and labyrinth disorders 5 (2.76)
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Infections and infestations 3 (1.66)

Eye disorders 3 (1.66)
Investigations 2 (1.1)
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Blood and lymphatic system disorders 2 (1.1)

Cardiac disorders 1 (0.55)
Reproductive system and breast disorders 1 (0.55)
a
favorable outcome: completely resolved or improved; unfavorable outcome: unchanged.
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The total number of SOCs (N=181) exceeds the number of ICSRs (N = 82) because a single report might include more than one AEFI and
consequently more than one SOC.
RNF Database from Campania Region, Southern Italy.
Table 2. Serious ICSRs related to HPV vaccines in Campania Region

Ca Causality assessment
se Seriou
n. sness Outcome AEFIs
1 Serious Hyperpyrexia, Hypotonia, Fainting, Pain at injection site, Loss Consistent causal association to
-H NA of consciousness, Pallor immunization
2 Serious Favorable - Consistent causal association to
-H I Headache, Hyporeflexia, Hypotonia, Pyrexia immunization
3 Serious Favorable - Consistent causal association to
- MS CR Respiratory distress, Sweating, Tachycardia immunization
4 Joint pain (upper arm), Body numbness, Pain at lower limbs, Inconsistent causal association to
Serious Muscle weakness, Pelvic pain, Daytime sleepiness: suspicious immunization
-H NA case of Guillain Barre' syndrome
5 Serious Favorable - Consistent causal association to

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-H I Joint disease, Mononeuritis at upper arm, Tingling, Edema immunization

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6 Serious Favorable - Consistent causal association to
-H CR Headache, Loss of consciousness immunization
7 Serious Favorable - Respiratory distress, Urticarial rash Consistent causal association to

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-H CR immunization
8 Serious Favorable - Maculopapular eruption Consistent causal association to
-H CR immunization
9 Serious Favorable - Consistent causal association to

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-H CR Syncope immunization
10 Serious Consistent causal association to
-H NA Fainting immunization
11 Serious Favorable - Pruritus, Urticarial rash Consistent causal association to
- MS CR
an immunization
12 Serious Unfavorabl Weakness Inconsistent causal association to
-H e-U immunization
13 Serious Favorable - Consistent causal association to
- MS I Amnesia, Stiffness, Weakness, Tremor immunization
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14 Serious Loss of consciousness Consistent causal association to
- MS NA immunization

Serious - H: AEFI that requires inpatient hospitalization or prolongation of existing hospitalization; Serious - MS: AEFI that was medically
significant (it is considered serious because treatment/intervention would be required to prevent one of the preceding criteria - death, or life-
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threatening, hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, congenital anomaly); NA: not
available; Favorable - I: improved; Favorable - CR: completely resolved; Unfavorable – U: unchanged.
RNF Database from Campania Region, Southern Italy.
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