vaccin anti VHB et SEP vaccin anti VHB et SEP chez l’enfantchez l’enfant

rapport AFSSAPS rapport AFSSAPS SEPTEMBRE 2008SEPTEMBRE 2008

Marc SznajderMarc SznajderMars 2009Mars 2009

The National Advisory Board of PharmacovigilanceThe National Advisory Board of Pharmacovigilance examined: examined:

The results of a The results of a case control studycase control study carried out on the carried out on the French KIDSEP French KIDSEP neuropaediatric cohortneuropaediatric cohort evaluating the risk of occurrence of a first event of evaluating the risk of occurrence of a first event of acute acute CNS inflammatory demyelinationCNS inflammatory demyelination between 1994 and 2003 after between 1994 and 2003 after vaccination against hepatitis B virusvaccination against hepatitis B virus (HBV) (HBV) (Mikaeloff Y. (Mikaeloff Y. et al. Neurology et al. Neurology 20082008

Up to date Up to date pharmacovigilance datapharmacovigilance data on on spontaneous notificationsspontaneous notifications of of multiple sclerosismultiple sclerosis ( (MSMS) in children of 15 year old or less ) in children of 15 year old or less vaccinated vaccinated against HBVagainst HBV during the period of the case control study (1994-2003) (J.L. during the period of the case control study (1994-2003) (J.L. Imbs, CRPV Strasbourg);Imbs, CRPV Strasbourg);

Data on the Data on the mechanistic assumptionsmechanistic assumptions likely to explain a likely to explain a linklink between between vaccination against HBV and of an event of acute CNS inflammatory vaccination against HBV and of an event of acute CNS inflammatory demyelination (V. Gazin, D. Masset, Département de Toxicologie, Afssaps)demyelination (V. Gazin, D. Masset, Département de Toxicologie, Afssaps)

Epidemiologic dataEpidemiologic data on on vaccine coveragevaccine coverage and hepatitis B in France (D. and hepatitis B in France (D. Levy-Bruhl, InVS);Levy-Bruhl, InVS);

Données chez l’adulteDonnées chez l’adulte notification of notification of first acute SNC demyelination eventsfirst acute SNC demyelination events after the after the

administration of administration of vaccines against hepatitis B vaccines against hepatitis B =>=> official official pharmacovigilance investigation in pharmacovigilance investigation in June 1994.June 1994.

To date, To date, thirteen epidemiologic studiesthirteen epidemiologic studies ( (three in childrenthree in children) : ) : NoneNone of of these studies have shown any statistically significant result in favour of a these studies have shown any statistically significant result in favour of a connection between vaccination against HBV and the occurrence of CNS connection between vaccination against HBV and the occurrence of CNS demyelination disorders (demyelination disorders (follow up <12 monthsfollow up <12 months), ),

except for one case control studyexcept for one case control study ( (Hernan MrHernan Mr. . et al. Neurology et al. Neurology 2004; 63: 2004; 63: 838-42): 838-42): =>=>significant connectionsignificant connection between vaccination against HBV and the between vaccination against HBV and the occurrence of multiple sclerosis (MS) occurrence of multiple sclerosis (MS) in certain adultsin certain adults of 18 years old or of 18 years old or more when vaccinations had been made out more when vaccinations had been made out in thein the three years beforethree years before the appearance of the first symptoms of MS: the appearance of the first symptoms of MS: OR = 3.1; IC 95% = [1.5; 6.3OR = 3.1; IC 95% = [1.5; 6.3]]OR was equal to 1.8 and OR was equal to 1.8 and non-significant non-significant (IC 95% =[0.5; 6.3]) when the (IC 95% =[0.5; 6.3]) when the period of observation between vaccination against HBV and the first period of observation between vaccination against HBV and the first symptoms of MS was limited to symptoms of MS was limited to 12 months12 months..

Chez l’enfantChez l’enfant

The studies undertaken on the The studies undertaken on the French KIDSEP neuropaediatric French KIDSEP neuropaediatric cohortcohort ( (≈500 children≈500 children of less than 16 years old in whom an of less than 16 years old in whom an acute acute SNC demyelinating eventSNC demyelinating event had been diagnosed between 1994 and had been diagnosed between 1994 and

2003) 2003) =>=> did not confirmdid not confirm the risk of a recurrence of MS (Mikaeloff the risk of a recurrence of MS (Mikaeloff Y. Y. et al. Brain et al. Brain 2007) nor any increase in the risk of MS in a child 2007) nor any increase in the risk of MS in a child vaccinated against HBV (Mikaeloff Y. vaccinated against HBV (Mikaeloff Y. et al. Arch Pediatr Adolesc et al. Arch Pediatr Adolesc Med DEC Med DEC 2007). 2007).

In September 2008 In September 2008 third case control studythird case control study carried out on the carried out on the KIDSEP cohort: KIDSEP cohort:

““Case control study on the risk of occurrence of a central nervous Case control study on the risk of occurrence of a central nervous system demyelination event in children vaccinated against Hepatitis system demyelination event in children vaccinated against Hepatitis BB " [Y. Mikaeloff " [Y. Mikaeloff and Al. Neurology and Al. Neurology 2008)2008)

MéthodeMéthode [Y. Mikaeloff [Y. Mikaeloff and Al. Neurology and Al. Neurology 2008)2008)

Case control studyCase control study carried out on the French KIDSEP neuropaediatric carried out on the French KIDSEP neuropaediatric cohort cohort

principal objective: principal objective: evaluation of the risk of occurrenceevaluation of the risk of occurrence of a of a firstfirst acute acute SNC demyelinating event (whatever the later progression of the event) in SNC demyelinating event (whatever the later progression of the event) in children children vaccinated against HBVvaccinated against HBV over various periods following over various periods following vaccination.vaccination.

CasesCases : : patientspatients for whom a first acute SNC demyelinating event had been for whom a first acute SNC demyelinating event had been diagnosed between January 1994 and December 2003.diagnosed between January 1994 and December 2003.

Controls: Controls: free of a first acute SNC demyelination event (n=free of a first acute SNC demyelination event (n=12 at the most 12 at the most for each casefor each case) chosen ) chosen at randomat random in the general population were paired in the general population were paired with the cases on the basis of with the cases on the basis of ageage (± 6 months), (± 6 months), sexsex and and geographical geographical localizationlocalization; ; standardized questionnairestandardized questionnaire. The . The validation of vaccine validation of vaccine statusstatus was based on a was based on a copy of the families’ health recordscopy of the families’ health records. .

The comparison of the cases and controls’ vaccination history against HBV The comparison of the cases and controls’ vaccination history against HBV before the reference date was carried out using before the reference date was carried out using conditional logistic conditional logistic regressionregression..

RésultatsRésultats

403 patients403 patients diagnosed with a confirmed first acute SNC diagnosed with a confirmed first acute SNC demyelination even. The demyelination even. The analysisanalysis was carried out on was carried out on 349 cases349 cases able to provide a copy of their vaccination records along with able to provide a copy of their vaccination records along with 2941 2941 controlscontrols ( (1666 refus sur 5838 eligibles=28,5%1666 refus sur 5838 eligibles=28,5%).).

The results The results do not show any increase riskdo not show any increase risk of the occurrence of a of the occurrence of a first acute inflammatory demyelination event in the children first acute inflammatory demyelination event in the children in the in the three years following vaccination against HBVthree years following vaccination against HBV, ,

the result even being very close to a the result even being very close to a reduction reduction of the risk being of the risk being statistically significant: statistically significant: OR = 0.74; IC 95% [0.54- 1.02]) OR = 0.74; IC 95% [0.54- 1.02])

nor in the following yearsnor in the following years (OR = 0.93; IC95% [0.65-1.31]). (OR = 0.93; IC95% [0.65-1.31]).

Résultats (suite)Résultats (suite)

HoweverHowever, a , a sub-group analysissub-group analysis in the children in the children having respected having respected the vaccine recommendations (to avoid selection bias ?)the vaccine recommendations (to avoid selection bias ?)

significantly increased risksignificantly increased risk of the occurrence of demyelination of the occurrence of demyelination events (events (OR = 1.74; IC 95% [1.03- 2.95])OR = 1.74; IC 95% [1.03- 2.95])

and of MS (OR = 2.77; IC95% [1.23-6.24])and of MS (OR = 2.77; IC95% [1.23-6.24])

more than three years after vaccinationmore than three years after vaccination in children in children vaccinated by Engerix B®

OR= NS after Genhévac BOR= NS after Genhévac B

Discussion Afssaps (I)Discussion Afssaps (I)

=>=> Taking into account all the Taking into account all the sub-group analysessub-group analyses carried out, carried out, and thus the and thus the multiplicity of testsmultiplicity of tests performed (approximately 160), performed (approximately 160), there is a very big increase in the there is a very big increase in the chance of type I errorchance of type I error, and the , and the probability of detecting a probability of detecting a significant connection by chancesignificant connection by chance is thus is thus very high. very high. (mais prévu au protocole, MS)(mais prévu au protocole, MS)

=>=> analyses carried out analyses carried out without the main results being without the main results being significantsignificant and and without an interaction testwithout an interaction test..

Discussion (II)Discussion (II)

The justification for an analysis limited to children The justification for an analysis limited to children following the following the vaccine recommendationsvaccine recommendations depends on the hypothesis of a depends on the hypothesis of a possible bias in the responses from the controls, in favour of those possible bias in the responses from the controls, in favour of those children who are generally better vaccinated than the general children who are generally better vaccinated than the general population, and this could have meant that OR has been population, and this could have meant that OR has been undervaluated?undervaluated?

Actually absence of difference in recommendation compliance Actually absence of difference in recommendation compliance

rate between the cases and the controlsrate between the cases and the controls

Discussion (III)Discussion (III)

Sub-group analyses considerably Sub-group analyses considerably reduce numbersreduce numbers : :≈1/2≈1/2 All of these reductions in number lead to a All of these reductions in number lead to a selection biasselection bias which is which is

impossible to assessimpossible to assess

In addition, In addition, about half of the controls were excludedabout half of the controls were excluded in order to in order to maintain case-control pairing for the conditional logistic regression maintain case-control pairing for the conditional logistic regression

modelmodel

Discussion (IV)Discussion (IV)

An increased risk in the sub-group compliant with vaccine An increased risk in the sub-group compliant with vaccine recommendations recommendations cannot be plausibly explainedcannot be plausibly explained from a medical from a medical point of view.point of view.

It could suggest an It could suggest an interactioninteraction between vaccination HBV and other between vaccination HBV and other vaccinations which does not correspond to current scientific vaccinations which does not correspond to current scientific knowledge on the subject.knowledge on the subject.

Discussion (V)Discussion (V)

The results of the analyses carried out The results of the analyses carried out according to the length of according to the length of timetime between the vaccination and the occurrence of an acute between the vaccination and the occurrence of an acute demyelination event demyelination event are far from coherent are far from coherent (?):(?):

in the subanalysis in in the subanalysis in children following the vaccination children following the vaccination recommendationsrecommendations, OR is 0.45 (IC95% = [0.20-1.01]) for a period , OR is 0.45 (IC95% = [0.20-1.01]) for a period ranging between ranging between 1 and 2 years1 and 2 years i.e. almost significant protection i.e. almost significant protection

while it moves to 1.50 (IC95% = [0.93-2.43]) when a period of while it moves to 1.50 (IC95% = [0.93-2.43]) when a period of more more than three yearsthan three years before the event is considered. before the event is considered.

The same thing is observed with episodes of MS.The same thing is observed with episodes of MS.

In addition, these results are In addition, these results are not coherent (?)not coherent (?) with the results of with the results of Hernan Hernan et al. et al. which were increased to a significant degree during which were increased to a significant degree during the ≤ 3 years period. the ≤ 3 years period.

Discussion (VI)Discussion (VI)

To conclude that there is a difference between Engerix B® and the To conclude that there is a difference between Engerix B® and the other vaccines because the connection to a risk of MS is significant other vaccines because the connection to a risk of MS is significant for Engerix B® and non-significant for the other vaccines comes for Engerix B® and non-significant for the other vaccines comes down to an down to an error of interpretation?error of interpretation?

(“le fait d’être significatif est indépendant du fait qu’on puisse (“le fait d’être significatif est indépendant du fait qu’on puisse ou non en cas d’association conclure sur sa ou non en cas d’association conclure sur sa causalité”D.Costaglia, RESP dec 08)causalité”D.Costaglia, RESP dec 08)

Without a significant interaction, such a conclusion is highly Without a significant interaction, such a conclusion is highly debatable, debatable,

and the OR confidence intervals which overlap to a largeand the OR confidence intervals which overlap to a large extent for the different vaccines, a significant interaction could not extent for the different vaccines, a significant interaction could not

be shown.be shown.

Comments on the spontaneous notifications of MS collected in Comments on the spontaneous notifications of MS collected in children up to 15 years old vaccinated against hepatitis B during children up to 15 years old vaccinated against hepatitis B during

the period of the studythe period of the study

0.45/100 000 for Engerix B® 10 0.45/100 000 for Engerix B® 10 0.64/100 000 forGenhevac B®. 0.64/100 000 forGenhevac B®.

=>=> These values do not indicate that the use of Engerix B® carries These values do not indicate that the use of Engerix B® carries any more risk than Genhevac B®.any more risk than Genhevac B®.

Evaluation of the mechanistic assumptions supporting a Evaluation of the mechanistic assumptions supporting a connection between vaccinationagainst HBV and an acute CNS connection between vaccinationagainst HBV and an acute CNS

inflammatory demyelination event (V. Gazin, D. Masset,inflammatory demyelination event (V. Gazin, D. Masset,Département de Toxicologie, Afssaps)Département de Toxicologie, Afssaps)

On a mechanistic level, the authors of the case control On a mechanistic level, the authors of the case control study suggest two hypotheses to explain the possible study suggest two hypotheses to explain the possible difference in risk between Engerix B® and GenHevac B® difference in risk between Engerix B® and GenHevac B® vaccines:vaccines:

molecular mimicry between neuronal proteins and vaccine molecular mimicry between neuronal proteins and vaccine antigens and/or yeast protein contaminants from the antigens and/or yeast protein contaminants from the production system? production system? Risque > avec Genhevac BRisque > avec Genhevac B

the triggering of an auto-immune reaction by contaminant the triggering of an auto-immune reaction by contaminant yeast proteins? yeast proteins? Pas démontréPas démontré

Updating the epidemiological data on Hepatitis B in France Updating the epidemiological data on Hepatitis B in France (D. Levy-Bruhl, InVS)(D. Levy-Bruhl, InVS)

The development of The development of vaccine coveragevaccine coverage since 1998 has since 1998 has demonstrated demonstrated insufficient ratesinsufficient rates for newborns (< 30%), for young for newborns (< 30%), for young teenagers (approximately 40%) and for populations at risk.teenagers (approximately 40%) and for populations at risk.

In France, since the reintroduction of the mandatory declaration In France, since the reintroduction of the mandatory declaration (DO) of acute infections by HBV, (DO) of acute infections by HBV, the number of annual casesthe number of annual cases reported reported from 2003 to 2007 is from 2003 to 2007 is stable stable (140 to 180 on average). (140 to 180 on average).

the (corrected) incidence of acute hepatitis B is the (corrected) incidence of acute hepatitis B is estimatedestimated to be to be between 600 and 800 cases /year compared to approximately 8500 between 600 and 800 cases /year compared to approximately 8500 cases/year before 1994cases/year before 1994

=>=> “These results prove the beneficial impact of the anti-HBV “These results prove the beneficial impact of the anti-HBV

vaccination campaign started in 1994”vaccination campaign started in 1994”

Conclusions of the discussions of the National Advisory Board of Conclusions of the discussions of the National Advisory Board of PharmacovigilancePharmacovigilance

23 votes for, 7abstentions and 1 vote against23 votes for, 7abstentions and 1 vote against

the main result of this study the main result of this study does not demonstrate any linkdoes not demonstrate any link in in children between exposure to vaccinations against Hepatitis B Virus children between exposure to vaccinations against Hepatitis B Virus and a central acute demyelinising event ;and a central acute demyelinising event ;

because of several limiting factors brought up during the meeting, because of several limiting factors brought up during the meeting, the National Advisory Board of Pharmacovigilance considers that the National Advisory Board of Pharmacovigilance considers that the the results of the sub-group analysisresults of the sub-group analysis of children of children having having respected vaccine recommendationsrespected vaccine recommendations present the features of a present the features of a fortuitous resultfortuitous result

the the benefit /risk ratiobenefit /risk ratio of vaccination against HBV, whatever the of vaccination against HBV, whatever the vaccine used against Hepatitis B, vaccine used against Hepatitis B, can not be called into questioncan not be called into question on the basis of this analysis of a sub-group in the paediatric on the basis of this analysis of a sub-group in the paediatric population.population.

Questions RESPQuestions RESP

Pourquoi ne pas insister sur le risque entre 1 et 2 ans (OR: 0,45; 95%CI Pourquoi ne pas insister sur le risque entre 1 et 2 ans (OR: 0,45; 95%CI 0.20-1.01)0.20-1.01)

Si biais de sélection important, pourquoi publier ?Si biais de sélection important, pourquoi publier ? Pourquoi ne pas sélectionner cas et témoins compliants en nombre Pourquoi ne pas sélectionner cas et témoins compliants en nombre

suffisant ?suffisant ?

Analyse de sensibilité pour évaluer association s avec autres Analyse de sensibilité pour évaluer association s avec autres vaccinations ?vaccinations ?

Méthode des « self-controlled cases » pour limiter les biais de sélection ?Méthode des « self-controlled cases » pour limiter les biais de sélection ?

Fenêtre de risque > 3 ans discutable (pharmacovigilance, études Fenêtre de risque > 3 ans discutable (pharmacovigilance, études précédentes, mécanismes possibles)précédentes, mécanismes possibles)