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PubMed2005

HIV vaccine development by computer assisted design: the GAIA vaccine.

The design of epitope-driven vaccines that address the global variability of HIV has been significantly hampered by concerns about conservation of the vaccine epitopes across clades of HIV. We developed two computer-driven methods for improving epitope-driven HIV vaccines: the Epi-Assembler, which derives representative or "immunogenic consensus sequence" (ICS) epitopes from multiple viral variants, and VaccineCAD, which reduces junctional immunogenicity when epitopes are aligned in a string-of-beads format for insertion in a DNA expression vector. In this study, we report on 20 ICS HIV-1 peptides. The core 9-mer contained in these consensus peptides was conserved in 105-2250 individual HIV-1 strains. Nineteen of the 20 ICS epitopes (95%) evaluated in this study were confirmed in ELISpot assays using peripheral blood monocytes obtained from 13 healthy HIV-1 infected subjects. Twenty-five ICS peptides (all 20 of the peptides evaluated in this study and 5 additional ICS epitopes) were then aligned in a pseudoprotein string using "VaccineCAD", an epitope alignment tool that eliminates immunogenicity created by the junctions between the epitopes. Reordering the construct reduced the immunogenicity of the junctions between epitopes as measured by EpiMatrix, an epitope mapping algorithm. The reordered construct was also a more effective immunogen in vivo when tested in HLA-DR transgenic mice. These data confirm the utility of bioinformatics tools to design novel vaccines containing "immunogenic consensus sequence" T cell epitopes for a globally relevant vaccine against HIV.

AIDS Vaccines↗

PubMed1995

Progress in AIDS vaccine development.

Because of a unique combination of challenges facing human immunodeficiency virus vaccine developers, a number of traditional and novel vaccine designs are being evaluated essentially in parallel. Monomeric proteins, poxvirus vectors, peptides, and particle-based candidate vaccines have entered or will soon enter human trials. Other designs are at earlier stages of development. All candidates evaluated to date in phase I/II human trials have proven safe and immunogenic. One or more of the most promising designs will soon progress to 'test of concept' clinical trials to determine efficacy.

AIDS Vaccines↗

PubMed1993

Challenges and strategies for AIDS vaccine development.

The major topics covered at this conference included the relevance of the SIV-macaque model for HIV vaccine development, an evaluation of the methods for producing inactivated vaccine, and the possibility of developing attenuated retrovirus vaccines. The possibility that there might be a Graft Versus Host Disease component in human AIDS was discussed, and also the recent discovery that the 'original antigenic sin' phenomenon encountered in influenza vaccines may also be seen in AIDS. It was concluded that results from animal models were encouraging in the quest for an HIV-1 vaccine.

AIDS Vaccines↗

PubMed1993

T cell responses to pre-erythrocytic stages of malaria: role in protection and vaccine development against pre-erythrocytic stages.

Malaria remains a leading cause of human morbidity and mortality due to the inability of insecticides and chemotherapy/chemoprophylaxis to eliminate the vectors or disease caused by this protozoan parasite. In an effort to develop new methods of control, vaccines targeted to the various stages of the complex life cycle of Plasmodium have been developed. This review describes recent advances in the elucidation of cell-mediated immune mechanisms directed against sporozoites and liver stages of malaria parasites, their role in protection, and their relation to vaccine development. Recent data on the molecular basis of sporozoite-liver cell interaction are presented, and these may provide new approaches for chemoprophylaxis and immunoprophylaxis. We describe the role of the circumsporozoite protein, the major sporozoite surface antigen, in sporozoite movement and as a target of humoral immunity. The recognition of the circumsporozoite protein by human T cells is reviewed with emphasis on cytotoxic T cells and immune resistance against the exo-erythrocytic stage of the parasite. Earlier concepts regarding the polymorphisms of the circumsporozoite protein, the immunological relevance of this polymorphism, and predictions regarding vaccine development are reevaluated on the basis of recent data from different malaria endemic areas. Non-CS sporozoite antigens and liver stage antigens are discussed as potential targets for immune intervention. Recent experimental approaches such as multiple antigen peptides, recombinant live vectors, and new more potent adjuvants are considered for the development of more effective malaria vaccine formulations.

Amino Acid Sequence↗

PubMed1981

Incidence and severity of rotavirus and Escherichia coli diarrhoea in rural Bangladesh. Implications for vaccine development.

In a 1 year study of diarrhoea in a village in rural Bangladesh, enterotoxigenic Escherichia coli (ETEC) were the most frequently detected enteropathogens; shigellae were the second most commonly detected enteropathogens and rotaviruses the third. ETEC and rotavirus were found in 31% of diarrhoea episodes experienced by children aged less than 2 years and in 70% of episodes associated with dehydration. Furthermore these two pathogens were identified in the stools of 77% of young children with life-threatening dehydration seen at a diarrhoea treatment centre. The association of ETEC and rotavirus with such a substantial proportion of cases of dehydrating diarrhoea suggests that immunoprophylaxis to reduce the high incidence of deaths from diarrhoea in developing countries may be feasible and that vaccine development should concentrate on these two enteropathogens.

Bangladesh↗

PubMed2005

Rapid size dependent deletion of foreign gene sequences inserted into attenuated HIV-1 upon infection in vivo: implications for vaccine development.

Live attenuated HIV vaccines offer a means to introduce exogenous sequences into the viral genome to target the virus elimination in vivo. Foreign genes inserted into the nef region of HIV-1 NL4-3 were found to be rapidly deleted following virus infection and/or replication, in a size dependent manner, in the human fetal Thymus/Liver implants of severe combined immunodeficient mouse (SCID-hu) model. When the murine heat stable antigen (HSA) of 283 bp was substituted into HIV-1 nef region, the viral loads in vivo were comparable to the negative control nef attenuated HIV-1, and the reporter HSA gene was not deleted upon infection. However, the murine Thy1.2 gene (505 bp) substituted into the nef attenuated HIV-1, upon infection and replication, deleted 441 bp in vitro and 437 bp in vivo, of the inserted Thy1.2 gene. When the enhanced green fluorescence protein (eGFP) gene (720 bp) was substituted for nef, virus replication was aborted in vivo in the Thy/Liv implants, as seen by the background levels of viral loads, comparable to mock infected implants, and the eGFP gene was deleted. When the herpes simplex virus thymidine kinase gene, HSV-TK (1.15 kbp), or HSA gene, was substituted into the viral vpr gene, TK but not HSA gene was deleted, upon infection in vitro. Moreover, NL-TKI reporter virus with both intact nef and vpr genes shows deletion of TK gene both in vitro and in vivo. Excision of foreign genes occurred within the exogenous segments but not in the viral own regions. These results suggest that larger "suicide" genes introduced via HIV-1 can be deleted upon infection. However, smaller size nucleotide sequences or genes (approximately 300 bp) inserted in place of viral nef or vpr gene may be used to target the virus or its components, for attack and elimination in vivo, and thus have implications for the development of live attenuated HIV vaccines.

AIDS Vaccines↗

PubMed2000

A proposed national strategy for tuberculosis vaccine development.

The global tuberculosis epidemic causes approximately 5% of deaths worldwide. Despite recent concerted and largely successful tuberculosis control efforts, the incidence of tuberculosis in the United States remains 74-fold higher than the stated elimination goal of <1 case per million population by the year 2010. Current bacille Calmette-Guérin vaccines, although efficacious in preventing extrapulmonary tuberculosis in young children, have shown widely variable efficacy in preventing adult pulmonary tuberculosis, confound skin test screening, and are not recommended for use in the United States. The Advisory Council for Elimination of Tuberculosis recently stated that tuberculosis would not be eliminated from the United States without a more effective vaccine. Recent scientific advances have created unprecedented opportunity for tuberculosis vaccine development. Therefore, members of the broad tuberculosis research and control communities have recently created and proposed a national strategy, or blueprint, for tuberculosis vaccine development, which is presented here.

Adult↗

PubMed1998

Human papillomavirus vaccine development.

The greatest successes in combating important viral infections have been achieved using vaccines. A vaccine to prevent genital tract human papillomavirus (HPV) infections, especially those types associated with genital tract malignancy, could significantly reduce morbidity and mortality from cervical and other genital tract cancers. However, several barriers currently stand in the way of HPV vaccine development. The immunological response to natural HPV infection is incompletely understood and there is uncertainty about which viral antigen(s) should be included in a candidate vaccine. It is clear that immunization of several animal species with the L1 major capsid protein (usually in the form of virus-like particles) spurs the production of anti-HPV antibodies that are neutralizing in several assay systems. However, it is not clear if neutralizing antibody will be present in the genital tract in sufficient quantities to block infection. A second problem is the lack of a reliable serological assay for HPV. This is a major problem for clinical trials in which the identification of susceptible individuals, and incident infections, usually relies on serological diagnosis. Finally, there is also interest in the development of a vaccine that is used to treat individuals who are already infected--a therapeutic vaccine. It is likely that a therapeutic vaccine will need to target different or additional antigens to those comprising a prophylactic vaccine.

Animals↗

PubMed2005

Preparing for pandemic vaccination: an international policy agenda for vaccine development.

The international use of influenza vaccine is growing, especially in developing countries. Since 1997, avian H5N1 influenza in Southeast Asia has caused several human infections and high mortality. Experts warn that the next influenza pandemic is imminent and could be severe. Prevention and control will depend on the rapid production and worldwide distribution of specific pandemic vaccines. If the vaccine supply is to be sufficient to meet global demand, issues related to the intellectual property rights for the reverse genetics technology essential for vaccine production must be resolved. In addition, candidate "pandemic-like" vaccines must be developed and tested in clinical trials to determine the most antigen sparing formulation and the best vaccination schedule. These studies must involve all vaccine companies and will require international coordination and public funding. Whether this international policy agenda for pandemic vaccine development will succeed is uncertain, but it will provide a good indication of whether "good governance" for global public health can be achieved.

Disease Outbreaks↗

PubMed1993

Potentially negative effects of AIDS vaccines based on recombinant viruses carrying HIV-1 derived envelope gene. A warning on AIDS vaccine development.

Various candidate AIDS vaccines based on HIV-1 envelope glycoprotein (gp120/160) are currently under clinical trials (phase 1 and 2) in healthy, HIV-negative volunteers, as well as in HIV-infected persons. Most of these vaccines use recombinant viral vectors carrying the HIV-derived gp120/160 gene. Possible negative effects of recently reported sequence and gene similarities between HIV-1 gp120 and the variable region of human immunoglobulins on further development and current application of such AIDS vaccines are discussed.

AIDS Vaccines↗

PubMed2000

MHC: function and implication on vaccine development.

The purpose of this State of the Art review is to present an overview of structural and functional aspects of human MHC molecules and how polymorphisms in HLA molecules determine the nature of the antigenic peptides bound and how such may impact upon rational vaccine development. The following areas will be discussed: elements of immune recognition, class I and class II structure and function, the class I antigen processing pathway, class II antigen processing and presentation, functional divergence among T-cells recognizing class I or class II MHC molecules, and rational vaccine development. While the first section will review our current understanding of MHC structure and function, the latter part will draw on my own work with Hepatitis C Virus (HCV) antigens.

Epitopes↗

PubMed1998

Testis-specific proteins and their role in contraceptive vaccine development.

Development of a vaccine(s) based on sperm antigens represents a promising approach for contraception. The utility of an antigen in immunocontraception is contingent upon its testis/sperm specificity and involvement in spermatogenesis and/or fertilization. The aim of the present article is to review the information regarding the proteins that have been reported to be testis/sperm-specific and may have an important function in spermatogenesis and/or fertilization. The potential role of these proteins in the development an antisperm contraceptive vaccine(s) is discussed.

Contraception, Immunologic↗

PubMed1998

HIV vaccine development and evaluation: realistic expectations.

As of January 1998, more than 85 vaccines for 24 clinical indications are currently licensed in the United States. From the time of discovery of the etiologic agent to the development of a licensed vaccine, many years have usually been required. Although many vaccines have been licensed on the basis of one efficacy trial, multiple vaccine concepts and multiple efficacy trials (both in the United States and internationally) have at times been necessary. Over a relatively short period of time, there has been remarkable progress in human immunodeficiency virus (HIV) vaccine development, with over 34 different HIV candidate vaccines having been tested in phase 1 trials, and three having been tested in phase 2 trials. In spite of our incomplete understanding of HIV pathogenesis and correlates of protection, the first phase 3 efficacy trial has been initiated in the U.S. and tentative plans have been announced for three other phase 3 efficacy trials with the most advanced HIV candidate vaccines to begin in the next 3 years. Like many previous vaccine development efforts, these initial HIV vaccine efficacy trials could be the first of many large-scale efficacy trials in the future, testing various vaccine design concepts among different high-risk populations in both developed and developing countries. The choice of when and how to proceed to phase 3 trials remains a complex decision, but it is likely that only through such trials will further knowledge be gained to advance this important effort and reach our goal of a safe and effective HIV vaccine.

AIDS Vaccines↗

PubMed1992

Hepatitis A in the US Army: epidemiology and vaccine development.

Control of hepatitis A has been an important concern for US military forces in war and peace. Immune serum globulin, although effective, is exceedingly cumbersome to use. The prevalence of antibody against hepatitis A is decreasing in young American soldiers, putting them at risk of hepatitis A during deployment. The US Army has been an active participant in development of hepatitis A vaccine. The first successful cell-culture-derived, formalin-inactivated hepatitis A vaccine was developed at the Walter Reed Army Institute of Research. This prototype vaccine was shown, in 1986, to be safe and immunogenic for humans. Since then we have evaluated the following issues related to the use of inactivated hepatitis A vaccines in military populations. Immunogenicity of vaccine derived from the CLF and HM175 strains; immunogenicity of hepatitis A vaccine given by jet injector; immunogenicity of hepatitis A vaccine when given with hepatitis B vaccine; immunogenicity when given in shortened schedules; safety and immunogenicity in Thai children; and efficacy under field conditions in the tropics. The hepatitis A vaccines which we tested are safe and highly immunogenic. Immunization by jet gun confers immunity equivalent to immunization by needle. Hepatitis A vaccine is equally potent when given with hepatitis B vaccine. Data on rapid immunization schedules and efficacy are under evaluation. We conclude that hepatitis A vaccine is a major improvement in our ability to prevent hepatitis A in soldiers.

Hepatitis A↗

PubMed2004

Prospects for new TB vaccines: Stop TB Working Group on TB Vaccine Development.

Research towards the development of improved TB vaccines has reached an important turning point. A large number of vaccine candidates such as modified BCG, attenuated Mycobacterium tuberculosis and protein or DNA subunit vaccines, resulting from over a decade of work in experimental laboratory models, are now getting ready for clinical testing. The transition from laboratory to clinical trials has a wide range of strategic and technical implications. Facilities and funding need to be identified for the production of clinical vaccine lots, an issue that is difficult to tackle due to the live organisms in some of the new vaccine candidates; regulatory hurdles need to be overcome; protocols and trial sites need to be developed, for phase III clinical efficacy trials in particular. The Stop TB Working Group on TB Vaccine Development provides a global forum that brings laboratory and clinical researchers together with experts in tuberculosis control and representatives from commercial and non-profit funding agencies to address these issues and to facilitate progress towards the common goal of improved vaccination strategies for tuberculosis.

Animals↗

PubMed2005

The L.E.A.P.S. approach to vaccine development.

The Ligand Epitope Antigen Presentation System (L.E.A.P.S.) approach to vaccine development utilizes immune peptides to promote the immunogenicity and influence the type of immune response generated towards epitopes in peptides which may be too small to elicit an immune response. The covalent attachment of these immune peptides to the antigenic peptide promotes the interaction of the epitope with T cells (T cell binding ligand (TCBL)) or antigen presenting cells (immune cell binding ligand (ICBL)) and ultimately promotes binding with the T cell receptor on CD4 or CD8 T cells. The, J, ICBL/TCBL peptide derived from the beta-2-microglobulin chain of MHC I molecules promotes Th1 type responses to the antigenic peptide while the, G, ICBL/TCBL peptide derived from the beta chain of MHC II molecules promotes Th2 types of responses. The efficacy of this approach has been demonstrated by characterization of the immune responses to L.E.A.P.S. vaccines and by elicitation of protection from infectious challenge with herpes simplex virus and other pathogens. The protection studies show that the L.E.A.P.S. approach allows customization of the immune response appropriate for inducing protection from disease. The theory, background, examples and studies of the mechanism of action of the L.E.A.P.S. vaccines will be discussed.

Animals↗

PubMedDate not supplied

HIV pathogenesis and vaccine development.

New information on the crystal structures of the HIV and the simian immunodeficiency virus (SIV) envelopes represented one of the scientific highlights of the 12th Annual Conference on Retroviruses and Opportunistic Infections. Numerous presentations also underscored the increasing recognition of the central role of gut-associated lymphoid tissue in AIDS pathogenesis and helped reveal a better understanding of the multiple mechanisms underlying CD4+ T lymphocyte depletion in AIDS. Progress on vaccine development was largely incremental but was strongly influenced by the impact of an expanding array of flow cytometric assays that have revealed significant functional and phenotypic differences in virus-specific CD8+ cells. The interplay between host cellular and humoral immune responses and virus evolution was another prominent theme, and it underscored the challenge facing host immune responses and vaccine developers in attempting to thwart an ever-mutating virus.

AIDS Vaccines↗

PubMed2002

Challenges and issues in new vaccine development.

The Euroconference on Vaccines of the Future: from Rational Design to Clinical Development was held at the Pasteur Institute, Paris, France from 17-19 October 2001.

Acquired Immunodeficiency Syndrome↗