COMMENTARY Vaccines for the Third World Barry R. Bloom New vaccines, developed through genetic engineering, can make immunization an even more effective weapon for tackling disease in developing countries. So what is preventing progress? Where there is no vision, the people perish available, as well as inherent limitations in Any new or improved vaccine to be ... Proverbs 29:18 each of the currently used vaccines. Only considered for inclusion in the EPI two EPI vaccines- BCG, used to immu­ should, ideally, have the following attri­ THE Third World is the place where three­ nize against tuberculosis, and oral polio butes: (1) it must be inexpensive; (2) it quarters of the people of this planet live, vaccine-can be given at birth or any time must be safe; (3) it must be extremely where 86 per cent of all births and 96 per thereafter, and BCG and measles are the effective, inducing protection in 90-100 2 cent of child and infant deaths occur'· • At only vaccines that require a single immu­ per cent of recipients; (4) it should both a national and a human level the nizing dose. DPT and polio must be given engender lifetime immunity; (5) it should diverse problems of the developing be heat-stable and not need to be kept countries are of staggering proportions. ~ cold at all stages (a cold chain), which is Most have heavy foreign debt and, as ~ both expensive and subject to catastrophe; a consequence, these countries now (6) it should require only one shot or be transfer to the developed countries more compatible with the schedule for other hard currency than they receive ($31.1 vaccines; (7) it should be simple to give, billion in 1987)'. Most are burdened by and because of the problems of reuse of disease (Table 1, see over)\ the reality is needles and of HIV infection it should that millions of people are sick because be given by a non-invasive route; and (8) they are poor, and poorer because they it should be capable of being given as are sick. Some indicators of the quality of close to birth as possible. Dr W. Foege, life of people of the 40 poorest countries Chairman of the Task Force on Child are listed in Table 2 (see over), and the Survival, has described the ideal vaccine trends have not been encouraging. Per as one in which "single administration at capita income has declined over the past birth will provide protection from multiple five years and the percentage of national diseases". budgets spent on health has been un­ changed or has diminished for eight years. New vaccines from old. There are basic­ Yet one aspect of life there has ally four kinds of vaccine, each of which improved profoundly. The number of has strengths and limitations for use in the children receiving immunizations has Third World. risen from 5 per cent in 1974 to over 60 • Killed vaccines are among the sim­ per cent this year. The World Health plest and least expensive to prepare. They Organization Expanded Programme for contain many antigens and assure some Immunization (EPI) prevented the deaths This was smallpox, a disease that has been responsiveness in virtually all individuals. of 2.2 million children last year. Through eradicated through immunization. But even under defined production condi­ the efforts of 25,000 professional national several times to achieve protective levels tions, some vary in reproducibility, and all and international staff and hundreds of of antibodies. Because maternal anti­ require careful monitoring to assure that thousands of field workers, 60 million bodies circulating in the infant inactivate no viable organisms are present. As in the children are now vaccinated annually the vaccines, DPT can be given only at six case of pertussis, killed vaccines often against diphtheria, pertussis, tetanus weeks of age, and then at monthly inter­ have a higher level of reactigenicity or (DPT), polio, measles and tuberculosis. vals up to 14 weeks. The dropout rate is toxicity than is desirable. The number of cases of paralytic polio­ high- about 20 per cent fail to return for • Subunit vaccines prepared from myelitis has declined in the Americas from each required booster shot. In the case of individual components of a pathogen, by 4,500 ten years ago to fewer than 200 this the vaccine against measles, which is chemical synthesis or recombinant DNA year, and WHO has just made the eradi­ responsible for the death of 2 million technology (for example tetanus and cation of polio one of its goals'. Immuni­ children annually in the developing world, diphtheria toxoids) have several advan­ zation is the most cost-effective weapon the presence of maternal antibodies that tages. They are chemically defined, for disease prevention in developing coun­ neutralize the vaccine in young children reproducibly prepared and assayed, and tries, and new molecular and genetic tech­ represents a 'wall' that scientists have are usually inexpensive to manufacture. nologies are making new types of vaccines not yet been able to hurdle. If measles Carbohydrate antigens are important for feasible. The eradication of smallpox vaccine were given to children in develop­ protection against many pathogens. demonstrated that they can be effective ing countries at 12-15 months, the time Because complex carbohydrates cannot everywhere. What is lacking is the will to recommended in the developed world, up be produced by recombinant DNA tech­ make the advances of modern biomedical to 30-50 per cent would have contracted nology, subunit vaccines, particularly science available to the poorest people of the disease before receiving the vaccine. carbohydrate-carrier-protein conjugate the world. Measles vaccine is given at 9-12 months vaccines, are the only feasible strategy at and a new strain may even be effective at 6 present for producing protective immu­ Vaccine problems and constraints. As months. In all, a total of five contacts are nity to pathogens such as Hemophilus impressive as the results of global child­ required between the child and the health influenza b and Streptococcus pneu­ hood immunization have been, there are services, which represents a considerable moniae, which cause meningitis, mental many diseases for which vaccines are not logistical problem. retardation and pneumonia. ~ NATURE · VOL 342 · 9 NOVEMBER 1989 115 © 1989 Nature Publishing Group COMMENTARY A general drawback of both killed and different pathogens. Such multivaccine TABLE 1 Diseases of the Third World that subunit vaccines is the need for several potentially could be prevented by vaccines* vehicles can be developed from either immunizations and boosters - immuno­ viral or bacterial vaccines, and each logical memory benefits from repeated Condition Deaths per Estimated approach has its particular advantages. stimulation by antigens. Some chemically year (million) episodes • Live attenuated viral vaccine vehicles. defined subunit or peptide vaccines or incidence per Smallpox was eradicated by the use of live contain a desired antigenic determinant year (million) attenuated strains of vaccinia virus, origi­ (epitope) that elicits B-cell-produced nally derived by Jenner from a cowpox neutralizing antibodies, but they may not Respiratory virus. Although vaccinia may be of some­ disease 10 15 what dubious provenance, it has been engender immunological memory to the Diarrhoea 4.3 28 infectious agent which requires expansion Tuberculosis 3t 10 astoundingly effective. The virus is a large of specific T-helper cells as well; thus Measles 2 67 double-stranded DNA virus of about reinfection will not result in a boosting of Malaria 1.5 150 185,000 base pairs that contains all the the immune response. The possible use of Hepatitis B 0.8 3.7 information for its own transcription and small synthetic epitopes in subunit vaccines Meningitis 0 .35 1 replication in the cytoplasm of a wide raises the concern that polyclonal anti­ Schistosomiasis 0.33 10 range of host cells. Large amounts of bodies developed against a single epitope AIDS 0 . 1~ 0.75 DNA, approximately 25,000 base pairs, of a pathogen may function very much like Worm infections <0.06 4,900 are expendable and not required for vaccinia replication. The molecular monoclonal antibodies and select for * Modified from J .A. Walsh (ref. 4). escape mutants - that is, antigenic t Data from WHO Tuberculosis Unit. strategy to develop vaccinia into a multi­ mutants with altered epitopes on neutrali­ :t: Data from WHO, unpublished estimates. vaccine vehicle is based on the ability to zing antigens that are not neutralized by replace non-essential viral DNA with existing antibodies in the population. foreign genes, and have them expressed Although this would not be catastrophic TABLE 21ndicators of the quality of life in the under the control of the vaccinia-virus for a single epitope in the first instance, world's 40 poorest countries, 1988 promoters and transcription system. new antigenic mutants could be created Plasmids have been constructed contain­ that would, in time, accumulate and possi­ Average annual gross national ing one or more promoters, cloning sites bily become resistant to normal acquired product per capita $270 for introducing DNA for foreign antigen immune defences. Literacy genes, and a selectable marker, all flanked Males 42% • Live attenuated vaccines have largely Females 21% by DNA sequences that complement been derived by empirical methods, and segments of non-essential DNA of the those in current use have the advantages Population with access to water virus. When cells containing the plasmid of generally inexpensive