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Candidate Viral Diseases for Elimination or Eradication
This article discusses the possibilities for elimination or eradication of four viral diseases -- measles, hepatitis B, rubella and yellow fever.
The results of a preliminary survey to identify the top three or four viral diseases that could be considered as candidates for eradication or elimination resulted in the following scores (on an arbitrary scale): 185 for measles, 90 for hepatitis B, 71 for rubella, 42 for yellow fever, 27 for rabies, and 27 for mumps -- with hepatitis A, rotaviral enteritis and varicella as also-rans. In view of the conclusions of the Dahlem Workshop in 1997 (1), it is surprising that yellow fever and rabies, which have animal reservoirs, were included, because these diseases cannot be candidates for either elimination or eradication, although their control could be greatly improved. The present article will deal with the first four diseases on the above list -- measles, hepatitis B, rubella and yellow fever -- and also briefly, mumps.
Progress on the eradication of measles, which poses a heavy disease burden (about 36 million cases and a million deaths annually) and satisfies the biological criteria that were considered essential for eradication by the Dahlem Workshop, has already been presented by de Quadros (2). The criteria are as follows:
Measles shares these features with smallpox, which has been eradicted globally, but, as predicted, measles eradication is proving more difficult -- partly because it is much more infectious than smallpox and partly because there is a window of vulnerability between the duration of protection by maternal antibody (and concomitant resistance to measles vaccination) and attainment of the age of 12 months, at which time vaccination is assured of being effective. Because of the inevitability of repeated reintroduction of infection, countrywide elimination does not constitute a satisfactory outcome, except as a preliminary step to global eradication. Some innovative measures for improving vaccine coverage capitalize on strategies developed during the poliomyelitis eradication campaign. In addition to its intrinsic importance, a campaign to eradicate measles by mass vaccination with a combined vaccine may simplify the eradication of rubella and, potentially, mumps as well.
Although not listed as the second candidate, I will consider rubella next, because the campaign to eradicate it could usefully be linked with the measles eradication programme. Rubella resembles measles not only in having a generalized rash, but also in being a specifically human, acute, self-limiting disease, except that the rare cases of congenital infection may continue to excrete virus for years. Although it is suspected to be a potential trigger for autoimmune diseases, acute rubella is a trivial disease, hardly worth worrying about; however, congenital rubella is a severe disease. Since postnatal rubella is such a mild disease, with many subclinical cases, effective surveillance will be difficult. It might be useful to link the countrywide elimination and ultimate global eradication of rubella with that of measles, by using a combined measles-rubella vaccine, or even better, a measles-rubella-mumps vaccine, so as to minimize the numbers of inoculations. It may be that this scheme is not practicable or too costly, but the chance of eliminating and subsequently eradicating three diseases "at the cost of one" makes the use of a triple vaccine attractive. Since measles is probably the most highly infectious of these three diseases, and the most easily recognized, a good surveillance system for measles might prove to be an effective surrogate for good surveillance for rubella and mumps as well as in judging the efficacy of immunization campaigns.
The eradication of rubella, like measles, calls for an intensive, relatively short campaign, so that all countries can maintain their enthusiasm and commitment.
Like measles and smallpox, hepatitis B virus is a specifically human pathogen and a good vaccine is available. It is clearly a major disease burden in countries where it is common. However, unlike any of the other viral diseases cited by the survey teams, it is a disease in which many persons, especially those infected in infancy, become chronically infected and are persistent or recurrent excretors of the virus. This presents a particularly difficult problem for surveillance, requiring careful laboratory screening on large numbers of infants and older people, most of whom are not sick. Inclusion of hepatitis B vaccination in the EPI schedule, as proposed by WHO, would be a valuable first step towards control. However, many countries in which the incidence is low are reluctant to spend the money needed for vaccination against a disease that does not present them with a substantial health problem; yet, if eradication is to be achieved, an early start in all countries is highly desirable.
Countrywide elimination of hepatitis B requires countries to enter into programmes that call for a long-term commitment, over decades, to outlast cases of chronic infection already present in the population at the start of the programme. This is something that will be difficult to ensure even in the absence of war or serious civil disturbances, which experience in the last 50 years suggests are inevitable. Nevertheless, there is every reason to encourage more countries to include hepatitis B vaccine in their childhood immunization schedules, as suggested by WHO. Countries where the disease is common should be encouraged to screen for chronic hepatitis B infection in pregnant women and vaccinate their infants at birth.
In 1801 Jenner made the optimistic statement: "it now becomes too manifest to admit of controversy, that the annihilation of the Small Pox, the most dreadful scourge of the human species, must be the final result of this practice" (vaccination). A hundred and seventy-six years later, his prediction was realized. The next disease for which such a forecast was made was yellow fever (3). After eliminating yellow fever from Havana and controlling it in Panama, Gorgas wrote in his report in July 1902: "I look forward in the future to a time when yellow fever will have entirely disappeared as a disease to which mankind is subject." After a visit to Asia in 1914, Dr W. Rose, Director of the International Health Commission of the newly established Rockefeller Foundation, found that health officials there were profoundly concerned that yellow fever might be brought to Asia as a consequence of the opening of the Panama Canal that year and the resulting increase in maritime traffic. After consultation with Gorgas, by now Surgeon-General of the United States Army, Rose promised the Rockefeller Foundation's help in the global eradication of yellow fever. This prospect was based on control of the urban mosquito Aedes aegypti, which was thought to be the only vector. It was believed that there were a few endemic centres of disease that served as seedbeds, and that if they were destroyed, yellow fever would disappear forever. Early efforts in South America were dramatically successful, but then there were disturbing small outbreaks in forest areas, where A. aegypti could not be found. Although this situation had been first reported in Colombia in 1907, it was not until 1932 that Soper obtained definitive evidence that monkeys constituted a jungle reservoir of yellow fever, and all hopes of global eradication of the disease were dispelled.
This piece of history is relevant for two reasons. First, although the fact sheet prepared for this conference speaks of elimination rather than eradication, if we follow the definitions of the Dahlem Workshop, "control" would be a better term than elimination. Second, I believe that in addition to preventing unnecessary illness and death in Africa and South America, a major reason for pressing ahead with efforts at controlling the disease (this time by vaccination rather than mosquito control) is to prevent its spread to Asia. Rose was concerned about this in 1914; I participated in a conference in Kuala Lumpur in 1954 to discuss the same problem, and here we are again discussing it in 1998. It would be disastrous to see the spread of yellow fever in the reverse direction to that of dengue and dengue haemorrhagic fever over the last 20 years. This is an additional reason for trying to improve the coverage of vaccination in Africa and South America.
In 1988, WHO and UNICEF recommended routine childhood and catch-up yellow fever vaccination in Africa, but coverage rates are still low. Although the 17D vaccine is probably the best live virus vaccine that has ever been developed, there may be problems in using it in infants and immunosuppressed persons (4). This matter should be investigated, and if there is a significant risk, the potential of a recombinant vaccine or a DNA vaccine should be considered.
Smallpox was successfully eradicated because it was a specifically human disease, with no subclinical cases so that effective surveillance was relatively easy, there was a good vaccine with production facilities in many countries, and the wealthy countries had a strong self-interest in supporting eradication -- to free them from the necessity of vaccinating outgoing travellers and the danger of importations. Poliomyelitis is proving more difficult than smallpox (5), because there are so many subclinical infections, but has the great advantage that there is an excellent oral vaccine.
Because there is an animal reservoir for yellow fever virus, only three of the four viral diseases listed for discussion could be "eradicated." For all four, there is an effective method of intervention, namely a good vaccine, although improvements could be made. Each of the three eradicable diseases presents problems. For measles, the main problem is to ensure the political and financial support required to achieve and maintain high immunization levels in both industrialized and developing countries, which are necessary because of its extremely high infectivity. As with all specifically human infectious diseases, the desirability of targeting eradication rather than countrywide elimination is underlined by the frequent reports of measles outbreaks in countries with low levels of the diseases, due to the arrival by air from other countries of infected persons during the incubation period.
For rubella, the difficulty of diagnosis, and hence of surveillance, constitute the principal problem. An eradication programme might be more effective if, instead of having to mount a rather difficult surveillance programme for rubella, the campaign was linked with the measles eradication campaign by the use of a combined vaccine, a measles-rubella or a measles-mumps-rubella vaccine. For hepatitis B, the prolonged infectivity of chronic cases constitutes a problem in that it calls for a very long-term commitment for continued universal childhood vaccination, as well as vaccination at birth of infants born by mothers who are carriers of hepatitis B virus.
However, by far the most important difficulty with all elimination/eradication programmes is the cost, which is beyond the resources of the poor countries. None of these diseases presents the risk to the wealthy countries that smallpox did, hence it is proving much more difficult to persuade these countries to expand their moral and financial support to the extent that will be required for the eradication of measles, let alone hepatitis B and rubella. The political will is lacking. Despite the cost, it would to be highly desirable to tie efforts to eliminate and ultimately eradicate as many diseases as possible together, by using combination vaccines such as measles-mumps-rubella.
Control of yellow fever appears to be a more practicable proposition, but judging by the response to the 1988 recommendation of WHO/UNICEF, the countries most concerned do not appear to be seized of its value. They need support not only from the wealthy countries, but also, on grounds of self-interest, from the countries most at risk of its extension, namely countries in Asia whose territories include areas infested with A. aegypti.
* Visiting Fellow, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
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