Gineco Articulo vacunas oara la fiebre amarilla

8/9/2019 Gineco Articulo vacunas oara la fiebre amarilla

1/18

Safety profile of the yellow

fever vaccine Stamaril

: a17-year reviewExpert Rev. Vaccines 12(11), 1351–1368 (2013)

Pascale Cottin*1,Matthias Niedrig2 andCristina Domingo3

1Global Pharmacovigilance Department

Sanofi Pasteur, 2 avenue du Pont Pasteur, 69367 Lyon cedex 07, France2Robert Koch Institute, Centre for

Biological Threats and Special

Pathogens (ZBS-1), Nordufer 20,

13353 Berlin, Germany 3Robert Koch Institute, Centre for

Biological Threats and Special

Pathogens (ZBS-1), Nordufer 20,

13353 Berlin, Germany

*Author for correspondence:

[email protected]

Since the creation by the manufacturer in 1993, of an electronic pharmacovigilance databasefor all spontaneous, voluntary reports of adverse events (AEs) after vaccination, 276 milliondoses of Stamaril have been distributed worldwide. We review this database for the safetyof Stamaril with emphasis on yellow fever (YF) vaccine associated acute viscerotropic andneurotropic diseases, anaphylaxis and on specific at risk groups: elderly adults, pregnant andlactating women and the immunosuppressed. Findings confirm that the vaccine’s safetyprofile in routine practice is favorable and consistent with the summary of productcharacteristics. Estimated reporting rates of serious adverse events associated after Stamarilvaccination are lower than the previously published and widely cited estimates of theworldwide reporting rate for YF vaccines in general. These data provide important additionalinformation for the prescribers in assessing the risks and benefits associated with the use ofStamaril in individuals exposed to YF virus.

KEYWORDS: adverse events • anaphylaxis • live vaccine • neurotropic disease • pharmacovigilance • pregnancy• serious adverse events • viscerotropic disease • yellow fever vaccine

Yellow fever (YF) is a mosquito-borne hemor-

rhagic disease caused by the prototype virus of the genus Flavivirus . Infection causes a spec-trum of clinical signs ranging from a mildundifferentiated febrile illness to severe diseasewith jaundice and hemorrhagic manifestations,and death.

More than 900 million people live in at risk areas in Africa between latitudes 15˚ northand 10˚ south (the so-called YF belt) where90% of cases occur, and in tropical and sub-tropical areas of Central and South America.Estimates published by the US Centers forDisease Control and Prevention (CDC)place the number of individuals infectedeach year at 200,000, and the number of deaths at 30,000 worldwide [1]. Othersreported that the incidence is higher [2]. Casefatality rates are high compared to other fla-viviral diseases and may exceed 50% during epidemics in unvaccinated populations [201].

The risk to unvaccinated travelers to theseareas is difficult to estimate due to fluctuationsof the disease by year and season, varying vac-cination coverage of resident populations andincomplete surveillance data. There is no

specific treatment for YF, and while intensive

supportive care may improve the prognosticfor seriously ill patients, it is rarely available indeveloping countries.

Vaccination against YF began in the 1930s,with widespread use of commercial vaccinessince the middle of the century [3]. The WHOrecommends vaccination as the single mostimportant measure for preventing YF and anInternational Certificate of Vaccination docu-menting YF vaccination is often mandatory forindividuals residing in, traveling to or evenpassing through an endemic area. In addition,vaccination is mandatory for individualsexposed to potentially infectious materials,such as laboratory personnel.

One of the available vaccines is the live,attenuated, 17D-204 vaccine Stamaril (SanofiPasteur, France), available in more than100 countries, including Europe, and indicatedfor vaccination against YF in individuals olderthan 9 months. Since its licensure in 1983,more than 300 million doses of Stamaril havebeen distributed worldwide, 276 million since1993 when an electronic pharmacovigilancedatabase was created at Sanofi Pasteur.

Review

www.expert-reviews.com 10.1586/14760584.2013.836320 2013 Informa UK Ltd ISSN 1476-0584 1351

mailto:[email protected]:[email protected]


2/18

Vaccination against YF has been associated with rare cases of viscerotropic (yellow-fever vaccine-associated viscerotropic dis-ease [YEL-AVD]) and neurotropic disease (yellow-fevervaccine-associated neurotropic disease [YEL-AND]). Before2001, when cases were recognized and classified as YEL-AVD

and YEL-AND, YEL-AVD was referred to as post-vaccinationmultiple organ system failure [4–7]. It is a condition similar towild-type YF disease with nonspecific initial symptoms, includ-ing fever, headache, malaise, myalgia, arthralgia, nausea, vomit-ing and diarrhea, starting 2–8 days after vaccination. Jaundicecan appear, along with thrombocytopenia and elevation of hep-atic transaminases, total bilirubin and creatinine. Severe YEL-

AVD is characterized by hypotension, hemorrhage, acute renaland respiratory failure, leading to multi organ system failure.There is no specific therapy for YEL-AVD. Similarly, YEL-

AND was previously referred as to post-vaccinal encephalitis. Itwas identified in early 1940s when multiple cases of encephali-

tis associated with vaccine administration were considered to beattributable to few or too many passages of the virus during the attenuation process [8]. This observation led to the estab-lishment of a vaccine seed lot system. Later, recommendationwas made to restrict the use of YF vaccine to infants older than6 months and the number of cases of encephalitis reported ininfants diminished [9,10]. Studies in mice showed that among a panel of different YF viruses, including wild-type viruses andvarious vaccine strains, the survival time after intracerebralinoculation was longest in the case of YF17D-204 viruses [11].These studies also showed YF17D-204 to be avirulent whenadministered intranasally.

YEL-AND classically includes post-vaccinal encephalitis but

also autoimmune disease with CNS or PNS involvement suchas acute disseminated encephalomyelitis or Guillain–Barré syn-drome. The clinical presentation varies but includes high feverwith headache associated with one or more of confusion, leth-argy, encephalitis, encephalopathy and meningitis. The casefatality rate for YEL-AND is low and most patients recover.

Using post marketing surveillance data from the last17 years of use, we reviewed the safety of Stamaril with spe-cial emphasis on YEL-AVD, YEL-AND, anaphylaxis and onspecific groups: elderly adults, pregnant or lactating womenand the immunosuppressed.

Materials & methodsTo monitor the safety profile of vaccines in use, adverse event(AE) surveillance systems are managed by manufacturers andregulatory agencies in many countries, based on the spontane-ous, voluntary reporting of serious adverse events (SAEs) orother AEs [12]. The Sanofi Pasteur Global PharmacovigilanceDepartment captures safety data collected from various sources,including clinical trials, weekly literature reviews and reportsfrom health care professionals, health authorities or patients.Events are processed by trained and qualified personnel accord-ing to standard operating procedures and processed into a vali-dated, global pharmacovigilance database (ARISg, Stamford,

USA). Cases are reviewed both individually and as part of

regular reviews of cumulative data for qualitative or quantitativesafety signals.

We reviewed all medically-confirmed AEs (i.e., thosereported by a healthcare professional, health authorities or sci-entific publication), that fulfilled International Conference on

Harmonization criteria and were recorded in the Sanofi Pasteurpharmacovigilance database from its initiation on 1 January 1993 to 30 September 2010. We estimated reporting rates inEurope, Australia and New Zealand, since the majority of the AEs were reported from these countries, as well as theworldwide reporting rate, using the corresponding number of doses distributed.

Report MedDRA selection & case classification

The terms YEL-AND and YEL-AVD were added to the Medi-cal Dictionary for Regulatory Activities (MedDRA) dictionary in version 12.1 dated 1st September 2009. Cases recorded in

the database prior to this were retrieved using the following MedDRA terms, and retrospectively coded accordingly: systemorgan classes ‘Infections and Infestation’, ‘Neurological Disor-ders’, ‘Blood and Lymphatic System Disorders’ and preferredterms multi organ system failure, liver disorders, hepatitis, jaun-dice, acute disseminated encephalomyelitis, encephalomyelitis,encephalitis, encephalitis post-immunization, encephalopathy,meningitis and Guillain–Barré syndrome.

We reviewed all SAEs recorded in the database by searching for potential YEL-AVD and YEL-AND cases using the CDC

YF Vaccine Working Group case definitions [1,13]. In summary,for YEL-AVD this meant fever with at least one systemicsymptom among vomiting, malaise, myalgia, arthralgia or dysp-

nea, and at least one of the following quantifiable symptoms: jaundice, liver dysfunction, renal impairment, tachycardia orbradycardia, rhabdomyolysis, respiratory distress, thrombocyto-penia, hypotension, myocarditis, disseminated intravascularcoagulation or hemorrhage, while for YEL-AND, this meantidentifying all cases with fever and headache for more than24 h, or with at least one of following: focal neurologic dys-function, mental status change, seizure, CSF pleocytosis or ele-vated CSF protein. Cases of YEL-AND then further classifiedinto CNS infections (meningitis encephalitis) or autoimmunedisorders (YEL-AAD-CNS), or PNS autoimmune disorders(YEL-AAD-PNS) based on a clinical review of each case. The

level of diagnostic certainty was also rated as suspect, prob-able or definite, based on histopathology findings or on thepresence and concentration of YF 17D virus or specific anti-gens in blood, CSF or tissue. In autoimmune disorders, thereis no ‘definite’ level of certainty [1,13].

The same review was performed using the recently publishedBrighton Collaboration case definitions of viscerotropicdisease [14].

Cases with a clinical description suggestive of YEL-AVD or YEL-AND, and those reported with the corresponding Med-DRA Preferred Terms were reviewed and included in the listof YEL-AVD and YEL-AND if they met the case definition

from the CDC classification.

Review Cottin, Niedrig & Domingo

1352 Expert Rev. Vaccines 12(11), (2013)


3/18

Other adverse event of specific interest

Anaphylactic reactions were identified using standardized Med-DRA queries: narrow anaphylactic reaction, anaphylactic andanaphylactoid shock conditions, angioedema (MedDRA version13.1). Events were reviewed and classified according to the level

of diagnostic certainty and where possible using the definitionsof the Brighton Collaboration [15]. For all levels of diagnosticcertainty, anaphylaxis is a clinical syndrome characterized by sudden onset (only events occurring within 3 days after vacci-nation were retrieved) and rapid progression of symptomsinvolving multiple systems organ classes: dermatologic, cardio-vascular and respiratory. Cases that were most likely vaso-vagalreactions or events linked to the injection procedure, ratherthan events due to anaphylactic mechanisms were excluded.Reports of inadvertent vaccination during pregnancy, lactationor of immunocompromised patients were also identified using the relevant fields.

Age distribution of YF recipients

The general age distribution worldwide of YF vaccine recipientsis not available. For travelers, an estimation is provided by European databases such as the UK Health Improvement Net-work database (THIN database) of anonymous computerizedinformation entered by general practitioners. As of September2010, the THIN database contained information on over6 million patients from 382 general practitioners in the UK and is representative of the UK population. Stamaril becamethe only available YF vaccine in the UK in 2000, we there-fore limited our use of this database to data collected from2000–2010 onwards.

Results

Over the 17 year-period of this review, during which time276 million doses of Stamaril were distributed worldwide(5.8% of which, that is 16.2 million doses, were distributed to

YF non-endemic countries), 1460 medically-confirmed reportswere received at the Global Pharmacovigilance Department. Of these, 805 (55.1%) reports met criteria for seriousness. In addi-tion, the vaccine’s safety has been also assessed in nine clinicaltrials in a total of 1900 individuals, including 626 children,102 HIV+ adults and 43 elderly with no SAE reported [16–24].FIGURE 1 provides an overview of the general safety profile of Sta-

maril in terms of the System Organ Class encompassing at least5% of AE reports.

Almost all (95%) reported events concerned travelers fromEurope, Australia and New Zealand (Stamaril is not distributedin North America), with only 2% of cases reported fromendemic countries in South America, mainly Brazil, Mexico,

Argentina. The overall AE reporting rate was therefore five permillion doses distributed worldwide, and AE reporting ratein travelers was 92 per million doses distributed. The corre-sponding SAE reporting rates were three (overall) and 51 (trav-elers) per million doses distributed, respectively. The majority of reports concerned adults younger than 60 years (FIGURE 2),

with older adults affected by 11.4% of AEs and 14% of SAEs.

The overall AE reporting rate in the elderly was 0.5 per milliondoses distributed worldwide, and AE reporting rate in elderly travelers was 9.5 per million doses distributed. The correspond-ing SAE reporting rates were 0.4 and 7 per million doses dis-tributed, respectively.

In the overall vaccinated population, as well as in elderly adults in particular, the reported events were most frequently categorized into the MedDRA System Organ Class ‘GeneralDisorders and Administration Site Conditions’, ‘Nervous Sys-tem Disorders’ and ‘Musculoskeletal Disorders’; each of theseSystem Organ Classes contained more than 10% of all reported

AEs (FIGURE 1). The number of AEs reported in elderly represents11.4% of all AEs. The percentage of SAEs among all AEs inelderly adults was 56%, compared to 42% in the overall popu-lation. The distribution of the vaccination by age group is notavailable. However, data from UK ’s THIN database suggestthat the distribution of AEs per age group is similar to the

distribution of vaccinations (FIGURE 2)

.

YEL-AVD

Twelve cases of YEL-AVD have been reported after vaccinationwith Stamaril (T ABLE 1). All are SAEs, and most of these havebeen published as case reports [4,6,7,25–31]. The reporting ratewas 0.004/100,000 doses distributed worldwide (T ABLE 2). Sincethe majority of the reports are from non-endemic countries, inother words, Europe, Australia and New Zealand, the reporting rate for YEL-AVD among travelers can be estimated to be0.07/100,000 doses.

Two cases were classified as ‘definite’ YEL-AVD cases [6,31],three were ‘probable’ and seven were classified as ‘suspect’according to the CDC YF Working Group definitions. Accord-ing to the Brighton Collaboration viscerotropic disease causality criteria, the relationship of these events to vaccination wasdefinite in two cases, probable in three cases and suspect intwo cases. Five cases had an insufficient amount of data todetermine causality.

Of these 12 cases, 10 patients recovered and two died(0.0007/100,000 doses distributed worldwide): a 26-year-oldfemale from Spain and a 56-year-old male from Australia.Patients with YEL-AVD were aged 26–73 years, with a meanand median age of 56 years. Nine were male. Four patientsreceived concomitant inactivated vaccines (diphtheria tetanus

vaccine, inactivated poliomyelitis vaccine, hepatitis A vaccine),none were reported to have received concomitant live-attenuatedvaccines. Three patients had been prescribed statins for hyper-cholesterolemia, and a 50-year-old man had undergone thymec-tomy for benign thymic tumor. The mean time to onset aftervaccination was 5 days (range: 2–20). In most cases it wasunknown whether this was the first YF vaccination. No caseswere reported from countries where YF is endemic.

A specific database query for thymus disorders revealed anadditional, non-severe case, in addition to the case of YEL-

AVD referred to above. However, no information on thenature of thymoma, or the age of occurrence of thymus disease

was provided.

Safety profile of the YF vaccine Stamaril: a 17-year review Review

www.expert-reviews.com 1353


4/18

YEL-AND

Twenty-four cases of YEL-AND were reported after vaccina-tion with Stamaril (T ABLE 3). Six have been published[28,32–34]. The reporting rate was 0.008/100,000 dosesdistributed worldwide and 0.15/100,000 doses among trav-elers from non-endemic countries in Europe, Australia andNew Zeealand (T ABLE 2).

Four cases were classified as ‘definite YEL-AND’, six were

‘probable’ and 14 were classified as ‘suspect’ according to theCDC YF Working Group. Fifteen patients recovered andone died, and eight patients were lost to follow-up. With theexception of one case reported from Thailand, all werereported from Europe. Only one fatal case has been reported

specifically following Stamaril vaccination; this case was a

Thai patient with unrecognized HIV infection and who

developed meningoencephalitis and died [33].These patients included children, adolescents, adults and

elderly adults, with a mean age of 39 years (range: 1–78). Fivecases were elderly adults. Sixteen patients were males. The clini-cal presentation varied and included high fever with headacheassociated with at least one of the following: confusion, leth-argy, encephalitis, encephalopathy or meningitis and neurologi-cal symptoms including convulsion, Guillain–Barré syndromeor focal neurological deficit. The mean time to onset was11 days (range: 1–20) but was reduced to 3 days for definiteand probable YEL-AND.

In most cases it was unknown if this was the first YF vacci-

nation. Seven patients received at least one other vaccine on

0

50

100

150

200

250

300

350

400

P y r e x i a

A s t h e n i a /

f a t i g u e

I n f l u e n z a

l i k e i l l n e s s

H e a d a c h e

P a r a e s t h e s i a

E n c e p h a l i t i s

G B S

M y a l g i a

A r t h r a l g i a

R a s h

U r t i c a r i a

N a u s e a

V o m i t i n g

D i a r r h e a

M e n i n g i t i s

Y E L - A N D

Y E L - A V D

P y r e x i a

A s t h e n i a /

f a t i g u e

I n f l u e n z a

l i k e i l l n e s s

H e a d a c h e

P

a r a e s t h e s i a

E n c e p h a l i t i s

G B S

M y a l g i a

A r t h r a l g i a

R a s h

U r t i c a r i a

N a u s e a

V o m i t i n g

D i a r r h e a

M e n i n g i t i s

Y E L - A N D

Y E L - A V D

Nervous system

654 AEs,

including354 SAEs

Musculoskeletal/ connective

tissue

529 AEs,including

167 SAEs

Skin/

SC. tissue320 AEsincluding

92 SAEs

GastrointestinalInfection/ infestation

174 AEsincluding

118 SAEs

General/

administration site1060 AEsincluding

314 SAEs

All ages

0

5

10

15

20

25

30

3540

Nervous system

66 AEs,including

51 SAEs

Musculoskeletal/ connective

tissue

Skin/ SC. tissue

43 AEs

including10 SAEs

GastrointestinalInfection/

infestation27AEs

including23 SAEs

General/ administration site

115AEs

including51 SAEs

53 AEs,including

16 SAEs

34 AEsincluding

16 SAEs

Aged ≥60

N u m

b e r o f r e p o r t s

N u m b e r o f r e p o r t s

Other AEs

SAEsSAEs

Other AEs

SAEsSAEs

300 AEsincluding

129 SAEs

Figure 1. General safety profile of the licensed YF vaccine, Stamaril, in terms of most frequently reported AEs during theperiod 1 January 1993 to 27 September 2010. Events are listed by MedDRA System Organ Class and Preferred Term for each SystemOrgan Class that includes at least 5% of reported AEs. Top panel presents number of events reported, regardless of age, bottom panelpresents number of events reported for adults older than 60.AEs: Adverse events; SAEs: Serious adverse events YF: Yellow fever.




5/18

the same day. These were mainly inactivated vaccines (includ-ing typhoid fever, hepatitis A or hepatitis B vaccines) orMMR. Three patients were known to have underlying medicalconditions (hypothyroid condition in an elderly adult, hyper-cholesterolemia and testicular adenocarcinoma in an adult andcellular immunodepression and upper respiratory infection in a child). In one case thymoma of unspecified type was diagnosedand surgically removed during follow-up investigations.

Despite the fact that immunodepression is a contraindica-tion for immunization with Stamaril, we retrieved 19 reports

(in addition to the Thai case report referred to above) of immunization of patients receiving long term immunosup-pressive therapy including methotrexate, azatioprine, cyclo-sporine and steroids or HIV seropositive individuals withlow CD4 cell counts. None of these 19 reports reported

YEL-AVD or YEL-AND.

Anaphylaxis

We found 33 reports (all from Europe or Australia) of anaphy-laxis meeting the Brighton Collaboration’s Level 1, 2 or 3 of diagnostic certainty [15].

Twelve out of the 33 reports were possibly anaphylactic

shock based on the clinical description or the use of hydrocorti-sone or intravenous adrenalin. These patients included children,adolescents and adults with a mean age of 26 years (range:4–59). Seven individuals received concomitant vaccines.Twenty three patients reported full recovery, but the recovery status of the remaining 10 adults is unknown. Food allergy orhypersensitivity to antibiotics were documented in five cases,including two patients with an allergy to eggs which is a con-traindication for immunization with Stamaril due to the use of eggs in the production process and in eight case-reports, 1–3 other vaccines were co-administered.

The reporting rate of individual case reports of possible ana-

phylaxis meeting the level 1, 2 or 3 of the Brighton case

definition was respectively of 0.2 case reports per 100,000 dosesdistributed in European countries and 0.01/100,000 dosesdistributed worldwide.

We also reviewed 10 records of vaccinees with an egg allergy;none were reported to have had AEs.

Vaccination during pregnancy & breastfeeding

Stamaril is contraindicated during pregnancy and breastfeeding.Inadvertent vaccination during pregnancy, mainly during thefirst trimester, was reported 195-times (T ABLE 4). Except for one

report from South Africa, all reports were from Europe. In43% of the reports, other vaccines or antimalarial drugs werealso administered, either on the same day or within one week of YF vaccination.

Of these 195 reports, 159 (84.5%) were reported à priori ,in other words, during pregnancy and followed up to its out-come, while 36 (18.5%) were reported à posteriori , in otherwords, after the outcome of pregnancy. Of a total of 14 reports of congenital abnormalities or developmental dis-orders, six (43%) were à priori reports and eight (57%) wereà posteriori reports, suggesting a bias toward in reporting inthe event of unfavorable outcomes.

Of all 195 reported cases, the outcome of pregnancy wasreported in 138 cases (71%), and the outcome for the infantor fetus was reported in 109 cases.

Uncomplicated, full-term pregnancy was reported for 97 outof 138 cases of pregnancy and the birth of a healthy infant wasreported for 87 out of 109 cases. Spontaneous abortion wasreported in 24 cases out of all 195 cases (i.e., 12.3%), or24 out of the 138 cases with a reported outcome (i.e., 17.4%)which is consistent with the 10-15% rate reported for the gen-eral population in Europe [35]. Among all 159 reported birthsto mothers vaccinated with Stamaril during pregnancy, congeni-tal anomalies or psychomotor retardations were reported in

14 cases (T ABLE

5). No abnormalities were consistently identified.

0

5000

10000

15000

20000

25000

30000

0–18 19–29 30–39 40–49 50–59 60–69 70+

N u m b e r o f v a c c i n e e

s i n t h e U K

0

5

10

15

20

25

30

R e p o r t e d c a s e

s w i t h

a g e g r o u p d o c u m e n t e d

( % )

0–17 18–29 30–39 40–49 50–59 60–69 70+

Figure 2. Age distribution of AE reports after vaccination with the YF vaccine, Stamaril, as documented in the vaccine man-ufacturer’s worldwide pharmacovigilance database (left), and of UK recipients of Stamaril from 2000–2010 (right) as recordedin the UK THIN database (as of 2010).

AEs: Adverse events; UK THIN: United Kingdom Health Improvement Network; YF: Yellow fever.




6/18

T a b l e 1 .

S u m m a r y o f r e p o r t e d Y E L - A V D c a s e s a f t e r v a c c i n a t i o n

w i t h S t a m a r i l f r o m

1 9 9 3 – 2 0 1

0 .

V a c c i n a t i o n

P a t i e n t

Y E L - A V D

Y e a r , c o u n t r y

P r i m a r y /

b o o s t e r

S e x , a

g e

M e d i c a l h i s t o r y

O n

s e t ( d a y s )

D i a g n o s t i c

c e r t a i n t y

C l i n i c a l

f e a t u r e s

S e r o l o g y /

v i r o l o g y

O

u t c o m e

R e f .

2 0 0 1 , A u s t r a l i a

N R

M , 5 6

H y p e r c h o l e s t e r o l e m i a

t r e a t e d w i t h s t a t i n s

3

D e f i n i t e

M u l t i o r g

a n s y s t e m

f a i l u r e

Y F v i r e m i a ( P C R ) ,

Y F i s o l a t e d f r o m

t i s s u e

C o u n c i l m a n b o d i e s ,

e x t e n s i v e

m i c r o v e s i c u l a r

s t e a t o s i s a n d

h e p a t o c e l l u l a r

n e c r o s i s

F a

t a l

[ 6 , 3

0 ]

2 0 0 4 , S p a i n

P r i m a r y

F , 2 6

C o n c o m i t a n t d i p h t h e r i a

t e t a n u s v a c c i n a t i o n

N o o t h e r m e d i c a l h i s t o r y

3

D e f i n i t e

M u l t i o r g

a n s y s t e m

f a i l u r e

Y F v i r e m i a ( P C R ) ,

Y F V p r e s e n t i n t h e

l i v e r ( 6 . 2 x 1 0 9

g e n o m i c

e q u i v a l e n t s / g ) a n d

k i d n e y ( 8 . 4 x 1 0 9

g e n o m i c

e q u i v a l e n t s / g )

H i g h n e u t r a l i z i n g

a n t i b o d y t i t e r

( m i c r o n e u t r a l i z a t i o n

t i t e r 1 : 5 1 2 )

C o u n c i l m a n b o d i e s ,

e x t e n s i v e -

m i c r o v e s i c u l a r

s t e a t o s i s a n d

h e p a t o c e l l u l a r

n e c r o s i s .

F a

t a l

[ 3 0 , 3

1 ]

2 0 0 2 , F r a n c e

N R

M , 5 0

B e n i g n t h y m o m a ;

t h y m e c t o m y 1 0 y e a r s

e a r l i e r ;

d i p h t e r i a t e t a n u s

v a c c i n a t i o n

4

P r o b a b l e

H i g h f e v e r ,

t h r o m b o p e n i a

A n t i - Y F V I g M

p o s i t i v e 2 w e e k s

a f t e r v a c c i n a t i o n

w i t h o u t I g G , Y F

v i r e m i a 1 3 d a y s

a f t e r v a c c i n a t i o n .

R e c o v e r e d

[ 2 7 , 3

0 ]

2 0 0 5 , G e r m a n y

N R

M , 6 7

N e p h r e c t o m y 3 0 y e a r s

e a r l i e r f l u x o e s o p h a g i t i s ;

T h e r a p y w i t h s t a t i n s

( f l u v a s t a t i n )

G a m m o p a t h y d i a g n o s e d

w i t h P r o t B e n c e J o n e s +

4

P r o b a b l e

H e p a t i t i s ,

t h r o m b o c y t e - p e n i a ,

p a n c a r d i t i s

A n t i - Y F a n t i b o d i e s

( P R N T t i t e r

1 : 1 0 2 4 0 ) ;

Y F V P C R n e g a t i v e

R e c o v e r e d

[ 2 8 ]

C R P : C - r e a c t i v e p r o t e i n ; F : F e m a l e ; I P V : I n a c t i v a t e d p o l i o v a c c i n e ; M : M a l e ; N R : N o t r e p o r t e d ; P D

: P a r k i n s o n ’ s d i s e a s e ; P R N T : P l a q u e r e d u c t i o n n e u t r a l i z a t i o n t e s t , Y E L - A V D : Y e l l o w - f e v e r v a c c i n e - a s s o c i a t e d v i s c e r o t r o p i c

d i s e a s e ; Y F : Y e l l o w f e v e r .




7/18

T a b l e 1 .

S u m m a r y o f r e p o r t e d Y E L - A V D c a s e s a f t e r v a c c i n a t i o n

w i t h S t a m a r i l f r o m

1 9 9 3 – 2 0 1 0 ( c o n t . ) .


P a t i e n t

Y E

L - A V D

Y e a r , c o u n t r y

P r i m a r y /

b o o s t e r

S e x , a

g e


O n

s e t ( d a y s )

D i a g n o s t i c

c e r t a i n t y

C l i n i c a l f e a t u r e s

S e r o l o g y /

v i r o l o g y

O u t c o m e

R e f .

2 0 0 5 , S p a i n

P r i m a r y

M , 6 4

A t r i a l f i b r i l l a t i o n , n o t

t r e a t e d

2

P r o b a b l e

T h r o m b o l e u c o -

p e n i a , l i v e r

c y t o l y o s i s

P e r s i s t e n c e o f Y F V

r e p l i c a t i o n

R e

c o v e r e d

[ 2 9 ]

2 0 0 1 , G e r m a n y

N R

M , 7 1

B o r r e l i o s i s 1 0 y e a r s e a r l i e r

5

S u s p e c t

F e v e r , l i v e r c y t o l y s i s

N e g a t i v e P C R , a n t i -

Y F a n t i b o d i e s

( P R N T t i t e r

1 : 1 0 2 4 0 )

R e

c o v e r e d

[ 2 5 ]

2 0 0 3 ,

N R

N R

M , 5 1

N o m e d i c a l h i s t o r y

L i m i t e d i n v e s t i g a t i o n s

t e s t s

C R P n o r m a l ;

C o n c o m i t a n t I P V


2 0

S u s p e c t

L i v e r c y t o

l y s i s ,

v a s c u l i t i s

N o t d o n e

R e

c o v e r e d

2 0 0 3 , F r a n c e

B o o s t e r

M , 5 5

H y p e r t e n s i o n t r e a t e d w i t h

e n e l a p r i l f r o m 2 0 0 0 ;

P D t r e a t e d w i t h

t r i h e x y p h e n i d y l e ,

c a r b i d o p a , l e v o d o p a ;

r e n a l c o l i c / h e p A i n f e c t i o n

1 4 y e a r s e a r l i e r

2

S u s p e c t

P o l y a r t h r a l g i a , l i v e r

c y t o l y s i s

L i m i t e d

i n v e s t i g a t i o n s

p e r f o r m e d

R e

c o v e r e d

2 0 0 5 , B e l g i u m

P r i m a r y

M , 6 1

I s c h e m i c c a r d i o m y o p a t h y ;

h y p e r c h o l e s t e r o l e m i a

t r e a t e d w i t h s t a t i n s ; m i l d

c h r o n i c a l c o h o l a b u s e

5

S u s p e c t

L i v e r c y t o

l y s i s ,

l e u k o p e n i a

A n t i - Y F V a n t i b o d i e s

( P R N T t i t e r 1 : 7 4 )

R e

c o v e r e d

[ 2 8 ]

2 0 0 5 , F r a n c e

N R

F , 7 3

N o m e d i c a l h i s t o r y

5

S u s p e c t

R h a b d o m

y o l y s i s ,

l i v e r c y t o l y s i s ,

t h r o m b o p e n i a


( P R N T t i t e r 1 : 8 0 )

R e

c o v e r e d

2 0 0 6 , U K

P r i m a r y

M , 4 7

A s t h m a ;

C y t o k i n e e l e v a t i o n ;

c o n c o m i t a n t

v a c c i n a t i o n s : d i p h t h e r i a

t e t a n u s p o l i o , a n d

h e p a t i t i s A

5

S u s p e c t

M u l t i o r g

a n s y s t e m

f a i l u r e , l i v e r

c y t o l y s i s


( P R N T t i t e r 1 : 8 0 )

R e

c o v e r e d

[ 2 8 ]

2 0 0 9 , A u s t r a l i a

N R

F , 6 0

N R

5

S u s p e c t

H e p a t i t i s

N e g a t i v e ( Y F

t e s t i n g d o n e o n

D 1 3 )

R e

c o v e r e d

C R P : C - r e a c t i v e p r o t e i n ; F : F e m a l e ; I P V : I n a c t i v a t e d p o l i o v a c c i n e ; M : M a l e ; N R : N o t r e p o r t e d ; P D : P a r k i n s o n ’ s d i s e a s e ; P R N T : P l a q u e r e d u c t i o n n e u

t r a l i z a t i o n t e s t , Y E L - A V D : Y e l l o w - f e v e r v a c c i n e - a s s o c i a t e d v i s c e r o t r o p i c

d i s e a s e ; Y F : Y e l l o w f e v e r .




8/18

Our review of these cases did not reveal any safety concern.Two AEs of fever were reported during pregnancy.

One mother breastfeeding her infant was vaccinated withStamaril, despite the contraindication. No AE was reported forthe infant.

Discussion

Postmarketing surveillance collects information from a largenumber of individuals across a wide range of medical practices,including previously unstudied uses. This provides the potential

to detect rare and unexpected AEs, making postmarketing sur-veillance an invaluable tool for the ongoing safety assessment of licensed vaccines [36].

Since 1993 when the pharmacovigilance database was estab-lished, 1460 voluntary AE reports following vaccination withStamaril were submitted to Sanofi Pasteur, during which timeapproximately 276 million doses were distributed worldwide,representing an overall AE reporting rate of 0.5/100,000 dosesdistributed. Our evaluation of the available data confirms thatthe vaccine is generally safe and well tolerated with a profileconsistent with clinical study results and the current corporatecore data sheet [1,16,23,36]. There is no evidence in our analysis

that suggests that the safety profile of this live-attenuated vac-cine in adults older than 60 years is less favorable than inyounger adults, as could be expected owing to comorbidity andadvanced age.

YEL-AVD was recognized as a rare AE in 2001, and as of September 2010 more than 50 cases of YEL-AVD werereported to manufacturers worldwide [1]. Initial assessments of

YEL-AVD after YF vaccination in general estimated the risk tobe approximately 0.3/100,000 doses administered, increasing to1.1/100,000 in individuals aged 60–69 years and 3.2/100,000in individuals older than 70 years [37]. Similarly, based on a review of Vaccine Adverse Event Report System (VAERS) data

in the USA, the risk of YEL-AND has been estimated to be

0.4–0.8/100,000 doses distributed, with increased rates inolder adults (1.6/100,000 doses in 60–69 year olds, 1.1–2.3/100,000 in ‡70 year olds) [1,38]. Patients with underlying thymus disorders have also been identified as being atincreased risk for YEL-AVD [39,40]. In contrast, more recentanalyses have highlighted that nine of the recorded cases of

YEL-AVD have occurred in individuals younger than30 years, none of whom had thymus disorders, and fatalcases of YEL-AVD also occur in young women without any known immunodeficiency [41,42]. Compared with the risk

rates reported in the literature after vaccination against YF ingeneral, our review found that the risk of these SAEs occur-ring after vaccination with Stamaril in particular wasmarkedly lower: YEL-AVD was reported at a rate of 0.07/100,000 doses Stamaril distributed in Europe, Australia and New Zealand, and that of YEL-AND was0.15/100,000 doses distributed in Europe, Australia andNew Zealand [1]. These are conservative estimates based onevents reported from these areas. The observed risk ratedecreases by more than 10-fold when we consider eventsreported and doses distributed worldwide. Another impor-tant observation in our review is that the risk of YEL-AVD

or YEL-AND after vaccination with Stamaril does notappear in this series to be higher in adults older than60 years, compared with that in younger adults (the meanage of occurrence YEL-AVD and YEL-AND cases wasrespectively 56 years and 39 years). Post-marketing surveil-lance data have also been published on other YF vaccines.

A 2010 review of the Brazilian Bio-Manguinhos 17DD vac-cine covered the period 1999–2009 during which time closeto 110 million doses had been administered. AEs werereported to have occurred at an overall rate per100,000 doses, of 0.020 YEL-AVD events and 0.084 YEL-

AND events, although these estimations excluded a number

of YEL-AVD events from outside of Brazil [43]. Another

Table 2. YEL-AVD and YEL-AND reporting rates after vaccination with Stamaril; post-marketing surveil-lance from 1993–2010.

Category Number of cases Reporting rate per 100,000 dosesdistributed

Total Definite Probable Suspect Europe, Australia,New Zealand(N dose distributed:16.2 million)

Worldwide(N dose distributed:276 million)

YEL-AVD 12 0.07 0.004

YEL-AVD, fatal outcome 2 0.01 0.0007

YEL-AND 24 4 6 14 0.15 0.009

YEL-AND 4 1 6 0.06 0.004

YEL-AAD-CNS N/A 1 5 0.02 0.002

YEL-AAD-PNS N/A 4 3 0.06 0.003

N/A: Not applicable; YEL-AAD-CNS: Yellow fever vaccine associated autoimmune disorders CNS; YEL-AAD-PNS: Yellow fever vaccine associated autoimmune disorders

peripheric nervous system; YEL-AVD: Yellow-fever vaccine-associated viscerotropic disease; YEL-AND: Yellow fever vaccine associated -neurotropic disease.




9/18

T a b l e 3 . Y E L - A N D c a s e s a f t e r v a c c i n a t i o n w i t h S t a m a r i l f r o m

1 9 9 3 – 2 0 1 0 .


P a t i e n t

Y E L - A N D

Y e a r ,

c o u n t r y

P r i m a r y /

b o o s t e r

S e x ,

a g e


O n s e

t

( d a y s

)

C e r t a i n t y /

c l a s s i f i c a t i o n


S e r o l o g y /

v i r o l o g y

O u t c o m e

R e f .

1 9 9 7 , F r a n c e

P r i m a r y

M , 1 . 5

C o n c o m i t a n t t o n s i l l i t i s

1 9

D e f i n i t e

Y E L - A N D

M e n i n g i t i s


i n

C S F S e r u m / C S F I g M

r a t i o N R

R e c o v e r e d

2 0 0 2 , T h a i l a n d

N R

M , 5 3

U n k n o w n H I V

s e r o p o s i t i v i t y

3

D e f i n i t e

Y E L - A N D

M e n i n g o e n c e p h a l i t i s

H I V + i n f e c t i o n

( C D 4 c o u n t 1 0 8 / m m 3 )


i n

C S F

D e a t h

[ 3 3 ]

2 0 0 5 , F r a n c e

P r i m a r y

M , 4 1

N R

D e f i n i t e

Y E L - A N D

M e n i n g i t i s


i n

C S F , s e r u m a n d

p l a s m a

S e r u m / C S F I g M

r a t i o N R

N o v i r u s d e t e c t e d

b y Y F V P C R o r

c u l t u r e i n V e r o a n d

C 6 3 6 c e l l s

R e c o v e r e d

[ 3 2 ]

2 0 1 0 , G e r m a n y

P r i m a r y

F , 1 7

H y p o t h y r o i d i t i s t r e a t e d

w i t h L t h y r o x i n ;

c o n c o m i t a n t u r i n a r y t r a c t

i n f e c t i o n ;

c o n c o m i t a n t

v a c c i n a t i o n : h e p a t i t i s A ,

h e p a t i t i s B

2 0

D e f i n i t e

Y E L - A N D

M e n i n g o e n c e p h a l i t i s


i n

C S F S e r u m / C S F I g M

r a t i o N R

R e c o v e r e d

2 0 0 2 , S p a i n

P r i m a r y

F , 3 4

T h y m o m a o f u n s p e c i f i e d

t y p e d i a g n o s e d a n d

e x c i s e d d u r i n g f o l l o w - u p

6

P r o b a b l e

Y E L - A N D

P o s t - v a c c i n a t i o n

e n c e p h a l i t i s

C S F n o t t e s t e d f o r

Y F V H u m o r a l a n t i - Y F V

n e u t r a l i z i n g

r e s p o n s e o n

1 2 d a y s a f t e r

v a c c i n a t i o n ( P R N T

t i t e r : 1 : 1 0 2 4 ) .

R e c o v e r e d

[ 2 8 ]

1 9 9 4 , B e l g i u m

P r i m a r y

M , 1 0

N R

1 4

S u s p e c t

Y E L - A N D

E n c e p h a l o p a t h y

m e n i n g i t i s

N R

R e c o v e r e d

C S F : C e r e b r o s p i n a l f l u i d ; F : F e m a l e ; I P V : I n a c t i v a

t e d p o l i o v a c c i n e ; M : M a l e ; N R : N o t r e p o r t e d ; P R

N T : P l a q u e R e d u c t i o n N e u t r a l i z a t i o n T e s t ; Y E L - A A D - C N S : Y e l l o w f e v e r v a c c i n e a s s o c i a t e d a u t o i m m

u n e d i s o r d e r s c e n t r a l

n e r v o u s s y s t e m ; Y E L - A A D - P N S : Y e l l o w f e v e r v a c c

i n e a s s o c i a t e d a u t o i m m u n e d i s o r d e r s p e r i p h e r i c n

e r v o u s s y s t e m ; Y E L - A V D : Y e l l o w - f e v e r v a c c i n e - a s s

o c i a t e d v i s c e r o t r o p i c d i s e a s e .




10/18


1 9 9 3 – 2 0 1 0 ( c o n t . ) .


P a t i e n t

Y E L - A N D

Y e a r ,

c o u n t r y

P r i m a r y /

b o o s t e r

S e x ,

a g e


O n s e

t

( d a y s

)

C e r t a i n t y /



S e r o l o g y /

v i r o l o g y

O u t c o m e

R e f .

2 0 0 1 , I t a l y

P r i m a r y

F , 1

C o n c o m i t a n t M M R


L i k e l y i m m u n o s u p p r e s s i o n

( l y m p h T p o p / C D 4 )

7

S u s p e c t

Y E L - A N D

M e n i n g o e n c e p h

a l i t i s

O t i t i s g i n g i v o -

s t o m a t i t i s a n e m i a

N R

N o t r e

c o v e r e d

2 0 0 3 , I t a l y

N R

F , 2 7

N R

1 6

S u s p e c t

Y E L - A N D

C S F t e s t a b n o r m

a l ,

h e a d a c h e , s k i n

d y s e s t h e s i a o f t h

e

l i m b s , d i f f i c u l t y i n

w a l k i n g

N R

N R

2 0 0 0 , F r a n c e

N R

M , 5 6

C o n c o m i t a n t t y p h o i d

f e v e r v a c c i n a t i o n

2 0

S u s p e c t

Y E L - A N D


a l i t i s

o n s e t d u r i n g t r a v e l

a b r o a d

Y F t e s t i n g n o t d o n e

R e c o v e r e d

2 0 0 4 , U K

N R

M , 4 7

C o n c o m i t a n t

v a c c i n a t i o n s : r a b i e s ,

h e p a t i t i s A , t y p h o i d f e v e r ;

d i c l o f e n a c f o r g o u t

6

S u s p e c t

Y E L - A N D


a l i t i s ,

Y F V n e g a t i v e ( t e s t

n o t s p e c i f i e d )

R e c o v e r e d

2 0 0 1 , F r a n c e

P r i m a r y

M , 3 8

C o n c o m i t a n t u r i n a r y t r a c t

i n f e c t i o n

1 6

S u s p e c t

Y E L - A N D

M e n i n g i t i s ( C R P

n o r m a l r a n g e )

Y F t e s t s n o t d o n e ;

N e g a t i v e t e s t

r e s u l t s

f o r : e n t e r o v i r u s e s ,

h e r p e s v i r u s e s ,

c y t o m e g a l o v i r u s ,

a n d E p s t e i n – B a r r

v i r u s , s y p h i l i s a n d

L y m e d i s e a s e

R e c o v e r e d

[ 3 2 ]

2 0 0 8 , S w e d e n

P r i m a r y

M , 4 9

N R

1 0

P r o b a b l e

Y E L - A A D - C N S

A c u t e d i s s e m i n a t e d

e n c e p h a l o m y e l i t i s

A n t i - Y F V I g M i n

C S F ( I g G n o t

r e p o r t e d )

S e r u m / C S F I g M

r a t i o N R

B l o o d a n d C S F

n e g a t i v e f o r : W e s t

N i l e v i r u s , S a i n t

L o u i s v i r u s ,

e n t e r o v i r u s B o r r e l i a

b u r g d o r f e r i

R e c o v e r e d

C S F : C e r e b r o s p i n a l f l u i d ; F : F e m a l e ; I P V : I n a c t i v a t e d p o l i o v a c c i n e ; M : M a l e ; N R : N o t r e p o r t e d ; P R

N T : P l a q u e R e d u c t i o n N e u t r a l i z a t i o n T e s t ; Y E L - A A D - C N S : Y e l l o w f e v e r v a c c i n e a s s o c i a t e d a u t o i m m

u n e d i s o r d e r s c e n t r a l

n e r v o u s s y s t e m ; Y E L - A A D - P N S : Y e l l o w f e v e r v a c c

i n e a s s o c i a t e d a u t o i m m u n e d i s o r d e r s p e r i p h e r i c n

e r v o u s s y s t e m ; Y E L - A V D : Y e l l o w - f e v e r v a c c i n e - a s s

o c i a t e d v i s c e r o t r o p i c d i s e a s e .




11/18


1 9 9 3 – 2 0 1 0 ( c o n t . ) .


P a t i e n t

Y E L - A N D

Y e a r ,

c o u n t r y

P r i m a r y /

b o o s t e r

S e x ,

a g e


O n s e

t

( d a y s

)

C e r t a i n t y /


C l i n i c a l f�

Gineco Articulo vacunas oara la fiebre amarilla

Documents

Transcript of Gineco Articulo vacunas oara la fiebre amarilla