7200AA25RFA00001- NPI THRIVE NOFO.pdf

Issue Date: December 18, 2024

Deadline for Questions: December 27, 2024, 5:00PM EDT

Closing Date and Time for CONCEPT NOTE: January 28, 2025, 5:00PM EDT

Closing Date and Time for FULL APPLICATION: TBD

Subject: Notice of Funding Opportunity (NOFO), Number: 7200AA25RFA00001

Program Title: New Partners Initiative Translational HIV Research for Innovative Vaccines

Ecosystem (NPI THRIVE)

Federal Assistance Listing Number: 98.0001

Ladies/Gentlemen:

The United States Agency for International Development (USAID) is seeking applications for cooperative agreements from qualified entities to implement activities under the Translational HIV Research for Innovative Vaccines Ecosystem (NPI THRIVE) Program. NPI-THRIVE is a New Partnerships Initiative (NPI) Activity, meaning it encourages the use of innovative, locally-led approaches with new, nontraditional, and local partners. Eligibility for these awards is not restricted.

USAID intends to award at least two Applicants, at least one for each of the two objectives of this funding opportunity, based on the merit review criteria described in this NOFO and subject to a risk assessment. Parties interested in applying are encouraged to read this NOFO thoroughly to understand the type of program sought, application submission requirements, and selection process.

This funding opportunity is posted on www.grants.gov, and may be amended. It is the Applicant's responsibility to regularly check the website to ensure they have the latest information pertaining to this NOFO and to ensure that the NOFO has been received from the internet in its entirety.

USAID bears no responsibility for data errors resulting from transmission or conversion processes.

If you have difficulty registering on www.grants.gov or accessing the NOFO, please contact the Grants.gov Helpdesk at 1-800-518-4726 or via email at support@grants.gov for technical assistance.

Unless an exception in 2 CFR 25.110 applies, Applicants must comply with 2 CFR 25 requirements to obtain a Unique Entity Identifier (UEI) and register in the System for Award Management (SAM.gov), as applicable. See Section E, Submission Requirements and Deadlines, for more information. The registration process may take many weeks to complete. Therefore, Applicants are encouraged to begin registration early.

http://www.grants.gov/

NOFO #7200AA25RFA00001

Translational HIV Research for Innovative Vaccines Ecosystem (NPI THRIVE)

Please send any questions to the point(s) of contact identified in Section A.4. The deadline for questions is shown above. Responses to questions received prior to the deadline will be furnished to all potential Applicants through an amendment to this notice posted to www.grants.gov.

Please note that applications must be RECEIVED by USAID before the deadline. Applicants are highly encouraged to submit their application prior to the deadline to account for any delays in transmission.

English is the official language of all award documents. In the event of inconsistency between any terms of this NOFO and any translation into another language, the English language version will control.

Issuance of this NOFO does not constitute an award commitment on the part of the Government, nor does it commit the Government to pay for any costs incurred in preparation or submission of comments/suggestions or an application. Applications are submitted at the risk of the Applicant.

All preparation and submission costs are at the Applicant’s expense.

Thank you for your interest in USAID programs.

Sincerely, /S/

Elton Fortson

Administrative Agreement Officer

THE REMAINDER OF THIS PAGE LEFT BLANK INTENTIONALLY

mailto:efortson@usaid.gov

TABLE OF CONTENTS

SECTION A: BASIC INFORMATION 8

SECTION B: ELIGIBILITY 10

SECTION C: PROGRAM DESCRIPTION 12

SECTION D: APPLICATION CONTENT AND FORMAT 14

SECTION E: SUBMISSION REQUIREMENTS AND DEADLINES 27

SECTION F: APPLICATION REVIEW INFORMATION 30

SECTION G: AWARD NOTICES 34

SECTION H: POST-AWARD REQUIREMENTS AND ADMINISTRATION 35

SECTION I: OTHER INFORMATION 38

ANNEX 1 - SUMMARY BUDGET TEMPLATE 39

ANNEX 2 - STANDARD PROVISIONS 40

ANNEX 3 - ABBREVIATIONS AND ACRONYMS 43

SECTION A: BASIC INFORMATION

1. Executive Summary

The overall goal of NPI THRIVE is to accelerate the development of a safe and globally effective HIV vaccine by supporting a collaborative research ecosystem led by scientists and institutions from countries in Africa with high burdens of HIV working in close partnership with leading scientific institutions from other regions. This will be achieved through pursuing two complementary objectives, one focusing on clinical research and the other on preclinical research.

Objective 1 of NPI THRIVE is to utilize collaborative, African-led systems for clinical immunology, virology, bioinformatics, and innovative clinical trials to contribute novel scientific knowledge to accelerate the development of preventive HIV vaccines. This will involve 1) conducting-depth laboratory analyses of immune responses that inform HIV vaccine development; 2) identifying, sequencing, characterizing, and utilizing currently circulating HIV viruses to develop improved reagents and immunogens; 3) storing, managing, sharing, and analyzing data and samples from HIV vaccine-related clinical studies; and 4) accelerating clinical development of HIV immunogens and bnAbs for infant prophylaxis.

Objective 2 of NPI THRIVE is to rapidly advance promising immunogens toward first-in-human studies through strategic partnerships between organizations in African countries, other LMIC, and the US that promote efficient manufacturing, preclinical testing, and scientific innovation. This will involve: 1) manufacturing HIV immunogens affordably, efficiently, and sustainably through partnerships between organizations in African countries, other LMIC, and the US, with staged capacity transfer and co-investment from the private sector over the life-of-project; 2) refining and advancing promising HIV immunogens through the battery of tests and supportive activities needed to enter first-in-human studies, while strengthening related capabilities for preclinical development in Africa; and 3) developing innovative concepts that address key obstacles to eliciting protective bnAb responses through partnerships between academic institutions in African countries and the US.

Eligibility for this NOFO is not restricted. This is a multi-tiered NOFO. Selection under this NOFO will be based on a three-step process, involving: 1) concept paper submission and evaluation; 2) co-creation, including virtual and in-person sessions; and 3) full application submission and evaluation.

This NOFO is issued under USAID’s New Partnerships Initiative. NPI leads USAID’s work to diversify the Agency’s partner base, contributing solutions-oriented support, while serving a pivotal coordination and exchange role with internal and external stakeholders to make USAID a more equitable partner and produce more sustained and locally-led development and humanitarian outcomes. Applicants must apply using one of the three specific NPI partnership approaches described in the NOFO. These include: 1) direct awards to local entities, new and underutilized organizations, or locally-established partners; 2) mentoring https://www.usaid.gov/npi awards, for partners of any type to apply to serve as prime recipients, but requires that at least 50% of the total award amount go to organizations that meet local entity, or regional partner criteria; or 3) partners of any type to serve as Prime recipients as long as Primes meet a minimum of a 1:2 cash leveraging of other public or private sector resources OR the implementation of the activity will significantly strengthen community financing ecosystems.

2. Estimate of Funds Available and Number of Awards Contemplated

USAID intends to award one or two Cooperative Agreements pursuant to this NOFO. Subject to funding availability and at the discretion of the Agency, USAID intends to provide up to $98,500,000 in total USAID funding over a five-year period, including up to $61,500,000 to support activities under Objective 1 and up to $37,000,000 to support activities under Objective

2. The estimated funds available for each year are as follows:

Objective 1

Year 1 Year 2 Year 3 Year 4 Year 5

$8,500,000 $10,500,000 $13,000,000 $17,000,000 $12,500,000

Objective 2

Year 1 Year 2 Year 3 Year 4 Year 5

$4,500,000 $6,000,000 $8,000,000 $10,000,000 $8,500,000

3. Start Date and Period of Performance for Federal Awards

The anticipated period of performance is five years. The estimated start date will be upon signature of the Award and is anticipated before September 30th, 2025.

4. Agency Point of Contact

Name: Elton Fortson Title: Administrative Agreement Officer Email: npithrive@usaid.gov mailto:npithrive@usaid.gov

Name: Koni Demissie Title: Agreement Specialist Email: npithrive@usaid.gov

5. Acquisition and Assistance Ombudsman

The A&A Ombudsman helps ensure equitable treatment of all parties who participate in USAID’s acquisition and assistance process. The A&A Ombudsman serves as a resource for all organizations who are doing or wish to do business with USAID. Please visit this page for additional information: https://www.usaid.gov/work-usaid/acquisition-assistance-ombudsman.

The A&A Ombudsman may be contacted via: Ombudsman@usaid.gov

6. Authorized Geographic Code

The geographic code for the procurement of commodities and services under this program is Code 935. The work to be conducted under the NPI THRIVE Program will support research conducted within the United States and with global research partners in geographic areas outside of the United States in accordance with Code 935. Additionally, some research and development collaborations may engage institutions and researchers that receive national or government-supported funding, which may be considered partner government entities under ADS 220. Except as may be specifically approved in advance by the Agreement Officer, all commodities and services that will be reimbursed by USAID under this award must be from the authorized geographic code specified in this NOFO, and must meet the source and nationality requirements set forth in 22 CFR 228.

7. Expected Performance Indicators, Targets, Baseline Data, and Data Collection

Program goals and objectives should be responsive to the technical, programmatic, and operational aims of the NPI THRIVE Project as described in Section A.

8. Intellectual Property

Intellectual Property is discussed in Mandatory Provision “M7. Title to and Use of Property (December 2014)” for non-US NGOs. In general, awardee(s) may elect to pursue ownership of intellectual property that is developed as a result of an award. In such cases, USAID would typically retain a nonexclusive, non-transferable, royalty-free license to use any such intellectual property. Please see Annex 2 to review the mandatory provision.

mailto:npithrive@usaid.gov https://www.usaid.gov/work-usaid/acquisition-assistance-ombudsman

SECTION B: ELIGIBILITY

1. Eligible Applicants and NPI Partnering Approaches

Eligibility for this NOFO is not restricted.

Faith-based organizations are eligible to apply for federal financial assistance on the same basis as any other organization and are subject to the protections and requirements of Federal law.

Additionally, USAID welcomes applications from organizations that have yet to previously receive financial assistance from USAID.

This NOFO invites applications for one or more awards (cooperative agreements), anticipating making at least one award for each of the two objectives of the NPI THRIVE program. (Note: USAID may issue one award to one entity if the entity has submitted proposals for both objectives and the Merit Review Committee finds this entity to provide the strongest proposal for both objectives according to the evaluation criteria in Section F) Interested Applicants may submit no more than one application under this NOFO for Objective 1 and no more than one application for Objective 2. Individual organizations may be sub-partners on multiple applications that address each objective.

Applicants must apply using one of the three specific NPI partnership approaches described below. Note that organizations only need to use one of the three approaches:

1.1. Direct Awards.

Approach #1 focuses on empowering partners with strong local ties to national communities, including marginalized and underserved communities, and relies heavily on these partners during co-creation processes to offer innovative ideas and solutions to the development challenges. Under Approach #1, awards may be issued only to Prime recipients that meet one or more of the definitions below:

A. Local Entities1

I. An individual or organization that:

i. Is legally organized under the laws of a country that is receiving assistance from USAID;

ii. Has its principal place of business or operations in a country receiving assistance from USAID;

1 As defined in Automated Directive System (ADS) Chapter 303.

iii. Is majority-owned by individuals who are citizens or lawful permanent residents of a country receiving assistance from USAID; and

iv. Is managed by a governing body, the majority of whom are citizens or lawful permanent residents of the country receiving assistance from

USAID.

B. New and Underutilized Organizations are those that have never received any funding from USAID, or have received less than $25 million cumulatively in direct or indirect awards from USAID over the last five years. Under this approach, nontraditional partners including (but not limited to) local, government, faith-based, diaspora, minority-serving, and volunteer organizations, are encouraged to apply.

Regional partners may also apply for awards under this approach if they also meet the definition of a new and underutilized organization.

Regional Partners are:

I. An individual, a corporation, a nonprofit organization, a government entity, or another body of persons that:

i. Is legally organized under the laws of, and has as its principal place of business in, a country which is part of the same region as a country(ies) it is providing assistance; and

ii. Is providing assistance in one or more countries in the same region where it is legally organized and has its principal place of business.

C. Locally Established Partners (LEPs)

I. A U.S. or international organization that works through locally-led operations and programming models. LEPs:

i. Have maintained continuous operations in-country for at least five years and demonstrate a long-term presence in a country through adherence or alignment to the following:

● Local staff comprise at least 50% of office personnel;

● Maintenance of a dedicated local office;

● Registration with the appropriate local authorities,

● A local bank account; and

● A portfolio of locally implemented programs.

1.2 Mentoring Awards.

Approach #2 allows for partners of any type to serve as prime recipients, but requires that at least 50% of the total award amount go to organizations that meet local entity, or regional partner criteria.

This approach requires prime recipients to provide grants to and engage with local partners to build feedback loops with relevant actors engaged in the development challenge and serve as mentors to the sub-awardee partners, providing knowledge, learning, monitoring, or capacity strengthening that supports locally determined objectives.

1.3. Nontraditional Financing Partnerships:

Approach #3 allows for partners of any type to serve as Prime recipients as long as Primes meet a minimum of a 1:2 cash leveraging of other public or private sector resources OR the implementation of the activity will significantly strengthen community financing ecosystems. The objective of these awards is to ensure that applications include ideas for maximizing USAID investments by identifying additional resources to support the achievement of development objectives. These awards may also strengthen local philanthropy, support community financing, or develop models that provide sustained funding for local organizations over time.

A. Leverage Awards: NPI seeks to support partnerships with organizations that can leverage private, non-U.S. Government, and/or local funding sources. Organizations of all types can qualify for these awards if they are able to propose and demonstrate commitment of leveraged funds worth a minimum of 50 percent of the total value of the award they seek from USAID. The leveraged funds can include non-Federal grants, contributions from local philanthropic sources and external awards, and/or in-kind contributions of intellectual property and volunteer hours provided by third-party actors.

Applicants are encouraged to seek multiple funding sources to reach the 50 percent requirement. The leveraged funds cannot include additional types of in-kind contributions from the awardee.

B. Awards to Strengthen Local Funding Networks: NPI seeks to support approaches that will strengthen local philanthropic organizations’ and community-based financing models that have the ability to provide sustained funding over time to local organizations. This model aims to strengthen local philanthropic and community-based financing models to reach common development objectives. Organizations of all types can apply and do not need to propose leveraged funding. At least 25% of the proposed activity must have the objective of leveraging local philanthropic contributions, strengthening philanthropic networks locally, supporting alternative financing methods for local actors, and supporting community-based financing models or similar activities.

2. Cost Sharing

Cost Sharing is not required for this activity.

SECTION C: PROGRAM DESCRIPTION

This funding opportunity is authorized under the Foreign Assistance Act (FAA) of 1961, as amended. The resulting awards will be subject to 2 CFR 200, 2 CFR 700, and 2 CFR 200 Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards. Cost Principles, and Audit Requirements for Federal Awards; and/or Standard Provisions for US and Non-U.S. Organizations; as well as the additional requirements noted in this NOFO.

Note: The term “program” as used in 2 CFR 200 and this NOFO is typically considered by USAID to be an Activity supporting one or more Project(s) pursuant to specific Development Objectives.

Please see 2 CFR 700 for the USAID specific definitions of the terms “Activity” and “Project” as used in the USAID context for purposes of planning, design, and implementation of USAID development assistance.

1. Background

New Partnerships Initiative (NPI)

This NOFO is issued under USAID’s New Partnerships Initiative. NPI leads USAID’s work to diversify the Agency’s partner base, contributing solutions-oriented support, while serving a pivotal coordination and exchange role with internal and external stakeholders to make USAID a more equitable partner and produce more sustained and locally-led development and humanitarian outcomes.

NPI advances this mission by diversifying its partner base and changing how the Agency establishes partnerships based on six key principles:

1. Promote local leadership. NPI works with local actors, traditional partners, and nontraditional partners to strengthen local and national systems in ways that advance locally-led development.

2. Improve equity and inclusivity within partner relationships. NPI proactively seeks opportunities to engage local communities more equitably and increase intentional inclusion in operations and programming, particularly for those communities that traditionally have been overlooked and underserved by USAID and other donor agencies—including faith-based organizations (FBOs); marginalized, underserved, and underrepresented communities; and diaspora communities.

3. Demonstrate accountability to constituents. Recognizing that USAID’s work is “from the American people” to the people of the world, NPI emphasizes the need to be accountable to all members of the communities in which we work as well as to the American taxpayer.

https://www.usaid.gov/npi

4. Seek innovative approaches. NPI capitalizes on the full marketplace of ideas and solutions by collaborating with partners from all sectors of society, while developing partnerships that foster mutual accountability and strengthen local capacity.

5. Lower barriers to partnerships. NPI identifies processes, policies, norms, and regulations that prohibit potential partnerships and finds ways to mitigate them while maintaining appropriate safeguards on taxpayer resources.

6. Identify new and nontraditional sources of funding. NPI fosters partnerships that leverage non-U.S. government funding sources to enhance local ownership and support effective collaboration across the spectrum of humanitarian and development funders.

USAID’s Support for HIV Vaccine Research and Development

The world still needs an HIV vaccine to sustainably control the HIV pandemic. Despite the significant progress in combating HIV and achieving epidemic control, 39.9 million people were living with HIV in 2023 globally. The highest burden of HIV globally occurs in countries in Africa, where 65% of the world's people living with HIV reside. Moreover, 62% of new HIV infections that occurred in these African countries were among women and girls. While new biomedical tools, such as oral and long-acting injectable pre-exposure prophylaxis, offer promise for continuing to reduce HIV incidence, a safe and effective preventive HIV vaccine could enable a more durable, rapid, and cost-effective reduction than would be possible by employing currently available interventions. Considering the profound HIV burden in many African countries, it is critical that HIV vaccine candidates are designed to effectively neutralize viruses circulating in this region.

Recent studies suggest that an HIV vaccine can be effective if it generates robust, broadly neutralizing antibodies (bnAbs) that can block a variety of HIV strains. However, traditional approaches to vaccination have yet to induce bnAbs effectively. The HIV vaccine research field is, therefore, focusing on using a variety of groundbreaking approaches to develop innovative vaccine candidates that have been rationally designed to stimulate the human immune system to produce bnAbs along with complementary T-cell responses. Over the next decade, there will be a need to conduct many small-scale trials to test new HIV vaccine immunogens, iteratively improving them until they generate high enough titers of bnAbs to justify testing them in larger-scale efficacy trials.

USAID has invested in HIV vaccine research and development (R&D) since 2001, gaining a deeper understanding of the global challenges facing the development of a safe, globally effective, preventive HIV vaccine. The Agency’s investments so far have centered on strengthening and utilizing the capacity of African scientists and institutions to lead in the design, implementation, and analysis of early-stage HIV vaccine trials and more fully participate in the pre-clinical design of innovative HIV vaccine concepts. Going forward, USAID intends to support the evolving ecosystem for HIV vaccine R&D that encourages African investigators to utilize the skills they have built over these past two decades. In part due to USAID’s long-standing support, the scientists in countries most affected by the HIV/AIDS pandemic are well-positioned to design and test immunogens best suited for their populations. THRIVE is designed to implement, monitor, and evaluate HIV Vaccine R&D programs that elevate local/indigenous leadership and advance gender equality and inclusive development to achieve more effective, equitable, and sustainable outcomes. These principles are central to this NOFO.

As a key PEPFAR implementer, USAID works in concert with the State Department’s Bureau of Global Health Security and Diplomacy (GHSD) to shape the strategic and technical direction of its HIV Vaccine R&D Program. The Program is further guided by the Agency’s (a) Global Health Research and Development Strategy 2023-2028 and (b) localization vision and approach. In accordance with the Global Health Research and Development Strategy 2023-2028, USAID’s HIV Vaccine R&D Program strives to define, design, develop, and deliver new, innovative, and effective products and interventions through a dynamic and iterative process.

The search for a safe, effective, preventive HIV vaccine must be sustainable, cost-effective, and equitable. To achieve this, scientists and institutions in countries most impacted by the HIV/AIDS pandemic must lead in designing and testing vaccine candidates. Accordingly, the HIV Vaccine R&D Program’s implementation of the Agency’s localization vision and approach involves a gradual transition of resources and leadership from US- to LMIC-based R&D partners to directly implement research programs and lead the way toward a sustainable R&D landscape through robust South-South and triangular collaboration. USAID’s collaboration with these partners and their networks, combined with the Agency’s extensive field presence and experience in LMIC, make it uniquely positioned to leverage and coordinate across public-sector agencies, private foundations, and private-sector partners.

2. Goals and Objectives

The overall goal of NPI THRIVE is to accelerate the development of a safe and globally effective HIV vaccine through supporting a collaborative research ecosystem led by scientists and institutions from countries in Africa with high burdens of HIV working in close partnership with leading scientific institutions from other regions.

This will be achieved through pursuing two complementary objectives:

Objective 1: To utilize collaborative, African-led systems for clinical immunology, virology, bioinformatics, and innovative clinical trials to contribute novel scientific knowledge to accelerate the development of preventive HIV vaccines.

Objective 2: To rapidly advance promising immunogens toward first in human (FIH) studies through strategic partnerships between organizations in African countries, other LMIC, and the US that promote efficient manufacturing, preclinical testing, and scientific innovation.

3. Geographic Focus

Activities supported under the NPI THRIVE project should predominantly be implemented within https://www.usaid.gov/reports/usaid-global-health-research-and-development-strategy-2023-2028#:~:text=This%20strategy%20describes%20USAID's%20renewed,of%20both%20local%20health%20research https://www.usaid.gov/sites/default/files/2022-12/USAIDs_Localization_Vision-508.pdf countries in Africa with high burdens of HIV, but they may also be implemented in other low- and middle-income countries with high HIV incidence and/or burden and where strategic opportunities exist. In seeking to meet each of the two results described below, at least 70% of direct costs of the projects should be incurred in African countries (although funding devoted to vaccine manufacturing under Objective 2 may be excluded from the 75% threshold), and no more than 40% of direct costs should be incurred in any one country. For Objective 1, activities should occur in at least four countries in Africa, and for Objective 2, activities should occur in at least two countries in Africa.

4. Technical and Strategic Approach

In responding to Objective 1 or Objective 2, Applicants should propose an approach that utilizes the existing capacity, indigenous scientific talent, and ingenuity across Africa and other LMICs to generate knowledge that advances the HIV vaccine field. Approaches should also intentionally encourage the enhancement of local institutional structures, individual leadership, and relevant partnerships essential to R&D that are capable of outlasting the NPI THRIVE project. The approach should also identify and frame how gender-related considerations will be addressed in the design and implementation of the proposed HIV vaccine R&D.

As applications for Objective 1 and Objective 2 would be submitted separately, the objectives and results under each are described separately below.

A. Objective 1: Utilize collaborative, African-led systems for clinical immunology, virology, bioinformatics, and innovative clinical trials to contribute novel scientific knowledge to accelerate the development of preventive HIV vaccines.

Under Objective 1 of THRIVE, activities will focus on support for clinical HIV vaccine research and development, aiming to achieve the four interrelated results below through a cohesive approach that builds on the connections between them to expand impact.

Result 1.1: In-depth laboratory analyses of immune responses that inform HIV vaccine development are completed in African countries by utilizing existing and enhanced lab capacity expanded via partnerships with US institutions

Many new HIV immunogens designed to elicit broadly neutralizing antibodies (bnAbs) will be tested in clinical trials in the next 5-7 years. To evaluate and refine these immunogens, in-depth analyses of B-cell responses will be needed using a variety of methods, including cell sorting and sequencing, binding antibody multiplex assays (BAMA), neutralization assays, analyses of allelic diversity, surface plasmon resonance (SPR), electron-microscopy-based polyclonal epitope mapping (EMPEM), and other approaches. To achieve Result 1.1, a high priority should be placed upon supporting one or more centers of excellence with advanced B-cell analytic capabilities to probe B-cell immune responses to vaccine immunogens in clinical trials, partnering with a variety of clinical trial sites across Africa and immunogen developers from around the world in a collaborative manner that advances the HIV vaccine field. These advanced capabilities could also be utilized to probe HIV-associated immune responses from epidemiological or pathogenesis studies if promising opportunities are identified. While a few African laboratories have already established capabilities for sorting and sequencing, BAMA, and neutralization assays, the equipment, facilities, and training for EMPEM and SPR may still need to be fully established.

Partnerships with and leveraging of US institutions with such capabilities are encouraged so that even if it is not feasible to establish EMPEM and SPR in Africa with the funding available under the current NOFO, African scientists can be trained by fellowship programs or other means to utilize and interpret them.

Although a relatively lower priority under the NOFO than B-cell analytics, support of laboratories in Africa to conduct analyses of T-cell responses in samples from clinical studies is also encouraged, particularly analyses of CD4/T follicular helper cells, given their importance in influencing B-cell responses. Utilizing the sorting and sequencing capabilities established for B-cell analytics to more deeply probe T-cell responses in existing samples from epidemiological studies of early HIV infection, for example, USAID-funded (IAVI) Protocol C, is also encouraged, as sequencing T cell receptor (TCR) repertoires and better characterizing T cell phenotypes and functions with new technologies could provide essential and fresh insights into determinants of effective T cell responses.

To achieve Result 1.1, support could be considered to strengthen labs at select clinical trial sites in Eastern, Central, and Western African countries so that they have strong capabilities to conduct standard immune endpoint analyses needed for trials and will no longer need to send these samples out to labs in other countries. Such support would need to be prioritized for sites in East, Central, and West Africa that have not been the beneficiaries in the past of extensive USAID-supported HIV vaccine laboratory strengthening, with the selection of sites based upon an objective assessment of where the impact of lab capacity augmentation is likely to be the greatest. Along with this, strengthening capabilities in LMIC outside of Africa to enable them to conduct clinical trials of next-generation HIV vaccine immunogens, including strengthening clinical capabilities to conduct leukapheresis and lymph node fine-needle aspiration and potentially advanced B-cell laboratory analytics, could be considered if there is national government support and scientific rationale. In particular, such support could be considered for countries in Asia such as India, given the very high absolute numbers of HIV infections occurring there, and/or Thailand, given the strong record of HIV vaccine clinical trials in that country.

Support could also be provided to improve procurement and management of laboratory commodities in African countries.

Result 1.2: Viruses from early infections are identified, sequenced, characterized, and used to develop improved reagents and immunogens through cost-effective approaches, linking to national programs and leveraging existing samples.

Having up-to-date sequences and phenotypic information for viruses that are representative of new HIV infections currently occurring in countries in Africa and other LMIC with high or increasing incidence or burden is critically important for HIV vaccine and monoclonal antibody research so that reference reagents such as pseudoviruses for neutralization panels are appropriately reflective of global viral breadth and diversity and to prioritize and design vaccines and antibodies that can be highly effective against a wide range of global isolates. However, current virus panels are not well representative of the most recent viruses circulating in many countries with high incidence and/or burden, especially in countries where non-B and non-C clades predominate. Among African countries in particular, viral phylogeny is widely divergent between viruses in West, Central, East, and Southern Africa, with viral samples from West Africa being the most underrepresented. Moreover, even viruses sampled from countries where subtypes B and C predominate are not systematically representative of the viruses currently circulating in such countries, both because a substantial proportion of the samples were taken many years previously and may provide an overly optimistic picture of neutralization sensitivity, and because many derive from clinical trials that were not designed to sample new infections in a population-based, structured way. Such prevention efficacy trials will likely be less common in the coming decade than in the past, making fewer samples available. Given the costs and limitations of relying on future clinical trials and cohort studies as the primary sources of viral samples from very early infection time points, new approaches are required.

To achieve Result 1.2, a high priority should be placed on implementing cost-effective systematic approaches to enable ongoing identification, sequencing, and characterization of viral samples that are representative at the population level of new infections occurring in LMIC with high and/or rising incidence and/or high burden, and in sub-populations that are at highest risk, including key populations (people who inject drugs, female sex workers, men who have sex with men, transgender persons) and adolescent girls and young women, as well among HIV-exposed infants in countries with high antenatal prevalence. Rather than implementing new and costly epidemiological studies to gather samples, the focus would be better placed on developing sustainable partnerships to leverage existing samples where these are available, including through sequencing existing samples from underrepresented regions and through linking to national recency testing efforts using sequencing to estimate the degree of intraindividual viral variation to refine which viruses are most likely to be very early after initial infection and could be close approximations to transmitted founder viruses. Where feasible, samples from bio-behavioral surveys of key populations could also be employed. In addition to benefiting HIV vaccine design and monoclonal antibody development efforts, such approaches could have a secondary benefit in refining recency testing data by reducing the number of false positives, thereby providing more precise population-based information about where new infections are occurring, which could help to plan future efficacy trials and to feedback useful data to inform national HIV programs. Population-based sequencing data might also be valuable in providing phylogenetic data regarding transmission patterns and networks to some countries that could inform prevention strategies. Although these sequencing efforts could focus on countries in Africa with high burdens of HIV, expanding efforts to identify viruses from key populations in other regions with high burden or increasing incidence, such as Asia and Eastern Europe, is also highly encouraged if valid links can be made to samples from those regions.

Along with developing sustainable approaches to identify and sequence viruses from early time points after initial infection, the widespread sharing of HIV viral sequences is important to assist scientists in efforts to develop a globally effective HIV vaccine. While the sharing of HIV sequences between different countries and partners is occurring, there may be opportunities to further strengthen this through targeted support for more intentionally coordinated action.

Furthermore, the development and sharing of up-to-date viral reference reagents to use in neutralization panels is important, as is the sharing of neutralization data between different scientists around the world. To achieve Result 1.2, activities that enhance such collaboration and sharing are highly encouraged.

Result 1.3. Data and samples from HIV vaccine-related clinical studies are securely stored, managed, shared, and analyzed by African scientists to inform HIV vaccine development using augmented capacity in bioinformatics and artificial intelligence.

Over the last three decades, numerous clinical trials and epidemiologic and immunological studies have been conducted in Africa that are relevant to HIV vaccines. Moreover, many early-phase trials will provide new data in the coming years. Significant potential exists to obtain insights through analyzing immunological and virologic data and samples using new laboratory technologies and bioinformatic tools that have become available, including artificial machine learning/artificial intelligence. However, for these resources to be optimally utilized, intentional and coordinated support to facilitate collaboration is needed.

To achieve Result 1.3, a high priority should be placed on enhancing the storage of samples and data from past and future studies conducted on the sub-continent and facilitating the sharing of these samples and data within Africa and more widely as there is demand and scientific justification. Cost-effective approaches that build on existing biorepository and cloud-based data warehousing capabilities in one or more countries in Africa are preferred, with an emphasis on providing a service to the entire field that enables scientists to collaborate more effectively, reducing logistical and financial burdens on individual institutions by subsidizing to some degree the costs involved in supporting long-term storage of samples and data from HIV vaccine studies.

While some charges for storing HIV samples and data may still be required of individual institutions, to enhance sustainability, approaches are encouraged that leverage funding from the private sector and from other sources that will support the storage and sharing of data and samples related to other diseases and health conditions beyond HIV, resulting in cost-reductions for HIV programs.

To capitalize on these opportunities provided by the samples and data, approaches are encouraged that will also build robust bioinformatics capacity in countries in Africa, which is critically important to handle increasing demands arising from the need to conduct immunological analyses from discovery medicine trials and increasing analysis of data related to identification, sequencing, and characterization of currently circulating HIV strains. This could include capacity among individual African scientists as well as institutional capacity related to computing equipment needed for advanced bioinformatic analyses. In coordination with these efforts, an approach could also be employed to enable African scientists to collaborate across institutions to identify and support promising early and mid-career investigators who can work on projects that involve analyzing the data and samples to inform HIV vaccine development efforts.

Along with the need to store, share, and utilize samples and data, there is a need to enhance capacity across Africa for clinical trial monitoring and the associated database development and data management. Approaches are encouraged that will expand the capacity for African-led clinical trial monitoring, particularly where this can be done more efficiently and at a lower cost than other existing options. Supporting the clinical trial monitoring for HIV vaccine studies in Africa by using this expanded capacity could be an area of focus to reduce the financial and management burden on African institutions implementing trials.

Result 1.4. Clinical development of HIV immunogens and bnAbs for infant prophylaxis is accelerated in Africa through collaborative clinical trial platforms, regulatory engagement, and coordinated support for strategic actions to address key challenges.

Many new HIV immunogens will hopefully become available for Phase I testing within the next 5-10 years, and investigators from countries that HIV highly impacts must play a leading role in the design and implementation of the trials of the immunogens. Additionally, the testing of HIV immunogens in special populations, including infants and people living with HIV (PLHIV), has great potential to advance the development of preventive HIV vaccines. However, navigating the scientific complexities and ethical considerations involved in conducting clinical trials in such populations will require leadership from scientists in Africa and collaboration to guide the field as it moves forward. Along with this, given the need to test multiple immunogens efficiently and in ways that allow for valid comparisons and potentially for future combinations among them, innovation in clinical trial platforms may be required, possibly through approaches that involve a master clinical trial protocol, with a standardized design and procedures, which can still be adapted somewhat if needed for specific immunogens or adjuvants. Moreover, using bnAbs for passive immunization of infants also holds promise, and candidate products may advance into initial proof-of-concept efficacy testing within the next five years. However, for an infant bnAb product to advance through clinical trials and eventually reach licensure, several challenges need to be addressed related to clinical trial design and implementation, product optimization for LMIC, manufacturing strategy, and mobilizing resources from the private sector. Accelerating the development of both vaccine candidates and bnAbs for infant prophylaxis will require African leadership, and coordinated engagement of regulators, bioethicists, and other stakeholders will be important to develop consensus on how to address a variety of complex issues that will be involved in the clinical development of these products.

Under Result 1.4, a high priority should be placed on supporting leadership, collaboration, and collective action by scientists and other stakeholders from African countries with high burdens of HIV, and potentially other LMICs, to prioritize, design, and implement clinical trials and related clinical-stage activities to accelerate HIV vaccine development. Support could also be provided for the clinical trials and other activities to accelerate the development of bnAbs for infant prophylaxis, assuming that a strong public health investment case can continue to be made for how a product can be feasibly developed and scaled up to achieve high public health impact in an era in which long-acting PrEP may become increasingly available for pregnant and lactating people. Partnerships for early-phase HIV vaccine clinical trials that would be led or co-led by African scientists could involve diverse collaborations beyond Africa with scientists in US academic institutions, not-for-profit organizations, and private sector partners. While resources from the NOFO that contribute to Result 1.4 should primarily be focused on supporting African scientific leadership in advancing the global HIV vaccine enterprise, it may also be strategic to include sites from other LMIC in regions where there is a high burden of HIV and/or high incidence in key populations since it will be important to understand how vaccines that are designed to induce bnAbs perform in populations with different germline repertoires and environmental influences. If countries outside of Africa are included, support could be considered to strengthen capabilities in these countries to enable them to conduct clinical trials of next-generation HIV vaccine immunogens, including strengthening clinical capabilities to conduct leukapheresis and lymph node fine-needle aspiration and potentially advanced B-cell laboratory analytics, if there is national government support, along with scientific rationale and complementary resources to leverage. In particular, such support could be considered for clinical trials in countries in Asia such as India, given the very high absolute numbers of HIV infections occurring there, and/or Thailand, given the strong record of HIV vaccine clinical trials in that country.

Regarding broad priority areas for the types of trials supported under the NOFO, Applicants are especially encouraged to consider including at least one trial among each of two priority populations that have to date been understudied in HIV vaccine trials but which could provide important insights to guide HIV vaccine development. One of these populations is infants and/or children, who typically have a more plastic immune system than adults and who may be able to develop bnAbs more frequently than adults in response to vaccination. A second priority population is PLHIV, in whom immunization experiments may provide unique insights to inform the development of a preventive HIV vaccine. In this regard, several trials are ongoing involving boosting people living with HIV with envelopes to drive antibodies toward broader neutralization, but now that germline targeting immunogens are beginning to show good results in priming responses, new opportunities may emerge to explore a potentially more promising approach involving priming PLHIV with these immunogens and then, through carefully monitored analytical treatment interruptions, identifying HIV envelopes that may drive response toward broad neutralization. Such trials in Africa involving PLHIV who have been primed with germline targeting vaccine immunogens would leverage the viral diversity that exists in PLHIV in Africa and could help identify envelope immunogens that have particularly strong potential for broadening responses in African populations, both for preventive and therapeutic vaccines.

Analyses of such trials could also take advantage of the immunological and sequencing capabilities that would be supported under Results 1.1 and 1.2.

Along with trials in PLHIV and infants, which could be relatively small if other promising clinical trial priorities that require more resources are identified by scientists in African countries and other LMIC with high burdens of HIV, Applicants are encouraged to prioritize testing those immunogens that these scientists, in consultation with other global experts, determined to be the most promising. Ideally, this would include at least one that has been developed in some form of partnership between scientists in Africa and the US, which could be an immunogen developed through support under the Objective 2 project described below. Maximizing approaches that leverage funding from other donors and LMIC governments are encouraged.

Efforts are also strongly encouraged to include clinical trial sites outside of South Africa alone and equitably include the most capable clinical trial sites with proven experience conducting complex HIV vaccine trials. This could include support for one or two sites outside of South Africa to participate in larger trials funded primarily by donors other than USAID if such support helped make the population in the trial better representative of the countries with the highest incidence or burden of HIV. Support under the NOFO could also be considered for efforts to stabilize the clinical trial workforce in Africa and for improving infrastructure at clinical trial sites through generators, or internet connectivity (although no new construction would be supported under the NOFO) to help ensure the quality of clinical research executed.

B. Objective 2: To rapidly advance promising immunogens toward first-in-human studies through strategic partnerships between organizations in African countries, other LMIC, and the US that promote efficient manufacturing, preclinical testing, and scientific innovation.

Under Objective 2 of THRIVE, activities will focus on support for preclinical HIV vaccine research and development, aiming to achieve the three interrelated results below through a cohesive approach that builds on the connections between them to expand impact.

Result 2.1 HIV immunogens are manufactured affordably, efficiently and sustainably through partnerships between organizations in Africa, other LMIC, and the US, with staged capacity transfer and co-investment from the private sector over the life-of-project

Although RNA vaccines offer a promising platform to enable innovators to develop new HIV immunogens, only a few RNA-delivered HIV immunogens have yet entered early-phase…