Oral HIVacc: Oral Mucosal Immunization Approaches for HIV Prevention (R01)

RFA-DE-16-006HVAD_Logo_1.1
Oral HIVacc: Oral Mucosal Immunization Approaches for HIV Prevention (R01)
Department of Health and Human Services
National Institutes of Health

Funding Opportunity Purpose

This Funding Opportunity Announcement (FOA) solicits research projects to develop and test novel HIV vaccines for direct administration into oral lymphoid tissues to trigger protective, local and systemic immunity.  Specifically, this FOA seeks research projects to: 1) define the mechanisms by which direct HIV vaccination of oral lymphoid tissues induce oral innate as well as local and systemic adaptive immune responses; 2) determine the mechanisms by which new adjuvants used together with oral HIV vaccine candidates enhance local and systemic immunity; 3) test innovative, oral vaccine vectors expressing HIV vaccine antigens to trigger protective immunity; 4) compare different HIV vaccine immunization strategies and schemes for the oral mucosa to maximize protection; and 5) delineate the role of dynamic changes in oral and immune cell subsets and their interactions to enhance immunity upon oral HIV vaccination.

Key Dates
Posted Date

August 10, 2015

Open Date (Earliest Submission Date)

October 24, 2015

Letter of Intent Due Date(s)

30 days prior to the application due date

Application Due Date(s)

November 24, 2015 and November 23, 2016, by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on these dates. No late applications will be accepted for this Funding Opportunity Announcement.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

AIDS Application Due Date(s)

Not Applicable

Scientific Merit Review

March 2016 and March 2017

Advisory Council Review

May 2016 and May 2017

Earliest Start Date

June 2016 and June 2017

Expiration Date

November 24, 2016

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

There are several options to submit your application to the agency through Grants.gov. You can use the ASSIST system to prepare, submit and track your application online. You can download an application package from Grants.gov, complete the forms offline, submit the completed forms to Grants.gov and track your application in eRA Commons. Or, you can use other institutional system-to-system solutions to prepare and submit your application to Grants.gov and track your application in eRA Commons.

Research Objectives

This Funding Opportunity Announcement (FOA) solicits research projects to develop and test novel HIV vaccines for direct administration into oral lymphoid tissues to trigger protective, local and systemic immunity.  Specifically, this FOA seeks research projects to: 1) define the mechanisms by which direct HIV vaccination of oral lymphoid tissues induce oral innate as well as local and systemic adaptive immune responses; 2) determine the mechanisms by which new adjuvants used together with oral HIV vaccine candidates enhance local and systemic immunity; 3) test innovative, oral vaccine vectors expressing HIV vaccine antigens to trigger protective immunity; 4) compare different HIV vaccine immunization strategies and schemes for the oral mucosa to maximize protection; and 5) delineate the role of dynamic changes in oral and immune cell subsets and their interactions to enhance immunity upon oral HIV vaccination.

Background

Substantial progress has been made worldwide in improving life expectancy and quality of life for millions of people infected with HIV by introducing antiretroviral therapy.  Of equal importance is the goal of preventing HIV infections.  One of the most cost effective and safe strategies to prevent HIV/AIDS globally is through the development and application of a prophylactic HIV vaccine.  This is especially urgent for the developing world where this pandemic has caused devastating effects.

Historically, two institutes of the National Institutes of Health have supported HIV vaccine research.  The National Institute of Allergy and Infectious Diseases (NIAID) has led the field of antigen discovery, systemic HIV vaccine development and clinical testing.  NIDCR has complemented the NIAID efforts by focusing on oral mucosal prophylactic HIV vaccines for two reasons.  First, the oral cavity is an excellent model to understand innate and mucosal immunity against infectious diseases such as AIDS.  Second, the oral lymphoid tissue is an effective and easily accessible immunization route against HIV.  One of the goals in prevention efforts is to use an oral mucosal prophylactic HIV vaccine injected directly into the oral lymphoid tissue in combination with other HIV vaccinations administered through other immunization routes to confer protective immunity.

During vaccination, the immune system is optimally primed and boosted with an immunogen or combination of immunogens in the presence or absence of adjuvants that serve as immune enhancers.  Then, upon an infectious challenge, a quick and effective immune response is generated that clears the infection with no permanent health effects.  There are many considerations when developing and using a vaccine, including: the nature and composition of the immunogen or mix of immunogens; adjuvant use; immunization route; vaccination scheme; age, gender, and genetic makeup of cohorts; and the breadth and the quality of the immune responses induced.  Currently, the HIV vaccine pipeline is complex and includes developing and testing strategies that differ in the following: vaccine vectors, multiple combinations of HIV antigens from different subtypes, adjuvants, routes of immunizations, vaccination schemes and geographical areas reflecting different genetic makeup.

Vaccine strategies include testing candidates that stimulate immune responses in the mucosal surfaces such as the gut and the oral cavity.  The development and use of an effective mucosal HIV vaccine offers the advantage of inducing protective immunity at the first line of defense as well as conferring systemic immunity.  As most HIV infections begin at mucosal surfaces, induction of innate as well as mucosal humoral and cellular immunity post-vaccination is essential to arrest and clear HIV infections before systemic dissemination.  The richness of the lymphoid tissue and immune cells in the oral cavity offers an easily accessible site for direct vaccination.  The oral cavity contains a regional lymphatic ring called the Waldeyer’s tonsillar ring (WTR), which is an intrinsic part of the systemic lymphatic network.  The WTR is a complex lymphoid arrangement located in the naso- and oropharynx.  The WTR is comprised of the pharyngeal tonsils or adenoids (located posterior to the nasal cavity, in the roof of the nasopharynx), bilateral tubal tonsils (placed posterior to the opening of the Eustachian tube into the nasopharynx), bilateral palatine tonsils (situated at the back of the throat), and the lingual tonsils (found on the dorsal surface at the base of the tongue).

Direct oral lymphoid vaccination in combination with other immunization routes, may confer effective immune protection against HIV infection.  Findings from Simian Immunodeficiency Virus (SIV) vaccine studies in animal models support this strategy.  For example, the DNA prime and boost vaccination strategy has been successfully used with different SIV genes for priming and diverse SIV proteins for boosting the sublingual lymphoid tissue of rhesus macaques in independent vaccine studies.  These vaccines have been immunogenic and the sublingual, prime/boost immunization strategy has induced diverse and significant mucosal and systemic immune responses.  Additionally, direct prophylactic SIV vaccination of the oropharynx/tonsils of animal models has also been reported.  These studies have demonstrated the induction of immune responses distantly at the genital mucosa and the gastrointestinal system.

Despite the progress described above, many aspects of oral HIV vaccine development, testing and induction of immune responses remain unclear and require further investigation.  For instance, persisting gaps include: lack of oral immune correlates of protection; absence of an efficacious vaccine that confers protection against HIV acquisition at mucosal surfaces, including the oral cavity; incomplete understanding of vaccine induced immune responses at mucosal sites such as the oral mucosa and systemically; insufficient knowledge about the immune enhancing role of adjuvants; and fragmented information regarding the impact that genetic makeup of populations has on vaccine-induced oral immune responses.  It is critical to build upon the results obtained to develop and test effective oral mucosal prophylactic HIV vaccines that will elicit protective mucosal and systemic immune responses against HIV.

Examples of Research Considered within the Scope of this FOA
  • HIV-specific immunity induced by direct immunization of the oral mucosa
  • Mucosal adjuvants to enhance vaccine immunogenicity and efficacy
  • Immune control of HIV infection, replication and spread upon oral vaccination
  • HIV/SIV/SHIV antigens expressed in new oral vaccine vectors for testing in animal models
  • Cross-talk between oral and systemic immunity upon oral mucosal, prophylactic HIV vaccination
  • Changes in oral innate immunity post-HIV/SIV/SHIV oral mucosal vaccination
  • Responses in oral cell types post-vaccination and interactions to trigger immunity
  • Oral vaccines that induce sustained high levels of broadly reactive neutralizing antibodies
  • Oral vaccine-enhanced immunologic memory and long term protection against HIV
  • Changes in helper and cytotoxic immunity post-vaccination and enabling protective immunity
  • Oral microbiome, mycobiome and viriome’s influence in oral mucosal, prophylactic HIV vaccine-induced immunity and protection
  • Immune correlates of oral and systemic protection against HIV defined with new approaches

The following areas will be considered non-responsive to this FOA.  Applications focused on these areas will not proceed to review.

  • Planning, piloting or conducting clinical HIV vaccine trials
  • Secondary data analysis of previously collected datasets on HIV vaccine testing
  • Theoretical or computational modeling studies on HIV vaccines
  • Studies solely focused on systemic immunization with new HIV/SIV/SHIV vaccines
  • Enteric vaccines for oral lymphoid tissue immunization
  • Nasal HIV/SIV/SHIV immunization methods
  • Therapeutic HIV vaccine development and testing
  • Vaccine antigen discovery research
Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s