7200AA21RFA00005 RFI DEEP VZN - Appendix I.docx

APPENDIX I

DISCOVERY & EXPLORATION OF EMERGING PATHOGENS - VIRAL ZOONOSES (DEEP VZN)

Draft Program Description

11/18/2020

TABLE OF CONTENTS

DISCOVERY & EXPLORATION OF EMERGING PATHOGENS - VIRAL ZOONOSES

(DEEP VZN)

1. Introduction

The emergence of numerous novel zoonotic viruses [1], over the past few decades is a vivid reminder that countries and the global community remain vulnerable to outbreaks caused by diseases for which there are no specific diagnostics, medicines, or vaccines. Many of these new viruses originated in wild animals before spreading to people directly or through livestock. The health and economic impact associated with these events can be significant [2].

Detection and characterization of unknown zoonotic viruses before they cause outbreaks, epidemics, or pandemics in human populations enables more efficient and effective preparedness, prevention, and response efforts, saving lives and limiting economic damage. COVID-19’s severe impacts (more than 51.5 million cases and 1.2 million deaths along with major economic disruptions spread over 220 countries and territories in Africa, Asia/Pacific, the Americas, Europe, and the Middle East [3]) demonstrate the perils of not having advanced information on possible public health threats that can be used to develop tools to inform monitoring and response.

USAID has invested more than $1.1 billion in Global Health Security since 2005. A significant area of work between 2009 and 2020 has been viral discovery and characterization in locations where there is high risk for spillover, amplification, and spread of emerging zoonotic viruses [4]. USAID’s on-going multi-sectoral Global Health Security program and its partnerships place the Agency in a unique position to advance efforts related to discovery and characterization of unknown viruses.

Through DEEP VZN, the U.S. Agency for International Development (USAID) seeks to assist a limited number of countries, with a focus on Asia and Africa, to conduct intensive applied research to detect and characterize previously-unknown viruses that have originated in wildlife [5]. DEEP VZN will build on more than 15 years of USAID investments in promoting a multisectoral [6] (One Health) approach to addressing emerging zoonotic viruses before they pose an overwhelming epidemic or pandemic threat. Specifically, DEEP VZN will assist targeted African and Asian countries in strengthening their research capacities to detect and characterize unknown viruses at highest-risk interfaces where risk profiles favor spillover, amplification, or spread of emerging zoonotic viruses. Detection will be complemented by efforts to assess the zoonotic and pandemic potential of these viruses. These activities will appropriately address gender in the development of research tools and strategies and in the application of evidence-based viral zoonoses risk mitigation.

2. Overview of USAID’s Global Health Security Program

Global Health Security (GHS) programming enables the U.S. government (USG)—in partnership with other nations, international organizations, and public and private stakeholders—to prevent avoidable epidemics, detect threats early, and respond rapidly and effectively to disease outbreaks. In May 2019, the Global Health Security Strategy (GHSS) [7] was approved, outlining the USG’s approach to strengthening global health security, including accelerating the capabilities of targeted countries to prevent, detect, and respond to infectious disease outbreaks. The Strategy pursues three interrelated goals: 1) strengthened partner country global health security capacities; 2) increased international support for global health security; and 3) a homeland prepared and resilient against global health threats. Given its foreign affairs mandate, USAID directly contributes to the first two goals. USAID funds and programming focus on: addressing the health security capacity gaps in targeted countries at high risk of infectious disease threats and outbreaks (USAID’s major contribution to the Global Health Security Agenda [GHSA]); targeted, applied GHS research; and critical policy and advocacy support for GHS. DEEP VZN will focus on identifying novel viral threats which is critical to addressing the alarming increase in the frequency and severity of infectious disease outbreaks occurring globally.

3. Evolution of USAID’s Global Health Security Investments

For more than 15 years, USAID has been a leader in the global response to the dangers posed by emerging pandemic threats and has invested in GHS activities with the dual goals of minimizing the impact of existing pandemic influenza threats and pre-empting the emergence and spread of novel pandemic and epidemic threats arising from animal populations. The first phase of the USAID’s GHS program primarily focused on supporting countries to address these zoonotic threats and understanding overall risk of spillover, amplification, and spread in animal and human populations. The One Health approach for achieving these goals was built around a suite of investments and targeted partnerships designed to give earlier insight into the emergence of new public health threats and enhance country-level capacities across sectors to mitigate their potential impact. With a total investment of over $1.1 billion covering countries in Africa, Asia, Latin America, and the Middle East, USAID’s GHS program is the largest and most-extensive One Health program ever implemented. The guiding principles for USAID’s GHS program (2009-2020) have been to:

· build on the understanding that the future well-being of humans, animals, and the environment are inextricably linked, a concept known as “One Health”;

· promote a cross-sectoral, gender-responsive One Health approach that spans the animal health, public health, environmental, and conservation communities;

· support countries to conduct applied research to understand risk of spillover, amplification, and spread of known and unknown emerging zoonotic viruses;

· target promotion of policies and strengthening of skills and capacities critical for both minimizing the risk of new disease emergence and the ability to limit their social, economic, and public health impact; and

· use a risk-based approach to target investments where the likelihood of disease emergence is greatest.

Emerging Pandemic Threats-1 (2009-2014): The first iteration of EPT built off of a previous One Health line of work supported by USAID between 2005 and 2009 which was aimed at addressing the immediate threat posed by highly pathogenic H5N1 avian influenza (AI). The EPT-1 portfolio was focused on building the capacities and evidence base needed to mitigate the impact of novel “high-consequence pathogens” arising from animals. Specifically, the EPT-1 portfolio consisted of four complementary activities, including strategic partnerships with the Food and Agricultural Organization of the United Nations (FAO), World Health Organization (WHO) and World Organization for Animal Health (OIE), and was implemented in more than 20 countries across Africa, Asia, and Latin America:

· PREDICT-1: Focused on building a global early warning system for the emergence of diseases that move between wildlife and people, primarily through detection and discovery of viruses from 28 high-consequence viral families in wildlife species that have frequent contact with humans.

· PREVENT: Aimed at characterizing risks associated with practices and behaviors that facilitate disease transmission between animals and humans and developing strategies for lowering the risk of disease spillover.

· IDENTIFY: A partnership among WHO, FAO, and OIE, focused on strengthening laboratory capacities to safely diagnose and report priority animal and human pathogens.

· RESPOND: Focused on the central role of local universities to train cadres of upcoming professionals and practitioners responsible for supporting, promoting, and implementing the One Health approach.

Key accomplishments:

· Established the “proof of principle” that countries can carry out safe capture and sampling of wildlife followed by conventional PCR testing of blood, urine, feces, or oral/nasal swabs for up to 28 families of zoonotic viruses; sampled more than 56,000 animals and identified 815 novel viruses and 169 known viruses, making it the most comprehensive viral detection and discovery effort at that time; identified which animal species (i.e. rodent, bats, and non-human primates) were most associated with spillover of emerging zoonotic viruses; developed a global “hot spots” map for emergence of viral zoonoses. PREDICT-1 final report: https://ohi.sf.ucdavis.edu/sites/g/files/dgvnsk5251/files/files/page/predict-final-report-lo.pdf.

· Identified that new zoonotic viruses that are capable of infecting diverse host species have higher pandemic potential since these viruses are more likely to amplify by human-to-human transmission with spread on a global scale. https://www.nature.com/articles/srep14830

· Created region-specific lists of high-risk, human and animal diseases, developed/updated standard lab procedures for these diseases, and provided viral identification training for laboratories in Africa and Asia. https://www.usaid.gov/sites/default/files/documents/1864/IDENTIFY-Compilation-of-Accomplishments__1 -13-2014.docx

· Characterized the nature and frequency of human contact with animals in Africa and Asia. https://www.fhi360.org/projects/prevent-%E2%80%94-emerging-pandemic-threats

· Improved the effectiveness of poultry vaccination in Indonesia (with demonstrated decrease in reported poultry outbreaks and human infections) by identifying which licensed vaccines were efficacious against the specific H5N1 avian influenza virus present in the country. https://ec.europa.eu/food/sites/food/files/animals/docs/ad_cm_ai_nrl-annual-meetings-14_pres-17.pdf

· Established two regional university networks (Central/East Africa and Southeast Asia) and four country university networks (Indonesia, Malaysia, Thailand, Vietnam) to formulate and introduce standardized One Health curricula for pre- and in-service training and serve as a One Health hub across participating universities and countries.

Lessons learned:

· The understanding of risk associated with spillover of emerging zoonotic viruses from animals to people could be further improved by focusing on a smaller subset of viral families and animal species (to allow for larger sample sizes for testing), adding surveillance of humans (virology and serology), focusing on common points where animals and humans interact (with behavioral surveillance), and sampling longitudinally in order to gain insight on any seasonality associated with spillover of emerging zoonotic viruses from animals to people.

· Universities play a critical role in creating long-term changes to workforce skills. They work on the cutting edge of their fields to educate students who will comprise tomorrow’s workforce. Universities are also testing sites for education, where innovative and trans-disciplinary approaches to training professionals are constantly introduced and refined, including One Health approaches. By investing in universities in developing countries, we can create a long-term in-country capability for improved human resource capacity.

· Focused public sector investments in filling key knowledge gaps related to spillover, amplification, and spread of emerging zoonotic viruses can lead to private sector poultry producers changing their practices (if cost-neutral) based on evidence, thereby increasing the likelihood of sustainability.

· Behavior change communications for AI that were targeted at households increased knowledge, but did not change behaviors possibly because doing so cost more (e.g. buying fencing for household birds, buying feed for caged birds that were previously free-ranging) and/or because the risk of human infection was perceived to be much lower than other common diseases such as malaria or tuberculosis.

· Countries which did not have a strong history of cross-sectoral collaboration on zoonotic diseases, especially those in Africa, would benefit from support to establish or strengthen in-country platforms to coordinate zoonotic disease activities across sectors, especially public health, livestock, and wildlife.

EPT-2 (2014-2020): The second iteration of EPT built on the investments, partnerships, and lessons learned from EPT-1. The focus remained on preventing, detecting, and responding to emerging viral diseases using a One Health approach, but broadened investments around preparedness. The scope of the program also was expanded to address the threats posed by antimicrobial resistance (AMR), as the inappropriate use of antibiotics in animal husbandry and inappropriate “prescriber-user” practices associated with antibiotic use in clinical care were increasingly understood to be core drivers behind the emergence and global spread of antibiotic-resistant organisms. EPT-2 worked in more than 30 countries across Africa [8], Asia, and the Middle East [9], and was comprised of three activities as well as partnerships with FAO and WHO:

· PREDICT-2: Consolidated the scopes of EPT-1’s PREDICT-1 and PREVENT to more-precisely identify and characterize emerging zoonotic viruses in animals and people, as well as behaviors, practices, and conditions associated with viral evolution, spillover, amplification, and spread. The number of targeted viral families was reduced to four [10] and targeted animal-human interfaces reduced to households, markets, and livestock/agricultural production. Longitudinal monitoring at high risk interfaces, human surveillance, animal and human serology, and a focus on Middle East Respiratory Syndrome coronavirus (MERS-CoV) in northeast Africa were also added.

· Preparedness and Response (P&R): Assisted countries in establishing and strengthening national One Health platforms to develop, formalize, and maintain multisectoral collaboration as well as develop country-specific plans for responding to public health events of unknown etiology.

· One Health Workforce (OHW): Built on the investments of EPT-1’s RESPOND by strengthening the capacity of the One Health university networks to address the current workforce needs of ministries in addition to building a pipeline of future One Health workers, expanding the networks to include more countries, and strengthening the operational capacities of the university networks.

· FAO: Focused on risk characterization activities to understand biological drivers of zoonotic virus spillover (including AI and MERS-CoV), amplification, and spread; studied and promoted risk mitigation policies and practices for livestock that reduce the risk of zoonotic virus spillover, amplification, and spread; supported national One Health platforms (in coordination with P&R); strengthened national preparedness within the livestock sector to respond to events of public health concern including epidemiology training for veterinarians; strengthened global livestock surveillance networks; and provided emergency lab, commodity, and other support for outbreaks in livestock.

· WHO: Focused on strengthening influenza surveillance; strengthening national preparedness within the public health sector to respond to events of public health significance; supported One Health national platforms through the development of tools (in coordination with P&R) and invested in a One Health workforce (in coordination with OHW); and provided emergency lab, commodity, and other support for outbreaks in humans.

Key accomplishments:

· Conducted standardized and synchronized monitoring of wildlife, humans, and associated behaviors at specific animal-human interfaces across 28 countries; sampled >100,000 animals and humans and identified an additional 200 novel viruses (including a new Ebola species in Sierra Leone and Guinea and a new coronavirus associated with swine deaths in China) and 88 known viruses (in addition to those detected under PREDICT-1); and identified an association between RNA virus shedding by wildlife and animal value chains.

https://www.nature.com/articles/s41564-018-0227-2 https://www.nature.com/articles/s41586-018-0010-9 , https://www.sciencemag.org/news/2019/01/bat-species-may-be-source-ebola-epidemic-killed-more-11000-people-west-africa, https://ohi.vetmed.ucdavis.edu/programs-projects/predict-project/reports , https://static1.squarespace.com/static/5c7d60a711f7845f734d4a73/t/5e95fb725309184f8a1e76b2/15868875%2090640/PREDICT+March+18+Data+Discussion.pdf , https://p2.predict.global/interventions , https://p2.predict.global/insights , https://ohi.vetmed.ucdavis.edu/programs-projects/predict-proect/publications PREDICT final report (unpublished); weblink to be provided when available

· With CDC, co-identified Marburg virus in Sierra Leone, the first-ever detection of the virus in West Africa. https://www.ucdavis.edu/health/news/deadly-marburg-virus-found-sierra-leone-bats/, https://www.nature.com/articles/s41467-020-14327-8

· Collected evidence indicating previously-unrecognized spillover of Ebola viruses in the Democratic Republic of the Congo and Uganda and provided evidence that Ebola/Bombali is zoonotic. https://academic.oup.com/jid/article/218/suppl_5/S277/5039952; https://link.springer.com/epdf/10.1186/s42522-020-00028-1?sharing_token=J6AZyoFlW_WXSCHlhrCB2m_BpE1tBhCbnbw3BuzI2RMvLJRJHNUVHei-FofO0OKe-pIHezGL0eAuEIr6l4pqvwl2HiTJ1uK7ENb4miIpp90R0pBn4tk8Jkh1T3HM1jnl0Qny1-ns6xNrk5LC44OB-iT3a6VVSHNO4DKeZxY8N7A%3D

· Identified a SARS-like coronavirus from bats in China that had spilled over to people https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6178078/

· To overcome low positivity rates for filoviruses among healthy animals, a strategy was developed and deployed in Guinea, Liberia, and Sierra Leone to generate large numbers of samples among the most-likely animal hosts (based on evidence from previous studies) and testing was intentionally conducted for filoviruses rather than narrowly for Ebola/Zaire which was the cause the 2014-2016 human epidemic in West Africa.

· Developed and validated a rapid, easy-to-use field diagnostic for identifying H5 and H7 influenza A viruses in birds which allows for faster response to contain these viruses in infected flocks and prevent spread to additional animals or people. https://onlinelibrary.wiley.com/doi/pdf/10.1111/irv.12646.

· Developed “Living Safely with Bats” (https://p2.predict.global/living-safely-with-bats-book) and “Living Safely with Animals” communication tools to convey risk and possible risk-reduction options to communities in West and East African countries. [Note: these two tools have not yet been evaluated for effectiveness in increasing knowledge or changing behaviors.]

· With the Australian Department of Foreign Affairs and Trade and FAO, enhanced farm and market biosecurity, flock health and hatchery management practices contributing to reduced disease and AMR risk in Cambodia, Laos, Myanmar, and Vietnam.

http://www.fao.org/3/ca5608en/CA5608EN.pdf http://www.fao.org/3/ca5515en/ca5515en.pdf http://www.fao.org/3/ca5516en/ca5516en.pdf http://www.fao.org/3/ca6642en/CA6642EN.pdf http://www.fao.org/3/ca7319en/CA7319EN.pdf http://www.fao.org/3/ca6114en/CA6114EN.pdf

· Refined the global “hot spots” analyses for emergence of viral zoonoses. https://www.ecohealthalliance.org/wp-content/uploads/2017/10/s41467-017-00923-8.pdf.

· Further refined the understanding of Nipah virus dynamics in bats and implications for spillover to humans. https://www.pnas.org/content/early/2020/10/27/2000429117

· Developed tools, lessons learned, and economic analyses related to One Health programming and provided technical assistance and operational support to 15 One Health platforms in Africa and Asia.

· Developed and began implementing a district-level, in-service applied veterinary epidemiology training program (ISAVET) in East, Central, and West African countries. http://www.fao.org/resilience/news-events/detail/en/c/1171750/

· Provided classroom and hands-on training in One Health core competencies to over 13,300 undergraduate students and 33,500 current One Health professionals across Africa and Asia.

· Developed gender-responsive curriculum and training of One Health professionals: Gender One Health and Infectious Disease Training Module. http://afrohun.org/index.php?option=com_content&view=article&id=168&Itemid=1055

· Supported prevention, detection, and response to infectious disease threats through the Global Health Security Agenda. https://www.state.gov/wp-content/uploads/2020/09/GHSA_ProgressImpactFY19_final.pdf Lessons learned:

· Concurrent, focused, and longitudinal surveillance of wildlife and human populations have provided additional insight on where, when, and how emerging zoonotic viruses (including Ebola) spill over at specific animal-human interfaces; this insight is critical to strengthening the ability of countries to begin developing and testing the effectiveness of interventions to reduce the risk of spillover of these threats from animals to people (although additional information related to spillover risk is needed for viruses such as Ebola, Nipah, animal-origin coronaviruses, and animal-origin influenzas).

· Data (unpublished) from northeast Africa suggest that camels have high exposure rates to MERS-CoV viruses, but that these viruses appear to be mainly from a non-zoonotic clade of the MERS-CoV family, meaning that not all of the MERS-CoV viruses from camels in Africa have public health importance.

· In Africa and Asia, the continued spillover, amplification, and spread of emerging zoonotic viruses highlight the large gaps that still exist in biosafety and biosecurity, particularly along animal value chains; the private sector so far has been an underutilized partner for broadly (as opposed to addressing disease by disease) reducing risk along livestock value chains. Reducing the risk of spillover of zoonotic viruses from wildlife to livestock and people (including through animal value chains) is also a gap that needs to be addressed.

· Workforce transformation is a long-term process that requires consultation and collaboration with a diverse set of stakeholders and a better understanding of labor markets’ supply and demand curves. In order to better understand and target training opportunities and educational offerings, One Health university networks (OHUNs) must consult and collaborate with governments, non-governmental organizations (NGOs), donors, and the private sector on their needs and capacities.

· While countries appear to understand the benefits of One Health platforms and have utilized new tools developed with support from EPT-2, the degree to which countries engage with and support their platforms varies, and this has implications for long-term sustainability and the ability to attract donor funding. GHSA: In 2014, USAID, along with other USG partners, including the National Security Council, Department of State, the U.S. Centers for Disease Control and Prevention (CDC), and the Department of Defense, joined more than 60 countries in implementing the GHSA. At the core of the GHSA is the goal of strengthening capacities for prevention, detection, and response for infectious disease outbreaks using multisectoral collaboration across public health, medicine, agriculture, animal/veterinary health, environment, education/academia, and defense/security agencies. USAID’s GHSA activities have been geographically focused in 16 countries in Africa and Asia and used to build workforce capacity and surveillance, laboratory capacity, and preparedness and response systems for addressing prioritized endemic and emerging zoonotic threats. Going forward, USAID’s emerging threats and GHSA activities constitute the agency’s global health security investments under the GHSS. Countries supported by USAID under EPT-1 and EPT-2/GHSA are shown in the map below. Between 2020 and 2025, USAID will continue its global health security investments with a primary focus on countries in Africa and Asia. DEEP VZN will complement other USAID partnerships that are described below in section 5 (“Collaboration with Other USAID/External Partners”).

4. DEEP VZN Goal & Objectives

Problem Statement

An analysis of 335 emerging infectious diseases (EID) in humans between 1940 and 2004 revealed a number of important characteristics including: (1) the incidence of EID events is increasing over time; (2) 60% of EIDs are zoonotic and, of those, 72% are from wildlife; (3) the origins of EIDs are correlated with socio-economic, environmental, and ecological factors and are concentrated in tropical and subtropical regions of the world; and (4) global resources to address EIDs are poorly allocated [11]. Zoonotic diseases cause the loss of lives and livelihoods by disrupting local, regional, and global travel and trade, and by threatening the economic and political stability of some of the most vulnerable countries. Among zoonotic diseases, emerging zoonotic viruses are particularly problematic because (1) these pathogens generally lack specific treatments and vaccines (for animals or people), (2) human populations are more likely to be immunologically naive to novel viral zoonoses giving these pathogens a comparatively-higher likelihood of epidemic and pandemic potential, and (3) these pathogens are often detected during or after amplification or spread in human populations which makes containment very difficult and very expensive. The on-going pandemic caused by SARS-CoV-2 has once again highlighted the importance of these three points.

Multiple previously-unknown zoonotic viruses have emerged and caused outbreaks over the past three decades. Many of these viruses originated in wild animals before spreading to people directly or through livestock such as poultry, swine, horses, and camels. A recent study estimated that there may be an additional 1.67 million undiscovered viruses in mammals and birds, with between 631,000 and 827,000 capable of infecting people [12]. Countries would be better served, in terms of lives saved and economic damage limited, if they were able to detect and assess the threat of unknown zoonotic viruses before they cause epidemics and pandemics. However, countries do not routinely monitor for new public health threats.

The general lack of diagnostics and medical countermeasures for new emerging zoonotic viruses and the enormous challenge and cost of stopping their amplification and spread puts a premium on reducing the likelihood of their initial spillover from animals to people. Building on previous USAID global analyses of risk and investments in countries under EPT-1 and EPT-2/GHSA, the Agency is now employing a dual track strategy to enhance understanding of emergence and distribution of viral zoonoses of epidemic and pandemic potential and inform actionable risk mitigation. Track one aims to employ interventions to address the spillover, amplification, and spread of known emerging zoonotic viruses through a recently-awarded project, STOP Spillover, to assist countries to 1) understand the factors that contribute to the risk of spillover of pathogens from wildlife to humans; 2) develop, assess, and implement early risk-reduction interventions that will reduce the spillover and spread of these threats; and, 3) recognize and respond rapidly to zoonotic spillover events [13]. Track two of USAID’s strategy for addressing emerging zoonotic viruses includes the new DEEP VZN project, which will specifically focus on detecting unknown viruses and characterizing their zoonotic and pandemic potential. USAID’s support for viral discovery since 2009 and its multi-sectoral GHS Program and partnerships place the Agency in a unique position to meaningfully advance these lines of work.

Lessons learned from previous viral discovery and characterization efforts include:

· Previous work has identified interfaces, species, and geographic “hot spots” in Asia and Africa where viral detection rates are higher.

· Detecting known and unknown viral threats can be achieved by in-country laboratories and staff.

· While significant, the scale of viral discovery to date has been relatively small. Improvements in efficiency of sampling, detection, and characterization would increase yield.

· To date, there are a lack of efficient, low-cost, biosafe/biosecure, and standardized methods to reliably assess zoonotic and pandemic potential of newly-identified viruses.

· Access to research findings slowed by country approval processes and many people not aware viral testing results were publicly available prior to publication.

· Focused public sector investments can fill key knowledge gaps to help individuals, communities, governments, and private sector to reduce risk. However, there is room for improving the speed and extent to which the research findings are available to and taken up by those who assess risk, operate surveillance systems and laboratories, and mitigate risk.

Applied research supported by DEEP VZN will position participating countries to enhance understanding and characterize previously-unknown viruses. Data on the zoonotic and pandemic potential of novel viruses potentially can be used by other projects and programs—such as STOP Spillover—to strengthen country-level capacities to model disease emergence risk, update risk analyses, direct precision surveillance approaches, and implement targeted risk-reduction measures. In addition, information from DEEP VZN could be used by other partners, including donors and the private sector, to develop and pre-position diagnostics, medicines, and vaccines ahead of costly epidemics and pandemics. Because spillover, amplification, and spread of unknown emerging zoonotic viruses potentially affects wildlife, livestock, and human populations, efforts to detect and characterize unknown threats will require in-country partnerships that are collaborative and multisectoral.

Goal: Deepen and share knowledge on unknown viruses from wildlife including their zoonotic and pandemic potential.

Overarching DEEP VZN Expected Results:

· Unknown viruses detected and their zoonotic and pandemic potential characterized

· Higher-yield methods and strategies to detect and characterize unknown viruses developed and deployed

· Capacity of specific in-country institutions to conduct applied research and analyze and share findings strengthened.

Project Approach. Building upon an institutional legacy in viral zoonoses landscaping and risk analyses, USAID’s DEEP VZN Project seeks to expand partnerships that will considerably advance detection and characterization of unknown viruses of epidemic and pandemic potential. Since existing animal-human contact promotes spillover of both known and unknown viruses, it is anticipated that DEEP VZN will work in a sub-set of countries that STOP Spillover has targeted because of their known spillover of emerging zoonotic viruses. This arrangement will allow both projects to leverage resources. DEEP VZN will build on data, tools, and strategies--including those previously developed by USAID under PREDICT and FAO--to strengthen the capacity of a limited number of in-country institutions that will conduct the research to detect and characterize unknown emerging zoonotic viruses.

The knowledge gained by DEEP VZN on novel viruses assessed to be zoonotic or pandemic threats will be immediately available to the in-country owners of the data and, once approved for release, policy makers, the private sector, and implementing partners to improve surveillance and reduce the risk of viral spillover [14]. Opportunities may be explored to leverage private sector capacities in research and development of diagnostics, therapeutics, and vaccines associated with data and insights developed under DEEP VZN and in partnership with governments.

Priority Countries. Within anticipated resource parameters, DEEP VZN initially will be implemented in two countries. It is anticipated these countries would be in Africa and/or Asia. Preliminary criteria for selecting focus countries include:

· history of spillovers of emerging zoonotic viruses from animals to people;

· host-country engagement and buy-in to include: interest in providing human or financial resources; commitment to using the research results in-country to reduce risk of emerging zoonotic viruses; support for coordination/collaboration within the country and with regional partners; complementary in-country initiatives such as infectious disease programs and regulation of animal markets or wildlife trafficking and trade;

· history of sharing surveillance and outbreak data within and outside of country in a timely manner and willingness to share findings and samples with the global community to reduce risk of emerging zoonotic viruses in other countries;

· rapid start-up potential for projects;

· ability (or potential) to safely conduct viral discovery and characterization in-country at the scale needed; and

· presence of complementary USAID, U.S. Government, or other investments in GHS (including previous viral discovery). Countries listed in the STOP Spillover Notification of Funding Opportunity [15] are possible candidates due to the potential for DEEP VZN’s risk understanding activities to complement STOP Spillover’s risk reduction activities.

Please note that countries may be added or removed, before or after award, based on the availability of funds and at the discretion of USAID due to changing priorities, policies, or global health events.

Local Partnerships and Capacity Strengthening for Participating Institutions. DEEP VZN will work directly with in-country institutions and staff to include strengthening their capacity to design and safely conduct applied research to identify unknown emerging zoonotic viruses and their animal hosts. The applied research will be coordinated with and leverage relevant efforts of in-country (e.g. academia, private and public entities, civil society, NGOs) and international partners (including other USG, FAO, and WHO) and be conducted in a way that maximizes detection of unknown viruses using the limited resources available while supporting multi-sectoral (i.e. One Health) collaboration and coordination.

It is anticipated that in-country partners will have the following characteristics:

· ability to safely conduct sampling and/or laboratory testing at the scale (to be determined) required by the project;

· previous experience with viral detection and characterization;

· established linkages with host government, private sector, and other multi-sectoral partners;

· demonstrated history of sharing research findings in a transparent and timely manner; and

· ability to receive, track, and report on funding from grants or sub-awards.

Strengthening the capacity of select in-country institutions to conduct applied research will require an understanding of the specific contexts within the targeted countries, including unique cultural, political and gender considerations. DEEP VZN is also expected to be familiar with the many risk assessments and research findings (including those included above and below) already supported by USAID as well as other publicly-available resources to inform strategic planning, baseline analyses, and proposed activities in order to ensure DEEP VZN activities are not duplicative of these or other efforts. USAID supported work related to risk understanding and research:

· FAO: http://www.fao.org/emergencies/fao-in-action/ectad/en/ PREDICT: https://ohi.vetmed.ucdavis.edu/programs-projects/predict-project ; PREDICT final report (unpublished); weblink to be provided when available

· PREVENT: https://www.fhi360.org/projects/prevent-%E2%80%94-emerging-pandemic-threats

· One Health Workforce: http://afrohun.org/index.php?option=com_content&view=article&id=169&Itemid=1056 Objectives and Illustrative Activities. DEEP VZN will work to enhance the detection of unknown viruses and characterize their epidemic and pandemic potential. USAID seeks strategies that will measurably advance the efficiency, improve the efficacy (e.g. signal/noise), and reduce the cost of efforts across the sampling—detection—characterization continuum. Interventions are particularly valued that have shown paradigm-shifting promise, enabling viral detection and characterization at a scale as yet unrealized.

The main focus of DEEP VZN is to support focus counties to conduct applied research to deepen the knowledge available on previously-unknown viruses within select viral families to include assessing the zoonotic or pandemic potential of any new viruses. Since this research may identify additional knowledge gaps regarding animal hosts and spillover dynamics associated with new viruses, it is anticipated that some additional applied research will be necessary.

Objective 1: Conduct Sampling for Unknown Viruses in Select Countries In-country sampling for unknown viruses serves two very important functions. First, the data generated can identify future infectious disease threats before large outbreaks occur which potentially allows time for the development or updating of surveillance postures and risk-reduction measures as well as pre-positioning of diagnostics, medicines, and vaccines. Second, the laboratory techniques may also be used to assist in the investigation of events of unknown etiology when common differentials have been ruled out. While some lower-income countries have developed strategies for sampling for emerging zoonotic viruses over the past decade, this ability is presently limited in size and scope and not sustainable without external donor funding.

USAID will invest in DEEP VZN to develop more-efficient and cost-effective strategies, methods, and tools for detection of unknown viruses. A key part of this is having an evidence-based sampling strategy designed specifically for a country to increase detection rates for unknowns in targeted viral families. Such approaches have been successfully employed in China where geography and host taxa have been important considerations for coronaviruses [16, 17]; Vietnam where sampling interface impacts detection rates for coronaviruses along wildlife value chains [18]; and East Africa where shedding of coronaviruses by bats occurs at specific times of the year [19].

The ultimate aim of activities under DEEP VZN’s Objective 1 is to collect high-quality samples from geographic locations and interfaces where there is (1) a higher probability of finding unknown viruses from wildlife (either in wildlife or people) and (2) where there are conditions that would favor spillover, amplification, and spread of emerging zoonotic viruses from wildlife. This may include interfaces at the beginning, middle, or end of wildlife value chains (which may overlap with livestock value chains to some degree) and may include rural and urban settings. Additional samples may originate from archived repositories of biological material considered relevant for viral discovery, and from human and animal specimens associated with events of unknown etiology occurring during the implementation period of DEEP VZN. Samples collected during DEEP VZN will feed directly into Objective 2 (viral detection) or Objective 3 (viral characterization) depending on the sequencing of the testing and characterization processes. Over the life of DEEP VZN, information from Objectives 2 and 3 may be used to refine the sampling sites and sampling strategies to further improve the efficiency of detecting unknown viruses.

Please note that sampling sites and species to be sampled may be added or removed, before or after award, based on the availability of funds and at the discretion of USAID due to changing priorities, policies, or global health events.

Illustrative Activities for Objective 1 may include, but are not limited to:

· Support institutional capacities to conduct predictive modeling and analytics that will inform the architecture for detection of unknown viruses at high risk locations, interfaces, and time scales;

· Support in-country institutions and staff in focus countries to design an innovative strategy for sampling followed by detecting and characterizing unknown viruses to maximize discovery efforts; to include training, a sampling plan with defined methods, species to be sampled, and sampling sites that are representative of key points of spillover, amplification, and spread along wildlife value chains in both rural and urban settings;

· Identify any equipment, supplies, and approvals (e.g. sampling of animals and people) needed by the participating in-country partners;

· Provide training on biosafety/biosecurity, safe sampling, and safe processing of samples;

· Safely sample key species (animals and people) at selected research sites in focus countries;

· Safely transport and biobank samples at participating laboratories.

Objective 1 expected results:

· Institutional capacity to conduct regular risk modeling that will inform ongoing monitoring efforts established;

· Innovative strategy for sampling of unknown viruses from wildlife at key points for spillover, amplification, and spread developed and approved;

· Key species sampled at research sites;

· Samples safely and appropriately stored.

Objective 2: Strengthen Detection of Novel Viruses Detection of unknown viruses is an expensive and time-consuming process. However, experience has repeatedly shown a substantial return on investment for strengthening capacities to prevent, detect, and contain zoonotic viruses before they cause epidemics and pandemics. Recently, the utility of being able to strategically identify unknown viruses during the early stages of an outbreak was demonstrated by Thailand’s use of consensus viral family level testing protocols to detect and fully sequence a novel coronavirus [20] from a sick traveler from Wuhan, China two days before the causative agent was announced by China. Thailand’s rapid identification of the virus before there were standard diagnostic tests made it possible for the country to take early action, preventing onward transmission and enabling targeted screening protocols that limited health and economic impact.

Viral Detection Strategies. The overall strategic focus of DEEP VZN will be on intensive detection of unknown viruses and characterizing their zoonotic and pandemic potential. Accordingly, USAID seeks input on strategies and approaches that will substantially advance viral detection and enable viral characterization at scales previously unrealized.

USAID recognizes there may be multiple paths to achieve the viral detection objective through DEEP VZN. Consensus viral family level RT-PCR-based detection followed by whole genome sequencing; unbiased next generation sequencing; and virus isolation in cell culture followed by RT-PCR-based detection and sequencing are several such approaches. Through this RFI, USAID is interested in any approach that holds paradigm-shifting promise in achieving this objective.

Within the context of a possible viral family-based approach, DEEP VZN could focus on a limited number of prioritized viral families in order to provide depth to the availability of data regarding these families. Preliminary criteria for selecting viral families could include:

· Some members are zoonotic indicating ability to spill over from animals to people, and have demonstrated previous epidemic and pandemic potential;

· Some members can amplify and spread in people due to air-borne transmission indicating epidemic and pandemic potential;

· Relatively high detection rates from wildlife and human samples; and

· Priorities of host countries and the global research community.

Coronaviruses and paramyxoviruses are two viral families meeting these criteria. Three new coronaviruses (MERS-CoV, SAR-CoV-1, SARS-CoV-2) and two new paramyxoviruses (Hendra, Nipah) have emerged and manifested as epidemic or pandemic pathogens over the past 30 years. Both of these viral families include members that are priorities for CEPI, NIH, and WHO [21] and both viral families are considered to be constituted of a breadth of viruses not yet identified. Through existing support structures, USAID will also continue its efforts to prevent, detect, and mitigate impact from animal-origin influenzas of pandemic potential. Influenza viruses are therefore not anticipated as a focal area for DEEP VZN.

Please note that viral families may be increased or decreased before or after award, based on the availability of funds and at the discretion of USAID due to changing priorities, policies, or global health events. The ultimate aim of testing under DEEP VZN Objective 2 is to screen samples collected under Objective 1 for previously-unknown viruses, either for the prioritized viral families or using other novel approaches and platforms that may be agnostic to viral families, but likely to yield viral zoonoses of epidemic and pandemic potential. Other samples from the focus country, such as from outbreaks of unknown etiology or from previous projects, may also be considered for testing. Samples testing positive will feed directly into Objective 3 (viral characterization). Monitoring of test positivity rates based on species, sampling sites, sample types, seasonality, etc. may be used to periodically refine the sampling strategy under Objective 1.

Please note that methods for viral detection may be added or removed, before or after award, based on the availability of funds and at the discretion of USAID due to changing priorities, policies, or global health events.

Illustrative Activities for Objective 2 may include, but are not limited to:

· Support in-country institutions and staff in focus countries to develop a testing strategy to include methodologies and training, possible identification of archived samples that could be tested under DEEP VZN, and criteria for testing samples from outbreaks (in animals or people) of unknown etiology;

· Identify any equipment or supplies needed by the participating in-country partners;

· Provide training on biosafety/biosecurity and safe processing of samples;

· Assist in-country lab(s) with testing samples from research sites, outbreaks of unknown etiology, and archives;

· Test, validate and standardize protocols that will enhance the yield and efficiency of viral discovery, such as population-based serological studies intended to inform targeted discovery efforts;

· Develop processes to reduce the lag between viral detection and characterization, promoting actionable disease intelligence and risk mitigation interventions; and

· Convene multi-sectoral fora to share virus detection findings with in-country (and international, as appropriate) partners as the results become available and are approved for release by the owners of the samples/data.

Objective 2 expected results:

· Protocols or techniques to test, validate, and enhance the yield and efficiency of viral discovery improved;

· Testing for unknown viruses from research sites, limited outbreaks, and archives conducted; and

· Select in-country lab(s) positioned to provide technical assistance and/or testing for viral discovery and outbreaks of unknown etiology in-country and in the region.

Objective 3. Strengthen Characterization of Novel Viruses The processes of characterizing viruses for zoonotic and pandemic potential are complicated, expensive, and time-consuming. However, this step is crucial in being able to prioritize newly-discovered viruses based on risk so that governments, communities, private sector, and others can make informed decisions on how to address new public health threats. To date, several methods have been used to characterize novel viruses including: comparing genetic sequences with known viruses; evaluating host plasticity (ability to infect multiple species [22]); demonstration of previous infections in humans (by serology); demonstration of active infections (by viral detection); in vitro binding to human cells; and in vivo transmission studies using animal models. While the first four can be done in many countries with external support, the latter two require specialized assays and increased lab biosafety standards which makes them less practical in many lower-income countries. The in vitro and in vivo studies can be done in regional or global labs, but approvals for shipping samples outside of the host country are required which can add months to years to the timeline for assessing risks and informing stakeholders of new threats. Comparison of genetic sequences of novel viruses with those that are known and evaluating host plasticity is only possible if there are enough viruses that are similar and if enough information is available on which animals can host a virus. For example, host plasticity was unknown for SARS-CoV-2 when the COVID-19 pandemic started, but the ability of the virus to naturally infect humans, cats, dogs, mink, pumas, lions, and tigers has since demonstrated its considerable host plasticity which is consistent with it being a zoonotic virus.

The ultimate aim of virus characterization under DEEP VZN Objective 3 is to identify more-efficient methods to evaluate which of the novel viruses detected under Objective 2 have zoonotic and/or pandemic potential. In some instances, samples from Objective 1 could be first screened for ability to bind to human cells in vitro prior to viral detection or novel viruses previously detected by other projects could be characterized under DEEP VZN. Based on analyses for zoonotic and/or pandemic potential, viruses will be ranked by risk and this information made available through multi-sectoral fora so that other partners can update risk analyses, surveillance, risk reduction interventions, diagnostics, and biomedical countermeasures.