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OCR for page 98
4
Operational and Institutional Challenges
to Post-Eradication
OVERVIEW
The greatest impediment to eradication is the accidental or intentional
reintroduction or re-emergence of infection. Non-human reservoirs of in-
fection, accidental reintroduction from a stasis reservoir, reversion of the
vaccine strain virus to virulence, recombination between vaccine and wild-
type virus, the evolution of new viruses, ecological niches left vacant after
vaccination, and malevolent intent are all potential sources of reintroduc-
tion for which we need to be fully prepared.
Reintroduction could strike anywhere. Increased movement of people
across international borders complicates the challenge of combating unex-
pected disease outbreaks and preventing global spread. Prevention of rein-
troduction requires detecting infection while outbreaks are still locally
confined, which means that a national surveillance system supported by
accurate laboratory-based diagnosis must be firmly established. In addition
to serving as a regulatory framework for global surveillance, the proposed
revision of the International Health Regulations (IHR) provides a func-
tional and effective template for national surveillance in countries that do
not already have an effective system in place.
One of the greatest challenges in the IHR revision process is ensuring
that reporting of public health risk expands to all urgent international
public health events, instead of focusing only on specific diseases. Countries
and institutions need to be able to act as a network of networks in order to
identify and limit the damage caused by new outbreaks, while simulta-
98
OCR for page 99
OPERATIONAL/INSTITUTIONAL CHALLENGES TO POST-ERADICATION 99
neously minimizing unnecessary overreaction, economic hardship, and so-
cial instability.
In many countries, global eradication priorities override local health
priorities. In the past, this has been justified by cost-effectiveness analyses
demonstrating the enormous savings expected when an infectious agent is
declared eradicated. Now, however, we are beginning to realize that
strengthening local health service infrastructures can operate synergistically
with global priorities. Indeed, empowering communities with the resources
to manage their public health problems in a self-reliant way is the best
framework for dealing with disease outbreaks.
Finally, prevention of reintroduction requires the safe containment of
post-eradication agents in order to protect against accidental or intentional
transmission of eradicated agents. Good practices are needed for the acqui-
sition, preservation, authentication, and `distribution of infectious materials
for legitimate research and clinical purposes. Heightened laboratory con-
tainment and security will be an increasingly essential part of the biological
research infrastructure in the post-immunization era.
REVISION OF THE ~ERNATIONAL HEALTH REGULATIONS:
PROGRESS REPORT
Mario Libel, M.D., M.P.H.
Epidemiologist, Communicable Diseases Program
Division of Disease Prevention and Control
Pan American Health Organization, Washington, D.C.
a:
The International Health Regulations (IHR) were the first multilateral
initiative for the surveillance of cross-border transmission of infectious
diseases. They are currently the only binding set of regulations on global
surveillance for infectious diseases by WorId Health Organization (WHO)
member states. In response to the threat of cross-border transmission posed
by substantial increases in international travel, the World Health Assembly
(WHA) requested the revision of the IHR in 1995. The original public
health protection measures for international travelers, conveyances, goods,
and cargoes will remain in the revised IHR, but they will be subject to
review and consultation.
The fundamental principle of the IHR is to ensure maximum security
against international spread of disease with minimum interference with
world traffic and trade. To achieve this purpose, the present IHR oblige
member states to notify WHO of cholera, plague, and yellow fever out-
breaks in their territories, list the maximum measures applicable during
such outbreaks (based on evidence-based information), and make rules for
OCR for page 100
100
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
international traffic. Listing maximum allowable measures is essential for
preventing overreaction which could damage tourism, traffic, and trade
and lead to unnecessarily harsh economic consequences. During the early
l990s, for example, a cholera epidemic in the Americas cost Andean coun-
tries more than $1 billion because maximum allowable measures had not
been defined. These measures should be based on evidence-based informa-
tion.
Although the IHR are the only international, legally binding too! for
public health, they have limited use for the following reasons:
· They stipulate regulations for only three diseases (i.e., cholera
plague, and yellow fever).
· They render WHO wholly dependent upon the country suffering
the outbreak to make the official notification.
· They do not provide a mechanism for collaboration between mem-
ber states and WHO.
They lack event-specific measures and incentives for compliance.
.
With these major constraints in mind, key changes have been proposed
to develop an IHR that would adapt to emerging trends in 21st-century
epiclemiology and global travel.
Revised Core Concepts
Although there are some new core concepts proposed for the revised
IHR, most of the changes involve developing and fine-tuning already extant
rules:
Surveiliance
The new IHR will neither contain a list of notifiable diseases nor de-
pend solely on the use of syndromes for notification. Instead, they will
require the reporting of all "events of urgent international importance re-
lated to public health." The reason for this is two-fold. First, in the present
world of new and re-emerging diseases, any disease list could immediately
become obsolete. Second, a case of a disease in and of itself does not always
pose a danger of international spread or impact. The disease must be
coupled to circumstances, such as place, time, size of outbreak, closeness to
an international border or airport, speed of spread, mode of transmission,
and so on.
Thus, routine occurrence of endemic diseases will not be notifiable
under the revised IHR, and countries will not be able to send off reports
about diagnosed cases in an automatic fashion. When there is an event with
OCR for page 101
OPERATIONAL/INSTITUTIONAL CHA FLENGES TO POST-ERADICATION 1 01
possible international consequences, the national administration must
quickly decide if the event fulfills the WHO criteria and should be reported
to WHO. The new IHR will contain a test to help administrators decide if
an event is both urgent and international. An early draft of the algorithm,
which was tested during the Syndrome Pilot Study, contained the following
parameters:
High potential for spread outside the community/country,
Unexpectedly high case fatality ratio,
Unusual or unexpected event,
Country capacity to control and contain the event,
High international media profile,
Potential for imposition of trade/traffic barriers by other countries,
· Occurring in a high-density/urban area,
· Significant possibility of international transport of infected persons
or contaminated goods/conveyances, and
· Significant possibility of vector transport.
Communication
Because the new IHR will cover a much wider span of public health
events and outbreaks, and because these events may happen very quickly,
24-hour communication with WHO is critical. Information may need to be
distributed nationally to hospitals, health officials, ports, and airports very
quickly. Each member state should have a single, focal e-mail address that
leads to someone who is available at all times. This requires a reliable
electronic communication and back-up system within each member state.
Reporting Capaciry
a:
In order to ensure the quick dissemination of information regarding
urgent national events of potential international importance, each country
must have the capacity to quickly report, analyze, and determine the poten-
tial effect of national disease events on other member states. This will
require surveillance systems that allow for rapid analysis and transfer of
information on unusual and unexpected events from the periphery to the
center.
The revised IHR will contain a recommended template for core require-
ments for a national surveillance system. In many countries, this surveil-
lance/analysis capacity may already be in place. Others may need a grace
period to fulfill this IHR requirement, and external assistance and funding
may be necessary; the template could be used for defining core surveillance
needs to national health sectors and external donors.
OCR for page 102
102
Notification
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
Member states will have the option to make confidential, provisional
notifications to WHO. Currently, the IHR automatically lists notified cases
in the Weekly Epidemiological Record (WER). However, in the early days
of an event, it is often unclear if the criteria for an urgent international
event are fulfilled. With this proposed change, member states will have the
option to contact WHO on a provisional basis before any information is
made public. The member state and WHO can work together to assess the
extent and potential impact of the event anal issue a joint statement. By
collaborating with WHO before making a statement, the member state
would gain credibility ant! reduce the likelihood of overreaction.
Information
Other information in addition to official notifications will be used by
WHO to help identify and control urgent international events, and member
states will respond to requests from WHO to verify the reliability of this
information. Urgent international events often reach the global information
super-highway and become news even before the most efficient administra-
tion has had time to react to the events and make any sort of official
notification. To prevent threatened countries from responding to unverified
news by restricting cross-border traffic and trade, WHO will need to in-
form member states and issue recommendations on appropriate measures.
Economic Considerations
In order for a global surveillance system to function well, the economic
consequences of reporting disease events must be considered. If the WHO
notification and response system cannot help to reduce tourism and trade
losses to what is strictly required from a public health perspective, compli-
ance with IHR reporting and notification obligations will likely be ignored
by member states. Thus, the new IHR will establish a template for measures
to protect other member states from unnecessary economic losses. These
measures will be based on the actual public health threat or impact of the
event, as determined by all available evidence. Establishing these guidelines
will require input from all WHO departments involved in goods, such as
Food Safety, Environment, Pharmaceuticals, as well as a plethora of exter-
nal stakeholders.
Assistance
Many countries may neecl external assistance after provisional notifica-
tion or a request from WHO for further information. Under the new gu~de-
OCR for page 103
OPERATIONAL/INSTITUTIONAL CHALLENGES TO POST-ERADICATION 1 03
lines, WHO will be obligated to assist member states in rapidly assessing
and controlling outbreaks. If the extent and potential threat of the outbreak
is unclear, WHO will offer to send a response team to collaborate with the
member state government in controlling disease spread and minimizing
economic damage.
By working with ~IO, the affected country would receive interna-
tional recognition for its effort to prevent international spread, which should
reduce unnecessary economic hardship. The capacity of WHO to react and
assist in outbreaks, even when there are multiple outbreaks occurring si-
multaneously, must be improved.
Recommendations
A transparent, decision-making process will be established within WHO
to issue recommendations for member state action in case of imminent risk
of international disease spread. These recommendations could be ctirectect
either at the affected country, at all other member states, or both. This will
require a quick gathering of wide, representative consensus.
Preventive Measures
lust as it is impossible to list diseases, there is no way to describe
appropriate measures for each event in advance. However, the revised IHR
will contain a list of all key measures that could potentially be used in a
WHO recommendation to prevent international disease spread at embarka-
tion, during travel, and at point of entry. Some examples of measures
potentially applicable at point of entry into non-affected member states
from an affected member state are shown in Table 4-1.
During an urgent health event, TRIO would use appropriate measures
from the complete list as a basis for a recommendation to member states.
The recommendation wouIct be time-limited for the event, so a clear proto-
co! for ending the measures would need to be included. To create the
flexibility required to adapt to each major international threat, non-binding
recommendations will have to replace the fixed, binding measures in the
current IHR.
Review Process
A permanent IHR review body will be established in order to build
continuity within the IHR process. Lack of a mandatory review process has
rendered the existing IHR out-of-date. Plus, the new IHR will have much
broader provisions and will require continuous interpretation and prece-
dents setting.
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104
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
TABLE 4-1 Measures Potentially Applicable at Point of Entry into
Non-affected Member States from an Affected Member State
Travelers
Goods and Conveyances
-require travel history in affected country -require inspection of conveyance, cargo,
-require proof of medical examination or goods
-require medical examination on entry -require treatment of conveyance, cargo, or
-require proof of vaccination or
prophylaxis
-require vaccination or other prophylaxis goods
for entry -require destruction of cargo or goods
-require protective measures for suspected -refuse entry of conveyance, cargo, or
cases
-active or passive medical surveillance
if travel from affected area
-isolation of traveler for incubation
period of disease
-refuse entry of persons from affected area
goods
-require isolation of conveyance, cargo, or
goods
The Role of WHO
The new IHR will provide global regulatory guidelines for how to
respond to international disease threats, the implementation of which WHO
will coordinate. Even though the best way to prevent international spread
of disease is to detect public health threats early and stamp them out when
they are still a small, local problem, national efforts often require interna-
tional coordination. Many countries need assistance from multilateral insti-
tutions for their national surveillance systems. Plus, even localized national
events can quickly affect international traffic. Thus, an international coor-
dinator is critical for standardizing notifications, responses from other coun-
tries, and the global exchange of epidemiological information. Effective
notification of disease events to WHO will be facilitated by an assurance of
how this information will affect member states' economic interests. All of
the various functions that TRIO would serve as international coordinator
in response to a disease event are included in Figure 4-1.
IHR Benefits to Member States
The new IHR will benefit member states in a variety of ways:
National surveillance systems will need to be improved.
Modern communication systems for detecting and responding to
OCR for page 105
OPERATIONAL/INSTITUTIONAL CHALLENGES TO POST-ERADICATION 1 05
1. Media scans,
media reports
2. Provisional
notification to
WR, RO, HO
3. Official _
notification from
Member State
_
country c oes
Contact country to not verify
verify
Potential urgent
international event
verified
Offer assistance
work with Member Provisional
State; possibly status ending
sending team
Yes, urgent
international event
1
' . 1
. Together with
affected MS notify
all others
. ,
Recommendations
issued
1
Continuing reappraisal of evidence
of situation
Event controlled;
measures ended
If verified
-
FIGURE 4-1 Possible framework for IHR response. SOURCE: PAHO/WHO.
..~
potential international health events will need to be developed in countries
where they are not already available.
Disturbances to free traffic, which constitute an obstacle to report-
ing, will need to be thwarted.
.
.
A set of generic rules to handle different kinds of urgent events and
a rapid mechanism to agree on appropriate levels of national protection
within this set of rules will be clevelopect by the IHR for implementation in
member countries.
Ideally, the IHR revision process should involve broad consensus with
all member states. The current collaboration between the Secretariat and
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106
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
interested member states is designed to test proposed changes and seek
suggestions on how the member states want the new IHR to operate. An
electronic virtual discussion forum has been set up between the IHR team
and representatives of WHO member states, and the revision team has
written to all member states asking them to nominate individuals who will
provide input to the revision process. In Latin America, the Pan American
Health Organization (PAHO) has been working with Mexico, Peru, Brazil,
and signatory states of the Mercado Comun del Sur (MERCOSUR) to
establish formal collaboration partnerships for the IHR revision process,
and MERCOSUR has listed IHR revision follow-up as an agenda topic for
its health sector committee.
The next stage of consensus-building involves steering working rela-
tionships among WHO country representatives, member states, WHO re-
gional offices, and international agencies and institutions whose work is
related to the IHR. These international agencies include the Food and
Agriculture Organization (FAO), International Air and Transport Associa-
tion (IATA), International Civil Aviation Organization (ICAO), World
Trade Organization (~110), and International Maritime Organization
(IMO).
DISEASE SURVEILLANCE, PROGRAM MANAGEMENT, AND
SUSTAINMENT OF IMMUNIZATION PROGRAMS
Donald S. Burke, M.D.
Professor of International Health
Director, Center for Immunization Research
lohns Hopkins School of Hygiene and Public Health, Baltimore, MD
A major challenge to post-eradication is knowing how long disease
surveillance should be continued, both during immunization and after it.
Surveillance is also an important control issue for other viral diseases, such
as yellow fever, that are not currently slated for eradication but for which
vaccines are available and in various stages of implementation worldwide.
Following is a review of several disease control programs and lessons to
be learned from their historical examples.
Polio Surveillance and Program Management
Laboratory surveillance has been crucial to the success of the polio
eradication campaigns. Surveillance measures include:
.
detection and reporting of all cases of acute flaccid paralysis (AFP),
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OPERATIONAL/INSTITUTIONAL CHALLENGES TO POST-ERADICATION 107
.
collection of two stood specimens within the first 14 days after the
onset of paralysis,
· isolation and characterization of enteroviruses in cell cultures with
particular attention to the polioviruses, and
.
differentiation between the wild type and polio vaccine virus strains.
Differentiating the oral polio vaccine strains is a major challenge to
laboratory surveillance because it requires a relatively cumbersome cell
culture technique. This is true despite a global network of functional polio
eradication laboratories; most small country laboratories experience diffi-
culties performing the specialized technique.
An example of a typical surveillance caseload is Mongolia, where there
are about 1,000 reporting districts throughout the country that participate
in ongoing surveillance. Over the past three years, these reporting districts
have detected 90 cases of AFP. All 80% of the cases for which specimens
were available for laboratory differentiation were confirmed not to be po-
lio. The other 20%, for which specimens were unavailable or inadequate
for laboratory analysis, were confirmed not to be polio based on clinical
evaluation: either there was no residual paralysis on long-term follow-up
or, if there was, expert clinical review of the case confirmed that it was not
polio. The last confirmed case of polio in Mongolia was in 1993.
Measles Surveillance and Program Management
Measles cases can be mistaken for dengue, rubella, scarlet fever, and
roseola, the clinical manifestations of which overlap and make differential
diagnosis difficult. Consequently, as for polio, laboratory surveillance for
measles is very important, especially if eradication requires detecting and
reporting all compatible cases.
In contrast to polio, measles diagnosis is made by detection of IgM
antibodies, not virus isolation. Measles infection usually occurs 14 days
before the onset of rash, and anti-measles IgM typically appears within the
first few days after the rash. The sensitivity of the IgM assay in the first few
days after rash is 60 or 70°/O, and nearly 100% by the fourth day. Diagnos-
tic accuracy relies on the proper timing of specimen collection.
As with polio, routine diagnosis is usually done in one of the many
eradication network laboratories currently being developed worldwide.
Lessons from Yellow Fever Program Management
The first attempts at yellow fever eradication were the early campaigns
sponsored by the Rockefeller Foundation. In 1915, Wickliffe Rose, the
Director of the International Health Commission of the Rockefeller Foun-
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108
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
cation, said that the "international commission was prepared to give aid to
eradication of this disease in those areas where the infection is endemic and
where conditions would seem to invite cooperation for its control."
One of the major reasons these early yellow fever eradication efforts
failed was the presence of jungle yellow fever: a cycle of disease that existed
in non-human primates and was transmitted by vectors other than Aedes
aegypti. During his investigations of epidemics near Muzo, Columbia, in
1907, Colombian scientist Dr. Franco macle several observations that led
him to believe that jungle yellow fever existed: the disease could be con-
tracted in the forest as well as urban neighborhoods; it was transmitted by
other culicine vectors in addition to Ae. aegypti; and its transmission oc-
curred during daylight hours.
After the 1915 declaration to eradicate yellow fever, William Crawford
Gorgas famous for eradicating yellow fever from Cuba and the Panama
Canal Zone led a commission into Muzo, Colombia, to investigate re-
ports of yellow fever. The existence of jungle yellow fever was not recog-
nized at the time, and the commission believed that Ae. aegypti had to be
present in order for yellow fever to be transmitted. So when they found no
evidence of Ae. aegypti, they concluded that the reported disease could not
be yellow fever. Thus, the eradication campaign proceeded in the face of
what was most certainly unrecognized jungle yellow fever. It was not until
1935 that Dr. Fred Soper, Regional Director of the Rockefeller Foundation's
International Health Division in Rio de Taneiro, acknowledged Franco's
contribution and finally agreed that jungle yellow fever existed.
The Rockefeller yellow fever program extended into Africa as well,
where a yellow fever research laboratory was built in Entebbe, Uganda, in
1936. Although its primary focus initially was yellow fever, over the years
this laboratory has been involved with a variety of other viral diseases as
well. For example, the West Nile virus was first isolated there in 1938, and
studies conducted at the laboratory in the 1930s provided an early under-
standing of the ecology and epidemiology of this virus. The facility now
houses a major AIDS laboratory, as well as polio and measles surveillance
laboratories. Thus, the initial yellow fever investment has resulted in a
number of positive spin-offs.
The lessons to be learned from yellow fever eradication and control
initiatives are, first, that field research is essential to making sound policy
decisions. We need to beware of false epidemiological dogma. Second, even
a "failed" program can leave a strong legacy on which to build.
Influenza
Although influenza has never been eradicated, major variants of influ-
enza virus, such as HlN1, have spontaneously disappeared. By using
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110
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
vaccine, suggesting that adeno 7 had moved into a vacant niche previously
occupied by adeno 4.
These findings may have relevance for other immunization programs,
such as polio. For example, sequence analysis of the RNA polymerase of
the enteroviruses shows that the phylogenies of the Coxsackie A viruses and
the polioviruses are intertwined. It has been hypothesized that the only
difference between these viruses is the host recognition receptor: poliovi-
ruses use the CD155, and the Coxsackie viruses use the ICAM 1. It is
possible that a simple receptor switch would provide variants of Coxsackie
viruses with properties more like polioviruses. The question is, will Cox-
sackie A viruses fill the vacated poliovirus niche?
Poliovirus es
Detailed discussion about polio revertants and recombinants is pro-
vided elsewhere in this report. For example, known instances of reversions
of polio vaccines, including the Poland USOL and several Sabin strains, that
have led to vaccine-associated paralytic polio (VAPP) epidemics are pre-
sented in Table 4-2. Also, a natural recombinant polio wild type Sabin-1
circulated in China for several years; and toward the end of the polio
epidemic and the eradication of polio in China, a recombinant strain con-
taining sequences from the Sabin vaccine strain spread from person to
person, infecting thousands of Chinese. Early lessons learned from the
poliovirus are that viral evo~va~oiiity can introduce unexpected wild cards.
Viral evolvability raises concerns about all forms of live attenuated
vaccines with a proven capacity to efficiently swap genes between humans
and animals. Of particular concern are live attenuated vaccines with seg-
mented genomes, such as influenza and rotavirus, for which we can almost
certainly expect recombinant variants of wilct type and vaccine type to
emerge. Hopefully, none will be more virulent or more transmissible than
the wild type parent.
TABLE 4-2 Reversion of Polio Vaccine to Virulence with Epidemic
Spread
Year Country Virus (Vaccine) # Cases
1968 Poland Polio-3 (USOL) 464
1988-1993 Egypt Polio-2 (Sabin) 32
Mid-1990s China Polio-2 (Sabin) NR
Late-199Os Israel Polio-2 (Sabin) (0)
Dominican
2000 Republic/Haiti Polio-1 (Sabin) 19
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OPERA TIONAL/INSTITUTIONAL CHA ~ rENGES TO POST-ERADICA TION 111
Hepatitis B Virus
All current hepatitis B virus (HBV) vaccines are either inactivated or
not capable of replication. Immunity is directed largely against a particular
immunodominant hydrophilic loop of the surface antigen of hepatitis B. In
many inqmunized persons, the loop has significant amino acid substitutions
that substantially change immunogenicity. These variants are the predomi-
nant type of virus present in as many as 20-30% of vaccinees who become
infected. Long-term models predict that it will take 30 or 40 years for these
escape variants to predominate worldwide. The early lesson learned from
HBV is that virus variants may emerge, particularly for vaccines targeting a
single major epitope. Virus variants of live attenuated vaccines or complex
antigens are less likely to emerge.
Conclusion
.
Several lessons can be learned from our past efforts to control or eradi-
cate viral diseases:
Yellow fever: The presence of a non-human reservoir (i.e., jungle
yellow fever) creates the likelihood for continued reintroduction.
· Influenza: Accidental reintroduction can result from a stasis reser-
vo~r.
Smallpox: Malevolent reintroduction poses a serious threat.
Polio: A vaccine strain can revert to virulence anchor recombina-
tion between vaccine and natural virus.
· Hepatitis B: "Immune escape" mutants of wild-type virus can
. .. . . .. ..
evolve and eventually predominate worldwide.
· HIV: Natural viruses are actively emerging (see Chapter 2~.
Francois-Joseph Broussais (1772-1839), one of Napoleon's personal
physicians, referred to the "genius of the epidemic." Given the already
proven cleverness of the viruses in their ability to frustrate our immuniza-
tion strategies, we should carefully consider how viruses might thwart our
eradication efforts and how we can detect and promptly counter those
moves.
Surveillance is crucial to successful eradication. As eradication cam-
paigns near completion, the potential for viral surprises will increase, not
decrease. "Forward" laboratories are a vital part of surveillance. Labora-
tory capacity should be strengthened, especially in regions where eradica-
tion is difficult and/or variants are likely to emerge.
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112
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
THE CAPACITY OF PUBLIC HEALTH SERVICES TO RESPOND TO
AN OUTBREAK IN THE POST-ERADICA~ON EM
Car! E. Taylor, M.D., M.P.H.
Professor Emeritus, Department of International Health
Johns Hopkins School of Hygiene and Public Health, Baltimore, MD
During global eradication initiatives, global priorities tend to override
local priorities. Evidence suggests, however, that there are cost-effective,
synergistic ways to meet both objectives simultaneously. Indeed, empower-
ing local communities with strong primary health care infrastructures which
they can rely on to solve their own problems is the best way to prevent
emerging disease outbreaks. New advances in Community-Based Primary
Health Care (CBPHC) provide new hope for building synergisms between
competing goals in order to cope with emerging infections.
In accordance with the World Health Assembly resolution in 1988,
nations made a commitment to pursue polio eradication "in ways which
strengthen the development of immunization programmer as a whole, fos-
tering its contribution, in turn, to the development of the health infrastruc-
ture and of primary health care." Recently, this level of commitment has
been evaluated in several ways.
Recent Reports
A 1993 PAHO commission involving a detailed qualitative assessment
of polio eradication (PE) in six Latin American countries concluded that PE
strengthened health systems in countries that already had a basic health
infrastructure. This success could not, however, be extrapolated to coun-
tries with weak health systems. The greatest positive impact of PE was on
social mobilization and intersectoral cooperation, two of the three main
goals of the Alma Ata World Conference on Primary Health Care in 1978.
However, negative effects were also seen, mainly competition between com-
ponents of the health infrastructure as a result of aggressive targeting.
Other recent evaluations of the great progress in worldwide PE call for
a greater awareness of the fact that the eradication experience will be
different in places where health services are weak or nonexistent compared
to places with well-established health systems, as was shown in malaria
eradication efforts in the 1960s.
Comprehensive recommendations have been made about the many
"missed opportunities" and the need for a new organizational framework
to strengthen the health service infrastructure. Recommendations from a
WHO meeting in December 1999 include:
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OPERATIONAL/INSTITUTIONA ~ CHALLENGES TO POST-ERADICATION 1 13
Monitor "key indicators" of impact on health systems.
Compile existing documentation, especially gaps in equity, com-
munity ownership, political will, public-private partnership, peace build-
ing, Vitamin A supplements, laboratory capacity, and opportunity costs.
Establish an oversight committee for the health systems-strength-
ening aspect of the PE goal.
· Engage broader participation of those with expertise in health sys-
tems to ensure action on "missed opportunities."
.
The WHO report warned that "as polio eradication enters its most
difficult stages, many health experts express their concerns that the ARIA
promise ... will not be achieved, unless greater efforts are made. Intensive,
accelerated, polio activities are underway ... and the fear, expressed by
some, is that there will not be enough staff time or energy to take on the
broader agenda of strengthening routine immunization and health systems.
. . . Today, routine immunization coverage is at the lowest it has been in a
decade in many countries and health systems have not effectively responded
to decentralization, particularly in the provision of preventive services."
Finally, the report suggests that help will be needed from GAVI (Global
Alliance for Vaccines and Immunization), presumably because the amount
of money needed has dramatically increased.
Dilemma
Or
In the past, the costs of focusing only on direct eradication services
have been justified by cost-effectiveness calculations indicating that when
PE is declared there will be a savings of at least $1.5 billion per year per
country. Thus, countries where wild virus still occurs are pressured to pay
more attention to the global priority for PE rather than the diseases killing
their own children. Now, however, we are beginning to realize the impor-
tance of strengthening local health systems.
Deficiencies in diagnostic and treatment capacity decrease surveillance
capacity and can create a long time lag between the occurrence and identi-
fication of outbreaks. Identification of outbreaks will be especially impor-
tant after eradication is declared complete, and it is critical that local health
systems be strengthened in order to meet this demand. Stronger local health
systems are also needed to increase child immunization rates.
UNICEF is now using independent surveys for the State of the World's
Children Report and is changing some of its earlier claims about child
immunization patterns of the past decade. In India, between 1999 and
2000, the percentage of children reported as fully immunized dropped on
average 20 points, from the 80s to the 60s. In China, at the same time
immunization rates dropped on average 10 percentage points.
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CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
There are tremendous differences in immunization rates within coun-
tries, as shown by data from the USAID-funded Demographic and Health
Surveys in India. The Pulse Polio National Immunization Days (NIDs) that
began in 1995 have resulted in the greatest public health events in history
with reports of having reached more than 100 million children. Rates in the
advanced southwestern states of India were already good, and the NIDs
raised them to over 90%. However, in the north central states of India
where the rates were low, they remain low. Twenty-nine percent of children
in two Indian north central states (Uttar Pradesh and Arunachal Pradesh)
still had no reported immunizations. Uttar Pradesh's population is equiva-
lent to the 10th largest country in the world. Similar reports are emerging
from Africa.
3:
Need for Cooperation for Adequate Surveillance
There is abundant evidence that PE efforts and actions to strengthen
local health systems can produce powerful synergisms. PE depends on both
NIDs and surveillance, both of which in turn depend on technological
mobilization and research on the changing nature of health services. They
also depend on flexible methods of social mobilization to bring vaccines
and children together and ways to identify and diagnose acute flaccid pa-
ralysis (AFP). The technological mobilization is straightforward, especially
when outside funding for campaigns is available. However, the reality is
that equipment lasts only about 10 years in developing countries and vac-
cines have to be paid for annually.
There is great uncertainty about the sustainability of social mobiliza-
tion. In the past, social mobilization has been based on a passive and
unsustainable model. However, there is an alternative model which relies
on community empowerment that works amazingly rapidly if programs are
organized to promote community self-reliance rather than dependency. In
recent years, there has been great progress in understanding the process of
community empowerment. It is no longer necessary to assume, as we did
earlier, that community empowerment happens by chance.
It has, for many of us, been baffling and contrary to other experience to
see the success of social mobilization for polio. Everyone, and especially the
bureaucrats doing the implementation, have been amazed at the response.
Even the poorest countries can generate a local commitment that brings
together immunizations and mothers and children in the most massive
health events of all time. Global pressure has made leaders of the poorest
countries feel ashamed if they do not cooperate and mobilize all govern-
ment resources for this global priority. The local commitment was under-
standable for vaccine campaigns targeted at one of the main causes of child
death. But it is unclear why the commmitment persists for a disease that is
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OPERATIONAL/INSTI~TIONAL CHALLENGES TO POST-ERADICATION 1 15
so rare that local peoples have no name for it and, in some places, efforts to
educate the people about the disease involve searching for relatively rare
cases with residual paralysis to use as audiovisual aids. Why do the local
people think that there is so much official concern for these diseases? Do
they think that the vaccinations have some special power? Do they think
the oral drops will make it less necessary for their children to receive the
painful injections that make them cry? How long will poor countries con-
tinue to let global priorities completely override local priorities? And, most
importantly, what can we do so that the remarkable public enthusiasm for
PE social mobilization enhances other immunization programs and pro-
motes interventions for the main infections that cause death in each local-
ity, thereby truly balancing global and local priorities?
Although the amazing and highly publicized advances in technical and
social mobilization for PE are impressive, there have also been parallel but
not publicized advances in community-based primary health care. It is time
to bring the two streams of progress together. Evidence shows that building
primary health care infrastructure is not necessarily expensive and slow.
After the Alma Ata Conference, the claim was made by donors that com-
prehensive primary health care does not go to scale and only selective
approaches can be extended. However, we now know that sustainable
services can be expanded remarkably rapidly to cover whole regions.
The key issue is whether the social mobilization necessary for NIDs and
surveillance can be accomplished using an approach that will not collapse
when outside funding and expatriates are gone. Great effort is already
being directed toward building capacity and mobilizing volunteers, so it
will only take a little more patience to build a self-reliant community. Top-
down processes create dependency, not self-reliance.
A remarkable feature of the new process is that it includes the best hope
for long term financing. International Monetary Fund (IMP) economic
reforms cut health budgets in Africa by a third to a half in the 1980s.
Donors dumped responsibility for public health back onto countries, except
for the few diseases that could be attacked by campaigns, and countries
dumped responsibility onto communities. It is clear that communities will
eventually have to assume responsibility for self-financing, except for the
very poor who will need subsidization and for whom sustainable financing
must be found. Talk about insurance is relevant only for people with re-
sources. Now, with worldwide privatization of health care and pharmaceu-
ticals, the prospects for care for the poor seem even more jeopardized unless
. . . . .
ll:lternatlOna~ . equity IS ta ten serious Y.
Condusion
Objective research is needed to determine if scientific and technical
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CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
improvements in immunization strategies better control infectious diseases.
Research is also needed to gain a better understanding of the role of social
mobilization in successful immunization programs. How can this amazing
phenomenon be used to build a sustainable local capacity for solving a
nation's own public health problems? Strong local health services and em-
powered communities are the best framework for preventing the disease
outbreaks that this conference is addressing.
LABORATORY SECURITY AND REGULATIONS GOVERNING
VIRAL PATHOGENS IN A POST-IMMUNIZATION ERA
Raymond H. Cypess, D.V.M., Ph.D., President and CEO
Frank P. Simione, M.S., Vice President, Safety and
Regulatory Affairs
American Type Culture Collection (ATCC), Manassas, VA
Managing virus stocks under good laboratory security and in compli-
ance with current regulations can best be accomplished by applying prac-
tices currently in place at Biological Resource Centers (BRCs) (Table 4-3~.
BRCs play an essential role in the biological research infrastructure by
coordinating the shared use of validated biomaterial and data among gov-
ernment agencies, industry, academia, and the public. They serve as reposi-
tories, service providers, and knowledge managers. They authenticate, pre-
serve, and distribute living cells, genomes, model organisms, research tools,
and information relating to heredity and functions of living systems.
Of particular relevance to public health and infectious disease pro-
grams are BRCs that specialize in microbiology. These are collections of
culturable organisms, viable but not yet culturable organisms, replicable
parts of these materials, and associated data. BRCs relieve storage and
distribution burdens for investigators and institutions, and they provide
controlled on-site biosecurity and access to their holdings. Types of BRCs
included
1Key to abbreviations: ATCC, American Type Culture Collection; BDSC, Bloomington
Drosophila Stock Center, Indiana University; CBS, Centraalbureau voor Schimmelcultures;
CDC, Centers for Disease Control and Prevention; CGC, Caenorhabditis Genetics Center;
Coriell Institute for Medical Research, New Jersey; DSMZ, Deutsche Sammlung van
Mikroorganismen und Zellkulturen GmbH; IFO, Institute for Fermentation, Osaka; JCM,
Japan Collection of Microorganisms; NRCC, National Resource Center for Cephalopods,
University of Texas; RPRC, Regional Primate Research Center; RSMAS, Rosenstiel School of
Marine and Atmospheric Science; USDA, U.S. Department of Agriculture
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OPERATIONAL/INSTITUTIONAL CHALLENGES TO POST-ERADICATION 117
· Microorganisms (e.g., ATCC, CBS, CDC, DSMZ, ~CM),
· Plant germplasm, i.e., seeds, clones, cells, and tissue (e.g., ATCC,
DSMZ, USDA),
· Animal cells and tissue (e.g., ATCC, Coriell, IFO),
· Vertebrate models (e.g., rodents at Jackson Laboratories, primates
at RPRC, zebrafish at University of Oregon), and
.
Invertebrate models (e.g., Drosophila at BDSC, nematodes at CGC,
Aplysia at RSMAS, cephalopods at NRCC).
A challenge to eradication is identifying where viral stocks are currently
housed, which requires a systematic inventory of existing biorepository
holdings. Persons responsible for the materials must be forthcoming in
complying with requests for this information.
As laboratories are identified, an attempt should be made to transfer all
specimens to those biorepositories that demonstrate well-developed and
documented procedures for safe handling and security. Good biorepository
management practice requires documenting, managing and securing strain
data, ensuring safe handling in the laboratory and in the biorepository, and
strict management of access to and distribution of the agent.
Storage in select biorepository holdings will ensure that the agents are
available for ongoing laboratory studies, as needed, with minimal risk of
reintroducing the disease into the general population and environment.
Agents that present a grave cianger to a post-immunization community
TABLE 4-3 The Role of Biological Resource Centers
· Provide central source and controlled access to standard biomaterials, reagents,
and data
Provide controlled conditions for on-site biosecurity
Provide central source of technical support
Minimize redundancy of biomaterials
Relieve storage and distribution burdens for investigators
Coordinate regulatory compliance
Provide safety deposit for essential germplasm
Support equitable sharing of biomaterials
Provide intellectual property management and services
Provide knowledge management and distribution
Promote translation of research discoveries into practical applications
Facilitate industrialization of technologies in medicine, public health, pharmacy,
agriculture, food, and environment
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CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
should be stored in facilities with Biosafety Level 4 (BSL-4) containment
capability.
Admittance to material can be restricted by providing secure, con-
trolled access to the viral agents. Levels of access should be established so
that the most dangerous strains have the greatest restrictions for access and
use. End-users should be qualified to work with the agent, and their institu-
tions capable of ensuring adequate biocontainment and security.
BRC Lab Security
Acceptable acquisition practices start with a sound demonstrated
knowledge of the material and its potential hazards. Acquisition is usually
accompanied by material acquisition agreements which can be used to
record information on the agent, its potential laboratory risk, and condi-
tions under which the material is being provided to the biorepository. In
order to ensure that the agent is safely and securely maintained in a viable
unchanged state, low-temperature storage with redundant controls on
equipment should be used to maintain cryopreserved stocks, and multi-
response alarm monitoring should be available.
All work performed on the virus stocks in the laboratory must be
conducted under good biosafety practices. Potential hazards should be iden-
tified through risk assessments and, where appropriate, laboratory workers
should be immunized. However, live viral vaccines such as those available
for poliovirus may present a risk if immunized laboratory staff shed the
virus outside the laboratory and potentially expose a non-immunized com-
munity. Those agents posing serious risk to the community should be
handled under BSL-3 containment and practices, and some agents may
require BSL-4 containment.
Disposal must avoid risks associated with handling of infectious mate-
rials. The best practice is inactivation of biological materials in the labora-
tory, as required for BSL-3 and BSL-4 containment. Even in a BSL-2 labo-
ratory, accommodations should be made for destruction of biohazardous
agents within the laboratory area.
Internal security is especially important for stocks that cause disease for
which immunization has been discontinued or that create a high risk of life-
threatening disease. Physical access to the virus stocks can be controlled by
securing freezers with combination or key locks that require two people to
unlock the freezer and by controlling access to the area of the facility where
the freezers are housed. Physical access to the biorepository can also be
controlled by using key-card or other individual access identifiers. Acldi-
tiona! safeguards include denying individuals access to both the
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OPERATIONALnNSTITUTIONAL CHALLENGES TO POST-ERADICATION 119
biorepository and freezer, thus requiring two people to obtain or deposit
biohazardous agents.
Freezer inventories should be designed so that a locator code is needed
to find the desires! material. Locator codes can be kept in strictly controlled,
secure databases. Access to freezers wouict be denied to those who also have
access to the locator codes, again requiring two people to retrieve or deposit
material. Chain of custody documentation a system of sign-offs that tracks
the movement of materials should be established to verify authorized
access to the material. Evidence of the disposition of all material released to
a laboratory, including destruction of records, should also be documented.
Access and Transfer of BRC Materials to Outside Sources
A mechanism for verifying a recipient's legitimate need for the material
must be established and controlled independently of the biorepository. The
recipient should be located at an institution where work with the agent is
approved and all necessary safety and security policies and practices are in
place. A mechanism such as that used by the Centers for Disease Control
and Prevention (CDC) for controlling the transfer of designated select agents
should be used for agents for which immunization has ceased (Code of
Federal Regulations 42, Part 72.6~.
The greatest risk of transferring viral agents to an outside laboratory is
the potential for an unqualified end-user to gain access to the virus. There-
fore, there must be some way to ensure that the receiving laboratory is
capable of controlling access and preventing the release of restricted etio-
logical agents to known or suspected persons, institutions, or countries that
represent a proliferation risk for biowarfare or bioterrorism. With the aid
of appropriate federal authorities, including the departments of Commerce,
State, and Treasury, the biorepository must be able to screen potential
recipients.
Distribution of disease-causing viral agents requires strict adherence to
the permit and licensing requirements of local, state, federal, and interna-
tional agencies. End-users should process requests for their material through
an institutionally controlled system that identifies materials needing special
permits and licenses. The biorepository should be familiar with the regula-
tions on packaging, shipping, and tracking to ensure safe and controlled
transfer of material.
For example, the release of any biological material from ATCC- re-
gardless of risk category requires that the requester provide an organiza-
tional profile and documented assurance that the facility is equipped to
handle the material safely and securely. In addition, all requests for biologi-
cal materials from ATCC are screened against U.S. government lists of
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CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
denied individuals, entities, and embargoed countries, and all required per-
mits and licenses are applied where appropriate.
Conclusion
Assuring the security of post-eradication viral agents is critical to suc-
cessful eradication. But it is only achievable if good practices for the acqui-
sition, preservation, authentication, and distribution of the materials are
applied. BRCs can continue to provide safe and secure management and
control stocks of post-eraclication viral agents. It is critical, however, that
access to potentially dangerous microbial agents be controlled uncler strict
guidelines and regulations mandated outside the BRCs, and that BRCs
function solely as a means of ensuring compliance with these requirements.
Representative terms from entire chapter:
disease eradication
