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draadje tuberculose

1. flosz 12 januari 2010 15:48

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   Uit AMC-magazine.
   Fop de verkenners
   Er is grote behoefte aan een beter vaccin tegen tuberculose omdat de huidige BCG-prik onvoldoende bescherming biedt. Moleculair bioloog Adriaan Bins wil met de allernieuwste technieken een DNA-vaccin ontwikkelen, en kreeg een Veni-subsidie van NWO voor het opzetten van een eigen onderzoekslijn.
   ‘Tegen bacteriën die in je cellen gaan zitten, kunnen we door de bank genomen slechter vaccineren dan tegen bacteriën die dat trucje niet beheersen. Vooral tegen de tuberculosebacterie lukt dat erg slecht’, vertelt Adriaan Bins in het Almeerse Flevoziekenhuis, waar hij stage loopt voor zijn opleiding tot internist. De Bacillus Calmette-Guérin (BCG)-prik werd in 1921 ontwikkeld door de Franse bacterioloog Albert Calmette en diens collega, de dierenarts Camille Guérin. Zij gebruikten daarvoor een verzwakt broertje van de tuberkelbacil, die bij runderen tuberculose veroorzaakt.
   Inenting hiermee biedt kleine kinderen in lichte mate bescherming en ouderen vrijwel niet. En dat terwijl tuberculose een groot probleem vormt, vooral in ontwikkelingslanden. Patiënten moeten langdurig met verschillende soorten antibiotica behandeld worden, en dat is lastig in de Derde Wereld. Bovendien is er een reëel gevaar dat de bacterie resistent wordt tegen de medicijnen omdat mensen hun kuur vaak niet afmaken.
   Het zou dus veel beter zijn als je de ziekte kunt voorkómen. Maar dat is nog niet zo gemakkelijk. Vaccins hebben zo weinig succes tegen tuberculose omdat ze niet in staat zijn om het afweersysteem in de allerhoogste staat van paraatheid te brengen. ‘Bij veel virussen kun je volstaan met het opwekken van antilichamen’, legt Bins uit. ‘Maar bij de tuberculosebacterie moet het immuunsysteem alles uit de kast halen: je hebt cellulaire afweer nodig, wat betekent dat je T-cellen moet activeren. Dat is al tien jaar een grote uitdaging in het vaccinonderzoek.’
   Er wordt inmiddels volop geëxperimenteerd met methoden om T-cellen op te wekken. Zo is er veel aandacht voor het oude pokkenvaccin, dat hiertoe wel in staat is. Verschillende onderzoeksgroepen proberen dat vaccin zodanig aan te passen, dat het ingezet kan worden tegen ziekten als malaria en kanker, maar ook tegen tuberculose. Bins: ‘Deze aanpak heeft echter zijn nadelen. Daarom heb ik mijn zinnen gezet op een DNA-vaccin. Daarin stop je genen van de bacterie die coderen voor eiwitten die een goede afweerreactie uitlokken. In muizen en apen is aangetoond dat het veel beter is om op deze manier T-cellen op te wekken. Waarom dat zo goed gaat, begrijpen we echter nog niet helemaal.’
   tatoeageapparaat
   Een DNA-vaccin heeft nog meer voordelen. Het is goed in Afrika te gebruiken omdat het niet koud bewaard hoeft te worden, zoals bij een levende, verzwakte ziekteverwekker wel het geval is. Bovendien is het gemakkelijk toe te dienen. Het moet in de huid gespoten worden, en dat zou heel eenvoudig kunnen met behulp van een eerdere vinding die Bins deed: een tatoeageapparaat. Deze methode ontwikkelde hij vijf jaar geleden in het NKI/Antoni van Leeuwenhoek Ziekenhuis. In plaats van één injectienaald ponsen meerdere naaldjes in luttele seconden zo’n twintigduizend gaatjes in de huid. Het vaccineren in de huid leidt heel snel tot een cellulaire afweerreactie. Veel sneller dan wanneer je in de spier prikt. Reden hiervoor is dat de huid een natuurlijke barrièrefunctie heeft en daardoor veel afweercellen bevat.
   De manier van toedienen is er dus al, nu nog een goed DNA-vaccin ontwerpen. Daarvoor is basaal onderzoek nodig. Bins doet dat samen met researchers van het het AMC (prof. Tom van der Poll), het LUMC (prof. Tom Ottenhoff) en het NKI (dr. Ton Schumacher). ‘De truc is om een paar eiwitten te laten zien die zo gevaarlijk lijken dat het afweersysteem het onthoudt. Zodat het bij een bezoek van de echte bacterie snel kan reageren. Als de eiwitten onschuldig lijken, krijg je geen goed effect. Dan denken de T-cellen bij de tuberkelbacil: “Die kunnen we met rust laten, want die doet toch niks”.
   Je moet het bont maken voordat het lichaam de T-cellen uit de kast haalt; dat gebeurt pas als het gelooft dat het écht ernst is. Want de T-cellen zijn grof geschut, die zorgen vaak ook voor collateral damage tijdens het gevecht tegen de vreemde indringer.
   stuk uniform
   ‘We moeten het immuunsysteem dus een rad voor ogen draaien’, legt Bins uit. Maar dan heb je informatie nodig over het tot stand komen van cellulaire afweer. ‘Vergelijk het lichaam met een land en de afweer met het leger van dat land. Wat wij willen doen, is via zo’n vaccin flarden van de vijand in het land gooien: een arm, een bajonet en daartussen een stuk uniform. We hopen dat verkenners – de antigeen-presenterende cellen (APC’s) – dat uniform oppakken, ermee naar de kazerne (de lymfeklier) gaan en het presenteren aan de officieren, de T-cellen. Zodat die officieren de soldaten vertellen hoe de vijand eruit ziet, en dat ze op hem mogen schieten zodra ze hem tegenkomen.’
   ‘Mijn onderzoek draait om de vraag: hoe maken die verkenners de officieren paraat, zodat het leger de vijand te lijf gaat? De laatste jaren is steeds duidelijker geworden dat de verkenner die het uniform vindt, ontzettend belangrijk is. Hoe betreedt hij de kazerne? Komt ie naar binnen stormen, moord en brand schreeuwend, of wandelt hij nonchalant door de deur, en zegt hij: “O ja, en dit heb ik toevallig ook nog gevonden”?’
   ‘Het liefst willen we een vaccin dat ervoor zorgt dat hij binnenstormt. Daarvoor zou je in het land een bloedbad kunnen aanrichten en er een uniformpje tussen gooien, maar een bloedbad is niet wenselijk. We willen dat hij alleen dat uniform vindt, en dan toch in paniek die kazerne inrent. Dus zullen we de verkenner voor de gek moeten houden.’
   Met behulp van een soort super-fluorescentiemicroscoop – 2-photon intervital imaging – die twee millimeter diep in weefsels kan kijken, gaat Bins het gedrag van de verkenner uitvoerig bestuderen. Dat doet hij bij muizen, want in een petrischaaltje zou dat nooit lukken, vertelt hij. ‘Dan raken de antigeen-presenterende cellen de weg kwijt. Het is sowieso moeilijk om ze voor dat soort doeleinden te kweken.’
   Dankzij de supermicroscoop kan de onderzoeker van alles over de verkenner te weten komen: in welke broekzak hij het gevonden uniform stopt, of hij rennend naar de kazerne gaat, of hij de officier eerst een hand geeft, enzovoort. Vervolgens zal Bins gaan proberen om paniek te zaaien bij de verkenners om te zien hoe de hoofdrolspelers zich gedragen.
   Voordat daar een nieuw, bruikbaar DNA-vaccin uit komt, zullen er al gauw een jaar of tien voorbij zijn. Maar als het dan zo ver is, zal een goede inenting waarschijnlijk de nodige bijwerkingen hebben. ‘Je krijgt er vast wat koorts van of een grieperig gevoel. Dat komt omdat verkenners die in paniek zijn - ook al zijn ze voor de gek gehouden - altijd stofjes maken die koorts opwekken. Maar dat is altijd nog veel beter dan tuberculose krijgen.’
   Irene van Elzakker
   www.amc.nl/?pid=6486&&contentitemid=8...
   
2. aossa 14 januari 2010 15:32

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   New York, NY — January 14, 2010 The Global Alliance for TB Drug Development today announced the election of Dr. Maarten van Cleeff as President of its Stakeholders Association. Dr. van Cleeff will also serve as an Ex Officio member of the TB Alliance's Board of Directors.
   
   The TB Alliance is a not-for-profit, product development partnership leading the discovery and development of affordable, new TB drugs that will shorten and simplify treatment, be effective against drug-resistant strains, and be compatible with antiretroviral therapies for patients coinfected with HIV. The Alliance currently manages the largest portfolio of potential new TB drugs ever assembled, including three compounds in advanced clinical trials.
   
   "This is a wonderful opportunity for Dr. van Cleeff and the TB Alliance," said Dr. Mel Spigelman, President and CEO, TB Alliance. "As President of the TB Alliance Stakeholders Association, Dr. van Cleeff will utilize his extensive background in the field of tuberculosis research and delivery of care for the benefit of the millions of patients the TB Alliance is working to benefit."
   
   The TB Alliance's Stakeholders Association, includes representatives from a diverse set of organizations and governments from around the world who share a clear interest and a significant stake in developing new TB drugs.
   
   Dr. Maarten van Cleeff has nearly three decades of international experience in the TB field, and currently works at KNCV Tuberculosis Foundation as Project Director of The Tuberculosis Coalition for Technical Assistance (TBCTA). He served for 10 years working in Tanzania's National TB and Leprosy Program and an additional 11 years as a Public Health Consultant for the Royal Tropical Institute in Amsterdam, specializing in Tuberculosis Control. At that institution, he also served in prominent roles such as the head of the Infectious Diseases section and the head of the Health Department. Dr. van Cleeff holds an MSc from the London School of Hygiene and Tropical Medicine and a PhD from the University of Amsterdam.
   
   "TB control is a long fight and continues to face many hurdles and challenges," stated Dr. Maarten van Cleeff. "The Global STOP TB policy focuses on universal access to early diagnosis and quality treatment. The development and availability of new drugs is a top priority and involves a wide range of expertise. This is the aim of the TB Alliance, and it can be achieved with active participation of its Stakeholders. I am very pleased to contribute to this effort and feel honored to succeed Prof. Petro Terblanche as President of the TB Alliance Stakeholders Association."
   
   
3. harrysnel 15 januari 2010 11:27

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   "In 2002 Jaap Goudsmit has been affiliated to AMC through his appointment of Professor of poverty-related communicable diseases. In this capacity he will continue to chair the board of the in 2001 initiated Center of Poverty-related Communicable Diseases (CPCD), a joint initiative of the AMC, the Royal Tropical Institute (KIT), the Royal Netherlands Tuberculosis Association (KNCV), and PharmAccess International (PAI). As per March 2002 Jaap Goudsmit is affiliated with Crucell, a leading biotechnology company in Leiden."
   
   www.giichinese.com.tw/conference/worl...
   
4. MeawandMoo1 15 januari 2010 18:31

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   aeras.org/newscenter/presscoverage-de...
   
   Difficult progress
   Persistent poverty expands uncertainties around research into TB drugs and treatments
   
   The hope of getting new tuberculosis (TB) drugs in hand quickly did not come true. The Stop TB Partnership, a branch of the World Health Organization (WHO), forecast than in 2006 at least one new drug for one of humankind’s oldest diseases would be ready by 2010. “We failed,” recognized Christian Lienhardt, one of the representatives of the Stop TB Partnership at the TB congress held in early December in Cancun, a beach town in southeast Mexico, “but we´re closing up on our targets.”
5. aossa 12 februari 2010 12:54

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   Working Group on New TB Drugs Launches BlogInteractive Platform to Explore Key Issues in TB
   
   Drug DevelopmentThe Stop TB Partnership's Working Group on New TB Drugs (WGND) has launched an interactive platform that will mobilize robust discussion around the need to develop the new TB drugs that will save millions of lives, reduce the strain on overburdened health systems, and promote global prosperity. This platform will thrive with the active participation and engagement of the TB community, as it aims to foster education and collaboration, and increase cross-connectivity.
   
   blog.newtbdrugs.org/
   
   www.newtbdrugs.org/pipeline.php
6. MeawandMoo1 6 april 2010 21:40

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   Let maar niet op mij...
   Gewoon even een kleine update.
   
   Volgens jaarverslag AERAS (Rapport februari 2010: status 9 november 2009):
   aeras.org/newscenter/downloads/pubs/A...
   
   Kenya Walter Reed Project, Kombewa
   Phase I Adult, Prior BCG Vaccination C-012-402
   Follow-up complete; analysis ongoing
   
   South Africa University of Cape Town Lung Institute, Cape Town
   Phase II Adults, Active or Previous TB, Prior BCG Vaccination
   C-010-402
   Enrolling
   
   South Africa Aurum Institute, Johannesburg
   Phase IIb Adults, HIV-infected, Latent TB, Prior BCG Vaccination C-017-402
   Open to enrollment
   
   South Africa South African Tuberculosis Vaccine Initiative (SATVI), Worcester
   Phase I Infants <2 years, Prior BCG Vaccination C-018-402
   Enrolling
   
   United States Saint Louis University Center for Vaccine Development, St. Louis, Missouri
   Phase I Adults, No Prior BCG Vaccination,Receive BCG Prime
   C-009-402
   Follow-up complete; analysis ongoing
   
   United States Saint Louis University Center for Vaccine Development, St. Louis, Missouri
   Phase I Adults, No Prior BCG Vaccination, Receive BCG Prime
   C-008-402
   Follow-up complete; analysis ongoing
   
   United States Oregon Health Sciences University, Portland, Oregon
   Phase I Adults, No Prior BCG Vaccination, Receive BCG Prime
   C-021-402
   Open to enrollment
   
   United States PRA Clinical Pharmacology Center, Lenexa, Kansas
   Phase I Adults, No Prior BCG Vaccination, Receive BCG Prime
   C-022-402
   Follow-up complete; analysis ongoing
   
   Interessanter:
   archive.constantcontact.com/fs087/110...
   TB Vaccine Enters Testing in People Living with HIV
   
   A Phase IIb study testing the safety of AERAS-402/Crucell Ad35 in adults infected with HIV is underway at the Aurum Institute in Klerksdorp, South Africa. All Aeras-sponsored TB vaccine candidates have been or will be tested for safety in people living with HIV in countries with high TB prevalence. Ten study volunteers have been enrolled in the first stage of the trial, which will enroll 26 volunteers. This is the first study testing this TB vaccine candidate among this study population.
   
   AERAS-402/Crucell Ad35 has been previously tested for safety in healthy adults in the United States and in adults and infants in South Africa.
   
7. flosz 16 april 2010 09:03

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   Crucell Program Leaves Positive “Footprint” in South Africa
   2/18/2010
   
   www.aeras.org/newscenter/view-innews....
   ****************
   Plak....
   www.ncbi.nlm.nih.gov/pubmed/20167847
   timesofindia.indiatimes.com/life/heal...
   www.iex.nl/forum/topic.asp?forum=228&...
   www.iex.nl/forum/topic.asp?forum=228&...
   www.investorvillage.com/smbd.asp?mb=2...
   www.investorvillage.com/smbd.asp?mb=2...
   www.investorvillage.com/smbd.asp?mb=2...
   
8. flosz 30 april 2010 14:06

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   Our recombinant tuberculosis adenovirus based vaccine (rAd35) is currently in several Phase I trials with promising results, and in a recently started Phase II study. Given the uncertainties required to develop a 10,000-liter facility
   and the need to develop a 10,000L scale viral vaccine manufacturing process, we are focusing on intensification of rAd35 manufacturing using the
   PER.C6® cell substrate. We will show a 10-fold intensification at bench scale and, for the first time, results of the scaled-up upstream process in 50L single-use bioreactors and the impact on cost of goods at production scale.
   
   *************
   
   Based on our AERAS 402 vaccine, the benefits and challenges of manufacturing spray dried products will be discussed. Shorter processing
   cycle time and larger batch size per unit operation compared with lyophilization improve the commercial application of the spray drying
   technique. However, challenges exist in transferring the concept into a final product, such as: 1) Developing a stable formulation that gives a high recovery during the spray drying process and is hydrophobic during shelf
   storage; 2) The aseptic cGMP spray dryer design; 3) Powder filling; 4) Developing economic unit-dose packs or blister capsules for final product
   and DPI; 5) Cost effectiveness.
   
   www.iex.nl/forum/topic.asp?forum=228&...
   
9. flosz 30 april 2010 19:37

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   TB Vaccine trials moving in the right direction, but slowly
   Written by Aimable TWAHIRWA
   Thursday, 29 April 2010
   
   In an exclusive interview with Africa Science News Agency (ASNA), Tony Hawkridge, Head of AERAS Africa Office, a global initiative dedicated to the development of effective tuberculosis vaccine explains how the low participation of candidates in clinical trials impacts the development of TB vaccines in Africa and why it is important to emphasize on alternatives to a developed clinical research environment.
   Since early 1980, a number of TB vaccines have been developed, but a few numbers of candidates in Africa proved to have an immune response which is thought may be protective. Is this symbolic of the failure of clinical trials on the continent?
   
   
   The last decade has seen a steady increase in the number of new TB vaccine candidates which have been shown to be safe, well tolerated, immunogenic which means ‘capable of eliciting an immune response’ and efficacious (capable of protecting the recipient from TB when exposed to it) in animals. Some of these have now gone into clinical trials. Most of the countries in the world with high TB rates are in sub-Saharan Africa . Some Nations on the continent have, in addition to high TB rates, a well developed clinical research environment – experienced investigators, high quality laboratories, efficient referral systems and clinical backup, good surveillance for key events, etc. These countries are well placed to participate in TB vaccine trials. However, the later phase clinical trials (Phase 2b and 3), where one is actually testing whether the vaccine protects against TB, can only be done in areas where there is a lot of TB, where volunteers are likely to be exposed to TB in their homes, schools, workplaces, villages, etc., so that the investigators can see whether the vaccine works or not. Those which have not been in Africa yet will very likely be tested in trials at some point in their development.
   
   How many volunteers are set to take part in these clinical trials?
   The number of volunteers in each of these later phase studies is very large – in the thousands to tens of thousands of volunteers per trial. Most of the new vaccines were invented and are manufactured in Western Europe or North America . Before they go into trials in Africa they are first tested in animals (mice, guinea pigs, monkeys) and then in healthy adult volunteers in the countries where they were invented/manufactured. The regulatory authorities of the African countries where the trials are planned usually require this option.
   
   But, trials in Africa have recorded a low participation in terms of candidates. How valid is this argument?
   
   At least half of the 12 new TB vaccines mentioned on the Stop TB Vaccine Working Group website have been or are in clinical trials in Africa - these include MVA85A/AERAS485, AERAS402/Crucell ad35, SSI HYVAC 4/AERAS404, SSI Hybrid 1, GSK M72 and M Vaccae. Those which have not been in Africa yet will very likely be tested in trials on the continent at some point in their development - these include RUTI, rBCG30, the AERAS 407 rBCG and others. Early phase (Phase 1 and 2a) clinical trials of new TB vaccines can be performed virtually anywhere in the world where there is a good Phase 1 clinical trials unit – the volunteers need to be healthy and the set up needs to be adequate to monitor them closely. The number of volunteers in each of these early phase studies is usually small – less than 50 per trial.
   
   TB Vaccine trials seem to be new in Africa . From you experience, Am I right to say that things are developing around the continent?
   
   TB vaccine trials have actually been conducted in Africa for many years – large BCG trials were conducted in Malawi and M vaccae trials were done in S Africa and other countries in the 1980’s and 1990’s. So Africa is not new to TB vaccine trials. Much of what we know about BCG is based on research conducted in Africa . What is new is that a new generation of novel TB vaccines is now being trialed in Africa . The trial site near Cape Town which is run by the South African TB Vaccine Initiative, at the University of Cape Town, has in the last few years conducted trials on four different novel TB vaccines (MVA85A/AERAS 485, HYVAC 4 / AERAS 404, GSK M72, and AERAS 402/Crucell ad35).At first it was just a few African countries – notably The Gambia, Senegal and South Africa, but more countries are now participating – Kenya started a trial in 2008 and other countries are hoping to follow suit shortly (including Uganda, Mozambique and possibly others).
   
   Do you have any more specifications in terms of figures on candidates (volunteers) who have undergone these injections?
   
   No official figures, but , if you consider that each Phase I trial enrols up to 50 volunteers, each Phase 2A up to 200, each Phase 2B up to 4000 and each Phase 3 up to 30 000 (these are just rough estimates), and that each candidate requires 10-20 early phase trials and 2-3 late phase trials, then you can see that for the more advanced candidates we are talking about a few thousand individuals who have already received the vaccine (or placebo) and some tens of thousands who will have received it by the time it goes to registration. As I mentioned, for the late phase trials, all of these individuals have to be in high burden populations, usually in high burden countries and for the early phase trials some of them will be.
   
   The current available BCG (Bacille Calmette Guerin) is nearly 90 years old, how far are you confident for the success of the current trials?
   
   It is difficult to quantify how confident we are – developing vaccines against TB is extremely difficult and even if a candidate is shown to be safe, well tolerated and immunogenic in early studies, it may simply fail at the last stage and not show significant protection or there may be an unexpected safety concern that was not seen in early trials, such as happened with one of the first rotavirus vaccines. Having said that, we are very optimistic that there are so many apparently good candidates coming through and we are very hopeful that at least one of them will “go all the way”.
   
   Sub Saharan Africa is home to 9 of 22 countries with the highest TB burden, according your findings. What are the main constraints you are facing when conducting trials as regards to social, political and cultural environment in Africa
   
   There are constraints to doing trials anywhere in the world. Some of them are fairly constant – e.g. the high financial costs – whilst others vary with the setting. I think it is important to focus not only on constraints but on opportunities which working in Africa presents.
   
   It is true that in some areas of Africa infrastructure is less developed than in e.g. North America . This applies to both general infrastructure (e.g. roads, telephones, IT networks, banks, security, vehicle maintenance, etc.) and to clinical research infrastructure (e.g. the presence of TB and immunology laboratories, adequate surveillance systems for TB and other key events, referral systems for trial volunteers who become ill, facilities where TB can be accurately diagnosed, etc.). This can be a great challenge for researchers. In one area where we sponsor research, the terrain is so rough that the nurses have to ride off-road motorcycles to do home visits. That is obviously a challenge.
10. flosz 30 april 2010 19:38

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    Having said that, there has been great progress made in building infrastructure in Africa and there are now many centers of excellence which can boast facilities and expertise which rivals or exceeds that found in North America and Western Europe .
    
    TB is so well known in most African populations that it is not difficult getting political and community support for initiatives to develop new tools to fight the epidemic. The same might not be the case in areas of the world where TB is seldom or never seen.
    
    AERAS Global TB vaccine foundation is conducting research on TB vaccine, am I right to say that you are satisfied of what is being done to benefit from vulnerable group on the continent?
    
    In the long term, an effective TB vaccine which is made available to high burden countries at an affordable price will benefit everyone – rich and poor, but particularly the poor and marginalized, since TB is predominantly a disease of poverty. One can never be satisfied with what is being done, as long as there is a disease out there which is killing 3 million people a year worldwide and making 9 million sick. Yes, we would all like more to be done. We have been very generously funded by the Gates Foundation, the Dutch Government and other groups. However, as pointed out, vaccine development is extremely expensive, and it would be good to have additional funding in order to do everything we would like to do and not just the basics.
    
    From the epidemiological study you have been conducting, what is a realistic duration (viability) of a TB vaccine for candidates?
    
    We know that the protective effect of BCG, for what it is, does not last forever – it wanes after a few years. We do not know how long the protective effect of the new TB vaccines will last – right now, as I mentioned, we do not even know whether they will be protective – that will hopefully be shown in the current Phase 2B trials and ultimately in the Phase 3 trials. We hope that the protection they confer will be long lasting. It may be that one will require a number of booster doses of the vaccine.
    
    
    You have made a formal proposal urging African nations to earmark more resources in health infrastructure. How confident are you of a positive response to this proposal?
    
    We are hoping to have a new vaccine licensed and available by 2016 - the first new TB vaccine. We hope that others will follow. The effect of introducing a new, more effective vaccine will take some time to work through to the global epidemiology of the disease – there are about 2 billion people in the world infected with TB who could potentially develop TB disease and become infectious – so it will take time to turn things around.
    
    In the meantime it is vital that countries continue to do the basics right – that means ensuring that all infants who are not HIV infected receive BCG as per World Health Organization (WHO) recommendations. All persons who are suspected of having TB should be tested for both TB and HIV and those with disease diagnosed as soon as is possible and referred for appropriate treatment, and that all those placed on treatment for TB adhere to it, through the use of the DOTS strategy.
    africasciencenews.org/asns/index.php?...
    
12. flosz 5 mei 2010 10:33

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    Clin Infect Dis. 2010 May 15;50 Suppl 3:S178-83.
    
    Update on research and development pipeline: tuberculosis vaccines.
    Beresford B, Sadoff JC.
    
    Aeras Global TB Vaccine Foundation, Rockville, Maryland 20850, USA. bberesford@aeras.org
    
    Abstract
    Current tuberculosis (TB)-control methods, which do not include an adequate vaccine, do not effectively block transmission of TB. Modeling studies show that mass vaccination campaigns using new vaccines could prevent 85.9 million new cases and 14.5 million deaths from 2015 through 2050 in southern Asia alone. After a dearth of many years, the development pipeline now includes 7 vaccine candidates that are being tested in humans. Two nonreplicating viral vectored vaccines have very recently entered the first phase IIb efficacy trial in infants (the first such trial in 80 years) and in human immunodeficiency virus-infected adults. Science is moving forward, but the scientific advancements need to be accompanied by political mobilization to ensure that the resources are available to develop, manufacture, and distribute the new vaccines and, thus, save millions of lives.
    PMID: 20397946
    www.ncbi.nlm.nih.gov/pubmed/20397946
    
    Volledig art.: ...…. The second clinically advanced TB vaccine is AERAS‐402/Ad35 (Crucell), a nonreplicating Ad35‐vectored vaccine that [15, 16] has shown protection in nonhuman primate challenge models as a boost to recombinant BCG vaccine. When delivered to the lung of nonhuman primates as an aerosol, AERAS‐402 induced high levels of antigen‐specific CD4 T cells and CD8 T cells in bronchoaveolar lavage cells [17]. This vaccine induced antigen‐specific polyfunctional CD4 T cells and very high levels of antigen‐specific CD8 T cells in South African adult volunteers who had received BCG vaccine at birth ……
    www.journals.uchicago.edu/doi/pdf/10....
    
13. flosz 7 mei 2010 11:03

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    Vaccine. 2010 May 2.
    Stabilizing formulations for inhalable powders of an adenovirus 35-vectored tuberculosis (TB) vaccine (AERAS-402).
    
    Jin TH, Tsao E, Goudsmit J, Dheenadhayalan V, Sadoff J.
    Aeras Global TB Vaccine Foundation, 1405 Research Blvd, Suite 300, Rockville, MD 20850, United States.
    
    Abstract
    A powder vaccine intended for aerosol delivery was formulated by spray drying the Ad35-vectored tuberculosis (TB) AERAS-402 vaccine with mannitol-based stabilizers. Thermodynamic properties, water absorption, particle size distribution and morphology of the powders were evaluated. Virus survival during spray drying and storage was determined by medium Tissue Culture Infectious Dose (TCID(50)). A mannitol-based powder (mannitol-cyclodextrin-trehalose-dextran, MCTD) had a narrow size distribution with a median volume diameter around 3.2-3.5mum (suitable for pulmonary vaccination of humans) and good aerosolization characteristics. The spray dry powders generated from mannitol-based formulations were hydrophobic, which benefits virus survival during both production and storage at 4 degrees C, 25 degrees C and 37 degrees C as compared to the hygroscopic formulations (trehalose, sucrose, dextran, PVP, leucine).
    
    In conclusion, this study demonstrates that it is possible to produce in a one-step spray drying process a stable dry powder formulation of a TB vaccine suitable for mass vaccination.
    
    Copyright © 2010. Published by Elsevier Ltd.
    PMID: 20444437
    www.ncbi.nlm.nih.gov/pubmed/20444437
    
14. [verwijderd] 7 mei 2010 15:07

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    quote:

    flosz schreef:

    Vaccine. 2010 May 2.
    Stabilizing formulations for inhalable powders of an adenovirus 35-vectored tuberculosis (TB) vaccine (AERAS-402).
    ...
    

    Goede ontwikkeling. Hoe meer know-how Crucell ontwikkelt (in samenwerking met andere partijen) omtrent vaccin delivery, hoe beter. Wellicht ook nuttige kennis voor ontwikkeling van aerosole griep vaccins.
15. flosz 13 augustus 2010 21:06

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    Aeras Global TB Vaccine Foundation July 2010 Newsletter tinyurl.com/2bks2wr
16. flosz 22 september 2010 08:48

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    TB Vaccine 2010, September 21-24. Estonia
    
    Agenda
    Met o.a.:
    Diverse T Cell Activation of New Vaccines and Correlates of Protection
    Willem Hanekom,
    South African Tuberculosis Vaccine Initiative
    
    Report of Study on Barriers and Drivers for Introduction of New TB Vaccines
    Lew Barker,
    Aeras Global TB Vaccine Foundation
    
    Clinical Studies on TB Vaccines
    Co-Chairs:
    Harriet Mayanja-Kizza, Kampala University
    Greg Hussey, University of Cape Town
    
    Stop TB Task Force Presentation
    Clinical Research Issues in TB Vaccine Development
    Hassan Mahomed,
    South African Tuberculosis Vaccine Initiative
    
    Clinical Trial Challenges
    Thomas G. Evans, MD,
    Aeras Global TB Vaccine Foundation
    
    TB Vaccines in Clinical Trials:
    MVA85A Helen McShane, Oxford University
    AERAS-402/Crucell Ad35 Jerald Sadoff, Crucell
    SSI Vaccines Søren Hoff, Statens Serum Institut
    M72 Opokua Ofori-Anyinam, GlaxoSmithKline Biologicals
    
    Session III: Manufacturing, Regulation & Vaccine Access
    Chair:
    Jerald Sadoff, Crucell
    *******************
    
    Aeras and Crucell Announce Phase II Clinical Trial Start in Kenya www.aeras.org/newscenter/news-detail....
    (Zie ook post huppel www.iex.nl/forum/topic.asp?forum=228&... )
17. flosz 22 september 2010 09:06

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    Tackling TB to reach MDG targets: The promise of new vaccines
    sciencespeaks.wordpress.com/2010/09/2...
    "Elderly May Not Benefit From TB Vaccines in Development" ow.ly/2H7wY
    
    Meer TB via twitter:
    twitter.com/TBVI_EU
    twitter.com/aerasglobaltb
    twitter.com/TB_Alert_UK
    twitter.com/SciSpeaksBlog
    
18. flosz 23 september 2010 12:44

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    Having a TB vaccine that won't be affordable to developing countries won't be helpful, Crucell's Jerald Sadoff said today at #tbvax2010
    *
    
    Today majority of 12 promising TBvaccines in clinical trials being discussed at #tbvax2010 Very big chance 1st will be on market around2020
    ************************
    
    9.23.2010
    New TB Vaccine Enters Clinical Testing
    Rockville, MD, USA and Tallinn, Estonia (September 23, 2010) – At an international gathering of TB vaccine researchers in Tallinn today, the Aeras Global TB Vaccine Foundation announced it will initiate a clinical trial of an investigational live recombinant tuberculosis vaccine to be led by researchers at Saint Louis University in St. Louis, Missouri, USA. The announcement was made at the Second Global Forum on TB Vaccine Development.
    
    Building on more than a decade of global scientific research, Aeras scientists have engineered a new investigational vaccine, called AERAS-422, which will undergo clinical trials to evaluate its properties for interrupting TB at all stages of infection, including initial infection, latency and reactivation.
    
    “Moving our lead in-house vaccine from the laboratory into clinical testing is an important milestone for Aeras and its partners. Finding a potential replacement for the currently available TB vaccine, which was invented almost 90 years ago, is a primary goal in our mission,” said Thomas G. Evans, MD, Aeras’ Chief Scientific Officer. “Based on data from pre-clinical studies, we are cautiously optimistic about the potential of this vaccine candidate to be safer and more immunogenic than the currently available vaccine.”
    
    The new vaccine, called AERAS-422, is a modernized version of the currently used TB vaccine – Bacille Calmette Guérin (BCG). BCG is widely viewed as insufficient in preventing pulmonary TB, and this trial is part of a wider global effort to develop safer and more immunogenic TB vaccines that would be effective against all forms of TB.
    
    AERAS-422 has been modified with an endosome escape mechanism and over-expresses three key proteins: 85A, 85B and Rv3407. The bacterium that causes TB hides inside cells. Therefore, the endosome escape mechanism is designed so that the proteins will escape an internal compartment of the cell and be more efficiently presented to the immune system to elicit a greater protective response in the body.
    
    “The TB epidemic continues to become more complex and difficult to control, especially in South Africa where resistance to available TB treatments is on the rise,” said Bernard Fourie, PhD, Chief Scientific Officer of Medicine in Need and Managing Director of Mend South Africa. “The scientific community has made developing a safer and more effective TB vaccine a priority and we are pleased that there is progress in the field.”
    
    The Phase I clinical trial to test the safety of AERAS-422 will be led by Principal Investigator Daniel Hoft, MD, PhD, at Saint Louis University’s Center for Vaccine Development. The trial will enroll healthy adults who have never received a vaccination against tuberculosis. Dr. Hoft’s team will also conduct initial immunological assessments.
    
    “The TB vaccine field has made tremendous progress over the past 10 years,” said Daniel Hoft, MD, PhD, of the Center for Vaccine Development at Saint Louis University. “Not only is the start of the clinical trial of AERAS-422 another important benchmark in the search for more effective TB vaccines, it is also an opportunity to learn more about cellular immunity, a less well understood but critically important component of TB vaccine development.”
    
    Aeras is pursuing a TB vaccine development strategy based on a prime-boost approach that incorporates an initial BCG or rBCG vaccination for infants at birth to be followed by a booster vaccine later in infancy to adolescence. In addition to AERAS-422, developed as a “prime,” Aeras is also supporting the clinical development of four TB vaccine candidates designed as “boosters” in the prime-boost vaccine scenario. Two have reached the Phase IIb proof of concept stage.
    www.aeras.org/newscenter/news-detail....
    
19. flosz 1 oktober 2010 12:16

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    TB vaccine to cut infections by 90%
    
    Friday, 1 October 2010
    by Mico Tatalovic
    
    LONDON: A new vaccine for tuberculosis – second biggest killer globally after HIV/AIDS – will be available by 2020, that could cut infections by 90% experts said.
    Tuberculosis infects almost 10 million and kills almost two million people each year, and is increasingly untreatable due to antibiotic resistant strains that are especially dangerous to HIV positive people – 500,000 million of HIV positive people die each year due to TB infections.
    Although a BCG vaccine has long been in use against TB, it only prevents so called ‘disseminated TB’ in small children up to age of five and is useless in adults or against the most common pulmonary TB.
    
    Huge impact possible
    Chris Dye, director of Health Information in the Office of HIV/AIDS, Tuberculosis, Malaria & Neglected Tropical Diseases at the WHO, Switzerland, said: "If we had a vaccine of moderate good efficacy it's pretty clear from the kind of calculations that I normally do that we could have a huge impact on tuberculosis pretty quickly."
    Since the TB community met at the First Global Forum for TB Vaccines in the late 1990s, 13 new candidate vaccines have entered clinical trials in humans and over 40 are in the pipeline.
    One of these is expected to enter phase 3 efficacy trials by 2013 and if successful it may be rolled out as early as 2016, scientists have said at the Second Global Forum on TB Vaccines in Tallinn, Estonia, 21-24 September.
    
    TB experts think out of the box
    "There has been a tremendous progress done in only last 15 years," said Christine Sizemore, senior director of vaccine assessment and quality control at the National Institutes of Health, in the USA.
    The conference concluded with recommendations for the ‘Blueprint to TB Vaccines’ – a document that will guide the field over the next decade, in which a first new vaccine is expected.
    "The conference was a success," Brennan said. "While there were no big surprises, it brought a diverse group of people working on TB together and this has sparked some innovative, out-of the-box thinking, and challenged some long-held dogmas".
    
    One big challenge in the coming decade will be to develop molecular markers of immunity for TB vaccines: so the efficacy of vaccine candidates could be assessed with a simple blood test instead of lengthy and often unreliable clinical diagnoses of infection, he said, adding that this would bring the costs of clinical trials down and make them more feasible.
    
    Although TB infects almost two million people each year, number of infections in any one place is small, driving the number of people needed for phase 3 efficacy clinical trials up to range of 40,000-100,000, said Jerald Sadoff, chief medical officer at Crucell.
    "It's like 'water, water everywhere, but not a drop to drink'," he said, calling for more innovative approaches to getting new TB vaccines approved and manufactured, that bypass the usual route of having phase 3 clinical trials.
    
    Only 16% of global funding
    Brennan agreed that "this is a good time to start talking to regulatory agencies [about approving new TB vaccines]". "If you have the political will, things will be done, we just need to convince policy-makers TB is important."
    Although TB is the second biggest killer globally after HIV/AIDS it represents only 16% of the global funding for research and development into neglected disease, according to a 2008 report by the George Institute for International Health.
    Global research investments into TB add up to some five billion annually, 22% of which goes towards vaccine research.
    
    Need for new new diagnostics and drugs
    But vaccines are just a part of the equation, said Michael Brennan, from the Aeras Global TB Vaccine Foundation, development of new diagnostics and drugs will play an equal role in global goal to eliminate TB by 2050.
    The recommendations will now be taken forward through Stop TB Partnership’s Vaccine Working Group, which will organise further focus groups to put the blueprint together and publish it in a special issue of the Tuberculosis journal together with papers from the conference in late 2010 Brennan said.
    tinyurl.com/2aklsqm
    
20. flosz 8 oktober 2010 14:28

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    Hope for Expanded Protection Against TB
    KIGALI, Oct 8 (IPS) - Despite the availability of a vaccine, 1.3 million people worldwide died from tuberculosis (TB) in 2008, according to the World Health Organisation. Most of them lived in Africa and Southeast Asia.
    
    Administered to infants throughout the developing world and in certain countries in the developed world, the Bacille Calmette-Guérin (BCG) vaccine, which was invented almost 90 years ago, provides some protection against paediatric TB. However, it only provides variable protection against pulmonary tuberculosis and none at all against other types of TB.
    
    To change this, non-profit research organisation Aeras Global TB Vaccine Foundation has been trying to find a replacement for BCG. The new vaccine, called AERAS-422, is a modern version of BCG that it is hoped will provide long-term protection against all forms of TB. It is about to undergo first medical trials in the United States.
    
    In addition, Aeras is also supporting, in collaboration with Dutch biopharmaceutical company Crucell, the research of four TB vaccine candidates designed as booster vaccine that can be administered to children or teenagers who received an initial BCG vaccination for infants at birth.
    
    Anthony Hawkridge, a senior researcher at the Aeras Foundation, says the booster vaccine clinical trials have now reached Phase IIb and will soon begin in infants in Kisumu, Kenya. Other trial sites will be Worcester in South Africa and Kampala, Uganda, as well as Bangalore, India. Phase IIb is specifically designed to study efficacy – how well the drug works at the prescribed dose.
    
    Q: Why did you choose to conduct Phase IIB of the booster vaccine trials in Africa and India?
    
    A: The later phase clinical trials, such as IIB and III, during which one is actually testing whether the vaccine protects against TB, can only be done in areas of the world where there is a lot of TB, where the volunteers are likely to be exposed to TB in their homes, schools, workplaces, villages, and so on.
    
    Q: The currently available BCG vaccine has several downsides: it neither fully protects children from developing TB, nor does it protect adults already infected with TB. Moreover, protection is not life-long. How will the new vaccine change this?
    
    A: We hope that at least one of the new vaccine candidates will prove to be more efficacious in preventing TB, not just in infants, but in all age groups and in varied populations, such as people infected with HIV.
    
    We hope that protection will be long lasting, but until we have done the trials and got the product registered and used by a sizeable number of people, we won't know.
    
    We have data from animal studies and from early phase clinical trials, but it is not possible to extrapolate from that and say that the new vaccines will definitely work. We can only hope that they will.
    
    Q: What are the expected outcomes of Phase IIB of the trials?
    
    A: It is difficult to quantify the outcomes. Developing vaccines against TB is extremely difficult.
    
    Even if a vaccine candidate is shown to be safe, well tolerated and immunogenic [able to provoke an immune response] in early studies, it may simply fail at the last stage and not show significant protection.
    
    Or there may be an unexpected safety concern that was not seen in early trials, like it happened with one of the first rotavirus vaccines. However, we are very optimistic about the fact that there are so many apparently good candidates coming through. And we are very hopeful that at least one of them will "go all the way".
    
    Q: What ethical standards do you set to protect infants who participate in trials?
    
    A: Sponsors and investigators conduct trials according to what is called GCP, Good Clinical Practice. This is an international set of standards for clinical research and part of what they do is ensuring that trial participants are protected.
    
    One thing they specify is that any trial protocol is reviewed by a competent and independent research ethics committee whose job it is to ensure that the rights and safety of the trial participants are given due consideration.
    
    But, ultimately, it is the responsibility of the trial’s principal investigator to ensure that the research is conducted according to the highest internationally accepted standards.
    
    Q: If the trials go well, when do you expect the new vaccine to be available?
    
    A: Well, for years we have been saying 2015 to 2016. I did not attend the recent TB vaccine conference in Estonia, but I believe that the experts are now saying that it may take a bit longer, possibly until 2020.
    
    Given that the first Phase IIB trial [which will take place in Kenya] is not yet fully enrolled, requires two years of follow-ups, and there still needs to be a Phase III, which will take at least three years to conduct, I cannot see a product being registered before 2017. Maybe 2020 is more realistic.
    
    Q: What impact do you hope the new vaccine will have on TB incidence in Africa?
    
    A: It will depend on the vaccine’s efficacy, but without a better TB vaccine it will be difficult to turn the TB epidemic in Africa around. www.ipsnews.net/africa/nota.asp?idnew...
    *
    Uit AMC Magazine:China moet aan de bak Tuberculosestammen die ongevoelig zijn voor verschillende soorten medicijnen rukken op…. tinyurl.com/2dtkuwj
21. flosz 18 oktober 2010 20:41

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    IDRI Develops Novel Tuberculosis Vaccine
    www.idri.org/index.php?name=press&sub...
    ffzwaaiennaarSteve