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PubMed1999

Molecular basis for vaccine development against the ehrlichial pathogen Anaplasma marginale.

Anaplasma marginale is a tick-transmitted ehrlichial pathogen causing severe morbidity and mortality in livestock on six continents. Development of safe effective vaccines would be greatly facilitated by identification of the protective immune mechanisms and by understanding how the pathogen evades immune effectors to establish persistent infection. In this article, Guy Palmer and colleagues review recent progress in identifying how defined epitopes induce protective immunity and the role of antigenic variation in these epitopes as a mechanism of persistence.

Anaplasma↗
PubMed2000

Bacterial interplay at intestinal mucosal surfaces: implications for vaccine development.

The discovery of 'molecular syringes' in several important gastrointestinal pathogens including Escherichia coli, Salmonella, Shigella and Yersinia, together with a better understanding of M cells and the mucosal immune system, has advanced our appreciation of multistage microorganism-host cell interactions. Recent studies suggest that these molecular strategies could be adapted for the development of modular mucosal vaccines.

Bacterial Proteins↗
PubMed2002

Animal usage in vaccine development and production: maximising results while minimizing use.

The Third International Symposium on Advancing Science and Elimination of the Use of Laboratory Animals for Development and Control of Vaccines and Hormones, organized by the National Institute of Public Health and the Environment (RIVM, The Netherlands) under the auspices of the International Association for Biologicals (IABS), was held in Utrecht, The Netherlands, 12-14 November 2001.

Animal Use Alternatives↗
PubMed2003

HIV-1 vaccine development: constrained peptide immunogens show improved binding to the anti-HIV-1 gp41 MAb.

The human immunodeficiency virus type I (HIV-1) transmembrane glycoprotein gp41 mediates viral entry through fusion of the target cellular and viral membranes. A segment of gp41 containing the sequence Glu-Leu-Asp-Lys-Trp-Ala has previously been identified as the epitope of the HIV-1 neutralizing human monoclonal antibody 2F5 (MAb 2F5). The 2F5 epitope is highly conserved among HIV-1 envelope glycoproteins. Antibodies directed at the 2F5 epitope have neutralizing effects on a broad range of laboratory-adapted HIV-1 variants and primary isolates. Recently, a crystal structure of the epitope bound to the Fab fragment of MAb 2F5 has shown that the 2F5 peptide adopts a beta-turn conformation [Pai, E. F., Klein, M. H., Chong, P., and Pedyczak, A. (2000) World Intellectual Property Organization Patent WO-00/61618]. We have designed cyclic peptides to adopt beta-turn conformations by the incorporation of a side-chain to side-chain lactam bridge between the i and i + 4 residues containing the Asp-Lys-Trp segment. Synthesis of extended, nonconstrained peptides encompassing the 2F5 epitope revealed that the 13 amino acid sequence, Glu-Leu-Leu-Glu-Leu-Asp-Lys-Trp-Ala-Ser-Leu-Trp-Asn, maximized MAb 2F5 binding. Constrained analogues of this sequence were explored to optimize 2F5 binding affinity. The solution conformations of the constrained peptides have been characterized by NMR spectroscopy and molecular modeling techniques. The results presented here demonstrate that both inclusion of the lactam constraint and extension of the 2F5 segment are necessary to elicit optimal antibody binding activity. The ability of these peptide immunogens to stimulate a high titer, peptide-specific immune response incapable of viral neutralization is discussed in regard to developing an HIV-1 vaccine designed to elicit a 2F5-like immune response.

AIDS Vaccines↗
PubMed1995

Production of infectious human respiratory syncytial virus from cloned cDNA confirms an essential role for the transcription elongation factor from the 5' proximal open reading frame of the M2 mRNA in gene expression and provides a capability for vaccine development.

Infectious human respiratory syncytial virus (RSV) was produced by the intracellular coexpression of five plasmid-borne cDNAs. One cDNA encoded a complete positive-sense version of the RSV genome (corresponding to the replicative intermediate RNA or antigenome), and each of the other four encoded a separate RSV protein, namely, the major nucleocapsid N protein, the nucleocapsid P phosphoprotein, the major polymerase L protein, or the protein from the 5' proximal open reading frame of the M2 mRNA [M2(ORF1)]. RSV was not produced if any of the five plasmids was omitted. The requirement for the M2(ORF1) protein is consistent with its recent identification as a transcription elongation factor and confirms its importance for RSV gene expression. It should thus be possible to introduce defined changes into infectious RSV. This should be useful for basic studies of RSV molecular biology and pathogenesis; in addition, there are immediate applications to the development of live attenuated vaccine strains bearing predetermined defined attenuating mutations.

Base Sequence↗
PubMed1995

T cell proliferative responses to five human cytomegalovirus proteins in healthy seropositive individuals: implications for vaccine development.

Cell-mediated immunity plays an important role in the host response against human cytomegalovirus (HCMV) infection. For the development of HCMV subunit vaccines it is essential to identify which HCMV proteins can induce protective immune responses in humans. We have studied the T cell proliferative responses to five HCMV proteins (IE1, IE2, pp71, gpUL18 and gB). These five proteins were produced using the maltose-binding protein (MBP) fusion protein system. T cell proliferative responses in 23 seropositive and six seronegative individuals were evaluated. None of the six seronegative individuals showed significant responses to any of the proteins. Of the 23 seropositive individuals, five responded to all five proteins, 14 responded to between one and four proteins and four responded to none of the proteins. The most commonly recognized proteins were gB (17/23, 74%) and IE2 (16/23, 70%). pp71 and IE1 were recognized by 10 of 23 (43%) individuals. Nine of 22 (41%) individuals tested responded to gpUL18, providing evidence that this protein is produced during infection. Our data indicate that a subunit vaccine composed of gB alone may not be sufficient to induce protective immunity in all individuals. The combination of two or three proteins may be more efficient as a potential vaccine.

Capsid↗
PubMed1990

Overview of flavivirus molecular biology and future vaccine development via recombinant DNA.

Studies in many laboratories over the last several years have elucidated the structures of several different flavivirus genomes. Conserved features include the production of at least 10 different virus encoded proteins from a single long open reading frame by a combination of host and virus-encoded proteases. The established gene order is 5'-C- prM(M)-E-NS1-NS2A-NS2B-NS3-NS4A-NS4B-NS 5-3' and these proteins exhibit varying degrees of homology in comparisons among flaviviruses. Conserved RNA sequences and structures have also been identified for the mosquito-borne flaviviruses but are absent in sequenced tick-bone viruses. Relevant to the development of efficacious flavivirus vaccines, studies aimed at defining the antigenic determinants necessary for eliciting protective immunity have focused primarily on the structural proteins, in particular the E protein, as well as the nonstructural secreted glycoprotein, NS1. Other work, which has led to the derivation of live-attenuated flavivirus strains, should eventually allow the genetic determinants of flavivirus attenuation and pathogenesis to be understood at the molecular level. The successful recovery infectious flaviviruses from cloned cDNA raises the possibility of manipulating these viral genomes as cDNA to construct or propagate candidate live-attenuated vaccine strains. Several applications of this technology are discussed.

Amino Acid Sequence↗
PubMed1979

Malaria vaccine development.

Prospects for the development of effective malaria vaccines have greatly improved over the last 15 years. For further progress to be achieved rapidly, the need for clinical research centres, where exposure and re-exposure to infection can be carefully controlled, is paramount. At such centres, it is possible to evaluate the safety and efficacy of vaccine preparations, using different strams and species of parasite, and to undertake studies in both nonimmune and partially immune volunteers. However, as efficacy under these conditions may not be a good indicator of efficacy under other conditions, the results of such studies should be complemented by field trials in endemic areas. It seems probable that vaccines may show degrees of partial effectiveness in relation to different strains, species, intensities of parasite inocula, and hosts.

Animals↗
PubMed1989

Application of exoantigens of Babesia and Plasmodium in vaccine development.

The University of Illinois malaria vaccine programme uses culture-derived soluble exoantigens of Plasmodium falciparum and the squirrel monkey as an experimental model. Exoantigens are soluble polypeptides naturally released into the blood plasma of animals infected with Babesia or Plasmodium species, or into the supernatant medium of in vitro cultures of these organisms. Immunization with soluble B. bovis and B. bigemina exoantigens prepared from culture supernatant fluids protected cattle against homologous and heterologous challenge. Similarly, vaccination of squirrel monkeys with supernatant fluids from P. falciparum cultures containing exoantigen induced protective immunity against acute clinical malaria. Susceptible monkeys have been vaccinated with an aluminium hydroxide-fortified antigenic fraction partially purified from supernatants of P. falciparum strains Indochina I and Genève/SGE-1; this conferred significant clinical protection against needle challenge with the homologous Indochina I strain, and a moderate degree of immunity to the heterologous strain. Following sequential purification by high performance liquid chromatography, the N-terminal amino acid sequences of P. falciparum 100 kDa, 83 kDa and 70 kDa exoantigens were determined. A 29 amino acid peptide constructed from the N-terminal sequence of the P. falciparum (Genève strain) 83 kDa exoantigen has been synthesized. When coupled to a carrier protein, the peptide was immunogenic in rabbits, mice and squirrel monkeys, inducing antibodies which were trophozoite-specific, reactive to native parasite proteins in a two-site enzyme immunoassay (EIA) and in Western blots, and which inhibited P. falciparum growth in vitro. Using this synthetic peptide, EIAs are being developed for the detection of antibodies to P. falciparum blood-phase parasites in individuals living in malaria-endemic areas of Africa, Asia and South America.

Animals↗
PubMed2004

Past and present vaccine development strategies for the control of foot-and-mouth disease.

Foot-and-mouth disease (FMD) virus (FMDV) was the first animal virus to be identified. Since then, it has become a model system in animal virology and more information has been obtained about FMDV. The disease causes heavy economic crises in enzootic countries both due to loss of animal health and productivity. The only way of its control in an enzootic area is strict vaccination and restricted animal movement. The first experimental vaccine against FMD was made in 1925 using formaldehyde inactivation of cattle tongue infected with the virus and this approach remained the basic one until late 1940s. Antigenic plurality and continuous co-circulation of different serotypes in a given geographical region and persistence of virus in infected or vaccinated animals make the disease very difficult to control. The latter is solely based upon the application of isolation, slaughter or aphtisation, and vaccination. With the advent of recombinant DNA technology, recombinant protein and/or DNA-based vaccines are being tested in various heterologous systems for development of FMD vaccines. The subunit vaccines, synthetic peptide vaccines, DNA vaccines, cytokine-enhanced DNA vaccines, recombinant empty capsid vaccines, chimeric viral vaccines, genetically engineered attenuated vaccines, recombinant viral vector vaccines, self-replicating genetic vaccines and transgenic plants with expressed FMDV proteins represent the present vaccine development strategies for control of FMD.

Animals↗
PubMed1992

Bacterial enteric infections and vaccine development.

There is a great need for effective vaccines against the major bacterial enteropathogens. Bacterial enteric infections resulting in diarrhea, dysentery, or enteric fever constitute a huge public health problem, with more than a billion episodes of disease and several million deaths annually in developing countries. Diarrhea caused by a bacterial enteric infection is also the commonest illness experienced by international travellers. Studies of pathogenesis have established the importance of specific ligand-receptor interactions between the enteropathogens and the intestinal epithelium, resulting in attachment and colonization of the bacteria and production of disease through either invasive mechanisms or production of toxins. Studies of protective immune mechanisms have emphasized the importance of secretory IgA antibodies and mucosal memory for protection against noninvasive, enterotoxigenic infections such as cholera and ETEC diarrhea and also drawn attention to the possible protective role of IFN-gamma production by intestinal T cells in these secretory diarrheas. In invasive dysenteric and enteric-fever infections caused by such organisms as Shigella and Salmonella, optimal protection may depend on a combination of mucosal and systemic immunity. On the basis of this knowledge, several new vaccines have been developed and proved to be efficacious in large field tests. These include an oral killed B-WC vaccine and a killed WC-alone vaccine against cholera, and both a live attenuated oral vaccine (Ty21a) and an injectable Vi antigen vaccine against typhoid fever. In addition, a killed oral ETEC vaccine and live attenuated oral Shigella vaccines have begun to be tested in phase 1 and phase 2 studies in humans. The properties of the new vaccines against bacterial enteric infections give promise that these vaccines should be useful both in control programs in developing countries and for immunoprophylaxis against travellers' diarrhea.

Bacteria↗
PubMed1999

Rabies vaccine. Developments employing molecular biology methods.

Rabies vaccines produced by means of molecular biology are described. Recombinant vaccines employing either viruses as vectors (vaccinia, adenovirus, poxvirus, baculovirus, plant viruses) or a plasmid vector carrying the rabies virus glycoprotein gene are discussed. Synthetic peptide technology directed to rabies vaccine production is also presented.

Adenoviridae↗
PubMed1992

Geographically restricted heterogeneity of the Plasmodium falciparum circumsporozoite protein: relevance for vaccine development.

The design of a subunit vaccine against the malaria parasite relies on the epitopes recognized by T cells being identified and polymorphisms therein being defined. Here we present the analysis of a 354-bp fragment of the circumsporozoite (CS) protein encompassing defined proliferative and cytotoxic T-cell recognition regions. We reveal that the polymorphism of CS protein T-cell sites appears to be very limited among Plasmodium falciparum isolates prevalent in certain geographical regions, in particular Papua New Guinea. Furthermore, the more extensive polymorphism noted in other areas appears to be restricted. Although the extent of variation observed for the T-cell recognition domains suggests that any vaccine designed to stimulate this form of immunity will need to be polyvalent, this variation appears to be finite and the combination of peptides necessary for inclusion in a polyvalent vaccine may be small. If ways to increase immune responsiveness can be found, then a vaccine designed to stimulate CS protein-specific T-cell activity may prevent malaria.

Amino Acid Sequence↗
PubMed2000

Suppression of endogenous IL-10 gene expression in dendritic cells enhances antigen presentation for specific Th1 induction: potential for cellular vaccine development.

A new paradigm for designing vaccines against certain microbial pathogens, including Chlamydia trachomatis, is based on the induction of local mucosal Th1 response. IL-10 is an anti-inflammatory cytokine that exerts negative immunoregulatory influence on Th1 response. This study investigated whether biochemical modulation of endogenous IL-10 expression at the level of APCs is a practical strategy for enhancing the specific Th1 response against pathogens controlled by Th1 immunity. The results revealed that the high resistance of genetically engineered IL-10-/- (IL-10KO) mice to genital chlamydial infection is a function of the predilection of their APCs to rapidly and preferentially activate a high Th1 response. Thus, in microbiological analysis, IL-10KO mice suffered a shorter duration of infection, less microbial burden, and limited ascending infection than immunocompetent wild-type mice. Also, IL-10KO were resistant to reinfection after 8 wk of the primary infection. Cellular and molecular immunologic evaluation indicated that IL-10KO mice induced greater frequency of chlamydial-specific Th1 response following C. trachomatis infection. Moreover, IL-10KO APCs or antisense IL-10 oligonucleotide-treated wild-type APCs were potent activators of Th1 response from naive or immune T cells. Furthermore, both Ag-pulsed dendritic cells from IL-10KO mice and IL-10 antisense-treated dendritic cells from wild-type mice were efficient cellular vaccines in adoptive immunotherapeutic vaccination against genital chlamydial infection. These findings may furnish a novel immunotherapeutic strategy for boosting the Th1 response against T cell-controlled pathogens and tumors, using IL-10-deficient APCs as vaccine delivery agents.

Adjuvants, Immunologic↗
PubMed2006

Building collaborative networks for HIV/AIDS vaccine development: the AVIP experience.

The need for an effective HIV/AIDS vaccine is imperative to halt a pandemic that involves more than 40 million individuals worldwide as of 2005 and is causing enormous socio-economic losses, especially in developing countries (DC). The overall failure of more than two decades of HIV vaccine research justifies the demands for a concerted effort for the rapid development of new and efficacious vaccines against HIV/AIDS. In this context, building international collaborative networks is a must for speeding up scientific research and optimizing the use of funding in a synergistic fashion, as resources for HIV/AIDS are limited and do not involve most of the biggest Pharmas that are more interested in drug discovery. The AIDS Vaccine Integrated Project (AVIP) consortium is an example of synergistic partnership of international European Union and DC experts with a common research goal. AVIP is a European Commission-funded (FP-6), consortium-based, 5-year program directed to the fast development of new HIV/AIDS vaccine candidates to be tested in phase I clinical trials in Europe for future advancement to phase II/III testing in DC. To ensure their rapid development, AVIP novel combined vaccines include both regulatory and structural HIV antigens, which have already been tested, as single components, in phase I clinical trials. In particular, such combination vaccines may be superior to earlier vaccine candidates, the vast majority of which are based only on either structural or regulatory HIV products. In fact, the generation of immune responses to both types of viral antigens expressed either early (regulatory products) or late (structural products) during the viral life cycle can maximize immune targeting of both primary or chronic viral infection. Further, the rational design of combined vaccines allows exploitation of immunomodulatory functions of HIV regulatory proteins, which can improve immunity against structural vaccine components. The building of the AVIP consortium and its scientific strategy will be reviewed in this paper as an example of the establishment of a consortium regulated by a specific intellectual property agreement.

AIDS Vaccines↗
PubMed2001

Tuberculosis subunit vaccine development: on the role of interferon-gamma.

Tuberculosis (TB) remains a major global health problem and subunit vaccines for the control of the disease are presently under development. This vaccine strategy requires an in vitro correlate of protection for the identification of relevant vaccine candidate antigens and for monitoring the induction of a protective cell-mediated immune response after vaccination. New studies of experimental vaccines in the mouse model of TB support interferon-gamma as a relevant marker for the induction of a protective immune response. In contrast, searching for immunodominant antigens capable of inducing strong interferon-gamma responses in PPD positive healthy or TB infected individuals may not identify all relevant candidate antigens for inclusion in a novel TB subunit vaccine.

Animals↗