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Antiviral cytotoxic T lymphocyte induction and vaccination.

In developing vaccines to counteract viral infections, it is important to produce reagents that engender the type of immune response best suited to provide protection and avoid immunopathology. Recovery from infection is the principal role of T cell immunity, and cells that recognize virus-infected cells (cytotoxic T lymphocytes) and kill them--often before new virus is replicated--represent a crucial component of the recovery process. The cytotoxic T lymphocytes are particularly important in situations where the load of infection is high. In this review the cells and mediators, as well as the viral and host cell antigens involved in antiviral induction of cytotoxic T lymphocytes, are discussed. Particular attention is paid to the importance of the intracellular pathway of processing taken by viral antigens and the outcome in terms of the recognition of cytotoxic T lymphocytes. The new types of vaccines--especially subunits, antiidiotypes, and recombinant viral vectors--are discussed in terms of their likely effectiveness at inducing cytotoxic T lymphocytes.

Animals↗

Recent trends in veterinary vaccines.

Recent developments in the fields of molecular biology and immunology have made possible the synthesis of proteins and peptides that closely mimic antigenic sites. The potential for developing vaccines from this technology is reviewed.

Animal Diseases↗

PneumoADIP: an example of translational research to accelerate pneumococcal vaccination in developing countries.

Historically, the introduction of new vaccines in developing countries has been delayed due to lack of a coordinated effort to address both demand and supply issues. The introduction of vaccines in developing countries has been plagued by a vicious cycle of uncertain demand leading to limited supply, which keeps prices relatively high and, in turn, further increases the uncertainty of demand. The Pneumococcal Vaccines Accelerated Development and Introduction Plan (PneumoADIP) is an innovative approach designed to overcome this vicious cycle and to help assure an affordable, sustainable supply of new pneumococcal vaccines for developing countries. Translational research will play an important role in achieving the goals of PneumoADIP by establishing the burden of pneumococcal disease and the value of pneumococcal vaccines at global and country levels. If successful, PneumoADIP will reduce the uncertainty of demand, allow appropriate planning of supply, and achieve adequate and affordable availability of product for the introduction of pneumococcal vaccines. This model may provide a useful example and valuable lessons for how a successful public-private partnership can improve global health.

Developing Countries↗

Strategies for the development of vaccines against HIV.

Possible approaches to the development of vaccines against HIV are reviewed in the light of experience with existing virus vaccines and understanding of the process of viral infection. While HIV infection presents serious theoretical problems in developing vaccines most are also encountered in some form with other virus infections. The very nature of HIV infection raises objections to using live attenuated or inactivated virus vaccines, as it is difficult to ensure that they are non-infectious or completely inactivated. The most promising types of vaccine involve expression of viral antigens in acceptable vectors either as virus vectors, or recombinant DNA products. However, the problem of identifying the antigen needed to induce adequate protective immunity remains and there is a clear need for a usable animal model to establish the potential of vaccines for human use.

Acquired Immunodeficiency Syndrome↗

Utilization of genomic sequence information to develop malaria vaccines.

Recent advances in the fields of genomics, proteomics and molecular immunology offer tremendous opportunities for the development of novel interventions against public health threats, including malaria. However, there is currently no algorithm that can effectively identify the targets of protective T cell or antibody responses from genomic data. Furthermore, the identification of antigens that will stimulate the most effective immunity against the target pathogen is problematic, particularly if the genome is large. Malaria is an attractive model for the development and validation of approaches to translate genomic information to vaccine development because of the critical need for effective anti-malarial interventions and because the Plasmodium parasite is a complex multistage pathogen targeted by multiple immune responses. Sterile protective immunity can be achieved by immunization with radiation-attenuated sporozoites, and anti-disease immunity can be induced in residents in malaria-endemic areas. However, the 23 Mb Plasmodium falciparum genome encodes more than 5,300 proteins, each of which is a potential target of protective immune responses. The current generation of subunit vaccines is based on a single or few antigens and therefore might elicit too narrow a breadth of response. We are working towards the development of a new generation vaccine based on the presumption that duplicating the protection induced by the whole organism may require a vaccine nearly as complex as the organism itself. Here, we present our strategy to exploit the genomic sequence of P. falciparum for malaria vaccine development.

Animals↗

Non-viral vector as vaccine carrier.

Over the last several years, advances in gene-based delivery technology arising from the field of gene therapy have helped revitalize the field of vaccine development. Genetic vaccination encoding antigen from bacteria, virus, and cancer has shown promise in protective humoral and cellular immunity; however, the potential disadvantages of naked DNA vaccine have reduced the value of the approach. To optimize antigen delivery efficiency as well as vaccine efficacy, the non-viral vector as vaccine carrier, for example, the cationic liposome, has shown particular benefits to circumvent the obstacles that both peptide/protein- and gene-based vaccines have encountered. Liposome-mediated vaccine delivery provides greater efficacy and safer vaccine formulation for the development of vaccine for human use. The success of the liposome-based vaccine has been demonstrated in clinical trials and further human trials are also in progress.

Animals↗

Simultaneous administration of hepatitis B vaccine with other E.P.I. vaccines.

Development of recombinant DNA vaccine against hepatitis B grown on cultured yeast cell has made it possible to mount a world-wide effort to control and eradicate Hepatitis B infection. However, the currently recommended schedules (0, 1 & 2 months, and 0-1 and 6 months) do not coincide with the scheduled visits for other E.P.I. vaccines, and necessitate additional visits for Hepatitis B vaccination. This study was therefore carried out to find out if adequate seroconversion occurs to Hepatitis B vaccine when given with other EPI vaccines or not? Thirty nine infants born to Australia antigen positive mothers from among 850 screened pregnant mothers were recruited to receive Hepatitis B vaccine (Engerix B-10 micro gram each) at 0, 6 and 14 wks (group A) or at 0, 1 and 2 months (group B). Thirty-one infants were recruited in group A and 8 in group B. The cord blood was collected and the first dose of vaccine was given within 48 hours of birth. Simultaneous B.C.G. was given at the left deltoid. Other E.P.I. vaccines were given qt 6, 10 and 14 wks in group A and at 2, 3 and 4 months in group B. Repeat blood samples were collected prior to giving each dose of Hepatitis B vaccine, and 4 weeks after the last dose. All blood samples were assayed for HBsAg and HBsAb at the National Institute Of Communicable Diseases, utilizing standard ELISA kits. The seroconversion rates following one, two and three doses of Hepatitis B vaccine were 3.33%, 55.5%, 96.15% and 0%, 62.5% and 100% in group A and B respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

An algorithm for evaluating human cytotoxic T lymphocyte responses to candidate AIDS vaccines.

Development of an effective vaccine against HIV-1 will likely require the induction of a broad array of immune responses, including virus-specific CTLs and neutralizing antibodies. One promising vaccine approach involves live recombinant canarypox (CP)-based vectors (ALVAC) containing multiple HIV-1 genes. In phase I clinical trials in HIV-1-seronegative volunteers, the cumulative rate of detection of HIV-1-specific CTLs has been as high as 60-70%. In the present study, the factors associated with CTL responsiveness were evaluated in a subset of vaccinees immunized with a CP vector expressing portions of the gag, pro, and env genes of HIV-1 (ALVAC-HIV). CTL responses were detected in one of seven examined. While the responding individual had both CD4+ and CD8+ CTLs directed at multiple HIV-1 antigens, this response was not detectable 1 year after the last vaccination. In-depth characterization of "CTL nonresponders" showed that nonresponsiveness was not associated with defects in antigen processing or presentation. A generalized defect in CTL responsiveness was ruled out by parallel assays to detect CMV-specific CTLs from these same volunteers. Furthermore, HIV-1-specific memory CTLs were not detectable by peptide stimulation or by a novel technique for flow cytometric visualization of Gag epitope-specific T lymphocytes while HIV-1-seropositive donors frequently had 0.1-3% of CD8+ cells stain positively for this epitope (SLYNTVATL). Taken together, these results suggest that the lack of detectable HIV-1 CTLs in these volunteers was not due to classic MHC-linked nonresponsiveness.

AIDS Vaccines↗

Potential public health impact of new tuberculosis vaccines.

Developing effective tuberculosis (TB) vaccines is a high priority. We use mathematical models to predict the potential public health impact of new TB vaccines in high-incidence countries. We show that preexposure vaccines would be almost twice as effective as postexposure vaccines in reducing the number of new infections. Postexposure vaccines would initially have a substantially greater impact, compared to preexposure vaccines, on reducing the number of new cases of disease. However, the effectiveness of postexposure vaccines would diminish over time, whereas the effectiveness of preexposure vaccines would increase. Thus, after 20 to 30 years, post- or preexposure vaccination campaigns would be almost equally effective in terms of cumulative TB cases prevented. Even widely deployed and highly effective (50%-90% efficacy) pre- or postexposure vaccines would only be able to reduce the number of TB cases by one third. We discuss the health policy implications of our analyses.

Disease Outbreaks↗

Malaria vaccines in development.

The recent infusion of public and private funding for malaria vaccine development has greatly accelerated the pace at which candidate malaria vaccines are entering the clinic. Recent promising results from vaccine trials carried out in malaria-naive and -endemic populations have revealed important insights into what will be required of a successful vaccine. Significant challenges lie ahead, not the least of which is insuring access of a malaria vaccine to the populations that need it most. Creative strategies, strong partnerships with developing countries, industry-like approaches to product development, and political vision and leadership on the part of wealthy nations will be critical to the successful implementation of this important new tool to reduce the intolerable burden of malaria.

Animals↗

A multilateral effort to develop DNA vaccines against falciparum malaria.

Scientists from several organizations worldwide are working together to develop a multistage, multigene DNA-based vaccine against Plasmodium falciparum malaria. This collaborative vaccine development effort is named Multi-Stage DNA-based Malaria Vaccine Operation. An advisory board of international experts in vaccinology, malariology and field trials provides the scientific oversight to support the operation. This article discusses the rationale for the approach, underlying concepts and the pre-clinical development process, and provides a brief outline of the plans for the clinical testing of a multistage, multiantigen malaria vaccine based on DNA plasmid immunization technology.

Animals↗

Exploiting natural immunity to helminth parasites for the development of veterinary vaccines.

The development of subunit vaccines against most parasitic helminth infections will require a better understanding of the different components of a natural rejection process including (1) recognition of parasite antigens; (2) induction of protective immune response phenotypes; and (3) activation of appropriate immune effector mechanisms. While novel technologies have allowed significant progress to be made in the identification of candidate vaccine antigens, the large scale production of these antigens and their presentation to the host with appropriate adjuvant systems remains a major problem in vaccine research. Identification of the molecular interactions involved in the innate immune response to helminth infections and the application of new genomic and proteomic technologies are likely to lead to major advances in these research fields. Gastrointestinal nematode parasites and liver fluke are the most important helminth parasites of production animals. In recent years, a lot of new knowledge has been gathered on the immunobiology of the host-parasite interactions in these two infection systems, which has allowed new vaccination strategies to be considered. Functional genomic technologies such as gene expression analysis by microarrays, promise to further advance our understanding of the molecular pathways leading to protection against parasite infections. This will not only have implications for vaccine research, but also provide novel targets for drug development and genetic selection.

Animals↗

Influenza vaccines: new developments.

Current inactivated influenza vaccines are being produced with three influenza virus strains that are recommended annually by the World Health Organization on the basis of information obtained from global influenza surveillance. The use of these vaccines, for which the antigens are produced in embryonated chicken eggs, can result in a significant reduction of influenza-related morbidity and mortality. Nevertheless, there is still a demand for vaccines with a higher efficacy that can be produced more rapidly and more flexibly in response to an epidemic or a pandemic. New developments in the field of influenza vaccine preparation include novel vaccine production technologies, reverse genetics technology for the generation of vaccine strains and novel adjuvants for the improvement of vaccine immunogenicity.

Animals↗

The development of a bivalent vaccine against diarrhoeal disease.

The live oral typhoid vaccine Salmonella typhi Ty2la has been successfully used as an effective public health tool for the control of typhoid fever. This paper reviews the progress of one vaccine development programme, which uses this organism as a carrier of the O-antigens of Vibrio cholerae. It is already known that antibodies directed against the O-antigens have been previously demonstrated in animals to be protective against subsequent challenge with virulent organisms. This paper reports that the hybrid orally administrable typhoid/cholera vaccines that have resulted through this programme are immunogenic in humans, and therefore this represents the first significant step towards the development of an effective bivalent typhoid/cholera oral vaccine.

Antigens, Bacterial↗