TB Vaccine Accelerator - Announcing a Funding Opportunity
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Announcing a Funding Opportunity:
TB Vaccine Accelerator
To develop models of natural Mycobacterium tuberculosis transmission, define key
transmission properties, and develop new approaches to vaccination that will protect against
infection
The Bill & Melinda Gates Foundation
1Table of Contents
I. Summary Page 2
II. TB Vaccine Accelerator Program – Overview Page 2 ‐3
III. Scope of this RFA Page 3‐6
IV. LOI Submission Process Page 6‐7
V. Eligibility and Notifications Page 7‐10
2I. SUMMARY
The prevention of tuberculosis (TB) through the development and deployment of an effective vaccine is
a priority of the Bill & Melinda Gates Foundation (BMGF). To strengthen the pipeline of vaccine
candidates and enable a more rational and accelerated vaccine development process, BMGF, in
collaboration with its Product Development Partner Aeras, recently launched the TB Vaccine Accelerator
Program. With the assistance and support of the TB research and development community, a set of
obstacles to TB vaccine development—and integrated goals that, collectively, could help to directly
understand, overcome or work around these obstacles—have been selected. Through a research
program focused on achieving this defined set of interdependent goals, the TB Vaccine Accelerator aims
to address significant challenges in this field.
This Request for Applications (RFA) seeks to identify projects that will help meet one or both of the
following two interrelated goals—
(1) To develop novel approaches to vaccination against Mycobacterium tuberculosis (Mtb), with a
particular focus on approaches that aim to induce protection against infection with Mtb
(2) To develop models of natural Mtb transmission and/or methods for defining the relevant
molecular and biological characteristics of naturally transmitted mycobacteria and the
interactions of such with vertebrate hosts
These goals, along with proposal requirements and submission instructions, are described in greater
detail below. The selection of grantees will follow a two‐step process. At this time, we request that all
applicants submit a brief Letter of Inquiry (LOI) summarizing their proposed idea and project, and how
they will meet one of the above goals. To be considered, LOIs must be submitted no later than
November 26, 2012 (11:59am PST). Applicants with LOIs of significant interest will then be invited to
submit a full proposal.
II. TB VACCINE ACCELERATOR PROGRAM ‐ OVERVIEW
Obstacles to the development of protective TB vaccines are considerable. Namely, the mechanisms
underlying protection against infection and/or disease are not understood; there are no biomarkers
known to predict the efficacy of vaccine candidates; and commonly‐used animal models neither mimic
natural infection nor have been designed to define the mechanisms underlying (or the ability of vaccines
to induce) protection from infection as opposed to disease. Furthermore, much of the focus in the field
of TB vaccine development has been on driving T cell responses against immunodominant antigens with
the goal of increasing the proportion of infected individuals that remain disease‐free. Although a
plethora of candidate vaccines are in the pipeline, it is currently impossible to define efficacy without
the long and costly progression to Phase IIB/III clinical trials. (For additional information about current
candidates and ongoing assessment, see The TB Vaccine Blueprint. 2012. Tuberculosis. 92: S1‐S35.)
We are continuing the mission set forth in the Grand Challenges in Global Health initiative to overcome
persistent bottlenecks in creating new approaches and interventions that can radically improve health in
the developing world. Here we announce a new grant program within this initiative: the TB Vaccine
Accelerator Program. This program focuses on key areas where additional investments may be able to
fill critical knowledge gaps and generate much‐needed tools for enabling and accelerating TB vaccine
development. These include the development and characterization of natural transmission models; the
development and validation of human challenge models; the identification of correlates of risk and
3protection via systems biology; the generation of basic standards and common immunological reagents
that will allow for increased efficiency, collaboration, and direct comparison of vaccine candidates; the
generation of novel vaccine concepts, with an emphasis on those aimed at inducing protection against
infection (rather than, or in addition to, progression from infection to disease), the early testing of which
may be uniquely enabled by the availability of optimized natural transmission models. This RFA solicits
proposals that target two of these areas.
III. SCOPE OF THIS RFA
The purpose of this RFA is to define and develop ideas that, if pursued, will lead to the attainment of
two key goals within the TB Vaccine Accelerator Program. These goals are described below, along with
examples of ideas and projects that would be considered within (or outside) the scope of each goal.
Goal 1: To develop novel approaches to vaccination against Mtb, with a particular focus on
approaches that aim to induce protection against infection with Mtb
Background to Goal 1
TB vaccines currently in the pipeline all, fundamentally, aim to increase the proportion of individuals
that remain free of active disease after infection with Mtb. In the parlance of the HIV field, this is akin to
attempting to increase the proportion of “elite controllers”, with a critical difference being that, in the
case of Mtb, lifetime control is obtained by the majority (90%) of infected individuals in the absence of
immunosuppression. The majority of TB vaccines in the current pipeline also derive from a single
paradigm, that of driving T cell responses against immunodominant antigens, something that derives,
largely, from: (a) the notion that T cell responses are key to successful responses against largely
intracellular pathogens (despite, e.g., the demonstrated utility of antibody responses during diverse viral
infections) and (b) observed T cell responses against these antigens in latently‐infected individuals.
Alternatives to this paradigm are rarely explored despite recent data indicating that the genes encoding
the immunodominant antigens of Mtb are among the least variable in the Mtb genome—suggesting
that the ability to drive such T cell responses may be advantageous to the pathogen (Comas et al. 2010.
Nature Genetics. 42: 498‐505.)
The aim of Goal 1 is to facilitate the broadening of approaches to TB vaccination. Of particular interest
are approaches that aim to prevent the acquisition and establishment of infection. It is noted that,
especially in areas of high transmission, the bulk of disease may well be the result of supra‐infection of
latently‐infected individuals. Protection against primary infection or supra‐infection may represent the
induction of “uncommon immunity” (The existence of individuals with such protective, “uncommon
immunity” remains to be definitively documented in TB, but, in HIV parlance, uncommon immunity
would refer to what is observed in multiply exposed, persistently uninfected individuals.) Alternatively,
protection against infection may require the induction of completely “unnatural immunity”, which can
be defined as immunity that can be induced via a specific vaccination strategy but is never observed in
naturally exposed or infected individuals. A prime example of unnatural immunity induced by
vaccination is found in the case of one of the earliest effective vaccines still in use—the tetanus toxoid
vaccine. Survival of natural infection with Clostridium tetani does not lead to the generation of
protective titers of antibody to tetanus toxin, something robustly achievable with vaccination.
4Scope of Goal 1
Proposals are invited for projects that pursue hypothesis‐driven approaches aimed at developing, or
critically informing the development of, novel approaches to vaccination against Mtb. Approaches that
aim to induce protection against Mtb infection are of particular interest.
Examples of topics considered within the scope of Goal 1 include:
• Vaccine approaches aimed at inducing antibody‐mediated immunity, e.g., directed against the
surface constituents of naturally‐transmitted Mtb;
o Proof of concept testing of such in models of, or models mimicking, natural
transmission;
o Efficient identification of such surface constituents, their immunogenicity and if/how
these constituents differ in circulating strains;
• Definition of how above antibodies perturb the interaction of Mtb with host cells such as lung
macrophages and dendritic cells;
• Vaccine approaches aimed at the induction of durable innate lymphocyte responses to Mtb
glycolipids;
• Development of reliable methods for identifying highly‐exposed individuals who remain
uninfected and individuals who rapidly clear infection;
o Formal testing of the notion that individuals who skin‐test convert (TST+ to TST‐), or go
from IGRA+ to IGRA‐, have cleared prior infection;
o Identification of protective immune signatures in such individuals;
• Development of assays for measuring prevention of infection in animal models (applicable to
Goal 2 as well) or humans; assays that define whether Mtb is present or not in a model system;
• Other highly novel approaches to vaccination that induce protection against Mtb infection.
Examples of proposals that would be considered outside the scope of Goal 1 and, as such, would not be
considered for funding:
• Approaches that closely resemble those already being implemented or under investigation;
• Conventional T cell antigen discovery;
• Ideas or exploratory/unbiased discovery studies without a testable and feasible hypothesis;
• Incremental improvements to approaches already implemented or under investigation;
• Epidemiology or infection/disease prevalence studies;
• Studies based on hypotheses or ideas which, should they be proven, could not translate into
practical, long‐lasting, and widely‐available immunization or immunization‐like strategies;
• Genome association studies.
Goal 2: To develop models of natural Mtb transmission and/or methods for defining molecular and
biological characteristics of naturally transmitted mycobacteria and the interactions of such with
vertebrate hosts
Background to Goal 2
As described above, a second major area of focus in the TB Vaccine Accelerator Program is the
improvement of animal and human models for vaccination and challenge studies. While several models
are in use for vaccine development, it is unclear how predictive they are of outcomes in humans.
Without direct comparison with human clinical trial data, it will be impossible to determine the overall
predictive value of any model.
5Moreover, currently employed animal models would not allow for testing of the ability of a vaccine to
prevent infection because the robust challenge doses lead to infection in 100% of challenged animals.
(This is akin to strategies previously used in the HIV field involving intravenous challenge of macaques
with high doses of SIV or SHIV, as opposed to current strategies involving repeated, low dose mucosal
challenge.) Furthermore, while standard Mtb administration models may mimic the airway route of
natural exposure, the in vitro Mtb culture conditions employed—including, prominently, the use of
detergents that likely strip the natural mycobacterial surface—are unlikely to model natural conditions
of exposure such as Mtb phenotype and presentation, which are critical for evaluating the potential of
vaccination approaches aimed at preventing infection.
To model natural transmission, Mtb challenge must resemble (in both phenotype and infective dose)
that of naturally‐encountered infectious Mtb. Without a model in which natural phenotype and dose
are mimicked, or even a clear understanding of the phenotype of the subset of expelled bacteria that
establish infection in new hosts, direct artificial exposure will remain of uncertain value for testing
vaccines that aim to elicit a protective response against naturally‐transmitted bacteria at the site of
infection. One alternative is to use natural transmission models, where infectious animals (or humans)
are housed with naïve and vaccinated animals for a prolonged period of time.
While current natural transmission models allow for exposure to (and infection by) Mtb as typically
presented (e.g., within droplets, with typical surface phenotypes, and in realistic doses), these models
are far from optimal. Among the challenges of working with a natural transmission model are: (1) the
needed duration (and associated housing costs) of the experiment to ensure all animals have been
exposed and have experienced an ‘infection opportunity’; (2) the lack of sensitive assays for exposure;
and (3) the inability to detect early infection.
Scope of Goal 2
Proposals are invited for the development of solutions to the challenges described above. Through this
RFA, we seek a portfolio of projects that, in concert, will identify properties of Mtb and conditions of
exposure associated with the natural establishment of infection; allow such properties and conditions to
be mimicked in optimized models and Mtb to be tracked throughout exposure, elimination, transient,
and/or persistent infection; and identify host and/or mycobacterial markers that distinguish among
these outcomes. The identification of all critically relevant properties of these natural transmission
models could allow for their future duplication in artificial transmission models.
Examples of proposals that would be on the critical path to Goal 2, and as such would be considered
within the scope of this goal, include:
• Identification of markers of exposure, prevention of infection, transient infection, and clearance
of infection;
• Methods for: quantifying live, infectious Mtb in the air (i.e., inoculum load in closed natural
transmission settings); improving control and consistency in natural transmission models (e.g.,
time of exposure, level of exposure); and/or improving efficiency of natural transmission models
(e.g., time to universal exposure to infectious Mtb);
• Characterization of the relevant biological characteristics of Mtb transmitted from human‐to‐
human in typical settings, in concert with the development of in vitro Mtb growth and
preparation conditions that result in bacteria that closely approximate those of naturally‐
transmitted Mtb (particularly in their surface architecture) and which can be aerosolized and
transmitted without losing these relevant properties;
6• Highly sensitive methods for ‘marking’ mycobacteria subpopulations in order to allow tracking
of those with unique phenotypes and to explore key differences in infectivity and clearance.
Examples of types of proposals that would be considered outside the scope of Goal 2 include:
• Utilization or improvement of artificial challenge models that do not address shortcomings
discussed above;
• Studies of existing natural transmission models without a focus on optimization of the
parameters discussed above;
• Models of latency or disease.
IV. LOI SUBMISSION PROCESS
We are accepting LOIs addressing Goal 1 or 2, as described above. LOIs for projects that do not directly
relate to these Goals will not be reviewed, regardless of their quality. Please read through this RFA in its
entirety and ensure your application, budget and institution are in compliance with all rules and
eligibility criteria provided.
Up to $20 million will be available over the next three years ($5 to 8 million per year) for the pursuit of
the two goals described here. The sum cost of all projects ultimately selected, through this two‐stage
RFA process, may not exceed this amount.
This RFA is not an offer by BMGF to invest or partner. BMGF assumes no responsibility for costs
incurred in responding to this RFA or any further invitations or communications from BMGF. Moreover,
the RFA may be amended or withdrawn at any time and copies of the amendments or withdrawals of
the RFA will be sent to all those submitting an LOI. If BMGF receives and responds to clarifying
questions regarding this RFA, the questions and answers may be made available to all parties if they are
deemed to be of general interest to all those that have or may submit an LOI.
A. LOI application Instructions
1. Submission deadline: LOIs must be submitted electronically by 11:59am PST on November 26,
2012 using the forms and process described at the following address:
http://www.grandchallenges.org/GrantOpportunities/Pages/TBVaccineAccelerator.aspx
2. Heading: At the top of the LOI application form, please include the text, “In support of Goal # (1
or 2) of TB Vaccine Accelerator RFA 01.”
3. First Paragraph: Please ensure the first paragraph of the project description defines the specific
objectives of the project and how these project objectives will support the larger aims of the TB
Vaccine Accelerator Program—namely, how they will meet either Goal 1 or 2 of this RFA.
4. Milestones: Along with the overall project objectives, please identify interim milestones that are
crucial for the success of the project. Within the LOI application, please describe how each
milestone will be met, anticipated obstacles, how obstacles will be overcome, and why your
approach is likely to succeed—particularly where others have failed.
5. Timeline: The LOI application must include a timeline for the attainment of each objective and
milestone. The duration of the project cannot exceed 3 years.
76. Budget: A budget for the proposed project must be submitted using the template provided.
7. In‐form Instructions and Page Limits: Please follow all instructions on the LOI application form
and do not exceed the page limitations.
B. Anticipated Timeline
Date Activities
September 19, 2012 Begin accepting applications
November 26, 2012 (11:59am PST) Deadline for receipt of LOI
January 25, 2013 (or before): Select applicants will be asked to complete a full proposal
March 25,2013 Deadline for receipt of solicited proposals
June 21, 2013 (or before) Grant recipients notified
C. Evaluation Criteria
LOIs of interest will be selected and the applicant asked to submit a full proposal that describes the
proposed project in greater detail. A subset of full proposals will be selected for funding. All appropriate
applications will be reviewed by members of a review committee to assess the likelihood that the
proposed research will have a substantial impact on the pursuit of the goals outlined in this solicitation.
The following selection criteria will be implemented. The weight of each criterion will differ for
proposals aimed at supporting Goal 1 compared to those supporting Goal 2.
1. Significance. The proposed project is within the scope of one of the two Goals described above;
demonstrates a clear understanding of, and the hurdles that must be overcome to meet, the RFA
Goal in question; offers a novel and innovative solution to the challenges that have previously
prevented success in these areas; addresses an unmet and high priority need; and is based on a
sound hypothesis.
2. Approach. The project design is well‐developed, scientifically‐sound, and based on solid
assumptions. The methods and techniques are appropriate, well‐considered, and feasible; yet,
potential hurdles are recognized and alternative approaches are considered. Budgets and
milestones have, likewise, been well‐planned and are appropriate. Importantly, the project and
deliverables have a high value to cost ratio. (The cost of the project relative to the primary
deliverable will be a key factor in proposal evaluation, as will the duration of the project.)
3. Likelihood for success. The team that will carry‐out the proposed project is well‐positioned to
complete the scope of work, deliver the desired product, and meet milestones on time and
within budget. They have brought together all necessary expertise, have strong collaborations,
are effective communicators and are amenable to partnering with BMGF and other grantees with
complementary projects and aims.
V. ELIGIBILITY and NOTIFICATIONS
A. Institution Eligibility Criteria
8All applicant organizations are encouraged to apply. This RFA is not limited to any specific type of
organization.
B. Allowable Costs
Grant funds may be used for the following costs: personnel, necessary travel, supplies, contracted
services, sub‐grants, and consultants. Partial or full support for equipment may be requested subject to
the circumstances described below. Please provide budget estimates according to these categories.
1. Equipment. Use of any equipment purchased with grant funds is limited by law to charitable
purposes for the depreciable life of the equipment. Please note that for many non‐U.S. entities,
U.S. tax law considerations may affect whether BMGF will permit purchase of equipment with a
depreciable life that is greater than the grant period being requested. In such cases, leasing
would be preferable.
2. Indirect costs. BMGF provides a limited amount of indirect costs based on the nature of the
applicant organization.
D. Privacy Notice
To help BMGF staff in their evaluation and analysis of projects, all documents, communications and
associated materials submitted to BMGF (collectively, “Submission Materials”) will become the property
of BMGF and may be subject to confidential external review by independent subject matter experts in
addition to analysis by BMGF staff. Please consider carefully the information included in the Submission
Materials. If you have any doubts about the wisdom of disclosure of confidential or proprietary
information, BMGF recommends you consult with your legal counsel. You may wish to consider whether
such information is critical for evaluating the submission, and whether more general, non‐confidential
information may be adequate as an alternative for these purposes. We respect confidential information
we receive. Nonetheless, notwithstanding your characterization of any information as being
confidential, BMGF may disclose all information contained in Submission Materials to the extent it
determines is necessary to evaluate them and the manner and scope of potential funding and as may be
required by law.
E. Warranty.
By providing any Submission Materials, the senders warrant to BMGF that they (the senders) have the
right to provide the information submitted. Applicants with questions concerning the contents of their
Submission Materials may contact BMGF at: grandchallenges@gatesfoundation.org
F. Intellectual Property (IP)
Since the output of this program may lead to innovative technologies, techniques and/or products that
will result in improved vaccines for those in greatest need in the developing world, the successful
development of these high priority products may require substantial involvement and support of private
sector industries as sub‐contractors, and may also involve collaborations with multiple organizations,
including academic and/or non‐profit research institutions.
It is the intent of this program to support the formation of appropriate public‐private partnerships that
are essential to meet urgent global health needs. IP rights and the management of IP rights are likely to
play an important role in achieving the goals of this program. To this end, BMGF requires that, even at
the LOI stage, all applicants seriously consider their willingness to submit a full proposal in compliance
with BMGF’s proposal guidelines, a portion of which asks for certain information and intentions
regarding intellectual property and global access concerns. Specifically, BMGF requires that you agree to
use good faith efforts to conduct and manage the research, technologies, information and innovations
9involved in the Project in a manner that enables (a) the knowledge gained during the Project to be
promptly and broadly disseminated, and (b) the intended product(s) to be made available and accessible
at reasonable cost to the developing countries of the world. BMGF refers to this as “Global Access.”
As part of BMGF’s review and evaluation of each full proposal, due diligence will be conducted with
respect to each participant’s ability and commitment to manage intellectual property in a manner
consistent with the stated scientific and charitable goals of BMGF. Due diligence activities may include
inquiry into an applicant’s: (1) Freedom to operate (FTO) and ability to freely use and acquire needed
background technology; and (2) Commitment to promote the utilization, commercialization and
availability of inventions for public benefit in, or the benefit of, developing countries. In order to
facilitate this due diligence process applicants are encouraged to provide information with respect to
the items above in their submission materials.
Applicants are also expected to make new information and materials known to the research and medical
communities in a timely manner through publications, web announcements, progress reports to BMGF,
and other appropriate mechanisms. These concepts may be discussed at some length with the
applicants invited to submit full proposals, and will be addressed (to the extent appropriate) within each
final grant agreement. The Global Access Strategy will also include provisions defining these concepts.
G. Research Assurances
While not necessary for the LOI, as applicable to the individual project, BMGF will require that for each
venue in which any part of the project is conducted (either by your organization or a subgrantee or
subcontractor) all legal and regulatory approvals for the activities being conducted will be obtained in
advance of commencing the regulated activity. BMGF will further require you to agree that no funds will
be expended to enroll human subjects until the necessary regulatory and ethical bodies’ approvals are
obtained.
1. Research Involving Human Subjects. You agree that no funds will be expended to enroll human
subjects in any research project subject to Institution Review Board (IRB) or independent ethics
committee (IEC) approval until such approval has been obtained for each site.
2. Clinical Trials. We do not expect projects to require clinical trials on human subjects; however, if
human trials are included, a condition of a grant is your agreement that the appropriate Institutional
Review Boards (“IRBs”) and ethical committees will review and approve the clinical protocols prior
to trial initiation. You further agree to conduct clinical trials associated with the project under the
generally accepted principles of “Good Clinical Practices” as defined by the International Conference
on Harmonization (ICH) E‐6 Standard, the United States Food and Drug Administration (FDA) or the
European Agency for the Evaluation of Medicinal Products (EMEA), as applicable. You acknowledge
and agree that, as between you and BMGF, you take and will have full responsibility for all
compliance, data safety, monitoring, and audit requirements of the relevant regulatory agencies,
both for yourself and all other sites included in the project, including those activities conducted
through subgrants, subcontracts or other collaborative efforts. You acknowledge and agree that any
activities by BMGF as the grantor funding the Project, including its review of the Proposal or
suggested modifications to the Project, does not modify the provisions of this paragraph or
constitute the basis for any claim by you against BMGF.
3. Coverage for all Sites. You agree that for each venue in which any part of the Project is conducted
(either by your organization or a subgrantee or subcontractor) all legal and regulatory approvals for
10the activities being conducted will be obtained in advance of commencing the regulated activity.
You further specifically agree that no funds will be expended to enroll human subjects until the
necessary regulatory and ethical bodies’ approvals are obtained.
Regulated Activities. The coverage requirements set forth in the preceding paragraph include but
are not limited to regulations relating to: research involving human subjects; clinical trials, including
management of data confidentiality; research involving animals; research using substances or
organisms classified as Select Agents by the U.S. Government; use or release of genetically modified
organisms; research use of recombinant DNA; and/or use of any organism, substance or material
considered to be a biohazard, including adherence to all applicable standards for transport of
specimens, both locally and internationally, as appropriate. As applicable, regulated activities and
their documentation are to be conducted under the applicable international, national, and local
standards. Documentation of research results should be consistent with regulations and the need to
establish corroborated dates of invention and reduction to practice with respect to inventions
where this is relevant.
4. Institutional Review Board (IRB) Approval. You agree to obtain the review and approval of all final
protocols by the appropriate IRBs and ethical committees prior to enrollment of the first human
subject and when using human material. A similar provision applies to Institutional Animal Care and
Use Committee approval of studies involving animals and Institutional Biosafety Committee
approval for biohazards and recombinant DNA. You agree to provide prompt notice to BMGF if the
facts and circumstances change regarding the approval status of the IRBs or ethical committees for
any final protocol(s).
5. Provision of Care for Human Subjects Research. In keeping with “Good Clinical Practice” standards,
you will disclose to subjects and the IRBs what care and/or referrals will be available through
participation in the study. Institutional policies regarding what care will be provided to personnel
who are injured as a result of their work on the Project should similarly be developed, approved and
implemented with notice to the employees.
6. Use of Animals in Research. You agree to be responsible for the humane care and treatment of
animals in projects supported in part or whole by BMGF funds; and to adhere to the official
guidelines for animal research applicable in the country and locality where the trial is being
conducted. No grant funds may be expended on studies involving animals until all requisite
approvals are in place, and notification to that effect has been provided to BMGF. For purposes of
this provision, an “animal” is defined as any live, vertebrate animal used or intended for use in
research, research training, experimentation, biological testing or for related purposes. In the case
of multi‐national collaborations, the standards of each country may be followed, as long as (i)
differences do not interfere with the design and analysis of the Project, and (ii) regulations in your
institution and host country do not conflict with the management of the Project.
You agree to take responsibility for compliance of all subgrantees or subcontractors (if any) with the
appropriate animal welfare laws, rules and regulations. You must report annually as a part of your
progress report that the activities are being conducted in accordance with applicable laws in each
respective venue (e.g., U.S. grantees must use the U.S. Public Health Service standards. Non‐U.S.
grantees may cite national laws or the CIOMS International Guiding Principles for Biomedical
Research Involving Animals (see http://www.CIOMS.ch/frame_1985_texts_of_guidelines.htm) if
there is not a relevant national standard.
11Please direct all questions about this initiative to: grandchallenges@gatesfoundation.org
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