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PubMed2004

Shigella flexneri infection: pathogenesis and vaccine development.

Shigella flexneri is a gram-negative bacterium which causes the most communicable of bacterial dysenteries, shigellosis. Shigellosis causes 1.1 million deaths and over 164 million cases each year, with the majority of cases occurring in the children of developing nations. The pathogenesis of S. flexneri is based on the bacteria's ability to invade and replicate within the colonic epithelium, which results in severe inflammation and epithelial destruction. The molecular mechanisms used by S. flexneri to cross the epithelial barrier, evade the host's immune response and enter epithelial cells have been studied extensively in both in vitro and in vivo models. Consequently, numerous virulence factors essential to bacterial invasion, intercellular spread and the induction of inflammation have been identified in S. flexneri. The inflammation produced by the host has been implicated in both the destruction of the colonic epithelium and in controlling and containing the Shigella infection. The host's humoral response to S. flexneri also appears to be important in protecting the host, whilst the role of the cellular immune response remains unclear. The host's immune response to shigellosis is serotype-specific and protective against reinfection by the same serotype, making vaccination a possibility. Since the 1940s vaccines for S. flexneri have been developed with little success, however, the growing understanding of S. flexneri's pathogenesis and the host's immune response is assisting in the generation of more refined vaccine strategies. Current research encompasses a variety of vaccine types, which despite disparity in their efficacy and safety in humans represent promising progress in S. flexneri vaccine development.

Bacterial Vaccines↗
PubMed2002

HIV vaccine development.

Optimism prevails that a safe and at least partially effective HIV vaccine will be identified within this decade. Public, philanthropic and private sector efforts to expand the development pipeline and to indude candidates based on diverse HIV subtypes have proved successful. Yet both scientific and logistical obstacles remain. No vaccine candidate yet induces broadly neutralizing antibodies. The type, level, location and durability of immune responses necessary for protection remain unknown. For those vaccines that may not prevent HIV infection but control replication and prevent disease, the issue of transmissibility must be addressed. Other challenges indude improving infrastructure and research capabilities and establishing or strengthening regulatory agencies in developing countries. Another key issue is ensuring access to successful vaccines, which will require large-scale manufacturing and development of policies and processes to distribute vaccine to those most in need.

AIDS Vaccines↗
PubMed1996

Chimeric rhinoviruses as tools for vaccine development and characterization of protein epitopes.

Chimeric human rhinoviruses (HRVs) have the potential to serve as vaccines against a wide variety of diseases. Such vaccines can be developed optimally by generating libraries of chimeric HRVs displaying immunogens from dangerous pathogens or tumor cells in many different conformations. Extremely large numbers of conformationally defined presentations of foreign epitopes can be produced efficiently by flanking transplanted epitopes with linkers, or adapters, of small segments of randomized amino acids. In addition, the individual residues of the immunogenic sequences can be encoded in proportion to their prevalence in databases, generating composite immunogens that function as mimotopes. The diversity of sequences and conformations improves the likelihood of generating immunologically valuable vaccine candidates. Chimeric viruses thus generated can be propagated and purified to select for viruses whose growth and physical stability are like those of wild-type HRV. Viruses containing a foreign epitope in antigenically relevant conformations can then be captured by immunoselection with neutralizing antibodies directed against the foreign pathogen. Using this approach, we have been able to generate HRV chimeras that present V3 loop sequences of the human immunodeficiency virus type 1 (HIV-1) in immunologically relevant conformations. Antisera directed against such chimeras can neutralize multiple strains of HIV-1 in cell culture, suggesting that the HRV14:HIV-1 chimeras may be presenting their V3 loop sequences in manners that mimic those of multiple strains of HIV. Immunologically interesting chimeras can be examined using X-ray crystallography to yield detailed information about the structures of chimeras with immunogenic epitopes. This information may lead to a greater understanding of key functional and structural elements of immunogenicity. The chimeric HRV system allows one to present virtually any protein epitope or mimitope thereof, identify viruses with immunological characteristics that mimic those of the foreign pathogen, and examine the structures of these immunogenic sequences at the atomic level.

Epitopes↗
PubMed2001

Tick-Encoded serine proteinase inhibitors (serpins); potential target antigens for tick vaccine development.

Immunological protection of hosts against tick infestation is at present the most practically sustainable alternative tick control method to the current use of acaricides that is riddled with serious limitations. The current focus of tick vaccine research is the identification, cloning and in vitro production of recombinant tick vaccine candidate antigens. We have examined a selected number of reports on the roles of parasite-encoded members of the serine proteinase inhibitor (serpin) superfamily in modulation of mammalian anti-parasite defense and developed some food for thought commentaries on the possibility of targeting this class of proteins for anti-tick vaccine development.

Animals↗
PubMed1998

Meningococcal vaccine development: a novel approach.

Neisseria meningitidis is a major world-wide cause of meningitis. Effective capsular polysaccharide (CPS) vaccines that elicit CPS-specific bactericidal (BC) antibodies were previously developed and licensed to protect against meningococcal disease. However, due to their T-cell independent character, CPS vaccines are useless in infants and do not provide immunological memory or long-lasting protection in adults. CPS-protein conjugate vaccines are being developed to improve and broaden vaccine efficacy by creating T-cell dependent antigens. However, group B meningococci (GBM) are responsible for nearly half of meningococcal disease and possess a CPS, composed of polysialic acid, that is poorly immunogenic. N-propionyl (NPr) modification of the GBM polysaccharide (GBMP) has enhanced its immunogenicity, but BC antibodies are not induced at high levels, even when conjugated to conventional protein carriers, unless adjuvants stronger than aluminium hydroxide are used. We have chosen to couple the NPr-GBMP by reductive amination to a recombinant GBM class 3 porin (rPorB), which we have shown to modulate the immune response in animals towards the production of CPS-specific BC antibodies. We have also combined this conjugate with similar CPS-rPorB conjugates for groups A and C meningococci to form a trivalent A/B/C conjugate vaccine. This trivalent meningococcal vaccine has been shown to be safe and highly immunogenic in mice and non human primates, generating CPS-specific BC antibodies for each of the 3 major serogroups, which should provide world-wide protection against meningococcal disease.

Journal Article↗
PubMed2002

Vaccine Development for the Prevention of Urinary Tract Infections.

The effectiveness of antibiotic prophylaxis for recurrent urinary tract infections is being compromised as increasing numbers of uropathogens develop resistance to conventional antibiotics. Because one alternative to antibiotic therapy is immunization of susceptible patients to increase innate resistance, several different vaccines are currently being developed. Four of the vaccines contain a mixture of whole bacteria or an antigenic extract and are administered as a vaginal suppository or oral tablet. A parenteral route is being used in clinical trials of the Escherichia coli type 1 fimbrial adhesin and its chaperone protein. The safety of both the mucosal and parenteral vaccines has been demonstrated in phase 1 clinical trials. Phase 2 trials have shown the efficacy of a vaginal mucosal vaccine containing whole bacteria and an oral vaccine prepared from bacterial lysates. Further clinical trials will allow comparisons of the various vaccines and evaluation of their effectiveness relative to prophylactic antibiotic therapy.

Journal Article↗
PubMed1996

Evaluation of hepatitis C virus protein epitopes for vaccine development.

Infection with hepatitis C virus (HCV) leads to viral persistence and chronic disease in a very high proportion of cases, despite a broad immunological response to viral proteins. These responses may thwarted by the high rate of mutation, which leads to the generation of 'escape' variants of HCV that persist as a quasi-species in infected individuals. The specificity of the immuno response of infected patients suggests that responses directed at certain viral epitopes may be associated with less aggressive disease and, possibly, good interferon response and virus clearance. The identification of such epitopes may hold the key for future development both of prophylactic and therapeutic vaccines.

Animals↗
PubMed2006

Tuberculosis subunit vaccine development: impact of physicochemical properties of mycobacterial test antigens.

Tuberculosis caused by Mycobacterium tuberculosis continues to be one of the major public health problems in the world. The eventual control of this disease will require the development of a safe and effective vaccine. One of the approaches receiving a great deal of attention recently is subunit vaccination. An efficacious antituberculous subunit vaccine requires the identification and isolation of key components of the pathogen that are capable of inducing a protective immune response. Clues to identify promising subunit vaccine candidates may be found in their physicochemical and immunobiological properties. In this article, we review the evidence that the physicochemical properties of mycobacterial components can greatly impact the induction of either protective or deleterious immune response and consequently influence the potential utility as an antituberculous subunit vaccine.

Animals↗
PubMed2001

Plasmodium vivax malaria vaccine development.

Plasmodium vivax represents the most widespread malaria parasite worldwide. Although it does not result in as high a mortality rate as P. falciparum, it inflicts debilitating morbidity and consequent economic impact in endemic communities. In addition, the relapsing behavior of this malaria parasite and the recent resistance to anti-malarials contribute to making its control more difficult. Although the biology of P. vivax is different from that of P. falciparum and the human immune response to this parasite species has been rather poorly studied, significant progress is being made to develop a P. vivax-specific vaccine based on the information and experience gained in the search for a P. falciparum vaccine. We have devoted great effort to antigenically characterize the P. vivax CS protein and to test its immunogenicity using the Aotus monkey model. Together with other groups we are also assessing the immunogenicity and protective efficacy of the asexual blood stage vaccine candidates MSP-1 and DBP in the monkey model, as well as the immunogenicity of Pvs25 and Pvs28 ookinete surface proteins. The transmission-blocking efficacy of the responses induced by these latter antigens is being assessed using Anopheles albimanus mosquitoes. The current status of these vaccine candidates and other antigens currently being studied is described.

Animals↗
PubMed1996

The varicella vaccine. Vaccine development.

In this article, rationales and method of development of attenuated live varicella (Oka) vaccine are described, with biologic and biophysical characteristics of the vaccine virus. The results of early clinical trials in Japan are also described, along with the results of detection of viremia in vaccinees and a follow-up of incidence of zoster in acute leukemic children, which indicate possible immunopathogenesis of varicella and zoster.

Chickenpox↗