Developing vaccines against HIV: options for accelerated progress.
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AIDS Vaccines↗
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Nonhuman primate models for HIV vaccine development.
Animal models will be essential in developing a vaccine to protect against human immunodeficiency virus (HIV) infection. While HIV-1 infects great apes, it induces no disease in these species. Some simian immunodeficiency virus (SIV) isolates cause an AIDS-like disease in macaque monkeys. The SIV/macaque model has proven a valuable system for exploring AIDS pathogenesis and assessing strategies for HIV vaccination. Studies in nonhuman primates have shown that a variety of vaccine approaches transiently elicit immunity which can protect against a very small intravenous challenge of cell-free virus. Longstanding immunity which protects against cell-associated or mucosal virus challenge has not yet been achieved. Nonhuman primate models will be essential for achieving this goal.
AIDS Vaccines↗
Safety monitoring in vaccine development and immunization.
The development of vaccines has been one of the most important achievement in preventive medicine. As the incidence of vaccine-preventable diseases is reduced by immunization, general public becomes increasingly concerned about the safety associated with vaccine. Vaccine safety is extensively evaluated through animal safety studies, clinical trials, during manufacturing processes, and postlicensure surveillance. Safety monitoring in postlicensure surveillance has relied on passive reporting system and epidemiological studies, including Vaccine Adverse Event Reporting System (VARES), Vaccine Safety Datalink (VSD) Project and others. Approximately 10,000 reports per year are submitted to VAERS. About 15% of these describe serious events and 85% of reports are classified as not-serious events. The system analyzed frequently reported adverse reactions, rare events, intussusception after rotavirus vaccine, cases of sudden infant death syndrome (SIDS), and safety of various vaccines. The evidence for a causal relationship with vaccines can be classified into five categories: no evidence, evidence was inadequate to accept or reject, evidence favors rejection, evidence favors a causal relationship, and evidence established. Future challenges involve improving survey and monitoring system of adverse events after immunization, enhancing vaccine safety research and vaccine risk communication, and possibility of increased reactogenicity in new and combined vaccines.
Adverse Drug Reaction Reporting Systems↗
[Vaccine development. Obstacles in evaluating AIDS vaccines].
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Acquired Immunodeficiency Syndrome↗
Replicating and host-restricted non-replicating vaccinia virus vectors for vaccine development.
Vaccinia virus, effectively used for immunization against smallpox, now serves as a recombinant vector for the development of vaccines against other infectious agents and cancer. Recent advances have led to increased gene expression, enhanced immunogenicity, and greater safety. Both replicating and host-restricted non-replicating vectors are available.
Defective Viruses↗
New scientific opportunities and old obstacles in vaccine development.
The present status of and priorities for vaccine development are described, and the historical conditions under which vaccines have been developed are contrasted with newer technologies for such development. Current programs, the opportunities they present, and the obstacles to their implementation are summarized.
Biotechnology↗
The challenges of HIV vaccine development and testing.
A vaccine against HIV remains the best hope for bringing the epidemic under control. An intensive global effort is underway to develop such a vaccine; however, the challenges are considerable. Several new vaccine technologies that have been developed and shown promise in animal models are now being tested in early phase safety trials in humans. Because there is no laboratory assay that will predict whether an HIV vaccine can protect humans from infection, clinical trials involving thousands of volunteers will need to be conducted to determine the efficacy of HIV vaccines. These trials need to take place in the developing countries that bear the burden of the epidemic, requiring a substantial amount of infrastructure development and capacity building.
AIDS Vaccines↗
The impact of new technologies on vaccine development.
The ability to move genetic determinants between species using in vitro gene-manipulation techniques has opened up new approaches to vaccine development. This has rapidly grown into an exciting area of research in both academic and industrial laboratories. There are numerous scientific challenges which require multidisciplinary teams to solve problems in creating new immunogens. This has challenged our existing knowledge about protein structure and conformation, microbial pathogenicity and the immune system. Recombinant-DNA techniques are invaluable as tools of analysis and antigen production. The surface of micro-organisms can also be minutely explored with the use of synthetic peptides and monoclonal antibodies. Nevertheless, these new technologies do not allow us to circumvent the need for detailed understanding of pathogens and the disease process. What is apparent from the work carried out so far is that there are few easy answers to vaccine development and it is not realistic to expect rapid solutions to these problems. As there are many potential targets for constructing novel vaccines for both human and animal diseases, it is helpful to establish some priorities. There is a tendency to look at the existing effective vaccines and simply direct research at producing them more economically or with enhanced safety and stability. The advantage of this approach is that considerable background work will have already been carried out establishing the basis for the application of recombinant DNA techniques. However, this can also lead to conflicts (often within the same institute or company) between the new and old technologies. This could be to the detriment of the new technologies which are still only partly developed and may not be good enough yet to compete with existing vaccines in cost or efficacy. The more ambitious, and eventually more rewarding, approach is to attempt to develop new vaccines where none had existed before. There is a vast untapped market, especially in the parasitic diseases, but the scientific problems may be considerable and much more background work is likely to be necessary. Indeed, most of the work in this area is more accurately referred to as basic research rather than vaccine development as totally new, effective vaccines are still some way off. Having directed research towards a specific organism or disease there are still many options available as to the scientific strategy to adopt. As discussed in this review it may be possible to consider subunits, synthetic antigens and live (attenuated or heterologous) organisms as possible vaccines.(ABSTRACT TRUNCATED AT 400 WORDS)
Adjuvants, Immunologic↗
The future of respiratory syncytial virus vaccine development.
BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of viral lower respiratory tract illness in infants and children and is an important cause of lower respiratory tract illness in other populations. Despite decades of research there are currently no licensed vaccines for prevention of RSV disease. METHODS: A review of the obstacles to RSV vaccine development; current live, attenuated and subunit RSV vaccines in clinical development; and the potential for developing additional vaccine candidates based on recombinant technology. RESULTS: A number of biologically derived live attenuated RSV vaccines were evaluated in Phase I clinical trials in adults and children, and one vaccine (cpts 248/404) was evaluated in infants as young as 1 month of age. These vaccines displayed a spectrum of attenuation, with cpts 248/955 being the least attenuated and cpts 248/404 being the most attenuated candidate vaccine. None of these was sufficiently attenuated for young infants. The ability to generate recombinant RSV vaccines has led to the development of large numbers of candidate vaccines containing combinations of known attenuating point mutations and deletions of nonessential genes. Clinical evaluation of many of these candidates is in progress. Three types of RSV subunit vaccines have recently been evaluated in clinical trials: purified F glycoprotein vaccines (PFP-1, PFP-2 and PFP-3), BBG2Na and copurified F, G and M proteins. Additional studies of the F/G/M protein vaccine are being conducted. CONCLUSIONS: During the past 10 years, considerable progress has been made in RSV vaccine development. It is likely that different RSV vaccines will be needed for the various populations at risk.
Adult↗
Experimental models of immunization against schistosomes: lessons for vaccine development.
Schistosomiasis is a debilitating, and sometimes deadly, parasitic infection that afflicts hundreds of millions of people living in developing countries. One of the best hopes for control of this disease is vaccine development. Studies on experimental models of attenuated vaccines have proven that high levels of protective immunity can be achieved. In these systems, resistance has been shown to be directed against the migrating larval stages of the parasite and to have both cellular and humoral components. Several candidate vaccine immunogens have been identified on the basis of antibody reactivity. However, the level of protection induced by immunization with nonliving vaccines has at yet not approached the level observed with attenuated infection. Current challenges to vaccine development include identification of protective T cell immunogens, determination of ways to strengthen the immunogenicity of isolated parasite antigens, and development of methodologies to selectively stimulate protective, as opposed to ineffective or even detrimental, immune responses.
Animals↗
Involvement of cell envelope components in the pathogenesis of Vibrio cholerae: targets for cholera vaccine development.
Parenteral cholera vaccines have for some years been removed from the WHO recommendations. With a greater understanding of the immunology of gut infections has come the realization that oral vaccines are the most promising approach. There are several possible approaches: killed vaccines, attenuated Vibrio cholerae and true recombinants in which V. cholerae protective antigens are introduced into suitable carrier strains. This latter approach has perhaps greater potential as a carrier strain can be chosen/developed which most effectively stimulates the local immune response in the gut. This necessitates the identification of the important protective antigens. These antigens are thought to be components of the cell envelope which are involved in adhesion and colonization.
Bacterial Outer Membrane Proteins↗
Variations in "rescuability" of immunoglobulin molecules from different forms of human lymphoma: implications for anti-idiotype vaccine development.
Idiotypic (Id) vaccination has shown promising results in patients with follicular lymphoma (FL). However, it still remains unclear whether the same approach might be suitable for the treatment of other B-cell malignancies. For this reason, we recently performed an interim analysis of patients proposed to receive this treatment at our center. The feasibility of employing idiotype vaccines was evaluated for five different B-cell malignancies in their first relapse, both in terms of induction and fusion, as well as overall treatment. Our data suggest that, unlike follicular lymphoma (87%), this approach is not feasible to treat other B-cell malignancies (0-20%) such as mantle cell, small lymphocytic, diffuse large cell and Burkitt's lymphoma (P < 0.01). The main difficulties encountered were technical problems related to the survival of idiotype-producing hybridomas (83%) and the early loss of idiotype production by growing hybridomas (17%). However, it remains possible that an idiotype vaccine might still be produced through molecular means for most, if not all cases of relapsing B-cell malignancies.
Antibody Formation↗
Review of G and P typing results from a global collection of rotavirus strains: implications for vaccine development.
Candidate rotavirus vaccines have been prepared with reassortant strains specifically to protect against the 4 major rotavirus G serotypes (G1 -4). Many studies using P (VP4) genotyping methods have indicated that, worldwide, rotavirus strains of the 4 common G serotypes are each associated with 1 P genotype: GI, G3, and G4 are associated with P[8], and G2 is associated with P[4]. In contrast, G and P genotyping of rotavirus in specimens from India revealed that a high percentage of the childhood diarrhea strains belong to genotype P[6], and the most common strain had an unusual G serotype, G9. Similarly, in all regions surveyed in Brazil, apparent reassortants of genotype P[8], G5 were found in children with gastroenteritis. These studies indicate that while rotavirus strains have limited diversity in many settings, reassortment between common and uncommon serotypes or animal strains can arise in some settings and, thus, lead to unusual diversity.
Child↗
Differentiation of CD8 T cells in response to acute and chronic viral infections: implications for HIV vaccine development.
Successful HIV vaccine strategies will likely require the induction of robust cellular immune responses, in addition to strong humoral responses. Unfortunately, there is no clear molecular definition of an effective HIV-specific CD8 T cell response. In this review, we discuss the differentiation of CD8 T cells in response to acute and chronic viral infections. We then apply concepts derived from these studies to predict the desirable characteristics of HIV-specific CD8 T cell memory.
AIDS Vaccines↗
Advances in cancer vaccine development.
Traditionally, cancer vaccines have used whole tumour cells administered in adjuvant or infected with viruses to increase the immunogenicity of the cells. With the identification of tumour-associated and tumour-specific antigens (TAA, TSA), antigen and epitope-specific vaccines have been designed. Compared to tumour cell vaccines, antigen and epitope vaccines are more specific and easier to produce in large quantities but may display lower immunogenicity and lead to the in vivo selection of antigen or epitope-negative escape tumour variant cells. The optimal vaccine will elicit both humoral and cellular immunity in the patients as both parameters have been positively correlated with the induction of beneficial clinical responses. The choice of adjuvant, costimulation and delivery mode greatly determines the outcome of vaccinations and may favour the induction of T-cell responses of T helper (Th)1, Th2, or both Th1 and Th2 types. Animal models of TAA vaccines must take into account the normal tissue expression of TAA, which may induce immunological tolerance to TAA. With the identification of homologues of human TAA in animals, novel experimental models of cancer vaccines which mimic the condition in patients are now available. Several vaccines comprising tumour cells, TAA or anti-idiotypic antibodies mimicking TAA have recently entered phase III of clinical evaluation.
Animals↗
Malaria vaccine development: recent progress towards a sporozoite vaccine.
Malaria affects the lives of hundreds of millions of people. Drug therapy is becoming less effective, a vaccine has yet to be developed, and one to two million children die annually as a result of malaria. In the last 10 years, however, there has been great progress towards a vaccine. A number of important antigens have been cloned, including the circumsporozoite (CS) protein which covers the sporozoite and which is a target for antibody and cytotoxic T lymphocytes. In laboratory models, successful vaccination has been achieved with some CS constructs. Although successful immunization with irradiated sporozoites has been achieved in the laboratory, the lack of immunity following natural exposure to sporozoites in endemic countries is puzzling. Parasite variation, host genetic factors and immunological tolerance may each contribute to this situation. Identification of other important antigens and a better understanding of host immune responses to sporozoite and liver stage antigens should be important steps towards rational vaccine design.
Antigens, Protozoan↗
Functional analysis of Plasmodium falciparum merozoite antigens: implications for erythrocyte invasion and vaccine development.
Malaria is a major human health problem and is responsible for over 2 million deaths per year. It is caused by a number of species of the genus Plasmodium, and Plasmodium falciparum is the causative agent of the most lethal form. Consequently, the development of a vaccine against this parasite is a priority. There are a number of stages of the parasite life cycle that are being targeted for the development of vaccines. Important candidate antigens include proteins on the surface of the asexual merozoite stage, the form that invades the host erythrocyte. The development of methods to manipulate the genome of Plasmodium species has enabled the construction of gain-of-function and loss-of-function mutants and provided new strategies to analyse the role of parasite proteins. This has provided new information on the role of merozoite antigens in erythrocyte invasion and also allows new approaches to address their potential as vaccine candidates.
Animals↗
Vaccine development reconsidered.
This paper briefly reviews work on vaccine development since the early 1950s with special emphasis on identification of immunogens and their presentation to the host so as to elicit an immune response. This is illustrated primarily by a discussion of the development of a candidate meningococcal B vaccine based on a capsular carbohydrate outer membrane protein complex. Work on malaria and living Salmonella typhi vaccine is also discussed.
Antigens, Bacterial↗