Report of the 

Defense Science Board Task Force 

on 

Smallpox Vaccine Down Select Process 

Report Summary 

May 2004 

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For Acquisition, Technology, and Logistics 

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Report of the Defense Science Board Task Force on Smallpox Vaccine

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This report is a product of the Defense Science Board (DSB). The DSB is a Federal 

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necessarily represent the official position of the Department of Defense.
OFFICE OF THE SECRETARY OF DEFENSE

3140 DEFENSE PENTAGON

WASHINGTON, DC 20301-3140

DEFENSE SCIENCE

BOARD

MEMORANDUM FOR THE ACfING UNDER SECRETARY OF DEFENSE

(ACQillSmON, TECHNOLOGY AND LOGISTICS)

SUBJECT: Final Report Summary of the Defense Science Board Task Force on

Smallpox Vaccine Down Select Process

I am pleased to forward the Final Report Summary of the DSB Task Force on

Smallpox Vaccine Down Select Process, which was chaired by Dr. George Poste. The

Task Force was tasked to perform an independent evaluation of the Department of

Defense and Department of Health and Human Services smallpox vaccine candidates.

The Task Force developed a set of scientific and manufacturing related criteria to

evaluate the smallpox vaccine candidates. Using this set of evaluation tools, the Task

Force was able to perform a qualitative evaluation of the smallpox vaccine candidates.

The results of this evaluation are contained in the full report. Additionally, valuable the

criteria matrix developed during the course of this study should be a valuable tool is

accessing other DoD vaccine programs.

Furthermore, the Task Force strongly recommends that DoD continue to maintain

a close relationship with a vaccine R&D group/company in order to respond to potential

biological threats to our armed services.

I endorse the recommendations of this Task Force and propose you forward the

report summary for distribution and comment.

~-~, ~

William Schneider, Jr

Chairman
iv 
v 

TABLE OF CONTENTS

DSB Transmittal Letter.......................................................................................... iii 

I. Introduction.....................................................................................................1 

II. Current Vaccination Methods & Initiatives....................................................2 

III. Recommendations................................................................................3 

Appendices 

A. Terms of Reference.........................................................................................7 

B. Task Force Membership ...............................................................................11 

C. Overview of Definition Criteria....................................................................15 

D. Acronyms......................................................................................................21 
vi 
1 

I. INTRODUCTION: A SHORT HISTORY OF EFFORTS 

TO ERADICATE SMALLPOX 

Early Attempts at Immunization and the Vaccinia Vaccine 

In the 17th century, physicians in China blew powdered smallpox scabs into sinuses 

and prepared pills made from the fleas of cows. In India, physicians applied scabs to the 

scarified skin of the healthy. This technique migrated westward to Turkey where it was 

discovered by western physicians. Other early attempts to control smallpox included 

inoculation with material from smallpox lesions. This practice was known as variolation. 

In 1796, Edward Jenner noted that milkmaids were free of the facial scars that 

marked most of the population of that time. The observation that they “cannot take 

smallpox” was attributed to the localized pox lesions that they developed in their hands. 

Jenner reasoned that infectious material from cowpox (caused by the vaccinia virus) 

lesions provided protection from smallpox (caused by the variola virus). He used it to 

vaccinate an 8-year-old boy. The boy later resisted infection, demonstrating the efficacy 

of the first vaccine. 

The World Health Organization (WHO) Smallpox Eradication Program 

Epidemics of smallpox inflicted mankind throughout history, and as recently as 1967, 

10-15 million cases were still occurring annually in more than 30 countries. On 1 January 

1967, the World Health Organization (WHO) launched the Intensified Smallpox 

Eradication Program. The program’s initial strategy was to rely solely on mass 

vaccination, an approach that successfully eradicated smallpox in Western Europe, North 

America, Japan, and other areas. However, eradicating the disease via mass vaccination 

alone proved untenable in densely populated countries such as India. Nevertheless, forced 

to fight outbreaks in Kenya in 1966 and India in 1970 with a constrained supply of 

vaccine, the WHO developed a more effective strategy of surveillance and containment 

coupled with mass vaccination. This evolution in strategy eventually led to the 

elimination of smallpox. Smallpox is the only major human disease to have been 

eradicated. 

The success of the eradication program required the capability to produce (at high 

volume) potent and reliable vaccines and an efficient and inexpensive means of 

delivering the vaccine. Three major technological innovations greatly facilitated the 

smallpox program: the development of the ability to mass-produce high-quality freezedried vaccine in several countries, the development of the hydraulic-powered jet injector, 

and the development bifuricated needle. 

Although these innovations were milestones in the smallpox campaign, the program 

would not have succeeded without the ingenuity and creativity of the field staff, which 

surmounted a host of local problems. Important innovations such as smallpox recognition 

cards, watchguards, rewards, rumor registers, and containment books all came from 

fieldworkers. 

The smallpox eradication program of 1967 was guided by a plan that embraced the 

two complementary approaches of mass vaccination campaigns and surveillance systems. 
2 

The WHO program functioned in a collegial structure of many independent national 

programs. As a result, programs differed greatly from one country to another, as well as 

from one time period to another. 

II. CURRENT VACCINATION METHODS & INITIATIVES 

Current U.S. Military Smallpox Vaccination 

With the eradication of smallpox worldwide, vaccinations against this disease were 

ended. When it was learned, however, that the Soviet Union had weaponized smallpox 

and that other countries (including Iraq and North Korea) may have been able to obtain 

the virus, the United States determined that it was necessary to vaccinate its forces 

following procedures outlined in DoD Directive 6205.3, “DoD Immunization Program of 

Biological Warfare Defense.” The DoD’s Smallpox Vaccination Program is consistent 

with Food and Drug Administration (FDA) guidelines and the best practice of medicine. 

This program supports the national smallpox preparedness plans, but is tailored to the 

unique requirements of the Armed Forces. Under the program, DoD ensures preparedness 

by immunizing selected personnel. Selection is based on occupational responsibility; 

high-priority occupations include smallpox epidemic response teams and hospital 

workers and other designated forces having critical mission capabilities (for example, 

those forces essential to accomplishing the U.S. Central Command’s mission). 

Current Smallpox Vaccine Initiatives 

 On 2 October 2002 the Undersecretary of Defense for Acquisition, Technology, and 

Logistics (USD(AT&L)) requested the Defense Science Board stand up a task force to 

identify the criteria by which the Department of Defense would select the next smallpox 

vaccine from a list of various candidates available at the time. The DSB Smallpox Down 

Select Process Task Force (SDTF) stood up under the leadership of Dr. George Poste.1

 

The task force’s terms of reference included several key parameters by which the 

SDTF would develop the criteria. These parameters included an assessment of: 

• The cell line and viral strain to be used; 

• Preclinical data; 

• Vaccine production methodology, to include rates of production and surge 

capacity; 

• Protocols for clinical trials, including adverse reaction rates; 

• Cost issues related to production of the vaccine; 

• Critical regulatory, legal, and ethical issues; and 

• Any other relevant issues. 

The task force met several times from December 2002 through October 2003 and 

developed insights into the status of the vaccine candidates. These insights allowed us to 

 

1

 Appendix A contains the task force’s terms of reference. Appendix B lists the task force membership. 
3 

inform some of the requests for information which would guide the specificity of the 

criteria, and their subsequent discriminatory power. In addition, we believe the 

companies actually benefited from some of the requests for data and feedback from the 

SDTF, and that this allowed us to better characterize the criteria as they applied to each 

of the candidate vaccines. 

The appended chart contains the definitions the task force used in the analysis of 

the criteria. These definitions constitute a basis of consistent assessment of the criteria for 

all candidates. Appendix C also contains the important characteristics considered in 

studying each of the parameters, provides a risk assessment for that parameter as it 

applies to each product, highlights the preferred method the task force applied to that 

specific parameter, and lists the type of information requested from each candidate 

company as it related to that parameter at the time of the request. 

III. RECOMMENDATIONS 

1. Candidate overall assessment

The Task Force developed a matrix using the developed criteria (Appendix C). A matrix 

(containing proprietary information) was populated for the smallpox vaccine candidates. 

These matrices are contained in the full report. 

2. DoD vaccine expertise 

The Task Force strongly recommends that DoD continue to maintain a close 

relationship with a vaccine research and development group/company in order to respond 

to potential biological threats to our armed services. 
4 
5 

Appendix A 

TOR 
6 
7 

A. TERMS OF REFERENCE 
8 
9 

Appendix B 

Membership 
10 
11 

B. TASK FORCE MEMBERSHIP 

CHAIRS 

Mr. John Dingerdissen 

 Dr. George Poste 

Private Consultant 

Health Technology Networks

MEMBERS 

Dr. Barry Bloom

Dr. Robert Couch 

Dr. Rebecca Devine

Dr. Jerome Donlon 

Dr. Dorothy Margolskee

Dr. Richard Whitley 

Dean of the Faculty of Public Health 

Baylor College of Medicine 

Private Consultant 

Public Health Emergency Preparedness 

Private Consultant 

University of Alabama

GOVERMENT ADVISORS 

LTC Robert Borowski Senior Medical Advisor, DATSD 

EXECUTIVE SECRETARY 

Dr. Joseph Palma Deputy Assistant to the Secretary of 

Defense/CB

DSB SECRETARIAT 

 CDR David Waugh Defense Science Board 

SUPPORT 

Ms. Michelle Ashley 

Ms. Allison Balzano 

 Ms. Cara Sievers 

SAIC 

SAIC 

SAIC
12 
13 

Appendix C 

Overview of Definition Criteria 
14 
15 

C. OVERVIEW OF DEFINITION CRITERIA 

Parameter Important 

Characteristics 

Parameters Driving Risk 

Assessment Preferred method Requested Information 

Product 

specifications/ 

description 

Liquid vs lyophilization; 

storage conditions; # doses 

per vial; potency (i.e. 

PFU/ml) to assure 

appropriate dose with 

bifurcated needle. 

Availability of cold chain; 

ease of administration; best 

stability profile & longest 

shelf life. 

Lyophilized product if more 

stable; > 24 month shelf life 

(longer duration preferred); 

refrigerator storage of 

sufficient duration to allow 

vaccination of military in the 

field; 10^8 PFU/ml. Product, 

dose & method of 

administration (including 

dilution if applicable) must 

be fully licensed by FDA 

prior to use by DOD. 

Product profile of 

candidate vaccines from 

companies. 

Cell culture 

substrate 

Cell type used; Master & 

Working Cell Bank 

characterization; number & 

results of release assays; 

vaccinia virus yields 

(PFU/cell) 

Prior FDA approval (yes/no); 

Detailed history (i.e. GMP 

documentation of passages, 

sources of raw materials with 

especial note of animal-based 

products etc.); results of 

adventitious agent testing. 

Previously unapproved 

continuous cell lines (e.g. 

Vero) represent a regulatory 

risk. Virus infectivity/ cell 

productivity (PFU/cell) 

critical to assure 

manufacturing capacity & 

vaccine supplies. 

Must pass required ICH 

guidelines, including full 

battery of adventitious agent 

testing selected on basis of 

cell passage history etc. 

Prior FDA approval & 

sourcing of original cell 

premaster from FDA or other 

approved source would be 

optimal to start premaster, 

master & working cell banks. 

Details re cell line, 

characterization & release 

data. FDA reviews, 

comments re cell line. 

Source of 

vaccine stock 

seed 

Compliance with general 

ICH guidelines where 

possible. Identification of 

source; full history details 

(including passage 

descriptions, starting 

material lists & sourcing, 

with special note of animal 

derived components). 

Adventitious agent testing 

results available & 

acceptable. 

ICH guidelines & general 

safety expectations drive 

regulatory risk assessment. 

Potential exists for unknown 

adventitious agents in 

original sample (associated 

with prior passage in 

animals). 

Stock seed derived from 

demonstrated clinicallyeffective vaccine is preferred. 

Additional passages past the 

original vaccine lot, 

especially passages in cell 

substrates as opposed to 

animals (cow, sheep) may 

alter clinical efficacy/ safety 

profile. ICH guidelines 

should apply, including 

adventitious agent testing, 

sterility, potency etc. Results 

must be acceptable to FDA & 

clinical community with 

respect to vaccine safety. 

Details re stock seed 

characterization & release 

data, including detailed list 

of adventitious agents in 

screening assay. 

Source of 

vaccine stock 

seed (con't) 

Vaccine virus chosen for 

expansion & subsequent 

use as seed lots. 

Stock seed may require 

procedures to optimize 

sterility, etc. However, 

clonal selection could alter 

anticipated vaccine 

performance (either efficacy 

or safety). 

Prefer vaccine stock seed that 

has not been cloned, since 

vaccinia virus characteristics 

that correlate with clinical 

safety & efficacy are 

unknown. 

Details re vaccine stock 

seed source, history. 
16 

Vaccine virus strain & 

association with clinical 

efficacy; # passages from 

original clinically-proven 

material 

Passage history past clinically 

proven material may alter 

vaccine performance 

(especially efficacy) 

Limiting cell-based passages 

to ~1or 2 past clinical 

material is preferred. 

Nature of passages 

(animal, cell-based, type of 

cells) 

 Prior animal passages 

preferable to cell-based 

passage if passage history 

extends past 1-2 cycles 

Details re vaccine 

relationship to clinically 

proven material, # & 

details re subsequent 

passages etc. 

Seed lot 

analysis & 

release 

Compliance with general 

ICH guidelines; 

development, validation 

(yes or no) & utilization of 

vaccinia-vaccine specific 

assays. 

Historically, plaque assay, 

chick allantoic membrane 

(CAM), rabbit scarification & 

suckling mouse LD50 assays 

were used. Need to establish 

whether 2nd & 3rd will be 

required for release (may be 

hard to validate - may be 

possible to run as 

characterization "for 

information only"). 

Choice of potency assay(s) 

will need confirmation with 

FDA. Results from all 

assays would be useful for 

information, given lack of 

data correlating potency 

assays with clinical efficacy. 

Reincarnation of past assays 

may need standardization vs 

"gold standard" - because of 

difficulties with that 

approach, FDA may accept 

plaque assay as release & 

others for information only. 

Needs to be 

negotiated/confirmed. 

Details re potency assays 

& their validation (if 

possible). Criteria for 

success. Release assays. 

Results. FDA 

correspondence, 

communications if any. 

Master virus 

seed 

characteristics 

Proposed identity & 

potency assays for release; 

extent of passage allowed 

past original stock seed; 

assay results compared to 

"gold standard"; nonclonal 

origin (but if needed 

"clean-up" from original 

stock seed, how was this 

done?) 

Passage alters phenotype of 

vaccinia virus, with unknown 

impact on potency. 

Conservative approach 

would minimize passages to 

1-2 past stock seed, if 

possible. Productivity 

(PFU/cell) becomes a critical 

issue to minimize passage 

number. Anticipate yields of 

10-50 PFU/ cell or better. 

Details re potency assays 

& their validation (if 

possible). Criteria for 

success. Release assays. 

Identification of vaccine 

denoted as "gold 

standard". Assay results 

for both "gold standard" & 

for master seed. 

cGMP 

production of 

cell banks 

ICH & GMP compliance 

documented 

 ICH & GMP compliance 

documented 

Manufacture 

of clinical 

material & 

incorporation 

of full scale 

manufactured 

vaccine in 

consistency 

lots/ Phase III 

clinicals 

Process, scale, impact of 

scale on productivity, 

identity potency etc. 

Formulation definition, 

stability program & results. 

Scale can impact vaccine 

performance (safety & 

efficacy parameters). 

Productivity (PFU/cell) is 

again a critical issue to 

minimize passage number, 

assure manufacturing 

capacity & subsequent 

vaccine supply. Shelf life of 

frozen product at least 24 

months (longer is preferred). 

Acceptable stability at 2-8 

degrees (refrigerator) for at 

Phase III should be 

performed with consistency 

lots manufactured at full 

scale. 

Documentation. Current 

status, process & 

purification steps; plans 

for scale up. Formulation 

development, results of 

stability testing etc. 
17 

least 3 months required for 

military use. 

Preclinical 

safety 

assessment 

package. 

Studies required by FDA - 

LD50, local tolerability. 

New guidelines include 

safety in 2 species (which) 

& reproductive toxicology 

studies. Will 

neurovirulence studies be 

required? 

Safety evaluations on original 

vaccine did not require 

current-day standards. 

Monkey neurovirulence 

testing, reproductive 

toxicology studies may be 

required. If so, would need to 

compare results to a "gold 

standard" (Dryvax?). Method 

to show "equivalency" would 

need confirmation with FDA.

Wyeth "Dryvax" recently relicensed & therefore may be 

acceptable as "gold 

standard". Discussions with 

FDA needed. 

Results to date & plans. 

FDA communications if 

any. 

IND status Contents of IND filing. 

FDA response. General 

clinical plan & FDA 

feedback. Endpoints for 

safety, tolerability. 

 Any vaccine that has passed 

initial IND approval to 

proceed to Phase I is 

preferred to one still in 

preclinical (implies FDA 

initial approval of vaccine 

source, safety testing etc). 

Development status of 

vaccine candidate. IND 

sections. 

Clinical assays Development & validation 

of immunogenicity assays, 

including measurement of 

antibody responses 

(ELISA, plaque 

neutralization) & cellmediated responses 

(cytotoxic lymphocyte 

killing - CTLs and/or ELIspot assay). 

Development of cellmediated immunity assays 

requires significant effort & 

care with respect to sample 

handling etc. For all 

immunogenicity assays, 

correlation of efficacy not 

established & will require 

attention during Phase I-II 

clinical trials (comparison to 

Dryvax-induced responses). 

 Information re current 

assay development, results 

etc.. FDA 

communications, if any. 

Clinical 

studies & 

results 

Safety, tolerability, 

comparison to Dryvax, 

including results of 

immunogenicity assays 

noted above. 

Designation of "efficacy" 

parameters past "take". Will 

FDA require other 

immunologic assays as 

primary endpoints & if so, 

what will be the "cut-offs" for 

acceptable results, given no 

established correlation to 

clinical efficacy? 

Phase I revaccination study 

in healthy adults followed by 

primary vaccination of naïve 

adults. Phase II rollout of 

vaccinations across age 

groups (including older 

adults & children ages 5-18 

y.o.), with attention to take 

rates, immunologic assay 

results versus positive control 

(Dryvax, full strength) to 

determine size of Phase III. 

Clinical 

package for 

BLA approval 

Extent of Phase III: FDArequired # of subjects by 

age; endpoints (& 

similarity to Dryvax?). 

Plans to provide Vaccinia 

Immunoglobulin (VIG) to 

manage potential adverse 

events in field use/ 

marketed use. 

Safety: infrequent but severe 

adverse experiences 

(occurring at 10 - 70/10^6 

doses) will not be 

characterized in Phase III. 

Efficacy: is "take" sufficient 

as a primary endpoint? 

Because of concomitant 

vaccinations required for 

military recruits prior to 

deployment, label should 

provide guidance & allow 

concomitant administrations 

when possible. Availability 

of VIG should be assured 

prior to use in the field. 

Results of both safety & 

immunogenicity 

assessments to date. 

Populations studied & # 

subjects per age group. 

Frequency & size of 

cutaneous lesions 

associated with "take" & 

comparison to active 

comparator (Dryvax, full 

strength). Data regarding 

ELISA, plaque 

neutralization & cellmediated immunity assays. 

Plans (or results) of Phase 

III clinicals. Level of 

commitment to Phase IV 

monitoring. 
18 

Final 

manufacturing

process & 

facility 

Yield, consistency, 

capacity, cost. 

 Facility already inspected & 

approved by FDA preferred. 

Any documentation re FDA 

or other government audits of

interest in assessing risk. 

Status & plans. 

Company 

history 

Demonstrated record of 

FDA approvals for 

vaccines (yes/no); 

management capabilities, 

technical expertise for live 

virus vaccine development 

& manufacture; 

sophistication of key 

regulatory & research 

personnel 

Successful manufacture & 

commercialization of live 

virus vaccines are extremely 

challenging activities. Until a 

company & its technical staff 

have demonstrated their 

success in bringing a live 

virus vaccine to market, their 

endeavor should be 

considered high risk. 

Demonstrated ability with 

small molecule drugs, 

biologics and/or proteinbased vaccines should not be 

considered sufficient, given 

the unique requirements for 

live virus vaccine products. 

 Company history. CVs of 

management & key 

technical staff associated 

with project. 

Company 

capabilities 

Scale of manufacturing 

facility; demonstrated 

technical expertise; 

willingness to perform 

post-licensure studies; 

level of motivation 

Technical staff expertise in 

live virus vaccines will drive 

level of risk. Major delays in 

program can be incurred if 

attention to detail & 

compliance with regulatory 

expectations are not taken 

into account. 

Regulatory staff experienced 

in dealing with live virus 

vaccines & CBER 

requirements mandatory. 

Integration of regulatory, 

bioprocess, analytical, 

clinical, clinical assay groups 

mandatory. Availability of 

well-integrated, thoughtful 

strategy, plan & timeline 

with project details 

projecting out through BLA 

would provide some 

assurance of technical knowhow. 

 

Other 

comments/ 

risks 

 
19 

Appendix D

Acronyms 
20 
21 

D. ACRONYMS 

DHHS Department of Health and Human Services 

DoD Department of Defense 

DSB Defense Science Board 

FDA Food and Drug Administration 

GMP Good Manufacturing Practice 

ICH International Congress of Harmonization 

IND Investigational New Drug 

PFU Plaque Forming Unit 

SDTF Smallpox Downselect Task Force 

USAMRIID U.S. Army Medical Research Institute of Infectious Diseases 

USD(AT&L) Undersecretary of Defense for Acquisition, Technology, and 

Logistics 

WHO World Health Organization 
22