Needs and Recommendations for the United States Poliovirus Vaccine
Stockpile

Report of the Joint Working Group of the National Vaccine Advisory
Committee (NVAC) and Advisory Committee on Immunization Practices (ACIP)

**National Vaccine Advisory Committee Meeting**

**February 3-4, 2004**

###  

**TABLE OF CONTENTS**

WORKING GROUP MEMBERS & PARTICIPANTS 3

[EXECUTIVE SUMMARY 4](#executive-summary)-6

[JOINT WORKING GROUP REPORT 7](#joint-working-group-report)-13

[SUMMARY 13](#summary)-14

[RECOMMENDATIONS 14](#recommendations-1)-15

[APPENDIX I 16](#appendix-i)-17

[REFERENCES 18](#references)-21

### 

###  

### 

+-----------------------------------+-----------------------------------+
| Working Group Members             |                                   |
+-----------------------------------+-----------------------------------+
| ACIP:                             | NVAC:                             |
+-----------------------------------+-----------------------------------+
| Guthrie Birkhead MD MPH           | Fernando Guerra MD                |
|                                   |                                   |
| Director, Center for Community    | San Antonio Metropolitan Health   |
| Health                            | District                          |
|                                   |                                   |
| New York State Department of      | San Antonio, TX                   |
| Health                            |                                   |
|                                   |                                   |
| Albany, NY                        |                                   |
+-----------------------------------+-----------------------------------+
| Samuel Katz MD                    | Charles Helms MD PhD, Chairman    |
|                                   |                                   |
| Wilburt C. Davison Professor      | Professor of Medicine             |
|                                   |                                   |
| Duke University Medical School    | University of Iowa Hospitals and  |
|                                   | Clinics                           |
| Durham, NC                        |                                   |
|                                   | Iowa City, IA                     |
+-----------------------------------+-----------------------------------+
| John Modlin MD                    | Alan Hinman MD MPH                |
|                                   |                                   |
| Professor of Pediatrics and       | Senior Consultant Public Health   |
| Medicine                          | Programs                          |
|                                   |                                   |
| Dartmouth Medical School          | Task Force for Child Survival and |
|                                   | Development                       |
| Lebanon, NH                       |                                   |
+-----------------------------------+-----------------------------------+
| ##### Working Group Participants  |                                   |
+-----------------------------------+-----------------------------------+
| National Vaccine Program Office:  | Food and Drug Administration:     |
+-----------------------------------+-----------------------------------+
| Bruce Gellin MD MPH               | Norman Baylor MD                  |
|                                   |                                   |
| National Vaccine Program Office   | Office of Vaccines Research and   |
|                                   | Review                            |
| Washington DC                     |                                   |
|                                   | Rockville, MD                     |
+-----------------------------------+-----------------------------------+
| **Centers for Disease Control and |                                   |
| Prevention:**                     |                                   |
+-----------------------------------+-----------------------------------+
| Lorraine Alexander RN MPH (Staff  | Charles LeBaron MD                |
| Author)                           |                                   |
|                                   | Kevin Malone                      |
| Jim Alexander, MD                 |                                   |
|                                   | Trudy Murphy MD                   |
| Victor Caceres MD MPH             |                                   |
|                                   | Walter Orenstein, MD              |
| Steve Cochi MD MPH                |                                   |
|                                   | Ismael Ortega PhD                 |
| Rex Ellington                     |                                   |
|                                   | Jane Seward MBBS MPH              |
| Demetria Gardner                  |                                   |
|                                   | Roland Sutter MD MPHTM            |
| John Glasser PhD                  |                                   |
|                                   | Margaret Watkins BSN MPH          |
| Hamid Jafari MBBS                 |                                   |
|                                   | Eddie Wilder                      |
+-----------------------------------+-----------------------------------+

Acknowledgements: Thanks to those vaccine manufacturers interviewed
regarding manufacturing issues in the development of an oral poliovirus
vaccine stockpile. We are also indebted to Pam Jenkins, MD PhD, of
Dartmouth Medical School for work on the decision analysis model.

# EXECUTIVE SUMMARY

**BACKGROUND:** Paralytic poliomyelitis was once an endemic disease in
the United States. High levels of vaccination eliminated the disease,
with the last case of wild disease occurring in 1979. Because of
vigorous international vaccination efforts, worldwide eradication of
paralytic poliomyelitis may be achieved in the near future. However, in
the interim before worldwide eradication is achieved, there is a risk
that wild virus may be imported into the United States. This risk,
coupled with the presence of under-vaccinated children in urban areas
and of under-vaccinated individuals in groups who refuse vaccines in
various communities, creates a potential risk for a polio outbreak. The
outbreak risk, while currently small, may increase if under-vaccination
or vaccine-refusal rates increase. Prudent public health preparedness
dictates that the nation be prepared to control and eliminate such polio
outbreaks should they occur before worldwide eradication is
accomplished.

In 1999, the ACIP recommended that inactivated poliovirus vaccine (IPV)
be used for routine immunization of the US population and that oral
poliovirus vaccine (OPV) be reserved for "mass vaccination campaigns to
control outbreaks of paralytic polio." The sole US manufacturer of OPV
has subsequently withdrawn from the market making implementation of this
recommendation in domestic outbreaks currently problematic.

**WORKING GROUP CHARGE AND PROCESS:** In February 2003, a joint working
NVAC/ACIP Working Group was charged to report to its parent bodies
concerning the needs for a poliovirus vaccine stockpile in the current
US context where IPV is manufactured and available but OPV is not. The
Working Group met seven times as a whole and over ten times in subgroups
in telephone conferences between February 2003 and January 2004 to
review and discuss issues inherent in the above charge and to draft this
report and recommendations.

### RECOMMENDATIONS:

**IPV Stockpile.** The current projection of 8 million doses of IPV for
the stockpile appears adequate. In the event of an outbreak in which OPV
continues not to be available, IPV should be used for control. Given the
lack of collateral spread of vaccine virus, high two or more dose
vaccination levels may need to be achieved among the previously
unvaccinated. In the future, should IPV be manufactured only in
combination with other vaccines, CDC should take appropriate procurement
actions to assure that non-combined IPV should continue to be available
for outbreak response. Even should an OPV stockpile become available, an
IPV stockpile will continue to be necessary in outbreak response in
order to raise immunization levels outside the outbreak zone and to
provide immunizations within the outbreak zone to those for whom OPV is
contraindicated or unacceptable.

**OPV Stockpile.** The Working Group feels that prudent preparedness
requires that the US have access to and be able to utilize a stockpile
of OPV effectively in the event of an outbreak. A quantity of 8 million
doses of trivalent OPV (tOPV) or 8 million of each of the three types of
monovalent OPV (mOPV) appears adequate.

**Overcoming Special OPV Stockpile Challenges.** In the absence of a
domestic manufacturer of OPV products, building an OPV stockpile will
likely require use of a non-licensed vaccine manufactured outside the
US. The regulatory and public health issues inherent in stockpiling and
using a non-licensed vaccine are substantial and make achieving this
objective difficult. Assertive facilitation at high levels of the
federal government and careful planning at the state and local level
will be required. For optimal public understanding, initial and periodic
updated explanations by the US Public Health Service and HHS of the
rationale and circumstances under which OPV would be used in an outbreak
will be needed.

> *[Regulatory Issues]{.underline}:* Many of the requirements to use of
> OPV in an outbreak could be eliminated if procedures existed for
> emergency US licensure of vaccines available in other nations.
> Creating procedures for such emergency US licensure should be
> investigated. In the meantime, the Office of the Health and Human
> Services (HHS) Secretary, Centers for Disease Control and Prevention
> (CDC), and Food and Drug Administration (FDA) should work together to
> assure that an appropriate Investigational New Drug protocol is
> developed and in place for creation of an OPV stockpile and effective
> utilization of OPV in case of an outbreak. To be prudent, this
> protocol should include both tOPV and mOPV, since, should mOPV become
> available, it may be preferable to tOPV.
>
> *[Collaboration with WHO and Other International
> Partners]{.underline}:* Rather than attempting to create a separate US
> stockpile of OPV, CDC and FDA should work with WHO and other
> international partners to help finance, create, and maintain a global
> poliovirus vaccine stockpile that provides the US with immediate and
> guaranteed access. This may involve acceptance by FDA of certification
> of OPV by organizations (e.g. UNICEF, WHO) other than itself.
>
> *[Collaboration with State and Local Health Authorities]{.underline}:*
> CDC should work with state and local health departments to develop
> plans for polio outbreak response. An OPV response plan should be
> available and include aggressive education and clear articulation on
> public health and individual benefits and risks of OPV**.** Obtaining
> consent for use of an unlicensed vaccine poses unique challenges in an
> emergency setting. Experience with planning for use of vaccinia and
> for bioterriorism events may provide useful insight into practical
> approaches to implement control measures in an outbreak of acute
> paralytic poliomyelitis. These should be explored, including novel
> approaches to rapidly obtain informed consent of potential vaccine
> recipients. Individuals, and their close contacts, at increased risk
> of adverse events with the use of OPV (e.g. immunodeficient patients)
> must be quickly identified. Informed consent must be obtained for all
> recipients. The consent must inform recipients that the Vaccine Injury
> Compensation Program will compensate adverse events in all age groups
> resulting from use of OPV under IND and that a licensed alternative
> (IPV) is available. The Working Group recognized that not all
> potential recipients will accept OPV, and that some potential
> recipients will not accept any poliovirus vaccine.

# JOINT WORKING GROUP REPORT

## INTRODUCTION: In February 2003, a joint NVAC/ACIP Working Group was charged to report to its parent bodies concerning the needs for a poliovirus vaccine stockpile in the current US context where IPV is licensed and available, but OPV is not.

## BACKGROUND:

**Poliovirus Infection and Disease.** Like other enteroviruses,
polioviruses replicate in the gut and the pharynx and are transmitted by
direct or indirect contact with stool and saliva^1^.  High rates of
transmission occur within households in all settings. Under good
hygienic conditions, community spread may depend on the oral-pharyngeal
route, while fecal transmission may enhance transmission in communities
with poor sanitation ^2-4^. Less than 1% of those who are infected with
poliovirus are paralyzed ^5^, which makes case-based surveillance for
poliovirus infection insensitive, but the virus can be detected in
sewage, making environmental surveillance possible ^6-8^. Once a global
disease, wild poliovirus was endemic in only 6 countries by 2003, as a
result of the WHO Global Eradication Program ^9^.

**Risk of a Wild Poliovirus Outbreak in the US.** The last case of wild
polio occurred in the US in 1979 ^10^ and in the Western Hemisphere in
1991 ^11-13^.  Data from the 2002 National Immunization Survey suggest
that, among 78 state/local grantees, the lowest two-dose polio
vaccination coverage was 93% (unpublished data, CDC ), and 86% to 100%
school age children had received at least 3 doses of poliovirus vaccine
^14^. The threshold of polio herd immunity is thought to be 60%-80%
^15,\ 16^.

However, polio outbreaks have occurred in Western Europe among poorly
immunized populations living in an environment of high coverage ^15^. In
Finland, ten polio cases occurred despite 80% coverage when a wild virus
was imported for which Finnish vaccine provided inadequate immunity
^17,\ 18^. In the Netherlands, hundreds of cases occurred among poorly
immunized members of a conservative religious sect despite data
suggesting general population immunity \>90% ^19-21^. In 1979, outbreaks
of poliomyelitis that occurred in Amish communities refusing
immunizations in the United States and Canada were determined to have
been imported from the previous Netherlands epidemic ^22^ ^10^.
Additionally, the US measles resurgence suggests that pockets of urban
under-immunization, combined with in-migration from countries with low
immunization rates and active disease transmission, can provide
opportunities for sustained epidemics of vaccine-preventable diseases
^23-25^. Thus, the risk of a naturally occurring US polio outbreak is
low, but not zero.

The risk of a polio bioterrorism attack is difficult to evaluate.
Although, poliovirus has been synthesized in a laboratory, ^26,\ 27^
synthesized or naturally occurring wild poliovirus would not appear to
represent an ideal biologic weapon if directed against the US or other
developed nations. This is because: (1) viral communicability is low
compared to other pathogens;^28^ (2) viral spread is impeded by high
levels of hygiene as present in the US and other developed nations;^16^
(3) 99% of those infected do not develop paralysis; ^29^, and (4) polio
immunization levels are currently high in the US ^14,\ 30^.
Internationally, polio immunization levels may exceed those for other
vaccines because of eradication efforts ^31-33^.

In the current context, the need for a poliovirus vaccine stockpile
would be based on prudent public health preparedness, rather than data
suggesting the high likelihood of an impending outbreak or attack.

### Poliovirus Vaccines.

> *[Oral Poliovirus Vaccine (OPV)]{.underline}:* OPV is a live
> attenuated vaccine that replicates in the gut and pharynx. Infection
> induces humoral immunity (protecting against paralysis), as well as
> gut and pharyngeal immunity (protecting against wild virus replication
> and transmission).  Even before immunity is established, replication
> of the vaccine virus in the gut/pharynx may interfere with wild virus
> replication ^34^. Transmission of the vaccine virus through stool and
> saliva provides secondary vaccination and boosting to contacts ^16^.
> Vaccine virus can revert to a neurovirulent form ^35^ and rarely cause
> paralysis (approximately one case per 750,000 OPV-naïve vaccinees)
> ^36-38^. Where coverage is low, vaccine-derived neurovirulent strains
> can circulate in the community ^39,\ 40^. Because of ease of oral
> administration and low cost on the global market (pennies a dose), OPV
> is the vaccine of choice throughout the developing world and in many
> developed nations as well ^16,\ 41^. In the US, it was the primary
> vaccine from the early 1960s until 2000 when its use was discontinued
> because the risk of paralysis of vaccinees appeared to outweigh the
> risk of wild type disease ^42,\ 43^. Both domestically and
> internationally, OPV has a long record of effective outbreak control
> ^15,\ 16,\ 44^. OPV can be administered either as a trivalent
> formulation (tOPV, including all three polio serotypes) or three
> different monovalent formulations (mOPV1, mOPV2, mOPV3) each
> consisting of only one polio serotype. Monovalent OPV induces
> type-specific immunity more quickly than tOPV (generally one dose of
> mOPV provides type-specific protection equivalent to two doses or more
> of tOPV), but only protects against the single serotype present in the
> formulation, leaving the vaccinee potentially susceptible to the other
> two serotypes ^45^. Monovalent OPV is not licensed for use anywhere in
> the world, but in a post-eradication environment mOPV may become the
> vaccine of choice for outbreak control because of its high single-dose
> protection and inability to introduce the other two OPV types into
> circulation.
>
> *[Inactivated Poliovirus Vaccine (IPV)]{.underline}:* IPV is a killed
> vaccine containing all three polio serotypes. It induces humoral and
> pharyngeal immunity equivalent to OPV, but less gut immunity -- thus
> it may permit more wild virus transmission than OPV in certain
> settings ^34^.  It does not provide interference with wild virus
> replication in the gastrointestinal tract nor is it transmitted to
> non-immune contacts. However, for the same reason, it would not create
> the risks of reversion to neurovirulence or production of circulating
> vaccine-derived strains. Two or more doses are required to provide
> adequate protection ^46^. Though IPV was used to eliminate polio in
> four European nations and reduced disease by 96% within five years of
> introduction in the US, IPV has not been used for outbreak control
> since the 1950s ^47^.

**ACIP Position on OPV Use in Outbreaks.** On June 17, 1999, the ACIP
recommended that as of January 1, 2000, all US children should receive
routine vaccinations as IPV because the risk of vaccine-associated
paralysis with OPV appeared to exceed the risk of paralytic disease with
wild virus ^42,\ 43^. Nevertheless, because of the literature suggesting
biologic advantages to OPV over IPV in outbreak control and the
extensive outbreak-control experience with OPV compared to IPV, the ACIP
recommended that OPV be utilized in "mass vaccination campaigns to
control outbreaks of paralytic polio" ^48^.

**Status of Poliovirus Vaccine Stockpile.** IPV has been the sole
poliovirus vaccine available in the US since 2000, and a stockpile of 4
million doses of trivalent IPV already exists, with a goal of 8 million
doses by 2005^49^. Neither tOPV nor mOPV is available in the US, nor is
a current stockpile of OPV available. Hence, in the event of an outbreak
of polio, the US would be unable to adhere to the ACIP recommendation
for use of OPV in outbreak control.

**Joint NVAC/ACIP Poliovirus Vaccine Stockpile Working Group.** In
February 2003, the Working Group was formed consisting of members from
the National Vaccine Advisory Committee and the Advisory Committee on
Immunization Practices and participants from academic medicine, local
public health, the Food and Drug Administration (FDA), non-governmental
organizations, and CDC. It was charged with evaluating the polio-
vaccine stockpile situation and providing recommendations to assure the
adequacy of polio outbreak-control preparedness. The Working Group
decided that this question was best evaluated in four components: 1)
rationale for the selection of vaccine for the stockpile, 2)
characteristics of the stockpile, 3) manufacturing factors, and 4)
implementation issues. These components were addressed by four
subgroups. Input was solicited from, among others, the World Health
Organization and pharmaceutical firms that might manufacture OPV for the
stockpile. Reports by the subgroups were edited and approved by the
overall Working Group and form the basis for the overall report that
follows below.

## RATIONALE FOR A POLIOVIRUS VACCINE STOCKPILE

The United States currently maintains a very high overall level of
immunity against poliomyelitis, but immunization rates have been low in
the past ^50-52^ and under-immunization remains a concern, particularly
among pre-school aged children residing in disadvantaged communities.
Susceptibility rates may be increasing among these populations because
OPV viruses are no longer circulating. Should IPV immunization rates
decline in the future for any reason, the degree of concern would
increase. The inclusion of IPV in childhood combination vaccines may
reduce the risk of declining polio immunization rates, but might make
non-combined IPV unavailable for outbreak control.

The susceptibility level required to prevent transmission of virulent
polioviruses within a community is not known. Outbreaks of wild type
polioviruses have occurred with immunization levels of \< 60% in
affected populations in the Netherlands ^53,\ 54^ ^19^, and more
recently with vaccine-derived virulent polioviruses in Haiti, the
Philippines, Egypt and Madagascar ^39,\ 40,\ 55,\ 56^.

The theoretical advantages of OPV for outbreak control have not been
subjected to a controlled trial, and have been neither proven nor
disproven by experience in a country or region that has controlled
poliomyelitis. A recent decision analysis model developed during the
activities of the Working Group (Appendix I) and a review by Caceres et
al ^45^ suggests that monovalent OPV vaccine would be the most
advantageous strategy for outbreak control, especially since optimum
control can be achieved with one dose. The model predicts that OPV would
have a slight advantage over IPV for outbreak control. Since both tOPV
and IPV require at least two doses to achieve adequate protection, the
number of doses appears more important than which vaccine is used.

Outbreaks are not environments in which randomized vaccine trials are
easily conducted, so the above assessment is unlikely to change.
Existing data do not demonstrate the need for a tOPV stockpile to
supplement the already-existing IPV stockpile, but existing data also do
not demonstrate that a tOPV stockpile would never be needed under any
circumstance. Stockpiles are specifically developed for unlikely
situations. In a context where polio vaccination coverage has been low
in the past and where the potential exists for use of poliovirus as a
weapon of bioterrorism, an inclusive and consensus approach to a
poliovirus vaccine stockpile appears prudent, particularly where the
safety of the nation is involved.

Data available suggest that use of the current IPV stockpile would
probably be sufficient to control outbreaks in the United States under
current circumstances of high overall immunity. However, circumstances
may change, and it would be prudent for the US to create a mechanism to
access the large stores of tOPV currently available on the international
market. Should safe and effective mOPV become available to the US
through either a domestic or a global manufacturer, it should be the
preferred formulation.

## CHARACTERISTICS OF POLIOVIRUS VACCINE STOCKPILE

**IPV.** The IPV stockpile currently has 4 million doses on hand, with a
goal of 8 million doses, or enough to provide the US birth cohort with
two-dose protection -- but the primary purpose of this stockpile is to
overcome a temporary manufacturing shortage, rather than outbreak
control. Nevertheless, these quantities should be more than sufficient
for outbreak control in the current context where OPV is not available.
Should OPV become available for outbreak control, the IPV stockpile
would be needed for rapid improvement of routine immunization levels
outside the outbreak zone and for use within the outbreak zone among
those persons with conditions for whom OPV is contraindicated (e.g.,
AIDS).

OPV.

> *[Type:]{.underline}* Monovalent OPV has advantages over trivalent OPV
> in polio outbreak control and may eventually be the vaccine of choice
> in response to a polio outbreak. However, monovalent OPV is not
> currently licensed anywhere in the world, and trivalent OPV is the
> vaccine of choice for routine vaccination in most nations as well as
> the only vaccine used for outbreak control globally. The United States
> has extensive prior experience with administration of tOPV. Therefore,
> at this time, the trivalent, rather than monovalent, formulation is
> the only practical alternative for an OPV stockpile. In a
> post-eradication environment, with global outbreak control relying on
> monovalent OPV, this recommendation should be reexamined.
>
> *[Quantity of Doses:]{.underline}* Given existing high levels of
> vaccination, the stockpile need not provide doses for vaccination of
> the entire US population. For the worst plausible case scenario, an
> outbreak centered in an inadequately vaccinated urban population, 8
> million doses should be enough to provide control. We would optimally
> want sufficient supply for two doses for children \< 5 years of age
> regardless of vaccination status; should this occur in a large city
> (i.e. 125,000/year birth cohort) we estimate a maximum need of 1.25
> million doses. Eight million doses would cover six large city
> outbreaks or two doses for one entire US birth cohort. A stockpile
> consisting of a larger number of doses would be appropriate if
> vaccination coverage in the U.S. population declines. (Note: WHO has
> an outbreak protocol under development. The number of doses may need
> to be re-examined based on finalization and adaptation of the protocol
> to the US environment). Since international health organizations may
> create OPV stockpiles of hundreds of millions of doses, access to such
> stockpiles would be more than adequate for any US outbreak. Rapid and
> unfettered US access to such international stockpiles would need to be
> guaranteed, in the event of a domestic outbreak, for this cooperative
> approach to fulfill the requirements of national security.
>
> *[Standards of Quality:]{.underline}* Since OPV is not currently
> licensed in the US, production would be outside the US and not subject
> to normal FDA standards of quality control for licensed vaccines.
> However, vaccine in the stockpile should be produced by manufacturers
> approved by UNICEF for production of OPV and meet the standards
> required by FDA for investigational new drugs in the US.

## MANUFACTURING ISSUES FOR A POLIOVIRUS VACCINE STOCKPILE:

**IPV.** The IPV stockpile has encountered few manufacturing issues,
since IPV is the only licensed US poliovirus vaccine and acquisition of
additional vaccine for creation of a stockpile is only a question of
procurement and cost. These issues may become more complex if IPV is
only manufactured as a combination product with other vaccines, in which
case special procurement issues will need to be addressed to assure an
adequate supply of IPV for outbreak control.

**OPV.** Since OPV is only manufactured outside the US, a variety of
complex issues arises. Of four pharmaceutical firms currently certified
by WHO for manufacture of OPV internationally, the Working Group
interviewed representatives of two firms.

> *[Production Capacity:]{.underline}* Each company distributes OPV to
> more than 60 nations, supplies the world with 800 million doses of
> vaccine annually, and expects to continue production at this rate in
> the near future. Both companies expressed that they would be readily
> able to supply 8 million doses for the US stockpile and have adequate
> "surge capacity" to handle more production for US needs. They
> anticipate that this "surge capacity" will increase as the demand for
> OPV internationally diminishes with progress toward polio eradication.
> Charges for OPV were not disclosed by the companies, but they
> indicated that this information could be obtained from WHO or UNICEF.
> If special US requirements were imposed, prices would be higher.
> Cold-chain, potency testing, and safety protocols are followed, as
> required by WHO. One company currently supplies mOPV to two countries
> in bulk form and would be willing to supply it to the US in this form;
> the other company was not interested in discussing monovalent OPV.
>
> *[Regulatory Issues:]{.underline}* Both companies are certified by WHO
> to manufacture tOPV and each vaccine is licensed in the country in
> which each manufacturer is situated, but not in the US. Neither
> company would be interested in submitting a Biologics License
> Application for tOPV to the US Food and Drug Administration (FDA) for
> evaluation and eventual licensure, nor in submitting an
> Investigational New Drug (IND) application to the FDA to obtain
> permission for use of a non-licensed vaccine. However, if CDC were to
> submit the IND, they would consider participating in the stockpile,
> although the formulation would need to be the same as for WHO/UNICEF
> requirements. Both companies stated that, although their production
> facilities and practices meet WHO standards, FDA standards were
> different and in certain areas more stringent. It would require
> substantial outlays to upgrade their facilities and practices to meet
> the FDA periodic inspections, outlays that might well exceed the cost
> of the stockpiled vaccine, perhaps many-fold. Additionally, it is
> unlikely that either company would be willing to invest money and time
> into performing clinical and toxicology studies if the FDA were to
> require it.

Both companies anticipate that labeling issues would be a dominant
consideration in production. If the vaccine were labeled for WHO/UNICEF
use, the vaccine could not be used in the US, but if produced with a US
IND label, the product could not be rotated for use to other countries.
Hence, creating a "bulge in the supply chain" would be administratively
difficult, particularly given the relatively small number of doses
needed by the US stockpile compared to international needs. A dedicated
US stockpile of IND-labeled vaccine with periodic destruction of
out-dated lots appeared administratively simpler and less costly to the
manufacturers than attempting to produce a "multi-use" product. The
companies would store the vaccine in their respective home countries.
Given a preformed stockpile of US labeled product, speed of delivery
would depend only on speed of transportation, in theory as short as
overnight shipment. Neither company would invest in production of OPV
for a US stockpile unless these regulatory issues were resolved, and a
contract in place. US collaboration with the WHO and UNICEF may help
overcome OPV manufacturing challenges.

## IMPLEMENTATION ISSUES FOR A POLIOVIRUS VACCINE STOCKPILE:

**IPV.** Since IPV is the only vaccine in routine use in the US, and an
IPV stockpile already exists, IPV use in polio outbreak control would
proceed in the same fashion as with any other vaccine-preventable
disease.

**OPV.** Since OPV is not manufactured in the US, the creation and
utilization of an OPV stockpile raises issues not previously encountered
in outbreak control. Presently, OPV could only be administered in the US
under an IND protocol accepted by FDA. Since no OPV supply chain exists
in the US, the stockpile would necessarily be located outside the US,
requiring special transportation arrangements for speedy use. As an IND,
OPV would need to be administered under a research protocol, involving
informed consent for the potential adverse effects of OPV, including the
risk of paralysis that caused its removal from the US market.  The
advance of medical treatments and increasing prevalence of disease
states associated with immune deficiency has created a larger population
for whom OPV would be contraindicated. The logistics of such protocols
and the potential liability for providers might well preclude
participation by most health professionals in the private sector who
currently administer 50%-75% of routine vaccinations in the US ^57^.
Each outbreak "study subject" would have to be offered the option of
IPV. Public educational efforts would be needed to convince such
subjects to expose themselves to the risk, however small, of vaccine
paralysis, when tOPV offers no advantage over IPV in personal protection
against paralysis from wild disease.

## SUMMARY

Biologic considerations, recent decision analysis results, and a long
successful history of outbreak control suggest that OPV, particularly in
monovalent formulation, has advantages over IPV in control of outbreaks
of polio. Though an IPV stockpile already exists, and can be accessed
swiftly and easily for outbreak control in the US, no stockpile of OPV
currently exists. Regulatory issues in the creation of an OPV stockpile
for the US must be considered well in advance of any polio outbreak.

# RECOMMENDATIONS

**IPV Stockpile.** The current projection of 8 million doses of IPV for
the stockpile appears adequate. In the event of an outbreak in which OPV
continues not to be available, IPV should be used for control. Given the
lack of collateral spread of vaccine virus, high two or more dose
vaccination levels may need to be achieved among the previously
unvaccinated. In the future, should IPV be manufactured only in
combination with other vaccines, CDC should take appropriate procurement
actions to assure that non-combined IPV should continue to be licensed
and available for outbreak response. Even should an OPV stockpile become
available, an IPV stockpile will continue to be necessary in outbreak
response in order to raise immunization levels outside the outbreak zone
and to provide immunizations within the outbreak zone to those for whom
OPV is contraindicated or unacceptable.

**OPV Stockpile.** The Working Group feels that prudent preparedness
requires that the US have access to and be able to utilize a stockpile
of OPV effectively in the event of an outbreak. A quantity of 8 million
doses of trivalent OPV (tOPV) or 8 million of each of the three types of
monovalent OPV (mOPV) appears adequate.

**Overcoming Special OPV Stockpile Challenges.** In the absence of a
domestic manufacturer of OPV products, building an OPV stockpile will
likely require use of a non-licensed vaccine manufactured outside the
US. The regulatory and public health issues inherent in stockpiling and
using a non-licensed vaccine are substantial and make achieving this
objective difficult. Assertive facilitation at high levels of the
federal government and careful planning at the state and local level
will be required. For optimal public understanding, initial and periodic
updated explanations by the US Public Health Service and HHS of the
rationale and circumstances under which OPV would be used in an outbreak
will be needed.

> *[Regulatory Issues]{.underline}:* Many of the requirements to use of
> OPV in an outbreak could be eliminated if procedures existed for
> emergency US licensure of vaccines available in other nations.
> Creating procedures for such emergency US licensure should be
> investigated. In the meantime, the Office of the Health and Human
> Services (HHS) Secretary, Centers for Disease Control and Prevention
> (CDC), and Food and Drug Drug Administration (FDA) should work
> together to assure that an appropriate Investigational New Drug
> protocol is developed and in place for creation of an OPV stockpile
> and effective utilization of OPV in case of an outbreak. To be
> prudent, this protocol should include both tOPV and mOPV, since,
> should mOPV become available, it may be preferable to tOPV.
>
> Obtaining consent for use of an unlicensed vaccine poses unique
> challenges in an emergency setting. Experience with planning for use
> of vaccinia and for bioterriorism events may provide useful insight
> into practical approaches to implement control measures in an outbreak
> of acute paralytic poliomyelitis. These should be explored, including
> novel approaches to rapidly obtain informed consent of potential
> vaccine recipients. Individuals, and their close contacts, at
> increased risk of adverse events with the use of OPV (e.g.
> immunodeficient patients) must be quickly identified. Informed consent
> must be obtained for all recipients. The consent must inform
> recipients that the Vaccine Injury Compensation Program will
> compensate adverse events in all age groups resulting from use of OPV
> under IND and that a licensed alternative (IPV) is available. The
> Working Group recognized that not all potential recipients will accept
> OPV, and that some potential recipients will not accept any poliovirus
> vaccine.
>
> *[Collaboration with WHO and Other International
> Partners]{.underline}:* Rather than attempting to create a separate US
> stockpile of OPV, CDC and FDA should work with WHO and other
> international partners to help finance, create, and maintain a global
> poliovirus vaccine stockpile that provides the US with immediate and
> guaranteed access. This may involve acceptance by FDA of certification
> of OPV by organizations (e.g. UNICEF, WHO) other than itself and will
> require legislation.
>
> *[Collaboration with State and Local Health Authorities]{.underline}:*
> CDC should work with state and local health departments to develop
> plans for polio outbreak response. An OPV response plan should be
> available and include aggressive education and clear articulation on
> public health and individual benefits and risks of OPV**.**

### APPENDIX I

## DECISION ANALYSIS MODEL

Because a multiplicity of factors could affect the success of any polio
immunization strategy for outbreak control, and the influence of any one
factor is difficult to estimate, we chose to construct a decision
analysis model in which different vaccination strategies could be
compared quantitatively, and the effect of variable input assumptions
could be assessed. This work was performed at Dartmouth Medical School
by Pamela Jenkins, M.D. and John Modlin, M.D., with considerable
assistance from Victor Caceres, M.D., Margaret Watkins, M.P.H., Trudy
Murphy, M.D., Lorraine Alexander, M.P.H., and Charles LeBaron, M.D. from
CDC.

Seven poliovirus vaccine strategies were compared with a "do nothing"
response in which no supplemental vaccine is given by the use of a
non-dynamic decision tree in which it assumed that spread of virulent
polioviruses would continue to occur in the population at risk until
there was sufficient herd immunity to interrupt transmission. The
variables included in the model (Table 1) are based on data from the
literature when available, or are imputed from available data. The
outcomes are based on a hypothetical outbreak in the year 2010 when all
children under 10 years would have been eligible for IPV only and would
not have been exposed to live polioviruses.

#### Table 1. 

Variable assumptions included in the model.

+-----------------------------------------------------------------------+
| 1.  Proportion of population who have received 3 doses of IPV         |
+-----------------------------------------------------------------------+
| 2.  Proportion of population who have received 3 doses of tOPV        |
+-----------------------------------------------------------------------+
| 3.  Proportion of unimmunized population who are immune from exposure |
|     to OPV viruses                                                    |
+-----------------------------------------------------------------------+
| 4.  Proportion of population exposed to virulent polioviruses         |
+-----------------------------------------------------------------------+
| 5.  Likelihood of infection with virulent polioviruses based on past  |
|     vaccination history                                               |
+-----------------------------------------------------------------------+
| 6.  Rate of paralysis per number of poliovirus infected persons in    |
|     non-immune persons                                                |
+-----------------------------------------------------------------------+
| 7.  Proportion of population immunized in response to the outbreak    |
+-----------------------------------------------------------------------+
| 8.  Seroconversion rates following implementation of each vaccine     |
|     strategy                                                          |
+-----------------------------------------------------------------------+
| 9.  Proportion of population exposed to circulating OPV viruses       |
+-----------------------------------------------------------------------+
| 10. Risk of OPV-associated paralytic poliomyelitis                    |
+-----------------------------------------------------------------------+

(Table 2) shows the number of cases of paralytic poliovirus infection
predicted for types 1, 2, and 3 by the model. Strategies employing
monovalent OPV vaccines resulted in the fewest cases of paralysis, and
one mOPV dose was as effective as two doses. The mOPV strategies were
modestly more effective than the two dose strategies employing tOPV or
IPV. The two-dose tOPV and IPV strategies were generally superior to the
one dose tOPV and the one-dose IPV strategies and the advantage of tOPV
over IPV when given in two doses was small.

#### Table 2. 

### Predicted Cases of Paralytic Poliomyelitis, per 100,000 population. 

  -------------- -------------- -------------- -------------- --------------
  **Vaccine**    **\# Doses**   **Type 1**     **Type 2**     **Type 3**

  mOPV           2 doses        9              8              10

  mOPV           1 dose         9              8              11

  tOPV           2 doses        12             8              11

  IPV            2 doses        15             10             16

  tOPV           1 dose         19             14             16

  IPV            1 dose         25             25             26

  do nothing     n/a            36             33             41
  -------------- -------------- -------------- -------------- --------------

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