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Therapeutic vaccines such as those used to combat cancer or persistent viral infection are required to reprogramme a downregulated immune system. This presents a difficult challenge for vaccine design and merits the development of novel immunization protocols. Currently, we know that mobilization of dendritic cells (DCs) to present antigens to T lymphocytes is crucial for effective immunization. Our increasing understanding of DC biology, coupled with the growing sophistication of viral vectors developed for gene therapy, makes more rational vaccine design an exciting possibility. Here we propose that engineering viral vectors to express antigens in activated DCs will provide the most effective vaccines for priming an immune response.
Developing a vaccine able to prevent HIV infection would be a great benefit to the world. Vaccines have contributed to substantially reduced morbidity and mortality from several important infectious diseases. However, HIV has some characteristics that distinguish it from many other viruses and make vaccine development challenging. This article discusses scientific strategies, obstacles, and progress to date towards the development of a preventive HIV vaccine.
Lately, the magnitude of cumulative diseases burden caused by flaviviruses, such as dengue virus, Japanese encephalitis virus, tick-borne encephalitis virus, West Nile virus and yellow fever virus, has reached an unprecedented level with the sizes of human and animal populations at risk increasing sharply. These diseases present highly complex medical, economic and ecologic problems, some effecting primarily human and others affecting human, livestock and wildlife. The large body of recent publications on the development of vaccines taking advantage of new generations of bio-engineering techniques clearly reflects the profound interests and deep sense of urgency in the scientific and medical communities in combating those diseases. This review reveals a collection of remarkable progresses thus far made in flaviviral vaccine research not only employing a diverse range of new strategies but also re-tooling old techniques to improve the existing vaccines. The efficacy and safety of some of the new vaccine candidates have been evaluated and proven in human clinical trials. Besides the technical advancement in vaccine development, in this review, the importance of somewhat neglected and yet critical subjects, such as adequacy of animal model, vaccine safety, vaccine formulation and delivery, complication in serodiagostics and economic factor, was examined in-depth.
Sheep-associated malignant catarrhal fever is emerging as a significant problem for several ruminant species worldwide. The inability to propagate the causative agent, ovine herpesvirus 2, in vitro has seriously hindered research efforts in the development of effective programs for control of the disease in clinically susceptible hosts. Recent molecular technologic advances have provided powerful tools for investigating this difficult-to-study virus. Identification of the infectious virus source, establishment of experimental animal models and completion of sequencing the genome for ovine herpesvirus 2 have put us in a position to pursue the development of vaccines for control of the disease. In this review, the authors briefly describe the current understanding of ovine herpesvirus 2 and prospectively discuss vaccine development against the virus.
New developments in biotechnology have led to a number of new approaches for the development of vaccines aimed at preventing infectious disease. This report summarizes some of the principles underlying these new technologies and illustrates some applications of these technologies to practical vaccine development.
During the last century several approaches have been followed for the development of vaccines. These include live-attenuated viruses and bacteria, killed microorganisms and the subunit vaccines [1]. With the introduction of recombinant DNA technologies, new approaches have been exploited for vaccine manufacturing. However, the major problem remains the rapid identification of highly immunogenic and protective antigens suitable for vaccine development, which still relies on standard biochemical and microbiological techniques. The advent of genomics has greatly contributed to providing a new impulse to the microbial field. The complete genomic sequence of a human pathogen represents a new unexploited field, to be used for the design of novel vaccines and antimicrobial drugs. In the case of meningococcus B, four decades of continuous efforts, using conventional technologies of purifying antigens from the microorganism, had not been sufficient to deliver an effective and universal vaccine. It was therefore decided to obtain the genomic sequence of serogroup B Neisseria meningitidis (MenB) and use this information to identify vaccine candidates. This approach was named "reverse vaccinology"[2].
Vaccines against childhood diseases represent some of the most important applications of 20th-century pediatric research. This survey examines how the components of the current U.S. immunization schedule emerged in three phases during the course of the century. The first phase, after the development of bacterial culture techniques, witnessed numerous efforts in the early 1900s to develop bacterial vaccines. It proved most fruitful with respect to diphtheria, tetanus, and pertussis. The rise of viral tissue culture techniques in the 1950s brought about a second phase of innovation resulting in vaccines against polio, measles, mumps, rubella, and varicella. A third wave of innovation, still very much alive, has drawn on a variety of new technologies and led to vaccines against hepatitis B, Haemophilus influenzae type b, pneumococcus, and still other organisms. Although basic science research has thus been a primary factor shaping the history of vaccine development, the collaboration between the academic, private, and public sectors critical to its application has not always proceeded smoothly. The history of vaccine research and development has important implications for today, as a variety of factors threaten to fragment this network.
There is an urgent need to develop an effective vaccine against malaria--a disease that has approximately 10% of the world population at risk of infection at any given time. The economic burden this disease puts on the medico-social set-up of countries in Sub-Saharan Africa and South East Asia is phenomenal. Increasing drug resistance and failure of vector control strategies have necessitated the search for a suitable vaccine that could be integrated into the extended program of immunization for countries in the endemic regions. Malaria vaccine development has seen a surge of activity in the last decade or so owing largely to the advances made in the fields of genetic engineering and biotechnology. This revolution has brought sweeping changes in the understanding of the biology of the parasite and has helped formulate newer more effective strategies to combat the disease. Latest developments in the field of malaria vaccine development will be discussed in this chapter.
Recent vaccine trials utilizing the simian immunodeficiency virus/macaque model of AIDS are beginning to yield clues regarding mechanisms of protective immunity. Although cytotoxic T lymphocyte responses to SIV may play a role in mediating protection against infection, protective immunity appears to correlate best with the development of antibodies able to neutralize primary or heterologous pathogenic viruses. Protection against disease or persistent infection may be achieved in the absence of sterilizing immunity, suggesting that new benchmarks for AIDS vaccines may be in order.
Cattle grubs (Hypoderma lineatum and H. bovis) are obligate parasites of cattle for most of their one year life cycle. Previously exposed animals become resistant to productive reinfestation, presumably as a result of immune system involvement, suggesting potential control by vaccination. Research progress towards development and utilization of a recombinant subunit vaccine for hypodermosis is described.
The development of single-dose vaccines, mainly those administered during childhood, which would effectively protect against certain diseases, would be a very important advance towards better immunization coverage and protection against the respective pathogens. Biodegradable polymeric microspheres which are 'programmed' to deliver the antigen when a boost of the immune response is required, may be a possible way of achieving this goal.
Current vaccination strategies mainly target antigens into the phagosomal, major histocompatibility complex class II antigen-processing pathway and thus lead predominantly to humoral immune responses. The elicitation of cytotoxic T-cell responses instead requires introduction of antigens into the cytosol of professional antigen-presenting cells (APCs). The intracellular bacterium Listeria monocytogenes gains access to the host cell cytosol by means of a cytolysin, listeriolysin O. Vaccine researchers have successfully employed listeriolysin in novel vaccination approaches to provide access to the cytosol of professional APCs for purified protein antigens, attenuated bacterial vaccine strains, DNA vaccines and liposome contents.
Various vaccination strategies were compared for their ability to elicit antigen-specific tumour immunity, using the SV40-BALB/c murine tumour system. Specifically, mice were injected with baculovirus-derived recombinant SV40 Tag (rTag), synthetic peptides corresponding to B cell epitopes on SV40 Tag or a plasmid DNA construct encoding the gene for SV40 Tag. In vivo tumour immunity was determined by a lethal tumour challenge with syngeneic SV40-transformed tumour cells. SV40 Tag-specific antibody titres were induced in mice immunized with rTag or Tag synthetic peptides. Partial tumour protection was observed in mice that were immunized with SV40 Tag peptides, where as complete tumour immunity was observed in mice immunized with rTag. Although protective tumour immunity was also observed in mice immunized with DNA, negligible levels of antibodies to SV40 Tag were detected. Examination of the cytotoxic T lymphocyte (CTL) activity in mice injected with the SV40 Tag-DNA construct revealed Tag-specific lysis of syngeneic SV40-transformed tumour cells. Conversely, little to no CTL activity was detected in mice immunized with rTag. However, antigen-specific antibodies from rTag immunized mice were capable of mediating antibody-dependent cell-mediated cytotoxicity against SV40-transformed cells. These data indicate that the immune mechanisms elicited for protection against SV40 induced tumours in mice appeared to be dependent on the vaccination strategy employed and included both humoral and cell-mediated immune responses.
Cytomegalovirus (CMV) infection is the most common intrauterine infection in the United States, and it exacts a heavy toll when it infects children and immunocompromised individuals. A CMV vaccine was assigned the highest priority by the Institute of Medicine in its 1999 assessment of targets for vaccine development. The priority was based on the cost and human suffering that would be alleviated by reducing the disease burden of congenital CMV infection. The National Vaccine Advisory Committee and invited experts examined the prospects for a CMV vaccine and the actions needed to bring about successful vaccine development at a National Vaccine Program Office workshop in October 2000. This article summarizes information about the changing epidemiology of CMV and immune responses to infection and immunity, and it reviews the current status of several vaccine candidates. Support of government agencies for CMV vaccine research and development is critical to address this need.
Vaccines effective against intracellular pathogens could save the lives of millions of people every year, but vaccine development has been hampered by the slow largely empirical search for protective antigens. In vivo highly expressed antigens might represent a small attractive antigen subset that could be rapidly evaluated, but experimental evidence supporting this rationale, as well as practical strategies for its application, is largely lacking because of technical difficulties. Here, we used Salmonella strains expressing differential amounts of a fluorescent model antigen during infection to show that, in a mouse typhoid fever model, CD4 T cells preferentially recognize abundant Salmonella antigens. To identify a large number of natural Salmonella antigens with high expression levels during infection, we used a quantitative in vivo screening strategy. Immunization studies with five particularly attractive candidates revealed two highly protective antigens that might permit the development of an improved typhoid fever vaccine. In conclusion, we have established a rationale and an experimental strategy that will substantially facilitate vaccine development for Salmonella and possibly other intracellular pathogens.
The conventional approach to vaccine development requires cultivation of the pathogenic microorganism and its dissection using biochemical, immunological, and microbiological methods in order to identify the components important for immunity. This method, while successful in many cases, failed to provide a solution for many of those pathogens for which a vaccine is not yet available. Today, the possibility of using genomic information allows us to study vaccine development in silico, without the need of cultivating the pathogen. This approach, which we have named 'reverse vaccinology', reduces the time required for the identification of candidate vaccines and provides new solutions for those vaccines which have been difficult or impossible to develop. The potential of this new approach is illustrated by the use of reverse vaccinology for the development of a vaccine against serogroup B meningococcus. The application of reverse vaccinology to other fields, including viral vaccines is discussed.
The principles of viral vaccine development and the immune responses to vaccination are described. An effective vaccine should stimulate both cellular and humoral immune responses to provide lasting protection against infection and disease. We describe specific problems associated with the development of an AIDS vaccine i.e. lack of experience with human retroviruses, the integration of the HIV genome in cellular DNA, HIV infection of critical cells in the immune system, persistence of HIV in the brain, large variations in the virus envelope gene, immune interactions with the CD-4 protein and the generation of infection enhancing antibodies. The strategies of AIDS vaccine development are discussed and the candidate vaccines are described with a report on the status of each vaccine trial in progress.