LETTER TO THE EDITOR

Authors Reply: Human Papilloma Virus Vaccine

and Primary Ovarian Failure
To the editor:
We thank Dr. Wiznitzer for expressing his concern
questioning the objectivity of our paper on HPV vaccine and primary ovarian failure (POF) published
recently in this journal.1
While we acknowledge that the declaration of
conflict of interests should have been more explicit
to include the statement that Dr. Shoenfeld was specifically involved as an expert witness in the Vaccine
Injury Compensation Program (VCIP) in two of
three cases described in our report,1 this omission
was neither premeditated nor Machiavellian in its
intent as Dr. Wiznitzer seems to suggest.
The point could equally be made that Dr. Wiznitzer was not fully transparent in his declaration of
potential conflicts as he omitted to specify that he is
presently involved in an active litigation in the VCIP
providing opposing testimony to Dr. Shoenfeld.
Thus, Dr. Wiznitzers present critique of Dr. Shoenfelds paper needs to be viewed in light of this fact.
While we try our best to do our work without
errors, we are not infallible, as infallibility is not in
human nature. As Dr. Wiznitzer correctly noted, Dr.
Shoenfeld had previously identified himself as the
expert witness for the subject of a published article,
not only in the report cited by Dr. Wiznitzer,2 but
also in a more recent publication.3 Hence, rather
than assuming the worst scenario, perhaps Dr. Wiznitzer could have considered the possibility that the
omission of such explicit declaration in the article
published in American Journal of Reproductive Immunology1 was simply a non-intentional error.
With reference to HPV vaccination and POF, the
three cases we described1 are not the only cases
reported in the literature.4,5 Moreover, since the
publication of our paper, we have received numerous notifications from both physicians and parents
reporting other cases of POF which occurred in short
temporal association with HPV vaccination.
Generally, vaccine adverse event notifications of
amenorrhea are poorly investigated and followed up.
Additionally, pre- and post-licensure studies on HPV
vaccines were inadequately designed to monitor for
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ovarian function. For example, the major postlicensing study of HPV4 safety6 reviewed 189,629
vaccinated females including 44,000 who had
received three doses. Selected outcome measures
were subjects hospitalizations and emergency
department visits following vaccination. In this
study, 1112 year olds who received three doses
comprised 4.3% of the overall study population;
915 year olds comprised 12.9%.6 The consultation
context for seeking medical management of oligomenorrhea or amenorrhea is not normally the emergency
department
and
will
not
require
hospitalization. Hence, this study had no capacity to
evaluate ongoing ovarian health or to monitor ovarian safety.
Similarly, other post-licensure studies7,8 due to
their limited design and narrow range of preselected
outcomes lacked the capacity to assess the risk of
POF following HPV vaccination.
With regard to pre-licensure phase II studies (protocols 007,9 016,10 and 01811) and phase III protocols 013 (Future I)12 and 015 (Future II),13 only
phase II protocols 01610 and 01811 studied adolescents under 16 years. A vaccine report card recorded
temperatures and adverse events occurring within
2 weeks of each vaccination and prompted for
recording of local site reactions. Protocol 01610 studied 506 healthy girls aged 1015 years. Only 240
girls, 47.4%, completed the planned 12-month follow-up. The unexplained loss of the majority of participants to 12-month follow-up and small numbers
of those remaining who had reached menarche precluded this study from competence to evaluate
ongoing ovarian function.10
In preventive vaccination, where a relatively new
vaccine is administered to healthy individuals, an
increased emphasis on safety should not be viewed
as unreasonable. Thus, at present, we cannot
exclude the possibility that the reason why there
are very few POF reports in the medical literature
is simply because the medical community is not
aware of the possibility that POF may be triggered
by the HPV vaccine. We felt it was our ethical duty
to raise awareness among physicians of this possibility. Apparently, there are others who noted the
same.4,5
American Journal of Reproductive Immunology 72 (2014) 260261
2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

LETTER TO THE EDITOR

References
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Yehuda Shoenfeld1,2, Lucija Tomljenovic1,3

Zabludowicz Center for Autoimmune Diseases Sheba
Medical Center, Tel-Hashomer, Israel
2
Incumbent of the Laura Schwarz-Kipp Chair for
Research of Autoimmune Diseases, Sackler Faculty of
Medicine, Tel Aviv University, Tel Aviv, Israel
3
Neural Dynamics Research Group, Faculty of Medicine,
University of British Columbia, Vancouver, BC, Canada
1

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.12286

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