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 production, per­ Urban 61% are infected with vaccinia virus, a low sisting immunity and a good safety record. Rural 21% frequency of double recombinations can Nevertheless, there are considerable occur between the flanking DNA se­ problems with existing live vaccines in Government expenditure quences surrounding the foreign DNA terms of reversion to virulence (polio, Health 5.5% in the plasmid and the non-essential DNA Sabin type 3), reactigenicity (BCG), Education 14% of the virus, resulting in the precise Defence 13.8% need for a cold chain, and possible replacement of the viral DNA sequences induction of disease in immunodeficient Population per physician 6,050 by the desired promotor and foreign anti­ and some normal individuals (for example with access to health services 40% gen gene. A wide range of viral, bacterial polio). and protozoal antigens has been expres­ • Anti-idiotype vaccines are a novel Life expectancy at birth 48yr sed in vaccinia, as many as four antigens concept that has yet to be realized. They being expressed simultaneously in a single Infant mortality (<1yr per 6 are based on the principle that because recombinant virus • antibody active sites (the idiotype) are 1,000 births) 130 The principal disadvantage of vaccinia complementary to the specific antigenic Mortality rate of children aged is the frequency of complications, which under 5 (per 1,000 births) 211 determinant to which they bind, some Population annual growth rate approaches the limits of current accept­ antibodies raised against a particular (1973-84) 2.6% ability. Although only 1 in 300,000 antibody active site may indeed mimic Children suffering malnutrition 31% recipients of the least troublesome antigen. Although immunization has been Children immunized with DPT, vaccinia strain developed severe neuro­ achieved in some experimental systems polio, measles and BCG 61% logical effects, the incidence of serious with anti-idiotype or anti-antibody vac­ complications, including disseminated cines, so far there has been difficulty in have certain advantages: they express vaccinia and vaccinia gangrenosum, was achieving high levels of immunization and antigens in eukaryotic cells with correct of the order of 1 in 1,000 in New York immunological memory because T cells folding, proteolytic processing, glycosyla­ State, and is certainly higher in some 7 are not developed against antigens of the tion, secretion and subunit assembly; and developing countries • (It is regrettable pathogen. It remains to be seen in what they can stimulate the production of cyto­ that data on complications in developing circumstances anti-idiotype vaccines will toxic T-lymphocytes as well as antibodies. countries are not available from the global prove to be useful. Bacterial vaccines have a special ability to eradication campaign.) By genetic engin­ In considering the various criteria for immunize for long periods and engender eering it should be possible to define viral new vaccines for the Third World, geneti­ local immunity, for example in the gut, genes involved in neurovirulence and cally engineering live attenuated vaccines and cell-mediated immunity. reactigenicity and to create new, less to become multivaccine vectors that can reactigenic, vaccine strains. It has also immunize simultaneously against multiple The technology: the power of molecular been possible to incorporate genes for antigens is particularly appealing. Two biology and genetics. The ability to lymphokines such as interleukin-2 to basic strategies are being developed, one change living organisms by genetic engin­ enhance immune responses to foreign using viral vaccines, the other using eering has given rise to the possibility of antigens and the virus itself. bacterial vaccines as recombinant multi­ devising vaccine vehicles that can immu­ Because recipients produce neutraliz­ vaccine vehicles. Viral vaccines in general nize simultaneously against antigens of ing antibodies to the virus, a second

116 NATURE · VOL 342 · 9 NOVEMBER 1989 © 1989 Nature Publishing Group COMMENTARY limitation of vaccmta is that it is not the developed countries, because essen­ feasible, at least in the short term, to give tially all cases of poliomyelitis there result booster shots, because reintroduced from reversion of vaccine strains to viru­ recombinant vaccinia will simply be lence. Because Sabin type 3 vaccine neutralized. Practically speaking, vaccinia differs from virulent poliovirus type 3 by is a one-shot vaccine by necessity, and that only two mutations, reversion to virulence shot must be highly effective to make it is an intrinsic problem. useful. Recombinant vaccinia expressing The key to the genetic manipulation of the glycoprotein antigen of rabies virus is polio was the discovery that artificially extraordinarily immunogenic and, despite produced complementary DNA to the some uncertainty about vaccinia's accept­ viral RNA is infectious and, on transfec­ ability in human beings, recombinant tion of cells, produces infectious polio­ vaccinia has recently been introduced in virus. Of the several neutralizing epitopes Belgium, and a region of France, in bait to on polioviruses, all but one are conforma­ protect foxes against rabies. More tional and composed of discontinuous importantly, perhaps, there is an epidemic sequences of amino acids, the exception 9 in West Africa of rinderpest, a cattle being a single loop of linear sequence • disease caused by a measles-like morbilla­ Several laboratories have been able to virus, and the International Commission recombine eDNA sequences of the loop of Epizootics plans to immunize hundreds that generate the main neutralizing epi­ of millions of cattle with recombinant topes, for example, from type 3 into the vaccinia expressing rinderpest antigens. very stable polio type 1 vaccine, to create In an experiment of that scale, with hybrid vaccines that generate neutralizing perhaps 100,000 vaccinators, there is antibodies to both types 1 and 3 polio­ The campaign against smallpox continued bound to be adventitious infection of virus"H'. The eDNA sequences encoding even after the last endemic case. This poster human beings with the recombinant the loop can be modified to express advertises a $1,000 reward for anyone report• vaccine. It will be essential that they are sequences for small epitopes of foreign ing an occurrence. pre-immunized against vaccinia virus. antigens, including HIV. At present, attenuating mutation in Ty21a must have Adenovirus vaccines have been used in however, there is no evidence that these been in a gene other than GalE. Equally tens of millions of US military recruits to recombinant vaccines can immunize by distressing, three oral immunizations protect against respiratory disease, essen­ oral administration. of Ty21a were required to achieve 67 per tially without serious complications. One of the safest and most effective live cent protection, an efficiency insufficient Curiously, the vaccine is not an atten­ attenuated viral vaccines known is the for a useful anti-typhoid vaccine or multi­ uated strain, but rather consists of two 17D vaccine against yellow fever. A single vaccine vehicle. virulent strains, types 4 and 7, that are immunization results in sustained neutr­ To avoid the vagaries of chemical muta­ given by an unnatural route, orally, that alizing titres for periods of over 40 years, genesis, the genetic strategy for salmon­ immunizes without producing disease. and complications are very rare. It has ella vectors is to delete genes required for The use of enteric-coated lyophilized recently been possible to produce infec­ pathogenesis or survival, then to insert vaccine tablets represents a distinct tious eDNA from the 17D vaccine 13 and foreign genes into the chromosome by advantage for delivery. The virus has a one hopes that the possibility of develop­ gene replacement, or express them on rather small DNA genome, but a limited ing 17D as a recombinant vaccine vector plasmids in the cytoplasm. A promising number of foreign genes have been intro­ will be rapidly explored. set of targets for gene deletion has been duced and expressed in adenoviruses by a • Live attenuated bacterial vaccine genes (aroA, C and D) of the aromatic­ similar, precise gene-replacement strategy, vehicles. The first modern approach to a amino-acid pathway required for syn­ including the hepatitis-B surface antigen rationally designed live attenuated vaccine thesis of folate and enterochelins (iron­ 1 that is not well expressed in vaccinia". was the production, by chemical muta­ binding proteins) as well as proteins '. Concerns include the role of the ElA genesis, of an auxotrophic mutant of These are auxotrophic mutants that can­ gene, which functions like certain proto­ the virulent bacterium Salmonella typhi. not grow without added aromatic amino oncogenes in transformation of cells in A mutant in galactose epimerase (GalE) acids, and thus they too function as time­ culture, and the fact that the safety of was selected that could not convert UDP­ bombs. Vast amounts of foreign genetic existing adenovirus vaccines in children is galactose to UDP-glucose. This strain, material can be introduced and expressed unknown. Herpes viruses are large DNA Ty21a, retained the ability to infect after in bacteria, and these salmonella auxotro­ viruses that, like vaccinia, have large oral administration and to colonize the phic mutants have immunized animals amounts of expendable DNA; they could gut, essential for producing secretory against introduced recombinant antigens. be developed into recombinant multi­ immunity. The mutation was designed to A second genetic strategy used to pro­ vaccine vehicles, provided that the genes be a time-bomb; Ty21a can grow for duce recombinant Salmonella typhi­ for neurovirulence can be identified and several days, and then, when it accumu­ murium vectors has been deletion of the deleted. lates more UDP-galactose than it can genes for adenylyl cyclase (cya) and the Two RNA viruses offer promise as tolerate, it dies, liberating antigens. This cAMP-binding protein ( crp - catabolite recombinant vaccine vectors. The live strain has proven to be remarkably stable repressor protein) which, together with attentuated polio vaccine is one of the and safe, and has been tested in field trials removal of a plasmid containing virulence most effective vaccines in the developed in Egypt and Chile against typhoid fever. genes, has eliminated pathogenicity. world, but it has been disappointingly in­ Ty2la suffers from two disadvantages. Genes for foreign antigens expressed on effective in many developing countries One never knows precisely what gene(s) plasmids introduced into these strains 15 with up to 30 per cent of recipients failing is affected by chemical mutagenesis. have persisted and immunized mice • The to produce acceptable neutralizing titres, Indeed, when the GalE gene from S. typhi great advantage of salmonella recombi­ generally to type 3. There has been a was deleted by another group and the nant vectors is that they can be given return to multiple injections of killed deleted strain was tested in volunteers, orally, and, in experimental animals, they polio vaccine in some places. Polio vac­ two out of the four recipients developed immunize both locally and, at the T-cell cines are not without problems, even in typhoid fever, revealing that the key level, systemically. ..,..

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Unfortunately, the few trials in human volunteers with recombinant salmonella vectors have indicated that the strains tested have been overattenuated and do not produce adequate secretory IgA anti­ bodies. Patient efforts are required to construct salmonella strains that can achieve the delicate balance between appropriate attenuation and effective colonization leading to immunization. They must immunize not only against typhoid but against introduced recombin­ ant antigens; of particular interest are those for cholera, shigella and enterotoxi­ genic E. coli. The oldest and most widely used live attenuated vaccine in the world is, per­ haps surprisingly, BCG - Bacille Cal­ mette-Guerin - an attenuated bovine tubercle bacillus used to immunize against tuberculosis. This mycobacterial vaccine has been given to over 1.5 billion people with a low frequency of serious complica­ tions, although it has the highest rate of minor reactions of any of the EPI vac­ cines. Its effectiveness in protecting against pulmonary tuberculosis has varied The logistical problem- an immunization team in the Philippines sets out by canoe. greatly in different parts of the world, but HIV seropositive. One died of general- alone should spur efforts to develop effec- BCG requires only a single shot to engen­ ized vaccinia. (One cannot help but tive vaccines against AIDS. der cell-mediated immunity for periods of wonder, as, by convention, study or use 5-50 years. It is known to be an effective of smallpox (variola) virus has been dis- Single-dose, controlled-release vaccines. adjuvant, enhancing immune responses to continued and all strains presumably The requirement for several injections is many different antigens. BCG can be locked away in three safe repositories, the main limitation to subunit vaccines. administered at birth or at any time there­ why anyone in the world is being vaccina- Almost 800,000 neonates per year still die after, and can be given repeatedly. Like ted against smallpox.) Several major of tetanus, which can be prevented simply most bacterial vaccines, it is very inexpen­ cohort studies are underway in Africa to by immunizing women of childbearing sive ($0.055 per dose). evaluate the consequences of standard age. Controlled-release systems are In contrast to E. coli, BCG grows very childhood vaccination in HIV-seroposi- already being used in man (and cattle) to slowly and requires about 24 days to tive compared to HIV-seronegative chi!- deliver an array of drugs and hormones. produce a colony (E. coli takes 8 hours). dren. It is encouraging that so far no dis- Some of these systems have been used by Because it seemed unlikely that direct cernible differences in untoward compli- the WHO Special Programme on Human genetic manipulation of mycobacteria cations of any of the vaccines have been Reproduction (HRP), which has suppor- would prove efficient, a 'shuttle' strategy observed. It may be that there is a window ted research on anti-fertility vaccines. has been devised to introduce and express in time in congenitally infected children Taking advantage of HRP expertise in the foreign genes in BCG. Basically, phages during which they can be immunized and area, development of single-dose vaccines or plasmids were constructed that can before which any significant immuno- has become a goal of the WHO Special replicate both in E. coli and in mycobac­ depression occurs. Because children who Programme for Vaccine Development teria'6. Foreign genes and selectable will be immunocompromised are even with neonatal tetanus as its first target. markers can be introduced by standard more susceptible to the principal child- Basically, polymers of lactic and gly- molecular genetic techniques in E. coli, hood diseases, particularly measles, it is colic acids (PLAIPGA) approved for and the recombinant DNA is then 'shut­ strongly recommended by WHO that human use are being incorporated into tled' into BCG. Foreign genes can then be these children receive all the childhood controlled-release microspheres or micro- expressed either by replacing non-essen­ vaccines, except for BCG in children with capsules which can provide either con- tial BCG chromosomal genes or from symptomatic immunodeficiency. tinuous release of tetanus toxoid over a multicopy plasmids in the cytoplasm. It The basic premise of existing vaccines period of several months, or a pulsed remains to be seen, however, how effec­ has long been the utilitarian principle of release similar to booster shots, that tive antigens known to be immunogenic providing the greatest good for the greatest would occur, for example, 4 and 8 weeks when mixed with mycobacterial adjuvants number of people; it has long been recog- after a single immunization. Should this are when expressed by the organism nized that small numbers of individuals prove effective, DPT, and a number of itself. will suffer severe complications. At the other subunit antigens could be incorpora- very least, antidotes to restrict dissemi- ted into this type of one-shot vaccine - The spectre of AIDS. There is a serious nated infection of recombinant live vac- not the least important of which will be risk with any live vaccine, namely dis­ cines should be available (for example, epitopes from human chorionic ganado- 17 semination and serious complications in vaccinia immune globulin, isoniazid for trophin or sperm to control fertility • immunodeficient individuals. The current BCG, antibiotics for salmonella). Because HIV epidemic in many countries heightens of the high cost of drugs potentially useful Immunological problems. At a scientific concern about side effects from childhood against AIDS, it is sadly likely that most level, the constraints on development of vaccination. For example, vaccinia has will not be available to patients in de- new vaccines are not likely to come from been adminstered to US military person­ veloping countries in the foreseeable molecular biology and genetics; rather nel, 28 of whom were later found to be future; consideration of cost effectiveness they will be biological and immunological. 118 NATURE · VOL 342 · 9 NOVEMBER 1989 © 1989 Nature Publishing Group COMMENTARY

Although antigens have been cloned from Research (TDR) programme a compo­ that have a competitive advantage over virtually every known pathogen, and nent was mandated in addition to the the vaccine, or that maternal antibodies many T and B epitopes have been mapped scientific research programmes for "insti­ neutralize the vaccine? Or is it simply that on various antigens, there are very few tutional research strengthening" in the the vaccine sold in the United States pathogens for which the mechanism of countries worst afflicted. This support, contains six times more viral particles? protection is understood. Nor is it clear representing 25 per cent of the budget, has Until two years ago, EPI's mandate which antigens are required to engender been used to set up and modernize labor­ was 'implementation' only, and it lacked those protective responses. atories, and to train bright students a research component. The tragedy, A multitude of unanswered questions abroad (and, occasionally, even to make it measured in lost lives, has been mis­ remain. Must a protective vaccine against sufficiently attractive for them to return apprehension that there can be implemen­ malaria sporozoites generate antibodies, home). As a consequence, in many devel­ tation without research. In this context, I or T cells, or both? Can production of oping countries there are laboratories that mean not only laboratory-based research, specific immunoglobulin isotypes be are able to tackle tropical diseases. but social and economic research to pro­ targeted (for example IgA for intestinal What has been largely overlooked, vide information on costs and benefits, pathogens, IgE for killing schistosomes, however, is the role of field and epidemi­ and to provide the means to understand IgG2 for carbohydrate antigens)? Can the ological research in developing countries. how best to design and implement control type of T cells (for example helper T­ Almost all incentives- financial, work­ programmes and identify and overcome cells, cytotoxic T-cells, gamma-delta T­ ing conditions and personal recognition­ obstacles to their effectiveness. cells, and lymphokines) produced be con­ motivate people to go into medical The main trend in development since trolled (for example by targeting the practice, laboratory-based research or, the Second World War, as the Nobel vaccine to the cytoplasmic compartment most commonly, administration. There prize-winning economist Theodore or endosomal compartments of antigen­ are few rewards for health workers in the Schultz pointed oue', has been investment presenting cells)? Can T-cell responses field. Yet the field worker is the mainstay in physical capital- dams, factories and against important protective antigens be for acquiring information about local so on - with little recognition of the generated in individuals of all histocom­ health problems, for evaluating new potential for investment in 'human patibility types? Can nonvarying epitopes interventions and for integrating, main­ capital'. The role of health, education and be found on highly polymorphic protec­ taining and monitoring them in control quality of life in development has general­ tive antigens that can be effective against programmes. Recognition of their im­ ly been underestimated, because it is genetic variants of the pathogens (for portance through the development of much easier to measure direct industrial example malaria, HIV, African trypano­ appropriate career structures and educa­ and agricultural productivity than the somes)? tional and material incentives is a major indirect political and economic effects of At the same time, immunology offers challenge to the developing countries. health and knowledge on the economies novel solutions for basic vaccine problems. At the same time, the development of or political stability of developing Measles vaccine cannot be used in child­ new drugs and vaccines (38 new products countries. ren under the age of 6-9 months because it that have resulted from the WHO-TDR Vaccines are clearly not the key to is inactivated by maternal antibodies, but programme are currently in field trials) development. Yet they can and do serve it is conceivable that appropriate measles provides a unique opportunity for building as an entry point both to strengthening T-cell epitopes could be given at birth in scientific and field infrastructures in the science and primary health-care infra­ one of the recombinant vaccine vectors, Third World. Field-research and control structures. The infrastructure for vaccines such that T-cell memory is generated to infrastructures need no longer be tied can be extended to other low-cost/high­ measles and a protective response would directly to one drug or vaccine, but can be impact medical technologies on a mass follow natural infection. Clearly, the easy continuing mechanisms to assess different scale, including oral rehydration, and vaccines have already been made; new health strategies and disease-control maternal and child care and education, vaccines pose greater challenges for activities. Much of the same technology­ especially breastfeeding, food sup­ research. enzyme-linked immunosorbent assays plementation and family planning. In (ELISA) or polymerase chain reactions 1984, for example, Colombia vaccinated 'It Is only a matter of Implementation'. (PCR), for example- can be used in the three-quarters of its children under five There are few more portentous words same place to assess the distribution of years of age through three national than these to be found in any health parasites in mosquitos and the incidence immunization days, and has subsequently document. For most scientists engaged in of multiple infections by multiple patho­ mobilized complementary efforts for the development of new health inter­ gens in the population. The epidemio­ primary health care and education. ventions, the fulfilment of their research logical tools for testing different drugs Much ink has been spilled on 'appro­ is a product that goes through clinical against one disease are often applicable to priate technology' for the Third World, testing and is eventually licensed for use. trials against anotht;r and can be adapted but there has been almost no consideration In international health, the historical to evaluating vector control and vaccines of 'appropriate science'. Research on record belies such optimism. For example, as well. The result of this research is not vaccines involves a knowledge of mol­ all of the vaccines in the EPI programme papers; it is the control of disease. ecular biology, genetics, immunology and were available before 1974, but only 5 A vital aspect of implementation has epidemiology, and could serve as a per cent of the world's children received almost invariably been ignored. Fifteen stimulus to the educational and scientific them - it was clearly only a matter of years ago it became clear that although advancement important to development. implementation. oral polio vaccine is superbly effective in Even the poorest countries have need for Certainly, the main limiting factor is developed countries, it was proving expertise and access to biomedical cost, but it is not the only one. The scient­ disappointing in developing countries. science; they cannot afford to squander ific infrastructure for evaluating new Studies show that only 40 - 80 per cent of their resources on iron lungs. drugs and vaccines relevant to Third children receiving oral polio vaccine World diseases is also limiting. It is diffi­ produce antibodies sufficient to ensure The bottom line. It is ultimately, one cult and expensive to carry out clinical protection. To this day, it is unclear why supposes, a matter of priorities. The trials in industrialized countries in which oral polio vaccine is so ineffective in annual budget for the entire World Health the diseases do not occur. From the developing countries. Is it that children Organization is $327 million. The TDR beginning of the WHO-Tropical Disease are already colonized with enteric viruses Programme for six tropical diseases has a

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ing the quality of life in the Third World could be addressed. The First World is the place where 13 per cent of the world's people consume the major part of the planet's crude resources, most of which come from the Third World. In the United States we spend annually over $300 billion on 'defence'; a single B-2 'stealth' bomber costs $532 million. In terms of personal consumption, $55 billion ($287 per adult) is spent annually on alcohol, $38 billion on tobacco and $22 billion on toys'". We can afford to do more for health in the Third World. Conscience should motivate us to do so, and self-interest supports the claims of conscience. In the first place, good public health translates into good econ­ omics. We save over $0.5 billion per year Out of the laboratory and into practice- announcement of an immunization day in Bolivia. in no longer having to control smallpox budget of $30 million, and the budget for young children around the world. It (the global figure is $2.5 billion). Second, the Special Programme for Vaccine consists simply of a bacterial carbohydrate in our world there is nothing which is truly Development has a budget of $2.8 million. conjugated to tetanus or diphtheria remote and no one frotn whom we are The annual cost of childhood immuniza­ toxoids to augment the immunogenicity. disconnected. AIDS has again demon­ tion is some $500 million, averaging The cost for each of the companies trying strated that; another example, dengue approximately $10 per immunized child. to develop that vaccine has been $8-12 haemorrhagic fever, which has been The vaccines themselves represent less million. The cost would almost certainly ravaging the Caribbean, and for which an than 10 per cent of the cost of immuniza­ be higher for live vaccine vectors. effective vaccine does not yet exist, is tion; of the remaining costs for personnel, Another example: hepatitis-B virus is predicted to spread in epidemic propor­ transport and logistics, 70 per cent is not only the cause of a serious infectious tions to parts of the United States. Finally, borne by the countries themselves. The disease, but the principal known risk it is becoming more and more clear that major advance in vaccine coverage has factor for hepatocellular carcinoma, which poverty and disease have not only a moral been accomplished largely through the is particularly prevalent in Asia. Several impact but a political price. Ultimately, combined efforts of the EPI of WHO, vaccines are currently being produced, what is the cost of political turmoil? We UNICEF, The World Bank, and the UN one of which is available to EPI for large­ have the resources to make vaccines and Development Programme, with support scale public health use at $1 per dose. essential drugs available to the people of from non-governmental organizations, Nevertheless it cannot be included in EPI the Third World; what we need are the particularly the Rockefeller Foundation, because of cost. Because of the numbers imagination and the will. D Rotary International and the Save the of people involved, there must be incent­ Barry R. Bloom is in the Department of Micro• Children Fund, which together coordinate ives to develop and deliver vaccines and biology and Immunology, Albert Einstein their efforts through the Task Force for essential drugs to the Third World. It College of Medicine, 1300 Morris Park Child Survival. Behind the scenes scien­ should at least be possible to establish Avenue, Bronx, New York 10461, USA. tists trying to develop new or improved cost-plus agreements with international 1. State of the World's Children (UNICEF, Oxford, 1988). vaccines scramble for support, most of it agencies to develop potentially useful 2. World Development Report (The World Bank, Oxford, coming from the US National Institute for interventions, or joint ventures or affilia­ 1988). 3. World Debt Tables, 1988. (The World Bank, Oxford, Allergy and Infectious Diseases or the tions in developing countries. 1988). Department of Defense, or from WHO's The imagination and resources of the 4. Walsh, J.A. Establishing Health Priorities in the Develop• Special (extrabudgetary) Programmes for ing World (United Nations Development Programme, New private sector that were so instrumental in York, 1988). Research and Training in Tropical Dis­ developing biotechnology should be 5. Henderson, R. in Biomedical Science and the Third eases, Human Reproduction, or Vaccine engaged, and the private sector may find World: Under the Volcano (eds Bloom, B.R. & Cerami, A.) (New York Academy of Sciences, in the press). Development. A decade ago, some foun­ that it has something both to contribute 6. Moss, B. & Flexner, C. A. Rev. lmmun. 5, 305-324 dations were generous contributors to and to gain. Failing that, developing (1987). 7. Fenner. F. Annis /nst. Pasteur(in the press). research on diseases of the Third World, countries that can afford it will have to rely 8. Morin, J.R. eta/. Proc. natn. Acad. Sci. U.S.A. (in the but their interest seems more to have on their own abilities, intellectual and press). reflected fashion than a serious commit­ 9. Hogle, J.M. Scient. Am. 256, March 42-49 (1987). material, for developing their own bio­ 10. Burke, K.L., Glynnis, D.. Morag, F., Minor, P.O. & ment to the problem. And one must add technology. This is already happening in Almond, J.W. Nature 332, 81-82 (1988). that, regrettably, few Third World leaders Cuba, India, Brazil and Mexico. It is 11. Murray, M.G. et a/. Proc. natn. Acad. Sci. U.S.A. 85, 3203-3207 (1988). have made health a high priority. important to note that several new vaccines 12. Nomoto, A., Lizuka, N., Kogara, M. &Arita, M. Vaccine&, There has been only limited interest by now in field trials have, in fact, been 134-137 (1988). 13. Rice,C.M.eta/. TheNewBiologist(inthepress). the private sector in development of developed by scientists in the Third World 14. Hoiseth, S.K. & Stocker, B.A.D. Nature 291, 238-9 vaccines for the industrialized world, and - vaccines against leprosy (developed in (1981). virtually none in vaccines for the Third Venezuela and India), leishmaniasis 15. Curtiss, R. Ill & Kelley, S.M. Infect. Immunity 55, 3035- 9 3043 (1987). World' • The reasons are simple. Vaccines (Venezuela and Brazil) and dengue 16. Snapper, S.B. et a/. Proc. natn. Acad. Sci. U.S.A. 85, account for only 1 per cent of the profits of haemorrhagic fever (Thailand). Finally, 6987-6991 (1988). 17. Talwar, G.P. (ed.) Immunological Approaches to Contra• the pharmaceutical industry, and a greater Third World countries have enormous ception and Promotion of Fertility (Plenum, New York percentage of their liability. One of the foreign debt, much of which will clearly 1986). 18. Schultz, T.W. Investing in People (University of Cali• two new vaccines licensed in the past ten have to be written off. If even a small fornia, Berkeley, 1982). years is a subunit vaccine against portion of that debt were restructured to 19. Robbins, A. & Freeman, P. Scient. Am. 258, November Hemophilus influenza b, the main cause of be spent in local currency for health and 126--131 (1988). 20. Statistical Abstract of the United States (Government meningitis and mental retardation in education, several of the problems affect- Printing Office, Washington, D.C., 1988). 120 NATURE · VOL 342 · 9 NOVEMBER 1989 © 1989 Nature Publishing Group