Treatment Action Group Online Toolkit

1 1 Treatment Action Group Online Toolkit INTRODUCTION The aim of the TB/HIV Activist Toolkit is to provide activists with fundamental information about tuberculosis (TB) and TB/HIV coinfection in order to strengthen their science, research, and policy literacy. We hope that activists will use this information to inform their advocacy and to develop community education materials and sessions on TB and TB/HIV. The facilitator notes and slide set are teaching tools that can be used as is or modified to suit your needs and audience. We estimate that it will take 75 minutes to complete this module using the accompanying slide set. The module is broken up into sections that can be taught as separate units or as one workshop. Time estimates have been included for each section of the module for your reference, but will vary based on the facilitator s comfort with and the participants understanding of the material. Please use the time allotments as a planning guide rather than a rule. The information in the facilitator notes is organized into five main categories: 1. Fundamental information provides further explanation of the information on the slides and slide notes, and is what we consider to be need-toknow information. 2. Teaching points/exercises are optional and are meant to provide an opportunity to reinforce information and/or stimulate discussion. 3. Review revisits key points of each section and provides an opportunity for clarification or further explanation. 4. Definitions provide explanation of commonly used and/or key terms. These terms are italicized in the main text. 5. Nice to know information is not considered necessary or fundamental to understanding basic concepts of this module but is nice to know. Please be careful before citing this information in a workshop because too much information may overwhelm some participants who are new to TB and TB/HIV advocacy. These facilitator notes are to be used as a guide for and explanation to the slide set. However, facilitators should feel free to develop their own slide sets or teaching tools using the notes and/or modifying the slides depending on your needs. Introduction to Module (5 minutes)! Display slide 1 MODULE 5: TB VACCINE MODULE The goal of this module is to provide activists with an understanding of the current TB vaccination strategy and the challenges of developing a new vaccine that is effective against all forms of TB in all populations, including HIV-positive people. At the end of this module participants will current knowledge about how it works positive infants! Display slide 2 : Topics to be covered

2 2 SECTION 1 What are vaccines, and how do they work? (slides 3 6; 10 minutes)! Display slide 3: What are vaccines, and how do they work?! Display slide 4: Primary and secondary prevention EXERCISE: ASK PARTICIPANTS TO DESCRIBE THE GOALS OF PRIMARY PREVENTION (TO BLOCK INFECTION) AND SECONDARY PREVENTION (TO BLOCK PROGRESSION OF INFECTION TO DISEASE). TB and HIV primary prevention interventions reduce the transmission and acquisition of infection, and secondary prevention strategies are aimed at early intervention to prevent disease progression.! Display slide 5: Primary and secondary prevention EXERCISE: ASK PARTICIPANTS TO PROVIDE EXAMPLES OF PRIMARY PREVENTION (TO BLOCK INFECTION) AND SECONDARY PREVENTION (TO BLOCK DISEASE PROGRESSION). Latent TB infection refers to the period of time when the immune system of an infected individual has been successful in containing TB bacteria and preventing disease. Active TB disease refers to the period of time when TB breaks out of latency and causes disease. Pathogens are any disease-causing biological substances or agents specifically bacteria, viruses, and other microbes. Pathogens are commonly referred to as germs.! Primary HIV prevention techniques may include safer sex practice (e.g., condom use), syringe exchange for IV drug users, preexposure prophylaxis with antiretroviral therapy (ART) for prevention of mother-to-child transmission. Primary TB prevention strategies may include infection control (e.g., increased air ventilation, cough hygiene). Because secondary HIV and TB prevention strategies aim at early intervention to prevent disease progression, they may include early use of ART before a person with HIV develops clinical symptoms or the use of isoniazid preventive therapy (IPT) to prevent progression of latent TB infection into active TB disease. In fact, secondary TB prevention strategy. *More on BCG in section 2 of this module. *For more information on TB primary and secondary prevention methods among people with HIV, see the Reducing the Burden of TB module.! Display slide 6: What are vaccines, and how do they work? Vaccines are compounds that create immunity that provide protection from a pathogen without causing the suffering of the disease itself. Dr. Edward Jenner discovered the first vaccine in the late 18th century, by demonstrating that exposure to the cowpox virus provided protection against the smallpox virus. After observing that milkmaids infected with cowpox virus were not affected by smallpox outbreaks, Dr. Jenner tested his theory by infecting a young boy with cowpox and then weeks later challenging his immunity with smallpox. He found that, like the milkmaids, the boy was unaffected by the smallpox. Dr. Jenner s experiment was groundbreaking and has led the development of thousands of vaccines, but it was highly unethical and dangerous to knowingly infect the boy with cowpox and thus put him at serious risk. *For more on research ethics go to the U.S. National Cancer Institute s research ethics course at http://web.ncifcrf.gov/campus/ethicscourse/. Prior to the discovery and development of effective vaccines, people had to suffer through a bout of illness to train the immune system to respond to the pathogen. Vaccines train the immune system to respond to a pathogen by creating immunological memory. The idea is that a vaccine exposes the immune system to a non-disease-causing version of the pathogen (it could be a bacterium, virus, parasite, or fungus) in order to train immune cells to respond rapidly if they encounter the pathogen. These memory cells enable the immune system to respond to future challenges of the pathogen

3 3 Live, attenuated vaccines, like BCG and measles, mumps, rubella (MMR), are made from pathogens whose disease-causing ability has been weakened by growing them over and over again. Inactivated (killed) vaccines, like the influenza vaccine, contain the pathogen that has been killed by some chemical or heat so that it cannot cause an infection but can still stimulate a protective immune response. Toxoid vaccines like tetanus are made by treating toxins (or poisons) produced by pathogens with heat or chemicals. So far this strategy is not relevant to TB because of lack of identified toxins in Mycobacterium tuberculosis (MTB). Component vaccines, like those for hepatitis A and B viruses, are made by using only parts of the viruses or bacteria to stimulate immune response to the whole pathogen. This process usually requires the purification of components from pathogens and mixture with factors called adjuvants that enhance the immune response. quickly so that infection or disease cannot be established in the body at all. This is what is called immunity. Not all vaccines work the same way. Some are weakened live versions of the pathogen, others are killed versions, and some include proteins from or other components produced by the pathogen. *For more on the immune response, see the TB Basics module. SECTION 1 REVIEW: Q1: prevention. A1: Primary prevention interventions aim to reduce the transmission and acquisition of infection. Examples of primary TB prevention interventions are cough hygiene, increased air ventilation, and other examples of infection control. Q2: secondary TB prevention. A2: Secondary prevention interventions are aimed at early intervention to prevent disease progression. Examples of secondary TB prevention interventions are the use of IPT for people who are latently infection with Q3: What is a vaccine? A3: A vaccine is a compound that creates immunity to provide protection from a pathogen without causing the suffering of disease. * N o t e t o f a c i l i t a t o r : t h e s e r e v i e w q u e s t i o n s a r e s u g g e s t i o n s a n d s h o u l d b e a d a p t e d b a s e d o n t h e p r e s e n t a t i o n.

4 4 SECTION 2 What is the current TB vaccine strategy, and why isn t it sufficient? (slides 7 11; 25 minutes)! Display slide 7: What is the current TB vaccine strategy, and why isn t it sufficient?! Display slide 8: What is the current TB vaccine?! Bacteria are single-celled microorganisms that are found virtually everywhere earth. Mycobacteria are a type of bacteria that have waxy cell walls that are resistant to digestion and live inside human cells. It is estimated that over 100 million doses are administered per year making it the most widely implemented vaccine in the world and saving the lives of approximately 40,000 children annually. It is part of the World Health Organization s (WHO s) Expanded Programme on Immunization (EPI) schedule of recommended routine immunizations for children living in countries with a high TB burden and high-risk children (e.g., those in close contact with adult TB patients who are untreated for TB disease) living in countries with a low TB burden. In countries such as the United States, of the low risk of infection. *For more information on the EPI immunization recommendations go to http://www.who.int/immunization/policy/immunization_tables/en/index.html. *For more information on the U.S. Centers for Disease Control recommendations on BCG vaccination go to http://www.cdc.gov/tb/ publications/factsheets/prevention/bcg.htm.! Display slide 9: How does BCG protect against TB?! Dr. Guérin and Dr. Calmette Pulmonary TB refers to TB in the lungs. Extrapulmonary TB (EPTB) refers to TB outside of the lungs. Tuberculosis is caused by Mycobacterium tuberculosis (MTB). There are over 70 types of mycobacteria not all of them are harmful, but MTB is the most common and the most deadly in humans. MTB is named for its appearance (myco- means waxy in Latin), the type of pathogen (bacteria), and the disease it causes (TB). Mycobacterium bovis (M. bovis) is another type of mycobacteria that causes a TB-like disease in cows and humans. Based on Dr. Jenner s use of cowpox M. bovis (referred to as culturing) in order to weaken the bacteria until it was unable to cause disease. After 11 years of culturing M. bovis they found that the bacteria did not cause disease in animals but could stimulate a protective immune response to MTB, and in in the world, yet there is still a lot of misunderstanding about it. Because conjunction with a host of other vaccines (including those for measles, polio, and tetanus) throughout the world. Little explanation is given to parents about these vaccines, and many people misunderstand the that because they were vaccinated against TB as infants that they are protected against all forms of the disease for their entire lifetime. In fact, the vaccine does not protect against pulmonary TB, the most extrapulmonary TB. Miliary TB (TB disseminated throughout the body) and meningial TB (TB in the lining of the brain) are two of the most severe forms of pediatric TB. Because infants and young children are much more

5 5 NICE TO KNOW It has been hypothesized that other mycobacteria or nontuberculosis mycobacteria (NTM) that are found throughout the environment may interfere with BCG vaccination. The concern is that infection with NTM could appear to provide protection against TB that mirrors the protection conferred by the BCG vaccine. This would mean that BCG would appear less effective in reducing the incidence of TB among populations that have high rates of infection due to NTM. Nontuberculous mycobacteria (NTM) also known as environmental mycobacteria are mycobacteria that can infect humans but may or may not cause disease and do not cause tuberculosis or leprosy (which is caused by mycobacteria leprae). likely to have extrapulmonary disease and get ill and die more quickly, received as infants is no longer effective and that it never protected against and its limitations.! Display slide 10: What are the limitations of BCG? intervention because it prevents latent TB infection from progressing to active TB disease rather than preventing infection after exposure to the evidence that does exist is not consistent. Two studies conducted significantly different efficacy. The British study showed about 80% efficacy while the efficacy rate in the U.S. study was just 14%. In the studies that have demonstrated efficacy the duration of protection varies widely. The by the time of adolescence. Because different manufacturers from around administered, and this may explain some of the observed differences in efficacy. Unlike other vaccines like tetanus and measle, mumps and rubella, additional doses (or boosters) do not extend the period of protection. *For more information on mycobacteria see the TB Basics module. * For more information on WHO recommendations on BCG vaccination in HIV-positive infants go to http://www.who.int/immunization/wer8221bcg_ May07_position_paper.pdf. NICE TO KNOW Despite its variability and limitations, it is estimated that the BCG vaccine saves the lives of over 40,000 children annually (of over 100 million vaccinated). This makes the decision of whether or not to vaccinate HIVexposed children where HIV RNA testing is not available a challenge for both parents and health care providers. Without being able to confirm an HIV diagnosis using RNA testing soon after birth, parents and their health care providers are forced to weigh the risks (BCG disease) versus the benefits (protection against severe forms of pediatric TB) of BCG vaccination. Some possible strategies to address the challenge of BCG in HIVexposed infants are early initiation of ART; BCG while on ART; IPT until HIV status is confirmed; and delaying BCG! Display slide 11: BCG in HIV-positive infants vaccination that cause significant morbidity in multiple organs among HIVpositive infants and young children particularly those not on ART. The protection for HIV-positive infants, particularly those with more advanced HIV disease. The WHO revised its guidelines in 2007 to recommend that The WHO recommendation is difficult to implement in many high-burden settings because of limited access to the HIV RNA testing needed to rapidly confirm HIV diagnosis in infants exposed to HIV.

6 6 SECTION 2 REVIEW: Q1: What is the only effective TB vaccine? A1: Q2: A2: extrapulmonary TB miliary TB (disseminated throughout the body) and meningeal TB (TB in the lining of the brain). Q3: A3: It is not effective in preventing pulmonary TB and most forms of EPTB; repeated vaccination; it is contraindicated for use in HIV-positive infants. Q4: infants? A4: among HIV-positive infants and young children particularly those not on ART. * N o t e t o f a c i l i t a t o r : t h e s e r e v i e w q u e s t i o n s a r e s u g g e s t i o n s a n d s h o u l d b e a d a p t e d b a s e d o n t h e p r e s e n t a t i o n.

7 7 NICE TO KNOW Who are some of the major players in TB vaccine development? (http://www.stoptb.org/wg/new_vaccines/) is one of seven working groups of the Stop TB Partnership, and acts as a central coordinating body of vaccine development. The goal of the Working Group on New TB large-scale efficacy trials by 2016. (Aeras; http://aeras.org/home/home. php) is a nonprofit product development partnership dedicated to the development of effective TB vaccine regimens that will prevent tuberculosis in all age groups and will be affordable, available, and adopted worldwide. Aeras is guiding many of the current vaccine constructs through clinical development and has six vaccines in or about to enter phase I and II clinical trials. Initiative ac.za/) is the largest dedicated TB vaccine research group on the African continent, and its long-term aim has been to develop capacity to conduct registration standard current the only research institution that has the capacity to conduct a phase III vaccine efficacy trial. http://www.tbvi.eu/) is an independent nonprofit organization that stimulates and coordinates the development of new, globally accessible and affordable from governments, nongovernmental organizations, foundations, private industry, and other private funders and distribute these funds among different research projects. SECTION 3 What is the status of TB vaccine research? (slides 12 17; 25 minutes)! Display slide 12: What is the status of TB research?! Display slide 13: What is in the pipeline? An effective vaccine is key to reaching the goal of TB elimination. Evidence suggests that mass vaccination, pre- and postexposure, will be required on new TB Vaccines there are nine vaccine candidates currently being evaluated in phase I and II clinical trials; note that as of December 2010 there are 12 vaccine candidates listed as in clinical trials on the working M. smegmatis are inactive and a phase III study of M. vaccae has been completed. enabling the immune system to get a head start when exposed, reducing bacterial load and preventing progression to clinical disease. No current TB vaccine candidate is designed to prevent infection altogether. Rather, current vaccines in clinical studies are designed to stimulate immune vaccine candidates fall into three categories: priming, boosting, and immunotherapeutic. immune system how to respond to a pathogen by creating immune cells specific to whatever components are in the vaccine. strengthens the immune response induced by the priming vaccine. postinfection and prevents disease progression or improves the impact of treatment. Most of the vaccine candidates that have entered into clinical studies are part of a prime-boost strategy. This means that they were designed to boost the efficacy, potency, and durability of a priming vaccine. The premise behind prime boost vaccines is that infants who have been vaccinated vaccine weeks, months, or years later (depending on the vaccine) to strengthen the immune response that was induced by the priming vaccine by increasing the number or broadening the activity of TB-specific immune cells. Most of the booster vaccine candidates in clinical trials are being * For more on the status of the TB vaccines pipeline go to http://www.stoptb. org/wg/new_vaccines/assets/documents/tb%20vaccine%20pipeline%2009%20 final.pdf.! Display slide 14: Vaccines farthest along in the pipeline. N o t e t o f a c i l i t a t o r : B e s u r e t o u p d a t e t h i s i n f o r m a t i o n b e f o r e f i n a l i z i n g y o u r p r e s e n t a t i o n s, a s t h e s t a t u s o f vaccines may change based on new clinical evidence.

8 8 TB Vaccine Pipeline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ntigens are the active components of a vaccine that stimulate the body to produce an immune response to fight off disease. Adjuvants, while not having any specific immunogenic effect in themselves, are compounds that stimulate the immune system, increasing the response to a vaccine. prevent progression to TB disease. candidates being evaluated in phase I and three in phase II clinical trials: two are viral vectored vaccines meaning that they use non-diseasecausing versions of viruses combined with TB antigens to stimulate an immune response to TB. The M72 is a vaccine that is made up of an adjuvant a molecule that stimulates an immune response and two recombinant TB proteins meant to strengthen the immune response to two highly immunogenic fragments of the TB bacterium. (non-disease-causing) version of the vaccinia virus (cowpox) combined with TB antigen 85A is being considered as a booster of preexisting immune responses to antigen 85A, which is present in most people most advanced TB vaccine candidate and a phase IIb study in infants is currently underway. Oxford University developed the vaccine and has partnered with Aeras to conduct clinical trials. deficient adenovirus (Ad35) that serves as a vector for DNA expressing TB antigens 85A, 85B, and 10.4. Adenoviruses are potent inducers an effective vaccine-induced immune response. A phase IIb study evaluating safety and efficacy in HIV-negative infants is about to begin. primate model. Early results suggest that the vaccine is clinically well tolerated and produces a measurable immune response. Subsequent clinical trials are now planned for adolescents and infants in TBendemic regions.

9 9 NICE TO KNOW Adenoviral vectors have been used in investigational vaccines for a number of diseases, including HIV, herpes, and rabies, because they can be easily modified to deliver genetic material from an organism to trigger an immune response and because they are potent inducers of CD8 cell responses. There is a concern that for individuals who have preexisting antibodies to Ad35 or Ad5 these adenoviral vaccines Aeras 485/Crucell 402 and Ad5Ag85A may be less effective. The prevalence of antibodies varies geographically. Immunogenicity is the degree to which a vaccine is able to illicit an immune response to a pathogen, and is used as an early measurement of a vaccine s activity against a pathogen. NICE TO KNOW Mycobacterium vaccae (M. vaccae) is a heat-killed NTM that was originally evaluated as an immunotherapeutic vaccine to strengthen the immune system of people already infected with TB with the aim of preventing disease progression or improving the impact of treatment. The limited data on M. vaccae are uninspiring. A number of studies showed no immunotherapeutic benefit for people with TB and therefore no further trials were warranted. However, evidence from the Dar Dar study has suggested that a multidose M. vaccae vaccination was associated with protection against TB disease in people with HIV with CD4 counts above 200. The Dar Dar study results would need to be confirmed via additional studies before any conclusions could be made about effectiveness, yet there are no plans for additional studies at this time. As of December 2010, there are six candidates being evaluated in phase I studies: subunit protein vaccines combined with adjuvants (immune-stimulating factors) under development by the Statens Serum Institute with partners including Aeras and Sanofi Pasteur. HyVac4 contains the MTB Hybrid1, containing the MTB antigens 85B and ESAT6, is combined with vaccines and have completed safety studies in humans. strain. The vaccine was originally made by the Max Planck Institute for Infection Biology and is now being developed by Vakzine Projekt Management. The vaccine has induced TB-specific immune responses, and a phase Ib trial is currently underway that evaluates safety, tolerability, and immunogenicity immunization as a comparator. is based on the possibility of using the vaccine to accelerate the treatment of latent TB in combination with isoniazid. McMaster University are interested in pursuing intranasal (through the nose) delivery.! Display slide 15: TB vaccine development timeline TB Vaccine Development Timeline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here is overwhelming agreement that a safe, tolerable, easy-to-administer vaccine that provides lifetime protection against all forms of TB infection and disease in all populations and age groups is key to reaching the goal of eliminating TB by 2050. However, there are currently few who are willing to pay for the research and development required. The revised cost estimates in the Global Plan to Stop TB 2011 2015 estimate that the direct costs to develop one TB vaccine candidate for one target population could be as much as $315 million. But much more is needed to keep the pipeline filled with viable candidates and to keep those candidates moving through the pipeline.

1010! Display slide 16: Funding needs 2011 2015 Funding Needs 2011-2015: US$1.9B The Global Plan to Stop TB 2011 2015 is a comprehensive assessment of the action and resources needed to implement the Stop TB strategy and make an impact on the global TB burden. This is the third revision since the original plan was released in 2001. A significant change to this edition is the updated research agenda that now includes basic science and operational research and more realistic costing of each component to include capacity building, infrastructure, and research advocacy. * The Global Plan to Stop TB 2011 2015 can be found at http://www.stoptb.org/assets/documents/ global/plan/tb_globalplantostoptb2011-2015.pdf. As vaccine candidates progress through the pipeline and more candidates are added to the pipeline, the costs of doing vaccine research rise. The Global Plan to Stop TB 2011 2015 estimates that $1.9 billion will be needed for the years 2011 2015 in order to have three vaccine candidates in phase III efficacy trials. But the costs of doing research are not just those of a trial alone but also include investment in preclinical and basic science research to better understand how the immune system responds to TB and to identify and develop potential vaccine candidates. Resources need to be dedicated to manufacturing the vaccine and building the capacity of clinical trial sites to conduct later stage trials that are larger and more complex. As a vaccine trial nears regulatory approval advocacy is needed to clarify the regulatory pathway and create demand for a new vaccine. * For more information on the Global Plan to Stop TB 2011 2015 go to http://www.stoptb.org/assets/documents/global/plan/tb_ GlobalPlanToStopTB2011-2015.pdf.! Display slide 17: TB Vaccine Funding 2009 Without a great increase in funding, TB vaccine research will stagnate. After years of flat funding, TB vaccine spending received a big boost in accounted for the great majority of funding for TB vaccine research contributed $67 million. This amount accounted for 61% of all funding for TB vaccines that year. Reliance on one or a few funders may result in donor fatigue and a shrinking pool of institutions and researchers able to contribute to vaccine development. In 2009 TB vaccine research funding representing 18% of overall TB R&D research funding remained flat at $108.8 million after growing by 33% in area, though its contribution, compared to the previous year, declined by 40% from $66.9 million to $47.6 million. * For more information on TB R&D funding trends go to www.treatmentactiongroup.org/ TBRD2010.aspx. The funding targets for new vaccine development in the Global Plan 2011 2015 estimate $1.9 billion will be needed by 2015 to expand clinical trial and manufacturing capacity while also maintaining a strong pipeline of new vaccine candidates. Annual TB vaccine funding must reach $250 million in 2011 and nearly $440 million in 2015 in order to develop and introduce a vaccine effective against all forms of TB and across all age groups and among people with HIV.

1111! Display slide 18: Challenges for TB Vaccine Research EXERCISE ASK PARTICIPANTS TO IDENTIFY CHALLENGES FOR TB VACCINE RESEARCH. N o t e t o f a c i l i t a t o r : t h i s l i s t i s n o t e x h a u s t i v e a n d s h o u l d b e u s e d a s a g u i d e b a s e d o n t h e i n f o r m a t i o n d i s c u s s e d i n this module. best. Efforts need to be directed toward increasing the awareness of new vaccine. Without community demand for a new vaccine it is unlikely that any new vaccine will be scaled up rapidly if at all. Significant progress has been made in TB vaccine development despite the fact that there is limited understanding of infection, latency, and disease. But a better understanding of the immune response to TB and what host and pathogen factors contribute to establishment of infection and reactivation could expedite the development and evaluation of new vaccines. There are no validated correlates of protection for TB vaccines. Defined correlates of immunity immune responses that indicate a person is protected against TB are critical for measuring vaccine efficacy and getting regulatory approval. scale phase III licensure study. There are capacity building efforts underway, but given the number of candidates in the pipeline it is unlikely that there will be enough infrastructure in place to support laterstage clinical trials of all of the candidates. to be safe in HIV-positive infants. But all the current prime-boost contraindicated for use in HIV-positive infants. vaccination but there are varying levels of adenoviral antibodies in the general population that may impact the efficacy of adenoviral vector vaccines. There are not the necessary resources available to conduct phase III vaccine efficacy studies. It is estimated that there is a funding shortfall of about $1 billion for TB vaccine research.

1212 SECTION 3 REVIEW: Q1: What are the three vaccine categories being pursued in TB vaccine research? A1: boosting, and immunotherapeutic. Priming vaccine induces an initial immune response by teaching the immune system how to respond to an organism by creating immune cells specific to whatever components are in the vaccine. Boosting vaccine may be given months or years after the primer and strengthens the immune response induced by the priming vaccine. Immunotherapeutic vaccine strengthens the immune response postinfection and prevents disease progression or improves the impact of treatment. Q2: Name two challenges for TB vaccine research. A2: Note to facilitator: this list is not exhaustive and should be used as a guide based on the information discussed in this module. at best. Efforts need to be directed toward increasing the awareness need for a new vaccine. Without community demand for a new vaccine it is unlikely that any new vaccine will be scaled up rapidly if at all. Significant progress has been made in TB vaccine development despite the fact that there is limited understanding of infection, latency, and disease. But a better understanding of the immune response to TB and what host and pathogen factors contribute to establishment of infection and reactivation could expedite the development and evaluation of new vaccines. There are no validated correlates of protection for TB vaccines. Defined correlates of immunity immune responses that indicate a person is protected against TB are critical for measuring vaccine efficacy and getting regulatory approval. scale phase III licensure study. There are capacity building efforts underway, but given the number of candidates in the pipeline it is unlikely that there will be enough infrastructure in place to support later-stage clinical trials of all of the candidates. intended to be safe in HIV-positive infants. But all the current prime- which is contraindicated for use in HIV-positive infants. for vaccination but there are varying levels of adenoviral antibodies in the general population that may impact the efficacy of adenoviral vector vaccines. There are not the necessary resources available to conduct phase III vaccine efficacy studies. It is estimated that there is a funding shortfall of about US$1 billion for TB vaccine research.

1313 * N o t e t o f a c i l i t a t o r : t h e s e r e v i e w q u e s t i o n s a r e s u g g e s t i o n s a n d s h o u l d b e a d a p t e d b a s e d o n t h e p r e s e n t a t i o n.! Display slide 19: Module review (10 minutes) prevention. secondary TB prevention. infants? research? * N o t e t o f a c i l i t a t o r : t h e s e r e v i e w q u e s t i o n s a r e s u g g e s t i o n s a n d s h o u l d b e a d a p t e d b a s e d o n t h e p r e s e n t a t i o n. We would like to thank Mike Brennan, Senior Advisor for Global Affairs at Aeras Global TB Vaccine Foundation and Richard Jefferys, Basic Science, Vaccines, and Prevention Project Coordinator at Treatment Action Group, for taking the time to review this module and providing valuable feedback.

1414 References Abu-Raddad LJ, Sabatelli L, Achterberg JT, Sugimoto JD, Longini IM Jr., Dye vaccines, drugs, and diagnostics. Proceedings of the National Academy of Sciences USA 2009;106(33):13980 85. States. Am Rev Resp Dis 1966;93(2): 171 83. hlthaff.24.3.611. Science, 14 May 2010, 856 861. immunity. Lancet 1995; 346(8986):1339 45. Doi:10.106/S0140-67636(95)92348-9. bmj.2.6082.293. patterns, new challenges. Health Affiars 2005;3: 611 21. with an inactivated whole-cell mycobacterial vaccine. AIDS 2010;24(5):675 85. World Health Organization. 2007. WHO recommended routine immunizations-summary of position papers. http://www.who.int/immunization/ policy/immunization_routine_table1.pdf. of tuberculosis in children with HIV: Randomised controlled trial. British Medical Journal 2007;334:136.