Notice of Special Interest (NOSI): Mechanisms of Mycobacterial-Induced Immunity in HIV-Infected and/or Uninfected Individuals to Inform Innovative Tuberculosis Vaccine Design
Notice Number:

Key Dates

Release Date:

September 10, 2020

First Available Due Date:
October 05, 2020
Expiration Date:
January 08, 2023

Related Announcements

PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)

Issued by

National Institute of Allergy and Infectious Diseases (NIAID)


The purpose of this Notice of Special Interest (NOSI) is to stimulate innovative studies to identify and understand the immune responses that mediate protection fromMycobacterium tuberculosis(Mtb) infection or progression to active tuberculosis (TB) disease. Studies may focus on any stage of mycobacterial infection or following vaccination with Bacillus Calmette-Gu rin (BCG) or investigational TB vaccines and may include HIV-infected or uninfected individuals.

Research supported under this NOSI should go beyond descriptive information currently known about Mtb infection, immune responses to TB vaccines, or immune modulation by non-tuberculous mycobacterial (NTM) infection, or by HIV/AIDS. Applications that include characterization of the timing, anatomical location, and contribution to disease outcome, of mucosal and/or systemic immune responses to mycobacterial infection and/or vaccination are sought. This research is expected to advance understanding of immune mechanisms in Mtb infection/vaccination and contribute to the advancement of new TB vaccines, including in populations also infected with HIV.


Tuberculosis (TB) is caused by infection with Mycobacterium tuberculosis (Mtb), a slow-growing pathogen that infects a variety of host cells, including macrophages and epithelial cells. While it is estimated that TB rates are slowly decreasing globally, TB continues to have a major negative impact on public health systems and individuals. According to the World Health Organization (WHO), in 2018, an estimated 10 million individuals developed TB disease, and 1.5 million died from TB. In addition, TB has been intricately associated with HIV infection and has been responsible for one fourth of all HIV-related deaths since the beginning of the AIDS epidemic, making it a leading cause of death in HIV-positive individuals. The rise in multi-drug or rifampicin-resistant TB (estimated 3.4% of new cases and 18% of treated cases) also poses a major challenge to TB treatment and underscores the need for development of effective vaccines to prevent Mtb infection and/or TB disease.

NIAID supports a comprehensive research portfolio in both immunology and vaccine R&D to facilitate development of TB vaccines. Some of this work is achieved through the development and application of animal models, reagents, and assays to better assess Mtb pathogenesis and immunity, and through translational work performed in clinical trials of Mtb-uninfected, latently infected, and HIV co-infected individuals. Collaborative funding between NIAID and other agencies/partners has supported academia, product development partnerships, and pharmaceutical companies; and has contributed to the development of many of the candidate vaccines that are currently in pre-clinical and clinical development. Vaccine design and development are also supported through basic and applied science to better understand host responses in infection and disease and in individuals able to contain Mtb naturally. Clinical studies of vaccine candidates have led to the identification of knowledge gaps in how we measure immunity, what animal models may be predictive of human responses, and our understanding of vaccine and adjuvant design.

BCG, one of the most commonly administered pediatric vaccines worldwide, does not provide lasting protection against pulmonary TB in adolescents and adults. Furthermore, exposure to environmental mycobacteria varies in different geographical regions and is thought to impact BCG vaccine efficacy. More recently, two phase II trials conducted in Southern Africa, demonstrated that BCG revaccination may prevent establishment of Mtb infection in adolescents, and that recombinant adjuvanted M72 vaccination provides protection against development of active pulmonary tuberculosis disease in adults previously infected with Mtb. However, correlates of vaccine-induced protection have not yet been identified, which would greatly accelerate selection of next-generation vaccine candidates. Although numerous studies have identified immunodominant Mtb antigens that trigger T cell responses and immune parameters that may be associated with some level of protection such as 1) production of TNF-alpha, IL-1, IL-6, IL-17, GM-CSF and IFN-gamma; 2) generation of lung-resident poly-functional CD4 T cells; or 3) activation of innate T cells; none of these parameters appear to sufficiently provide long-term protective immunity against Mtb infection or prevent development of TB disease. Studies suggest that humoral immune responses may play a role in TB immunity, and more work is needed to expand our understanding of humoral immune responses to Mtb infections/vaccines. Mtb also has evolved numerous immune evasion mechanisms that disrupt the generation of protective immunity and facilitate pathogen survival within the host. Finally, the specific mechanisms in children, the elderly and HIV-infected individuals that increase the probability of progression to active TB disease remain unclear, as do those that support growth of the pathogen in these vulnerable populations.

A number of studies have used systems immunology approaches to characterize human immune signatures of different vaccines. For example, some studies have described immune profiles that identify and predict immunogenicity to the yellow fever vaccine in humans, while other studies have described signatures of the early response to influenza vaccination that identified gene expression patterns that could predict the production of influenza specific antibodies at titers expected to induce protection. While TB researchers are conducting some systems immunology studies, further application of advanced immunologic analyses of systemic and tissue-specific responses to the TB field would dramatically enhance our understanding of immune mechanisms required for protection and provide fundamental information to improve TB vaccine design.

This NOSI seeks to support innovative research in deciphering immune mechanisms in humans required for protection from Mtb infection or TB disease, or induced by TB vaccines, that go beyond what have traditionally been investigated in TB. Animal models also provide valuable insights into these processes, as they permit studies of potentially important immune mechanisms that may not be possible to study in humans. In addition, animal efficacy data from TB vaccine candidates that are advancing to phase I clinical trials may provide valuable data on immune correlates of protection. Therefore, results from both human and animal studies have the potential to provide new insights into mechanisms of protective immunity against Mtb and TB disease and help identify immunologic and pathogen-specific mechanisms that may be effectively targeted by vaccines in HIV-infected and/or uninfected individuals.

Research Objectives

The purpose of this Notice of Special Interest (NOSI) is to stimulate innovative studies to identify and understand the immune responses that mediate protection from Mtb infection or progression to active TB disease. Studies may focus on any stage of mycobacterial infection or following vaccination with BCG or investigational TB vaccines and may include HIV-infected or uninfected individuals.

Examples of potential research areas of interest include, but are not limited to:

  • Elucidation of mucosal and systemic adaptive immune responses, including signaling networks and regulatory mechanisms, throughout the course of mycobacterial infection/disease or following vaccination and how HIV infection may shift the balance of these responses
  • Preclinical evaluation of novel TB vaccine candidates with concurrent in-depth immunologic analyses
  • Analysis of innate immune pathways and mechanisms in response to Mtb infection and/or TB progression, including trained immunity and the effect on downstream activation of adaptive immune responses
  • Application of systems immunology approaches for analysis of systemic and tissue-specific responses to Mtb, NTM, BCG or investigational TB vaccines
  • Immune mechanisms that result in direct killing or elimination of Mtb
  • Effect of prior/chronic exposure to mycobacterial species (including NTM) or BCG vaccination on subsequent immune responses to Mtb infection, TB reactivation, investigational TB vaccine efficacy or disease recurrence in HIV-infected or -uninfected individuals
  • Analysis of the role of non-classical T cells in immunity to Mtb infection
  • Determination of the contribution of the humoral immune response to protection against Mtb.
  • Identification of processes associated with mobilization/homing and maintenance of protective immune cells in the lung
  • Investigation of the timing/nature of immune responses leading to protection against disseminated TB in BCG vaccinated children to determine whether activity of BCG can be modified to protect adults against Mtb infection or disease
  • Development of novel functional assays to monitor protective host immune responses in humans against mycobacterial infections or candidate vaccines to increase information output and/or significantly minimize the sample amount needed for a given evaluation
  • Analysis of clinical trial samples evaluating TB vaccine candidates to identify immune correlates of protection from Mtb infection, or risk of TB disease progression

Applications proposing any of the following research topics will NOT be supported under this NOSI:

  • Projects focusing solely on mechanisms of TB pathogenesis that do not include analysis of immune parameters.
  • Projects focusing primarily on reagent or animal model development.
  • Projects addressing primarily Tuberculosis-Associated Immune Reconstitution Syndrome (TB-IRIS).

Application and Submission Information

This notice applies to due dates on or after October 5, 2020 and subsequent receipt dates through January 7, 2023.

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice.

  • PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
  • PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)

All instructions in the SF424 (R&R) Application Guideand the funding opportunity announcement used for submission must be followed, with the following additions:

  • For funding consideration, applicants must include NOT-AI-20-071 (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.


Please direct all inquiries to the contacts in Section VII of the listed funding opportunity announcements with the following additions/substitutions:

Que Dang, PhD
Division of AIDS (DAIDS)
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-292-6181

Katrin Eichelberg, MSc, PhD
Division of Microbiology and Infectious Diseases (DMID)
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-2921

Nancy V zquez-Maldonado, PhD
Division of Allergy, Immunology and Transplantation (DAIT)
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-5044

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices