1. Framework for Analysis of Multiple Near-Simultaneous Vaccinations and U.S. Military Hospitalizations
Charles Rose, PhD
Daniel Payne, PhD, MSPH

2. Purpose
Assess multiple near-simultaneous (MNS) vaccinations and frequency of hospitalizations for non-deployed, active duty, US military personnel using the DMSS database
The purpose of our study is to assess whether there is a significant difference between the hospitalization rates during the pre and post multiple vaccination exposure periods. In addition, we want to assess the magnitude, if any, of the post vaccination exposure period to the pre vaccination non-exposed period for the risk of hospitalization.

3. Why Study MNS Vaccinations and U.S. Military Hospitalizations?
At a 2004 Armed Forces Epidemiologic Board meeting, VAU was asked to investigate this as part of our research agenda
NVAC, CDC, DoD, and FDA collaborators concurred that this topic was sufficiently important to be included in the VAU research activities
In recent years there has been increased interest on adverse event health effects, if any, after receiving multiple vaccinations. This is an emerging safety research topic that has received more attention in the DoD because it is common in the military to receive multiple vaccinations within a short period of time.

4. Examples of Previous Studies on Multiple Vaccinations
Hotopf, et al. – cross-sectional study found a slightly increased risk of reporting multiple symptoms among Gulf War servicemen who received multiple vaccines.
Pittman, et al. – follow-up analysis of a cohort of DoD employees who received 5 or more vaccines in a year. With extensive laboratory, lifestyle, and medical data, this study revealed that no significant long-term health effects were associated with this definition of MNS.
There are two published studies in the area
[i] Hotopf M, David A, Hull L, Ismail K, Unwin C, Wessely S. Role of vaccinations as risk factors for ill health in veterans of the Gulf war: cross sectional study. British Medical Journal. 2000; 320(7246):
Pittman, et al.[i] [i] Pittman P, Coonan K, Gibbs P, et al. Long-term health effects of repeated exposure to multiple vaccines. Vaccine
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Pittman et al concluded that no long-term adverse effects were observed to be associated with these repeated, large-dosage vaccinations. Some evidence of a chronic inflammatory response was evident, but a causal association to the vaccinations could not be inferred.

5. Defense Medical Surveillance System (DMSS) Background
Active surveillance system of U.S. military (~1.4 million person years each year from 1998-present)
Database consists of numerous Oracle tables
Hospitalization and outpatient diagnostic (ICD-9), vaccination, demographic, administrative, and deployment data collected
A general background of the DMSS and the role of the VAU was presented earlier. The DMSS is a relational database and for this study information will come from several of the tables. The study period of interest is which includes the DoD’s anthrax vaccination program that began in 1998 and was put on hold in October 2004 and the smallpox vaccination program that began in 2003.

6. Development of the MNS Study Investigational Framework
Define
the vaccines to be included
an exposure to multiple near-simultaneous vaccinations
a hospitalization event
observation time period
the method for analyzing the MNS vaccinations and inpatient events
In the developing the framework for looking at multiple vaccinations and hospitalizations we defined several variables and developed our method. From previous literature and because of the commonality of some vaccines we developed a list of 10 vaccines of interest for this study. We defined a multiple near-simultaneous vaccination exposure. Hospitalization events are defined using ICD-9 codes; however, we excluded some codes for conditions shown considered unlikely to be related to receipt of a vaccine. Finally, we had to define a study time period and method for analyzing the data.

7. Vaccines of Interest Anthrax Hepatitis B Smallpox Influenza
Hepatitis A
Yellow Fever
Measles/Mumps/ Rubella
Typhoid
Meningococcal
Tetanus/Diphtheria
Any possible combinations of vaccine type(s), dose(s), and sequence(s)
The DMSS contains information on persons receiving up to
~150 different vaccines – there are about 30 predominant types of vaccines
The following were considerations used to include these 10 vaccines for the study:
1. Sample size – (and, commonly administered vaccines)
2. VAERS combinations
3. Mix of biodefense and non-biodefense vaccines

8. Defining a Multiple Near-Simultaneous Vaccination Exposure
Number of the 10 vaccines of interest received
We can also look at the number of
vaccine antigens introduced into the body
aluminum adjuvant–containing vaccines administered
live vaccines (or ratio of live to non-live) administered
There are several possible definitions for a multiple near-simultaneous vaccination exposure. We intend to look first using the number of the 10 vaccines of interest received. However there are other methods we can use e.g., the number of antigens introduced etc. In addition, we will look to see if there appears to be any dose response relationship between number of vaccines administered and rate of hospitalization for the pre and post exposure periods.

9. Live or Non-Live (attenuated) Aluminum adjuvant
Vaccine
Number of
antigens
Live or Non-Live (attenuated)
Aluminum
adjuvant
Anthrax 2
Non-live [Cell-free, inactivated]
Yes
Hepatitis B 1
Non-live [Inactivated]
Smallpox
198
Live [Lyophilized (freeze dried) live virus] No
Typhoid fever:
Vi-CPS (IM)
Ty21a (oral)
Phenol-killed*
Acetone-killed**
Live [Purified capsular polysaccharide]
Live [Live attenuated]
Non-live [Whole cell killed]
Influenza (IM) 3
Yellow fever 10
MMR 24
Tetanus/Diphtheria
Non-live [Toxoid]
Hepatitis A
Meningococcal 4
Non-live [Freeze-dried preparation of polysaccharide antigens]
This table shows a list of the vaccines of interest according to the number of antigens contained, live/nonlive status, and whether they contain aluminum adjuvant (AVA does).

10. Defining Hospitalization Event of Interest
Group Code ICD9 set Description
( ) Infectious and parasitic diseases
( ) Neoplasms
( ) Endocrine, nutrition, immunity
( ) Hematologic disorders
( ) Mental disorders
( ) Nervous disorders
( ) Circulatory system
( ) Respiratory system
( ) Digestive system
( ) Genitourinary system
( ) Pregnancy * excluded *
( ) Dermatological diseases
( ) Musculoskeletal disorders
( ) Congenital anomalies * excluded *
( ) Conditions originating in the perinatal period
( ) Ill-defined conditions
( ) Injury and poisoning
(V-,E-codes) V-codes, E-codes
We excluded certain ICD-9 hospitalization codes because they were considered unlikely to related to receipt of a vaccine (pregnancy and congenital anomalies). However, during the analysis stage we will look at the frequencies of the ICD-9 grouping by pre and post exposure periods to determine if any abnormalities exist among the pre and post exposure groups.

11. Our intended study population includes all military personnel who received a vaccine between The same study subjects are in both time periods – their pre-vaccination baseline risk of hospitalization is compared to that of the period following the vaccination event. Note that we go back 180 days but we will only analyze the first 120 days because it is felt that there will be a natural drop-off in the number of hospitalizations as we move closer to the exposure date because of the healthy worker effect.

12. Study Design Pre / Post exposure cohort design
Eligible subjects for inclusion in study
Hospitalizations are observed during the pre/post exposure periods
Periods defined as 180 days
Analysis period is the first 120 days
No additional vaccines of interest are given during the post-MNS vaccination period
MNS vaccination event is defined as receipt of 2 or more vaccines within a day
This slide outlines our study. We will compare the risk of hospitalization from the same group of subjects before and after their multiple vaccine exposures. We intend to focus on non deployed, active duty, years of age eligible subjects. We have chosen a period of observation, pre and post exposure, of 180 days. However, we will only analyze the first 120 days as explained earlier. We will also exclude from the analysis any person who received any of the 10 vaccines after the exposure period and the end of the observation period, i.e., anyone who had one of the 10 vaccine from day was excluded. Although we define a MNS as receipt of 2 or more vaccines within a 2 day period we intend to further analyze the data to determine if there is a dose response relationship.

13. Model Covariates: Static
Race
black
white
other
Ethnicity
Hispanic
non-Hispanic
Gender
All multivariable modeling efforts will begin by including the following static and dynamic (next slide) covariates. We will account for the change in status within a subject for the time varying covariates.

14. Model Covariates: Dynamic
Service
Army
Marines
Air Force
Navy
Age Categories
18 to <25 years
25 to <35 years
35 to <45 years
45 to 65 years
Occupation Categories
Medical/Research/Science
Hazardous
Front-line
Office/Administrative
Communication

15. Modeling Methods Cox proportional hazards model
Account for time varying covariates
Assess the risk of hospitalization of the pre versus post exposure period after controlling for considered variables
Dose-response, e.g., is there a trend in the post versus pre exposure risk as the number of vaccines administered increases?
We will fit a Cox proportional hazards model for 2 or more vaccines. In addition, we will fit the Cox model for 1, 2, 3, … vaccines independently to determine if there appears to be a dose response pattern.

16. Next Steps Complete analysis Share with collaborators
We are currently beginning the analysis of the data and expect to have results to disseminate by late May 2005.

17. MNS Vaccination Future Topics
Broaden our scope to include all vaccines
Define and account for a cumulative effect of vaccination
Data mining
Others?
Our future plans include assessing these additional approaches to the topic in the near future. I mentioned earlier the database has information on individuals who have received more than ~100 vaccines. We will also look at the cumulative effect of receiving many vaccines and see if there is a dose response relationship. Some of the future topics may be handled using data mining techniques.

18. Acknowledgements CDC DoD NVAC FDA (Robert Ball)
Anthrax Vaccine Safety Team (Aaron Aranas, Susan Duderstadt, Mike McNeil)
Immunization Safety Branch (Frank DeStefano)
DoD
Army Medical Surveillance Activity (Col. Mark Rubertone)
MILVAX (Col. John Grabenstein)
NVAC
FDA (Robert Ball)