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PubMed2002

CD8+ T-cell immunity to HIV infection.

Fifteen years after the first, definitive reports of HIV-1-specific, CD8+ T cells [147,148], there is ample evidence for the importance of these cells in control of HIV-1 infection. As much is known of their role in the natural history of HIV-1 infection and their cellular and molecular mechanisms of reactivity than of T-cell responses to any other human virus. Indeed, HIV-1-related research has led the scientific field in revealing many new, fundamental principles of cellular immunity in the last 15 years. From these data, there are multiple, posited mechanisms for loss of CD8+ T-cell control of HIV-1 infection. These include both intrinsic defects in T-cell function and loss of T-cell recognition of HIV-1 because of its extraordinary genetic diversity and disruption of antigen presentation. Efforts have begun on devising approaches to reverse these immune defects in infected individuals and develop vaccines that induce T-cell immunity for protection from infection. Combination antiretroviral drug regimens now provide exceptional, long-lasting control of HIV-1 infection, even though they do not restore anti-HIV-1 T-cell immunity fully in persons with chronic HIV-1 infection. Very encouraging results show that such treatment can maintain normal T-cell reactivity specific for this virus in some persons with early HIV-1 infection. Unfortunately, the antiviral treatment does not cure the host of this persistent, latent virus. This has led to new strategies for immunotherapeutic intervention to enhance the level and breadth of the T-cell repertoire specific for the host's residual virus in persons with chronic HIV-1 infection. Although the principles of immunotherapy stem from early in the last century, modern era approaches are integrating highly sophisticated, molecular and cell biology reagents and methods for control of HIV-1 infection. The most promising immunotherapies are autologous virus activated in vivo by STI or administered in autologous DC that have been engineered ex vivo. There are also compelling rationales supported by animal models and early clinical trials for use of cytokines and chemokines as recombinant proteins or DNA to augment anti-HIV-1 T-cell reactivity and trafficking of T cells and APC to tissue sites of infection. For prevention of HIV-1 infection, the discouragingly poor results of vaccine development in the late 1980s and early 1990s have led to very encouraging, recent studies in monkeys that show partially protective and possibly sterilizing immunity. Finally, clinical trials of new-generation DNA and live vector vaccines already have indications of improved induction of HIV-1-specific T-cell responses. Knowledge of HIV-1-specific T-cell immunity and its role in protection from HIV-1 infection and disease must continue to expand until the goal of complete control of HIV-1 infection is accomplished.

CD8-Positive T-Lymphocytes↗
PubMed1986

Novel hepatitis B vaccines.

Development of vaccines against hepatitis B has proceeded along four main lines. Human plasma-derived vaccines are safe, effective, and in general use. Subunit polypeptide vaccines formulated in micelles have reached the stage of clinical trials. Recombinant DNA vaccines have been produced in prokaryotic and eukaryotic cells, notably in yeast. The yeast-derived recombinant vaccine has proved safe and effective in extensive clinical trials, eliciting antibodies of equal quantity and quality of specificity to those elicited by plasma-derived vaccine. DNA recombination has also been applied to the development of hybrid vaccinia virus vaccines which are capable of immunological 'priming'. Finally, chemical synthesis has succeeded in producing small peptides which include specific epitopes eliciting antibody responses in experimental animals. This last approach offers a prospect of ultimately producing multivalent synthetic vaccines against several microbial agents.

Animals↗
PubMed2005

Current issues in the development of a vaccine to prevent human immunodeficiency virus: insights from the society of infectious diseases pharmacists.

Infection with the human immunodeficiency virus (HIV) continues to affect millions of people worldwide. Preventive measures have done little to slow the transmission of the virus. Discovery of an effective vaccine to prevent HIV could have a tremendous impact on this global pandemic. However, the complex interactions between HIV and the host immune system have limited the progress in vaccine development. Traditional vaccination strategies have shown little promise. Currently, subunit vaccines, DNA vaccines, recombinant vector vaccines, and prime-boost strategies are being evaluated in clinical trials. Although many breakthroughs have been made in HIV vaccine research, only three candidate HIV vaccines have been studied in phase III clinical trials. The current strategies being investigated in the development of preventive HIV vaccines are reviewed.

AIDS Vaccines↗
PubMed2000

Pathogenesis of Helicobacter pylori infection.

Helicobacter pylori, a gram-negative, microaerophilic, motile, spiral-shaped bacterium, has been established as the etiologic agent of gastritis and peptic ulcers and is a major risk factor for gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma (MALT). The ability of H. pylori to cause this spectrum of diseases depends on host, bacterial, and environmental factors. Bacterial factors critical for H. pylori colonization of the gastric mucosa include urease, flagella, adhesins, and delta-glutamyltranspeptidase. Lipopolysaccharide, urease, and vacuolating cytotoxin are among the factors that allow H. pylori to persist for decades and invoke an intense inflammatory response, leading to damaged host cells. Genes in the cag pathogenicity island also contribute to the inflammatory response by initiating a signal transduction cascade, resulting in interleukin-8 production. Proinflammatory cytokines and a Th-1 cytokine response further exacerbates the inflammation. Products of the enzymes nitric oxide synthase (iNOS) and cyclooxygenase may perturb the balance between gastric epithelial cell apoptosis (ulcer formation) and proliferation (cancer). The host Th-1 response and antibodies directed against H. pylori do not eliminate the organism, which presents challenges to vaccine development. Vaccines that include urease have shown some promise, but improved adjuvants and animal models should hasten progress in vaccine research. H. pylori is the most genetically diverse organism known, and the panmictic population structure may contribute to the varying ranges of disease severity produced by different strains. The complete genome sequence of two strains of H. pylori has propelled this field forward, and numerous groups are now using genomic, proteomic, and mutagenetic approaches to identify new virulence genes. Discovered only in 1982, H. pylori is now among the most intensely investigated organisms. This review summarizes recent progress in this rapidly moving field.

Journal Article↗
PubMed1993

Protection of cats against feline leukemia virus by vaccination with a canarypox virus recombinant, ALVAC-FL.

Two ALVAC (canarypox virus)-based recombinant viruses expressing the feline leukemia virus (FeLV) subgroup A env and gag genes were assessed for their protective efficacy in cats. Both recombinant viruses contained the entire gag gene. ALVAC-FL also expressed the entire envelope glycoprotein, while ALVAC-FL(dl IS) expressed an env-specific gene product deleted of the putative immunosuppressive region. Although only 50% of the cats vaccinated with ALVAC-FL(dl IS) were protected against persistent viremia after oronasal exposure to a homologous FeLV isolate, all cats administered ALVAC-FL resisted the challenge exposure. Significantly, protection was afforded in the absence of detectable FeLV-neutralizing antibodies. These results represent the first effective vaccination of cats against FeLV with a poxvirus-based recombinant vector and have implications that are relevant not only to FeLV vaccine development but also to developing vaccines against other retroviruses, including human immunodeficiency virus.

Animals↗
PubMed2003

Generating neutralizing antibodies, Th1 response and MHC non restricted immunogenicity of HIV-I env and gag peptides in liposomes and ISCOMs with in-built adjuvanticity.

For enhancing immunogenicity and develop vaccine strategies using peptide based constructs against HIV-1, a chimeric peptide containing V3 loop and transmembrane sequence of gp41 with two glycine motifs as spacer was constructed. The V3-gp41, gp41 peptide and p17 and p24 peptides separately or in a cocktail were entrapped with or without MA729 as an immunoadjuvant in liposomes or ISCOMs. The immunogenicity, antigen induced T-cell proliferation and cytokine profiles of various formulations were studied in four different inbred strains of mice of H-2d, H-2b, H-2k and H-2q haplotypes, keeping alum as a control adjuvant. Both liposomes and ISCOM preparations elicited high titer and long lasting antibody response (60 days and above). When compared to the alum formulation, the liposomes co-entrapped with MA729 produced high antibody levels, comparable with that induced by ISCOMs. Peptide in alum, liposomes and ISCOMs enhanced both antigen specific IgG2a and IgG2b isotypes and high T-cell stimulation index. Peptide formulations also induced antibodies with high affinity and in vitro neutralizated the formation of HIV-1 syncytia. T-cell supernatants contained high levels of IFN-gamma and IL-2. Thus formulation in these adjuvants induced a predominant Th1 like response with MA729 as a versatile novel delivery vehicle for stimulating the appropriate arm of the immune response that can selectively modulate MHC class I or MHC class II response. The above peptide can be of wide vaccination interest as a means to improve immune responses to several other HIV-1 antigens and may serve as candidates for vaccine development.

Journal Article↗
PubMed1990

Use of prior vaccinations for the development of new vaccines.

There is currently a need for vaccine development to improve the immunogenicity of protective epitopes, which themselves are often poorly immunogenic. Although the immunogenicity of these epitopes can be enhanced by linking them to highly immunogenic carriers, such carriers derived from current vaccines have not proven to be generally effective. One reason may be related to epitope-specific suppression, in which prior vaccination with a protein can inhibit the antibody response to new epitopes linked to the protein. To circumvent such inhibition, a peptide from tetanus toxoid was identified that, when linked to a B cell epitope and injected into tetanus toxoid-primed recipients, retained sequences for carrier but not suppressor function. The antibody response to the B cell epitope was enhanced. This may be a general method for taking advantage of previous vaccinations in the development of new vaccines.

Amino Acid Sequence↗
PubMed2002

Generation of Th1 immune responses to inactivated, gp120-depleted HIV-1 in mice with a dominant Th2 biased immune profile via immunostimulatory [correction of imunostimulatory] oligonucleotides--relevance to AIDS vaccines in developing countries.

Vaccination against HIV-1 of hosts with a dominant Th2 immune profile may fail to induce essential protective Th1 immune responses. By using Schistosoma-infected mice, with a pre-existent Th2 immune background, we demonstrate that oligodeoxynucleotides (ODN) containing unmethylated cytosine-phosphate-guanosine (CpG) immunostimulatory sequences co-administered with inactivated, gp120-depleted HIV-1 viral particles (HIV-1 immunogen) lead to potent Th1 anti-HIV-1 immune responses overcoming the Th2 bias. In contrast, Schistosoma-infected mice immunized with HIV-1 immunogen in incomplete Freund's adjuvant only, induced Th2 anti-HIV-1 immune responses. These findings strongly support the advisability of using CpG ODN as a Th1 inducing adjuvant when immunizing human populations with a strong pre-existent Th2 immune profile.

AIDS Vaccines↗
PubMed1986

Biotechnology in the development of vaccines for animal parasites.

Attempts to develop vaccines for protozoan and helminth parasites of livestock have been generally unproductive. Difficulties have been encountered in identifying antigens which induce protective immune responses and in obtaining sufficient quantities of antigens for vaccine trials. Use of monoclonal antibody and genetic engineering technologies provides the necessary tools to overcome these problems. Application of these technologies in animal parasitology should provide for significant breakthroughs in vaccine development.

Animals↗
PubMed2006

Biomarkers for the development of cancer vaccines: current status.

Significant improvements in our knowledge of tumor immunology have resulted in more sophisticated vaccine approaches for the treatment of cancer. However, research into biomarkers that correlate with the clinical outcome of immunotherapy has lagged behind vaccine development. To this extent, very few immunological or other markers exist that can be used in clinical trials for immunotherapy. In this review, we discuss the current status of biomarker development specifically for the monitoring and development of cancer vaccines. This includes immunological biomarkers (measurement of T-cell and cytokine responses), autoimmunity as a correlate for treatment outcome, and the possible development of multiple biomarkers using high-throughput proteomics technologies. The generation of such biomarkers will allow us to make clinical decisions about patient treatment at an earlier stage and should aid in shortening the development time for vaccines.

Animals↗
PubMed2004

Approaches towards the development of a vaccine against tuberculosis: recombinant BCG and DNA vaccine.

The last few years have witnessed intense research on vaccine development against tuberculosis. This has been driven by the upsurge of tuberculosis cases globally, especially those caused by multi-drug-resistant Mycobacterium tuberculosis strains. Various vaccine strategies are currently being developed which can be broadly divided into the so-called living and non-living vaccines. Examples are attenuated members of the M. tuberculosis complex, recombinant mycobacteria, subunit proteins and DNA vaccines. Given current developments, we anticipate that recombinant BCG and DNA vaccines are the most promising. Multiple epitopes of M. tuberculosis may need to be cloned in a vaccine construct for the desired efficacy to be achieved. The technique of assembly polymerase chain reaction could facilitate such a cloning procedure.

BCG Vaccine↗
PubMed2002

Clinical trials of HIV vaccines.

Development of a preventive vaccine for HIV is the best hope of controlling the AIDS pandemic. Evidence from natural history studies and experiments in animal models indicates that immunity against HIV is possible, suggesting that vaccine development is feasible. These studies have shown that sufficient levels of neutralizing antibody against HIV can prevent infection, although the effect is type-specific. In contrast, HIV-specific cytotoxic T lymphocyte (CTL) activity has broad cross-reactivity, and although CTL activity alone cannot prevent HIV infection, it can control the level of viremia at a low level. Evaluation of candidate vaccines in human trials has focused on approaches that can safely elicit HIV-specific antibody and T cell responses. Current strategies have been unable to induce antibody with broad neutralizing activity against primary HIV isolates. However, recombinant poxvirus and DNA vaccines have elicited CTL responses that are broadly cross-reactive against primary HIV isolates from diverse clades. Future advances will require the discovery of new immunogens that can induce neutralizing antibody, as well as efficacy trial evaluation of regimens optimized for CTL induction.

AIDS Vaccines↗
PubMed1977

[The development of vaccination as demonstrated on the development of the Bavarian State Vaccination Institute in the 19th and 20th centuries].

In 1801 the smallpox vaccination has been introduced in Bavaria by order of the Duke Franz Joseph. He appointed a Medical Superintendent, responsible for smallpox vaccinations for the whole country. This was the hour of birth for the Institute, too. The Institute developed quickly to a point of crystallization in the field of prophylactic medicine, research on infectious diseases and social pediatrics. By this Institute the "Retrovaccine" against smallpox was introduced 1856. 1967 -- 1976 an attenuated life smallpox-vaccine (MVA) has been developed. Some years ago the activities of the Institute had been focussed into research of complications after vaccinations and up to date, on the pathogenesis of Multiple Sclerosis. A historical review demonstrates the development of the Institute in the past up to modern activities in research, teaching students and postgraduate education and in medical practice.

Academies and Institutes↗
PubMed2004

Engineering immunogenic consensus T helper epitopes for a cross-clade HIV vaccine.

Developing a vaccine that will stimulate broad HIV-specific T cell responses is difficult because of the variability in HIV T cell epitope sequences, which is in turn due to the high mutation rate and consequent strain diversity of HIV-1. We used a new Class II version of the EpiMatrix T cell epitope-mapping tool and Conservatrix to select highly conserved and promiscuous Class II HLA-restricted T cell epitopes from a database of 18,313 HIV-1 env sequences. Criteria for selection were: (1) number of HIV-1 strains represented as measured by Conservatrix; (2) EpiMatrix score; and (3) promiscuity (number of unique MHC motifs contained in the peptide). Using another vaccine design tool called the EpiAssembler, a new set of overlapping, conserved and immunogenic HIV-1 peptides were engineered creating extended "immunogenic consensus" sequences. Each overlapping 9-mer of the 20-23 amino acid long immunogenic consensus peptides was conserved in a large number (range 893-2254) of individual HIV-1 strains, although the novel peptides were not representative of any single strain of HIV. We synthesized nine representative peptides. T helper cell responses to the peptides were evaluated by ELISpot (gamma-interferon) assay, using peripheral blood monocytes (PBMC) obtained from 34 healthy long term non-progressor (LT) or moderate-progressor (MP) donors (median years infected = 8.88, median CD4 T cells = 595, median VL = 1044). Nine peptides were tested, of which eight were confirmed in ELISpot assays using PBMC from the LT/MP subjects. These epitopes were ranked by Conservation and EpiMatrix score 1, 2, 3, 5, 7, 11, and 14 out of the set of 9 original peptides. Five of these peptides were selected for inclusion in an epitope-driven cross-clade HIV-1 vaccine (the GAIA vaccine). These data confirm the utility of bioinformatics tools to select and construct novel "immunogenic consensus sequence" T cell epitopes for a globally relevant vaccine against HIV.

AIDS Vaccines↗
PubMed2002

Opportunities and obstacles in developing a vaccine for Entamoeba histolytica.

The development of a vaccine against Entamoeba histolytica, the causative agent of amebic colitis and liver abscess, would reduce childhood mortality in countries such as Bangledesh where community-based studies have demonstrated a high prevalence of E. histolytica. Immunological studies from this population have shown that protection from amebiasis is associated with mucosal anti-E. histolytica Gal/GalNAc lectin antibodies, suggesting that a vaccine is an achievable goal. However, garnering resources for vaccine development is a challenge when the vaccine is targeted to poor people living in developing countries.

Animals↗
PubMed1989

Development of sporozoite vaccines for malaria.

Various candidate sporozoite vaccines have been produced and tested. These have been produced by genetic engineering techniques and by polypeptide synthesis. The immunity produced by these synthetic vaccines is mediated by antibody and weak. The antibody levels achieved in human volunteer tests were similar to those resulting form natural infection. Immunity resulting from immunization with irradiated sporozoites is multifactorial. It includes reaction to malaria antigens on infected hepatocytes and it has cell-mediated components; the synthetic vaccines do not induce such reactions. Genetic restriction of cell-mediated immune responses may also limit the utility of synthetic vaccines. Development of an effective vaccine to prevent malaria will not be accomplished easily.

Animals↗
PubMed2007

Biological feasibility of developing prophylactic vaccines for viral pathogens: incubation period as a critical parameter.

Vaccines for sixteen major human viral pathogens have been approved for use in humans. For most other major human viral pathogens, the absence of an efficacious prophylactic vaccine is not for lack of effort. To identify the key parameters of biologic feasibility that determine "certainty-of-success" for developing prophylactic vaccines for major human viral pathogens, basic characteristics of viruses, such as primary genomic structure, route of transmission, and durability of viral infection were reviewed. These basic characteristics of viruses simply do not associate with successful vaccine development, so one must look elsewhere for characteristics predictive of successful vaccine development. Herein existing data are put forth in a way that demonstrates the impact of the combined effect of incubation period and broadly protective, relative immunogenicity on the "certainty-of-success" of developing effective vaccines for thirty viral pathogens. Both incubation period and broadly protective, relative immunogenicity appear to have accounted for much of the past successes in vaccine development, and may be useful in predicting where near term successes are most apt to occur.

Antibodies, Viral↗