# Presentation: 739006

## Estimating Influenza Vaccine Effectiveness in the DoD

- Col James Neville, MD, MPH
- Deputy Director
- 210-536-2002

**Sustaining Readiness through Healthy Communities**

**Notes:**
I’m honored to be here.  Let me first mention that I am only representing a lot of people.  I do not claim this work for my own.  I am standing here because the Air Force Surgeon General has been designated the DoD Executive Agent for Influenza Surveillance.  The Air Force has been conducting influenza surveillance since the late 1970s, and in 1999 it became a DoD program.  My organization is the Air Force Institute for Operational Health located at Brooks City-Base in San Antonio Texas.  We collaborate with the Naval Health Research Center San Diego [logo], whose logo you see here.  In addition, Army [logo] Medical Centers conduct clinical virology services for beneficiaries around the world, and the DoD’s overseas labs participate in febrile respiratory illness projects to varying degrees.  The overall program is conducted largely under the auspices and guidance of the DoD Global Emerging Infections Surveillance and Response System, or DoD-GEIS [logo].
Later you will hear from Linda Canas, who will present her annual summary from the DoD laboratory-based surveillance program managed from Brooks.  I will not present her data, rather my intention is to describe other aspects of the DoD’s involvement in influenza surveillance with an emphasis on .

## Topics to be Covered

- Existing surveillance programs (overview)
- Data available for evaluation of VE
- Navy VE estimate (recruit centers)
- Army VE estimate (Ft. Lee outbreak)
- AF VE estimate (phone survey, underway)

## Existing Surveillance Programs-AF

- AF Program (AFIOH)
- 27 sentinel sites
- Clinical and convenience sampling
- 1**O** objective: isolates

**Notes:**
The AF program is laboratory-based or etiology-focused, its main purpose being the collection of respiratory pathogens from a variety of military bases around the world considered good sentinel sites.  (Don’t worry about the map; you’ll see it later in more detail during Linda’s presentation.)  Selection factors for sentinel sites include overseas location, major ports of entry, and a history of participation.  There are 27 sites from all three services.  In addition, the DoD overseas laboratory network supplies specimens from various countries where they are active.  Some of the overseas labs send isolates to us in San Antonio, some of them process their own or ship to regional WHO labs.  AFIOH has the only full-service virology lab in the AF.

## Existing Surveillance Programs-Navy

- AF Program (AFIOH)
- 27 sentinel sites
- Clinical and convenience sampling
- 1**O** objective : isolates
- Navy Program (NHRC)
- Military Training Centers
- Convenience sampling
- Objective: ILI rates, isolates

**Notes:**
The Navy’s Febrile Respiratory Illness surveillance program is managed by the Naval Health Research Center San Diego and focuses on 8 military training centers.  On-site investigators track FRI visits, validate denominator data, and collect specimens systematically from trainees who seek medical care and meet an FRI case definition.  Since these trainee populations are fairly well characterized and monitored, attack rates can be established with a high degree of confidence.  NHRC has the only full service virology lab in the Navy.

## Existing Surveillance Programs-Army

- AF Program (AFIOH)
- 27 sentinel sites
- Clinical and convenience sampling
- 1O objective: isolates
- Navy Program (NHRC)
- Military Training Centers
- Convenience sampling
- Objective: ILI rates, isolates
- Army Program
- MEDCENs, clinical virology labs
- Special studies

- - Army MEDCEN

**Notes:**
The US Army has 6 Regional Medical Centers, each with clinical diagnostic virology capability.  While there is no systematic influenza surveillance program per se in the Army, clinical results are characterized as needed, and local and regional preventive medicine staff track FRI rates and etiologies as needed.  Special outbreak investigations are conducted as needed, one of which I will briefly describe shortly.
I should mention that the 3 services have a plan for sharing laboratory resources in situations where demand outstrips capacity, such as major febrile respiratory illness outbreaks..

## ILI Activity Data Sources

**Notes:**
I will now briefly describe data sources readily available within the DoD. Certainly these are not unique to the DoD, but in the context of an urgent public health effort to estimate the effectiveness of a vaccine in the face of naturally occurring disease, these are the existing data sources that are used both to monitor disease activity and to attempt the evaluation of vaccine effectiveness.

## ILI Activity Data Sources

- Local public health officer reports

**Notes:**
The first line of defense is, no surprise, the local public health officer, where also the primary responsibility is placed for local disease monitoring and response.  Reports include routine reports of notifiable diseases and evidences of unusual patterns of disease or outbreaks which might require special responses or assistance. 

## Data Sources (cont’d)

- Local public health officer reports
- Coded ambulatory visits
- ESSENCE
- “DNBI”

**Notes:**
Our medical surveillance currently takes advantage of data collection systems that largely were not designed specifically for surveillance activities.  Among the existing data sources is the familiar ICD-9 coding for ambulatory visits.  Many of you are familiar with ESSENCE, which monitors ambulatory visits at every DoD healthcare facility.  These data can be manipulated in several ways, here the chart demonstrates a daily percentage of all visits that were coded for at least one of the ILI-defining codes, in this example aggregated for DoD facilities on the Pacific Rim.  Facility-specific data are also monitored.  A similar approach is used to monitor Diseases and Non-Battle Injuries for deployed locations, although data collection in those locations is often more problematic for a variety of reasons.

## Data Sources (cont’d)

- Local public health officer reports
- Coded ambulatory visits
- ESSENCE
- “DNBI”
- Laboratory results
- Surges from a site
- Unusual results

**Notes:**
Laboratory submissions and results can also be used to identify surges in pathogen activity generally or at specific sites.  This example from last year reflects an outbreak in the Tidewater region of Virginia.  The % of total submissions positive gives a good indication of pathogen activity separate from illness occurrence.  This is similar to the CDC’s display.

## Data Sources (cont’d)

**Cumulative AF Influenza Vaccination**

- Local public health officer reports
- Coded ambulatory
- ESSENCE
- “DNBI”
- Laboratory results
- Surges from a site
- Unusual results
- Immunization data
- Individual level

**Notes:**
The Services all track vaccination delivery, but these data show only the AF data, since that is most available to me.  Influenza vaccination is mandatory for military members, and high vaccination rates are achieved fairly quickly.  The graph may be a little difficult to read, but 80% coverage was achieved by Dec 2nd 2003 and Dec 6th in 2002.  A total of about 350,000 vaccinations are delivered to AF members each year.   Because influenza vaccination is mandatory and is a commander’s program, analyzing vaccine effectiveness during this time period would be a fairly complex undertaking.  And because such a small proportion of service members are remain un-vaccinated, comparing relative risks between vaccinated and unvaccinated groups is difficult.

## NHRC VE Data

- Existing data from surveillance program
- Trainees at 4 training bases
- December 2003
- Influenza culture positives only
- Person-time analysis
- Weeks at risk
- Vaccinated vs. unvaccinated (2 wks post vax)
- Basic trainees are vaccinated upon arrival

**Notes:**
As I described earlier, the Naval Health Research Center in San Diego monitors febrile respiratory illnesses among trainees of all three services.  They have used existing data to attempt to estimate influenza vaccine effectiveness.  The calculation is based on data from 4 representative training bases (Ft. Leonard Wood, Fort Jackson, Marine Corps Recruit Depot San Diego, and Lackland AFB).  For the month of December 2003, attack rates for influenza were calculated for vaccinated and unvaccinated trainees using an assumption of the proportion of vaccinated trainees (8 week training course, vaccinated within days of arrival, 2 weeks before considered vaccinated = 75% vaccinated in this cohort).  A case was defined as a positive influenza culture from a trainee.  2 weeks from the date of vaccination was used to mark the beginning of vaccinated time for each trainee. 

## NHRC data (cont’d)

**Notes:**
Just to display the data NHRC worked with, here are the numbers of influenza isolates from all 8 training bases together.  Only influenza A has been identified so far this season, and of the isolates sequenced, all display sequences consistent with the Fujian strain.  The dark red segments are influenza isolates from trainees who had been vaccinate at least 2 weeks prior to the onset of illness.  AS you can see, the number of culture-confirmed influenza cases is relatively small.

(This season, influenza A has been found among basic trainees at Fort Leonard Wood (17), Fort Jackson (26), Fort Benning (1), MCRD San Diego (21), MCRD Parris Island (14), NTC Great Lakes (9), Lackland AFB (11), and CGTC Cape May (3).)

## VE calculation

- AR vax   = 4 cases / 54278 person-wks
-  7.37/100,000 person-wks
- AR unvax = 15 cases / 18617 person-wks
- 80.6/100,000 person-wks
- RR = 7.37 / 80.6 = 0.0914
- VE = 1 – RR = 90.9%

**Notes:**
The number of cases is relatively small, but the estimate of cause-specific vaccine effectiveness is 90.9% among this group.  This is not published yet, and I don’t have other parameters like age ranges, gender, and so forth available at this time. 

## Ft Lee, Virginia

- US Army post - Quartermaster Training
- 3,200 trainees; courses of varying length; 12%/week turnover
- Influenza outbreak, 31 Oct-11 Nov 2003

**Notes:**
Fort Lee is a US Army post just southeast of Richmond, Virginia, and home to the Army’s Quartermaster Center and School.  An influenza outbreak began on Oct 31, 2003, confined almost exclusively to the students and staff of the 23rd Quartermaster Brigade.  Let me show the epidemic curve . . .

## Ft. Lee ILI Epi Curve

**Mass Immunizations**

**CHPPM/WRAIR EPICON**

**Notes:**
These are visit counts, showing the major epidemic occurred from 31 Oct through 11 Nov 2003.  These are data for the whole study population, trainees.  It is not possible to pick out the different training companies in this display.

## Ft Lee, Virginia

- US Army post - Quartermaster Training
- 3,200 trainees; courses of varying length; 12%/week turnover
- Influenza outbreak, 31 Oct-11 Nov 2003
- PH response: mass immunization, case isolation
- Vaccine Effectiveness Study Attempt
- 2 cohorts
- “tight” and “loose” case definition
- Limitations – temporality, highly immunized population, exhaustion of susceptibles, random mixing assumption

**Notes:**
Ft Lee had just begun their routine influenza immunization campaign and few were immunized when the outbreak started.  Post medical personnel responded with a mass immunization campaign that reportedly reached 95% of the target population and a rigorous isolation protocol, and the outbreak was over in two weeks.

Personnel from the US Army Center for Health Promotion and Preventive Medicine, Aberdeen, Maryland, responded to Ft. Lee to assist local staff with the investigation.  A 2nd team returned to Ft Lee two weeks later to gather data to study vaccine effectiveness.  The analysis was separated into 2 cohorts and “loose” vs. “tight” case definition.  “Loose” meant any ILI-related ICD-9 coded visit; “tight” meant a febrile illness with sore throat or cough or lab confirmed influenza infection.  Before I show the results, let me say up front that many limitations are recognized.  The study cohort had just experienced an influenza epidemic, wherein many of the cohort probably had been exposed if not infected, and an unknown level of individual and herd immunity could have developed.  A large proportion of the population was immunized, limiting the contribution of susceptible members.  The organizational structure is complex, with trainees assigned to groups of about 200, sleep in 3-4 person dormitory rooms, mix in dining facilities, and a 12% overall turnover per week.  We don’t have time to discuss all the details, but let me get to the results.

## VE Results

|  | “loose” case def. | “tight” case def. |
| --- | --- | --- |
| Cohort A:
arrival date
10 Nov 03 
(n=267) | 40.5%
[-48%,  76%]
(26 cases) | 51.2%
[-357%, 78.1%]
(5 cases) |
| Cohort B:
arrival date
17&24 Nov 03 (n=463) | 60.2%
[-167%, 86.4%]
(15 cases) | 100%; no CI by method used
(4 cases) |

**Notes:**
The 2 different cohorts are listed, population size for each.  The VE point estimates range from 40.5% to 100% with wide confidence intervals.  Obviously, other than the one estimate of 100%, which had zero cases among the group considered to be immune, the CIs include zero and thus no valid assumptions of VE can be made.  If one can assume that the “tight” case definition restricted the analysis to cases more likely to be actually infected with influenza, then one would naturally expect a better influenza VE against influenza disease, an argument these point estimates support. 

## AF IVE Evaluation: Plan A

- Identify exposed cohort (AF only, not Academy)
- Index cases: influenza culture positive in AFIOH lab
- Contact sponsor for household health histories
- Influenza vaccinations
- Febrile respiratory illnesses within 2 wks of index case
- Calculate secondary attack rate
- Compare vaccinated and unvaccinated
- IRB approved; telephone surveys began 2 Feb 2004
- results pending
- Annual routine study?

- # eligible      =  114

- Total # of family members=400

- # specimens=2459

- # positive     =  859

**Notes:**
The Epidemiology Service Branch at AFIOH has a telephone survey study underway.  Our plan is to identify an influenza-exposed cohort by identifying index cases, persons from our lab whose cultures have tested positive for influenza.  We will include only AF personnel for simplicity, exclude persons from the AF Academy because their setting is, well, atypical.  We contact the sponsor of each positive culture (which may be the person with the culture or the parent or spouse) and seek voluntary participation in a survey to collect self-reported occurrence of febrile respiratory illness within 2 weeks of the index case and vaccination status.  We calculate the secondary attack rate to estimate VE.  The survey began on 2 Feb 04.  We feel that this could be an recurring study conducted routinely and annually, and if done throughout the season would minimize the risk of recall biases.

Expedited IRB review.

Power estimate 0.80

## Identify site with ongoing transmission
Lab submissions, ESSENCE, other reports
Index cases: influenza culture positive in AFIOH lab
Decision: Launch on-site investigation vs. telephone only
Surveillance data sources to assess extent of local outbreak
Contact sponsor/parent directly for household health histories
Influenza vaccination history
Febrile respiratory illness within 2 wks of index case
Validate data with medical records, vaccination registry, labs
Use secondary attack rates to estimate VE

Annual routine study?
Pending IRB & AF approval

- Lab submissions, ESSENCE, other reports
- Index cases: influenza culture positive in AFIOH lab
- Decision: Launch on-site investigation vs. telephone only
- Surveillance data sources to assess extent of local outbreak
- Contact sponsor/parent directly for household health histories
- Influenza vaccination history
- Febrile respiratory illness within 2 wks of index case
- Validate data with medical records, vaccination registry, labs
- Use secondary attack rates to estimate VE
- Annual routine study?
- Pending IRB & AF approval

- AF IVE Evaluation: Plan B

**Notes:**
We also plan to pursue IRB approval for a more extensive study that would include more validations, such as medical record reviews to help validate illness occurrence, using the AF immunization database to validate vaccination, and potentially gathering cultures or serologic evidence of influenza as a cause of the secondary illnesses.  This study has not been started yet.

Longer IRB process

## Summary

- NHRC: VE = 91%
- CHPPM: VE = 40-100%
- AF: VE = pending
- Many details . . .

## Questions

**Questions**

**Contact information:**
**Col James Neville, MD, MPH**
**E-mail: james.neville@brooks.af.mil**
**Phone: 210-536-2002**

## Back-ups

## Specimen Results by Week of Training

## AF Lab Results 

## AF Lab Results