Crucell Terug naar discussie overzicht

draadje tuberculose

1. [verwijderd] 24 maart 2006 00:45

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   Reuters bericht mbt tot areas nieuws. Positief is dat Crucell's vaccin als eerste genoemd wordt.
   
   NTERVIEW-Foundation opens TB vaccine plant, no product yet
   23 Mar 2006 16:29:53 GMT
   
   By Maggie Fox, Health and Science Correspondent
   
   WASHINGTON, March 23 (Reuters) - Years ahead of having a new product, a foundation set up to develop a tuberculosis vaccine opened its first factory on Thursday.
   
   The Aeras Global TB Vaccine Foundation cut the tape on a research and production facility in Rockville, Maryland, that Chief Executive Officer Dr. Jerald Sadoff predicts will be able to produce 150 million doses of vaccine a year -- perhaps eventually 300 million a year.
   
   Sadoff is not disturbed that there actually is no modern tuberculosis vaccine yet.
   
   "We are going to be using it for making replacement BCG for the world," said Sadoff, a former Merck and Co. <MRK.N> vaccine executive, describing the Bacille Calmette-Guerin vaccine which has "been around for 80 years."
   
   "It sort of works but it doesn't really work very well," Sadoff said in an interview.
   
   "One of the things we think we can do is replace this very old vaccine with a modern vaccine using some modern technology."
   
   The World Health Organization estimates that 2 billion people, one-third of everybody alive, are infected with tuberculosis. Of these, about 8 million become ill every year and 1.75 million die.
   
   TB is the biggest killer of people with HIV, causing about 13 percent of AIDS deaths. The HIV pandemic has caused a resurgence in TB, which thrives in people with weak immune systems.
   
   BEST HOPE FOR CONTROL
   
   Intensive use of antibiotic cocktails for weeks on end can cure TB, but experts say a vaccine has better hope of controlling the bacterial-caused disease.
   
   "Vaccination with BCG still remains the standard for TB prevention in most countries because of its efficacy in preventing life-threatening forms of TB in infants and young children, and also because it is the only vaccine available, is inexpensive, and requires only one encounter with the baby," WHO says in a statement on its Web site, www.who.int.
   
   While a new TB vaccine is still 7 to 10 years away, the nonprofit Aeras wants to hit the ground running with an $80 million grant from the Bill and Melinda Gates Foundation.
   
   It also has projects going with Dutch biotechnology company Crucell NV <CRCL.AS> <CRXL.O>, Denmark's Statens Serum Institut, the University of Cape Town in South Africa, GlaxoSmithKline <GSK.L> <GSK.N> and others.
   
   "In private industry you really have to start building your factory early so there is no gap between time regulatory agencies allow you to sell it and the time you go to market," Sadoff said.
   
   "You need to be able to do your clinical trials with a final product. So we can have all that ready."
   
   Aeras has been running human, clinical trials since 2004 with rBCG30, a jazzed-up version of the original BCG vaccine.
   
   The BCG vaccine used a weakened version of M. bovis, the cattle version of Mycobacterium tuberculosis, which causes most cases of human TB.
   
   For its interim vaccine, Aeras genetically engineered the BCG bacteria to secrete large amounts of a protein of M. tuberculosis.
   
   QUICKEST DELIVERY
   
   "With more than 4,700 people dying every day from TB, the world needs an effective TB vaccine as soon as possible," Sadoff said. "This new facility can deliver a TB vaccine to the world as soon as one is available."
   
   Aeras is working on newer technology using Shigella, a bacteria that causes diarrhea. The new vaccine weakens Shigella so it does not cause illness, but instead delivers a tiny nanoparticle containing genetic material from M. tuberculosis. Like BCG, it would be an oral vaccine, Sadoff said.
   
   A vaccine plant on U.S. soil, like the Aeras facility, is a rare thing. Corporate vaccine makers have been fleeing the U.S. market, citing difficult regulations, fear of lawsuits and low profits. Nearly all U.S. vaccines are made in factories in other countries.
   
   Sadoff said the plant could be adapted to make other types of vaccines if needed.
   
   "We are confident this technology can be applied to just about any important vaccine -- such as malaria, HIV and flu and biodefense ones," he said.
   
   He is not afraid of competition.
   
   "For TB there just is not a market, let's face it," Sadoff said.
   
   "Even though it is the world's most widely used vaccine, the market is small compared to a new HPV virus (a vaccine against cervical cancer) or rotavirus (a vaccine against a common cause of fatal childhood diarrhea) or pneumococcal conjugate vaccine."
   
   Such vaccines can earn tens of millions of dollars for their makers.
2. [verwijderd] 24 maart 2006 19:28

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   Aeras vaccine could wipe out TB
   
   Rockville nonprofit hopes to provide world supply in next seven years
   
   Friday, March 24, 2006
   
   by Steve Berberich
   Staff Writer
   
   The key to limiting the world’s tuberculosis epidemic may lie in a new $10 million vaccine-manufacturing plant in Rockville .
   On Thursday, the eve of World TB Day 2006, the nonprofit Aeras Global TB Vaccine Foundation dedicated the facility, which CEO Jerald C. Sadoff hopes will produce the world’s supply of an improved TB vaccine in the next seven years.
   
   Although a minor disease in the United States and other developed nations, TB kills 1.75 million people a year and infects one-third of the world’s population, according to the World Health Organization.
   
   ‘‘More than 4,700 people die every day from TB, and the world needs an effective vaccine as soon as possible,” said Sadoff, a former vaccine researcher and manager at Merck Pharmaceuticals. ‘‘Waiting even one day would be unconscionable.”
   
   About 125 guests were on hand for the dedication, including Gov. Robert L. Ehrlich Jr. (R), Rep. Christopher Van Hollen Jr. (D-Dist. 8) of Kensington, leading vaccine scientists from the National Institutes of Health, Johns Hopkins Medical Center and Walter Reed Medical Center, and diplomatic officials from Uganda, Kenya, Zambia, Namibia, South Africa, Norway, England and Denmark.
   
   Aeras is focusing on only one disease, with the goal of providing the first effective TB vaccine since 1925.
   
   ‘‘Anyone connected with the public sector in Maryland has a smile on his face today,” Ehrlich said. ‘‘The facts on TB are staggering, are disquieting. And now you [Aeras] are a symbol of hope for millions of people around the world every day.”
   
   ‘‘It is great to be in a building where there is a goal of wiping out TB in our lifetime,” Van Hollen said.
   
   The foundation is supported by grants from the Bill & Melinda Gates Foundation, the Centers for Disease Control and Prevention, and the Danish government.
   
   The 20,000-square-foot facility is specially designed for producing TB vaccine, Sadoff said. He said the foundation has four versions of a TB vaccine and that all four will be in phase 1 clinical trials this year. The goal, he said is to be in phase 3 by 2009.
   
   ‘‘The science is available — we know how to do it — but the money is not all there yet,” Sadoff said. He said Aeras plans to be fully funded for the next decade through private support.
   
   Sadoff said the current TB vaccine is only 30 percent effective, at best, and is typically administered just once.
   
   ‘‘A vaccine like this should be given three or four times for boosters. Our vaccines will be at the 50 to 70 percent efficacy level,” he said.
   
   Aeras currently has more than 60 employees. In 2003, it raised $80 million, according to a foundation attorney.
   
   When in full production, the facility will be capable of producing 10 million doses per run. The vaccine will be shipped to needy areas in the developing world frozen in 5-liter packages. Aeras employees will be on-site to help ‘‘validate the vialing” of the vaccine as it arrives overseas, said laboratory technicians.
3. [verwijderd] 5 april 2006 08:38

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   Tuberculosis vaccines: past, present and future.
   Curr Opin Pulm Med. 2006 May;12(3):186-91.
   Martin C.
   
   PURPOSE OF REVIEW: The current vaccine against tuberculosis protects against severe forms of the disease in children but confers variable effectiveness against pulmonary disease. With tuberculosis eradication on the horizon new vaccines with better protection than Mycobacterium bovis bacillus Calmette-Guerin (BCG) are needed. This review will outline the most promising tuberculosis vaccine candidates from selected publications. RECENT FINDINGS: The enormous effort of the scientific community in the last 10 years has generated hundreds of tuberculosis vaccine candidates. These include sub-unit vaccines and live vaccines such as recombinant BCG and other attenuated live vaccines. Some of these are being included for the first time in phase I clinical trials. SUMMARY: For more than 80 years now no new tuberculosis vaccine has successfully been developed. There is now renewed optimism that vaccines superior to BCG can be developed in the coming years. The goal is to obtain a new generation of vaccines effective against more transmissible forms of tuberculosis. As a first step, good candidate vaccines able to boost BCG and improve BCG protection could be a reality in the near future. Tuberculosis vaccine candidates, able to replace the currently used BCG and make the eradication of tuberculosis feasible, can be expected in the mid-term, and live vaccines are reliable and promising candidates.
   
   Introduction
   Mycobacterium tuberculosis is one of the most successful pathogens, such that still, in some areas of the world, tuberculosis (TB) has reached alarming proportions with a growing number of cases and deaths linked to HIV [1]. The appearance of cases of multi-drug resistant tuberculosis, sometimes causing outbreaks, is a serious public health problem for any attempt to control this disease [2].
   
   The current vaccine against tuberculosis, M. bovis bacillus Calmette–Guérin (BCG), has been applied since the early 1920s and is the only vaccine available for prevention of TB in humans. BCG is an attenuated live vaccine that was obtained after 230 successive passages in the laboratory between 1908 and 1921, from a pathogenic strain of M. bovis. BCG confers a strong immune response, as much humoral as cellular, that is used for the treatment of bladder cancer. Recent studies demonstrated that a single dose in childhood maintains immunization for up to 50–60 years after vaccination [3]. Genomic studies demonstrated that BCG contains different deletion regions of its genome with the loss of more than 100 genes [4]. Since 1921, when BCG was used for the first time, different laboratories of the world have continued to sub-culture BCG, giving rise to the appearance of different variants such as BCG Pasteur, BCG Moscow or BCG Brazil. These variants contain different deletions that could be implicated in the degree of protection provided [5]. Since 1961 the World Health Organization (WHO) has recommended lyophilization of BCG vaccines stocks and storage at -80°C [5].
   
   Protection studies of BCG have showed a variable effectiveness against pulmonary TB that ranges from no protection in studies in India to 70% protection in the studies of the UK Medical Research Council. This lack of protection against pulmonary TB has enormous importance from the point of view of public health as regards eradication of TB [6]. It has been hypothesized that this failure of the BCG vaccine in southern countries could be due to previous exposure to environmental mycobacteria [7]. In parallel it has been clearly demonstrated that BCG protects against serious cases of childhood TB, including meningitis and disseminated TB, and this is why BCG continues to be recommended in the vaccination calendar of the WHO in countries with a high TB incidence. Even if BCG has been demonstrated to be extremely useful and at the moment is the most utilized vaccine in the world [8], the development of new vaccines against pulmonary tuberculosis, able to replace the current vaccine BCG, is an important challenge [9••]. Since the only reservoir of M. tuberculosis is humans, the development of more effective vaccines than BCG could make TB eradication possible.

   Bijlage:
4. [verwijderd] 7 april 2006 13:05

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   BCG vaccine cost-effective in TB control: study Thu Apr 6, 7:11 PM ET
   
   LONDON (Reuters) - The BCG vaccine against childhood tuberculosis is cost-effective and should be used in countries with a high incidence of the disease, researchers said on Friday.
   
   There has been debate in the medical and scientific community about the widespread use of BCG and its role in countries which do not have high infection rates.
   
   But an analysis of the impact and cost of the vaccine in different regions of the world showed it is particularly effectively in southeast Asia, Africa and the western Pacific region.
   
   "BCG vaccination is a highly cost-effective intervention against severe childhood tuberculosis; it should be retained in high-incidence countries," said Christopher Dye, of the World Health Organization (WHO), in a report in The Lancet medical journal.
   
   The bacille Calmette-Guerin (BCG), which was developed in the 1930s, reduces the risk and severity of TB in infants and young children. It is one of the world's most widely used vaccines.
   
   The scientists calculated the number of cases of the illness that have been and will be prevented in children born in 2002 by using annual estimates of risk, the number of children vaccinated, proportion of cases in unvaccinated children and BCG efficacy.
   
   They estimated that 100 million doses of the vaccine given to children born each year would prevent 40,000 cases of severe TB during their first five years of life.
   
   The WHO recommends that BCG should be given at birth or shortly after. In 2002, the vaccine was administered in 157 countries and territories.
   
   In some countries which do not have a high incidence of tuberculosis the vaccine is not used at all or is given only to school-age children or high risk groups.
   
   "Our results lend support to the continued use of BCG in countries where tuberculosis incidence remains well above the threshold set by the International Union Against Tuberculosis and Lung Disease," Dye said, adding they are typically low and middle-income countries.
   news.yahoo.com/s/nm/20060406/hl_nm/
   tuberculosis_dc;_ylt=AkF3V.Adwq68ql2pziaRdLAQ.3QA;_ylu=X3oDMTA5aHJvMDdwBHNlYwN5bmNhdA--
5. [verwijderd] 7 april 2006 13:10

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   The Lancet 2006; 367:1173-1180
   
   DOI:10.1016/S0140-6736(06)68507-3
   
   Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness
   B Bourdin Trunz b, PEM Fine b and C Dye a
   
   Summary
   Background
   BCG vaccine has shown consistently high efficacy against childhood tuberculous meningitis and miliary tuberculosis, but variable efficacy against adult pulmonary tuberculosis and other mycobacterial diseases. We assess and compare the costs and effects of BCG as an intervention against severe childhood tuberculosis in different regions of the world.
   
   Methods
   We calculated the number of tuberculous meningitis and miliary tuberculosis cases that have been and will be prevented in all children born in 2002, by combining estimates of the annual risk of tuberculosis infection, the proportion of infections that lead to either of these diseases in unvaccinated children, the number of children vaccinated, and BCG efficacy.
   
   Findings
   We estimated that the 100·5 million BCG vaccinations given to infants in 2002 will have prevented 29 729 cases of tuberculous meningitis (5th–95th centiles, 24 063–36 192) in children during their first 5 years of life, or one case for every 3435 vaccinations (2771–4177), and 11 486 cases of miliary tuberculosis (7304–16 280), or one case for every 9314 vaccinations (6172–13 729). The numbers of cases prevented would be highest in South East Asia (46%), sub-Saharan Africa (27%), the western Pacific region (15%), and where the risk of tuberculosis infection and vaccine coverage are also highest. At US$2–3 per dose, BCG vaccination costs US$206 (150–272) per year of healthy life gained.
   
   Interpretation
   BCG vaccination is a highly cost-effective intervention against severe childhood tuberculosis; it should be retained in high-incidence countries as a strategy to supplement the chemotherapy of active tuberculosis.
   
   Affiliations
   
   a. HIV/AIDS, Tuberculosis and Malaria, World Health Organization, CH-1211 Geneva 27, Switzerland
   b. Infectious Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine, London, UK
   
   Correspondence to: Dr C Dye
   www.thelancet.com/journals/lancet/art...
6. [verwijderd] 7 april 2006 15:33

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   draadje of geen draadje ik verkocht 8 dagen geleden RDS na 3 maanden van verlies en kocht het steeds maar stijgende Crusell. U wet dus wat U te wachten staat
7. [verwijderd] 17 april 2006 12:51

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   TB-draad even up ivm link uit de posting van Japie.
   ***************
   
   Japies - 16 apr 06, 23:20
   
   www.aegis.com/conferences/croi/2005/A...
   
   www.aeras.org/news/documents/Thalerle...
   
   Hebben de biotechneuten onder ons hier toevoegingen op?
   Waar zou Goudsmit dit gepresenteerd hebben, 31 pagina's aan slides????
   
   Japie
   ****************************
   www.iex.nl/forum/topic.asp?forum=228&...
   www.iex.nl/forum/topic.asp?forum=228&...
8. [verwijderd] 17 april 2006 13:09

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   Bravo jongens,
   
   Sorry, natuurlijk ook bravo meisjes.
   Nu Babs er nog even bovenop krijgen. Komaan aub, nie flauw doen.
   
   Doei,
   
   K.
   
   
9. [verwijderd] 22 mei 2006 13:23

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   Een interessant overzicht over TBC vaccins in
   Nat Rev Microbiol. 2006 Jun;4(6):469-476.
   
   Crucells onderzoek wordt ook aangehaald. zie onder.
   
   Advances in tuberculosis vaccine strategies.
   
   Skeiky YA, Sadoff JC.
   
   Yasir A. W. Skeiky and Jerald C. Sadoff are at the Aeras Global TB Vaccine Foundation, 1405 Research Blvd, Rockville, Maryland 20850, USA. yskeiky@aeras.org jsadoff@aeras.org.
   
   Tuberculosis (TB), an ancient human scourge, is a growing health problem in the developing world. Approximately two million deaths each year are caused by TB, which is the leading cause of death in HIV-infected individuals. Clearly, an improved TB vaccine is desperately needed. Heterologous prime-boost regimens probably represent the best hope for an improved vaccine regimen to prevent TB. This first generation of new vaccines might also complement drug treatment regimens and be effective against reactivation of TB from the latent state, which would significantly enhance their usefulness.
   
   Adenoviral vectors are potent vaccine-delivery vehicles. A recent study showed that vaccination of mice by the intranasal mucosal route with a recombinant adenoviral (Ad5 based) construct expressing the M. tuberculosis antigen Ag85A (AdAg85A) conferred protection (mediated by both CD4+ and CD8+ T cells) that was superior to that seen with BCG vaccination against a pulmonary M. tuberculosis challenge98. Aeras, in collaboration with Crucell, has constructed non-replicating Ad35 vectors that are less prevalent in the environment than Ad5 (Refs 99 and 100), and that express several M. tuberculosis proteins including Ag85A, Ag85B and TB10.4 (Refs 27,100). Vaccination of mice with a single dose of the rAd35–TB construct conferred protection against M. tuberculosis challenge107. BCG prime followed by a booster with a single dose of these adenovirus recombinant vaccines in mice have yielded significantly increased antigen-specific CD4+ and CD8+ T-cell responses compared with adenovectored TB vaccines or BCG administered alone. Aeras has constructed rBCG vaccines with over 50% escape from the endosome that overexpress these same antigens to function as a prime for this adenovector boost27 (R. Sun et al., unpublished observations).
   
   
10. [verwijderd] 26 mei 2006 09:33

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    New TB Drugs Urgently Needed to Replace Treatment from the 1960s
    Second Gates Grant to TB Alliance Quadruples Initial Support
    
    New York, NY (May 25, 2006) — The Global Alliance for TB Drug Development (TB Alliance) announced today that it is receiving $104 million from the Bill & Melinda Gates Foundation to advance a pipeline of new TB drugs over the next five years in the global pursuit to find a faster and more effective cure for tuberculosis.
    
    Since its formation in 2000, the non-profit TB Alliance has built the largest pipeline in history of potential new drugs for the treatment and cure of tuberculosis, a disease that kills someone every fifteen seconds.
    
    "Tuberculosis is one of the world's oldest infectious agents and has always posed challenges for the scientific community. But now, we have the technology and the know-how to find a faster, simpler cure," said Peter Small, M.D., Senior Program Officer at the Gates Foundation. "New treatments could free patients from a grueling six-month regimen and, ultimately, save millions of lives."
    
    The four standard drugs used to treat tuberculosis are more than 40 years old and take at least six months to work effectively. When the long treatment is not completed or drug supply is interrupted, multi-drug resistant forms of TB can emerge. In addition, TB is a leading killer of people living with HIV/AIDS, but current TB treatment cannot easily be combined with the anti-retrovirals used to treat HIV.
    
    "We are very grateful for this support that quadruples the initial funding the Gates Foundation provided to the TB Alliance and allows us to build on the enormous progress we have made toward shortening TB treatment," said Maria C. Freire, Ph.D., CEO and President, TB Alliance. "A package of powerful new drugs will mean we can treat more people better — including those co-infected with HIV and those suffering multi-drug resistant forms of the disease. It will be an historic milestone, and one we can achieve."
    
    Despite several regional successes in TB control, the best standard of care, called Directly Observed Treatment Short-course (DOTS), reaches less than half of the most infectious cases of TB.
    
    New Grant to Help Advance Promising Drugs
    In just five years, the TB Alliance has built a pipeline of 11 new drug candidates. The most advanced drug candidate, moxifloxacin, is in Phase II trials and based on preclinical findings, could help shorten TB treatment duration by at least one-third. Through a unique partnership with Bayer HealthCare AG, the TB Alliance is testing this broad-spectrum antibiotic for its effectiveness in treating TB, with a commitment from Bayer to price the drug affordably in developing countries where patients need it most.
    
    The Gates Foundation grant will allow the TB Alliance to:
    
    Advance moxifloxacin into Phase III trials, with the goal of demonstrating its effectiveness for TB by 2010;
    Pursue nine pre-clinical projects and identify the best of these compounds for clinical studies;
    Work with policymakers, TB treatment providers and advocates to ensure that new TB drugs will be adopted and made accessible in developing countries;
    Analyze drug market conditions and compliance issues to ensure the rapid adoption of a new drug regimen once it is shown to be effective.
    The grant will also support the TB Alliance as it evaluates a way to streamline the clinical trial process by testing new drugs in combinations earlier in the development process. This innovative approach could significantly shorten the time required to develop a new regimen of TB drugs.
    
    Today, it takes an average of 130 doses to cure TB. The long-term goal of the TB Alliance is to develop a new regimen that replaces all four current drugs and could be effective in as few as 10 doses. Public health experts agree that a faster-acting TB cure would improve compliance, lower relapse rates, and reduce health care costs by limiting the time required to monitor patients. Health care costs could be reduced by 65 percent and free health workers to identify and diagnose more cases.
    
    Call for Matching Funds from Governments
    "It's a global disease and it requires a global response. Leaders meeting at the G-8 in July have an historic opportunity to fill the funding gap and ensure that we achieve one of the great global health victories of our generation," said Dr. Freire, CEO and President, TB Alliance.
    
    The TB Alliance estimates it will need $100 million, in addition to the grant announced today, in order to advance the existing pipeline of 11 drugs. Since its inception, the TB Alliance has received funding commitments totaling more than $170 million, including $15.5 million from the Rockefeller Foundation, and a combined total of $26.6 million from the governments of Great Britain, the United States, the Netherlands, and Ireland.
    www.tballiance.org/gates.asp
12. [verwijderd] 26 mei 2006 09:43

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    Tjonge, flosz, ik ben blij dat jij of liever U met een dikke hoofdletter hier nog op dit forum aanwezing bent. Altijd goede en up to date info, ik zou bijna voorstellen om elke dag een flosz draadje te openen. Dat scheelt vele actieve beleggers/lezers per dag een uur troep doorspitten. Daar is het forum natuurlijk ook voor bedoeld (bagger spuien) maar de echte reden voor de vele hits van de CRXL link blijft de goede info van o.a. biocon, flosz, biostef.) Keep up the good work! Dikke aanbeveling. groet cowvet.
13. [verwijderd] 30 mei 2006 08:05

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    MULTIVALENT VACCINES COMPRISING RECOMBINANT VIRAL VECTORS
    
    Bibliografische gegevens Beschrijving Conclusies Mozaïekweergave Origineel document INPADOC statusgegevens
    
    Octrooinummer: WO2006053871
    Publicatiedatum: 2006-05-26
    Uitvinder: HAVENGA MENZO JANS EMCO (NL); VOGELS RONALD (NL); SADOFF JERALD (US); HONE DAVID (US); SKEIKY YASIR ABDUL WAHID (US); RADOSEVIC KATARINA (NL)
    Aanvrager: CRUCELL HOLLAND BV (NL); AERAS GLOBAL TB VACCINE FOUNDA (US); HAVENGA MENZO JANS EMCO (NL); VOGELS RONALD (NL); SADOFF JERALD (US); HONE DAVID (US); SKEIKY YASIR ABDUL WAHID (US); RADOSEVIC KATARINA (NL)
    Classificatie:
    - internationaal: C12N15/861; A61K39/04; C12N15/63; C12N15/85; A61K39/04; C12N15/63; C12N15/85; C12N15/861;
    - europees:
    Aanvraagnummer: WO2005EP55984 20051115
    Prioriteitsnummer(s): US20040628253P 20041116; EP20040106074 20041125; US20050651113P 20050208
    
    Samenvatting van WO2006053871
    
    The invention relates to vaccines comprising recombinant vectors, such as recombinant adenoviruses. The vectors comprise heterologous nucleic acids encoding for at least two antigens from one or more tuberculosis-causing bacilli. The invention also relates to the use of specific protease recognition sites linking antigens through which the encoded antigens are separated upon cleavage. After cleavage, the antigens contribute to the immune response in a separate manner. The recombinant vectors may comprise a nucleic acid encoding the protease cleaving the linkers and separating the antigens. The invention furthermore relates to the use of genetic adjuvants encoded by the recombinant vectors, wherein such genetic adjuvants may also be cleaved through the presence of the cleavable linkers and the specific protease.
    
    Informatie afkomstig uit database esp@cenet - Worldwide
    
    v3.espacenet.com/textdoc?DB=EPODOC&ID...
14. [verwijderd] 30 mei 2006 09:11

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    Contact: Anna-Lynn Wegener
    wegener@embl.de
    49-622-138-7452
    European Molecular Biology Laboratory
    
    New potential drug target in tuberculosis
    Scientists reveal structure of a key tuberculosis protein
    
    Tuberculosis remains one of the deadliest threats to public health. Every year two million people die of the disease, which is caused by the microorganism Mycobacterium tuberculosis. Roughly one third of the world's population is infected and more and more bacterial strains have developed resistance to drugs. Researchers from the Hamburg Outstation of the European Molecular Biology Laboratory (EMBL) and the Max Planck Institute for Infection Biology (MPIIB) in Berlin have now obtained a structural image of a protein that the bacterium needs for survival in human cells. This image reveals features of the molecule that could be targeted by new antibiotic drugs. The results appear in this week's online issue of the Proceedings of the National Academy of Sciences (PNAS).
    M. tuberculosis is dangerous because it hides and persists in the immune cells of our bodies. "It can only persist there because of the activity of key molecules," says Matthias Wilmanns, Head of EMBL Hamburg. "We are investigating the functions of tuberculosis proteins and determining their atomic structures, in hopes of finding weak points and new inhibitors."
    
    A protein called LipB is essential for the organism because it activates cellular machines that drive the bacterium's metabolism. Stefan Kaufmann's department at the MPIIB has specialised in the biology of M. tuberculosis infection and its ability to survive in immune cells. They discovered that LipB is highly active in acutely infected cells, particularly in patients infected by multidrug-resistant forms of M. tuberculosis.
    
    "In these cells we see a 70-fold increase in the production of LipB when compared to other cells," says Stefan Kaufmann, Director at the MPIIB. "This strongly indicates an involvement in pathogenesis and makes it a particularly interesting target where traditional drugs have lost their efficacy."
    
    A structural picture of the protein - a kind of technical diagram of its building plan - has yielded important clues about its activity. Qingjun Ma from Wilmanns' group purified LipB and obtained crystals of the molecule. Using the high-energy synchrotron radiation beamlines at EMBL Hamburg, on the campus of the German Electron Synchrotron Radiation Facility (DESY), he created an atom-by-atom map of the protein's structure. A high-resolution picture of the active site of LipB bound to a lipid inhibitor helped to determine the function of the enzyme. In collaboration with EMBL's Proteomics Core Facility in Heidelberg and researchers from the University of Illinois (USA), the Hamburg group discovered how LipB attaches specific fatty acids onto other proteins.
    
    "LipB is a very promising drug target," Wilmanns says, "because it belongs to a vital pathway. Unlike other organisms M. tuberculosis has no backup mechanism that could take over LipB's role. This means that an inhibitor blocking its active site would shut down key processes the bacterium needs to survive and replicate. This would be a very effective strategy for a drug."
    
    The scientists will now search for compounds that can do so. At the same time, they are continuing to look for other proteins as drug targets. Wilmanns and his colleagues from various other institutes are now focusing on structures of molecules that help M. tuberculosis to persist in its dormant state and could become drug targets.
    
    ###
    Over the past three years, EMBL has coordinated an "M. tuberculosis structural proteomics" consortium, supported by the German Ministry of Education and Research (BMBF), and produced high resolution images of more than 30 proteins. "Structure-based drug discovery has been a big success in the battle against many other diseases. We are now applying these tools to tuberculosis, one of the most devastating infectious diseases of mankind," Wilmanns concludes.
    (Via www.eurekalert.org )
15. [verwijderd] 19 juli 2006 22:42

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    Global Incidence of Multidrug-Resistant Tuberculosis
    
    Matteo Zignol, Mehran S. Hosseini, Abigail Wright, Catharina Lambregts–van Weezenbeek, Paul Nunn, Catherine J. Watt, Brian G. Williams, and Christopher Dye
    Stop TB Department, World Health Organization, Geneva, Switzerland
    
    
    
    Background. The global number of incident cases of multidrug-resistant (MDR) tuberculosis (TB) in 2000 was estimated to be 272,906 (95% confidence interval [CI], 184,948–414,295). For accurate planning of TB control programs, this estimate and others have been revised using data from additional countries and by including in the model previously treated TB cases, which had not been accounted for in the previous analysis.
    Methods. Multiple logistic regression was used to identify variables that were predictive of MDR-TB frequency among new and previously treated cases surveyed in 90 and 77 countries, respectively. These variables were then used to estimate MDR-TB frequencies in countries that had not been surveyed.
    Results. The total number of MDR-TB cases estimated to have occurred worldwide in 2004 is 424,203 (95% CI, 376,019–620,061), or 4.3% (95% CI, 3.8%–6.1%) of all new and previously treated TB cases. In the same year, 181,408 (95% CI, 135,276–319,017) MDR-TB cases were estimated to have occurred among previously treated TB cases alone. Three countries—China, India, and the Russian Federation—accounted for 261,362 (95% CI, 180,779–414,749) MDR-TB cases, or 62% of the estimated global burden.
    Conclusions. These updated sets of estimates incorporating previously treated TB cases call for an urgent plan to expand appropriate diagnostic and treatment services for patients with MDR-TB in low-resource settings.
    
    
    www.journals.uchicago.edu/JID/journal...
16. [verwijderd] 19 juli 2006 23:12

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    quote:

    Biocon schreef:

    Een interessant overzicht over TBC vaccins in
    Nat Rev Microbiol. 2006 Jun;4(6):469-476.
    
    Crucells onderzoek wordt ook aangehaald. zie onder.
    
    Advances in tuberculosis vaccine strategies.
    
    Skeiky YA, Sadoff JC.
    
    Yasir A. W. Skeiky and Jerald C. Sadoff are at the Aeras Global TB Vaccine Foundation, 1405 Research Blvd, Rockville, Maryland 20850, USA. yskeiky@aeras.org jsadoff@aeras.org.
    
    Tuberculosis (TB), an ancient human scourge, is a growing health problem in the developing world. Approximately two million deaths each year are caused by TB, which is the leading cause of death in HIV-infected individuals. Clearly, an improved TB vaccine is desperately needed. Heterologous prime-boost regimens probably represent the best hope for an improved vaccine regimen to prevent TB. This first generation of new vaccines might also complement drug treatment regimens and be effective against reactivation of TB from the latent state, which would significantly enhance their usefulness.
    
    Adenoviral vectors are potent vaccine-delivery vehicles. A recent study showed that vaccination of mice by the intranasal mucosal route with a recombinant adenoviral (Ad5 based) construct expressing the M. tuberculosis antigen Ag85A (AdAg85A) conferred protection (mediated by both CD4+ and CD8+ T cells) that was superior to that seen with BCG vaccination against a pulmonary M. tuberculosis challenge98. Aeras, in collaboration with Crucell, has constructed non-replicating Ad35 vectors that are less prevalent in the environment than Ad5 (Refs 99 and 100), and that express several M. tuberculosis proteins including Ag85A, Ag85B and TB10.4 (Refs 27,100). Vaccination of mice with a single dose of the rAd35–TB construct conferred protection against M. tuberculosis challenge107. BCG prime followed by a booster with a single dose of these adenovirus recombinant vaccines in mice have yielded significantly increased antigen-specific CD4+ and CD8+ T-cell responses compared with adenovectored TB vaccines or BCG administered alone. Aeras has constructed rBCG vaccines with over 50% escape from the endosome that overexpress these same antigens to function as a prime for this adenovector boost27 (R. Sun et al., unpublished observations).
    

    Postings go erbij:
    www.iex.nl/forum/topic.asp?forum=228&...
    **************************
    Online full text is only available to paid Institutional Subscribers.
    This item requires an Institutional subscription to Journal of General Virology Online.
    
    vir.sgmjournals.org/cgi/content/abstr...
    
    Toegang?
    
    Novel replication-incompetent adenoviral B-group vectors: high vector stability and yield in PER.C6 cells
    M. Havenga1, R. Vogels1, D. Zuijdgeest1, K. Radosevic1, S. Mueller2, M. Sieuwerts1, F. Weichold2, I. Damen1, J. Kaspers1, A. Lemckert1, M. van Meerendonk1, R. van der Vlugt1, L. Holterman1, D. Hone2, Y. Skeiky2, R. Mintardjo1, G. Gillissen1, D. Barouch3, J. Sadoff2 and J. Goudsmit1
    1 Crucell Holland BV, PO Box 2048, 2301 CA Leiden, The Netherlands
    2 AERAS Global TB Vaccine Foundation, 7500 Old Georgetown Road, Bethesda, MD 20814, USA
    3 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
    Correspondence
    M. Havenga
    m.havenga@crucell.com
    Adenoviral vectors based on adenovirus type 35 (rAd35) have the advantage of low natural vector immunity and induce strong, insert-specific T- and B-cell responses, making them prime-candidate vaccine carriers. However, severe vector-genome instability of E1-deleted rAd35 vectors was observed, hampering universal use. The instability of E1-deleted rAd35 vector proved to be caused by low pIX expression induced by removal of the pIX promoter, which was located in the E1B region of B-group viruses. Reinsertion of a minimal pIX promoter resulted in stable vectors able to harbour large DNA inserts (>5 kb). In addition, it is shown that replacement of the E4-Orf6 region of Ad35 by the E4-Orf6 region of Ad5 resulted in successful propagation of an E1-deleted rAd35 vector on existing E1-complementing cell lines, such as PER.C6 cells. The ability to produce these carriers on PER.C6 contributes significantly to the scale of manufacturing of rAd35-based vaccines. Next, a stable rAd35 vaccine was generated carrying Mycobacterium tuberculosis antigens Ag85A, Ag85B and TB10.4. The antigens were fused directly, resulting in expression of a single polyprotein. This vaccine induced dose-dependent CD4+ and CD8+ T-cell responses against multiple antigens in mice. It is concluded that the described improvements to the rAd35 vector contribute significantly to the further development of rAd35 carriers for mass-vaccination programmes for diseases such as tuberculosis, AIDS and malaria.
    Published online ahead of print on 2 May 2006 as DOI 10.1099/vir.0.81956-0.
    
17. [verwijderd] 26 juli 2006 15:31

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    The Lancet Infectious Diseases 2006; 6:483-495
    DOI:10.1016/S1473-3099(06)70549-7
    Towards universal access to HIV prevention, treatment, care, and support: the role of tuberculosis/HIV collaboration
    Alasdair Reid MD a, Fabio Scano MD a, Haileyesus Getahun MD a, Brian Williams PhD a, Christopher Dye DPhil a, Paul Nunn FRCP a, Kevin M De Cock MD b, Catherine Hankins FRCP c, Bess Miller MD d, Kenneth G Castro MD d and Dr Mario C Raviglione MD
    Summary
    Tuberculosis is the oldest of the world's current pandemics and causes 8·9 million new cases and 1·7 million deaths annually. The disease is among the most common causes of morbidity and mortality in people living with HIV. However, tuberculosis is more than just part of the global HIV problem; well-resourced tuberculosis programmes are an important part of the solution to scaling-up towards universal access to comprehensive HIV prevention, diagnosis, care, and support. This article reviews the impact of the interactions between tuberculosis and HIV in resource-limited settings; outlines the recommended programmatic and clinical responses to the dual epidemics, highlighting the role of tuberculosis/HIV collaboration in increasing access to prevention, diagnostic, and treatment services; and reviews progress in the global response to the epidemic of HIV-related tuberculosis.
    Affiliations
    
    a. Stop TB Department, WHO, Geneva, Switzerland
    b. HIV Department, WHO, Geneva
    c. UNAIDS, Geneva
    d. Centers for Disease Control and Prevention, Atlanta, GA, USA
    
    download.thelancet.com/pdfs/journals/...
18. [verwijderd] 26 juli 2006 21:46

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    26/07/2006 - Omnia Biologics has sealed a deal to help the Aeras Global TB Vaccine Foundation in its quest to make quantities of a new TB Vaccine that will “fulfil all the needs of the developing world.”
    
    Omnia is a biologics contract manufacturer offering services in the areas of process development, GMP manufacture and fill-finish for preclinical and Phase I clinical programs for therapeutics that do not have effective or known manufacturing protocols.
    Under the new deal, the firm will provide Aeras with vaccine process and production services in the development of a “promising new tuberculosis (TB) vaccine technology based on a validated platform,” said the firm.
    No other details were disclosed.
    Aeras is a non-profit organisation founded to help develop new vaccines to control and eliminate the global TB epidemic.
    Two billion people - one third of the world's population - have been infected with TB and it is the world's second deadliest infectious disease – killing two million people each year, primarily in the developing world.
    Aeras aims to develop at least one new TB vaccine within the next decade and in anticipation of success, has recently opened a new $10m (€7.9bn) laboratory and manufacturing facility, which it claims will be able to manufacture, in bulk, all of the developing world's needs for a new TB Vaccine.
    “Using advanced manufacturing technology and capable of producing 150m vaccine doses per year, the facility ensures rapid scale up of the production of new vaccines,” said the organisation.
    Aeras's vaccine-development programme, which began in 2004, is being funded by a five-year, $82.9m grant from the Bill and Melinda Gates Foundation.
    In 2004 Aeras also received a three-year, $2.7m grant from the US Centers for Disease Control and Prevention and in 2005 Danida, the Danish Government's development agency, also invested $785,000.
    www.in-pharmatechnologist.com/news/ng...
19. [verwijderd] 27 juli 2006 09:04

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    Een spannend en geheimzinnig bericht.
    Waarvoor dank flosz.
    Crucell inside???
    
20. [verwijderd] 27 juli 2006 09:40

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    quote:

    wpw schreef:

    Een spannend en geheimzinnig bericht.
    Waarvoor dank flosz.
    Crucell inside???
    

    Inderdaad zeer interessant....en daarom aanbevolen.
    Tal van verhulde verwijzingen naar Crucell naar mijn mening.
    
    Overigens, klik op "TB vaccine" en je krijgt meer nieuws uit hetzelfde magazine betreffende TB vaccins. Het voorlaatste artikel luidt:
    
    www.in-pharmatechnologist.com/news/ng...
    
    En beschrijft het bekende (zie dit draadje) 2005 nieuws:
    
    Crucell and Aeras announces (sic!) unique TB vaccine trials
    
    08/09/2005 - Dutch biotechnology company Crucell and the Aeras Global TB Vaccine Foundation has announced the initiation of a series of clinical studies for a unique TB vaccine, which allows millions of doses to be manufactured simultaneously while keeping costs relatively low.
    
    This is of utmost importance particularly in the case of poverty-related diseases such as HIV, malaria and TB. In approaching vaccine development in this way, the hope is that more people can be treated more effectively as well as more cheaply.
    The studies, which follow promising results for the vaccine obtained in animal studies, are scheduled to start in Europe, the US and Africa in the second quarter of 2006.
    
    The vaccine uses a combination of adenovirus serotype-35 (Ad35) and Crucell's PER.C6 production technology. The technology is a cell line developed for the large-scale manufacture of biopharmaceutical products including vaccines.
    
    The strengths of the PER.C6 technology lie in its safety profile, scalability and productivity under serum-free culture conditions.
    
    "We developed a vector system that is stable over enough passages to allow for the production of a large number of vaccine doses," commented Crucell's chief scientific officer, Dr Jaap Goudsmit.
    
    "It took us a substantial period of time to develop such a system for Ad35 vectors, particularly because our TB vaccine contains a combination of multiple antigens in a single vector," he added.
    
    AdVac technology is a vaccine technology developed by Crucell and is considered to play an important role in the fight against emerging and re-emerging infectious diseases and in biodefence.
    
    The technology supports the practice of inserting genetic material from the disease-causing virus or parasite into a 'vehicle' called a vector, which then delivers the immunogenic material directly to the immune system.
    
    Most vectors are based on an adenovirus, such as the virus that causes the common cold. The AdVac technology is designed to manage the problem of pre-existing immunity in humans against the most commonly used recombinant vaccine vector, adenovirus serotype 5 (Ad5), without compromising large-scale production capabilities or the immunogenic properties of Ad5.
    
    What is unique about the AdVac technology is that it is based on adenovirus vectors that do not regularly occur in the human population, such as Ad35.
    
    In contrast to the AdVac vectors, antibodies to Ad5 are widespread among people of all ages and are known to lower the immune response to Ad5-based vaccines, thereby impairing the efficacy of these vaccines.
    
    There is an urgent need for a fast, cost-effective way to contain tuberculosis in order to treat and control this highly contagious bacterium that infects one-third of the world's population,
    
    The spread of TB has been most prevalent in developing countries where the rate of infection has been soaring. In the developing world, with poor infrastructure like roads and communications, even six months may be too long for the people located there.
    
    Another factor has been the HIV pandemic, which has increased the problem of TB in addition to HIV itself.
    
21. [verwijderd] 27 juli 2006 10:20

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    quote:

    maxen schreef:

    Inderdaad zeer interessant....en daarom aanbevolen.
    Tal van verhulde verwijzingen naar Crucell naar mijn mening.
    [/quote]
    
    Aan de andere kant:
    
    Al eerder gepost door Biocon:
    www.aeras.org/news/documents/Financia...
    [quote=Aeras]
    ...
    "We wanted to guarantee delivering to the developing world at the cheapest price and with the
    highest quality," said Jerry Sadoff, a veteran vaccine scientist previously at Merck, who now runs
    Aeras. "I think this is the first time a non-profit is taking a product in development and
    contemplating its manufacture and distribution."
    ...
    With an initial investment of $10m, the Aeras plant will cultivate the vaccine in fermenters in
    powdered form for reconstitution in countries at risk, with far less wastage and at a lower cost
    than the existing dispersed methods.
    ...
    [/quote]
    
    Al eerder gepost door BioStefan:
    [quote=Biostefan]
    Aeras is working on newer technology using Shigella, a bacteria that causes diarrhea. The new vaccine weakens Shigella so it does not cause illness, but instead delivers a tiny nanoparticle containing genetic material from M. tuberculosis. Like BCG, it would be an oral vaccine, Sadoff said.
    

    Dit is dus een vaccin gemaakt van een gemodificeerde Shigella bacterie met stukjes DNA van de tbc bacterie. Deze technologie is vergelijkbaar met Crucell's vaccines op basis van een Adenovirus met een ingebouwd stukje DNA van een kwalijk virus.
    Deze door Aeras zelf ontwikkelde techniek is dus geen Per.C6-gebaseerd vaccin.
    
    Het zou kunnen dat de hardware in de nieuwe Aeras faciliteit specifiek geschikt is voor het kweken van deze bacterien, en niet voor (Per.C6) cellen...
    En dat de verwijzing in het persbericht van Omnia naar de "veelbelovende nieuwe TB vaccin technologie gebaseerd op een gevalideerd platform" naar deze Shigella techniek verwijst.
    (Maar vooral "gevalideerd platform" vindt ik nog steeds erg Per-C6-ig klinken....)