Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 1
Summary and Assessment
Joshua l~ed~erberg, Ph.D.
Nobel Laureate and Sackler Foundation Scholar
The Rockefeller University, New York, NY
lance;
The successful smallpox campaign demonstrates that global eradica-
tion of a disease is possible, given the necessary technical base, political
commitment, and economic resources for immunization and continued sur-
veiliance. Currently, there are three infectious viral disease candidates for
global eradication- polio, measles, and rubella each of which closely sat-
isfies necessary preconditions for eradication as outlined by the 1997
Dahiem Conference on Disease Eradication:
(1) no animal reservoir for the virus is known or suspected;
(2) sensitive and specific tools are available for diagnosis and surveil-
(3) transmission from one individual to another can be interrupted;
(4) non-lethal infection or vaccination confers life-Ion" immunity;
(5) the burden of disease is important to international public health
and
(6) political commitment to eradication efforts exists.
Of the three diseases, poliomyelitis is likely the next candidate for
global eradication. In the Americas, polio was eradicated in the early l990s,
and less than 3,000 cases were reported worldwide in 2000. The current
goal is certification of global eradication by 2005. Measles stands next in
line after polio, although no global goal has been set. In 2000, there were
only 1,500 reported cases of measles in the Americas; however, measles still
causes 900,000 deaths each year worldwide and accounts for some 30% of
1
OCR for page 2
2
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
all cleaths due to vaccine-preventable diseases. Rubella, which generates
100,000 cases of congenital rubella syndrome, is the furthest from global
. . .
eradication.
Many attributes of the disease uniquely favored smallpox eradication.
Its characteristic clinical features made diagnosis and surveillance for infec-
tion much easier than they are for polio, measles, and particularly rubella.
Every infected person had a characteristic rash; thus, the presence of the
virus in a geographic area could be readily determined. Containment was
easy since transmission was by droplets spread by face-to-face contact, and
the virus survived outside the human host for only a limited period of time
(in contrast to poliovirus, for example, which spreads through a fecal-oral
route and may remain viable in feces for six weeks or longer). Smallpox had
a higher average age at infection prior to wide-scale vaccination and thus
was less transmissible than either polio or measles. A safe, heat-stable
vaccine assured protection with only a single inoculation and could be
administered from the time of birth (in contrast to oral polio vaccine [OPV],
for example, which requires a three-dose regimen and special storage re-
quirements). Finally, an extraordinary international cooperative effort sup-
ported the campaign.
Despite these ideal criteria for disease eradication, the smallpox cam-
paign was not without technical, financial, and political challenges. Ex-
pected voluntary contributions to the program were sparse in fulfillment. A
number of endemic countries needed persuasion to undertake vaccination
and surveillance activities, and political and social upheaval seriously de-
layed or threatened the campaign. It was difficult to achieve sustained
interest and support for continued disease surveillance and immunization
after a nil incidence was achieved locally, even in light of rumors of spo-
radic cases and the threat of possible reintroduction. These challenges show
that eradication can be extremely difficult even when eradication is techni-
cally and operationally feasible and political commitment is strong.
The success of the smallpox eradication campaign and the title of this
meeting hint at future success. Indeed, the regional eradication and near-
eradication, respectively, of polio and measles in the Americas illustrate
tremendous progress. However, it is far from clear that success is just
around the corner. Interruption of the final chains of transmission faces
several difficult challenges, including high transmissibility in densely popu-
lated areas and public and professional complacency regarding continued
vaccination due to dwindling first-hand experience with the consequences
of infection and the increasing publicity on adverse reactions to vaccina-
tion. Even in developed countries where infections have been eradicated or
near-eradicated, mass vaccination will probably have to be maintained at
very high levels for an extended time in order to protect against reintroduc-
OCR for page 3
SUMMARY AND ASSESSMENT
3
tion from areas where poverty, civil unrest, or lack of political will impede
high vaccination coverage and sustain endemicity.
There is much concern that the sixth precondition for eradication as
outlined at Dahlem political commitment—is not being fully met with
respect to measles and rubella. This is evident by recent discussions among
members of the international public health community which reflect seri-
ous reservations about the feasibility and cost of attempting to eradicate
these two diseases. Indeed, operational feasibility, particularly with re-
gards to maintaining a strong routine immunization program, is consid-
ered by many to be an important additional criterion that was omitted
from the Dahlem list of preconditions for eradication. As was learned from
the Dominican Republic/Haiti polio outbreak, low routine coverage is a
critical problem that can lead to the circulation of a virus for several years.
Yet, in the case of measles, in many countries the feasibility of delivering
routine immunizations is too often ignored by those who advocate eradica-
tion. Thus, it is important to note that the current World Health Organiza-
tion (WHO) strategy for measles is "mortality reduction" and not "eradi-
cation". The failure to address the operational aspects of routine coverage
seriously threatens our ability to achieve mortality reduction and certainly
. .
erac Cation.
As the title of this report suggests, the focus of this workshop was
post-era~ication challenges. However, certification of eradication for other
infectious diseases besides smallpox may be years off. Eradication efforts
against polio, measles, and rubella represent a broad spectrum of achieve-
ment. The current status of and particular challenges to each were also
discussed during the workshop, the highlights of which are presented
below.
POLIO
The main challenges confronting global eradication of polio are main-
taining high levels of immunization in the population at large (the global
polio eradication initiative relies on national immunization days (NIDs)
with OPV offered two or more times annually for all children under five
years of age) and targeting high-risk areas with "mopping up" operations
in order to interrupt the last chains of transmission.
A major lesson from the regional polio eradication effort in the Ameri-
cas is the need for ongoing analysis of information gathered from the field
and for the flexibility to change eradication strategies as necessary. For
example, based on information gathered during the campaign, surveillance
units were increased and moved to match where patients were seeking
initial care. As another example, when it was discovered that a poliovirus
OCR for page 4
4
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
type 3 outbreak in Brazil could not be contained by the available vaccine,
the manufacturers were led to reformulate the vaccine.
However, as fewer cases are reported, intensified surveillance efforts
and immunization programs compete for limited resources with other pub-
lic health programs, even though laboratory surveillance is critical to the
success of the polio global eradication effort. Infection with enteroviruses,
echoviruses, and coxsackieviruses can cause an illness whose clinical fea-
tures emulate paralytic polio, and the OPV vaccine itself can (rarely) cause
paralysis. Differentiating OPV-derived viruses and these other causes of
paralysis from the wild-type polio virus requires a relatively specialized
laboratory technology not readily available in many lesser developed coun-
tries. These difficulties confound true incidence rates, encumber surveil-
lance efforts, and consume valuable resources.
Although intensifier! mopping-up and surveillance have proven to be
successful means of interrupting the last chains of polio transmission in the
Americas, they were introduced very late in the global program and their
implementation elsewhere has been slow. How well we address the chal-
lenges of continuing surveillance for poliovirus and in maintaining polio
vaccination in polio-free areas unfit global eradication is achieved will de-
termine whether the goal of certifying the world as polio-free by the year
2005 will be met.
MEASLES
Mathematical models predict that 95°/O population immunity is needed
to interrupt transmission of the measles virus. This is best achieved through
a two-close immunization strategy: once at nine months of age and then
again in the second year of life. Major success in prolonged interruption of
measles transmission in the Americas using this two-dose immunization
strategy, supplemented with nationwide "catch-up" and "follow-up" cam-
paigns targeting susceptible populations and geographic reservoirs, pro-
vides evidence for the feasibility of global eradication.
However, several impediments to global measles eradication remain.
First, large birth cohorts stay seronegative to measles, resulting in subse-
quent transmission among a susceptible adult population. Second, virus
transmissibility is high in densely populated urban areas where susceptible
children and immigrants serve as a source of outbreaks. Third, HIV-in-
fected persons could become chronic carriers of the measles virus and con-
tinue to shed the virus long after initial infection. Fourth, more than a
million travellers use the skies every day, making it very difficult to contain
spread. Fifth, the currently available vaccine is not 100% protective and
leaves a pocket of susceptibility that enables transmission.
To address these concerns, research is being done on aerosolization
OCR for page 5
SUMMARY AND ASSESSMENT
s
administration and a mucosal route of immunization (versus by injection);
however, there is concern about whether the pharmaceutical industry would
invest funds in a new vaccine that would entail new manufacturing plants
and regulatory compliance and introduction into an unknown market. Also,
even if an improved vaccine were developed, the focus of prevention efforts
should still be comprehensive immunization of all children.
Sixth, the greatest obstacle to measles eradication may be lack of politi-
cal will. Indeed, data from the Americas show that measles transmission
can be interrupted on entire continents, which means that interruption is
technically possible, given the necessary political commitment. While the
United States has made measles eradication a public health priority, some
of the lowest measles vaccine coverage rates are found among the world's
richest countries, where measles is not seen as a problem. These countries
need to be encouraged to maintain continued immunization and surveil-
lance as protection against reintroduction via immigration and transconti-
nentat travel. This may require legal mandates. It may also be helpful to
compile known risks of vaccination versus disease in some format that is
accessible to the public in an effort to assuage concerns about the risks of
vaccination. Equally important, health authorities in the developing world
need to be confident that embarking on measles eradication will not detract
from delivery of other health services and will lead to benefits for overall
health care.
As with polio, an important lesson learned from the measles eradica-
tion campaign in the Americas is the importance of learning by doing and
adjusting strategies based on newly acquired knowledge. For example,
measles epidemiology changed radically when immunization was intro-
duced; in particular, its relative incidence increased in older children and
young adults. This was particularly true in countries like the United States,
where older populations accounted for a greater percentage of cases be-
cause of continued susceptibility due either to a lack of vaccination or
vaccine failure, coupled with decreased exposure to the wild virus as infants
and young children. In response, mass "follow-up" campaigns targeting all
children between one and fourteen years of age were recommended every
four years in order to remove remaining susceptibility in this older age
group and achieve complete interruption of measles transmission.
CONGENITAL RUBELLA SYNDROME
Congenital rubella syndrome (CRS) is a serious disease caused by infec-
tion of the fetus with the rubella virus during early pregnancy. Although
CRS mortality is not as high as that of measles, the large number of CRS
cases (approximately 100,000 worIdwide) results in a large population of
disabled individuals.
OCR for page 6
6
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
In developer! countries, the current strategy of immunization is univer-
sal measles-mumps-rubella (MMR3 immunization at twelve to eighteen
months of age ant! again at four to twelve years. This strategy has proven
successful and should continue. The Pan American Health Organization
(PAHO) has recommence that cleveloping countries alit! rubella to the
measles vaccine; increase universal immunization of children between nine
ant! twelve years of age with the combination measles-rubelIa (MR) vac-
cine; ant! repeat mass vaccinations clirectect at children nine to fourteen
years of age. Vaccine manufacturers neec] to be proviclec! incentives to both
decrease the per close cost and increase the overall supply to meet the
clemancts of increased immunization.
One of the most important challenges to rubella eradication is that
clinical diagnosis of rubella is often inaccurate, unlike measles, since rubella
can occur without a rash or be completely subclinical. The most sensitive
laboratory tools currently available for diagnosis and surveillance are either
not suitable for use in the fielci, can only be uses! in the most sophisticated
laboratories, or are not commercially available. Improved diagnostic capa-
bilities must be clevelopeci to accompany rubella explication.
Another major impediment to CRS eradication is that failure to achieve
high immunization coverage in children coup leacl to increased susceptibil-
ity among aclult women who have grown up without contact with the virus
ant! thus are more susceptible to infection, which they can then pass on to
their fetuses cluring pregnancy. Ironically, this conic! potentially leac! to
more cases of CRS than occurred! prior to the implementation of a vaccina-
tion program ant! suggests that it would be prudent to decrease susceptibil-
ity in aclult women. But this poses a clifficult challenge since aclult women
have an increaser! risk of reactogenicity and contraindication for use (e.g.,
possible transmission of live virus to the fetus from vaccination cluring
pregnancy). Experimental work with vector genes and DNA vaccines sug-
gests that maternal immunity could be overcome with the appropriate vac-
cine. However, there is currently no financial incentive for the pharmaceu-
tical industry to clevelop a new vaccine or even a new route of
. . .
at ministration.
As with measles, garnering broad financial and political support is
perhaps the greatest challenge to CRS eradication. Although many years
have passed since Australian epiclemiologists confirmed CRS, the disabling
consequences of CRS are not well publicized, and policymakers in devel-
oped countries—where eradication priorities tend to be set are not as
aware of CRS as they are of, for example, polio and measles.
POST-ERADICATION CHALLENGES
Eradication must not beget complacency, but it almost certainly will.
OCR for page 7
SUMMARY AND ASSESSMENT
7
As has been learned from past control or eradication attempts with a vari-
ety of viral diseases, from yellow fever to influenza, accidental or inten-
tional reintroduction is a real threat - one that could strike anywhere and
for which we need to be fully prepared. This is especially true as immunity
wanes in the post-eradication era and the population at large grows more
susceptible to infection. Even after immunization ceases, it is crucial that
enough vaccine be stockpiled (or provision made for emergency replenish-
ment) to cope with potential outbreaks; that surveillance continues in order
to identify and stamp out local outbreaks quickly and before they spread to
other regions; that vaccine manufacture be continuously improved to keep
up with changing regulatory requirements and new technology; that vital
research on vaccine technology and viral biology continue; and that viruses
certified as eradicated in the wild be safely contained to minimize the risk of
either accidental or intentional reintroduction. Post-eradication strategies
need to- be carefully developed and implemented in order to secure the full
health, human welfare, and economic benefits of the eradication of a viral
disease.
Discontinuing immunization in the post-eradication era can yield large
cost savings, freeing health care resources for other interventions. However,
knowing if, how, and when to stop immunization in the post-eradication
era is a major challenge, especially for the polio eradication campaign.
Although the use of OPV has been crucial to the success of the polio
eradication effort thus far, unique properties of the vaccine complicate
decisions regarding if and when to cease vaccination. OPV-derived viruses
can revert to pathogenicity during replication in the gut and, if shed, can
circulate through the population. The problem of OPV persistence is fur-
ther complicated by the fact that immunocompromised individuals who are
vaccinated with OPV can excrete the virus for unknown, extended lengths
of time. Although there is a non-pathogenic alternative to OPV the inac-
tivated IPV several practical advantages to OPV make it the vaccine for
choice for polio prevention. OPV confers substantial immunity; because it
is transmissible, OPV can spread immunity, not just disease; and OPV is
much less expensive.
Ideally, a new, non-infectious vaccine that produces mucosal immunity
like OPV would be developed as an end-strategy for immunization against
polio—perhaps a DNA or some other vectored vaccine—although it is
unrealistic to expect either the private or public sector to invest in the
development and production of such a vaccine this close to eradication.
Different ways of combining OPV and IPV strategies have been considered
for use in the post-eradication era, but no decision has been reached about
which strategy would offer the best protection against OPV-derived viral
disease. For example, one suggested strategy is using an OPV-IPV combina-
tion vaccine initially and then eventually removing OPV so that only a
OCR for page 8
8
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
"protective IPV layer" remains. However, it is not at all clear that this
strategy would ever stop OPV transmission, thus raising the question,
should we continue with the cheaper OPV vaccine indefinitely?
Even if IPV could stop OPV transmission, a major disadvantage to
relying on IPV as an end-strategy is the enormous cost, considerable tech-
nology transfer, and several years that would be required to prepare an
adequate supply of IPV to meet the worId's needs. With regards to the
greater cost of IPV in comparison to OPV, it could be argued that as more
new vaccines are introduced into the developing world, the added cost of
adding an IPV component may become trivial. One argument for relying on
IPV as an end-strategy is that because IPV still allows some intestinal excre-
tion of the poliovirus, the excretion of wild-type virus could be detected in
situations where it was believed to have been eradicated. This would facili-
tate surveillance and detection of outbreaks.
The time is ripe for a decision about how to proceed with~vaccine
production in the post-eradication era. Wi11 there be an end game, or are we
going to vaccinate against polio for the indefinite future; Key to answering
this question is knowing whether IPV stops transmission of OPV-derived
viruses. It will be ironic if it becomes necessary to continue vaccination in
the post-eradication era as protection, not against wild polio, but against
polio vaccine-derived disease.
The post-eradication era is one for which we have no historical prece-
dent. We have no experience with the consequences of a reintroduction or
reemergence of previously eradicated organisms. We do not know how
viruses will evolve in the future; if and how current vaccines would be able
to protect us from disease caused by newly evolved viral variants; and if and
how our immune system may change as the selective pressures previously
imposed by eradicated viruses are lifted or altered. We have no experience
on which to base predictions about the rate or extent of spread of disease in
a population with zero immunity, especially as increased transcontinental
travel and movement of people across borders make containment increas-
ingly difficult. For the first time in human history we have a herd that, for
more than twenty years, has never been exposed to epitopes that could
potentially reappear in circulation. Ate need a better understanding of the
long-term biological implications of altering the host-virus interaction
through eradication and cessation of immunization in the post-eradication
era.
Post-eradication strategies need to be developed well before certifica-
tion of eradication. During the smallpox campaign, post-eradication strat-
egies were developed only after it became clear that the applied vaccine
technology had proven successful and that eradication was practical anct
attainable. That all available resources were devoted towards the goal of
interrupting smallpox transmission reflected the strong belief that any strat-
OCR for page 9
SUMMARY AND ASSESSMENT
9
egies that diverted resources away from achieving full eradication would be
pointless if the eradication campaign failed. At risk was the loss of billions
of clollars invested and gradual reversion to a pre-eradication status as
special funds and interest withered. More importantly, a failed eradication
effort would have undermined other global initiatives and confidence in
expert public health advice. We tend to worry more about the inability to
consummate eradication than the consequences of having done so. How-
ever, as we have learned, focusing too much on the immediate goal of
interrupting transmission without considering the consequences of having
clone so can leave the population very vulnerable to future public health
crises of unpredictable, potentially catastrophic, magnitude.
It has been over 20 years since the global eradication of smallpox.
However, several post-eradication challenges remain, including: safely con-
taining virus stocks still being stored in laboratories; renewing abandoned
smallpox surveillance efforts; producing a potent vaccine should an out-
break occur; and developing antiviral chemotherapy that might be appli-
cable to smallpox. The risk of reintroduction—especially via biowarfare or
bioterrorism highlights the threat of reversion to a pre-eradication status
and the need for developing post-eradication strategies early on during an
eradication campaign in order to avoid the need for costly catch-up efforts.
Following eradication, the consequences of reintroduction become in-
creasingly grave over time due to the decline of herd immunity and in-
creased susceptibility of the population to a pandemic, complacency in
surveillance and maintenance and improvement of diagnostic laboratories,
recluced medical awareness, and decreased research activity.
REINTRODUCTION OF DISEASE
IN THE POST-ERADICATION ERA
Reintroduction could strike anywhere, at any time. Bioterrorism is
generally considered the greatest risk of smallpox reintroduction, even
though it was initially dismissed as a possibility since all countries had
actively participated in eradication efforts. By the mid-199Os, however,
U.S. intelligence had learned of several countries that were considering
using smallpox as a potential bioweapons agent and that, in fact, smallpox
was widely considered the bioweapon agent of choice for some terrorist
activities. And, importantly, it is not the only choice. Both the measles and
polioviruses could be used as bioweapons, for example, as aerosols, the
pathogenicity and transmission about which we know very little. Impor-
tantly, with the increasing accessibility of sophisticated molecular and
bioengineering technology, all of these viruses could be genetically altered
in ways that pose a tremendous challenge to post-eradication diagnosis and
surveillance which, in order to be effective, must be able to detect novel
OCR for page 10
10
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
viral variants; and to the vaccine industry which must be encouraged to
continue research and development of new vaccines that offer protection
against a constantly changing viral genome.
Accidental reintroduction from a stasis reservoir is also an important
threat, as illlustrated by the 1977 re-emergence imputedly from frozen
stock of a major variant of an influenza virus that had disappeared from
circulation in the 1950s. Safe and secure biocontainment of the virus is
essential for protecting both the environment and workers from accidental
infection or contamination. Ensuring good biomanagement practices while
simultaneously allowing legitimate and necessary viral research to continue
presents a major challenge to post-eradication strategizing.
Although laboratory escape and the use of viruses for bioterrorism or
biowarfare may be the most obvious sources of reintroduction in the post-
eradication era, the evolution of new viral variants, reemergence from un-
known zoonotic reservoirs, and reactivation from chronic carriers are
equally important to consider. The rise of megacities and increasingly dense
human populations and high-density animal feed lots provide favorable
milieus for rapid microbial evolution. The creation of new reservoir hosts,
cross-species transfer of infectious agents, rise of antimicrobial resistance,
and immune evasion are all potential sources for the emergence of novel
viral variants. Important and often overlooked, mass vaccination itself can
also exert tremendous selective pressures and lead to the evolution of new
infectious agents.
Even though no non-human reservoir has been identified for smallpox,
polio, measles, or rubella, unknown non-human reservoirs may exist. The
HIV pandemic is testament to the extraordinary clinical impact that a single
zoonotic transmission event can have. In 2000, HIV-1 was estimated to
have caused over 50 million infections worldwide.
Data show that humans are routinely exposed to a plethora of primate
lentiviruses (SIVs) from which HIV is derived. Multiple incidents of zoonotic
transmission of a virus create the potential for recombination between the
human virus (e.g., HIV) and the newly introduced zoonotic virus (e.g.,
SIVs). If unknown non-human reservoirs are harboring variants or ances-
tors of the viruses responsible for disease, zoonotic transmissions may be a
potential source for other viral diseases as well. Theoretical concerns about
a non-human reservoir of measles, for example, raise questions about our
assurance that the smallpox virus no longer resides in the natural environ-
ment. Given the rapid evolvability of viruses and the rapidly changing
evolutionary pressures in a 21st-century world, it would not be surprising
to see the gradual evolution of new, previously enzootic, diseases with
human-to-human transmission properties.
Chronic carriers—HIV-infected persons, malnourished children, and
other immunocompromised individuals who can harbor and sheet unde-
OCR for page 11
SUMMARY AND ASSESSMENT
-
11
tected virus for extended lengths of time are another important potential
source of reemergence. More information is needed to better understand
how long immunocompromised carriers continue to shec! virus into the
environment and what proportion of immunocompromised individuals sheet
virus for prolonged periods of time. This information is crucial to planning
post-era;Jication vaccine production strategies, especially for polio. Because
of its ability to revert to pathogenicity during replication in the gut, the
oral, live-attenuated polio vaccine (OPV) used to prevent polio creates a
serious challenge. OPV is usually shed from immunocompromised carriers
for weeks to months but can be shed for as long as 10 years, compared to
less than 3 months for immunocompetent carriers.
Indeed, the probability of genetic reversion from attenuation to patho-
genicity must always be considered in the application of live-attenuated
vaccines. As disease due to wild-type virus is eliminated, vaccine-associated
cases become of increasing concern. Since 1973, the number of vaccine-
associated paralytic poliomyelitis (VAPP) cases has exceeded the number of
wild polio cases in the United States. Worldwide, there have been several
epidemics caused by reversion of the polio vaccine to virulence, the most
recent in 2000 in Hispaniola.
DETECTION AND SURVEILLANCE
Continued surveillance, improved surveillance methods, and assistance
to lesser developed countries in their efforts to implement national surveil-
lance campaigns are essential for the rapid detection of disease outbreaks.
Given the biological variability of vaccine strains, and the innumerable
array of samples in frozen storage, it is not a question of whether disease
outbreaks will occur in the post-eradication era, but, rather, when and
where.
Surveillance laboratory capacity must be strengthened, especially in
areas where eradication has proven difficult to achieve or variants are likely
to emerge. Surveillance tools must be sophisticated enough to detect differ-
ent and new viral variants. To this end, global laboratory networks cur-
rently in place need to be further developed, especially for measles surveil-
lance efforts. Measles surveillance is complicated by the fact that measles
cases can be mistaken for clengue, rubella, scarlet fever, and roseola; thus,
differential diagnosis based on clinical symptoms can be difficult, and labo-
ratory surveillance is very important for detecting and reporting all cases.
The measles laboratory network in the Americas is by far the most highly
developed and should serve as a model for networks in other parts of the
world.
National leaders must be convinced of the importance of strengthening
surveillance capacity—not only to monitor the increasing likelihood of viral
OCR for page 12
12
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
surprises as we enter a post-eradication era but also to more readily detect
pockets of low immunity as eradication campaigns near completion. Na-
tional surveillance programs must be strengthened and the WHO and able
countries encouraged to provide support, as needed, to countries who do
not already have national surveillance networks in place. To aid in this
effort, revised International Health Regulations (IHR) will provide a tem-
plate for core requirements for national surveillance systems in countries
where they do not already exist. Ideally, the IHR revision process should
involve broad consensus with all WHO member states; better working
relationships among WHO, member states, and other international agen-
cies whose work is related to the IHR need to be established.
The IHR are a set of global regulatory guidelines for how to respond to
international disease threats and are currently the only binding set of regu-
lations established on global surveillance for infectious diseases by WHO
member states. They are designed to ensure maximum security against
international spread of disease with minimum interference of world traffic
and trade. However, the current IHR are limited in several ways; thus, the
call for revision. Most importantly, they stipulate regulations for only three
diseases, none of which are currently slated for eradication. The revised
IHR will be more comprehensive and will apply to all "events of urgent
international importance related to public health." An algorithm—or "de-
cision tree" is being developed for use in determining whether an event is
of urgent, international public health importance.
Additionally, the current IHR regulations do not provide any mecha-
nism for collaboration between member states and WHO. Even though the
best way to prevent international spread of disease is to identify and stop
local outbreaks before they begin to spread, national efforts often require
international assistance. Such a conclusion recognizes the advantage of a
single international entity (e.g., WHO) coordinating and overseeing global
surveillance. Equally important, even local events can have international
impact, especially if unauthorized information is disseminated in such a
way that it causes overreaction and gratuitously damages tourism, traffic,
or tracle. Indeed, one of the motivations for revising IHR was the increasing
threat of cross-border transmission due to increased transcontinental move-
ment of people. The new IHR wit! require mechanisms to assure rapid
communication between member states and WHO in the case of an out-
break; they will involve more collaboration between WHO and member
states; and they will ensure the quick dissemination of information to ap-
propriate sources.
Knowing if and when to discontinue surveillance in the post-eradica-
tion, post-immunization era poses a great challenge. With the continued
threat of bioterrorism and reemergence of disease from unknown natural
reservoirs or new viral variants, in combination with a decreased immunity
OCR for page 13
SUMMARY AND ASSESSMENT
13
and increased susceptibility in the population at large, it is likely that sur-
vei1lance will need to be continued and strengthened even after immuniza-
tion ceases, perhaps indefinitely. The potential usefulness of immunological
surveillance- perhaps using a saliva antibody test to detect declining vacci-
nation rates and pockets of susceptibility—as a supplement to disease sur-
veilIance needs to be further examined.
CONllNUlED VIRAL RESEARCH
IN THE POST-ERADICATION ERA
Although it may not seem worth arguing over whether a virus that only
spreads among humans and has severe adverse health effects should be
completely eliminated to the point of extinction, even in the laboratory, it
may be necessary to retain samples for future study, especially given the
rapid pace of viral evolution, the loss of immunity as infection disappears
and immunization ceases, and the likelihood that new viral variants with
altered pathogenicities or routes of transmission will emerge at some point
in the post-eradication era. Too often, success or near-success at eliminat-
ing an infectious agent results in languished research efforts toward advanc-
ing knowledge of that agent.
In anticipation of polio eradication in the early 1990s, for example,
polio research laboratories were told they would be soon required to cease
poliovirus research and destroy all virus and infectious DNA stocks. The
unfortunate consequence was that many research programs that could have
contributed valuable information on new vaccines, new antiviral drugs, and
animal models for virus transmission were shut down. If new vaccines or
antiviral therapies are to be developed to cope with unforeseen viral chal-
lenges, basic scientific research on viral-host biology must continue even
after eradication. Maintaining research programs that address important
scientific questions about viral biology and pathogenesis will require an
increased investment in containment laboratories and improved communi-
cation between the public health sector and research community.
Before viral stocks and samples can be safely contained, they need to be
located. Inventories must include not only vials clearly labeled "measles"
and "polio," for example, but also any biological samples, such as stool
samples from patients who have had suspected enterovirus infections, that
carry the risk of contamination. This is a daunting challenge. To complicate
matters, many laboratories or clinics do not even realize that they have
virus specimens until somebody stumbles upon them inadvertently.
Once identified, all viral stocks and samples should be transferred to
biorepositories demonstrating well-developed and documented procedures
for safe handling and security. This will ensure that the viruses are available
for ongoing research, as needed, with a minimal risk of accidental reintro-
OCR for page 14
14
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
auction. Established standards, such as Biosafety Level 3 (BSL-3) and the
more stringent BSL-4, have generally proven very successsfu! at protecting
both workers and the environment from infection or contamination, where
they have been in force. However, intermediate systems that incorporate
more controls than BSL-3 but are not as stringent as BSL-4 often rely on
ambiguous language and ill-defined protocol. Virus-specific standards need
to be clearly established, based on known risks and properties unique to
each virus.
Not only must virus stocks be safely contained in order to prevent
accidental reintroduction, but precautions need to be taken to protect
against intentional reintroduction as well. Internal security measures at
biorepositories where the virus is housed should insure restricted physical
access to the viruses (e.g., by securing freezers with locks that require two
people to open), and freezer inventories should be designed in such a way
that a locator code is needed to find the material. All movement of material
should be tracked to verify authorized access. Only qualified end-users
should be allowed access to the virus, and it must be assured that the
receiving laboratory is capable of controlling access. End-users should dem-
onstrate knowledge of the material and its potential hazards. Potential
recipients should be screened by appropriate authorities, e.g., the depart-
ments of Commerce, State, and Treasury.
Undue proliferation of many regulations will hinder important scien-
tific research. Restrictions may be necessary to prevent samples from falling
into the "wrong hands," but the regime must acknowledge the need for
scientific progress. It is imperative that the scientific and research commu-
nity be proactive in presenting a reasonable framework for viral research to
policy makers and legislators.
Physical containment of laboratory virus stock may become irrelevant
with the advent of advancer] recombinant and synthetic molecular tech-
nologies. Viral genes could readily be synthesized from nucleic acid se-
quences, and viruses themselves could probably be reconstituted from se-
quences or clones, thus precluding the need for continued storage of intact
viruses. Importantly, however, individuals or organizations with bioterrorist
intentions could do this just as well as legitimate research labs. And, as
bioengineering technology advances, it becomes more possible to construct
new, chimeric viruses. Although this would require greater planning, re-
sources, and scientific expertise than simply removing intact stocks from a
freezer, it may be an attractive alternative for persons or institutions with
bioterrorist or biowarfare intentions. Although unlikely, the threat of a
bioterrorist or biowarfare attack with an infectious agent of unknown
properties reinforces the need to continue viral and antiviral research in
support of improved vaccine and drug development.
OCR for page 15
SUMMARY AND ASSESSMENT
VACCINES AND ANllVIRAL THERAPIES FOR USE
IN THE POST-ERADICATION ERA
15
Following eradication, smallpox vaccine production ceased in 1982. By
the time it was realized that malevolent use of the smallpox virus posed a
serious bioweapons threat and the Centers for Disease Control and Preven-
tion (CDC) issued a contract for the production of a new national vaccine
stockpile in 2000, the vaccine reserve was not only deficient but had cle-
cayed over time. The vaccine program infrastructure had deteriorated; vac-
cine technology used previously for smallpox vaccine production was out-
dated; and standards of vaccine production had changed.
In order for other disease post-eradication initiatives to avoid the type
of catch-up campaign that production of the smallpox vaccine currently
faces, vaccine production and research must continue even after immuniza-
tion has ceased. This poses a tremendous challenge, as the financial incen-
tives to clevelop and produce new vaccines are weak, and research leader-
ship in this area is lacking. An in-date supply of vaccine must be made
available for use in the event of an outbreak. Vaccine development must
keep up with changing regulatory requirements, and improved vaccines
must be able to protect against newly evolved or bioengineered viral strains
with altered pathogenesis or routes of transmission. Stockpiles should be
replenished regularly; expertise and experience of the manufacturing and
control personnel should be maintained; and facilities, equipment, and the
production process should be continually validated, as well as reliable means
of storage. The size of vaccine stockpiles should correspond, at minimum,
to the threshold immunity required to break transmission. New methods
for rapid large-scale vaccine administration need to be developed and their
immunogenicity demonstrated.
Given the tremendous success of vaccination in the prevention of infec-
tious disease, one might question the necessity to develop other antiviral
therapeutics. However, given the risk of reintroduction of disease, the
evolvabilit,v of viruses, and the unknown changes that the human immune
system will undergo against the background of zero immunity in the post-
eradication era, other potentially useful antiviral strategies must be consid-
ered as means to strengthen the immune system or serve as adjuvant or
prophylactic therapies.
Although diseases currently stated for eradication have never been con-
sidered targets for antiviral drug development, our knowledge of molecular
biology and viral-host interactions has advanced to a point where selective,
specific antiviral agents could be developed. Although broader-spectrum
antiviral drugs, like interferon, would probably be more applicable (and
more likely to attract investors) than narrowly focused drugs that only
target specific viruses, they are notorious for their toxicity and many side
OCR for page 16
16
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
effects; also, more research would be needed to identify host cell functions
that could be targeted with a broader-spectrum antiviral drug. Although
treatment with antivirals should never serve as a substitute for the preven-
tion of disease, they can impact public health, as evident by their ability to
reduce viral loact in HIV-infected individuals. However, there are few in-
centives for manufacturers to invest in antiviral research, especially for
vaccine-preventable diseases. If antiviral chemotherapy could be developed
for a broad range of viral infections, it would cirastically alter our assess-
ment of risk of resurgence post-eradication.
Immunoprophylactics are another option. Although nonspecific
immunoprophylactics (e.g., interferon) have been developed for treatment
of a wide variety of diseases, experiences! knowledge of toxicity and effec-
tiveness of general prophylaxis against chronic infections in humans is very
limited and would require extensive research before being considered for
widespread use. Plus, given the readiness with which wild-type viruses
i:
evolve ways to escape host cell antiviral activities, it is unlikely that a
universal prophylactic agent will be identified. More promising are prophy-
lactic agents that target specific viruses. As with antivirals, the technology is
now available to develop specific prophylactic agents against chronic infec-
tions like polio, measles, and rubella, but this has not been done.
Our approaches to disease prevention, mainly vaccination, rest upon
the presumption that the human immune response has not changed for
centuries and will remain strong for centuries to come, even as immunity
changes in the post-eradication era. However, we do not know how true
this is. In light of the possibility that our immune system may weaken in the
post-eradication era—for example, from changing selective pressures it
would be a good idea to do all that we can to strengthen the immune
response. Probiotic bacteria living microbes introduced into the body to
improve intestinal microbial balance- have great potential to sustain an
immune response in the post-vaccine era and may prove useful in strength-
ening the immune response in immunocompromised individuals who are at
risk for chronic infection. For example, recent studies have shown that
probiotic lactobacilli can have a beneficial effect on the immune response in
HIV-infected children.
It has long been understood that our human body space is shared with
a multitude of microbial species, inhabiting our skin and mucous mem-
branes. On the presumption that these may have varying effects on our
health from mutualistic enhancement through every grade of pathogenic-
ity we have been wont to regard them as a "microbiome", a collective set
of genomes to be compared with our own intrinsic "human genome". As
this is written, the day's headlines refer to studies regarding a protective
effect of coinfection with the GBV-C, a relative of hepatitis-C virus, on the
course of AIDS (Xiang et al., 2001; Tilimann et al., 2001~. Proof is hard to
OCR for page 17
SUMMARY AND ASSESSMENT
17
find, but it makes evolutionary sense that any chronically infecting member
of the microbiome would enhance its fitness by excluding the extinction of
the host by more virulent competitors. In similar vein, we should not be
surprised that Helicobacter secretes peptide antibiotics active against chol-
era, though there is not yet direct evidence that this has any clinical signifi-
cance.
After eradication, the natural tendency is for vaccine and other relevant
research funding both public and private to wither away. However, ba-
sic research on the immunological basis of protection will be vital to devel-
opment of new vaccines and other antiviral therapeutics. A strong federally
supported research program will be crucial to advancing our knowledge of
viral genomics and pathogenesis in support of vaccine and antiviral drug
development. Strong commitment is needed from both the public and pri-
vate sectors to share the costs and risks associated with developing products
which may have only a very short product life cycle. Research on non-
vaccine antiviral therapies must be continued and strengthened in light of
the fact that the post-eradication era may, ironically, pose even greater
challenges to the immune system as immunity wanes and viruses evolve.
INSTITUTIONAL AND SYSTEMS PREPAREDNESS
FOR DISEASE OUTBREAK
When discussing disease outbreaks in the post-eradication era, small-
pox is of foremost concern since it is the only disease that has already been
eradicated, plus we have a precedent for it. In 1946, in response to a new
outbreak of smallpox and a single import from Mexico, six million New
Yorkers were vaccinated. The question is, what would the situation be like
if there were a recurrence of that same event today? First and foremost,
would there be enough vaccine to vaccinate everyone who would need to be
vaccinated? Who would need to be vaccinated? Where would the vaccine
come from? And how would it be released? To complicate matters, today's
population is much more susceptible to infection than it was in 1946, and
emergency vaccination measures taken at that time were probably to some
extent supererogatory since at least half of all New Yorkers were probably
already vaccinated. It is likely that a newly introduced case would spread
much more rapidly today than it would have done several decacles ago.
Drawing on the lessons learned from smallpox eradication and as
summarized above and discussed in detail throughout this report, a re-
sponsible post-eradication strategy must include provisions for vaccine
reserves and contingency planning in case the disease re-emerges; contin-
ued surveillance and diagnostic activities; and research on and develop-
ment of new vaccines and antiviral therapeutic drugs. The federal govern-
ment will play a key role in supplying these provisions in the
OCR for page 18
18
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
post-eradication era. With regard to vaccine production, for example, vac-
cines will become much less profitable to market after certification of
eradication. Plus, over time, regulatory guidelines for vaccine manufacture
are likely to become more troublesome as unforeseen safety issues arise
(e.g., the risk of prion-mectiated diseases resulting from incorporation of
bovine derivatives into vaccines). Because of the increased cost of produc-
tion and stricter regulatory guidelines, the private sector will likely lose
interest in vaccine manufacture, and government-sponsored production
may be necessary to maintain adequate vaccine supply.
The security consequences of a post-eradication oubreak should be
assessed and prepared for from the outset of any eradication effort. Agents
with biowarfare potential should be included in formal biological control
negotiations, and information gathered to help determine if any nations or
groups have sought to develop the agent as a bioweapon. The intelligence,
arms control, law enforcement, and defense communities must be ad-
equately prepared since they are all likely to be involved in the event of a
disease outbreak with national security consequences. Intelligence informa-
tion may be required to help determine if the outbreak was a natural or
deliberate occurrence; evidence may need to be collected for legal or arms
control issues; recurrence of disease outbreak will need to be prevented; and
those responsible will need to be held accountable.
Hospitals serve as a major hub in the U.S. health care system and can
and should play a major role in an outbreak response. However, at present,
the U.S. health care system is not prepared to handle either a natural or
intentional disease outbreak. It lacks the capacity and infrastructure; has
neither incentives nor mandates that require preparedness; has no networks
in place to aid in the coordination of response among different health care
communities; and is plagued by unresolved staffing and legal policy issues.
In order to effectively confront the demands of an outbreak, including the
mass surge of people, the health care system must at least be operating
effectively prior to the outbreak. However, U.S. hospitals are currently
facing tremendous economic pressures, and current staff levels are insuffi-
cient to cope even with small and predictable influenza epiclemics. Without
funding incentives or mandates in place, it is unreasonable to expect that
hospitals will take the necessary measures to prepare for disease outbreaks
in the face of other, more pressing and immediate concerns.
Substantial communications barriers exist among and between public
health agencies, emergency and first response communities, and medical
care delivery communities. These barriers, combined with a climate of
competition among hospitals and distrust across the public/private sector
divide, prevent coordinated regional responses. Effective regional networks
will require adequate funding, designation of an in-charge organization and
individual, and development of a regional response plan.
OCR for page 19
SUMMARY AND ASSESSMENT
19
The consequences of a disease outbreak in a post-eradication era will
entail more than public health and security implications: the psychological
response particularly fear and panic could hinder intervention and con-
trol. The media, government, and medical communities will play large roles
in determining how the public will respond to an outbreak. While clevelop-
ing outbreak policies, the emotional and physical impact on leaders of these
communities will need to be taken into account. Over-declication, steep
deprivation, and the intensity of their roles during a crisis can lead to sub-
optimal decision-making and other manifestations of poor judgement. Pro-
tocols need to be developed for decision-making processes in the event of an
outbreak. Research is needed on how to address the psychological and
behavioral consequences of an outbreak, and the behavioral and societal
effects of past infectious disease outbreaks should be studied in order to
identify effects of different responses. Research is also needed on how best
to enlist media support in the management of outbreaks, and risk commu-
nication programs need to be developed.
By definition, post-eradication outbreaks would involve infections
rarely, if ever, seen in medical practice. Primary health care workers may
have limited knowledge of the pathogen in question, making disease diffi-
cult to diagnose and treat. Untrained or mistrained responders could con-
tribute to institutional breakdown. Poor medical knowledge can lead to
conflicting messages and confusion regarding an appropriate course of ac-
tion. While it is the nature of scientific discourse to debate and criticize, this
will not instill confidence in a time of crisis and can react to an undermining
of authority. We need a better understanding of how the public should be
trained to anticipate and cope with the diverse, and often conflicting, infor-
mation that may be disseminated in the wake of an outbreak.
CONCLUSION
The current state of the U.S. health care system reveals a weakness in
the United States' capacity to control outbreaks in a post-eradication era.
However, this capacity is even weaker or even non-existent in poor coun-
tries who do not have any health infrastructure or resources to cope with an
outbreak. Too often in the developing world, global eradication priorities
override local health priorities. In the polio eradication effort, for example,
countries have been pressured to focus on global priorities (to immunize
everyone, for example, even if polio is not a disease that the people have
witnessed) at the expense of eliminating other diseases that are killing their
children but for which there is no global eradication effort. Recent reports
indicate, however, that efforts to strengthen local health service infrastruc-
tures can operate synergistically with efforts to Oldness global priorities-
the two need not be mutually exclusive. In particular, evidence indicates
OCR for page 20
20
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
that eradication efforts are more successful in countries with a strong health
infrastructure in place. Focusing on building local health infrastructures
ant! empowering communities with the resources to address their own prob-
lems in a self-reliant way is the best framework for clearing with disease
outbreaks in a post-eradication era.
However, building local health infrastructure does not necessarily mean
implementing the "cloc-in-the-box" western model of primary health care
centers. An important lesson learned from smallpox eradication was that
vaccination could not be achieved by waiting for people to show up at a
primary health care center. Rather, the vaccinators had to go out into the
field and contact the people. Furthermore, what works in one locality may
not work in another. Priorities for action must be based on an assessment of
local resources and capabilities.
That so many countries still lack basic health services to prevent and
cope with current public health crises, let alone capabilities to respond to a
major disease outbreak in a post-eradication era, is indicative of the reality
that even though post-eradication challenges need to be considered and
prepared for concurrently with eradication efforts, still, except for small-
pox, the post-eradication era may not be foreseeable in the near future. This
is true even of polio, which is considered next in line for eradication.
However optimistic we are about global eradication of polio, measles,
rubella, or any other disease, current conditions in many parts of the world
still pose significant challenges to eradication, let alone post-eradication
strategizing.
There is some concern that too much focus on eradication, rather than
on control, could divert resources and effort away from more pressing and
serious public health crises. After all, the practice of good public health is
based on the judicious and wise use of limited resources to achieve maxi-
mum public benefit; neither the international public health community nor
any single nation has unlimited funds to support public health programs.
Eradication is expensive, thus the decision to eradicate must be based on an
in-depth review of all available funds and resources. Equally important, it
must also be based on a thorough evaluation of the opportunities that may
be lost by prioritizing actions and making decisions for the sake of eradica-
tion. For example, although polio is generally considered next in line for
eradication, some participants in this workshop questioned the wisdom of
focusing too much on polio eradication when there remain nearly a million
people dying each year from measles. This high opportunity cost of polio
eradication (i.e., lives lost) leads one to woncler if polio and measles eradi-
cation efforts should be conducted concurrently with more emphasis placed
on controlling both, rather than eradicating one or the other. Another
advantage to emphasizing control rather than eradication is that the former
keeps us on guard that there might be still somewhere on the planet a
OCR for page 21
SUMMARY AND ASSESSMENT
21
threat great enough to motivate continued surveillance, vaccination, and
research.
The information contained in this report provides important insights
that can and should be incorporated into the decision-making process about
whether to enter into future eradication efforts. With respect to polio eradi-
cation efforts, for example, a major selling point to political leaders was the
potential post-eradication cost savings. But if we had known that immuni-
zation would likely need to be continued even in the post-eradication era,
would the level of political commitment have been the same? If we had been
more aware of the post-eradication challenges, would we have favored
disease control rather than eradication and would development of the health
infrastructure have been a better overall investment? These are difficult
questions to ask. Many would contend that the eradication of smallpox is
one of public health's greatest victories, a feat worthy of being emulated.
Yet we must be cautious about embracing the ideology of eradication at the
expense of sound, rational judgement. Given the challenges of managing
the many post-eradication issues raised during this workshop, the public
health community must consider all available evidence when deciding
whether to launch similar efforts in the future.
Once a major disease has been eraclicated, too much is at stake to
return to a pre-eradication era. Post-eradication strategies need to be con-
sidered early on during an eradication campaign and developed when the
possibility of eradication is certain. As population immunity wanes, viruses
evolve, and complacency sets in, the catastrophic potential of a disease
outbreak in the post-eradication era increases. It is crucial that we ad-
equately prepare for recurrence of an outbreak, no matter how improbable.
The issues raised in this workshop provide a framework for thinking about
post-eradication policy and research needs that must be addressed now,
before eradication of any other disease is certified and while there is still
time to prepare and conduct crucial research that can influence how well
we will meet the challenges of the post-eraclication era.
REFERENCES
Tillmann HL, Heiken H. Knapik-Botor A, Heringlake S. Ockenga J. Wilber JC, Goergen B.
Detmer J. McMorrow M, Stoll M, Schmidt RE, and Manns MP. 2001. Infection with
GB virus C and reduced mortality among HIV-infected patients. New England Journal
of Medicine 345(10):715-724.
Xiang J. Wunschmann S. Diekema DJ, Klinzman D, Patrick KD, George SL, and Stapleton
JT. 2001. Effect of coinfection with GB virus C on survival among patients with HIV
infection. New England Journal of Medicine 345(10):707-714.
Representative terms from entire chapter:
disease eradication
