  United States Court of Appeals
      for the Federal Circuit
                ______________________

 CHERYL KOEHN, as Mother and Next Friend of,
           VANESSIA KOEHN,
           Petitioners-Appellants,

                           v.

      SECRETARY OF HEALTH AND HUMAN
                  SERVICES,
              Respondent-Appellee.
             ______________________

                      2014-5054
                ______________________

    Appeal from the United States Court of Federal
Claims in No. 1:11-vv-00355-EGB, Senior Judge Eric G.
Bruggink.
                ______________________

              Decided: December 4, 2014
               ______________________

    P. LEIGH O’DELL, Beasley, Allen, Crow, Methvin,
Prortis, & Miles, P.C., of Montgomery, Alabama, argued
for petitioners-appellants.

     DARRYL R. WISHARD, Trial Attorney, Torts Branch,
Civil Division, United States Department of Justice, of
Washington, DC, argued for respondent-appellee. With
him on the brief were STUART F. DELERY, Assistant Attor-
ney General, RUPA BHATTACHARYYA, Director, VINCENT J.
2                                               KOEHN   v. HHS



MATANOSKI, Deputy Director, and GABRIELLE                  M.
FIELDING, Assistant Director.
                 ______________________

    Before MOORE, O’MALLEY, and REYNA, Circuit Judges.
    Opinion for the court filed by Circuit Judge O’MALLEY.
    Concurring opinion for the court filed by Circuit Judge
                           MOORE.
O’MALLEY, Circuit Judge.
    Cheryl Koehn appeals from a U.S. Court of Federal
Claims judgment upholding a Special Master’s denial of
compensation for Koehn’s daughter’s systemic juvenile
idiopathic arthritis (“SJIA”) allegedly caused by a vaccine.
Although the Special Master’s assessment of Koehn’s
medical theory of causation contains several flaws, the
Special Master had a sufficient basis upon which to
determine that Koehn did not meet her burden of demon-
strating a proximate temporal relationship between her
daughter receiving the vaccine and developing SJIA. We
therefore affirm.
                        BACKGROUND
    Children with SJIA, an autoinflammatory disease,
exhibit symptoms including arthritis, a fever, and a rash,
and may experience flares involving similar symptoms as
well as muscle and joint pain. Many of these symptoms
result from dysfunctional production of proteins called
cytokines, which certain cells release almost immediately
after the body comes into contact with an antigen. Cyto-
kines signal other cells to generate an immune response.
Pro-inflammatory cytokines, like those associated with
SJIA, can lead to fever or other inflammation. Examples
of SJIA medication include prednisone, which reduces
inflammation and suppresses the immune system, and
etanercept, which inhibits a cytokine linked to SJIA.
KOEHN   v. HHS                                           3



    Gardasil is a vaccine that immunizes against four
strands of human papillomavirus (“HPV”). The vaccine,
administered in three doses, contains virus-like particles
created from an HPV protein, as well as an adjuvant,
which assists in generating a robust immune response to
promote long-term immunity.
                            I.
    Koehn’s daughter, Vanessia, was born in February
1995, and was generally healthy for the first twelve years
of her life. Dr. Elena Regala administered Vanessia’s first
dose of Gardasil in February 2008 and her second dose in
April 2008. On June 21, 2008, Vanessia experienced a
rash all over her body. Dr. Regala, believing it to be an
allergic reaction, prescribed Benadryl and prednisone
three days later. Vanessia’s rash disappeared within
three days. On June 28, 2008, Vanessia went to Marian
Medical Center for severe joint pain and high fever.
Vanessia had stopped taking prednisone by that time,
which coincided with her developing pain in her knees,
thighs, and calves. Vanessia saw a rheumatologist at the
hospital and received another prescription for prednisone.
The hospital discharged her on July 2, 2008 with a pre-
sumptive diagnosis of juvenile idiopathic arthritis. Va-
nessia’s only symptom at discharge was a rash.
    On July 8, 2008, Vanessia saw Dr. Deborah McCurdy,
a pediatric rheumatologist, who noted that Vanessia’s
family history included juvenile idiopathic arthritis and
concluded that SJIA was a likely diagnosis. Dr. McCurdy
communicated these findings to Dr. Regala, who adminis-
tered Vanessia’s third dose of Gardasil on August 19,
2008. Vanessia was no longer taking prednisone at that
time, but had started taking etanercept. Vanessia experi-
enced a flare of SJIA with fever, rash, and joint pain on
August 25, 2008. In September 2008, Dr. McCurdy
concluded that, though Vanessia had improved, she still
showed signs of SJIA. Dr. McCurdy noted that Vanessia
4                                             KOEHN   v. HHS



complained of SJIA symptoms after she stopped taking
prednisone, and that she had swollen ankles and knees.
                            II.
    On behalf of Vanessia, Koehn filed an off-Table injury
claim under the Vaccine Act. For off-Table injuries, which
are those that do not appear on the statutory Vaccine
Injury Table, 42 C.F.R. § 100.3 (2014), the petitioner must
prove causation-in-fact. Andreu v. Sec’y of Health &
Human Servs., 569 F.3d 1367, 1374 (Fed. Cir. 2009). A
petitioner must prove the following by a preponderance of
the evidence to establish causation: (1) a medical theory
causally connecting the vaccination to the injury; (2) a
logical sequence of cause and effect demonstrating that
the vaccination caused the injury; and (3) a proximate
temporal relationship between the vaccine and the injury.
Althen v. Sec’y of Health & Human Servs. 418 F.3d 1274,
1278 (Fed. Cir. 2005).
    Koehn presented the opinion of Dr. Michael McCabe,
who has a Ph.D. in microbiology and immunology and has
researched environmental factors that affect immune
response, to support her claim. Dr. McCabe asserted that
Vanessia had a predisposition for SJIA, and that Gardasil
was an environmental trigger because the vaccine caused
a strong response in the same cytokines which are
dysregulated in SJIA. He relied on several articles to
support his theory, including an article discussing a study
that tested cytokine levels in women who received an
HPV vaccine on a three-dose regimen similar to Gardasil
(“Pinto article”). In the study referred to by the Pinto
article, researchers gave twenty female participants an
HPV vaccine on the same three dose regimen as Gardasil,
and drew blood before the first injection and one month
after each of the second and third injections. The re-
searchers either stimulated the blood samples with vary-
ing amounts of a virus-like particle in the vaccine or
provided no stimulation at all. Cytokine levels were
KOEHN   v. HHS                                            5



relatively consistent in the vaccinated blood that received
no stimulation. Cytokine levels increased, however, for
the vaccinated blood that received the virus-like particle,
and the elevated cytokines were the same as those
dysregulated in SJIA. Dr. McCabe asserted that this
commonality supports his theory that Gardasil triggered
Vanessia’s SJIA.
    Dr. McCabe further testified that the lack of epidemi-
ological studies on SJIA shows that the disease is too rare
for scientists to be able to generate statistically relevant
epidemiological data. As an example, Dr. McCabe pre-
sented an article discussing a study that evaluated the
medical history of approximately 189,000 women to
determine whether they developed an autoimmune re-
sponse after receiving a quadrivalent HPV vaccine (“Chao
article”). Though the Chao article did not find such a
connection, Dr. McCabe relied on the article to demon-
strate that SJIA is so rare that, despite the large sample
size, it was not large enough to detect an increased rate of
SJIA following HPV vaccination.
    Finally, Dr. McCabe suggested that, because patients
who receive Gardasil develop sufficient antibodies for
immunity within seven months, Vanessia’s development
of SJIA within seven months after receiving Gardasil was
evidence of a proximate temporal relationship.
    The government’s expert, Dr. Carlos Rose, is a pediat-
ric rheumatologist and routinely treats children with
SJIA, but has not researched the HPV vaccine or the role
of cytokines in SJIA. Dr. Rose asserted that Vanessia’s
SJIA was more likely a coincidence. According to Dr.
Rose, the most relevant results from the Pinto article
were that the vaccinated blood samples with no stimula-
tion had relatively consistent cytokine levels, whereas
SJIA patients experience a pattern of up-regulated cyto-
kine levels. Dr. Rose also cited an article referring to a
study of roughly 60,000 individuals which found no in-
6                                             KOEHN   v. HHS



creased risk for autoimmune disorders for participants
who received vaccines, including an HPV vaccine called
Cervarix that uses a different adjuvant than Gardasil
(“Verstraeten article”).
                            III.
     The Special Master denied Koehn compensation. The
Special Master held that Koehn did not meet her burden
under the first Althen prong, finding that Dr. McCabe’s
medical theory was unprecedented and had not been peer-
reviewed or published. In addition, the Special Master
found that the relevant scientific community, pediatric
rheumatologists, did not accept Dr. McCabe’s theory,
primarily basing that conclusion on Dr. Rose’s testimony
that he, as head of pediatric rheumatology at his hospital,
did not recall ever hearing of such a theory. The Special
Master acknowledged that the Verstraeten article in-
volved a different HPV vaccine than Gardasil and that its
sample size was likely insufficient to produce statistically
significant results. But, because Chao involved Gardasil
and had more than double the sample size of the Ver-
straeten article, the Special Master held that the articles
“[t]aken together” weighed against Dr. McCabe’s theory.
J.A. 143. Finally, the Special Master focused on the Pinto
article’s results indicating that cytokine levels increased
only when the researchers stimulated the blood, and Dr.
Rose’s statement that “[o]f course when you stimulate
with an antigen you get more cytokines released.”
    Moving to the second Althen prong, the Special Mas-
ter held that Koehn did not establish a logical sequence of
cause and effect between Gardasil and Vanessia’s SJIA.
In reaching this conclusion, the Special Master found Dr.
Rose’s opinion more persuasive because he is a doctor that
treats patients, whereas Dr. McCabe does not treat pa-
tients.
   The Special Master further held that Koehn did not
meet her burden under the third Althen prong because
KOEHN   v. HHS                                           7



the record did not support Dr. McCabe’s assertion that
development of SJIA within a seven-month interval was
sufficient to establish a proximate temporal relationship.
Dr. McCabe reasoned that the onset of SJIA aligns with
the time period during which Gardasil patients develop a
sufficient immune response, which is seven months. The
Special Master found, however, that both Dr. McCabe and
Dr. Rose agreed that the immune system releases cyto-
kines soon after the body encounters an antigen, which is
inconsistent with Dr. McCabe’s theory that onset of the
disease could take many months. Dr. McCabe attempted
to explain this contradiction by asserting that there is an
“amplification process,” but the Special Master concluded
that he did not sufficiently support this explanation.
     The Court of Federal Claims upheld the Special Mas-
ter’s decision. Koehn timely appealed. We have jurisdic-
tion under 42 U.S.C. § 300aa–12(f) (2012).
                       DISCUSSION
    In Vaccine Act cases, we apply the same standard of
review that the Court of Federal Claims applied to the
Special Master’s decision. Moberly v. Sec’y of Health &
Human Servs., 592 F.3d 1315, 1321 (Fed. Cir. 2010).
Although we review legal determinations without defer-
ence, we review the Special Master’s findings of fact
under the arbitrary and capricious standard. Griglock v.
Sec’y of Health & Human Servs., 687 F.3d 1371, 1374
(Fed. Cir. 2012).
    Though the Special Master had sufficient grounds to
deny Koehn’s petition because Koehn failed to meet her
burden under the third Althen prong, we begin by recog-
nizing that the Special Master committed several errors
in the assessment of the first and second Althen prongs.
As to the first Althen prong, for instance, the Special
Master based his conclusion that the relevant scientific
community did not accept Dr. McCabe’s theory on Dr.
Rose’s statement that he did not recall ever hearing of
8                                             KOEHN   v. HHS



such a theory. 1 To impute Dr. Rose’s anecdotal statement
to the scientific community was wholly unreasonable.
Another example is the Special Master’s finding that,
under the second Althen prong, Dr. Rose’s opinion was
more persuasive than Dr. McCabe’s opinion because Dr.
Rose treats patients and Dr. McCabe does not. We see no
reasonable basis for why this distinction has any mean-
ingful effect on the cause and effect inquiry in this case,
and the Special Master provided none. While we recog-
nize that it is within the Special Master’s discretion to
weigh the relevant evidence, the Special Master cannot
manipulate the analysis in a manner calculated to arrive
at a conclusion that he or she has already reached.


    1    Had the Special Master properly evaluated the ev-
idence, we believe the Special Master would have likely
found that Koehn met her burden under the first Althen
prong. The Pinto article demonstrated that the partici-
pants who received the HPV vaccine had increased levels
of the same cytokines dysregulated in SJIA. Dr. Rose
asserted that the article showed increased levels only
when the vaccinated blood received a stimulus. Koehn
explains, however, that measurement of cytokine levels
can only occur in blood samples outside the body, and the
only way to “replicate what is going on in the body” is to
introduce an antigen to the blood sample assay. Oral Arg.
at 5:24–6:56, available at http://oralarguments.cafc.
uscourts.gov/default.aspx?fl=2014-5054.mp3. A stimulus
was therefore necessary to measure cytokine levels.
Especially given the low incidence rate of SJIA, requiring
a measurement without a stimulus would have compelled
Koehn to present more than what is scientifically possible
or legally necessary. Thus, Koehn likely presented a
viable, “legally probable” medical theory that “there would
only be an upregulation in cytokines [that are associated
with SJIA] if those cells are told to do so [by the HPV
vaccine.]” Id. at 6:50–6:56; Moberly, 592 F.3d at 1322.
KOEHN   v. HHS                                             9



    Because Koehn failed to meet her burden under the
third Althen prong, however, and failure to do so under
any one of the Althen prongs is dispositive of this case, the
Special Master correctly denied Koehn’s petition.
    We agree with the Special Master that Koehn’s evi-
dence failed to establish a proximate temporal relation-
ship between Vanessia’s Gardasil vaccine and
development of SJIA under Althen’s third prong. This
prong “requires preponderant proof that the onset of
symptoms occurred within a timeframe for which, given
the medical understanding of the disorder’s etiology, it is
medically acceptable to infer causation-in-fact.” de Bazan
v. Sec’y of Health & Human Servs., 539 F.3d 1347, 1352
(Fed. Cir. 2008).
    The record did not support Dr. McCabe’s suggestion
that the appropriate timeframe for first exhibiting symp-
toms of SJIA caused by Gardasil can extend up to seven
months. Dr. McCabe asserted that onset of SJIA can
occur within seven months of receiving Gardasil because
it normally takes patients seven months after receiving
Gardasil to develop a sufficient immune response. Dr.
McCabe did not, however, explain why the timing of SJIA
onset aligns with the timing of a sufficient immune re-
sponse in patients receiving the vaccine. Even Dr. McCa-
be agreed that the immune system produces cytokines
quickly after the body encounters an antigen, which is
inconsistent with his theory that onset of the disease
could take many months. Dr. McCabe’s position that the
amount of time for developing sufficient antibodies for
immunity after receiving a vaccine is always consistent
with injury from the vaccine is a proposition that, without
any evidentiary support, we simply cannot accept.
    Koehn argues that Dr. McCabe explained this contra-
diction by referring to an “amplification process.” But
Dr. McCabe only speculated that there was a delay in the
onset of SJIA because certain regulatory cells and in-
10                                            KOEHN   v. HHS



flammatory mediators in the body that are also purport-
edly active in response to an antigen may counteract the
effects of cytokines, and admitted that “none of this was
measured in” Vanessia. J.A. 232. We find the Special
Master’s conclusion that Dr. McCabe’s explanation lacked
sufficient support neither arbitrary nor capricious.
    Thus, while we find fault with aspects of the Special
Master’s Althen analysis, we ultimately affirm his deci-
sion to deny compensation to Koehn. We agree that
Koehn did not sufficiently establish why onset of SJIA can
occur within seven months after receiving the first dose of
Gardasil, especially when cytokine release is generally a
more immediate response.
                      AFFIRMED
                          COSTS
     No costs.
  United States Court of Appeals
      for the Federal Circuit
                 ______________________

 CHERYL KOEHN, as Mother and Next Friend of,
           VANESSIA KOEHN,
           Petitioners-Appellants,

                            v.

      SECRETARY OF HEALTH AND HUMAN
                  SERVICES,
              Respondent-Appellee.
             ______________________

                       2014-5054
                 ______________________

    Appeal from the United States Court of Federal
Claims in No. 1:11-vv-00355-EGB, Senior Judge Eric G.
Bruggink.
                ______________________

MOORE, Circuit Judge, concurring.
     I join fully in the majority’s analysis of the third
Althen prong. I recognize the strength of the reasons
cited by the majority for being troubled by the Special
Master’s analysis on the first and second Althen prongs. I
do not believe, however, that they present adequate
grounds for reversal given the highly deferential standard
of review we must apply.
