TuberculosisVaccines

1. Primary Sources

10 journal articles are required

I have:

1. The original sequencing effort, published in Nature.

2. On the Sanger Inst. site, there is a link to the latest re-annotation.

3. The articles I've read for short critical essays

4. I just got kicked of Web of Science, but next time, go back to the articles that cited the re-annotation, and check those out.

2. Secondary Sources

I have:

1. two ethics articles

Useful websites:

The Sanger Institute http://www.sanger.ac.uk/Projects/M_tuberculosis/

TIGR (The Institute for Genomics Research) http://www.tigr.org/tigr-scripts/CMR2/GenomePage3.spl?database=gmt This is a public resource that allows users to view all of the completed bacterial genomes.

The WHO on M. tuberculosis vaccines: http://www.who.int/vaccine_research/diseases/tb/en/

WHO page with a document about TB vaccine research http://www.who.int/vaccine_research/about/gvrf_2004/session_6/en/

WHO page about BCD, the currently available TB vaccine http://www.who.int/vaccine_research/diseases/tb/vaccine_development/bcg/en/

3. Mega Info. from Science Direct

Bavesh D. Kana and Valerie Mizrahi, Molecular genetics of Mycobacterium tuberculosis in relation to the discovery of novel drugs and vaccines, Tuberculosis, Volume 84, Issues 1-2, 2004, Pages 63-75. (http://www.sciencedirect.com/science/article/B6WXK-49VC704-1/2/243ddd7136540c01558edfa1ba92fc4c) Abstract: Genetic systems that allow mycobacterial genomes to be mutagenized in a targeted or random fashion have provided the means for developing new tools for the diagnosis, prevention and treatment of tuberculosis by allowing potential targets to be identified and validated. In this review, we highlight key historical developments in the field of mycobacterial genetics, which have yielded the powerful repertoire of genetic tools that are now in hand and provide examples that illustrate their use in exploring specific aspects of mycobacterial metabolism.

Philip D. Butcher, Microarrays for Mycobacterium tuberculosis, Tuberculosis, Volume 84, Issues 3-4, 2004, Pages 131-137. (http://www.sciencedirect.com/science/article/B6WXK-4C7DD0F-1/2/a0861a97748b697448cf93a409a99d1a) Abstract: This special microarray issue of Tuberculosis recognises the important contributions of M. tuberculosis whole genome DNA microarrays to tuberculosis research by bringing together a range of papers that address M. tuberculosis physiology, host-pathogen interactions, mechanisms of drug action, in vitro and in vivo gene expression, host responses, comparative genomics and functional analysis of particular genes. A number of complete datasets of M. tuberculosis mRNA expression levels are provided to facilitate multiple cross-condition comparison. Microarrays represent one of the new functional genomics technologies exploiting genome sequence information that will bring us closer to realising the scientific and moral imperatives of better vaccines, diagnostics and new drugs for the control of tuberculosis throughout the world.

Celia W. Goulding, L. Jeanne Perry, Daniel Anderson, Michael R. Sawaya, Duilio Cascio, Marcin I. Apostol, Sum Chan, Angineh Parseghian, Shui-Shu Wang, Yim Wu et al., Structural genomics of Mycobacterium tuberculosis: a preliminary report of progress at UCLA, Biophysical Chemistry, Volume 105, Issues 2-3, September 2003, Pages 361-370. (http://www.sciencedirect.com/science/article/B6TFB-49HM411-T/2/552f618827012294a0c846cb362e254b) Abstract: The growing list of fully sequenced genomes, combined with innovations in the fields of structural biology and bioinformatics, provides a synergy for the discovery of new drug targets. With this background, the TB Structural Genomics Consortium has been formed. This international consortium is comprised of laboratories from 31 universities and institutes in 13 countries. The goal of the consortium is to determine the structures of over 400 potential drug targets from the genome of Mycobacterium tuberculosis and analyze their structures in the context of functional information. We summarize the efforts of the UCLA consortium members. Potential drug targets were selected using a variety of bioinformatics methods and screened for certain physical and species-specific properties to yield a starting group of protein targets for structure determination. Target determination methods include protein phylogenetic profiles and Rosetta Stone methods, and the use of related biochemical pathways to select genes linked to essential prokaryotic genes. Criteria imposed on target selection included potential protein solubility, protein or domain size, and targets that lack homologs in eukaryotic organisms. In addition, some protein targets were chosen that are specific to M. tuberculosis, such as PE and PPE domains. Thus far, the UCLA group has cloned 263 targets, expressed 171 proteins and purified 40 proteins, which are currently in crystallization trials. Our efforts have yielded 13 crystals and eight structures. Seven structures are summarized here. Four of the structures are secreted proteins: antigen 85B; MPT 63, which is one of the three major secreted proteins of M. tuberculosis; a thioredoxin derivative Rv2878c; and potentially secreted glutamate synthetase. We also report the structures of three proteins that are potentially essential to the survival of M. tuberculosis: a protein involved in the folate biosynthetic pathway (Rv3607c); a protein involved in the biosynthesis of vitamin B5 (Rv3602c); and a pyrophosphatase, Rv2697c. Our approach to the M. tuberculosis structural genomics project will yield information for drug design and vaccine production against tuberculosis. In addition, this study will provide further insights into the mechanisms of mycobacterial pathogenesis.

Steven G Reed and Antonio Campos-Neto, Vaccines for parasitic and bacterial diseases, Current Opinion in Immunology, Volume 15, Issue 4, August 2003, Pages 456-460. (http://www.sciencedirect.com/science/article/B6VS1-48R20R7-2/2/e6746482e289e0799d7e6864d921f2f3) Abstract: The first decade of the millennium should mark the beginning of a new era in vaccine development, reaping the rewards of advances in genome characterization, antigen identification, understanding the molecular bases of protective immune responses, and adjuvant design and development. Advances in all of these areas have culminated in vaccine candidates entering clinical testing. These include vaccines against two of humankind's oldest and deadliest diseases, tuberculosis and malaria. Several vaccine candidates for each of these diseases will be tested in humans during the next few years. A candidate vaccine for leishmaniasis, an infection that has taught us much about T-cell regulation of protection and disease in animal models, has been developed and is now in the clinic. There are indications both in animal models and in patients that vaccines may be used not only to protect but also to treat leishmania infections.

Alain Delcayre, John S. Peake, Damian J. White, Shining Yuan, Megan K. McDonald, Andrew Liang, Paul L. Tan and James D. Watson, A genome-based functional screening approach to vaccine development that combines in vitro assays and DNA immunization, Vaccine, Volume 21, Issue 23, 4 July 2003, Pages 3259-3264. (http://www.sciencedirect.com/science/article/B6TD4-4891NFH-4/2/2a2ccfffa958f8dff253541acb3cc49c) Abstract: A two-step screening strategy was developed to identify strong immunogenic polypeptides with putative vaccine and/or adjuvant activity. In the first step, a mycobacterial genomic DNA library was screened in vitro to identify plasmids encoding polypeptides that stimulate splenocytes from mycobacteria-immunized mice and T cells from PPD-positive healthy donors to produce interferon-[gamma]. In the second step, plasmids were selected for their ability to induce protective immunity in a mouse model of tuberculosis following DNA immunization. The potential of this approach is illustrated by the identification of a panel of immunogenic polypeptides that may be used to engineer a new generation of vaccines.

Bryce M. Buddle, John M. Pollock, Margot A. Skinner and D. Neil Wedlock, Development of vaccines to control bovine tuberculosis in cattle and relationship to vaccine development for other intracellular pathogens, International Journal for Parasitology, Volume 33, Issues 5-6, May 2003, Pages 555-566. (http://www.sciencedirect.com/science/article/B6T7F-488VS96-2/2/308cee228953064af15b49a3dd6c3ae1) Abstract: Vaccination of cattle against bovine tuberculosis could be an important strategy for the control of disease either where there is a wildlife reservoir of Mycobacterium bovis infection or in developing countries where it is not economically feasible to implement a 'test and slaughter' control program. Advances in the understanding of protective immune responses to M. bovis infection in cattle and the advent of new molecular biological techniques, coupled with the sequencing of the M. bovis genome have provided opportunities for the rational development of improved tuberculosis vaccines. A number of new tuberculosis vaccines including attenuated M. bovis strains, killed mycobacteria, protein and DNA vaccines are under development and many are being assessed in cattle. Recent results have revealed several promising vaccine candidates and vaccination strategies. Ways of distinguishing between vaccinated and infected cattle are becoming available and the possibility of new approaches to the eradication of tuberculosis from domestic livestock is discussed. Similarities between the mechanisms of protective immunity against M. bovis and against other intracellular parasites continue to be found and discoveries from vaccine studies on bovine tuberculosis may provide helpful insights into requirements for vaccines against other intracellular pathogens.

S. G. Reed, M. R. Alderson, W. Dalemans, Y. Lobet and Y. A. W. Skeiky, Prospects for a better vaccine against tuberculosis, Tuberculosis, Volume 83, Issues 1-3, February 2003, Pages 213-219. (http://www.sciencedirect.com/science/article/B6WXK-47YPMV5-5/2/c4e08f50613d4ae14ad9035ae560bbff) Abstract: There have been many new promising approaches to developing human vaccines against tuberculosis (TB). Advances in gene and antigen identification, availability of genome sequences, a greater understanding of immune mechanisms in resistance to TB, the development of adjuvants and delivery systems to stimulate T-cell immunity, and increased funding from public and private agencies are some of the reasons for progress in this area. Dozens of vaccine candidates have been tested in animal models in recent years, and several of these are poised to move into clinical trials in the next several years. Thus, there is renewed optimism for the potential of developing new and improved TB vaccines.

Guido Dietrich, Jean-Francois Viret and Jürgen Hess, Mycobacterium bovis BCG-based vaccines against tuberculosis: novel developments, Vaccine, Volume 21, Issues 7-8, 30 January 2003, Pages 667-670. (http://www.sciencedirect.com/science/article/B6TD4-473N324-C/2/bdbaa4412c5deeb218fdc22c85b20768) Abstract: Mycobacterium bovis Bacille Calmette-Guérin (BCG) is one of the most widely used vaccines. Modern techniques in genome manipulation allow the construction of recombinant (r)-BCG strains that can be employed as highly immunogenic vaccines against tuberculosis (TB) with an enhanced safety profile. In addition, the development of novel procedures to cultivate BCG will allow the large-scale production of future BCG-based vaccines.

Abu Salim Mustafa, Development of new vaccines and diagnostic reagents against tuberculosis, Molecular Immunology, Volume 39, Issues 1-2, 15 September 2002, Pages 113-119. (http://www.sciencedirect.com/science/article/B6T9R-45FYXHP-2/2/f936885bf6edfe543141f0603a3af252) Abstract: Tuberculosis (TB) is a major infectious disease problem with one-third of the world population infected, 8 million people developing the active disease and 2 million dying of TB each year. The attenuated Mycobacterium bovis Bacillus Calmette Guerin (BCG) is the only available vaccine against TB. However, the trials conducted in different parts of the world have shown that this vaccine doe not provide consistent protection against TB. The purified protein derivative (PPD) of Mycobacterium tuberculosis is the commonly used reagent for the diagnosis of TB. However, PPD lacks specificity because of the presence of antigens crossreactive with M. bovis BCG and other mycobacteria. The studies to identify M. tuberculosis antigens and epitopes as candidates for new protective vaccines and specific diagnostic reagents against TB have led to the identification and characterization of several major antigens of M. tuberculosis including heat shock proteins (hsp) and secreted antigens present in the culture filtrate (CF) of M. tuberculosis. Some of these antigens have shown promise as new candidate vaccines (hsp60, Ag85 and ESAT-6, etc.) and specific diagnostic reagents (ESAT-6 and CFP10, etc.) for TB. Moreover, in the mouse model of TB, vaccination with DNA-hsp60 has immunotheraputic effects and helps in eradication of persisters. In addition, identification of proper adjuvant and delivery systems has shown the promise to overcome the problem of poor immunogenicity associated with subunit and peptide based vaccines. More recently, the comparison of the genome sequence of M. tuberculosis with M. bovis BCG and other mycobacteria has led to the identification of M. tuberculosis-specific genomic regions. Evaluation of these regions for encoding proteins with immunological reactivity can lead to the identification of additional antigens of M. tuberculosis useful as new vaccines and reagents for specific diagnosis of TB.

Anne S. De Groot, Andrew Bosma, Natasha Chinai, Julie Frost, Bill M. Jesdale, Michael A. Gonzalez, William Martin and Caitlin Saint-Aubin, From genome to vaccine: in silico predictions, ex vivo verification, Vaccine, Volume 19, Issue 31, 14 August 2001, Pages 4385-4395. (http://www.sciencedirect.com/science/article/B6TD4-43MDJSB-9/2/0d339ef415f436ad1dd9fd5815c080a7) Abstract: Bioinformatics tools enable researchers to move rapidly from genome sequence to vaccine design. EpiMer and EpiMatrix are computer-driven pattern-matching algorithms that identify T cell epitopes. Conservatrix, BlastiMer, and Patent-Blast permit the analysis of protein sequences for highly conserved regions, for homology with other known proteins, and for homology with previously patented epitopes, respectively. Two applications of these tools to epitope-driven vaccine design are described in this review. Using Conservatrix and EpiMatrix, we analyzed more than 10000 HIV-1 sequences and identified peptides that were potentially immunostimulatory and highly conserved across HIV-1 clades. MHC binding assays and CTL assays have been carried out: 50 (69%) of the 72 candidate epitopes bound in assays with cell lines expressing the corresponding MHC molecule; 15 of the 24 B7 peptides (63%) stimulated gamma-interferon release in ELISpot assays. These results lend support to the bioinformatics approach to selecting novel, conserved, HIV-1 CTL epitopes. EpiMatrix was also applied to the entire 'proteome' derived from two Mycobacterium tuberculosis (Mtb) genomes. Using EpiMatrix, BlastiMer, and Patent-Blast, we narrowed the list of putative Mtb epitopes to be tested in vitro from 1600000 to 3000, a 99.8% reduction. The pace of vaccine design will accelerate when these and other bioinformatics tools are systematically applied to whole genomes and used in combination with in vitro methods for screening and confirming epitopes.

F. -X. Berthet, T. Coche and C. Vinals, Applied genome research in the field of human vaccines, Journal of Biotechnology, Volume 85, Issue 2, 13 February 2001, Pages 213-226. (http://www.sciencedirect.com/science/article/B6T3C-4280YYJ-8/2/07c2b770b4767a29ac9588cf787c88b7) Abstract: Prophylactic vaccination has made an essential contribution to the improvement of human health over the 20th century. However, we still lack efficient vaccines against major human diseases such as malaria or tuberculosis. Today, the design of therapeutic vaccines referred to as 'pharmaccines' is actively investigated in order to treat diseases such as cancer. In that context, novel ways to rationalize and accelerate vaccine discovery are needed. A series of advances in the fields of molecular biology and computer science, have greatly accelerated the rate at which candidate vaccine antigens can be discovered. In this review, we will present and discuss how applied genome research may facilitate antigen discovery and the design of new prophylactic and therapeutic vaccines.

Ian M. Orme and John T. Belisle, TB vaccine development: after the flood, Trends in Microbiology, Volume 7, Issue 10, 1 October 1999, Pages 394-395. (http://www.sciencedirect.com/science/article/B6TD0-3XH9GRK-7/2/9cbe7b5cb4f93ce427f6eb61ae98549a) Abstract:

Sara Abdulla, Tuberculosis: milking the genome for drug targets and vaccines, Molecular Medicine Today, Volume 4, Issue 3, March 1998, Pages 104-105. (http://www.sciencedirect.com/science/article/B6T9S-3SK91CN-9/2/82736bca960966120dded56ffbb44c95) Abstract:

got this by searching for "tuberculosis vaccine genome"