LETTER TO THE EDITOR

Authors reply: Human papillomavirus vaccine

and primary ovarian failure
To the editor:
We are grateful for the interest of Drs. Pellegrino
et al. in our recent publication1 as well as their
effort in exploring further the possible association
between HPV vaccination and primary ovarian failure (POF). We completely agree with the authors
that further analyses are required to determine the
prevalence of POF among the populations exposed
to the HPV vaccine and, to identify the presence of
possible risk factors that may predispose to POF
following HPV vaccination.
At present, however, we cannot firmly conclude
that the causal relationship with the HPV vaccine is
unlikely simply because of the low number of POF
reports in various vaccine surveillance databases. In
particular, Pellegrino et al. retrieved four reports of
POF associated with the HPV vaccine from the US
Vaccine Adverse Event Reporting System (VAERS),
one from the Australian database and two from the
European database of suspected adverse drug
reaction reports. It should be noted that these
vaccine surveillance databases rely exclusively on
passive reporting, and hence, these systems cannot
be used to determine the presence or absence of
causality.
This fact was well recognized even by the Australian manufacturer of the HPV vaccine. In particular,
as noted by Little and Ward2 who reported the very
first case of POF in a 16-year-old girl following
Gardasil vaccination, the Australian sponsor of the
vaccine has stated after notification of the case that
the post-market reporting of adverse events is voluntary and from a population of uncertain size, and
consequently, it is not always possible to reliably
estimate the frequency of these reactions or establish
a causal relationship to product exposure.
Moreover, POF is currently not listed as a possible
adverse reaction in the HPV vaccine product leaflet.3
Thus, physicians as well as parents would most likely
not regard POF-related complaints in HPV vaccinated
girls as vaccine related. This would further lead to
underreporting of potentially vaccine-associated
American Journal of Reproductive Immunology 71 (2014) 295296
2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

events. Indeed, since the publication of our paper,

we have received numerous e-mails from both parents and doctors concerning other cases of possible
HPV vaccine-related POFs.
Primary ovarian failure is an extremely rare and serious occurrence in the teenage population, and the
emergence of POF cases following HPV vaccine (which
is a relatively young vaccine) should alert physicians
to more rigorous follow-up and monitoring of vaccinated girls. Many times symptoms start after the first
or second dose (two of three cases we described experienced adverse manifestations after the first dose).1 If
such symptoms consistent with POF are noted, the
vaccination may be contraindicated in such subjects.
Indeed, it is not unusual that a full-blown manifestation of autoimmunity occurs in individuals who have
previously reacted adversely to vaccination. For example, recently, we described six cases of systemic lupus
following Gardasil vaccination.4 In all six cases, several
common features were observed, namely a personal or
familial susceptibility to autoimmunity and an adverse
response to a prior dose of the vaccine, both of which
were associated with a higher risk of post-vaccination
full-blown autoimmunity.
Little and Ward2 have also cautioned that there
may be a group of women for whom the HPV vaccine is contraindicated. They further suggested that
long-term follow-up of ovarian function in a cohort
of vaccinated girls and women be undertaken as the
occurrence of POF may represent broader public
health implications.
The HPV vaccines do not replace currently available methods to screen or treat cervical cancer, and
their effectiveness in preventing any cancer death
will not be known for several decades.5,6 In preventive vaccination, where a relatively new vaccine is
administered to healthy individuals, an increased
emphasis on safety should not be viewed as unreasonable. Indeed, at present, we cannot exclude the
possibility that the reason why there are very few
POF reports in various vaccine surveillance databases
is simply because the public is not aware of the
possibility that POF may be triggered by the HPV
vaccine. Increased awareness and vigilance among
physicians is thus warranted.

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References
1 Colafrancesco S, Perricone C, Tomljenovic L, Shoenfeld Y: HPV
vaccines and primary ovarian failure: another facet of the
Autoimmune/Inflammatory Syndrome Induced by Adjuvants
(ASIA). Am J Reprod Immunol 2013; 70:309316.
2 Little DT, Ward HR: Premature ovarian failure 3 years after
menarche in a 16-year old girl following human papillomavirus
vaccination. BMJ Case Rep 2012. [epub ahead of print]. doi: 10.1136/
bcr-2012-006879.
3 Merck. Gardasil product sheet, Date of Approval 2006. http://www.
fda.gov/downloads/BiologicsBloodVaccines/Vaccines/
ApprovedProducts/UCM111263.pdf
4 Gatto M, Agmon-Levin N, Soriano A, Manna R, Maoz-Segal R,
Kivity S, Doria A, Shoenfeld Y: Human papillomavirus vaccine and
systemic lupus erythematosus. Clin Rheumatol 2013; 32:13011307.
5 Harper DM, Nieminen P, Paavonen J, Lehtinen M: Cervical cancer
incidence can increase despite HPV vaccination. Lancet Infect Dis
2010; 10:594595; author reply 595.
6 Tomljenovic L, Spinosa JP, Shaw CA: Human papillomavirus
(HPV) vaccines as an option for preventing cervical
malignancies: (How) effective and safe? Curr Pharm Des 2013;
19:14661487.

296

Serena Colafrancesco1,2, Carlo Perricone1,2, Lucija

Tomljenovic1,3, Yehuda Shoenfeld1,4
1
Zabludowicz Center for Autoimmune Diseases Sheba
Medical Center, Tel-Hashomer, Israel
2
Rheumatology Unit, Department of Internal Medicine
and Medical Specialities, Sapienza University of Rome,
Rome, Italy
3
Neural Dynamics Research Group, Faculty of Medicine,
University of British Columbia, Vancouver, BC, Canada
4
Incumbent of the Laura Schwarz-Kipp Chair for
Research of Autoimmune Diseases, Sackler Faculty of
Medicine, Tel Aviv University, Tel Aviv, Israel
Correspondence
Yehuda Shoenfeld, Department of Medicine, Chaim
Sheba Medical Center, Tel Hashomer 52621, Israel.
E-mail: Shoenfel@post.tau.ac.il
doi: 10.1111/aji.12200

American Journal of Reproductive Immunology 71 (2014) 295296

2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd