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PubMedDate not supplied

Immunopathology of RSV infection: prospects for developing vaccines without this complication.

Respiratory syncytial virus is the most important cause of lower respiratory tract infection in infants and young children. RSV clinical disease varies from rhinitis and otitis media to bronchiolitis and pneumonia. An increased incidence of asthma later in life has been associated with the more severe lower respiratory tract infections. Despite its importance as a pathogen, there is no licensed vaccine against RSV. This is due to a number of factors complicating the development of an effective and safe vaccine. The immunity to natural RSV infection is incomplete as re-infections occur in all age groups, which makes it challenging to design a protective vaccine. Second, the primary target population is the newborn infant, which has a relatively immature immune system and maternal antibodies that can interfere with vaccination. Finally, some vaccines have resulted in a predisposition for exacerbated pulmonary disease in infants, which was attributed to an imbalanced Th2-biased immune response, although the exact cause has not been elucidated. This makes it difficult to proceed with vaccine testing in infants. It is likely that an effective and safe vaccine needs to elicit a balanced immune response, including RSV-specific neutralising antibodies, CD8 T-cells, Th1/Th2 CD4 T-cells and preferably secretory IgA. Subunit vaccines formulated with appropriate adjuvants may be adequate for previously exposed individuals. However, intranasally delivered genetically engineered attenuated or vectored vaccines are currently most promising for newborns, as they are expected to induce a balanced immune response similar to that elicited to natural infection and not be subject to interference from maternal antibodies. Maternal vaccination may be the optimal strategy to protect the very young infants.

Adult↗
PubMed1989

Mutants of pertussis toxin suitable for vaccine development.

Immunization with chemically detoxified pertussis toxin can prevent severe whooping cough with an efficacy similar to that of the cellular pertussis vaccine, which normally gives unwanted side effects. To avoid the reversion to toxicity and the loss of immunogenicity that may follow chemical treatment of pertussis toxin, inactive toxins were constructed by genetic manipulation. A number of genetically engineered alleles of the pertussis toxin genes, constructed by replacing either one or two key amino acids within the enzymatically active S1 subunit, were introduced into the chromosome of strains of Bordetella pertussis, B. parapertussis, and B. bronchiseptica. These strains produce mutant pertussis toxin molecules that are nontoxic and immunogenic and that protect mice from the intracerebral challenge with virulent Bordetella pertussis. Such molecules are ideal for the development of new and safer vaccines against whooping cough.

Animals↗
PubMed1999

Potent and stable attenuation of live-HIV-1 by gain of a proteolysis-resistant inhibitor of NF-kappaB (IkappaB-alphaS32/36A) and the implications for vaccine development.

Live-attenuated human immunodeficiency viruses (HIVs) are candidates for Acquired Immunodeficiency Syndrome (AIDS) vaccine. Based on the simian immunodeficiency virus (SIV) model for AIDS, loss-of-function (e.g. deletion of accessory genes such as nef) has been forwarded as a primary approach for creating enfeebled, but replication-competent, HIV-1/SIV. Regrettably, recent evidence suggests that loss-of-function alone is not always sufficient to prevent the emergence of virulent mutants. New strategies that attenuate via mechanisms distinct from loss-of-function are needed for enhancing the safety phenotype of viral genome. Here, we propose gain-of-function to be used simultaneously with loss-of-function as a novel approach for attenuating HIV-1. We have constructed an HIV-1 genome carrying the cDNA of a proteolysis-resistant nuclear factor-kappaB inhibitor (IkappaB-alphaS32/36A) in the nef region. HIV-1 expressing IkappaB-alphaS32/36A down-regulates viral expression and is highly attenuated in both Jurkat and peripheral blood mononuclear cells. We provide formal proof that the phenotypic and attenuating characteristics of IkappaB-alphaS32/36A permit its stable maintenance in a live, replicating HIV-1 despite 180 days of forced ex vivo passaging in tissue culture. As compared with other open-reading frames embedded into HIV/SIV genome, this degree of stability is unprecedented. Thus, IkappaB-alphaS32/36A offers proof-of-principle that artifactually gained functions, when used to attenuate the replication of live HIV-1, can be stable. These findings illustrate gain-of-function as a feasible strategy for developing safer live-attenuated HIVs to be tested as candidates for AIDS vaccine.

AIDS Vaccines↗
PubMed1994

Malaria vaccine development.

The malaria parasite life cycle presents several targets for attack, but these different parts of the life cycle are susceptible to different types of host immune response. For example, the sporozoite is most sensitive to immune antibody, while liver stage parasites can be eliminated by cytotoxic T lymphocytes. Attachment of merozoites to erythrocytes, on the other hand, can be blocked by antibody. Convincing experimental evidence shows that completely protective immunity to malaria can be induced. The challenge now is to design recombinant or synthetic vaccines that induce the right types of immune responses to specific life cycle stages. This requires the identification and characterization of B- and T-lymphocyte epitopes expressed by the parasite or by parasitized host cells. These epitopes must be incorporated into a delivery system that maximizes the interaction between the vaccine epitopes and the host immune system. Many epitopes from several parts of the life cycle are already characterized; development of multivalent vaccines, that is, vaccines which contain immunogens from more than one part of the life cycle, is a promising area for research efforts.

Animals↗
PubMed1998

HIV vaccine development: a subtype E-specific strategy.

The pandemic of HIV/AIDS consists of multiple foci with distinct epidemiological characteristics. Among the approximately one million Southeast Asians infected with HIV, subtype (clade) E infections predominate. This subtype, a recombinant virus comprised of a clade A core (gag) gene and a mosaic clade A/clade E envelope (env) gene, became broadly epidemic in Thailand beginning in 1989. Since then, subtype E HIV has become increasingly prevalent throughout Southeast Asia. Consistent with the recent introduction of clade E HIV, the diversity of Southeast Asian subtype E viruses is narrow (6% nucleotide diversity across env). Since neutralizing antibodies may play a protective role against HIV infection, and are relatively clade specific for genotype E viruses, a subtype E-derived candidate vaccine tested in Southeast Asia would provide an optimal test of vaccine concept. It would also provide, for the first time to a developing region of the world, a non-B clade candidate vaccine designed specifically for the local epidemic. A consortium of industry (Chiron Vaccines and Pasteur Merieux Connaught), academic (Mahidol and Chiang Mai Universities) and military (United States and Royal Thai Army Medical Departments) medicine is working together to develop and test HIV vaccines for the genotype E epidemic. A genotype B recombinant glycoprotein (rgp)120 candidate vaccine has undergone phase I/II testing in Thailand and confirmed to be safe and immunogenic in this ethnic group. An rgp120 (E) has been produced and a phase I/II trial of the bivalent product (B/E) is in the final stages of approval. This vaccine construct is designed to elicit humoral immune responses. To augment these antibody responses with CD8+ CTL responses, an E-specific, live-vectored vaccine is being developed which will be used in conjunction with rgp120 in a second vaccine approach. Canarypox (ALVAC) constructs containing multiple HIV genes (gag/pol/env) currently designed for the subtype B epidemics will be modified to contain a clade E env gene sequence. After predetermined milestones have been met, these two subtype E-specific candidate vaccines will be assessed for protection in a large collaborative efficacy trial. Since neither animal models nor laboratory assays are validated as predictive of HIV vaccine efficacy, it must be through such a phase III trial that vaccine-induced protection and immunologic correlates will be determined.

AIDS Vaccines↗
PubMed2005

Developing vaccines to counter bioterrorist threats.

Large and innovative research programs are underway to define the immune parameters for vaccines against a wide array of pathogens considered to represent a potential bioterrorist threat. However, the development and utilization of such vaccines presents a number of predicaments that have not previously been addressed by the field of vaccinology.

Animals↗
PubMed1992

Round table on control of Aujeszky's disease and vaccine development based on molecular biology.

A summary is given on the 4 topics which were discussed during the round table and which represent current knowledge on the molecular biology of Aujeszky's disease (pseudorabies) virus. They include a review on 1. the genome and gene products of the virus; 2. the viral genes associated with virulence; 3. the immunological role of the viral gene products and 4. studies intended to compare the efficacy of several commercially available vaccines and to establish a possible correlation between antibodies against individual structural viral proteins and degree of protection. It was concluded that gI deleted vaccines appear to be the best choice for use in intensive vaccination programmes towards eradication of Aujeszky's disease virus. However, there remains a need for development of more potent vaccines which induce strong humoral and cell mediated immune responses and afford complete protection, virological protection included. It is often observed that live vaccine strains which are completely avirulent lose much capacity to replicate and spread within the vaccinated animal. It is, however, not excluded that a certain degree of dissemination may be needed to be fully efficacious. Loss of virulence may thus be accompanied by too much loss of immunogenicity. An improved genetic stability of live vaccine strains when they are obtained by genetic manipulation, possibly justifies a more widespread dissemination of the vaccine strain in the body compared to that with conventionally developed strains or compared to what is presently allowed.

Animals↗
PubMed2000

Vaccine development and diagnostics of Dictyocaulus viviparus.

Parasitic bronchitis is a serious disease of cattle and is caused by the nematode, Dictyocaulus viviparus. For over 30 years, a radiation-attenuated larval vaccine has been used for prevention of this disease. This vaccine has been used with considerable success in the UK and parts of Western Europe, however, it has several disadvantages. It has a short shelf-life and the vaccine has to be produced annually necessitating the use of donor calves. Following vaccination, calves must receive further boosting from natural challenge to maintain protective immunity. Sales of the irradiated larval vaccine have decreased dramatically since the 1970s. This is thought to be due to increased reliance of farmers on anthelmintic programmes to control lungworm infection. It is possible that, under certain circumstances, these programmes do not allow sufficient parasite exposure to stimulate protective immunity to further Dictyocaulus challenge. This is borne out by the recent documented increase in the number of outbreaks of parasitic bronchitis in the UK. A stable vaccine against D. viviparus that is capable of stimulating a more prolonged immunity would be beneficial. Recent research has been directed at identification and isolation of components thought to be involved in parasite survival in the host and examination of their potential as vaccine candidates. One of these components is acetylcholinesterase (AChE), an enzyme secreted by adult worms. This review describes the development of the secreted AChE as a vaccine candidate, as well as documenting recent developments in the immunodiagnosis of D. viviparus.

Animals↗
PubMed2002

Recent advances and novel strategies in vaccine development.

This review is intended to cover some recent advances in identification of vaccine candidates and in methods of delivery of vaccine antigens. Sequencing of bacterial genomes has led to rapid utilization of the predicted open reading frames to identify potential candidates for evaluation and, with improvements in proteomics combined with microanalytical sequencing techniques, to identify expressed proteins. Expression of vaccine antigens in human food sources has been greatly improved, opening the possibility of orally delivered subunit vaccines, as has the ability to modify the immune response with cytokines and chemokines. These techniques are slowly making their way to human studies and show great promise for future human use.

Antigens, Bacterial↗
PubMedDate not supplied

HIV pathogenesis and vaccine development.

Cautious optimism was a recurring theme of many of the AIDS vaccine-related presentations at the 13th annual Conference on Retroviruses and Opportunistic Infections. Several investigators suggested that the ability of HIV to escape cytotoxic T-lymphocyte responses may be more limited than previously thought, and encouraging results were presented regarding the ability of consensus ancestral sequences or polyvalent vaccines to increase the breadth of induced immune responses. A number of studies highlighted the potential efficacy of neutralizing antibodies: data from 2 groups suggested that neutralizing antibodies may play a role in preventing superinfection and previously unrecognized neutralizing epitopes were identified in the membrane proximal external region of envelope. Two studies documented that immunization with polyvalent simian immunodeficiency virus vaccines can induce sustained control of viremia following repeated low-dose mucosal challenge with pathogenic SIVmac strains and provided hope for the potential of T-cell-based vaccines to slow disease progression.

AIDS Vaccines↗
PubMed2004

Cancer vaccine development: on the way to break immune tolerance to malignant cells.

Exploiting a naturally occurring defense system, the immunotherapeutic approach embodies an ideal nontoxic treatment for cancer. Despite the evidence that immune effectors can play a significant role in controlling tumor growth either in natural conditions or in response to therapeutic manipulation, the cascade of molecular events leading to tumor rejection by the immune system remains to be fully elucidated. Nevertheless, some recent tumor immunology advancements might drastically change the way to design the next generation of cancer vaccines, hopefully improving the effectiveness of this therapeutic approach. In the present work, we will focus on three main areas of particular interest for the development of novel vaccination strategies: (a) cellular or molecular mechanisms of immune tolerance to malignant cells; (b) synergism between innate and adaptive immune response; (c) tumor-immune system interactions within the tumor microenvironment.

Animals↗
PubMed2003

HIV vaccine development: lessons from the past and promise for the future.

The global HIV epidemic continues to expand, exceeding previous predictions and causing tremendous suffering. An effective vaccine represents the best hope to curtail the HIV epidemic. The past fifteen years of HIV vaccine clinical trials have not identified an ideal HIV vaccine, but have provided many valuable lessons that contribute to the current generation of promising HIV vaccine regimens. An enhanced understanding of HIV and SIV immunopathogenesis has facilitated the design of vaccination regimens that elicit specific immune responses and effector mechanisms. Intensive investigation of recombinant gp120 subunit vaccines has revealed a previously unexpected complexity in eliciting neutralizing antibodies that are active against primary isolate viruses. The importance of CD8+ CTL responses in controlling HIV and SIV viremia has led to a series of vaccine candidates that effectively induce these responses. Proof that vaccination can prevent SIV/HIV disease has now been obtained in simian models of AIDS. A number of promising HIV vaccine regimens are currently being evaluated in human trials, and the pipeline of new vaccine vectors and combination regimens appears robust. Although challenges to the development of a safe and effective global HIV vaccine remain, the outlook for HIV vaccines in the future is bright.

AIDS Vaccines↗
PubMed2006

Poultry coccidiosis: recent advancements in control measures and vaccine development.

Coccidiosis is recognized as the major parasitic disease of poultry and is caused by the apicomplexan protozoan Eimeria. Coccidiosis seriously impairs the growth and feed utilization of infected animals resulting in loss of productivity. Conventional disease control strategies rely heavily on chemoprophylaxis and, to a certain extent, live vaccines. Combined, these factors inflict tremendous economic losses to the world poultry industry in excess of USD 3 billion annually. Increasing regulations and bans on the use of anticoccidial drugs coupled with the associated costs in developing new drugs and live vaccines increases the need for the development of novel approaches and alternative control strategies for coccidiosis. This paper aims to review the current progress in understanding the host immune response to Eimeria and discuss current and potential strategies being developed for coccidiosis control in poultry.

Animals↗
PubMed1999

The multivalent minigene approach to vaccine development.

Epitope based minigenes (epigenes) have been under investigation for several years as an experimental approach to vaccination against infectious diseases. The essence of this technology is that short DNA sequences, encoding well-defined cytotoxic T-lymphocyte- (CTL), antibody- (Ab) or helper T-lymphocyte- (HTL) specific epitopes are used as immunogens. Compared to other vaccine strategies, several potential advantages are apparent. These include the increased 'safety' of an immunisation strategy that mimics antigen processing and presentation during natural infections, without actually causing disease, and the 'flexibility' in epitope selection, which allows induction and optimisation of the desired type of immunity. In addition, the 'high immunogenicity' of epitope based constructs relative to constructs based on whole antigenic proteins is an important factor. This paper presents and discusses recent developments in the use of minigenes or multiple epitope genes that allow vaccines to be designed. The preclinical studies available to date clearly demonstrate the great potential of this vaccine approach, in terms of both prophylaxis and therapy.

Journal Article↗
PubMed2006

New strategies for immune-mediated anti-viral drug and vaccine development.

Substantial progress in the development of new anti-viral drugs has taken place in recent years. Most of these new drugs belong to three groups of compounds, nucleoside analogs, thymidine kinase-dependent nucleotide analogs and specific viral enzyme inhibitors. Although these drugs revolutionized the treatment of several viral diseases, the involvement of the immune system is crucial for complete recovery and prevention of re-infection. New advances in the understanding of immune regulation mechanisms, mainly the role of cytokines, led to the development of several new immunologically-based anti-viral drugs and treatments. The most studied group of immunomodulators is the cytokines, some of which were shown to act as potent stimulators of immune responses. Other, non-cytokine immune modulators have also been successfully employed in both humans and experimental animals as anti-viral drugs of which several are currently in clinical trials. Advances in genetic engineering and transgenic mouse technologies facilitated the production of humanized as well as authentic human anti-viral monoclonal antibodies. Some of these antibodies proved to be clinically efficacious and are commercially produced as anti-viral drugs. As is often the case in anti-viral treatments, a combination of conventional and an immune-mediated anti-viral drugs or a combination therapy involving immunomodulators, therapeutic vaccines, immune intervention and even gene therapy might prove most efficacious as a treatment for a particular virus. Most of the advances made in anti-viral treatments have also been applied to the development of new vaccines. Some of the classical attenuated viruses are being replaced by recombinant attenuated viruses. Recombinant viral vaccines containing genes encoding other viral antigens and/or cytokines are being tested as new vaccines. Several chimeric viral vaccines have proven efficacious in experimental animals and are now in different phases of clinical trials. This review will encompass the major new developments in this field, including some that have not yet been subjected to human trials.

Adjuvants, Immunologic↗