|
Items in cart [0] |
Questions? Call 888-624-8373 |
PAPERBACK + PDF PAPERBACK PDF BOOK PDF CHAPTERS Free Resources |
||||||||||||||||
|
||||||||||||||||
|
|
|||||||||||||||
| ||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||
| Copyright © 2009. National Academy of Sciences. All rights reserved. Terms of Use and Privacy Statement |
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 64
Biological Challenges to
Post-Eradication
OVERVIEW
All of the viruses currently under consideration for eradication rely on
highly effective vaccines and well-defined immunization programs to inter-
rupt transmission. Major biological challenges after eradication include:
.
knowing how and when to stop immunization;
· improving vaccine technology and production should a vaccine
ever be needed even after the cessation of immunization;
safely containing viruses in the lab in the post-eradication era; and
continuing and improving surveillance for the detection of vaccine-
associated cases, recrudescence of infection, new zoonotic transmissions,
and the emergence of recombinant viral strains.
Overcoming these challenges will require a better understanding of
pathogen transmission and viral biology.
For example, vaccine-preventable viruses (e.g., polio and measles) are
characterized by boom-and-bust epidemic cycles which exhibit extraordi-
nary non-linear dynamics due to the complex population-level interactions
that influence transmission. Mathematical modeling that takes these inter-
actions into account provides a robust scientific framework for predicting
the impact of mass vaccination and exploring immunization cessation strat-
egies. It can help us answer questions such as: How extensive must vaccina-
tion be to interrupt transmission in a clefined population? What age class
should mass vaccination target? Are catch-up campaigns effective?
64
OCR for page 65
BIOLOGICAL CHALLENGES TO POST-ERADICATION
6s
Even after eradication and the cessation of immunization, it may not be
desirable to completely eliminate all traces of the infectious agent because
of its use in basic scientific and vaccine advancement research, as well as the
need for an emergency stockpile in case of recrudescence. Thus, post-eradi-
cation strategies must consider safe laboratory containment of the virus to
minimize the risks of accidental or intentional re-introduction.
In addition to recrudescence of wild-type virus, other potential post-
eradication outbreaks could result from vaccine-associated infections, new
recombinant strains of virus (e.g., between circulating HIV and newly in-
troduced SIV), or new zoonotic transmissions (e.g., the existence of a pri-
mate reservoir must be taken into account while planning future eradica-
tion, and eventually post-eradication, strategies for HIV/AIDS). Most
notably, vaccine-associated paralytic poliomyelitis (VAPP) demonstrates
how vaccine-associated cases of disease can occur even when disease due to
wild-type virus is eliminated. Post-eradication strategies will require con-
tinual surveillance, more information about the duration of shedding and
the persistence of the vaccine-derived virus in the environment, and con-
tinuing vaccine coverage even in areas where wild-type virus has been
eraclicated.
Viruses have extraordinary evolutionary strategies about which we have
very little unclerstanding. Continual surveillance and improved sampling
methods are essential for tracking new genetic variants, particularly as
more vaccines are introduced worldwide and rarer genotypes are selected
for. The chance that new viruses could evolve underscores the need for
continuer! development of improved vaccines and vaccine delivery systems.
HERD IMMUNE Y AND TO DESIGN OF
VACCINATION PROGRAMS
Professor Roy M. Anderson, Ph.D., F.R.S.
Department of Infectious Disease Epidemiology
Imperial College School of Medicine
University of London, London, U.K.
The past four decades have witnessed remarkable success in the control
of viral diseases by mass vaccination. The most notable of these is the
eradication of smallpox in 1977 (Fenner et al., 1988), which resulted from
an intensive worldwide immunization campaign. The success of the small-
pox campaign has provided hope that other viral infections for which
effective and safe vaccines are available- particularly polio and measles-
can also be eradicated, given the will and financial resources. However,
there are still many problems associated with pathogen transmission that
OCR for page 66
66
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
must be resolved before eradication can be achieved. These problems result
from variation in vaccine uptake among countries, increased mixing of
populations between cities and towns worldwide, and the high transmissi-
bility of viruses within high-density populations.
The development of a safe, effective, and cheap vaccine is only the first
step albeit a vital one—toward community-based control of infectious
disease. Population-leve! processes, such as the demography of the human
host, human behavior, and the biological factors that influence transmis-
sion all play critical roles in determining the impact of mass vaccination.
The dynamics of the interaction between an infectious agent and its human
host population are complex and often highly non-linear in form due to
variation in the course of infection within the human host and the interac-
tion of demography (e.g., net birth rate) and host behavior (e.g., patterns of
mixing) (Anderson, 1994~. The resultant complex patterns are often sea-
sonal; they are driven by both climatic influences on the likelihood of
transmission and changes in behavior (e.g., school attendance and aggrega-
tion of children). They can also be longer-term as a result of the dynamic
interaction between the exhaustion (by infection) and renewal (by new
births) of the supply of susceptible individuals. Longer-term cycles occurred
in many developed countries prior to and after the initiation of routine
mass immunization and are a well-known phenomenon.
Once mass vaccination is initiated within a defined community, these
complex interactions may be influenced in a manner that is not easily
understood in the absence of a detailed template for analysis and interpre-
tation. Mathematical models that combine the processes underlying the
typical course of infection in the host with those that determine transmis-
sion between hosts provide a robust scientific framework for the prediction
of intervention impact and the formulation of cost-effective policies (Ander-
son and May, 1990; Anderson et al., 1997~. This summary provides a
review of recent progress in this type of mathematical modeling, with a
particular focus on the factors that influence the persistence of infection
and disease in communities with high rates of vaccine uptake. The child-
hooct vaccine-preventable viral and bacterial infections, such as measles,
mumps, rubella, polio, and pertussis, provide the empirical basis for much
of the theory.
Basic Principles
Simple theory provides many insights into the likely impact of a defined
immunization program targeted at a particular infectious agent. One of the
central epidemiological concepts underlying this theory is the basic repro-
ductive number, Ro' which is clefined as the average number of secondary
cases of infection generated by one primary case in a susceptible commu-
OCR for page 67
BIOLOGICAL CHALLENGES TO POST-ERaDICATION
67
nitv. The magnitude of Ro is determined by a blenci of parameters that
influence the typical course of infection within the human host with param-
eters that determine transmission between inclivicluals. For a clirectly trans-
mittec3 viral or bacterial infection that exhibits little antigenic variability
(i.e., one dominant serotype), the approximate value of Ro is given by the
expression:
Ro = [L - A]/[A - M],
where L is human life expectancy, M is the average duration of protection
from maternally derived antibodies, ancI A is the average age of infection in
an unvaccinated community. The value of L can be replaced by an equiva-
lent term representing the net birth rate of the community, since it is this
parameter that generates the renewal of the supply of susceptibles. For
example, for measles in the United States prior to wide-scale immunization,
with L, A, and M values of 70, 5, anc! 0.5, respectively, each primary case
of infection generated 14 to IS secondary cases in a totally susceptible
community.
In the case of endemic persistence within a community, where many
have recovered from infection and are immune to re-infection, the effective
reproductive number, R. is unity in value: each primary case generates, on
average, exactly one secondary case. The effective reproductive number, R.
is the average number of secondary cases generated by one primary case in
a population that is not entirely susceptible to infection (i.e., the presence of
those who are immune due to recovery or immunization). In cases where
seasonal factors influence transmission and the transmission dynamics of
the virus generates longer-term oscillations in incidence, the magnitude of R
will fluctuate above anci below unity in value.
The magnitude of Ro in an unvaccinated community can be determined
from either cross-sectional or longituclinal serological surveys which clefine,
by age, what percentage of the population is seropositive for specific anti-
gens of an infectious agent. The rate of increase in seropositivity between
two age classes provides a quantitative measure of the age-specific inci-
clence of infection, which is sometimes referrec3 to as the "attack rate" or
"force of infection."
A serological approach to epiclemiological surveillance is much more
accurate than case reports of infection, since the latter tend to vary in
reliability depending on the prevailing incidence of infection. Under-report-
. . . , . . . .
lIlg IS common w ten an infection IS rare, anc over-reporting can arise
cluring an epidemic phase in a recurrent epidemic situation. Serology works
well for viral infections but is more problematic for bacterial disease, due to
the decline over time in detectable antibodies to past infection.
A diagrammatic illustration of a cross-sectional serological survey is
OCR for page 68
68
:~ 0.6
Q
o
a)
In
C
o
o
0.9
0.8
0.7
0.5
0.4
0.3
0.2
0.1
o
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
Age-specific serology
l i....
~ ....
:~
1~,~.:
Used to calculate the average
age at infection, A, and the
average duration of maternal
antibody protection, M.
2.5 5 7.5 10
Age in Years
= Maternal Antibodies Antibodies from Infection
12.5 15 17.5 20
FIGURE 3-1 Diagrammatic example of a cross-sectional serological survey (L = 70
yrs, A = 5 yrs). It records the fraction of a sample of sera collected from a popula-
tion that are seropositive to the antigens of a defined infectious agent, stratified by
host age.
documented in Figure 3-1. The pattern displayed provides considerable
information relevant to the design of mass vaccination programs. For ex-
ample, the trough in susceptibility, which occurs after the decay of mater-
nally derived protection and before the rise resulting from infection, defines
the optimum age for vaccination, given the poor efficacy of many vaccines
if delivered when the titer of maternally derived antibody is high.
Cross-sectional surveys can be repeated yearly and then combined to
provide a longitudinal pattern of immunity and a precise picture of the
"herd immunity" profile of a population over time. The specificity and
sensitivity of saliva-based serological tests for many viral infections suggest
that surveillance based on herd immunity profiles should be more widely
adopted. Gaps or troughs in herd immunity profiles can provide policy
OCR for page 69
BIOLOGICAL CHALLENGES TO POST-ERADICATION
69
guidance for the introduction of "top up" age-targeted immunization pro-
grams in situations where overall levels of vaccine uptake are moderate to
high. If stratified by location and ethnic or other social group, the profiles
can also be used to identify social groups or communities with low uptake
levels. Finland is exemplary in the quality of serological data collected to
monitor infectious disease incidence and the impact of particular mass
vaccination programs. Few other countries use this approach to infectious
disease surveillance.
Mass Vaccination
Theory also sheds light on the degree of mass immunization required to
block transmission in a defined population. If the average age at immuniza-
tion is V, and A and L are as defined previously, then the critical proportion
of each yearly birth cohort that must be effectively immunized to block
transmission, Pc' is given by the simple expression (Anderson and May,
19921:
Pc = ILL - AJ/tA _ Ad.
The critical fraction is minimized by keeping the value of V as low as
possible. For infections, such as measles, that have a low average age at
infection (A), cohort immunization must be very high (typically in excess of
90% to 95%) to block transmission within most urban populations. Theo-
retically, in rural areas with lower densities and higher average ages at
infection, the critical level of uptake to block transmission is somewhat
lower. Practically, however, the values Of Pc derived for urban areas must
be applied even to rural communities due to ever-increasing connectedness
between urban and rural areas.
The expression for Pc defined above oversimplifies the tasks required
for eradication. For example, two important factors that affect the value of
Pc are a decrease in vaccine efficacy in the presence of high titers of mater-
nally derived antibody (these decline rapidly from birth, with a detection
half life of roughly 6 months for most viral infections), and vaccines of less
than perfect efficacy, even in the absence of maternal antibodies. Both of
these factors yield a more complex expression for the value °f Pc
Once Pc is derived, a graph can be plotted for any given infection and
vaccine of defined properties relating the average age at vaccination (V) and
vaccine efficacy (e) to the critical fraction of a cohort that must be immu-
nized (Pc) (see Figure 3-2; Anderson et al., 1997~. The efficacy of most
current vaccines is far less than perfect: estimates range from 72% to 88%
for mumps, 90°/O to 95% for measles, and 96% tO 99% for rubella (Plotkin
and Orenstein, 1999~.
OCR for page 70
70
0.99 -
-' 0.98 -
g
° 0.97-
a
._
0.96-
0.95 -
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
Fraction that must be vaccinated to block transmission
(A = 5 years)
lo\
Q-0.97
\ Q-0.98
Q = 1.0
1 . 1 1 1 1 1 1 1 1 1
-
-
-
/
Maximum
vaccine
efficacy, Q
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5
Average age at vaccination, V (years)
FIGURE 3-2 The impact of age at vaccination and vaccine efficacy on the critical
level of cohort vaccination required to block transmission.
NOTE: Vaccine efficacy changes with age due to presence of maternal antibodies.
In the case of highly transmissible infections (high Ro values), such as
measles, a lower than 100% vaccine efficacy strongly hinders the task of
blocking transmission. As illustrated in Figure 3-2, the fraction of the co-
hort that must be immunized in order to block transmission is greater than
one, implying that more than one round of immunization of a given cohort
is required for effective blockage (i.e., two-stage immunization policies)
(Bottiger et al., 1987~. Even two-stage immunization may not be sufficient
if either the average age at infection is very low, children who are not
protected by the first immunization can never be protected due to nutri-
tional or genetic factors, or if those not immunized in the first round of
immunization are also not immunized in the second round at a later age. An
example of the consequences of low average age at infection is the situation
in Lagos, Nigeria, a large city in a developing country with a high birth rate.
An average age at infection of around one to two years prior to mass
vaccination requires that immunization be effectively administered near
birth in order to block transmission. However, if delivered too soon after
birth, the presence of maternally derived antibodies significantly reduces
vaccine efficacy. In short, the combination of high transmissibility (low
average age at infection), imperfect vaccine efficacy, and behavioral or
OCR for page 71
BIOLOGICAL CHALLENGES TO POST-ERADICATION
71
social predisposition to remaining unimmunized suggests that eradication
in some parts of the world may be very difficult.
Mass immunization influences the epidemiology of infectious agents in
several ways. First, it lowers transmission success (i.e., from infected to still
susceptible individuals), thereby increasing the average age at infection. If
the likelihood of serious disease resulting from infection increases with age,
low to moderate vaccine coverage may increase net morbidity, a particu-
larly worrisome situation for rubella vaccination campaigns in developing
countries. Every effort should be made to achieve high uptake. Second,
immunization tends to lengthen the inter-epidemic period. Third, a trough
of susceptibility moves across the herd immunity profile in older age classes,
due to decreased transmission rates and exposure following the mass im-
munization (see Figure 3-3~. All of these epidemiological phenomena, which
have been both predicted by theory and observed in practice, need to be
considered when monitoring the impact of mass vaccination.
How to Vaccinate and at Which Age
The design of immunization programs involves many different factors,
such as cost and sustainability. Developed countries usually use cohort
immunization at one or two different ages for any given vaccine or combi-
nation of vaccines (e.g., measles-mumps-rubelIa [MMR]~. Practicalities dic-
tate that ease of access to infants and children via health clinics or schools
is critical in determining at what age vaccination is offered. It is essential
that as high a fraction of children as possible are immunized at as young an
age as possible, while taking into account the complexities induced by
maternal antibodies. For example, even though many countries offer MMR
vaccination at around two years of age, the observed distribution of ages at
immunization is not always clustered around this age as it should be.
An alternative or addition to cohort immunization is a pulse or "catch-
up" immunization strategy involving particular days (or weeks) designated
as "immunization days" and publicized by the press. On immunization
days, health care services offer vaccination to all children of a particular age
range. Immunization days must occur at regular intervals, perhaps every
one to two years in the early stages of the program and less frequently as
overall coverage rises and infection incidence falls. This approach has been
used with considerable success in South American countries (de Quadros et
al., 1996~.
Analyses based on mathematical models of viral transmission confirm
that catch-up campaigns can effectively disrupt spread, particularly when
infections exhibit seasonal oscillatory trends in incidence or inter-epidemic
periods lasting a few years (Agur et al., 19931. The optimum time for a
vaccination day or week is during a trough in incidence between epidemic
OCR for page 72
72
0.8
g
:~
An
o
~ 0.6
a)
00
o
._
~ 0.4
IL
0.2
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
Susceptibility
trough
0<1m 6-m 2-
<1 m 6-m 2 -
1-m 1- 4
1-m 1- 4-
r ~ H~;5
1981
1979
6- 10- 14- 20- 30- >60
8- 12- 16~ 25- 40-
Age
I so:'
1 987
1 985
1991
FIGURE 3-3 Herd immunity profile for rubella in Finland, recording the trough in
susceptibility moving across the surface following the initiation of mass immuniza-
tion in 1981. The y-axis records the fraction of a sample of sera collected from a
population that are seropositive to the antigens of the rubella virus, stratified by
host age and year of collection (Ukkonen, 1996~.
cycles. Catch-up campaigns are especially valuable in developed countries,
where they serve to mop up susceptible pockets within the population.
However, it is important to recognize that any cessation or decline in
effectiveness of either cohort or pulse programs will rapidly lead to a build-
up of susceptibles, particularly in high birth rate communities. Increased
OCR for page 73
BIOLOGICAL CHALLENGES TO POST-ERADICATION
73
susceptibility makes a population vulnerable to the reintroduction of infec-
tion from other countries or areas with lower vaccine coverage. Molecular
epidemiological studies have revealed how travelers carry infections, such
as measles and rubella, across continents, thereby creating short chains of
transmission within susceptible pockets in highly vaccinated populations
(Bellini and Rota, 1998~.
Persistence or Eradication
Chains of transmission often persist even within highly vaccinated com-
munities in developed countries. A number of factors create difficulties
cluring the final push for the elimination of indigenous transmission. First,
successful programs tend to increase the average age of infection. Conse-
quently, cases of infection are often observed in clusters in older age classes
(i.e., older than the age class for which immunization is first offered>.
Second, incidence increases in the younger age classes (i.e., younger than
the age class for which immunization is first offered). Third, the synchrony
of epidemics among different spatial locations decreases. Prior to wide-
spread immunization, the epidemic cycles of most childhood viral and bac-
terial infections are highly correlated in different spatial settings within
countries. However, synchrony decreases significantly as vaccine coverage
rises, incidence falls, and inter-epidemic periods lengthen (Bolker and
Grenfell, 19963. Controlling these minor epidemics may require that catch-
up campaigns be timed differently.
Eradication is especially difficult when there is variation in vaccine uptake
among regions, areas, or spatial locations. In developed countries, vaccine
uptake in poor inner-city communities is often low. Pockets of low immunity,
particularly if linked with overcrowding, poor public health care facilities, and
high birth rates, provide reservoirs of infection for the sustenance of transmis-
sion. The ever-growing connectedness of urban centers across the world via
air, road, anal rail (even within Africa) suggests that continued immunization
is necessary in all regions until vaccine uptake is uniformly high across the
globe. Increased vaccine uptake reduces effective community size, which re-
sults in greater fade-out (i.e., a greater number of weeks during which there
are no reported cases of infection) (see Figure 3-4~.
Cost-Effectiveness of Mass Immunization
The main obstacles to eradication of measles and polio are often per-
ceived to be financial. In today's world of rising health care costs, where
many different interventions are possible in both developed and developing
countries, cost-effectiveness is a major factor to consider when deciding
which intervention to use. An increasing number of vaccines are available
OCR for page 74
74
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
o
8
o
.=
o
~ 6
Q
o
a)
IL
4
2
o
~ ~ ~^
am.
rot
~ ~~ ~
US/Can. cities
1 921 -40
Various islands,
1 950-65
British cities,
1 960-64
_ · ~~,.~*.i7.~.~,=~.<'~.~.~.~ ~.~.~Y~
103 104
05 1 o6 107 5x107
Population size
FIGURE 3-4 Critical community size for measles, defined as the population size at
which fade-out (proportion of weeks in a year when no cases reported) of cases
rises rapidly to approach unity.
for both viral (e.g., varicella) and bacterial infections (e.g., pneumococcal
infections). Pharmaceutical companies and government health agencies of-
ten use cost-benefit analyses to determine which vaccine to use. However,
these analyses tend to grossly underestimate the benefit of vaccination pro-
grams, because the current health economic methods of analysis typically
only take into account the direct effects of immunization on the vaccinated
individual. In practice, immunization has important indirect effects as well
because it decreases transmission among those still unvaccinated. The mag-
nitude of these indirect benefits increases rapidly as overall vaccine cover-
age increases and, as illustrated in Figure 3-5, may comprise a significant
fraction of the overall benefit. The magnitude of the indirect benefit is
calculated in a way that takes into account the impact of immunization on
transmission success as a function of vaccination coverage. The time frame
over which benefit is calculated (i.e., the number of years) is critical for an
accurate assessment of cost versus benefit.
Morbidity Induces! by Immunization
All vaccines carry a small risk of adverse effects in the immunized
patient (Peltola and Heinonen, 1986~. When the disease is common, risk of
serious morbidity from infection is many orders of magnitude greater than
risk associated with immunization. The values of the two risks converge
when vaccine coverage approaches the level required to block local trans-
OCR for page 87
BIOLOGICAL CHALLENGES TO POST-ERADICATION
87
Known or believed to represent natural infections, and five of them have
been identified in chimpanzees from west central Africa (P. t. troglodytes).
A sixth strain was isolated from a wild-caught chimpanzee of unknown
geographic origin which was classified as a P. t. schweinfurthii on the basis
of mtDNA analyses (Gao et al., 1999; Peeters et al., 1992~. All three groups
of HIV-1 are significantly more closely related to the five SIVcpz(P.t.t.)
isolates than to the one SIVcpz(P.t.s.) strain, indicating that the cross-
species transmissions that gave rise to all three groups of HIV-1 (M, N. and
O) occurred in west central Africa (Gao et al., 1999~. HIV-1 groups N and
O viruses are essentially restricted to west central Africa (Mauclere et al.,
1997; Simon et al., 1998), and chimpanzee and group N human viruses
from Cameroon form a unique subcluster in phylogenetic trees, implicating
this country as the likely site of origin for HIV-1 group N (Corbel et al.,
2000; Simon et al., 19981. Although HIV-1 group M is spreading globally,
the greatest diversity of group M viruses has been found in the western
parts of the Democratic Republic of Congo (i.e., Kinshasa), which is consis-
tent with this being the region of the initial group M expansion (Vidal et al.,
2000~. Kinshasa is outside the range of chimpanzees, but it is close to the
natural range of P. t. troglodytes and is by far the largest city in the region.
Together, these findings provide compelling evidence that HIV-1 arose as a
consequence of three independent SIVcpz transmissions from naturally in-
fected chimpanzees in west central Africa.
Although the routes and circumstances of cross-species transmissions
are unknown, it is believed that human infection with SIVcpz and SIVsm
resulted from exposure to infected blood during the hunting and field dress-
ing of animals, the preparation of primate meat for consumption, and bites
and scratches from infected pets or wounded animals (Hahn et al., 2000~.
Given that humans throughout sub-Saharan Africa are in frequent contact
with primate species other than chimpanzees and sooty mangabeys, the
possibility of additional zoonotic transfers of primate lentiviruses must be
considered. Indeed, a recent survey of bushmeat markets in Cameroon
revealed that up to one-third of all primates offered for sale were SIV-
infected (Peelers et al., 20013. Peeters and colleagues found that over 130 of
400 wild-caught monkeys from 13 different species had serum antibodies
that cross-reacted with HIV-1 andlor HIV-2 antigens. PCR amplification of
viral sequences confirmed SIV infection in a subset of these animals and
revealed the existence of four new SIV lineages not previously known to
infect primates in the wild. This study thus provided conclusive evidence
that humans are routinely exposed to a wide variety of primate lentiviruses
through the hunting and handling of SIV-infected primates.
Commercial logging represents an important economic activity in many
west central African countries; it has led to road construction into remote
forest areas, human migration, and the development of social and economic
OCR for page 88
88
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
networks which support this industry (Auze! and Hardin, 2000; Geist,
1988; Wilkie et al., 2000~. Hunters are now penetrating previously inacces-
sible forest areas and using modern weapons and a newly developed infra-
structure to capture and transport bushmeat, including many primates,
from remote areas to major city markets. These socioeconomic changes,
combined with current data on SIV prevalence and genetic complexity in
mild living primates, strongly suggest that the magnitude of human expo-
sure to SIV has increased dramatically, as have the social and environmen-
tal conditions that support the emergence of new zoonotic infections.
It remains unknown whether SIVs other than SIVcpz and SIVsm have
the ability to infect humans. Molecular evidence for such cross-species
transmissions does not exist; however, such infections might have gone
unrecognized. An example is the recent identification of a Cameroonian
man who had an indeterminant HIV serology but reacted strongly with an
SIVmnd V3 loop peptide (Souquiere et al., 20011. Although SIV infection
was not confirmed in this individual, the finding suggests that at least some
naturally occurring SIVs (other than SIVcpz and SIVsm) have the potential
to infect humans. In fact, several recently reported SIV isolates (Georges-
Courbet et al., 1998; Souquiere et al., 2001) replicate well in primary
human lymphocytes in vitro, as do SIVcpz (Gao et al., 1999; Peeters et al.,
1992) and SIVsm (Peelers et al., 1994~. Thus, to determine whether addi-
tional zoonotic transmissions of SIVs have already occurred, screening as-
says that can reliably recognize and distinguish the wide variety of SIVs
now known to infect wild-living primates will have to be developed.
It is also important to distinguish between the initial transmission of a
new SIV and the many additional factors that promote secondary transmis-
sions and, ultimately, epidemic spread in the human population. The fac-
tors that trigger epidemic outbreaks of newly introduced SIVs are unknown
but could possibly involve situations where the recipient of a cross-species
transmission event is already infected by an existing HIV. In these cases,
superinfection and recombination could generate mosaic viruses of consid-
erable genetic and biological complexity. Evidence that such events have
taken place in primates has come from studies of SIVs infecting sabaeus
monkeys (SIVagmSab), red-capped mangabeys (SIVrcm), and mandrills
(SIVmnd2) (Georges-Courbet et al., 1998; fin et al., 1994b; Souquiere et
al., 20011. In each case, mosaic viruses comprised of different SIV lineages
are widely distributed in their respective host species and thus represent
cases where cross-species transmission and recombination have led to suc-
cessful virus adaptation and dissemination, perhaps even outcompeting the
previous incumbent SIVs. As the prevalence rates of HIV-1 group M viruses
are rising in west central Africa, recombination of newly introduced SIVs
with circulating HIVs has become a more probable scenario.
OCR for page 89
BIOLOGICAL CHALLENGES TO POST-ERADICATION
TABLE 3-1 SIV Reservoirs and Human Zoonotic Risk: Future Studies
89
Determine the full spectrum of SIV-infected non-human primates in equatorial Africa:
.
Identify all SIV-infected primate species.
· Assess the prevalence, geographic distribution, and natural history of SIV
infection in wild primate populations.
· Determine the frequencies, routes, and circumstances of primate-to-primate
. . .
cross-species transmissions.
Characterize all major SIV lineages at the biological and molecular level:
.
Determine the spectrum of SIV genetic and biological diversity.
· Molecularly clone and sequence representatives of all major SIV lineages.
.
. . .
lentlvlruses.
Characterize the origins and evolutionary history of the entire group of primate
Determine to what extent humans are exposed to SIV and whether such exposure has
led to additional zoonotic transmissions:
· Develop novel screening and confirmatory assays that can detect and distinguish
the wide variety of SIV infections now known to exist in wild primate populations.
· Establish effective surveillance mechanisms for humans at risk for zoonotic
. , .
ntectlons.
· Elucidate the viral, host, and environmental factors that facilitate zoonotic
transmission and promote subsequent epidemic spread.
· Monitor the emergence of HIV/SIV recombinants.
In summary, the current HIV-1 group M pandemic provides compel-
ling evidence for the rapidity, stealth, and, ultimately, the extraordinary
clinical impact that can result from even a single zoonotic transmission
event. It is now clear that humans are routinely exposed to a plethora of
primate lentiviruses through the hunting of primates, and that the magni-
tude and breadth of this exposure has previously been underestimated.
In light of these data, a complete and accurate assessment of all SIV-
infected non-human primate species in geographic areas where these are
abundant seems necessary (Table 3-1~. Since most SIV-infected primates,
especially the great apes, are endangered, strategies that avoid a further
increase in hunting will need to be employed. Such strategies would rely on
non-invasive methods, such as the use of urine and fecal samples to detect
SIV-specific antibodies and viral nucleic acids (Santiago et al., 2001~. Stud-
ies are also needed to determine whether transmission of simian lentiviruses
other than SIVcpz and SIVsm to humans have already occurred. This will
require the screening of human sera with diagnostic tests which can detect
and distinguish a wide range of primate lentiviral infections.
OCR for page 90
i:
9o
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
Finally, the potential of recombination between currently circulating
HIVs and newly introduced SIVs must be considered, and surveillance
mechanisms must be established to detect their possible emergence. Such
recombinants could evade susceptibility to vaccines that are based on only
one virus group or subtype. Because experimental HIV vaccines will even-
tually be tested in countries worldwide, the occurrence of new zoonotic SIV
infections and their possible impact on immunization efforts will need to be
examined. The existence of a primate reservoir must be taken into account
while planning future eradication strategies for HIV/AIDS.
VACClNE-ASSOCIAl~D CASES DUE TO IMMUNIZATION WITH
LIVE VIRUS VACCINES
Jeffrey I. Cohen, M.D.
Head, Medical Virology Section, Laboratory of Clinical Investigation
National Institutes of Health, Bethesda, MD
Live virus vaccines, including those for smallpox, measles, and poliovi-
rus, have dramatically reduced or in some cases eliminated disease caused
by these viruses. As disease due to wild-type virus is eliminated, however,
vaccine-associated cases become of increasing concern.
Vaccinia, which has been used for 200 years to prevent smallpox, can
cause postvaccinal encephalitis, progressive vaccinia, eczema vaccinatum,
and generalized vaccinia. In a national survey in 1968, about 300 of 14
million vaccinees suffered severe side effects, and 9 fatalities were reported.
All but one of the fatalities were due to postvaccinal encephalitis or pro-
gressive vaccinia. Fatal cases of eczema vaccinatum have been reported in
contacts of vaccinees. A case of severe generalized vaccinia occurred in a
vaccinated asymptomatic HIV military recruit. The smallpox viral genome
contains 150 genes that are very similar to vaccinia and 37 genes that are
smallpox-specific or divergent from those in vaccinia. These latter genes
frequently encode host-interactive proteins.
The vaccine strain of measles virus rarely causes disease. Vaccine virus
has been detected in lung, liver, bone marrow, or brain tissues of only three
patients who had severe disease after vaccination. One patient had HIV,
one had severe combined immunodeficiency, and one had no known immu-
nocleficiency. The latter two patients died from measles vaccination. The
measles vaccine and wild-type virus share more than 95.5°/O of the same
nucleotide sequences. The changes that are responsible for attenuation of
the measles virus are unknown.
OCR for page 91
BIOLOGICAL CHALLENGES TO POST-ERADICATION
Vaccine-Associated Paralytic Poliomyelitis
91
The first reports of vaccine-associated paralytic poliomyelitis (VAPP)
occurred shortly after the introduction of the oral polio vaccine (OPV).
Since 1973, the number of VAPP cases has exceeded the number of cases of
wild-type polio in the United States. From 1980-1989, VAPP was associ-
ated with 1 out of every 2.5 million doses of OPV in the United States.
VAPP occurs primarily in unvaccinated or inadequately vaccinated persons,
and more commonly in infants. In the United States from 1980 to 1995,
about 40% of VAPP cases occurred in OPV recipients, 30% in close con-
tacts, 25% in immunodeficient persons, and 5°/O were community acquired.
The latter persons had not been recently vaccinated and were not known to
be in direct contact with vaccine recipients. The percentage of patients in
each risk group has remained fairly stable over time.
Immunodeficient patients have a 3,000- to 6,000-fold greater risk of
developing VAPP. In one study (Sutter and Prevots, 1994J, 96% of VAPP
cases were due to B cell deficiency; the other 4°/O were due to long-term
corticosteroid use. So far, there have been only two cases of VAPP associ-
ated with HIV. In Romania, but not in the United States, VAPP has been
associates} with increasing numbers of intramuscular injections given nine
to thirty days before OPV.
Nucleotide sequencing indicates that less than 1% of OPV bases (polio
is an RNA virus and does not have base pairs) differ from those of its
neurovirulent parent. Only two or three base changes are needed for OPV
type 2 (OPV2) or OPV3 to revert to neurovirulence, while several base
changes are needed for OPV1. This coincides with the fact that OPV2 and
OPV3 are isolated more frequently than OPV1 from patients with VAPP.
VAPP may be due to neurovirulent revertant viruses that develop dur-
ing replication in the gastrointestinal tract, recombination between differ-
ent strains of OPV, or recombination between OPV and wild-type strains.
In one study, within 2 days of receiving OPV3, one of the attenuating
mutations in the virus reverted to the wilcl-type sequence, and the shed virus
was more neurovirulent (Evans et al., 19853.
When OPV was the preferred vaccine, there were eight to nine VAPP
cases per year in the United States. After the initiation of a sequential
regimen of inactivated poliovirus vaccine (IPV)-OPV, the number of cases
declined to two to five per year. With an all IPV regimen, VAPP should be
virtually eliminated. However, there is concern about the continued release
of neurovirulent revertants of live OPV into the environment even after
vaccination is terminated. Thus, VAPP may continue to occur for some
finite period of time. Recently, two antibody-deficient patients with VAPP
shed virus in their stool for over five years after their last vaccination.
Comparison of the sequence of these viruses with that of OPV suggests that
OCR for page 92
92
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
the viruses had been replicating in the patients for about ten years. How-
ever, most antibody-deficient patients probably shed virus for less than six
months. In contrast, immunocompetent persons usually shed virus for less
than three months.
Several studies have suggested that OPV has a limited circulation in the
environment. In Cuba, for example, where OPV is administered for two
months of the year, the virus has been detected for only 2 or 3 months after
vaccinations (Ochoa and Lago, 19871. Similarly, VAPP cases in Romania
have been closely associated with specific vaccination campaigns (Strebel et
al., 1994~. In most cases, sequencing of VAPP isolates shows greater than
99°/0 similarity to OPV, indicating that the VAPP isolates have circulated
for a very short period of time.
However, other studies show that neurovirulent forms of OPV can
circulate at length. For example, analysis of the nucleotide sequence of
OPV2 isolated from sewage in Israel suggested that the virus had been
circulating for six years (Shulman et al., 2000~. A similar study from Japan
found neurovirulent virus in sewage and river water three months after
OPV vaccination (Yoshida et al., 2000~. These neurovirulent strains of
OPV were not associated with VAPP in either of these two studies.
In Poland, from March to December 1968, there was an outbreak of
poliovirus type 3 four months after vaccination with a live attenuated
OPV3, USOL virus. There were 464 cases of paralytic disease. Nucleotide
sequencing of isolates from seven epidemic cases, four healthy vaccinees,
and one healthy contact all showed USOL-like viruses. The seven isolates
exhibited a change in sequence associated with neurovirulence; none of the
healthy vaccinees or contacts exhibited such a change.
A large number of cases of polio occurred in China from 1991 to 1993.
Sequencing of isolates from 34 patients indicated that the virus was a
recombinant derivative of wild-type polio type 1 and OPV1. Analysis of the
sequenced viruses suggested that all of the recombinants were derived from
a mixed infection of a single person with wild-type and OPV type 1. The
recombinant virus spread rapidly over 2,200 kilometers in 3 years.
Recent outbreaks of paralytic polio have occurred clue to circulating
vaccine-derived poliovirus (cVDPV) in several areas, suggesting that
neurovirulent revertants of OPV can persist. For example, from July to
November 2000, 20 cases of cVDPV due to OPV1 occurred in the Domini-
can Republic and Haiti. About 85% of the patients were under six years of
age, and all of the patients were either unvaccinated or inadequately vacci-
nated. The viral nucieotide sequence showed a 97°/O genetic similarity to
OPV, suggesting that the virus had either circulated for two years in the
area or had undergone prolonged replication in an immunodeficient per-
son. The epidemic was rapidly terminated after intensive vaccination with
OPV. A similar epidemic of cVDPV due to OPV2 occurred in 32 persons in
OCR for page 93
BIOLOGICAL CHALLENGES TO POST-ERADICATION
93
Egypt from 1988-1993. Analysis of the viral sequence suggested that the
virus had circulated for 11 years. Like the Caribbean epidemic, vaccination
coverage was low in Egypt cluring this time, anct circulation of OPV-derivect
virus stopped when vaccine coverage increased. From March to fuly 2001,
3 cases of cVDPV occurred in the Philippines. These cases were clue to virus
cleriveci from OPV1.
Conclusion
These VAPP cases emphasize (a) the need for continuing polio vaccina-
tion in polio-free areas until global eradication is achieved, (b) the necessity
of continued surveillance for poliovirus and flaccid paralysis, (c) the need
for aciclitional information about duration of shecicling and persistence of
virus in the environment, and (cl) the importance of global eradication of
. .
pot .lovlrus.
Remaining questions, ancI possible answers, inclucle the following:
1. Will immunocompromised carriers of OPV continue to shed the
virus into the environment? Yes, but only for a limited time- most often
weeks to months, but in some cases for up to as long as 10 years.
2. What proportion of immunocompromised persons (including those
with HIV) shed OPV for prolonged periods of time? Probably less than
10% of antibocly-cleficient patients sheet virus for long periods of time; the
percentage is probably lower among HIV-infectec! patients since they often
retain the ability to produce antibodies.
3. How long will neurovirulent revertants of OPV be shed into the
environment? Basec3 on results from sewage studies in Japan and Israel,
OPV can be cletecteci for up to nearly five years after vaccination.
4. What is the threshold rate of vaccine coverage needed to suppress
circulation of OPV, and upon what does the rate depend? The rate is
probably similar to that required to prevent circulation of wilcl-type polio,
and it probably clepencis on the strain of OPV, population density, level of
hygiene, and climate.
5. How long can OPV circulate in populations, anal how transmis-
sible is it? OPV can circulate for 11 years according to the Egyptian out-
break of polio associated with OPV, and 2 years according to the Carib-
bean outbreak.
6. Should IPV be given for a period of time after OPV is discontinued
to allow clearing of virus from shedders? Yes, if possible, especially since
infants have the highest risk for VAPP and will not be immune when
. . .
VaCClIlatlOI1 IS stoppec .
7. How long should intensive surveillance be continued" after IPV is
OCR for page 94
94
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
stopped Probably at least 10 years, in view of the long shedding period and
the recent occurrence of polio due to circulating vaccine-related virus.
8. What is the best way to detect circulating OPV and respond to
outbreaks? Intensive surveillance for cases of acute flaccid paralysis and
poliovirus is required, and further research is needed.
REFERENCES
Agur Z. Cojocaru L, Mazor G. Anderson RM, and Danon YL. 1993. Pulse mass measles
vaccination across age cohorts. Proceedings of the National Academy of Sciences
90:11698-11702.
Anderson RM. 1994. Populations, infectious disease and immunity: A very nonlinear world.
Philosophical Transactions of the Royal Society of London, Series B 346:457-505.
Anderson RM and May RM. 1990. Immunization and herd immunity. Lancet 335:641-645.
Anderson RM and May RM. 1992. Infectious Diseases of Humans: Dynamics and Control.
Oxford: University of Oxford Press.
Anderson RM, Donnelly CA, and Gupta S. 1997. Vaccine design, evaluation, and commu-
nity-based use for antigenically variable infectious agents. Lancer 350:1466-1470.
Auzel P and Hardin R. 2000. Colonial history, concessionary politics, and collaborative
management of Equatorial African rain forests. Pp. 21-38 in Hunting and Bushmeat
Utilization in the African Rain Forest, M Bakarr, G Da Fonseca, W Konstant, R
Mittermeier, and K Painemilla, eds. Washington, D.C.: Advances in Applied Biodiversity
Science Series, Conservation International.
Bellini WJ and Rota PA. 1998. Genetic diversity of wild-type measles viruses: Implications for
global measles elimination programs. Emerging Infectious Diseases 4:29-35.
Bibollet-Ruche F. Galat-Luong A, Cuny G. Sarni-Manchado P. Galat G. Durand JP, Pourrut
X, and yeas F. 1996. Simian immunodeficiency virus infection in a pates monkey
(Erythrocebus patas): Evidence for cross-species transmission from African green mon-
keys (Cercopithecus aethiops sabaeus) in the wild. The Journal of General Virology
77:773-781.
Bolker BM and Grenfell BT. 1996. Impact of vaccination on the spatial correlation and
persistence of measles dynamics. Proceedings of the National Academy of Sciences
93:12648-12653.
Bottiger M, Christenson B. Romanus V, Taranger J. and Strandell A. 1987. Swedish experi-
ence of two-dose vaccination program aiming at eliminating measles, mumps, and ru-
bella. British Medical Journal 295:1264-1267.
Chen Z. Telfer P. Gettie A, Reed P. Zhang L, Ho DD, and Marx PA.1996. Genetic character-
ization of new West African simian immunodeficiency virus SIVsm: geographic cluster-
ing of household-derived SIV strains with human immunodeficiency virus type 2 sub-
types and genetically diverse viruses from a single feral sooty mangabey troop. Journal
of Virology 70:3617-3627.
Chen Z. Luckay A, Sodora DL, Telfer P. Reed P. Gettie A, Kanu JM, Sadek RF, Yee J. Ho
DD, Zhang L, and Marx PA. 1997. Human immunodeficiency virus type 2 (HIV-2)
seroprevalence and characterization of a distinct HIV-2 genetic subtype from the natural
range of simian immunodeficiency virus-infected sooty mangabeys. Journal of Virology
71 :3953-3960.
OCR for page 95
BIOLOGICAL CHALLENGES TO POST-ERADICATION
95
Corbet S. Muller-Trutwin MC, Versmisse P. Delarue S. Ayouba A, Lewis J. Brunak S. Martin
P. Brun-Vezinet F. Simon F. Barre-Sinoussi F. and Mauclere P. 2000. Env sequences of
simian immunodeficiency viruses from chimpanzees in Cameroon are strongly related to
those of human immunodeficiency virus group N from the same geographic area. Jour-
nal of Virology 74:529-534.
Courgnaud V, Pourrut X, Bibollet-Ruche F. Mpoudi-Ngole E, Bourgeois A, Delaporte E, and
Peeters M. 2001. Characterization of a novel simian imm~'nodeficiency virus from
Guereza Colobus (Colobus guereza) in Cameroon: A new lineage in the nonhuman
primate lentivirus family. Journal of Virology 75:857-866.
de Quadros CA, Olive ~M, Hersh BS, Strassburg MA, Henderson DA, Brandling-Bennett D,
and Alleyne GA. 1996. Measles elimination in the Americas: Evolving strategies. Journal
of the American Medical Association 275:224-229.
Evans DM, Dunn G. Minor PD, Schild GC, Cann AJ, Stanway G. Almond JW, Currey K, and
Maizel JV Jr. 1985. Increased neurovirulence associated with a single nucleotide change
in a noncoding region of the Sabin type 3 poliovaccine genome. Nature 314(6011):548-
550.
Fenner F. Henderson DA, Arita I, Jezek Z. and Ladnyi ID. 1988. Smallpax and Its Eradica-
tion. Geneva: World Health Organization.
Gao F. Yue L, White AT, Pappas PG, Barchue J. Hanson AP, Greene BM, Sharp PM, Shaw
GM, and Hahn BH. 1992. Human infection by genetically diverse SIVsm-related HIV-2
in west Africa. Nature 358:495~99.
Gao F. Yue L, Robertson DL, Hill SC, Hui H. Biggar RJ, Neequaye AK, Whelan TM, Ho DD,
Shaw GM, Sharp PM, and Hahn BH. 1994. Genetic diversity of human immunodefi-
ciency virus type 2: Evidence for distinct sequence subtypes with differences in virus
biology. Journal of Virology 68:7433-7447.
Gao F. Bailes E, Robertson DL, Chen Y. Rodenburg CM, Michael SF, Cummins LB, Arthur
LO, Peeters M, Shaw GM, Sharp PM, and Hahn BH. 1999. Origin of HIV-1 in the
chimpanzee Pan troglodytes troglodytes. Nature 397:436~41.
Geist V. 1988. How markets for wildlife meat and parts, and the sale of hunting privileges,
jeopardize wildlife conservation. Conservation Biology 2:15-26.
Georges-Courbot MC, Lu CY, Makuwa M, l~elfer P. Onanga R. Dubreuil G. Chen Z. Smith
SM, Georges A, Gao F. Hahn BH, and Marx PA. 1998. Natural infection of a household
pet red-capped mangabey (Cercocebus torquatus torquatus) with a new simian immuno-
deficiency virus. Journal of Virology 72:600~08.
Hahn BH, Shaw GM, De Cock KM, and Sharp PM. 2000. AIDS as a zoonosis: Scientific and
public health implications. Science 287:607014.
Jin MJ, Rogers J. Phillips-Conroy JE, Allan JS, Desrosiers RC, Shaw GM, Sharp PM, and
Hahn BH. 1994a. Infection of a yellow baboon with simian immunodeficiency virus
from African green monkeys: Evidence for cross-species transmission in the wild. Jour-
nal of Virology 68:8454-8460.
Jin MJ, Hui H. Robertson DL, Muller MC, Barre-Sinoussi F. Hirsch VM, Allan JS, Shaw
GM, Sharp PM, and Hahn BH. 1994b. Mosaic genome structure of simian immunodefi-
ciency virus from west African green monkeys. The European Molecular Biology Orga-
nization Journal 13:2935-2947.
Kaye JA, de Mar Melero-Montes M, and Jick H. 2001. Mumps, measles, and rubella vaccine
and the incidence of autism recorded by general practitioners: A time trend analysis.
British Medical Journal 322:460~63.
Kuiken C, Foley B. Hahn BH, Marx P. McCutchan F. Mellors J. Mullins }, Wolinsky S. and
Korber B. 1999. Human Retroviruses and AIDS: A Compilation and Ana,lysis of Nucleic
Acid and Amino Acid Sequences. Los Alamos, NM: Los Alamos National Laboratory.
OCR for page 96
96
CONSIDERATIONS FOR VIRAL DISEASE ERADICATION
Mauclere P. Loussert-Ajaka I, Damond F. Fagot P. Souquieres S. Monny Lobe M, Mbopi
Keou FX, Barre-Sinoussi F. Saragosti S. Brun-Vezinet F. and Simon F. 1997. Serological
and virological characterization of HIV-1 group O infection in Cameroon. AIDS 11:445-
453.
Ochoa EG and Lago PM. 1987. Epidemiological surveillance and control of poliomyelitis in
the Republic of Cuba. Journal of Hygiene, Epidemiology, Microbiology, and Immunol-
ogy 31(4):381-389.
Peeters M, Honore C, Huet T. Bedjabaga L, Ossari S. Bussi P. Cooper RW, and Delaporte E.
1989. Isolation and partial characterization of an HIV-related virus occurring naturally
in chimpanzees in Gabon. AIDS 3:625-630.
Peeters M, Fransen K, Delaporte E, Van den Haesevelde M, Gershy-Damet GM, Kestens L,
van der Groen G. and Plot P. 1992. Isolation and characterization of a new chimpanzee
lentivirus (simian immunodeficiency virus isolate cpz-ant) from a wild-captured chim-
panzee. AIDS 6:447~51.
Peeters M, Janssens W. Fransen K, Brandful J. Heyndrickx L, Koffi K, Delaporte E, Piot P.
Gershy-Damet GM, and van der Groen G. 1994. Isolation of simian immunodeficiency
viruses from two sooty mangabeys in Cote d'Ivoire: virological and genetic characteriza-
tion and relationship to other HIV type 2 and SIVsm/mac strains. AIDS Research and
Human Retrovi7uses 10:1289-1294.
Peeters M, Pourrut X, Bibollet-Ruche F. Courgnaud V, Abela B. Mpoudi E, Hahn B. and
Delaporte E. 2001. Ongoing exposure of humans to simian immunodeficiency viruses in
West Central Africa poses a risk for additional zoonotic transmissions. Paper presented
at 8th Conference on Retroviruses and Opportunistic Infections, Foundation for
Retrovirology and Human Health, Chicago, February 4-8, 2001.
Peltola H and Heinonen OP. 1986. Frequency of true adverse reactions to measles-mumps-
rubella vaccine: A double-blind, placebo-controlled trial in twins. Lancet 1:939-942.
Plotkin SA and Orenstein WA, eds. 1999. Vaccines, 3rd ed. Philadelphia: WB Saunders.
Santiago M, Rodenburg C, Mamaeva O. Kilby J. Moldoveanu Z. Fahey B. Muller M, Ayouba
A, Shaw G. McClure H. Heeney J. Nerrienet E, Boesch C, Wrangham R. Gao F. and
Hahn B. 2001. AIDS as a zoonosis: characterizing the primate reservoir. Paper presented
at 8th Conference on Retroviruses and Opportunistic Infections, Foundation for
Retrovirology and Human Health, Chicago, February ~8, 2001.
Sharp PM, Bailes E, Chaudhuri RR, Rodenburg CM, Santiago MO, and Hahn BH. 2001. The
origins of AIDS viruses: where and when? Pl7ilosophical Transactio'~s of t1,e Royal
Society of London, Series B 356:867-876.
Shulman LM, Manor Y. Handsher R. Delpeyroux F. McDonough MJ, Halmut T. Silberstein
I, Alfandari J. Quay J. Fisher T. Robinov J. Kew OM, Crainic R. and Mendelson E.
2000. Molecular and antigenic characterization of a highly evolved derivative of the type
2 oral poliovaccine strain isolated from sewage in Israel. Journal of Clinical Microbiol-
ogy 38(10):3729-3734.
Simon F. Mauclere P. Roques P. Loussert-Ajaka I, Muller-Trutwin MC, Saragosti S. Georges-
Courbot MC, Barre-Sinoussi F. and Brun-Vezinet F. 1998. Identification of a new hu-
man immunodeficiency virus type 1 distinct from group M and group O. Nature Medi-
cine 4:1032-1037.
Souquiere S. Bibollet-Ruche F. Robertson DL, Makuwa M, Apetrei C, Onanga R. Kornfeld
C, Plantier JC, Gao F. Abernethy K, White LJ, Karesh W. Telfer P. Wickings EJ,
Mauclere P. Marx PA, Barre-Sinoussi F. Hahn BH, Muller-Trutwin MC, and Simon F.
2001. Wild Mandrillus sphinx are carriers of two types of lentivirus. Journal of Virology
75:7086-7096.
OCR for page 97
BIOLOGICAL CHALLENGES TO POST-ERADICATION
97
Strebel PM, Aubert-Combiescu A, Ion-Nedelcu N. Biberi-Moroeanu S. Combiescu M, Sutter
RW, Kew OM, Pallansch MA, Patriarca PA, and Cochi SL. 1994. Paralytic poliomyelitis
in Romania, 1984-1992. Evidence for a high risk of vaccine-associated disease and
reintroduction of wild-virus infection. American Journal of Epidemiology 140(12):1111-
1124.
Sutter RW and Prevots R. 1994. Vaccine-associated paralytic poliomyelitis among immuno-
deficient persons. Infections in Medicine 11(6):429038.
Ukkonen P. 1996. Rubella immunity and morbidity: impact of different vaccination programs
in Finland 1979-1992. Scandinavian Journal of Infectious Diseases 28(1):31-35.
UNAIDS (Joint United Nations Programme on HIV/AIDS). 2000. AIDS Epidemic Update:
December 2000. Online. Available at www.unaids.org.
van der Loeff MFS and Aaby P. 1999. Towards a better understanding of the epidemiology of
HIV-2. AIDS 13 Suppl A:S69-S84.
van Rensburg EJ, Engelbrecht S. Mwenda J. Laten JD, Robson BA, Stander T. and Chege GK.
1998. Simian immunodeficiency viruses (SIVs) from eastern and southern Africa: Detec-
tion of a SIVagm variant from a chacma baboon. Journal of General Virology 79:1809-
1814.
Vidal N. Peeters M, Mulanga-Kabeya C, Nzilambi N. Robertson D, Ilunga ~7, Sema H.
Tshimanga K, Bongo B. and Delaporte E. 2000. Unprecedented degree of human immu-
nodeficiency virus type 1 (HIV-1 ) group M genetic diversity in the Democratic Republic
of Congo suggests that the HIV-1 pandemic originated in central Africa. Journal of
Virology 74:10498-10507.
Wilkie D, Shaw E, Rotberg F. Morelli G. and Auzel P. 2000. Roads, development, and
conservation in the Congo Basin. Conservation Biology 14:1614-1622.
Yoshida H. Horie H. Matsuura K, and Miyamura T. 2000. Characterisation of vaccine-
derived polioviruses isolated from sewage and river water in Japan. Lancet
356(9240):1461-1463.
Representative terms from entire chapter:
biological challenges
