Vaccine Healthcare Centers VHC Network Update on Rare Adverse Events Armed Forces Epidemiological Board 11 May 2004 131

1. Vaccine Healthcare Centers (VHC) NetworkUpdate on Rare Adverse EventsArmed Forces Epidemiological Board11 May 2004 (1315-1330) COL Renata Engler, MC, USA Director, Vaccine Healthcare Centers Network Allergy-Immunology Consultant, Army OTSG Walter Reed Army Medical Center, Wash., DC Kathleen L. Martin RADM SHCE USN Deputy Surgeon General Vice Chief, Bureau of Medicine and Surgery (202)762-3702 Fax: 3750 Kathleen L. Martin RADM SHCE USN Deputy Surgeon General Vice Chief, Bureau of Medicine and Surgery (202)762-3702 Fax: 3750

2. VHC NetworkUpdate on the Network Official opening of Naval Medical Center Portsmouth (NMCP): 26 April 2004 Other sites operational with opening ceremony pending: Womack AMC, Fort Bragg, NC Wilford Hall MC, San Antonio, Texas Funding for Network with 4 regional sites supporting DoD worldwide FY04: no unfunded requirement FY05: unfunded requirement Submission for FY06 POM completed

3. VHC NetworkUpdate on the Network Request for consultative support continue Staff at each of sites collaborative in virtual Network to support mission requirements > 1000 cases reviewed by VHC Network since 2001 opening of 1st regional site Emergent response in 2003 to support in depth VAERS reviews for myopericarditis 71 cases meet CDC/DoD case definitions 6 additional under review 23 cases did not meet CDC/DoD case definitions but are being followed for outcomes

4. Oropharyngeal Shedding of Vaccinia Post Immunization Questions/concerns regarding risk of vaccinia transmission through oropharyngeal shedding Jan 2003: started protocol to determine if viral shedding could be detected in the oropharynx Viral culture by gold standard method Specific antigen by electrochemiluminescence Specific DNA by PCR 144 subjects studied with 89 completing all post vaccination swabs (0,1-3,4-6,7-9,10-12,13-15 days) All studies negative = 95% CI of less than 3.3% chance of any evidence of vaccinia shedding in the oropharynx Data supports ACIP guidelines and reassures those with continued concerns about risk of respiratory transmission

5. Vaccinia Contact Transmission VHC Network provided in-depth VAERS reports � Support for review of risk factors and outcomes Presentation at National Immunization Conference: Vaccinia Contact Transfer: The US Military Smallpox Vaccination Experience MT Huynh*, MD, MPH; LL Duran, APRN; LC Collins, Jr., MD; D Bradshaw, MD, MPH; J Grabenstein, RPh, Ph.D. Risk factors for contact vaccinia: 29 cases Intimate and/or close or personal skin-to-skin contacts: e.g., wrestling No unexplained transmission events

6. Myopericarditis Post Vaccinia Immunization VHC Network staff supported VAERS case review process critical to the data review that follows this presentation Dr. Eckart � update on follow up VAERS information on cases meeting CDC/DoD case definitions Dr. Atwood � DoD dilated cardiomyopathy cases update Prospective myopericarditis protocol fully approved at WRAMC and BAMC

7. Myopericarditis Post Vaccinia & Influenza Vaccination Prospective protocol: WRAMC & Brooke AMC approved 600 primary vaccinia recipients � pending modification based on ACAMBIS study � include vaccinees receiving other vaccines 200 influenza vaccinees Hypothesis: 2-3% incidence of subclinical myopericarditis Assess incidence of clinical & subclinical myopericarditis: monitor pre and post ECGs, enzymes, inflammatory markers Case identification: run case controlled study for more detailed immunologic assays & immunogenetics Initial funding through collaboration with CDC-Clinical Immunization Safety Assessment (CISA) Center Northern CA Kaiser/U of Washington Molecular Immunology Dep Companion protocol needed to standardize special cardiac studies on all patients, assess inflammation & outcomes

8. Education of Healthcare Workers Providing Immunization Services Web-based, interactive Learning Management System (LMS) Designed for medical technicians, nurses and clinical providers Curriculum consensus committee identified 21 vaccine and vaccine-related topics for course modules Web-based education development company, was contracted to develop story boards supporting modules development. Modules peer-reviewed & approved by Department of Defense (DoD) multidisciplinary vaccine experts Self-paced, objective-testing education modules accessed via www.vhcinfo.org (PIR) for CME or CEU credit Users completed pre-test, interactive module, & post-test in sequence Learning gain indices were calculated based on average mean pre-test/post-test scores. Data collected with no personal identifiers as part of a quality assurance process attempting to address module effectiveness to produce learning gains in the user web-based, interactive Learning Management System (LMS) was developed for nurses, medical technicians and clinical providers to improve the quality and delivery of immunization care and services in DoD and TRICARE Military Healthcare System (MHS). A curriculum consensus committee identified twenty-one vaccine and vaccine-related topics as course modules. HealthSoft, Inc., a Web-based education development company, was contracted to write and program modules. The modules were peer-reviewed and approved by Department of Defense (DoD) multidisciplinary vaccine experts. These self-paced, objective-testing education modules were made available on the VHC website (www.vhcinfo.org) for use by Walter Reed Immunization/Allergy Specialty Course students and other DoD vaccine administration personnel. Users completed a pre-test, interactive module, and post-test in sequence. Learning gain indices were calculated based on average mean pre-test/post-test scores. Gain indices (0.82-0.96) demonstrated a significant increase in vaccine knowledge on all modules. Project Immune Readiness, effectively meets VHC objectives and is an added benefit to provide MHS quality educational standards for vaccines and vaccine safety. web-based, interactive Learning Management System (LMS) was developed for nurses, medical technicians and clinical providers to improve the quality and delivery of immunization care and services in DoD and TRICARE Military Healthcare System (MHS). A curriculum consensus committee identified twenty-one vaccine and vaccine-related topics as course modules. HealthSoft, Inc., a Web-based education development company, was contracted to write and program modules. The modules were peer-reviewed and approved by Department of Defense (DoD) multidisciplinary vaccine experts. These self-paced, objective-testing education modules were made available on the VHC website (www.vhcinfo.org) for use by Walter Reed Immunization/Allergy Specialty Course students and other DoD vaccine administration personnel. Users completed a pre-test, interactive module, and post-test in sequence. Learning gain indices were calculated based on average mean pre-test/post-test scores. Gain indices (0.82-0.96) demonstrated a significant increase in vaccine knowledge on all modules. Project Immune Readiness, effectively meets VHC objectives and is an added benefit to provide MHS quality educational standards for vaccines and vaccine safety.

10. Blistering Skin Rash or Oral Ulcers Post Anthrax Vaccine Three cases identified with history of new onset pemphigus vulgaris post vaccination Positive autoantibodies to desmoglein skin antigen 3 (DSG-3) not present pre-vaccination but appearing after vaccination VAERS reports of oral ulcers or blistering skin rashes in temporal association with anthrax vaccine: X out of Y total Protocol to assess frequency of new onset anti-DSG3 or �DSG1 post anthrax vaccine Fully approved mid-March 2004 Clinical observations antibody titer and disease activity neonatal pemphigus Experimental observation skin organ culture passive transfer to neonatal mice Clinical observations antibody titer and disease activity neonatal pemphigus Experimental observation skin organ culture passive transfer to neonatal mice

11. VHC Network Updates VAERS update as of 4 May 2004: ANT > 1.1 million immunized, > 4.2 million doses 34 VAERS with anthrax vaccine & rash vesicular bullous 19 anthrax alone, others anthrax plus other vaccines COSTAR search terms: rash vesic bull search 4 hospitalized Age distribution or reports 18-29 years 20 30-39 years 11 40-49 years 3 Onset of symptoms: 29/34 within 30 days Additional reports with oral ulcers 6 4 with prolonged symptoms �not recovered� VAERS update as of 4 May 2004: AVA > 1.1 million immunized,�> 4.2 million doses 34�Pv reports�with anthrax vaccine (19 anthrax alone) COSTART search terms: rash vesic bull search 4 hospitalizedVAERS update as of 4 May 2004: AVA > 1.1 million immunized,�> 4.2 million doses 34�Pv reports�with anthrax vaccine (19 anthrax alone) COSTART search terms: rash vesic bull search 4 hospitalized

12. Desmoglein Skin AntigensSpecific Antibodies Post Anthrax Vaccine Hypotheses Pemphigus vulgaris specific antibodies against skin antigens may develop following immunization with the anthrax vaccine in a subpopulation of the vaccinated individuals. � Populations who have received both smallpox and anthrax vaccination will develop auto-antibodies to skin antigens at higher titers and greater frequency than those seen with anthrax vaccination alone. Service members with new onset Pemphigus vulgaris will have evidence of anthrax vaccination within 3 months prior to the first presentation of disease and/or evidence of specific antibody to protective antigen (PA), which reflects anthrax vaccine exposure. Clinical observations antibody titer and disease activity neonatal pemphigus Experimental observation skin organ culture passive transfer to neonatal mice Clinical observations antibody titer and disease activity neonatal pemphigus Experimental observation skin organ culture passive transfer to neonatal mice

13. Objectives for Study Prevalence of measurable anti-DSG antibodies Baseline, pre anthrax versus post anthrax vaccination Baseline, pre versus post anthrax + smallpox vaccination Prevalence of measurable anti-DSG and anti-PA antibodies (as measure of anthrax vaccine exposure) in patients with Pemphigus vulgaris identified in DMSS Currently 11 out of 42 received anthrax vaccine repeatedly after diagnosis Determine if vaccine boosted pathogenic autoantibodies Implications of data: Consideration of clinical guidelines that would make Pemphigus vulgaris and blistering oral ulcers and/or blistering skin rashes a relative contraindication to continued anthrax vaccination Further studies on sub-clinical forms of this adverse event? Determine the prevalence of measurable anti-desmoglein (Dsg3 and Dsg1) antibodies in sera of service members following at least two (2) anthrax vaccinations. Determine the prevalence of measurable anti-desmoglein antibodies (Dsg3 and Dsg1) in sera of service members who have received anthrax vaccination versus the smallpox plus anthrax vaccination (if at least 1 or 2 of the samples studied under objective #1 demonstrates anti-desmoglein antibodies following anthrax vaccination). Determine the prevalence of cases of pemphigus vulgaris in the Defense Medical Surveillance System between 1998 through June 2003 and the frequency of those cases that received anthrax vaccination prior to the disease presentation. To determine the prevalence of measurable levels of anthrax vaccine specific anti-protective antigen antibody titers in sera of patients with pemphigus vulgaris pre and post disease presentation as well as following booster doses with anthrax Determine the prevalence of measurable anti-desmoglein (Dsg3 and Dsg1) antibodies in sera of service members following at least two (2) anthrax vaccinations. Determine the prevalence of measurable anti-desmoglein antibodies (Dsg3 and Dsg1) in sera of service members who have received anthrax vaccination versus the smallpox plus anthrax vaccination (if at least 1 or 2 of the samples studied under objective #1 demonstrates anti-desmoglein antibodies following anthrax vaccination). Determine the prevalence of cases of pemphigus vulgaris in the Defense Medical Surveillance System between 1998 through June 2003 and the frequency of those cases that received anthrax vaccination prior to the disease presentation. To determine the prevalence of measurable levels of anthrax vaccine specific anti-protective antigen antibody titers in sera of patients with pemphigus vulgaris pre and post disease presentation as well as following booster doses with anthrax

14. Pemphigus Specific AutoantibodiesProtocol Design Systems to be accessed DoD Serum Repository Immunization Registry Defense Medical Surveillance System Study Groups: sera for anti-DSG & anti-PA Ab 1: 300 subjects who received at least 3 doses of anthrax vaccine and no smallpox vaccine Sera within 1 year prior to 1st dose and sera 21-42 days post 3rd dose 2: 300 subjects similar to Group 1 but with smallpox vaccine within 72 hours of 1st dose of anthrax 3: All sera from patients with Pemphigus vulgaris (about 11 had anthrax vaccine at some time in course) �������� Group 1 a) Select those subjects who have had at least 3 doses of Anthrax vaccine 1999 to present b) Select those subjects who have sera sample available at least 1-year prior to receipt of anthrax vaccine dose # 1. c) Select those subjects who have sera samples 4 weeks (21-42 days range preferred) to 4 months post the receipt of the 3rd dose of anthrax vaccine. d) Subjects will be excluded who had hospitalizations within 1 year prior to the 1st dose of anthrax vaccine. e) Subjects to be excluded if hospitalized within 6 months post receipt of the 3rd dose of anthrax vaccine or prior to 2nd sample collection UNLESS hospitalization was for ICD-9 code specific for pemphigus or bullous skin disease. (PROVIDE ICD9 CODES TO NOT EXCLUDE HERE) f) No smallpox vaccination recorded prior to 2nd serum sample. �������� Group 2 a) Same criteria as for Group 1 but with evidence of the receipt of smallpox vaccine (1 dose of smallpox vaccination, within 72 hours of the 1st dose of anthrax vaccine) b) Paired sera collection (as outlined above) to be delayed pending results from Group 1. �������� Group 3 a) The committee agreed with criteria as outlined in the protocol for Group 3. b) All pre and post diagnosis sera would be collected on the subjects. Data on the subject�s immunization would be reviewed and provided in excel spreadsheet format. c) ICD-9 codes of all visits 1 year prior to the 1st anthrax dose and 3 months post anthrax boosters after the diagnosis would be reviewed. �������� Miscellaneous Zip codes of assignment of subjects� immunizations and 3rd dose of anthrax vaccine would be obtained for Group 1 and 2.�������� Group 1 a) Select those subjects who have had at least 3 doses of Anthrax vaccine 1999 to present b) Select those subjects who have sera sample available at least 1-year prior to receipt of anthrax vaccine dose # 1. c) Select those subjects who have sera samples 4 weeks (21-42 days range preferred) to 4 months post the receipt of the 3rd dose of anthrax vaccine. d) Subjects will be excluded who had hospitalizations within 1 year prior to the 1st dose of anthrax vaccine. e) Subjects to be excluded if hospitalized within 6 months post receipt of the 3rd dose of anthrax vaccine or prior to 2nd sample collection UNLESS hospitalization was for ICD-9 code specific for pemphigus or bullous skin disease. (PROVIDE ICD9 CODES TO NOT EXCLUDE HERE) f) No smallpox vaccination recorded prior to 2nd serum sample. �������� Group 2 a) Same criteria as for Group 1 but with evidence of the receipt of smallpox vaccine (1 dose of smallpox vaccination, within 72 hours of the 1st dose of anthrax vaccine) b) Paired sera collection (as outlined above) to be delayed pending results from Group 1. �������� Group 3 a) The committee agreed with criteria as outlined in the protocol for Group 3. b) All pre and post diagnosis sera would be collected on the subjects. Data on the subject�s immunization would be reviewed and provided in excel spreadsheet format. c) ICD-9 codes of all visits 1 year prior to the 1st anthrax dose and 3 months post anthrax boosters after the diagnosis would be reviewed. �������� Miscellaneous Zip codes of assignment of subjects� immunizations and 3rd dose of anthrax vaccine would be obtained for Group 1 and 2.

15. VHC NetworkAFEB Support Requested Recommendation that all patients with post vaccinia cardiac disease be referred to WRAMC or BAMC for standardized evaluation and follow up Difficulties encountered at other sites with obtaining needed studies such as MRI with gadolinium, Indium scan, etc. Recommendation that myopericarditis registry for follow up VAERS be extended to 2 years or longer if still symptomatic � objectify QOL impact Consider questions of evolution or recurrence Recommend registry for blistering skin disease and/or oral ulcers following vaccination with serum repository to assess anti-DSG autoantibodies

16. Points of Contact COL Renata Engler, Director Renata.engler@amedd.army.mil COL Bryan L. Martin, Deputy Director Bryan.martin@amedd.army.mil Limone C. Collins, MD, Medical Director Limone.Collins@amedd.army.mil Dr. Sandra Schneider Sandra.schneider@lackland.af.mil Walter Reed AMC, 6900 Georgia Ave, NW, Wash, DC 20307-5001 Phone: 202-782-8819/0411/9461 Fax: 202-782-7093/4658 Website: www.VHCinfo.org Distance Learning Tools: Go To Project Immune Readiness Clinical Consultations, Help, Advocacy Support for Service Members AskVHC@amedd.army.mil

17. Pemphigus VulgarisVHC Network Collaboration 2003 partnership with Dr. Stanley from U of Pennsylvania: immuno-dermatologist with PV expertise, auto-antibody assays Serial serum examinations performed under existing NIH grant for PV: pattern temporally associated Protocol developed to study pre & post anthrax vaccination sera: determine incidence of new onset anti-DSG AB�s in vaccinated/unvaccinated group Approved Dec 2003 � accessing DoD Serum Repository Funding for assays under Dr. Stanley�s NIH grant expansion VHC Network able to collaborate and leverage research $ Biologic plausibility of causal relationship Molecular mimicry as a potential mechanism?