Report of the Workgroup on Viral Diseases

J. Losos*

Introduction

The Workgroup identified measles, rubella, and viral hepatitis B as priority candidates for eradication. Viral hepatitis A is not recommended for elimination or eradication at the present time. Yellow fever, rabies, and Japanese encephalitis cannot be eradicated because they are found in animal reservoirs, but they can be controlled, in some cases to the point of elimination, through immunization programmes.

The group used the definitions of eradication and elimination adopted by the Dahlem Workshop on the Eradication of Infectious Diseases. Elimination refers to reducing the incidence of a disease to zero within a defined geographical area, with continued intervention measures as needed, while eradication refers to permanently reducing the incidence of a disease to zero worldwide, with no intervention measures required.

Viral Hepatitis A and B

Viral Hepatitis A

Hepatitis A virus (HAV) infects more than 80% of the population of many developing countries by late adolescence, and is common in developed countries as well (1-3). It produces a generally asymptomatic infection in under-5-year-olds, and an acute, self-limited disease in older children, adolescents, and adults (1,4).

Inactivated HAV vaccines, which only became commercially available in 1994, effectively confer protection in more than 95% of vaccinated persons (2,5,6). Routine vaccination of children aged greater than 2 years has effectively interrupted community-wide epidemics, and sustained vaccination has eliminated transmission of infection in these communities. While the potential for elimination of HAV exists, it cannot be recommended at this time, because of the impeding factors discussed below.

Essential facilitating factors. Routine childhood immunization with an effective, cell-culture-derived, inactive HAV vaccine has been shown to be cost-effective in populations with high rates of infection. The administration of the vaccine during community-wide outbreaks has been shown to be effective in interrupting transmission of the virus. The vaccine can also be administered with other vaccines and combined with other vaccine antigens (2).

Essential impeding factors. HAV vaccine is expensive, making large-scale purchases by developing countries difficult. Also, there is no vaccine formulation or schedule for use in infancy and early childhood, and it cannot be included in the Expanded Programme for Immunization (EPI).

Key strategies. It will be important to demonstrate the feasibility of eliminating HAV transmission in specific geographical areas. National acute disease surveillance must be improved to better differentiate viral hepatitis A from viral hepatitis B.

Research needs. Two areas of research are immediate priorities:

• development of decision/economic models for hepatitis A vaccination in developing countries; and
• development of vaccine formulations and schedules for infants and children less than 2 years old.

Conclusions and recommendations. These are as follows:

• eradication of HAV transmission appears to be both biologically and epidemiologically feasible;
• the time required to achieve cessation of transmission may be short;
• the coupling of HAV immunization with other vaccines appears to be feasible; and
• population-based projects to demonstrate sustained elimination of HAV transmission should be initiated as early as possible.

Viral Hepatitis B

Viral hepatitis B (HBV), which affects an estimated 360 million people worldwide, is a primary candidate for elimination or eradication. It occurs most often in Africa, the Pacific Islands, part of South America, most of Asia, and in ethnically defined populations in Australia, New Zealand, and the USA (7). Chronic infection, which usually begins in early childhood, is associated with risk of death from chronic liver disease, primarily as an adult, and with the risk of liver cancer, a leading cause of death among many adults in developing countries. These consequences generally develop among adults at the most productive times in their lives, creating a high economic burden worldwide.

Essential facilitating factors. Pre- and post-exposure immunization can prevent infection. Limited population-based studies have demonstrated that new infection can be prevented, resulting in a marked reduction in the chronic carrier state among routinely immunized cohorts of children. Progress towards ending transmission of the virus can be measured by the reduction in chronic viral hepatitis B infection within immunized cohorts in a geographic area.

HBV vaccine can be used in combination with other vaccines given to infants and children. High levels of infant immunization, beginning at a time that would prevent perinatal transmission (e.g. first dose at birth), may ultimately lead to global elimination of HBV transmission.

The framework for eliminating HBV transmission already exists. Nongovernmental organizations and voluntary health organizations interested in preventing viral hepatitis and HBV-related hepatotocellular carcinoma hepatitis can facilitate broader prevention partnerships, while practical diagnostic tools to detect infection are available commercially to both developed and developing countries. Many countries have demonstrated their commitment to eliminating HBV transmission by including the hepatitis B vaccine in the EPI.

Essential impeding factors. The cost per dose of hepatitis B vaccine is relatively high, preventing many poorer countries from including it in their EPI. However, significant cost reductions have been achieved through combined regional vaccine purchases. More seriously, while HBV transmission can be eliminated among immunized people, immunizations would have to be maintained for several generations for eradication to be achieved, because of the virus's persistence in chronically infected persons who did not benefit from immunization.

Key strategies. Routine immunization of infants through EPI is crucial, with vaccination beginning at a time that will prevent perinatal transmission. Immunizations near birth would have the subsidiary benefit of strengthening maternal and child health programmes and promoting the use of trained birth attendants. Current acute disease surveillance systems should be strengthened to identify the etiology of acute and chronic hepatitis, including HBV infection.

Research needs. The following are priority areas for research:

• development of economic models which can be used to convince policy-makers of the need for hepatitis B immunization;
• improvements in vaccines, including the development of vaccines which require fewer doses while providing long-term immune memory, or which are administered orally; and
• determination of HBV variations which may be resistant to vaccine-induced antibody.

Conclusion and recommendation. Hepatitis B immunization should become a component of EPI in all countries, with a vaccination schedule that maximizes the likelihood of eliminating transmission of HBV infection.

Measles

Highly contagious and easily transmitted, measles is responsible for fully 10% of deaths from all causes among less than 5-year-olds (8). It is the eighth leading cause of death worldwide, being responsible for an estimated one million deaths each year, or 2.7% of disability-adjusted life years in 1990 (9).

The availability of an effective vaccine which produces greater than or equal to 85% immunity after one dose administered at 9 months of age, and greater than or equal to 95% immunity after two doses (10), the fact that humans are thought to be the only reservoir capable of sustaining transmission, and the successful control of measles in the Americas make measles the next likely candidate for eradication. However, its highly contagious nature and the ease with which it can be imported from endemic areas by air travel mean that eradicating measles will require a coordinated global effort over a relatively short period of time. Global coverage with one dose of measles vaccine was estimated at 81% in 1996 (11). Two regions have already set a measles-elimination goal -- by the year 2000 for the Region of the Americas and 2010 for the Eastern Mediterranean Region. The European Region will be considering this year whether to set the same goal for 2007. China and several southern African and Pacific island countries have embarked on accelerated approaches for measles control or elimination.

Essential facilitating factors. Strategies developed in the Americas have demonstrated that it is technically feasible to interrupt measles transmission in a large area for a variable time period. However, it remains essential that the use of similar strategies demonstrate the same impact in other regions of the world. The experience gained and lessons learned from the poliomyelitis eradication programme will greatly facilitate the implementation of measles eradication, particularly with respect to political support, donor coordination, private sector involvement, and surveillance strategies.

Essential inhibiting factors. A weak health infrastructure in developing countries will inhibit the eradication of measles, which requires substantial effort and resources; in developed countries, the disease has not been perceived as a priority so that adequate efforts to control or eliminate it have not been made. Both of these factors pose a risk for those countries that have eliminated transmission, and they will have to sustain high levels of effort to ensure high immunity and careful surveillance. In addition, the safety of injections during campaigns and routine immunizations can be an issue if sufficient care is not taken.

Key strategies. The approach to measles eradication should be implemented in phases; the initial focus should be on elimination of the disease in the industrialized world, where both infrastructure and resources for elimination are readily available. This means fostering interest in measles elimination in the developed countries, while accelerating worldwide control of the disease, especially in those areas at high risk of measles mortality.

It will be important to capitalize on the experience of different regions of the world. For example, strategies developed and implemented by PAHO -- such as the one-time mass campaign (catch-up), the achievement and sustaining of a high measles coverage level among each cohort of newborns (keep-up), and periodic campaigns to prevent accumulation of susceptible individuals (follow-up) -- have interrupted transmission of measles over a prolonged period in many countries. Surveillance measures can be built on existing acute flaccid paralysis (AFP) surveillance developed for the poliomyelitis eradication programme.

Research needs. Priority areas for research include the following:

• study of changes in the patterns of transmission with increasing immunization levels, especially in adult populations, and development of methodologies for the evaluation of the build-up of susceptibility in different age groups to guide strategy selection;
• characterization of the immunobiology of measles virus infection and immunization;
• examination of alternative routes for administering the vaccine, including safety issues, and alternative methods of immunization at an earlier age;
• the need to develop adequate indicators for evaluating surveillance and documenting the impact of intervention; and
• development of a rapid diagnostic assay for field use.

Conclusions and recommendations. These are shown below.

• It is biologically plausible to eradicate measles with the present vaccine. In the Americas, measles transmission appears to have been interrupted in many countries for variable time intervals, but elimination has yet to be demonstrated in other regions.
• Measles elimination is technically feasible in developed countries, which should proceed with elimination as a step towards global eradication.
• In other countries, accelerating measles control should be the priority, especially in areas with high mortality.
• Experience from regional and country interventions should be used to refine the strategies for eventual eradication.
• Any consideration for elimination or eradication of measles should not jeopardize the poliomyelitis eradication effort.
• Countries undertaking measles elimination should incorporate measles surveillance into their poliomyelitis surveillance systems, including the poliomyelitis laboratory network.

Rubella

Rubella generally presents as a mild or asymptomatic infection in adults and children. In pregnant women, however, especially in the first trimester, rubella infection can result in stillbirth, miscarriage, or the constellation of birth defects known as congenital rubella syndrome (CRS) (12). The most commonly described CRS anomalies include nerve deafness, cataracts, cardiac anomalies, impaired intrauterine growth, inflammatory lesions of different organs, and mental retardation.

Rubella is endemic in most countries of the world. In the absence of major epidemics, it has been estimated that more than 20,000 infants are born with CRS each year in the Americas, and at least 236,000 cases in each nonepidemic year in developing countries. Approximately 30% of suspected measles cases in the English-speaking Caribbean and Mexico were laboratory confirmed as rubella. Eradicating rubella with the present vaccine is biologically plausible. However many other issues must first be addressed, including the marginal cost of adding rubella to measles eradication, and the determination of the best strategies to interrupt transmission (13).

Essential facilitating factors. Humans are the only known reservoir for rubella. Also, a highly effective rubella vaccine exists, and can be delivered in combination with the measles vaccine, leading to potential economic gains in health costs.

Essential inhibiting factors. The global burden of rubella and CRS remains undefined in many developing countries. However, in the absence of high coverage with the vaccine, there is a potential risk of CRS because of susceptible women not having been immunized or exposed to wild rubella during childhood. As a result, high levels of routine immunization must be maintained. Finally, depending on the vaccination programme implemented, there exists a potential risk for the age of infection to shift to older age groups.

Key strategies. The first step towards elimination or eradication of rubella is to gather data on the virus, by building epidemiological and laboratory surveillance for rubella in conjunction with the measles surveillance system, and by establishing a surveillance system for CRS. Owing to the different epidemiology of rubella, the target age groups to be immunized will need to be wider, and will need to include additional intervention in adults.

Research needs. Priorities for research include the following:

• determining the burden of CRS in developing countries;
• investigating the risk of shifting the age of infection to older age groups and the need to cover a wider target age group (other than young children) to interrupt transmission;
• developing a combined measles/rubella laboratory field test;
• establishing demonstration projects to show that rubella can be eliminated, and that elimination can be sustained in certain countries; and
• conducting studies of the epidemiology of rubella transmission in developing countries, particularly the role of adults in transmission.

Conclusions and recommendations. These are as follows:

• Countries undertaking measles elimination should add rubella vaccine to their measles vaccination programme as a way to improve control of rubella and as part of a sustainable national immunization programme.
• In these countries, rubella surveillance should be incorporated into the measles surveillance programme and CRS surveillance systems should be established.
• Countries wishing to control CRS rapidly should immunize women of childbearing age as part of a sustainable national immunization programme.
• Countries which implement routine childhood immunization should also make efforts to immunize susceptible women of childbearing age through programmes such as postpartum vaccination to prevent CRS.

Yellow Fever and Other Zoonotic Diseases

Yellow Fever

Yellow fever, a mosquito-borne viral disease, is not considered eradicable at the present time. However, an excellent and inexpensive vaccine exists, and its sustained use regionally has led to effective control of the disease and elimination of recognized outbreaks (14,15). The threat of introduction of yellow fever to Asia carries an urgency beyond its local impact in Africa and South America, and control of the disease deserves priority (16).

Essential facilitating factors. While there are major differences in disease epidemiology in South America and Africa, the yellow fever vaccine, which has a long history of safe and effective use, protects against all strains of the virus (14). It is heat stable, confers long-term immunity after a single dose, and, in limited studies, has been given with other vaccines, including measles and meningococcal vaccines, without interference. The vaccine can be produced in several countries where there is a risk of transmission, and highly specific international standards for vaccine production and quality have been delineated and promulgated.

Essential impeding factors. Sylvatic yellow fever in South America leads to sporadic cases and small outbreaks of the disease; focused immunization programmes may be effective and sufficient for control. In some areas, the vaccine has been incorporated into local EPI programmes. However, because outbreaks occur sporadically and in remote areas, it is politically difficult to justify the resources for universal coverage. This current inability to implement universal immunization at the present time complicates the vaccination programme. The real risk in South America is that of urban epidemics, as most urban centres have been reinfested by Aedes aegypti mosquitos, the principal transmitter of urban yellow fever (17,18). Rapid spread from South America by air travel could mean an increased risk of urban yellow fever in Asia and the Pacific (16).

In Africa, the burden of disease is comprised of both endemic transmission and epidemics (19,20). With few exceptions, vaccination programmes have not been initiated or maintained, owing to the lack of national resources and political will to sustain immunization programmes (21). The disease is a low priority because it occurs only in intermittent epidemics and mainly in rural areas, where it is less visible and has less political impact. Epidemiological assessments of the incidence and burden of the disease are also poor.

The relatively low volume of vaccine use prevents a reduction in vaccine costs and inhibits manufacturers from developments that could facilitate public health implementation, such as the formulation of combination vaccines. For example, development of a measles-yellow fever combination vaccine was initiated with WHO's encouragement by Pasteur-Merieux-Connaught in 1984, but was discontinued in 1992 when implementation of yellow fever vaccine in African EPI programmes did not evolve as expected.

Key strategies. Yellow fever is found in animal reservoirs, and therefore is not considered eradicable at the present time. However, wider use of a vac-cine could control and effectively eliminate the disease. This could be accomplished by including yellow fever vaccine in the EPI programmes of African countries at risk and implementing catch-up immunization, as recommended by WHO and UNICEF, immunizing selected groups of people at high risk of sylvatic yellow fever in South America, intensifying surveillance and immunization in areas at high risk for urban epidemics, and strengthening enforcement of international travel and vaccination requirements to prevent the spread of yellow fever to Asia.

Research needs. Priority areas for research include the following:

• improving disease burden estimates in Africa, especially a better assessment of the burden due to endemic transmission, as well as quantitative data on the incidence and economic costs of the disease and the costs of not taking preventive measures;
• establishing national and regional diagnostic laboratories to improve surveillance, and developing a diagnostic kit suitable for field use to facilitate surveillance in rural areas;
• developing yellow fever combination vaccines that will facilitate the inclusion of the vaccine in routine and catch-up immunization programmes;
• developing a greater understanding of the immunogenicity and safety of yellow fever vaccine in HIV-infected persons, including the potential for delayed vaccine clearance and subsequent transmission.

Conclusions and recommendations. These are as follows:

• Yellow fever virus is not considered eradicable; however, the availability of a vaccine of unparalleled safety and efficacy argues for its wider use to control and, effectively, to eliminate the disease. Barriers to its control are not due to scientific or technical limitations, but to administrative and economic considerations of health care delivery.
• In Africa, vaccine implementation has been inhibited by the perception of low public health priority and the absence of sufficient public will to sustain routine childhood immunization. Improved surveillance and quantification of the economic costs of the disease are needed to stimulate nongovernmental and governmental organizations into action.
• As a first step, obstacles to the implementation of the 1988 joint WHO/UNICEF recommendation to include yellow fever vaccine in African EPI programmes should be identified with a view to overcoming these barriers. A WHO technical consensus meeting, held on 3-4 March 1998, addressed these issues.

Rabies

Rabies is not considered eradicable at present. By controlling the infection in animal reservoirs, however, the disease can be controlled in humans as well (22-24). This will result in reduced human mortality due to rabies and reduced human morbidity and economic costs of post-exposure prophylaxis.

Essential facilitating factors. Because the burden of disease is primarily in urban areas (25), where dogs constitute the principal animal reservoir, control of rabies is more feasible, and has been demonstrated in many areas, most recently in Latin America. Rabies control in its wild animal reservoirs has achieved some measure of success, particularly in red foxes in western Europe and eastern Canada, through distribution of oral baited vaccines (26). Because of innate biological and ecological differences in reservoir species, however, further advances will require strategies to be specifically tailored for each reservoir.

Public awareness of the risks of rabies also facilitates control programmes, as does the wide availability of vaccines for both veterinary and human use. Epizootiological and epidemiological surveillance is facilitated by viral antigenic and genomic markers (27) associated with reservoir hosts.

Essential impeding factors. Effective control of rabies requires partnership between departments of health and agriculture, agencies responsible for environmental health and wildlife protection, and the private sector (23). Overlapping responsibilities among government agencies necessitate close coordination.

An essential component of effective rabies post-exposure prophylaxis includes rabies immune globulin, which is frequently in short supply and too costly for routine use in many developing countries. Licensed cell-culture-based vaccines are available for veterinary and human use.

Key strategies. A combination of dog control and immunization is the key to controlling urban rabies, as is the use of oral vaccine in baits to control or reduce sylvatic rabies transmission (26,28,29). Programmes to limit human exposure to animal bites should be promoted. Access to post-exposure prophylaxis should be made more available. Humans at high risk for rabies, such as veterinarians, persons with vocational risks, and members of certain occupational groups, should be immunized prior to exposure (23,24). Continued development and evaluation of oral vaccination, as an adjunct to traditional control measures, should be encouraged.

Research needs. Priorities for research include the following:

• developing a safe and effective vaccine for mass immunization of dogs, such as an oral bait vaccine (26), which does not pose a threat of inadvertent ingestion by children;
• replacing brain-derived vaccines, which cause neurological reactions, with existing cell-culture based vaccines (24);
• ensuring the safety and efficacy of currently manufactured rabies vaccines, since, in some instances, production and quality in many developing countries are not well controlled (28);
• identifying less costly, effective alternatives to human rabies immune globulin (30);
• developing a better understanding of all aspects of rabies transmission in bats, which has emerged as the most important cause of rabies in the USA (30) and the only recognized native rabies reservoir in Australia (31);
• exploiting existing knowledge of the virology of rhabdoviruses to develop safe and effective antiviral compounds that could be integrated into existing post-exposure regimens of passive and active immunization (23,24); and
• advancing wildlife rabies control through oral vaccination, continued development of novel vaccines, baits, and baiting strategies, and objective assessment and additional generation of cost-benefit analyses of such strategies (29).

Conclusions and recommendations. These are outlined below.

• Although rabies is not considered eradicable at the present time, control of the disease in urban areas worldwide is feasible, and would reduce human mortality due to rabies and significant morbidity and economic costs associated with administration of post-exposure prophylaxis.
• Control of rabies in these circumstances may be facilitated by the development of an oral bait vaccine (23) for dogs.
• Although both the public and governments are aware of the health risks of rabies, a cost analysis of rabies post-exposure prophylaxis in developing countries may stimulate greater efforts to control the disease in those countries (28).
• International efforts to ensure the quality of rabies vaccines should be strengthened, and manufacturers urged to replace reactogenic brain-derived vaccine with safer cell-culture derived vaccines, as recommended by the WHO Expert Committee on Biological Standardization (24).
• Recent discoveries of previously unknown bat reservoirs of rabies virus underscore the importance of continued research to define the natural history of the disease (30,31).

Japanese encephalitis

Japanese encephalitis cannot be eradicated because it is transmitted from natural reservoirs, but it can be controlled or eliminated with effective vaccines (32,33). Neglected in discussions of diseases of international importance, Japanese encephalitis has a significant regional public health impact in Asia, where its high mortality rate and the large proportion of surviving children with permanent neurological sequelae contribute to a considerable disease burden (34). In the past several decades, the disease has spread to previously unaffected areas in Asia, as well as to territories in Australia and the Pacific (35).

Essential facilitating factors. An effective vaccine for Japanese encephalitis exists, and universal childhood immunization has led to the near elimination of the disease in Japan, Republic of Korea, and China (Province of Taiwan), where previously thousands of cases were reported annually (33). A significant regional reduction in disease incidence has been noted in areas of Thailand where the vaccine has been incorporated into EPI programmes (34). Interruption of viral transmission in the animal reservoirs, by vaccinating or removing pigs or by vector control, is an adjunct strategy, but cannot be solely relied upon to control the disease (36).

Essential impeding factors. While the current vaccine, which is derived from infected mouse brain, is effective, it requires two doses for primary immunization and numerous booster doses to maintain immunity (33,37). The vaccine causes hypersensitivity reactions in 0.5% of those who receive it (37,38). Vaccine production, supply, and cost are limited by the technical complexity of the manufacturing process. For many developing countries, lack of resources limits its use, despite political will to implement the vaccine into national programmes.

An alternative, live attenuated vaccine, produced and distributed in China, is safe and effective and has been used in more than 100 million children (39). Despite requiring two doses, the vaccine could be available at a lower cost than the current vaccine; however, it is currently licensed only in China.

Key strategies. The key to controlling Japanese encephalitis is to incorporate the vaccine into EPI programmes in Asia, This strategy has already been shown to control the disease to the point of elimination in several countries.

Research needs. The priority for research is to develop an improved vaccine to replace the current inactivated vaccine. The live-attenuated vaccine available in China may fulfil some of the requirements, but there are uncertainties about its cost when produced under internationally accepted standards, and unresolved practical issues, such as its thermal stability, concurrent administration with other vaccines, and safety in HIV-infected children.

Conclusions and recommendations. These are shown below.

• Japanese encephalitis produces a significant burden of disease regionally in Asia, which can be prevented by routine childhood immunization.
• Control of the disease to the point of elimination has been demonstrated in several countries, and regional control is within reach with outside support of national programmes or by the development and use of a less expensive vaccine.
• With the emergence of the disease in new areas during recent decades, consideration should be given to more extensive control on a national and regional basis.

Acknowledgements

Thanks are due to Dr Hal Margolis, Dr Olen Kew, Dr J.M. Oliv, Dr Theodore Tsai, Dr Fred Robbins, Dr Luis Barreto, Dr Natth Bhamarapravati, and Dr Jaime Sepulveda for their special contributions to this report.

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* Assistant Deputy Minister, Health Protection Branch, Health Canada, Ottawa, Ontario, Canada.

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