Comparability of Vaccine Safety Data Dr. med. Jan Bonhoeffer Coordinator, The Brighton Collaboration University Children’s Hospital Basel

2 Challenges To Comparability Safety assessed indirectly No standardization: of Case definitions of Guidelines

Lack of Standardized Case Definitions WHO and CIOMS definitions - Not exaustive - Not widely used Literature search -Large diversity of safety methods

Temperature Cut-offs Study protocols and surveillance systems Number of Studies (N=120)* * Some studies with >1 cut off / “Fever” 37.8 Temperature (>=) °C

Cut-offs for Erythema & Swelling & Induration Studies and Surveillance Systems Number of studies* (N=102) * Some studies with >1 cut off Cut off points in mm

The Brighton Collaboration Enables Comparability Develops case definitions for AEFI Promotes global implementation of case definitions

4 Step Process To Develop Case Definitions 1)Search for existing case definitions 2)Develop draft definitions 3)Review and evaluate draft definitions 4) Finalize and disseminate definitions

First Six AEFI Definitions 1)Fever 2)Local Reactions 3)Intussusception 4)Persistent Crying 5)Generalized Convulsive Seizure 6)Hypotonic - Hyporesponsive Episode

Brighton Collaboration Case Definition Format Level 1 of diagnostic certainty Level 2 of diagnostic certainty Level 3 of diagnostic certainty

Intussusception Level 1 Surgical criteria AND/OR Radiological criteria AND/OR Autopsy criteria Level 2 Clinical criteria 2 major OR 1 major & 3 minor criteria Level 3 Clinical criteria > 4 minor criteria

Fever Level 1 Endogenous elevation of at least one measured body temperature of >38° C Level 2 Not applicable Level 3 Not applicable

4 Step Process To Develop Guidelines 1)Create draft definitions 2)Apply to real cases 3)Test for comparability 4)Formulate needed guidelines

Guidelines for Investigators Data collection e.g. vaccine, other medication, outcome Data Analysis e.g. 5 categories, predefined increments Data Presentation e.g. numerator and denominator, distribution of data

Five Categories for Data Analysis Level 1 of diagnostic certainty Level 2 of diagnostic certainty Level 3 of diagnostic certainty Additional categories for data analysis Reported [AEFI] with insufficient evidence to meet the case definition No, it is not a case of [AEFI] Case definition

AEFI Definition Document Format Preamble Definition Guidelines

Structure of Brighton Collaboration Steering committee Working groups: Case definition Working group: Methods Reference group

Steering Committee Board Elisabeth Loupi Bob Chen Phillippe Duclos Ulrich Heininger Harald Heijbel Tom Jefferson Secretariat Katrin Kohl Jan Bonhoeffer Bakary Drammeh

Next Steps Build reference group Build next 7 working groups Dissemination and Implementation Smallpox AEFI ParesthesiaCFS MyalgiaITP SIDSAllergic Reaction

Country Distribution of Participants Date: October Participants 42 Countries

Join the Collaboration ! Use definitions, guidelines Be part of reference group Be part of working groups We need a Working Group Coordinator NOW!!

Funding Centers for Disease Control and Prevention EUSAFEVAC – European Research Program of Improved Vaccine Safety Surveillance World Health Organization

Fever Level 1 Endogenous elevation of at least one measured body temperature of >38° C Level 2 Not applicable Level 3 Not applicable

Injection Site Nodule Level 1 The presence of Discrete or well demarcated soft tissue mass Firm AND At injection site In the absence of Abscess formationAND/OR Warmth Erythema Level 2 Not applicable Level 3 Not applicable

Abscess at injection site Abscess is defined by localized soft tissue collection of fluid with or without fluctuance at the site of immunization

The presence of Spontaneous or surgical drainage of purulent material from mass AND Laboratory confirmation Abscess of Infectious Etiology * Level 1 *may be accompanied by fever and/or regional lymphadenopathy.

Abscess of Infectious Etiology Level 2 The presence of Spontaneous or surgical drainage of purulent material from the mass OR Fluid collection diagnosed by imaging technique AND Localized sign(s) of inflammation AND/OR Prompt resolution with antimicrobial therapy

Abscess of Infectious Etiology Level 3 Not applicable

Swelling at injection site Level 1* The presence of Measured enlargement of injection site / limb OR Visible enlargement of injection site / limb described as "joint to joint" or "crossing joints" * the swelling may be accompanied by some erythema and tenderness

Swelling at injection site Level 2* Reported visible enlargement of injection site/limb without objective measurement or specified anatomical description. Level 3 not applicable The following alone do not constitute 'swelling': An isolated injection site nodule, abscess, cellulites, induration * the swelling may be accompanied by some erythema and tenderness

Cellulitis at injection site Cellulitis is defined as an acute, infectious, expanding inflammatory condition of the skin that is characterized by ……

Cellulitis at injection site Level 1 The presence of (at least 3 of the following five) ● localized painAND/OR ● tenderness to light touchAND/OR ● intense erythemaAND/OR ● at least moderate induration AND/OR ● substantial local warmth AND ● is at the injection siteAND ● laboratory confirmation

Cellulitis at injection site Level 1 continued In the absence of ● spontaneous rapid resolution AND/OR ● fluctuance OR The presence of ● a physician diagnosis of cellulitisAND ● is at the injection siteAND ● laboratory confirmation

Cellulitis at injection site Level 2 The presence of (at least 3 of the following five) ● localized painAND ● tenderness to light touchAND ● intense erythemaAND ● at least moderate induration AND ● substantial local warmth AND ● is at the injection site AND ● health care provider diagnosis In the absence of ● spontaneous rapid resolutionAND/OR ● fluctuance

Cellulitis at injection site Level 3 The presence of (any of the following five) ● localized painAND/OR ● tenderness to light touchAND/OR ● intense erythemaAND/OR ● at least moderate indurationAND/OR ● substantial local warmth AND ● is at the injection site2AND ● health care provider diagnosis In the absence of ● spontaneous rapid resolutionAND/OR ● fluctuance

OR The presence of (at least 3 of the following five) ● localized painAND ● tenderness to light touchAND ● intense erythemaAND ● at least moderate indurationAND ● substantial local warmth AND ● is at the injection site AND ● non health care provider report Cellulitis at injection site Level 3 (continued)

Intussusception Level 1 Surgical criteria AND/OR Radiological criteria AND/OR Autopsy criteria Level 2 Clinical criteria 2 major OR 1 major & 3 minor criteria Level 3 Clinical criteria > 4 minor criteria

Inconsolable Crying Level 1 The presence of Loud sustained vocalization, which is persistent, i.e. continuous AND unaltered for > 3 hours In the absence of Response to any attempt to console the crying (e.g. by means of feeding, comforting, analgesics) Level 2 Not applicable Level 3 Not applicable

Generalized Convulsive Seizure Level 1 Witnessed sudden loss of consciousness AND Generalized, tonic, clonic, tonic-clonic or atonic motor manifestations

Generalized Convulsive Seizure Level 2 History of unconsciousness AND generalized tonic, clonic or tonic-clonic or atonic motor manifestations Level 3 History of unconsciousness AND Other generalized motor manifestations

HHE Level 1 The sudden onset of Limpness (muscular hypotonia) AND Hypo-responsiveness or unresponsiveness AND Pallor or cyanosis

HHE Level 2 The sudden onset of  Two of the three definite inclusion criteria Level 3 The sudden onset of  Two of the three definite inclusion criteria AND  The third one noticed to be absent

Top 10 Serious* AEFI**, by Age Group 1 year FEVER CONVULSION FEB SEIZURE RASH STUPOR AGITATION VOMIT OTITIS MED SOMNOLENCE APNEA 0-12 months FEVER CONVULSION AGITATION SIDS APNEA STUPOR HYPOTONIA CYANOSIS VOMIT SOMNOLENCE years FEVER CONVULSION VOMIT HEADACHE RASH ASTHENIA STUPOR SOMNOLENCE DYSPNEA HYPOKINESIA >18years FEVER ASTHENIA PARESTHESIA GUILLAIN BARRE PAIN MYALGIA ARTHRALGIA HEADACHE DYSPNEA MYASTHENIA * Per FDA criteria **Source: VAERS, Yellow = Currently included AEFI; Green = Next AEFI to be defined

0-12 months FEVER AGITATION SCREAMING CRY ABNORMAL HYSN INJ SITE EDEMA INJ SITE SOMNOLENCE RASH VOMIT HYPOTONIA 1 year FEVER RASH AGITATION HYSN INJ SITE RASH MAC PAP VASODILAT CONVULSION EDEMA INJ SITE URTICARIA RASH VESIC BULL 2-18 years FEVER HYSN INJ SITE VASODILAT EDEMA INJ SITE RASH URTICARIA PRURITUS PAIN INJ SITE VOMIT PAIN >18years HYSN INJ SITE FEVER VASODILAT MYALGIA PAIN INJ SITE EDEMA INJ SITE PAIN PRURITUS RASH HEADACHE Top 10 Non-Serious* AEFI**, by Age Group * Per FDA criteria **Source: VAERS, Yellow = Currently included AEFI; Green = Next AEFI to be defined