Since Jenner's time, there have always been enthusiasts and skeptics about the role of vaccines in the prevention of disease. This introduction explains why, at this time, it is crucial to assess the historical role vaccines have played in limiting damage caused by infectious diseases, the role they can play in the future, and the technologies that are best suited to achieving optimal gains for public health and development worldwide.

Efforts to provide the benefits of immunization to the world's children have reached an important crossroad. While remarkable progress has been achieved in successfully administering six important childhood vaccines (diphtheria, tetanus, polio, pertussis, measles, and tuberculosis), the benefits of new vaccines, such as hepatitis B and Haemophilus influenzae type B glycoconjugate vaccines, have not been realized except in the most developed countries. The three reasons often cited to explain this problem include poor access to immunization services, the evolution of complex primary immunization schedules, and the additional expense associated with new vaccines, potentially depleting scarce resources. The establishment of the Children's Vaccine Initiative is an organized effort to improve immunization by both technological and organizational innovation. Simplification of the vaccination process can be achieved by developing new combination vaccines or reducing the number of immunizations with vaccines that stimulate protective immune responses. Improvements in the organization of efforts to immunize children will also enhance the prospects of protecting the world's children from infectious diseases. To achieve the goals articulated in the Declaration of New York, the issues of transition from the old to the new vaccines must be addressed. Research on vaccines and technological innovation at all levels will be required to achieve these goals.

Most communicable diseases are caused by infectious agents that are not visible to the naked eye, which led earlier societies to believe in miasmas and control by quarantine. Although microscopes revealed the agents in the eighteenth century, they were not associated with disease syndromes until the late nineteeth century. Today, vaccines are the most cost-effective means of control.

Immunization received intensive support during the 1980s in light of its demonstrable value, relatively low cost, and established infrastructure. The goal of universal childhood immunization was achieved in 1990 on the basis of a strategy of expanding coverage, technological improvements, and social mobilization. Although its impact is difficult to quantify precisely, the Expanded Programme on Immunization (EPI) has had significant positive effects on national and household economies as a result of the reduction of morbidity and mortality. It also has contributed to the development of the managerial and operational capacity of health systems and to the generation of widespread social and political support for health actions through a variety of different mechanisms. Priorities for the next decade include attention to policies to ensure the maintenance of high levels of coverage, continued technical development, and further strengthening of EPI planning and management.

As a new global strategy for improving public health, the Children's Vaccine Initiative implicitly raises, once again, the question of the role of science in developing countries. If there are to be new and improved vaccines, better delivery systems, and simplified immunization schedules, there must be substantial analysis, laboratory activity, and fieldwork to ensure that the new products are ready for effective use. In the context of these requirements, this paper reviews the possibilities for vaccine research and development in middle-income countries and the benefits in terms of fostering socioeconomic development through integrated scientific health research.

Can the world respond to the demands of the Children's Vaccine Initiative (CVI) to produce large quantities of affordable vaccines that have never been manufactured previously? Vaccines for the world's birth cohort of 150 million will continue to be produced in the countries that use the greatest part of the global vaccine supply. Thus, the CVI will rely on increased self sufficiency in vaccine production in the developing world and “shared development” of new and improved vaccines. The CVI's goal is to direct product development to meet the needs of immunization programs, but it must not neglect production. Thus, from the start, investment at the front end of the development and production sequence requires attention to the ultimate production capacity.

Technological advances by developed countries are producing safer, more potent vaccines. In addition, the transfer of the technology of vaccine production to some developing countries has been taking place during the past five decades, thereby making possible the participation of developing countries in the production and supply of the essential biologicals that are required for immunization programs. Examples of successful transfers of technology, the decisive elements and factors that contribute to the transfers, and the major obstacles to such transfers are presented.

The Children's Vaccine Initiative (CVI) will result in profound changes in immunization practice. Before the CVI is fully developed, it will present numerous challenges to regulatory practice that will require new applications of existing ideas and innovative solutions to practical issues, especially in combining existing vaccines.

Although the vaccination initiatives undertaken during the past decade are the cornerstones for protecting the world's children and helping to ensure their survival and development, the vaccines currently being employed may become obstacles for further disease reduction or eradication. Their characteristics complicate or increase the burden on health care infrastructures to maintain or expand vaccine delivery systems. This paper examines an experience with the vaccine technologies that currently are being used by immunization programs in developing countries, illustrating the field problems and obstacles associated with their use. It discusses the advantages and benefits that would accrue if new or improved, heat-stable, multi-antigen vaccines that require only one or two, preferably oral, doses were to become available.

The efficacy of vaccines for prophylactic use is a function of the immune response elicited by activated lymphocytes. Based on the current understanding of these responses, their induction, and the most effective ways to obtain long-lived immunity, a novel protocol for the vaccination of children against seven childhood diseases, involving only two visits for vaccine administration, is proposed.

Adaptive immunity requires both specific recognition of an antigen and its translation into appropriate lymphocyte responses. This paper reviews the striking differences in B- and T-lymphocyte antigen recognition, details the pathways for conversion of protein antigens into peptide–major histocompatibility complex molecule ligands for T-cell receptors, and summarizes the roles of costimulatory signals in lymphocyte activation. This information is used to suggest new approaches for the rational design of vaccines.

It is now established that the mucosal immune system is a separate entity and is regulated in a different fashion than that in peripheral lymphoid tissues (the systemic immune system). In this brief review, five selected areas within the field of mucosal immunity are discussed in the context of the goals for vaccines for the Children's Vaccine Initiative.

Adjuvants increase cell-mediated and humoral immune responses to specific antigens. Used with recombinant viral antigens, they can elicit the production of T lymphocytes that lyse target cells, expressing the antigen in a genetically restricted fashion. Adjuvants can augment the production of interferon-gamma, thereby favoring the production of protective antibody isotopes, such as immuno-globulin G2a in the mouse. Modern adjuvants display the efficacy of Freund's complete adjuvant without its side effects. One such adjuvant is Syntex adjuvant formulation, a synthetic analogue of muramyl dipeptide in a microfluidized squalane/squalene-in-water emulsion. Monophosphoryl lipid A in a similar lipid emulsion is also effective. Immune-stimulating complexes of saponin and antigens elicit potent cell-mediated and humoral responses. A purified saponin component has adjuvant activity with reduced side effects; liposomes also can have adjuvant activity. Administering antigens in adjuvants can overcome low responsiveness in very young and old experimental animals and in those that are genetically low responders. Adjuvants are likely components of a new generation of recombinant and subunit vaccines.

Two strategies for vaccine-delivery systems, both relying on concepts of controlled-release technology, are described in this review. The first strategy involves using biodegradable polymer microspheres for parenteral and oral delivery of antigens. The other strategy combines two technologies, the encapsulation of antigen within liposomes and liposome encapsulation in hydrogels, to protect them from a rapid degradation in vivo. Both strategies have shown promise in terms of increasing the immunogenicity of poorly immunogenic peptides and protein vaccines. The microencapsulation process, antigen stability, mechanism of antigen release, and optimal release kinetics for vaccine delivery are reviewed, and the strengths and weaknesses of each approach are discussed.

Several different live attenuated vaccine vectors currently are under development. These vaccines are composed of living viruses or bacteria that are innocuous to the host but can replicate in host tissues and induce immune responses. The genes encoding foreign antigens can be inserted into these vectors to produce multivalent vaccines that promise to induce immunity to more than one target disease after the administration of a single dose of vaccine.

The approach of providing passive protection to young infants by immunizing pregnant women can bypass the problems of immunological immaturity in the neonate, avoid or delay active immunization of the infant in the first year of life, and prevent transmission of an infection from the mother to the neonate. Optimal vaccines for this approach should induce high immunoglobulin G antibody titers that quickly reach their maximum level after immunization and persist at protective levels for several years, thus providing passive protection in subsequent pregnancies. Specific applications of this approach include the worldwide practice of maternal immunization with tetanus toxoid vaccine and ongoing studies of maternal immunization to prevent Haemophilus influenzae type b, group B strepto-coccal, pneumococcal, meningococcal, and human immunodeficiency virus infection in the infant. Addressing the cultural, sociological, and legal aspects of maternal immunization will be required to ensure the success of this approach.

The generation of diversity of T and B cells begins early in gestation. Selective restrictions in expression of V genes occur in fetal life, but insufficient clonal diversity is not likely to limit newborn immune capabilities. The functional immaturity of neonatal T and B cells is beginning to be defined. Virgin T cells lack the capacity to produce diverse lymphokines, whereas neonatal B cells are less responsive to the lymphokines that promote terminal differentiation to plasma cells.

Molecular biology and, in particular, knowledge of the immune response at the molecular level provide the research community with the opportunity to design vaccines that will elicit the appropriate responses for many diseases. The critical issue is to identify the immune response that correlates with protection. It is remarkable how well the empirical approach has worked; it is essential, therefore, not to ignore the lessons to be learned from these successes. It is particularly essential that each disease and the immune response that affords protection be studied individually so that the appropriate responses can be induced.

The principle that infants can be protected from invasive diseases caused by encapsulated organisms has been proved with the introduction of Haemophilus influenzae type b conjugate vaccines. The use of glycoconjugates to implement some of the goals of the Children's Vaccine Initiative requires a clear delineation of the chemical and immunological specifications for optimal vaccines.

Technologies that promise to enhance the stability of vaccines are likely to be determined by the product-specific physical structure and biological functions of the specific vaccine immunogens. Research may define the extent to which the stability of oral poliovirus vaccine may be improved by the addition of certain antiviral components that bind to the poliovirus capsid or by the application of novel drying technologies.