DNA vaccines--designer vaccines for the 21st century.
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Animals↗
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Investigating genetic, antigenic, and structural diversity in the Neisseria gonorrhoeae outer membrane protein, PorB: implications for vaccine design.
UNLABELLED: Vaccines targeting Neisseria gonorrhoeae are needed to reduce disease burden and help address the problem of antimicrobial resistance, with an understanding of relationships between gonococcal genetics and molecules influencing diversity, infection, and the immune response essential for developing effective vaccine formulations. Whole-genome sequence data can be used to investigate these relationships among thousands of gonococcal isolates, allowing the study of antigenic diversity on a population scale. Such analyses typically examine antigenic diversity occurring in complete protein sequences, generating mean diversity indices and phylogenetic analyses that can inform on vaccine potential; however, to detect and measure the immune responses elicited, epitope characterization within an antigen helps guide vaccine formulations, with epitopes commonly located in surface-exposed regions of a protein. Here, we analyzed the genetic diversity of the major gonococcal antigen, PorB, in WGS from 22,227 N. gonorrhoeae isolates. We characterized the diversity of all eight surface-exposed outer membrane loops, or variable regions (VRs), and generated a PorB VR subtyping scheme to facilitate the global and temporal detection of circulating PorB subtypes. These analyses identified the presence of dominant VR combinations that persisted over time, indicative of (i) epistatic interactions between VRs and (ii) positive selection. Strain-specific, anti-PorB IgG responses directed toward distinct VR subtypes were detected in sera obtained from participants vaccinated with 4CMenB. The deconstruction of PorB into each surface-exposed loop provides a powerful approach for evaluating vaccine candidates: the methods used here allow immunodominant regions to be detected, which is invaluable for further vaccine investigations. IMPORTANCE: In the context of rising global gonorrhea cases, the development of vaccines becomes a priority; however, N. gonorrhoeae antigenic diversity and its ability to evade the immune system complicate vaccine development. This study characterizes the genetic diversity of the outer membrane protein, PorB, a key component of the outer membrane and a major gonococcal antigen. Using genomics and machine-learning techniques, this research identified dominant PorB variants that drive the immune response, proposing potential vaccine candidates and improving our understanding of the evolutionary forces maintaining genome structure and biological fitness. Understanding these processes is crucial for designing vaccines that effectively target N. gonorrhoeae and combat the spread of multidrug-resistant gonococci.
Neisseria gonorrhoeae↗
DyNAVacS: an integrative tool for optimized DNA vaccine design.
DNA vaccines have slowly emerged as keystones in preventive immunology due to their versatility in inducing both cell-mediated as well as humoral immune responses. The design of an efficient DNA vaccine, involves choice of a suitable expression vector, ensuring optimal expression by codon optimization, engineering CpG motifs for enhancing immune responses and providing additional sequence signals for efficient translation. DyNAVacS is a web-based tool created for rapid and easy design of DNA vaccines. It follows a step-wise design flow, which guides the user through the various sequential steps in the design of the vaccine. Further, it allows restriction enzyme mapping, design of primers spanning user specified sequences and provides information regarding the vectors currently used for generation of DNA vaccines. The web version uses Apache HTTP server. The interface was written in HTML and utilizes the Common Gateway Interface scripts written in PERL for functionality. DyNAVacS is an integrated tool consisting of user-friendly programs, which require minimal information from the user. The software is available free of cost, as a web based application at URL: http://miracle.igib.res.in/dynavac/.
Codon↗
[EVALUATION OF VACCINES AND THE EFFECTIVENESS OF VACCINATIONS AGAINST TYPHOID FEVER. III. SELECTION AND PRELIMINARY CHARACTERISTICS OF VACCINES DESIGNATED FOR CONTROL VACCINATIONS].
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Poland↗
The challenges of host and viral diversity in HIV vaccine design.
Rational HIV vaccine design is crucially dependent on a number of factors, including a detailed understanding of the immune responses that control infection in individuals that have non-progressing disease, the impact of host genetics on these responses, and the degree of immunological cross-reactivity between the vaccine immunogen and the encountered virus antigens. Significant progress has been made in a number of these areas over the past five years, which might help in the generation of a more effective immunogen design and will provide opportunities for novel vaccine delivery options. However, the understanding of immune response(s) that can mediate protection from infection or, if infection ensues, that slow the rate of HIV disease progression is still incomplete and will require detailed studies in unprecedentedly large populations infected with different HIV clades, combining advances in virology, immunology, human host genetics and bioinformatics analyses for the optimal design of vaccine immunogens.
AIDS Vaccines↗
Memory cytolytic T-lymphocytes: induction, regulation and implications for vaccine design.
The design of vaccines that protect against intracellular infections or cancer remains a challenge. In many cases, immunity depends on the development of antigen-specific memory CD8+ T-cells that can express cytokines and kill antigen-bearing cells when they encounter the pathogen or tumor. Here, the authors review current understanding of the signals and cells that lead to memory CD8+ T-cell differentiation, the relationship between the primary CD8+ T-cell response and the memory response and the regulation of memory CD8+ T-cell survival and function. The implications of this new knowledge for vaccine design are discussed, and recent progress in the development of lipidated peptide vaccines as a promising approach for vaccination against intracellular infections and cancer is reviewed.
Animals↗
Phase and antigenic variation--the impact on strategies for bacterial vaccine design.
Many pathogens have the ability to vary the antigenic composition of surface-associated antigens. Often, this variation is mediated by the regulation of gene expression. By varying its antigenicity, the pathogen is able to avoid host immune responses more efficiently; however, this makes the design of vaccines against pathogens that exhibit antigenic variation difficult. In this review, we use the pathogenic Neisseria as an example of antigenically variable bacteria and discuss some attempts to overcome the problems of vaccine design posed by such organisms.
Antigenic Variation↗
Vaccine design: future possibilities and potentials.
Recent developments in the understanding of the structure and replications of a wide range of pathogens, including viruses, bacteria and parasites have opened up ways of designing novel vaccines which should both improve the quality and extend the range and value of vaccines as major prophylactic and therapeutic tools of the future. Two main strategies have emerged, one involving the development of synthetic vaccines which are essentially composed of selected epitopes of the pathogenic agent that will elicit neutralising antibodies. The other strategy attempts to make use of chimeric agents that will allow live virus or bacteria to be used as vectors for carrying appropriate epitopes of the target pathogen. Current knowledge about the immunology and improvements in the presentation of antigen to the immune system will also play an important role in the rational design of vaccines. This review summarises present methods of producing vaccines and considers the development of more rational methods of vaccine design that will greatly influence the production of vaccines in the future.
Journal Article↗
Approaches to HIV vaccine design.
Contemporary vaccines are relying increasingly on modern biotechnology and a vaccine against the AIDS virus is expected to depend even more on new technological advances. Four basic areas of vaccine development are discussed in this context: (1) selection and preparation of candidate immunogens; (2) presentation of immunogens to the immune system; (3) pre-clinical testing of vaccine candidates; and (4) monitoring of vaccine clinical trials.
Acquired Immunodeficiency Syndrome↗
DCs as targets for vaccine design.
The increasingly stringent requirements laid down by regulatory authorities have brought to an end the largely empirical design of vaccines. Vaccines must now be designed rationally, in order that appropriate immune responses are elicited with few or no side effects. The DC plays a pivotal role in determining the type of immune response that ensues following exposure of the host to an Ag. In this review, we identify some of the features and properties of DCs, and how these properties can be exploited in the design of smart vaccines.
Adoptive Transfer↗
The potential role of fowlpox virus in rational vaccine design.
The design of optimal vaccines requires detailed knowledge of how protective immune responses are generated in vivo under normal circumstances. This approach to vaccine development, where the immune correlates of protection are defined and vaccines are designed to elicit the same response, is called rational vaccine design. Poxviruses are attractive candidates for inclusion in such design strategies owing to their large genome, which allows for the inclusion of multiple heterologous genes, including those encoding antigens, co-stimulatory molecules and cytokines. Fowlpox virus, the prototypical member of the Avipoxvirus genus, is particularly suitable, as it is also incapable of replicating in mammalian cells. The potential of recombinant fowlpox virus as a safe vaccine vector is being evaluated currently in a number of clinical trials for diseases, including HIV, malaria and various types of cancer. Despite their promise, intricate details regarding how fowlpox virus interacts with the host immune system have not been resolved. In this review, the issues surrounding the use of fowlpox virus as a vaccine vector and possible strategies for enhancing its efficacy are discussed.
AIDS Vaccines↗
Gene expression microarrays: a 21st century tool for directed vaccine design.
DNA microarray technology is a new and powerful tool that allows the simultaneous analysis of a large number of nucleic acid hybridization experiments in a rapid and efficient fashion. The development of the DNA microarray chip has been driven by modern techniques of microelectronic fabrication, miniaturization and integration to produce what is referred to as "laboratory-on-chip" devices. The application of DNA chip technology includes the comprehensive analysis of multiple gene mutations and expressed sequences with regard to newer drug designs, host-pathogen interactions and the design of new vaccines. An advantage of microarray technology is that it can assist researchers to better define and understand the expression profile of a given genotype associated with disease, adverse effects from exposure to certain stimuli, or the ability to understand or predict immune responses to specific antigens. This paper briefly reviews DNA microarray technology and its implications with special reference to vaccine design. The technical aspects comprising array manufacturing and design, array hybridization, formatting, scanning and data handling are also briefly discussed.
Animals↗
Artificial protein vaccines with predetermined tertiary structure: application to anti-HIV-1 vaccine design.
A successful approach to the development of a safe and effective synthetic vaccine requires that different B and T cell epitopes of the infectious agent be included in the vaccine construction. In this paper we suggest a new approach to vaccine design in the form of an artificial protein with a predetermined tertiary structure (PTS vaccines). Based on B and T cell epitope properties, we substantiate the possible use for vaccine construction of one well-known protein spatial motif--the four-alpha-helix bundle. Antigenic determinants of cellular immunity (amphipathic alpha-helices) and humoral immunity (flexible hydrophilic loop regions) are used as blocks for vaccine design. General principles of PTS vaccine construction have been applied to anti-HIV-1 vaccine design.
AIDS Vaccines↗
Vaccine design, evaluation, and community-based use for antigenically variable infectious agents.
A major challenge for vaccine design and development, and for trials of new vaccines, is to tackle antigenically variable infectious agents. Here we outline a few general conceptual issues and then discuss new frameworks that are being developed to help understand how vaccination might change the distribution, abundance, and type of strains in a population. Herd Immunity is a key concept in population-based immunisation programmes and has to be considered in vaccine design and use even though it may cause a conflict between the needs of the individual versus those of the community. This issue is of increasing importance since once common infections are becoming rare due to effective vaccination. Concomitantly, adverse effects arising from immunisation are becoming more apparent as infection-induced morbidity declines to very low levels. Efficacy is widely regarded as a key criterion in vaccine design but duration of protection is of equal importance. Whether it is possible to produce effective vaccines to antigenically diverse pathogens remains uncertain but progress towards this goal will be enhanced by a better understanding of the population genetics of the target infectious agent facilitated by molecular epidemiological studies to assess the genetic constitution of pathogen populations and changes therein over time.
Antigenic Variation↗
EBV structural antigens, gp350 and gp85, as targets for ex vivo virus-specific CTL during acute infectious mononucleosis: potential use of gp350/gp85 CTL epitopes for vaccine design.
For many years, EBV vaccine development efforts have concentrated on the use of structural Ag, gp350, and have been directed toward Ab-mediated blocking virus attachment to the target cell. There is increasing evidence to suggest that the development of neutralizing Abs in vaccinated animals does not always correlate with protection; nevertheless, it has been postulated that gp350-specific T cell-mediated immune responses may have an effector role in protection. This hypothesis has largely remained untested. In the present study, we demonstrate that CTL from acute infectious mononucleosis patients display strong ex vivo reactivity against the EBV structural Ags, gp85 and gp350. Moreover, long-term follow up studies on infectious mononucleosis-recovered individuals showed that these individuals maintain gp350- and gp85-specific memory CTL, albeit at low levels, in the peripheral blood. These results strongly suggest that CTL specific for EBV structural proteins may play an important role in the control of EBV infection during acute infection. More importantly, we also show that prior immunization of HLA A2/Kb transgenic mice with gp350 and gp85 CTL epitopes induced a strong epitope-specific CTL response and afforded protection against gp85- or gp350-expressing vaccinia virus challenge. These results have important implications for future EBV vaccine design and provides evidence, for the first time, that CTL epitopes from EBV structural proteins may be used for establishing strong antiviral immunity against EBV infection.
Acute Disease↗
Dissecting the role of peptides in the immune response: theory, practice and the application to vaccine design.
Analytical biochemistry and synthetic peptide based chemistry have helped to reveal the pivotal role that peptides play in determining the specificity, magnitude and quality of both humoral (antibody) and cellular (cytotoxic and helper T cell) immune responses. In addition, peptide based technologies are now at the forefront of vaccine design and medical diagnostics. The chemical technologies used to assemble peptides into immunogenic structures have made great strides over the past decade and assembly of highly pure peptides which can be incorporated into high molecular weight species, multimeric and even branched structures together with non-peptidic material is now routine. These structures have a wide range of applications in designer vaccines and diagnostic reagents. Thus the tools of the peptide chemist are exquisitely placed to answer questions about immune recognition and along the way to provide us with new and improved vaccines and diagnostics.
Animals↗
Structural features of T-cell recognition: applications to vaccine design.
T lymphocytes, in contrast to antibodies, appear to recognize primarily a limited number of antigenic sites on any given antigenic protein. We find that a single site can so dominate the T-cell repertoire that the presence or absence of a response to one immunodominant site can make the difference between a high responder and a low responder, even though low responders respond to other sites almost as well as high responders. Besides interaction with major histocompatibility complex (MHC) molecules, the mode by which the antigen is processed into fragments for T-cell recognition also determines which sites are seen. The products of natural processing of the protein appear to be larger than the synthetic peptides and contain structures which hinder binding to certain MHC molecules or to the T-cell receptor. A third factor in immunodominance is the intrinsic structure of the antigenic site. We have shown that amphipathic helices have a higher than random chance of being immunodominant, and have developed a computer program to locate such structures in protein amino acid sequences. We prospectively predicted sites in the malaria circumsporozoite protein and found that the four most widely recognized sites in an endemic area of West Africa were all predicted. Similarly, we identified two helper T-cell sites from the HIV (AIDS virus) envelope, and have now shown that immunization with these elicits enhanced antibody responses to the whole envelope when injected into monkeys. These sites are also recognized by human T cells from volunteers who had been immunized with a recombinant vaccinia virus expressing the HIV envelope. Also, because cytotoxic T lymphocytes (CTLS) may play a critical role in defence against AIDS, we have used a recombinant vaccinia virus and transfectants expressing the HIV envelope gene to induce specific CTLS against the HIV envelope. Using synthetic peptides, we were able to identify the first CTL recognition site in the AIDS virus. These results may contribute to the rational design of vaccines.
Animals↗
Optimizing vaccine design for cellular processing, MHC binding and TCR recognition.
In this review we describe the methods and processes that our group have developed while aiming to test and design multiepitope vaccines for infectious diseases and cancer. Testing the performance of vaccines composed of epitopes restricted by human leukocyte antigen (HLA) molecules is accomplished by in vitro antigenicity assays, as well as in vivo immunogenicity assays in HLA transgenics. The efficiency by which multiepitope vaccines are processed is optimized by spacer residues, which are designed to facilitate generation by natural processing of the various class I- and class II-restricted epitopes. Methods and strategies to test and optimize HLA binding affinity, patient coverage from the vaccine construct, and TCR recognition of HLA/epitope complexes are also discussed.
Epitopes↗