1. National Immunization Conference
Anthrax Vaccine and the Risk of Optic Neuritis U.S. Military,
Daniel Payne, PhD, MSPH
National Immunization Conference
March 7, 2006

2. Vaccine Analytic Unit (VAU)
A team of epidemiologists, biostatisticians, and clinical consultants conducting vaccine post-marketing surveillance investigations
CDC, DoD, FDA collaboration
Defense Medical Surveillance System (DMSS)
DoD longitudinal surveillance system for U.S.
military personnel
Integrates data on vaccinations, inpatient/outpatient
outcomes, demographics, and personnel
By collecting health and exposure data for a large population over a number of years, the DMSS database provides an opportunity to investigate rare adverse events in post-marketing surveillance investigations.

3. Anthrax Vaccine Adsorbed (AVA)
First licensed in 1970, currently the only FDA-licensed human anthrax vaccine in the U.S.
Approximately 5.3 million doses administered to U.S. military personnel (3/1998-9/2005)
IOM* found no evidence that people face an increased risk of experiencing life-threatening or permanently disabling adverse reactions
* Institute of Medicine Joellenbeck, LM, Zwanziger LL, Durch JS, Strom BL, eds. The Anthrax Vaccine: Is it Safe? Does it Work? Washington, D.C.: National Academy Press.
[i] Institute of Medicine Joellenbeck, LM, Zwanziger LL, Durch JS, Strom BL, eds. The Anthrax Vaccine: Is it Safe? Does it Work? Washington, D.C.: National Academy Press.
Minor injection site reactions (erythema, edema, and induration < 30mm) occurring in approximately 20% vaccinations usually within 24 hours and subsiding within 48 hours are the most common adverse reactions. Systemic reactions (chills, muscle aches, malaise, or nausea) may occur in 5-35% of vaccine recipients. AVA adverse reactions have been reported more commonly among women than among men.

4. Why is this investigation important?
Optic neuritis is one of 5 priority anthrax vaccine adverse event topics prioritized by a workgroup of the National Vaccine Advisory Committee
Questions concerning the safety of anthrax vaccine have been raised by the media, some scientists, and some members of the Armed Forces

5. Institute of Medicine An Assessment of the CDC Anthrax Vaccine Safety and Efficacy Research Program, 2002
Chapter 5, Findings and Recommendations:
“Analysis of DMSS data should be the primary approach for investigation of possible AVA-related health effects of medical significance that occur within the typical period of active duty following vaccination…”
Institute of Medicine (IOM) recommended that the Centers for Disease Control and Prevention (CDC) undertake additional studies using a large, relational surveillance database, the Department of Defense’s (DoD) Defense Medical Surveillance System (DMSS), for longer-term follow-up of military personnel who received AVA

6. Optic Neuritis
Acute inflammation of optic nerve – demyelination is frequent
Sudden, often severe onset of visual disturbances and pain
Irreversible nerve damage in ~85% of cases
65-80% regain an acuity of 20/30 or better
Strong linkage between optic neuritis and multiple sclerosis (MS) -- Approximately 1/3 of cases develop MS within 10 years (range %)

7. Common Symptoms of Optic Neuritis
Eye pain
53-88% of cases
Maximum severity within hours
Dyschromatopsia
Reduced color vision in 100% of cases
Also common: Phosphenes (visual flashes)
Loss of visual acuity
Ranging from mild (34% of cases) to complete blindness (54%)

8. Optic Neuritis: distribution and determinants
Female : Male ratio approximately 1.8 : 1
Mean age of onset = 30.2 yrs (♀), 31.1 yrs (♂)
Incidence highest among Caucasians esp. of northern European ancestry (range from /100,000)
Various genetic and environmental factors presumed to predispose cases; an assortment of infections, stressors, and exogenous antigens have been proposed as triggers

9. Scientific Findings
Case reports – predominantly hepatitis B and influenza vaccines reported in last 25 years
Kerrison, et al. – 2002 report of two U.S. military cases following anthrax vaccination by 1 day & 2 weeks
VAERS – 7 reports following anthrax vaccination alone (as of 08/24/2005)
AVEC Review ( ) – one VAERS report determined to have “unclassifiable causal relationship with anthrax vaccine”
Lange, et al. – post- versus pre- anthrax vaccination OR=2.74, 95% CI=(1.56, 4.80) for non-specific “disorders of optic nerve and visual pathways”
Destefano, et al. – VSD study found no association between several vaccines and MS or optic neuritis for 3 study intervals (<1, 1-5, >5 years)
Lange --analysis of unvalidated cases of 3-digit ICD-9-CM=377, non-specific “disorders of optic nerve and visual pathways”;

10. Research Objective
Courtesy of John Kerrison, MD
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To estimate whether anthrax vaccine or other vaccine exposures (smallpox, hepatitis B and influenza) are associated with optic neuritis while controlling for other factors
Image: MRI from an optic neuritis diagnosed case

11. Case Definition
Crude cases identified through DMSS: First-time diagnoses of ICD-9-CM = , , , and
January 1, 1998 through December 31, 2003
Excluded those with diagnosed nutritional-, toxic-, meningococcal-, and syphilitic-related optic neuropathies
Excluded for having diagnoses of ischemic and compressive optic neuropathies within one year prior to their 1st diagnosis of optic neuritis, or for having an injury to the eye or orbital region within 18 weeks of optic neuritis
Completed at least 18 weeks of military service before the diagnosis
Controls were selected if their DMSS diagnostic records indicated no history of an optic neuropathy, they served in the military on the same date of diagnosis as their matched case (index date), and they had at least 18 weeks of military service preceding the index date.
DMSS diagnostic histories and administrative data for all the remaining cases were reviewed by a neuro-ophthalmologist. Cases within a predefined category of unclassifiable diagnostic certainty (defined as those diagnosed with optic neuritis but having another concurrent optic condition (e.g. glaucoma, retinal scar), having numerous MS, migraine, and psychiatric diagnoses, or having a prior record of sarcoidosis or alcohol dependence) were analyzed in the full sample and were also restricted in a separate analysis.

12. Study Intervals
1st diagnosis
1 year
18 wks 12 wks 6 wks
Odds ratios calculated at 6 weeks (42 days), 12 weeks (84 days), and 18 weeks (126 days) prior to 1st optic neuritis diagnosis
Vaccinations with anthrax, smallpox, hepatitis B, and influenza captured in each interval

13. Matched Case-Control Study
1:3 match on gender, deployment within the 18 week interval, and military component (active, reserve & National Guard)
n= 1,131 cases, 3,393 controls
Controlled for: race, ethnicity, age, military service branch, occupational category, previous MS diagnosis
Exposure(s) to AVA, smallpox, hepatitis B, and influenza vaccines were included in a multivariable model with P values less than 0.05 considered statistically significant for each of the 6-, 12-, and 18- week intervals. Potential 2–way interactive terms with P values less than 0.15 were allowed into the model.

14. Analyses Bivariate Case-Control comparison
Phi coefficient to assess vaccine co-administration
Vaccine-vaccine interactions
Univariate analyses
Multivariable conditional logistic regression
Stratified models for study subjects by prior diagnosis of multiple sclerosis, military deployment during the 18-week period, and military component
Analyses were performed on the sample excluding those cases identified as having unclassifiable diagnostic certainty

15. Descriptive Statistics of Cases and Controls
Characteristic
Cases (n=1,131)
Controls (n=3,393)
Gender +
Female
Male
347 (30.7%)
784 (69.3%)
1,041 (30.7%)
2,352 (69.3%)
Military Deployment Within
the 18-week Study Interval +
None
Bosnia
Kosovo
Operation Enduring Freedom
Operation Iraqi Freedom
Southwest Asia
Other
1,094 (96.7%)
1 (0.1%)
6 (0.5%)
14 (1.2%)
4 (0.4%)
11 (1.0%)
3,282 (96.7%)
3 (0.1%)
18 (0.5%)
42 (1.2%)
12 (0.4%)
33 (1.0%)
Service Component +
Active
Reserve / National Guard
986 (87.2%)
145 (12.8%)
2,958 (87.2%)
435 (12.8%)
Matching criteria
+ indicates variables that were matching criteria

16. Descriptive Statistics of Cases and Controls
Characteristic
Cases (n=1,131)
Controls (n=3,393)
Race
White (referent)
Black
Other
Unknown
770 (68.1%)
263 (23.3%)
86 (7.6%)
12 (1.1%)
2,254 (66.4%)
736 (21.7%)
338 (10.0%)
65 (1.9%)
Ethnicity
Non-Hispanic (referent)
Hispanic
989 (87.4%)
130 (11.5%)
2,997 (88.3%)
331 (9.8%)
Age (years)
18-24 (referent)
25-34
>=35
281 (24.8%)
423 (37.4%)
427 (37.8%)
1,228 (36.2%)
1,214 (35.8%)
951 (28.0%)
Demographic data

17. Descriptive Statistics of Cases and Controls
Characteristic
Cases (n=1,131)
Controls (n=3,393)
Military Service Branch
Army (referent)
Air Force
Marines
Navy
406 (35.9%)
364 (32.2%)
83 (7.3%)
278 (24.6%)
1,275 (37.6%)
923 (27.2%)
324 (9.5%)
871 (25.7%)
Occupational Group
Med/Science/Research (referent)
Hazardous/Combat
Administration/Communications
Unknown
160 (14.2%)
416 (36.8%)
538 (47.6%)
17 (1.5%)
344 (10.1%)
1,323 (39.0%)
1,684 (49.6%)
42 (1.2%)
Occupational data

18. Distribution of subjects receiving specified vaccines within the 18 week study interval
Cases
(n=1,131)
Controls
(n=3,393)
Anthrax
64 (5.7%)
257 (7.6%)
Smallpox
11 (1.0%)
48 (1.4%)
Hepatitis B
37 (3.3%)
118 (3.5%)
Influenza
173 (15.3%)
510 (15.0%)
Fewer cases than controls (5.7% versus 7.6%, respectively) were administered AVA within 18 weeks of the diagnosis/index date (P=0.02). Of those cases receiving AVA, 41 (64.1%) received one dose and 23 (35.9%) received 2 or more doses within this study interval. Among controls receiving AVA, 163 (63.4%) received one dose and 94 (36.6%) received 2 or more doses within the 18-week study interval.

19. Correlations for vaccines administered within the 18 week study interval (Phi Coefficient values)
Anthrax
Smallpox
Hepatitis B
Influenza
0.31
0.06
0.11
0.05
0.04
Correlation tests for the administration of these vaccines showed that AVA and smallpox vaccine were the most frequently co-administered vaccines within the 18-week study interval (Phi=0.31).

20. Multivariable conditional logistic regression results: Odds for optic neuritis by vaccines received within the 6-, 12-, and 18-week intervals (n=4,524)
6-week observation period
12-week observation period
18-week observation period
Vaccine
Odds
Ratio
95% CI
Anthrax
1.18
(0.74, 1.87)
0.92
(0.63, 1.35)
0.81
(0.58, 1.14)
Smallpox
0.71
(0.22, 2.33)
0.66
(0.25, 1.73)
0.83
(0.37, 1.85)
Hepatitis B
0.67
(0.31, 1.46)
0.95
(0.57, 1.58)
1.02
(0.68, 1.54)
Influenza
1.01
(0.71, 1.45)
1.26
(0.95, 1.67)
(0.79, 1.29)

21. Multivariable conditional logistic regression results:
Odds for optic neuritis by number of anthrax vaccine doses received within 18-week study interval (n=4,524)
Anthrax Vaccine Dose
Odds
Ratio
95% CI
None (referent)
1.00
1 dose
0.82
(0.55, 1.21)
2+ doses
0.81
(0.48, 1.38)

22. Multivariable conditional logistic regression results:
Odds for optic neuritis by specified vaccines received in
6-, 12- and 18-week intervals
* Excludes study subjects having an optic neuritis diagnosis of unclassifiable certainty
6-week observation period
12-week observation period
18-week observation period
Vaccine
Odds Ratio
95% CI
Anthrax
1.15
(0.72, 1.84)
0.94
(0.64, 1.39)
0.83
(0.60, 1.16)
Smallpox
0.78
(0.24, 2.60)
0.67
(0.26, 1.75)
0.84
(0.37, 1.89)
Hepatitis B
0.62
(0.27, 1.41)
0.91
(0.54, 1.54)
1.00
(0.66, 1.53)
Influenza
1.03
(0.72, 1.49)
1.33
(1.00, 1.77)
1.04
(0.81, 1.33)
We conducted a separate analysis excluding those cases having unclassifiable diagnostic certainty and observed only minor differences between these results and the full sample results.

23. Stratified multivariable conditional logistic regression results:
Odds for optic neuritis from AVA received in 6-, 12- and 18 week intervals for defined subsets
6-week observation period
12-week observation period
18-week observation period
Vaccine
Odds Ratio
95% CI
No prior MS diagnosis only
1.19
(0.75, 1.89)
0.93
(0.64, 1.38)
0.82
(0.58, 1.14)
Non-deployed personnel only
1.21
(0.74, 1.95)
(0.62, 1.39)
0.83
(0.58, 1.17)
Active duty personnel only
1.12
(0.68, 1.83)
(0.54, 1.24)
0.76
(0.53, 1.08)
We conducted a separate analysis excluding those cases having unclassifiable diagnostic certainty and observed only minor differences between these results and the full sample results.

24. allowed us to use brief study intervals
Strengths
Large DMSS database for studying this extremely rare diagnostic endpoint
largest sample of optic neuritis cases in any known vaccine safety investigation
allowed us to use brief study intervals
Ability to adjust for any potential effects from other (smallpox, hepatitis B, and influenza) vaccines, and vaccine-vaccine interactions
Particular strengths of this epidemiologic assessment included the availability of the large DMSS database for studying this extremely rare diagnostic endpoint. No previously published study possessed a sufficiently large sample size to enable calculation of specific vaccine exposure risks within 6-, 12- and 18-week post-vaccination intervals. These relatively brief exposure intervals tend to lessen the opportunity for chance causations to be introduced in the analysis. A hypothetical vaccine-mediated onset of optic neuritis would not be expected to present clinically beyond 18 weeks post-vaccination (personal correspondence, Dr. John Kerrison, August 31, 2005). We were also able to adjust for any potential effects from other (smallpox, hepatitis B, and influenza) vaccines administered to study subjects within the same time intervals as AVA. In addition, we assessed individual effects and possible interactions between these vaccines.

25. No medical chart review to validate the optic neuritis diagnosis
Limitations
No medical chart review to validate the optic neuritis diagnosis
validity still probably high due to nature of condition
restricting diagnoses of unclassifiable certainty did not change results
Some exposures or diagnoses may remain misclassified
Could not rule out an infectious cause for a minority of cases
A possible weakness of our study was the omission to conduct a medical chart review to validate the diagnosis of optic neuritis. As stated by Lange et al., “In a database of the nature, size, and scope of the Defense Medical Surveillance System, misclassifications of exposures and/or outcomes are inevitable due to system limitations, administrative errors, and individual oversights”18. Nevertheless, we consider the level of diagnostic validity was probably high since the condition is typically associated with an acute, severe presentation which would likely result in the patient being clinically investigated and diagnosed by an ophthalmologist. While medical charts were not reviewed as part of this study, we retrieved complete DMSS diagnostic histories of all cases and these were individually reviewed for diagnostic quality by a trained neuro-ophthalmologist. In addition, when we repeated our analysis and excluded those cases suggested by this neuro-ophthalmic review to be of an unclassifiable diagnostic validity, the results did not change substantively. It is not known to what extent some exposures or diagnoses remained misclassified, however non-differential misclassification would be expected to bias the risk estimates towards the null. We could not rule out an infectious cause for a minority of cases, particularly those having diagnosed chronic sinusitis or unspecified viral infections within 18 weeks of the optic neuritis diagnosis. Finally, only three of our study subjects with a prior diagnosis of MS had received AVA within the 18-week interval and these odds ratios were unable to be calculated.

26. Conclusions
No evidence that receipt of AVA within a 6-, 12- and 18- week interval is associated with onset of optic neuritis in the U.S. military population
No statistically significant associations were observed between optic neuritis and prior receipt of smallpox, hepatitis B, and influenza vaccinations in any of the three study intervals

27. Conclusions
No significant interactive vaccine-vaccine effect was observed
No significant differences in the odds for developing optic neuritis were observed when analysis was restricted to study subjects having high diagnostic certainty, no prior history of MS, no deployment in the prior 18-week interval, and only active component personnel.

28. Conclusions
The results of this large, military population–based epidemiological study contribute to evidence that there is no association between the demyelinating central nervous system disease optic neuritis and AVA, smallpox, hepatitis B, and influenza vaccines, whether administered alone or in combination.

29. Authors: Acknowledgements: Daniel C. Payne, PhD, MSPH
Charles Rose, Jr., PhD
John Kerrison, MD (Johns Hopkins U.)
Susan Duderstadt, MD, MPH
Aaron Aranas, MPH, MBA
Michael McNeil, MD, MPH
Acknowledgements:
CDC: VSD, VAERS, ISO
DoD: Army Medical Surveillance Activity, MILVAX
FDA: Center for Biologics Evaluation and Research
National Vaccine Advisory Committee workgroup