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Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
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Page 65
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 66
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 67
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 68
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 69
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 70
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 71
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 72
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 73
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 74
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 75
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 76
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 77
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 78
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 79
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 80
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 81
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 82
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 83
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 84
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 85
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 86
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 87
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 88
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 89
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 90
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 91
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 92
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 93
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 94
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 95
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 96
Suggested Citation:"3 Biological Challenges to Post-Eradication." Institute of Medicine. 2002. Considerations for Viral Disease Eradication: Lessons Learned and Future Strategies: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/10424.
×
Page 97

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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

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

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-

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

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

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~.

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

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

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

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

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-

BIOLOGICAL CHALLENGES TO POST-ERADICATION 100 - ~n ° 80 - ~ 60 c -° 40 - ~: ._ 20 - O - 0.75 75 - - l 0.85 Proportion of cohort vaccinated 0.95 FIGURE 3-5 The indirect benefits arising from a mass measles vaccination pro- gram. mission. When the disease is very rare or eliminated, the risk from vaccina- tion is greater than the risk of morbidity from infection. At this point, the optimum strategy for each parent is to persuade every one else to immunize their children but not vaccinate their own! One way around the inevitable conflict between individual and com- munity interests is to pass legislation requiring vaccination before attending school or entering a country. For example, the United States requires evi- dence of immunization for school attendance (unless there are contraindi- cations for individuals). Such legislation has found little favor in Europe, but recent events may change this. For example, in the United Kingdom, in the past few years unfounded reports of an association between MMR vaccination and autism in children has resulted in a significant decline in vaccine uptake in the last two years. The spurious correlation arises from the fact that the average age of onset of autism prior to wide-scale immuni- zation was around two years of age, which is also the current average age at first immunization. Very recent detailed studies have shown no association between vaccination and autism (Kaye et al., 2001~. The net effect of the decline in vaccine uptake in the UK will probably be upcoming measles epidemics on a scale not seen since the late 1960s. Evolution Mass vaccination at high levels of uptake imposes a very significant selective pressure on infectious agents by favoring rare antigenic variants

76 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION whose major antigens, or major epitopes on defined antigens, are not ad- equately captured in the antigenic constituents of current vaccines. This problem has not arisen for measles, rubella, varicella, or mumps. However, antigenic variability in wild-type populations of hepatitis B. as well as several bacterial infections being targeted by new vaccines, is high. Greater antigenic variability allows for more opportunity for selection for rare variants. For infections that are targets for local elimination, surveillance based on molecular epidemiological approaches is essential for tracking evolutionary changes that might result in mutants prospering within highly vaccinated populations. Currently, surveillance is available only for infec- tions, such as influenza, for which vaccine development depends on the identification of the dominant antigenic variants circulating in any given year. Conclusion Much has been written in recent years about the prospects for the worldwide eradication of infections such as measles and polio. Indeed, the title of this meeting hints at future success. However, it is far from clear that success is just around the corner. A particular problem with both measles and polio is the high transmissibility of both infections in densely populated urban areas. The average age of infection is low for both diseases, and in most urban communities vaccine coverage must be greater than 95°/0 in order to block indigenous transmission. In contrast, smallpox had a high average age of infection prior to wide-scale vaccination, even in densely populated areas, and was much less transmissible than either polio or measles (Fenner et al., 19881. In developed countries, mass vaccination will probably have to be main- tained at very high levels for quite a while in order to protect against reintroductions from areas where poverty, human conflict, or absence of political will impedes high coverage. The only alternative to this would be demanding that travelers entering countries where the eradication of indig- enous transmission has been achieved (or will be in the near future) show evidence of vaccination (e.g., saliva-based serology) as a condition for en- try. The ever-increasing mobility of populations is a key factor in any elimination strategy. It must be assumed that if a directly transmitted infec- tion persists in any corner of the globe, it wit! eventually find its way back into highly vaccinated populations if herd immunity is allowed to decline. In highly vaccinated communities, the most immediate challenges to effective mass vaccination are public and professional complacency and the increasing publicity about adverse reactions to vaccination. For example, young physicians and health care workers in developed countries who have never witnessed measles infections may be unable to diagnose rare cases

BIOLOGICAL CHALLENGES TO POST-ERADICATION 77 and may not be diligent in recommending immunization to all their pa- tients. Similarly, in countries where infections are now rare, many young parents are unfamiliar with the serious morbidity associated with infection and may instead be influenced by the publicized risks associated with vacci- nation. Constant vigilance and effective education are essential. ERROR, HUBRIS, AND MALICE C.7. Peters, M.D. Professor, Departments of Pathology and Microbiology and Immunology University of Texas Medical Branch, Galveston, TX The interruption of viral transmission associated with viral disease eradication requires a high vaccination coverage of the human population, a vaccine that eliminates transmission in a certain region for the duration of intensive immunization, and an effective assay for the virus and its antibod- ies. The biological basis of these requirements necessitates a thorough un- derstanding of the viruses being targeted for eradication. An Anthropocentric Classification of Viruses Viruses can be divided into three groups: "true" human viruses that are maintained through chronic or latent infection; viruses that circulate in nature and infect humans from an extrahuman reservoir; and viruses trans- mitted among humans, without animal reservoir. "True" human viruses that are maintained through chronic or latent infection (e.g., herpesvirus and polyomavirusesJ. These viruses are believed to have shared a long co-evolutionary history with primates. They are generally not highly pathogenic except in immuno- suppressed hosts. Their tight linkage to humans over the centuries makes their eradication virtually impossible, even though many of these viruses have been eliminated in certain non-human primate populations. For ex- ample, herpes-free colonies of rhesus macaques exist, and it is probably possible to generate lentivirus-free Old World monkey colonies. Viruses that circulate in nature and infect humans from an extrahuman reservoir. These viruses often have complicated transmission cycles which create

78 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION more opportunities for interruption but also more strategies for survival. (Viruses, such as dengue, that have a non-human cycle but have adapted well to humans may be somewhat ambiguous.) Even though several vector-borne parasitic diseases, such as malaria, are readily transmitted over long distances, most arthropod-borne virus introductions fad! outside their usual range. There are some exceptions to this, such as the yellow fever and clengue viruses, and possibly the West Nile and Japanese encephalitis viruses. Also, even though Rift Valley fever failed to establish itself outside its sub-Saharan habitat after a large epidemic in Egypt in 1977, it continues to threaten distant spread. Successful long- distance introductions seem to involve vectors that are very adaptable and readily transportable (e.g., Aedes aegypti and Culex pipiens), or viruses (e.g., Venezuelan equine encephalitis and Rift Valley fever virus) that can be readily transmitted by multiple mosquito species in the presence of high viremias in imported vertebrate reservoirs (horses, sheep, and cattle). One strategy for regional disease eradication involves eliminating hu- man-virus contact, such as has been attempted for triatomid-Chagas or tsetse-trypanosomiasis parasite-vectors. These attempts have been relatively successful, but they fait when public health and social underpinnings col- lapse. Furthermore, other elements may intercede to change the dynamic; for example, the increased incidence of human AIDS has drastically altered the transmission of visceral leishmaniasis in the Americas. Another strategy for eliminating viruses that are transmitted via arthro- pods involves eliminating the arthropod vector, since most arboviruses are highly dependent on a single arthropod species. For example, malaria trans- mission was reduced in Brazil by eliminating introduced Anopheles gambiae from South America, and urban yellow fever has been controlled by re- gional elimination of Ae. aegypti. However, Ae. aegypti ultimately recurred for multiple reasons, and there is still a risk of reintroduction of the highly efficient malaria vector, Art. gambiae. This strategy requires a strong will and methodologies that are in short supply. Total elimination of a vector is unlikely. Arthropod-borne viruses could be eradicated by eliminating their reser- voirs. This is rarely desirable, however, except through vaccination of susceptibles, which is how Venezuelan equine encephalitis was eliminated from North, Central, and much of South America in the 1970s. Roclent-borne viruses (e.g., lymphocytic choriomeningitis virus in Mus musculus or Seoul virus in Rattus) are notably resistant to control strategies because they are tightly linker! to their host species and may move long distances as their hosts invade new geographic areas. The total elimination of a rodent species is generally neither desirable nor feasible. A possible elimination strategy involves selectively immunizing rodent populations that come into close contact with humans. For example, genetically engineered

BIOLOGICAL CHALLENGES TO POST-ERADICATION 79 grains containing protective genes against hantaviruses could be used to make homes safe against deer mouse-borne hantaviruses. In situations such as lentivirus infection of humans, multiple introductions indicate that aclap- tation and spread of the virus among humans over time is probably more relevant than any unique primate-human contact. This suggests that even though limiting primate-human interactions is impractical and wouIc! never be completely successful, surveillance of subsequent human spread could be an efficient mechanism to limit lentivirus interspecies adaptation. Viruses transmitted among humans, without animal reservoir. With viruses transmitted among humans without an animal reservoir and that do not chronically infect their usual human host (e.g., measles, polio, and smallpox); intervention strategies involve using highly effective vaccines to break the mandatory human link in transmission. All viruses currently under consideration for eradication are of this type. Post-Eradication Challenges Major challenges for post-eradication strategies include: 1. How can we assure that [aboratory-preserved virus stocks and vaccine strains that Co? potentially revert to wild-type are eliminated or safely contained? This includes vials clearly labeled "measles" or "polio," samples from respiratory disease patients who may have had measles, stool samples from patients who have had suspected enterovirus infections or asymptomatic poliovirus infection and so on. These samples are often re- tained through inertia but may also be archived for future study when new technology or information becomes available. Samples that may have ini- tially yielded negative results are often sources for the identification of important "new" diseases or their agents (e.g., Fort Bragg fever and Pontiac fever). Destruction of samples can be difficult even under the most coopera- tive situation. Some viruses, such as poliovirus, can survive in mechanical freezers and liquid nitrogen repositories for a very long time. 2. Are the viruses really "gone"? We are entering an era in which small viral genomes can be synthesized and converted to infectious agents. Soon, even larger viruses will likely be synthesized from sequence informa- tion or clones. Thus, an apparently eradicated virus may be recovered in infectious form to threaten humanity anew. 3. How will we continue research on important scientific questions that have already received enormous investment in terms of human effort and laboratory observation over the years? For example, we scarcely uncler- stancl the pathogenesis of the large, complicatecl smallpox virus, the exquis-

80 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION ite structure-function relationships of the much simpler poliovirus, and the subtle interactions of measles with the immune system. Unraveling these important infectious disease problems will require increased investment in containment laboratories, use of alternate virus-host systems for study, or investigations limited to a few expressed proteins. Control over virus gene distribution is problematic because many sequences have already been pub- lished, and the technology to reconstitute virtually any virus will soon be available. 4. How will continued vaccine availability, testing, and a surge capac- ity be assured? This may be only a short-term problem since eradication should eliminate the need for these. Repositories of vaccine could be re- tained to deal with short-term emergencies. Contemporary vaccine technol- ogy will still be available because uncertainties about eradication and on- going research will provide a need. However, there will quickly come a time when there will no longer be a capacity to manufacture vaccine. The pos- sible future needs, including surge capacity, should be provided for in long- term eradication plans, although the possible financial underpinnings of this requirement are unclear. 5. Are there solutions to potential long-term problems with vaccines that could arise during post-eradication? Recently, for example, the possi- bilities of the use of the smallpox virus in biowarfare or bioterrorism have necessitated the production of new vaccine stocks. But the technology is outdated. After the eradication of smallpox, vaccine stocks decayed, vac- cine program infrastructure deteriorated, standards of vaccine production changed, and risk-benefit considerations shifted. It is too late to develop an improved vaccine because the immune basis for protection has never been defined, plus it is impossible to test a vaccine after eradication. Fortunately, simple cell culture adaptation of vaccinia virus is highly likely to produce a vaccine with qualities similar to the classical vaccine. ~ t ~ ~ Another potential post-eradication need for vaccine or possibly anti-virals is the prevention or treatment of immunosuppressed individuals who develop vaccinia or vaccine-related poliovirus infection. In the case of poliovirus, for example, control would probably be impossible with the Salk vaccine because it is not known to reliably interrupt transmission and control with the Sabin vaccine would expose the borders of the vaccinated groups to partially re- verted virus transmission. A subunit or vectored vaccine with mucosal efficacy would be invaluable; it would prevent the risk of reversion to virulence asso- ciated with attenuated vaccines, and it would eliminate the possibility of residual live virus being present in inactivated vaccines (a known problem for several viruses, including poliovirus and the animal foot and mouth disease virus). More data need to be gathered, ideally using non-human primate models if not humans, to show how effective human vaccines can be produced . . . . . . Wit lout propagating infectious virus.

BIOLOGICAL CHALLENGES TO POST-ERADICATION Extinction 81 We live in a period of unprecedented extinction of plants, animals, and probably viruses. It is noteworthy that inventories of biodiversity rarely take viruses into account. Many feel it is not worth arguing over elimina- tion of a virus that only spreads among humans and has severe adverse health effects. If an infectious virus does go extinct but information is still needed that requires a viral genome or even a live virus, viral genes could readily be synthesized from nucleic acid sequences. The virus itself could probably be recovered from sequences or clones. For viruses maintained in nature with only incidental human infection, the consequences of extinction are unclear. Ecological systems are complex, interactive, and subtle, and loss of a key species can have important ramifi- cations for many other species. The impact of most viruses on ecology, apart from human infection, has received little direct attention. For ex- ample, the fitness effect of hantaviruses or arenaviruses on their rodent reservoirs has not been assessed beyond simple trap-release data. However, a number of parasite studies indicate that these agents have considerable potential to regulate their host populations, which suggests caution in any attempt to eliminate a given virus. Total elimination of an animal vector or reservoir would be even more problematic. A: Habitat destruction drives some important reservoirs to extinction, thereby facilitating control of disease. For example, the yellow fever situa- tion in the Americas will be expected to improve with extensive deforesta- tion and loss of its reservoir's habitat. The chimpanzee reservoir of the HIV-1 precursor virus wit! also likely be exterminated through the same mechanism. Infectious agents themselves may participate in extinctions. For ex- ample, trypanosome parasites have eliminated cattle from parts of Africa, and the African horse sickness virus has eliminated unvaccinated equines from certain areas. Small populations with limited genetic variability (e.g., cheetahs and viral peritonitis) or in close contact with cliseased populations (e.g., lions infected with distemper or tuberculosis) may be at an increased risk for extinction from viruses. Still, there is no known example of a virus having eliminated its host species when the host species is otherwise healthy in terms of ecology and habitat. Laboratory Containment Containment has two basic elements: protection of the environment from microbes in the laboratory, and protection of the workers (or by- standers) from infection or contamination. The former is essential to con- taining infectious agents when the external environment is receptive to

82 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION infection, and the latter is important when the worker serves as a route of escape for the agent. The use of established standards, such as BSL-4 or BSL-3, as a form of protection of both the environment and the laboratory worker has gener- ally been very successful. These standards have been applied to many haz- ardous viruses in the past and have not resulted in any environmental problems and only infrequent worker infections. It is generally recognized that BSL-4 is more stringent than BSL-3, but the differences are not well appreciated. BSL-3 is used for highly aerosol- infectious agents that cause human disease. For example, {ymphocytic chori- omeningitis virus is classified as BSL-3 because of its capability to efficiently infect the laboratory worker with low concentrations of small particle aero- sols. BSL-4 agents are also aerosol infections but they cause severe human disease for which there is no established vaccine or therapy. Lassavirus is an example of a BSL-4 agent. Other viruses that cause similarly severe diseases but are not infectious by aerosols (except by massive exposures) can be used at BSL-2. In BSL-2 aerosol exposure is minimized by using special precau- tions (for example, a laminar flow biosafety cabinet) while handling con- centrated virus or performing operations such as centrifugation that can generate high concentrations of aerosols. In BSL-3 all manipulations of virus are performed inside a biosafety cabinet or using other methods to contain aerosols. There are several differences between BSL-4 and BSL-3 containment. Most obviously, BSL-4 workers are encased in a flexible plastic "space suit" with their own air supply, or the viruses are segregated in a sealed negative pressure glove box. The suit serves to protect the worker from infection and in addition can be surface decontaminated when the worker leaves the BSL-4 environment. BSL-4 mechanical systems are more redun- ciant, particularly those used for air flow (e.g., two fans are used with a back-up generator, and the air passes through two HEPA filters). Also, BSL-4 sewage discharge is sterilized. Intermediate systems that incorporate more controls than BSL-3 but are not as stringent as BSL-4 are usually referred to as "BSL-3+." This terminology is ambiguous and dangerous. The facilities are usually not carefully evaluated for the exact safeguards that are needed and, in the absence of a defined standard, are not carefully controlled. Additionally, the staff is often inexperienced; it must be emphasized that even with BSL- 4, proper attitude, safety training, and experience are the most important elements of containment. Viruses like polio and smallpox have sustained continuous interhuman transmission for centuries. Their eradication may present a situation unlike any of our previous experience with biological containment. In the case of smallpox, however, the use of laboratories with filtered air and shower-out,

BIOLOGICAL CHALLENGES TO POST-ERADICATION 83 coupled with careful vaccination of the workers, has successfully contained the virus during times in which population immunity has been low. But to contain smallpox at the BSL-4 level reflects an "Ebola-doomsday-Franken- stein" mentality and the current trend to over-contain. With regards to containment of the poliovirus, factors to consider will include glove precau- tions, the comparatively high stability of the virus, and the consequences of any manipulations that might be done with the virus. Genetic Modification The age of bioengineering started with a very conservative approach which relied on experimental evidence from Escherichia coli, a well-under- stooct, innocuous organism, and careful oversight from the Recombinant Advisory Committee. Certain experiments with toxins or expression of physiological active molecules have been avoided. This experience has given us a tremendous amount of confidence with several engineered systems and has enormously loosened oversight. For example, careful work with the La Crosse virus and its relatives showed that reassortant viruses are no more virulent than their most virulent partner. This idea about the virulence of recombinant viruses seems to be a reasonable principle at this time; however, recent data raise some important questions. Reverse genetics has allowed the laboratory construction of a number of different viruses. Common sense suggests that certain experi- ments (e.g., such as reconstruction of the 1918 influenza virus) would be unreasonable. But would the poliovirus, for example, be a target for the virus equivalent of a "hacker"? Reverse genetics has also allowed the con- struction of chimeric viruses with surprisingly high fitnesses. Orthopox- viruses have proven to be useful and safe vectors for many genes, but the recent report of enhanced murine virulence of ectromelia expressing an IL4 gene is disquieting. Should there be more oversight of or discussion about these experiments? Biological Warfare or Terrorism This increasingly disquieting aspect of modern life must not be ignored. Reconstitution of poliovirus, release of hidden stocks of smallpox virus, and other mischief are all possible. Although they would limit the damage, precautions may not completely protect us (particularly against blackmail). We should actively pursue intelligence and law enforcement programs aimed at preventing bioterrorism with these agents. However, these programs should be designed in such a way that active research on the viruses can continue.

84 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION Conclusion Some research objectives in the post-eradication, and particularly in the post-vaccination period, may need to be abandoned. If they are unique to the agent in question, they may not be sufficiently important to justify continuation in a highly container! laboratory for an indefinite periocl. More general research may require investing in other virus-host systems that do not require expensive containment and do not carry the small but inescapable risk of virus escape. By allowing expression of only a limited number of viral genes, investigations of specific phenomena could continue without the use of infectious viruses. Containment of the eradicated organisms should be based on staff training and attitude, engineering redundancy, shower-out facilities, con- trol of effluent air and waste, and previous experience with the agent. Whenever possible, evidence should be collected from realistic settings in order to determine containment needs. Knee-jerk assertions that BSL-4 containment is necessary or sufficient should be avoided. Post-eradication strategies should involve consideration of how to deal with recrudescence of disease for at least several decades. This will require stockpiling a modest amount of a proven vaccine, renewing the stockpiles over time, and providing the capacity for surge production. The possibility of reversion of live-attenuated vaccines, as well as the possibility of residual live virus in inactivated vaccines, should also be considered. Ideally, the vaccine will be derived *am genes from the eradicated virus but will not involve the use of inactivated or attenuated immunogens from the virus. This type of vaccine would make containment during production easier. NATURAL SIV RESERVOIRS AND HUMAN ZOONOTIC RISK: CHALLENGES TO DISEASE ERADICATION Beatrice H. Hahn, M.D. Professor, Department of Medicine and Microbiology University of Alabama at Birmingham, Birmingham, AL Evidence of simian immunodeficiency virus (SIV) infection has been reported for 26 different species of African non-human primates. Two of these viruses, SIVcpz from chimpanzees and SIVsm from sooty mangabeys, have crossed the species barrier to humans on multiple occasions, generat- ing human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2), respectively. Thus, an important public health concern is whether and to what extent humans continue to be exposed to SIV, and whether such exposure has led to additional zoonotic transmissions. Such transmissions

BIOLOGICAL CHALLENGES TO POST-ERADICATION 85 could undermine AIDS vaccine efforts and other strategies aimed at HIV · · . eradication. Emerging infectious diseases represent a major threat to public health. The disease with the greatest global impact to have emerged recently is the acquired immunocleficiency syndrome (AIDS). First recognized in the early 1980s, AIDS represents the end-stage of infection with either human immu- nodeficiency lentivirus type 1 (HIV-1) or 2 (HIV-21. While HIV-2 is virtu- ally restricted to west Africa (van der Loeff and Aaby, 1999), HIV-1 has spread globally and is estimated to have caused over 50 million infections worldwide (UNAIDS, 2000~. Although antiretroviral therapies have siowect disease progression and reduced mortality, these treatments do not eradi- cate infection and are inaccessible in most developing countries. With 5 million new infections estimated annually worldwide, HIV/AIDS is now the leading cause of death in sub-Saharan Africa (UNAIDS, 2000~. A vaccine to prevent HIV infection anchor disease will ultimately be needed to control the explosive spread of HIV/AIDS, especially in the developing worm. The two types of human AIDS viruses, HIV-1 and HIV-2, are both of zoonotic origin (Hahn et al., 2000~. Analysis of available sequence data indicates that HIV-1 is comprised of three distinct virus groups (termed M, N. and O), with the predominant M group consisting of nine sequence subtypes (A-D, F-H, I, K) (Kuiken et al., 1999~. Similarly, HIV-2 strains have been found to be comprised of seven distinct phylogenetic lineages, designated subtypes A-G (Kuiken et al., 1999~. Current phylogenetic evi- dence indicates that the SIV counterparts of HIV were introduced into the human population on multiple occasions (Hahn et al., 2000; Sharp et al., 2001~. Yet, HIV-1 group M viruses, which are responsible for the great majority of all HIV infections worldwide, appear to have arisen from just one cross-species transmission event (Sharp et al., 2001~. This highlights the potential significance of even a single primate lentiviral transmission from primates to humans and illustrates the importance of surveillance of human and primate populations for novel SIV infections. African primates represent an extremely large reservoir of lentiviruses with the potential for infecting other species, including humans. A total of 26 different primate species are now known to harbor SIV (Hahn et al., 2000; Peeters et al., 2001~. The primate lentiviruses for which full-length genomic sequences are available fall into six major, approximately equidis- tant phylogenetic lineages (Courgnaud et al., 2001; Hahn et al., 2000~: 1. SIVcpz from chimpanzees (Pan troglodytes), together with HIV-1; 2. SIVsm from sooty mangabeys (Cercocebus atys3, together with HIV-2 and SIVmac from macaques (several Macaca spy.; 3. SIVagm from four species of African green monkeys (Chiorocebus spy.;

86 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION 4. SIVsyk from Sykes' monkeys (Cercopithecus albogularis); 5. SIV1hoest from I'Hoest monkeys (Cercopithecus {hoesti), SIVsun from sun-tailed monkeys (Cercopithecus solatus), and SIVmnd1 from a mandrill (Manctrillus sphinx); and 6. SIVco! from colobus monkeys (Colobus guereza). A: Partial sequences are available for a number of additional SIVs, but their phylogenetic relationships remain to be fully resolved. Phylogenetic analyses have shown that all viruses from any one simian species are generally much more closely related to each other than to viruses from other species (Hahn et al., 2000~. SIV transfers between different primate species in the wild have been documented; however, the frequency of such transmission events, the clinical outcomes, and the factors required for establishing new primate lentiviral infections are unknown. For ex- ample, transmissions of SIVagm to sympatric pates monkeys and baboons have been reported in the wild (Bibollet-Ruche et al., 1996; fin et at., 1994a; van Rensburg et al., 19981. Additionally, the analysis of several complex recombinant SIV strains, including SIVrcm infecting red-capped mangabeys (Cercocehus torquatus) (Georges-Courbot et al., 1998), SIVmnd2 infecting mandrills (Ma~z~rillus sphi~x) (Souquiere et al., 2001), and SIVagmSab infecting sabaeus monkeys (Chiorocebus sabaeus) (fin et al., 1994b) have provided indirect evidence of cross-species transmission (Hahn et al., 2000~. Strains of SIV closely related to HIV-2 have been isolated from sooty mangabeys (Cercocebus atys) and three different macaque (Macaca sp.) species. Only a few macaques, all in captivity in North America, have been found to carry these viruses; these species are not naturally infected with SIV in the Asian wild. In contrast, SIVsm has been isolated from wild sooty mangabeys in West Africa (Chen et al., 1996~. HIV-2 is only endemic in West Africa, and it seems clear that SIVsm has been transmitted to humans there, as well as to macaques in captivity. Detailed consideration of the phylogenetic relationships among SIVsm and HIV-2 strains indicates that cross-species transmission to humans has occurred on at least five different occasions (Chen et al., 1997; Gao et al., 1992; Gao et al., 19941. However, recent analyses of new SIVsm strains strongly suggest that each of the seven HIV-2 subtypes likely arose from separate cross-species transmission events (Sharp et al., 2001~. Strains of SIV closely related to HIV-1 have only been isolated from chimpanzees (Pan troglodytes). Seven SIVcpz-infected chimpanzees have thus far been identified, all of which were captured as young orphans (Corbel et al., 2000; Gao et al., 1999; Peeters et al., 1989; Peeters et al., 19923. Of these seven, one clearly acquired his infection in captivity from a naturally infected cage mate (Corbel et al., 2000~. The other six are either

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

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.

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.

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.

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

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

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

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Since smallpox eradication, the science of eradication has changed and with it, our definitions of what diseases are possible to eradicate. However, eradication must not beget complacency. As has been learned from past control or eradication attempts with a variety of viral diseases, from yellow fever to influenza, accidental or intentional reintroduction is a real threat -- one that could strike anywhere and for which we need to be fully prepared. The criteria for assessing eradicability of polio, measles, and other viral infections have been debated extensively. With the elimination and eradication of several viral diseases on the horizon, issues surrounding the cessation of immunization activities become exceedingly important. In an effort to better understand the dynamics of disease eradication and post--immunization policies, the Institute of Medicine Forum on Emerging Infections hosted a two-day workshop (February 1--2, 2001) on The Consequences of Viral Disease Eradication. This book explores the principles underlying the biological challenges, medical interventions, the continuing research agenda, and operational considerations for post--immunization strategies for vaccine--preventable viral diseases, and highlights important efforts that may facilitate wise decision making.

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