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PubMed2006

Proteomic analysis of Brucella abortus cell envelope and identification of immunogenic candidate proteins for vaccine development.

Brucella abortus is the etiologic agent of bovine brucellosis and causes a chronic disease in humans known as undulant fever. In livestock the disease is characterized by abortion and sterility. Live, attenuated vaccines such as S19 and RB51 have been used to control the spread of the disease in animals; however, they are considered unsafe for human use and they induce abortion in pregnant cattle. For the development of a safer and equally efficacious vaccine, immunoproteomics was utilized to identify novel candidate proteins from B. abortus cell envelope (CE). A total of 163 proteins were identified using 2-DE with MALDI-TOF MS and LC-MS/MS. Some of the major protein components include outer-membrane protein (OMP) 25, OMP31, Omp2b porin, and 60 kDa chaperonin GroEL. 2-DE Western blot analyses probed with antiserum from bovine and a human patient infected with Brucella identified several new immunogenic proteins such as fumarate reductase flavoprotein subunit, F0F1-type ATP synthase alpha subunit, and cysteine synthase A. The elucidation of the immunome of B. abortus CE identified a number of candidate proteins for developing vaccines against Brucella infection in bovine and humans.

Bacterial Proteins↗
PubMed2000

Heterogeneity of porcine reproductive and respiratory syndrome virus: implications for current vaccine efficacy and future vaccine development.

Porcine reproductive and respiratory syndrome virus (PRRSV) continues to be a major problem to the pork industry worldwide. Increasing data indicate that PRRSV strains differ in virulence in infected pigs and are biologically, antigenically, and genetically heterogeneous. It is evident that the current vaccines, based on a single PRRSV strain, are not effective in protecting against infections with the genetically diverse field strains of PRRSV. The recent outbreaks of atypical or acute PRRS in vaccinated pigs have raised a serious concern about the efficacy of the current vaccines and provided the impetus for developing more effective vaccines. Special attention in this review is given to published work on antigenic, pathogenic and genetic variations of PRRSV and its potential implications for vaccine efficacy and development. Although there are ample data documenting the heterogeneous nature of PRRSV strains, information regarding how the heterogeneity is generated and what clinical impact it may have is very scarce. The observed heterogeneity will likely pose a major obstacle for effective prevention and control of PRRS. There remains an urgent need for fundamental research on this virus to understand the basic biology and the mechanism of heterogeneity and pathogenesis of PRRSV.

Animals↗
PubMed1992

Mucosal immunity: implications for vaccine development.

The mucosal surfaces in e.g. the gastrointestinal, respiratory and urogenital tracts represent a very large exposure area to exogenous agents including microorganisms. Not surprising, therefore, those mucosal tissues are defended by a local immune system with properties and functions that in many respects are separate from the systemic immune system. The intestine is the largest immunological organ in the body. It comprises 70-80% of all immunoglobulin-producing cells and produces more secretory IgA (SIgA) (50-100 mg/kg body weight/day) than the total production of IgG in the body (ca. 30 mg/kg/day). The local immune system of the gut has two main functions: to protect against enteric infections, and to protect against uptake of and/or harmful immune response to undergraded food antigens. The best known entity providing specific immune protection for the gut is the SIgA system. The resistance of SIgA against normal intestinal proteases makes antibodies of this isotype uniquely well suited to protect the intestinal mucosal surface. The main protective function of SIgA antibodies is the "immune exclusion" of bacterial and viral pathogens, bacterial toxins and other potentially harmful molecules. SIgA has also been described to mediate antibody-dependent T cell-mediated cytotoxicity (ADCC), and to interfere with the utilization of necessary growth factors for bacterial pathogens in the intestinal environment, such as iron. It is now almost axiomatic that in order to be efficacious, vaccines against enteric infection must be able to stimulate the local gut mucosal immune system, and that this goal is usually better achieved by administering the vaccines by the oral route rather than parenterally. Based on the concept of a common mucosal immune system through which activated lymphocytes from the gut can disseminate immunity also to other mucosal and glandular tissues there is currently also much interest in the possibility to develop oral vaccines against e.g. infections in the respiratory and urogenital tracts. It has previously been widely assumed that only live vaccines would efficiently stimulate a gut mucosal immune response. However, an oral cholera vaccine, composed of the nontoxic B subunit of cholera toxin in combination with killed whole cell (WC) cholera vibrios has been shown to stimulate a strong intestinal SIgA antibody response associated with long-lasting protection against cholera. We have used this new cholera subunit vaccine and developed ELISPOT methods for examining at the clonal B and T cell level the dynamics of intestinal and extra-intestinal immune responses in humans after enteric immunizations.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1999

Lassa fever: implications of T-cell immunity for vaccine development.

Lassa fever is a re-emerging viral hemorrhagic fever, which causes significant human morbidity in endemic regions of West Africa. Attempts to vaccinate against this virus in animal models including non-human primates have revealed that eliciting a strong cellular immune response protects from clinical disease, but not infection, in the absence of measurable neutralizing antibodies. As there is renewed interest in developing a vaccine against Lassa fever for use in humans, several questions should be addressed in view of the scarce knowledge of the mechanisms of natural immunity against this disease. MHC-dependency of a vaccine relying mainly on the induction of T-cell immunity and its ability to cross-protect against different Lassa virus strains will be important issues. Furthermore, the question whether the vaccine can prevent human-to-human transmission of the virus should be discussed and the possibility that vaccination could predispose to immunopathology should be excluded. We are addressing some of the above mentioned problems concerning natural immunity through field studies in the Republic of Guinea, West Africa, and are presently studying the CD4 cell responses of Lassa antibody positive subjects on the basis of T-cell proliferation assays using recombinant Lassa virus proteins.

Animals↗
PubMed1998

Cancer vaccine development.

A new era involving the evaluation of recombinant cancer vaccines has begun with the concurrent emergence of insights and technologies in the fields of molecular biology and immunology. These advances include: The identification and cloning of an array of genes associated with the neoplastic process, such as oncogenes, suppressor genes, genes encoding oncofoetal antigens and tissue-lineage determinants. The development of a variety of viral and bacterial vectors to deliver and present gene products. The identification of numerous T-cell costimulatory molecules and an understanding of their mode of action. The cloning and analysis of the modes of action of an array of cytokines and other immunomodulatory molecules. More sophisticated knowledge of the mode(s) of antigen presentation and T-cell activation. One current challenge in cancer therapy is the delineation of strategies toward the rational design and implementation of recombinant vaccines that will be of therapeutic benefit to cancer patients and/or members of groups at high risk for specific neoplasias. Numerous concepts are emerging in this regard. The study of immunologic intervention using laboratory animal models demonstrates that no one approach will prevail for all cancer types or, perhaps, for the various stages of the neoplastic process of a given tumour type. The immunological role(s) of CD8+, CD4+, natural killer and other cell types, as well as the roles of antibodies, must all be taken into consideration. This article reviews some of the strategies currently undergoing evaluation toward the development of recombinant vaccines for several carcinoma types.

Journal Article↗
PubMed1996

Replacement, reduction or refinement of animal use in the quality control of veterinary vaccines: development, validation and implementation.

Various different methods have been developed to replace, reduce or refine the use of animals in batch quality control tests of veterinary vaccines. The development, validation and implementation of those alternatives which lead to a significant reduction in the numbers or the suffering of the animals used must receive priority. Validation is one of the hurdles to the implementation of alternative methods into relevant legislation, so it deserves special attention. For proper validation studies, co-operation between various organisations of both government and industry is necessary. International and national organisations such as ECVAM, FRAME, SIATT, ZEBET and the recently established Netherlands Centre Alternatives to Animal Use (NCA) could contribute significantly to the development, validation and implementation of alternative methods by simulating and co-ordinating research projects, by providing information through databases, and by co-ordinating validation studies.

Animal Testing Alternatives↗
PubMed2004

Advances in respiratory syncytial virus vaccine development.

Respiratory syncytial virus (RSV) is the most important causative agent of respiratory tract infections. Young children with chronic lung or congenital heart disease are at increased risk for severe disease. Intensive research into a candidate vaccine has yielded live attenuated vaccines and subunit vaccines, which have been studied in humans. Although immunogenic, occurrence of upper respiratory tract infection symptoms with live attenuated vaccine prohibits evaluation in young infants. Subunit vaccines include purified F protein (PFP-1 and -2) and BBG2Na. PFP vaccines are effective in seropositive children, but also induce upper respiratory symptoms. BBG2Na was being investigated in phase III clinical trials, however, further development has now been discontinued. This review discusses recent advances in RSV vaccine development.

Animals↗
PubMed1995

Caseous lymphadenitis vaccine development: site-specific inactivation of the Corynebacterium pseudotuberculosis phospholipase D gene.

Vaccines for ovine caseous lymphadenitis (CLA) are currently formulated using partially purified, formalin inactivated phospholipase D (PLD) derived from Corynebacterium pseudotuberculosis culture supernatants. Chemical treatment has been a common and effective way of inactivating bacterial toxins for use in toxoid vaccines. Genetic inactivation of toxin genes using site-specific mutagenesis has the potential to improve this process by providing a safer and more cost-effective product. In the present study amino acid substitutions at the putative catalytic site and metal binding domain of the PLD protein had a profound affect upon PLD activity and secretion from C. pseudotuberculosis. Two mutated PLD analogues that were secreted to a level of 40% compared to the wild-type and retained minimal activity showed promise for development as recombinant CLA vaccines. Further work will be required to establish their suitability for commercialization.

Animals↗
PubMed2006

Postgenomic approaches to cholera vaccine development.

Cholera remains an important public health threat. A cholera vaccine that provides durable protection at the mucosal surface, especially among children in endemic settings, is urgently needed. The availability of the complete genome sequence of a clinical isolate of Vibrio cholerae O1 El Tor has allowed for comparative and functional genomic approaches in the study of cholera. This work holds promise for the identification of bacterial targets of protective human immune responses and may contribute to the development of a new generation of cholera vaccines.

Animals↗
PubMed1999

Rotavirus vaccines: development and use for the prevention of diarrhoeal disease.

Rotavirus causes annually 600 000 deaths of young children worldwide, mainly in developing countries. The burden of rotavirus disease is significant also in developed countries and has not diminished with improved hygiene. Natural protective immunity against severe rotavirus disease is built up during the first 2-3 years of life. Likewise, studies with live attenuated oral rotavirus vaccines have shown that the majority of severe episodes of rotavirus diarrhoea are preventable by oral immunization. Candidate rotavirus vaccines were first developed by tissue culture adaptation and attenuation of bovine and rhesus rotaviruses, both of which share the inner core VP6 group antigen with human group A rotaviruses. Subsequently, such heterologous rotaviruses were improved for use as human vaccines by reassortment with human rotaviruses; the resulting reassortants express human rotavirus VP7 surface antigens. A rhesus-human reassortant tetravalent (RRV-TV) rotavirus vaccine was licensed in the USA in 1998, and is recommended for universal immunization of healthy children; licensure in Europe is also imminent. In Finland, this vaccine has prevented 90% of severe episodes of rotavirus gastroenteritis. Protective efficacy of RRV-TV vaccine in developing countries is lower and a more intensive immunization schedule may be needed. Several other candidate rotavirus vaccines, including bovine-human reassortants, are being investigated.

Animals↗
PubMed1999

A novel mammalian cell (Vero) derived influenza virus vaccine: development, characterization and industrial scale production.

Influenza virus for vaccine production are presently produced in embryonated chicken eggs. This conventional standard methodology is extremely cumbersome; it requires a huge amount of eggs and an extensive purification to reduce the amount of contaminating egg proteins and to minimize the risk of allergies against egg albumin. The shortage of eggs in a pandemic situation, the selection of egg-adapted variants and the presence of adventitious viruses has emphasized the necessity for production of influenza vaccines on a well characterized stable cell line. Our established Vero cell technology has been successfully adapted to large scale production of a variety of influenza virus strains. The production in 1200 litre fermenter cultures under serum-free conditions gave antigen yields comparable to the conventional embryonated egg technology. The development of a rapid and efficient purification scheme resulted in a safe high purity vaccine which was at least as immunogenic as conventional egg-derived vaccines in a mouse model. This vaccine has been shown to be safe and highly immunogenic in chimpanzees and to be capable of protecting ferrets against challenge with live virus. Clinical trials have now been initiated in the UK and Austria.

Animals↗
PubMed2003

Dengue 2 PDK-53 virus as a chimeric carrier for tetravalent dengue vaccine development.

Attenuation markers of the candidate dengue 2 (D2) PDK-53 vaccine virus are encoded by mutations that reside outside of the structural gene region of the genome. We engineered nine dengue virus chimeras containing the premembrane (prM) and envelope (E) genes of wild-type D1 16007, D3 16562, or D4 1036 virus within the genetic backgrounds of wild-type D2 16681 virus and the two genetic variants (PDK53-E and PDK53-V) of the D2 PDK-53 vaccine virus. Expression of the heterologous prM-E genes in the genetic backgrounds of the two D2 PDK-53 variants, but not that of wild-type D2 16681 virus, resulted in chimeric viruses that retained PDK-53 characteristic phenotypic markers of attenuation, including small plaque size and temperature sensitivity in LLC-MK(2) cells, limited replication in C6/36 cells, and lack of neurovirulence in newborn ICR mice. Chimeric D2/1, D2/3, and D2/4 viruses replicated efficiently in Vero cells and were immunogenic in AG129 mice. Chimeric D2/1 viruses protected adult AG129 mice against lethal D1 virus challenge. Two tetravalent virus formulations, comprised of either PDK53-E- or PDK53-V-vectored viruses, elicited neutralizing antibody titers in mice against all four dengue serotypes. These antibody titers were similar to the titers elicited by monovalent immunizations, suggesting that viral interference did not occur in recipients of the tetravalent formulations. The results of this study demonstrate that the unique attenuation loci of D2 PDK-53 virus make it an attractive vector for the development of live attenuated flavivirus vaccines.

Animals↗
PubMed2001

Are trials in New World monkeys on the critical path for blood-stage malaria vaccine development?

The development of malaria blood-stage vaccines is gathering momentum: there are several new funding initiatives, one multiantigen formulation is currently being tested and at least one other blood-stage vaccine is expected to begin trials in 2001. However, there is no consensus over the best way to select which form of an antigen to take into clinical testing. There is thus a danger that less-effective vaccines might be tested in the field in the order of their availability, rather than merit. Here, we argue that first proving efficacy in the New World monkey challenge model would accelerate development.

Animals↗
PubMed1993

The immune response to HIV: implications for vaccine development.

HIV infection is accompanied by a vigorous immune response to the virus consisting of humoral and cellular elements that effectively neutralize virus infectivity and lyse infected cells when analyzed in cell culture models. However, this immune response shows no evidence of being able to eliminate the infection. The inability to clear this infection places HIV in a category of viruses for which vaccines have yet to be successfully developed. Indeed, effective vaccines have emerged only for viruses where natural immunity is part of the pathogenic process; it is such immunity that became the guiding principle for the development of the respective vaccines. It follows that the unique features of HIV infection and pathogenesis are issues to consider carefully in formulating vaccine strategies, particularly those that relate to its susceptibility to immune attack on the one hand, and its mechanisms of immune escape on the other.

AIDS Vaccines↗
PubMed1995

From virus to vaccine: developments using the simple eukaryote, Dictyostelium discoideum.

Mass vaccination compaigns against viral diseases, both human and anim al, depend on the availability of cheap viral antigens. The eukaryote Dictyostelium discoideum has simple growth requirements and rapid growth rates and forms stable cell lines. These features, together with the possibility of secreting recombinant (glyco)proteins into a defined buffer, make the D. discoideum expression system an attractive option for producing economical recombinant subunit vaccines.

Animals↗
PubMed1987

Efficacy of murine malaria sporozoite vaccines: implications for human vaccine development.

As part of a study of potential vaccines against malaria, the protective efficacy of sporozoite subunit vaccines was determined by using the Plasmodium berghei murine malaria model. Mice were immunized with recombinant DNA-produced or synthetic peptide-carrier subunit vaccines derived from the repetitive epitopes of the Plasmodium berghei circumsporozoite gene, or with radiation-attenuated sporozoites. Immunization with subunit vaccines elicited humoral responses that were equivalent to or greater than those elicited by irradiated sporozoites, yet the protection against sporozoite challenge induced by either of the subunit vaccines was far less than that achieved by immunization with attenuated sporozoites. Passive and adoptive transfer studies demonstrated that subunit vaccines elicited predominantly antibody-mediated protection that was easily overcome whereas irradiated sporozoites induced potent cell-mediated immunity that protected against high challenge doses of sporozoites. These studies indicate that new strategies designed to induce cellular immunity will be required for efficacious sporozoite vaccines.

Animals↗