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. Author manuscript; available in PMC: 2023 Oct 19.
Published in final edited form as: Zoonoses. 2023 Apr 18;3(1):16. doi: 10.15212/zoonoses-2022-0047

The Coordinating Research on Emerging Arboviral Threats Encompassing the Neotropics (CREATE-NEO)

Nikos Vasilakis 1,2,3,4,5,6,*, Kathryn A Hanley 7,*
PMCID: PMC10586723  NIHMSID: NIHMS1893350  PMID: 37860630

Abstract

Arthropod-borne viruses, such as dengue, Zika and Mayaro, are emerging at an accelerating rate in the neotropics. The Coordinating Research on Emerging Arboviral Threats Encompassing the Neotropics (CREATE-NEO) project, a part of the NIH funded Centers for Research in Emerging Infectious Diseases (CREID) network provides a nimble and flexible network of surveillance sites in Central and South America coupled to cutting-edge modeling approaches in order to anticipate and counter these threats to public health. Collected data and generated models will be utilized to inform and alert local, regional and global public health agencies of enzootic arboviruses with high risk of spillover, emergence and transmission among humans, and/or international spread. Critically, CREATE-NEO builds capacity in situ to anticipate, detect and respond to emerging arboviruses at their point of origin, thereby maximizing the potential to avert full-blown emergence and widespread epidemics.

Keywords: Virus emergence, pandemics, spillover and spillback, CREATE-NEO, CREID Network

Introduction

In recent decades, Central and South America have experienced a series of emergence events including but not limited to: (a) spillover of endemic arthropod-borne viruses (arboviruses) from wildlife reservoirs into humans; (b) exchange of emerging arboviruses; (c) re-emergence of arboviruses that were previously controlled by vaccination and/or vector control; (d) introduction and spread of novel arboviruses, and (e) spread of viruses to other regions. Furthermore, there is great concern that Zika virus (ZIKV), an arbovirus introduced in the Western Hemisphere as early as 2013, may establish an autochthonous sylvatic transmission cycle. More broadly, the enormous vertebrate and invertebrate biodiversity of the region harbors a broad range of arboviruses whose risk of emergence and spread among humans is unknown. A world experiencing economic globalization, rapid population mobility facilitated by jet travel, uncontrolled urban expansion and slummification, deforestation, land use repurposing, breakdown of public health structures in countries experiencing societal, economic, and political unrest, and global climate change, all exacerbate the risk of arbovirus emergence in the neotropics.

The Coordinating Research on Emerging Arboviral Threats Encompassing the Neotropics (CREATE-NEO) provides a network of surveillance sites across Central and South America that are geographically broad, encompass hotspots of biodiversity and different degrees of urbanization, and are well integrated with appropriate modeling techniques that can anticipate, mitigate and counter the threat posed by emerging and resurging arboviruses. Therefore, collected surveillance and epidemiological data and generated predictive models will be leveraged to forewarn public health agencies at the local, regional, and global levels, of endemic arboviruses that could pose particularly high risk of spillover, emergence, and/or international spread. CREATE-NEO’s network will also be ready to detect the introduction of novel arboviruses from other continents and swiftly respond. The overarching goal of CREATE-NEO is to build local capacity to predict, detect and respond to emerging arboviruses at their point of origin, thereby maximizing the potential to avert full-blown emergence and large-scale epidemics across the region and beyond.

CREATE-NEO overview

Central and South America have borne the brunt of emerging arboviruses (1). Emergence in this context has taken multiple forms, including the spillover of enzootic arboviruses from wildlife reservoirs into humans (e.g., Oropouche (OROV) (2) and Rocio (ROCV) (3) among others), exchange of emerging arboviruses within the region (e.g., Mayaro (MAYV) (4, 5), Venezuelan equine encephalitis (VEEV) (6)), re-emergence of previously controlled arboviruses (i.e. yellow fever (YFV) and dengue (DENV)(1, 7, 8, 9, 10, 11)), and introduction and spread of novel arboviruses (i.e. West Nile (WNV) (12, 13), chikungunya (CHIKV) (14, 15) and Zika (ZIKV) (16, 17)). Furthermore, Central and South America have been exporting arboviruses to other regions (e.g., Madariaga (MADV) (18)) at increasing rates as global mobility accelerates.

Of all the recent arbovirus introductions to Central and South America, the introduction of ZIKV as early as 2013 and the consequent surge in congenital Zika syndrome constituted a true calamity for the region, particularly Brazil (19). Now there is considerable concern that ZIKV may spill back into an enzootic transmission cycle among non-human primates (NHPs) in the Americas, as YFV did centuries ago (20). Establishment of a sylvatic ZIKV cycle would complicate control of virus transmission and would render ZIKV eradication from the Americas unattainable. Although it received somewhat less attention, CHIKV was also introduced to the Americas in 2013 and exploded into a massive outbreak that created a staggering burden of clinical disease (21), sometimes resulting in prolonged disability (22). Within the last decade, WNV was also introduced to Brazil, which now faces an imminent WNV outbreak (12, 13). All three viruses can now be considered endemic in the neotropics.

Over the same time period, arboviruses that had previously been controlled via vaccination (YFV) or vector control (DENV) resurged dramatically (1, 7, 8, 9, 10, 11). Between 2016 to 2018, Brazil experienced an outbreak of yellow fever that was shocking in both its magnitude, the largest since the eradication of urban yellow fever in the region, and its location, on the east coast of the country, perilously close to the mega-cities of Sao Paolo and Rio de Janeiro (7, 23, 24). The thousands of human cases of yellow fever in this outbreak are thought to have derived entirely from sylvatic transmission from non-human primate reservoirs. Moreover, 2019 saw the highest number of DENV cases in the Americas in recorded history (25). With the exception of a well-established vaccine for YFV and a controversial vaccine for DENV (26), there are currently no licensed vaccines to protect against infection with any of these viruses, nor are there any licensed antivirals to alleviate disease.

Central and South America have also recently experienced an uptick in the spillover of endemic arboviruses from wildlife reservoirs into humans. This region encompasses much of the world’s diversity of vertebrate hosts and arthropod vectors (27, 28), and, as a consequence, many of the world’s zoonotic viruses (Fig. 1). In this context, Mayaro virus poses a particular concern (29, 30). MAYV is maintained in a sylvatic cycle involving non-human primates and Haemagogus mosquitoes, but readily spills over into humans, with a clinical presentation similar to, and easily mistaken for, chikungunya (31). Importantly, the range of hosts and vectors responsible for maintenance of MAYV is incompletely characterized at this time (32). Phylogenetic analyses have revealed exchange of MAYV viruses between Amazonia and the Caribbean, attributable to some combination of human movement between the regions and bird migration (5, 33). Similarly, MADV, which belongs to the eastern equine encephalitis virus complex, was initially exported from Brazil to other South and Central American countries (34, 35, 36, 37), raising fears that it might move further into the Caribbean or North America. Outbreaks of Oropouche fever, attributable to spillover of midge transmitted OROV, have occurred recently in Brazil and Peru (2). This virus is known to be maintained in a sylvatic reservoir, but the key host species in this cycle are not completely known, nor is the risk of full-blown OROV emergence into human circulation well understood.

Figure 1. The richness of zoonotic viruses.

Figure 1.

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A) across all mammal species currently associated with zoonoses, B) all mammal species associated with tick-borne diseases, C) all mammal species associated with mosquito-borne diseases, and D) all bats associated with zoonoses.

While the viruses discussed above have already demonstrated their capacity for spillover, many additional viruses have been detected in wildlife or arthropod vectors in Central and South America whose risk of spillover and spread is presently unknown (e.g. (38, 39, 40))

Unfortunately, rates of arbovirus spillover and spread in Central and South America are likely to accelerate in the future. Deforestation, already extensive in Central and South America, is expanding, primarily for commercial agriculture (41). Forest conversion may enhance contact between humans and sylvatic vectors and viruses at land cover edges (42) and favor competent arbovirus vectors (43), thereby precipitating arbovirus spillover (44). Global climate change is also expected to shift vector and arbovirus distributions (45, 46, 47) and to facilitate spillover of novel arboviruses. Ongoing urbanization is certainly a boon to key urban vectors such as Ae. aegypti (48) and Ae. albopictus (46, 49) and may also promote spillover of novel arboviruses (50). Globalization, particularly transcontinental movement of humans, affords both vectors and arboviruses the opportunity to move rapidly in to Central and South America from elsewhere or, conversely, from points of origin in Central or South America across the region or across the world (51, 52, 53). For example, as of September 22, 2022, hundreds of thousands of Venezuelans have emigrated to Panama and Brazil (54). The last decade’s political, societal and economic upheaval in Venezuela has led to the breakdown of public health structures, which occupies a critical juncture of Central and South America, and exacerbated the resurgence and regional spread of pathogens (55, 56, 57), measles (58), malaria (59), as well as the spillover and cryptic circulation of novel pathogens (60).

Across the world, there is an urgent need for broad and integrated surveillance networks to better confront the rising threat of emerging and resurging arboviruses (61). This need was recognized by the National Institutes of Health (NIH), with the issuance of a Funding Opportunity Announcement (FOA)(RFA-AI-19–028) on April 04, 2019, calling for the establishment a coordinated network of Centers for Research on Emerging Infectious Diseases (CREID) in regions around the globe where emerging and re-emerging infectious disease outbreaks are likely to occur. The Coordinating Research on Emerging Arboviral Threats Encompassing the Neotropics (CREATE-NEO), one of the ten funded CREIDs, integrates arbovirus surveillance across the region with summarizing and predictive modeling efforts to better anticipate and counter arbovirus emergence (Figure 2). Since its inception CREATE-NEO has built local capacity, including comprehensive genomic surveillance allowing teams to detect, predict and respond to emerging arboviruses at their point of origin. Critically, CREATE-NEO teams were able to quickly redirect their resources to respond to severe acute respiratory syndrome coronavirus 2 (SARs-CoV-2) allowing them to inform local and regional policy makers and public health authorities (62, 63, 64).

Figure 2.

Figure 2.

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Overview of CREATE-NEO surveillance of humans (human icon), vectors (mosquito icon) and wildlife (monkey icon) in Central and South America.

CREATE-NEO’s major areas of concentration involve:

  1. Virus discovery in wildlife and arthropod vectors in Central and South America. Members of CREATE-NEO have discovered, characterized, and annotated many known and new viruses in wildlife and vectors in Central and South America, of which select examples are listed in Table 1 below. Additionally, our group was the first to report evidence of natural ZIKV infection in neotropical non-human primates in Brazil (65), and a lack of evidence for SARS-CoV-2 spillover in wild non-human primates across several surveyed locations in Brazil (64).

  2. Development of novel diagnostic assays. Detecting and distinguishing arbovirus infections in human populations among asymptomatic individuals and symptomatic cases is an important activity of CREATE-NEO. Without sensitive and specific diagnostics, fever symptoms can be undiagnosed or misdiagnosed. We have developed affordable, easy to use rapid paper fluidic tests to detect and distinguish DENV and ZIKV (79) without crossover, permitting unambiguous virus identification. Currently our partners are developing nanoparticle-based methods for virus detection and pandemic preparedness (80), initially targeting neglected arboviruses (e.g., Ilheus (ILHV) and ROCV viruses) of great potential for emergence and significant impact for public health.

  3. Identification of key vectors and hosts in a regional hotspot for arbovirus spillover and spillback. CREATE-NEO is coupling geographically and taxonomically broad surveillance of arthropods and vertebrates with remote sensing and machine learning to predict the distribution of both known and as-yet undiscovered host-vector networks that sustain transmission of key arboviruses. The close integration of empirical sampling with these modeling approaches is a highly innovative aspect of the proposed work (81, 82, 83, 84, 85).

  4. Novel insights into arbovirus transmission and cross-protection from clinical studies. CREATE-NEO leverages ongoing human cohorts in geographically, demographically, and ecologically distinct regions in Central and South America that are hyper-endemic for various constellations of arboviruses to gain insights into how pre-existing immunity influences clinical outcomes upon infection. Understanding this interplay between different arboviruses mediated by cross-protection (or enhancement) is a highly innovative aspect of the proposed work, which will inform vaccine design and efficacy as well as risk of future arbovirus epidemics.

Table 1:

Examples of viruses discovered by CREATE-NEO partners in in Central & South America

Country Host Virus name Virus family Ref.
Colombia mosquitoes Sinu virus Orthomyxoviridae (66)
Brazil; Trinidad & Tobago mosquitoes Trinity virus Peribunyaviridae (67)
Brazil; Panama; Ecuador mosquitoes, birds Gamboa serogroup Peribunyaviridae (68)
Panama mosquitoes PanAr 395145 and PanAr 395144 Peribunyaviridae (69)
Colombia mosquitoes Chiqui virus Reoviridae (70)
Panama mosquitos Gamboa mosquito virus Flaviviridae (71)
Panama mosquitoes Mercadeo virus Flaviviridae (72)
Peru mosquitoes La Tina virus Flaviviridae (73)
Peru mosquitoes Arboretum, Puerto Almendras Rhabdoviridae (74)
Colombia mosquitoes Balsa virus Rhabdoviridae (39)
Panama mosquitoes Rio Chico Rhabdoviridae (39)
Brazil amphibian Cuiaba virus Rhabdoviridae (75)
Peru; Brazil mosquitoes Piura, Loreto and Santana viruses Negeviridae (76)
Colombia, Panama, Peru, Brazil mosquitoes Wallerfield, Brejeira and San Bernardo viruses Negeviridae (77)
Brazil NHPs Zika virus Flaviviridae (65)
Mexico mosquitoes Zika Virus Flaviviridae (17)
Panama equids Venezuelan equine encephalitis and Eastern equine encephalitis Togaviridae (78)
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Conclusion

CREATE-NEO is responding to the rising threat of emerging arboviruses in the Americas by linking a group of Brazilian, Panamanian and US scientists into a network that integrates arbovirus surveillance in vectors, wildlife, and humans across Central and South America. The data generated are analyzed with cutting-edge phylogenetic, statistical, and modeling approaches in order to better anticipate and counter arbovirus emergence. Close relationships with local, regional, and global public health agencies allow timely transfer of information on emerging arboviruses to agencies tasked with responding to such events. However, our ultimate goal is to head off emergence events at their source by building local capacity within Panama and Brazil that will expand the already impressive abilities at these sites to collect and assay key samples in situ.

Acknowledgments:

We acknowledge Adrian Castellanos and Barbara A. Han for figure 1 and Michaela Buenemann for figure 2.

Funding:

This research was funded by the Centers for Research in Emerging Infectious Diseases “The Coordinating Research on Emerging Arboviral Threats Encompassing the Neotropics (CREATE-NEO)” grant U01 AI151807 awarded to NV and KAH by the National Institutes of Health (NIH/USA). The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Biographies

Dr. Vasilakis is currently a professor with tenure and Vice Chair for Research in the Department of Pathology at the University of Texas Medical Branch (UTMB) in Galveston, Texas. He earned his BA and MA degrees in biology from Hofstra University and his PhD in Experimental Pathology from UTMB. He worked for a number of years in the pharmaceutical industry, where he developed vaccine candidates for pediatric diseases based on alphavirus gene delivery systems. His collaborative research program has been at the vanguard of research on the ecology and evolution of arboviruses and their vectors, as well as their pathogenesis, virus–mosquito, and virus–host interactions, for which our experimental studies have led to over 180 peer-reviewed publications (i10-index=136). He has been recognized by Clarivate as a Highly Cited Researcher continuously since 2019 and World’s Top 2% Scientist by the 2022 Stanford University Annual Influence Ranking. As a senior faculty member of the World Reference Center for Emerging Viruses and Arboviruses (WRCEVA), he utilizes Next Generation Sequencing (NGS) to discover, characterize and annotate new and novel viruses that could lead to the development of successful countermeasures for a number of veterinary and human diseases. He was awarded in 2009 with the Young Investigator Award and elected as chair of the American Committee on Arthropod-borne Viruses (ACAV) and as Fellow of the American Society of Tropical Medicine and Hygiene, in 2015 and 2016 respectively. His research program is supported by grants by the National Institutes of Health and pharmaceutical industry contracts. His currently funded Centers for Research In Emerging Infectious Diseases (CREID), The Coordinating Research on Emerging Arboviral Threats Encompassing the Neotropics (CREATE-NEO) (Hanley and Vasilakis co-PIs), provides a nimble and flexible network of surveillance sites in Central and South America coupled to cutting-edge modeling approaches in order to anticipate and counter emerging arboviruses.

Hanley Bio

Bio: For her entire career, Dr. Kathryn A. Hanley has been fascinated by the interactions between hosts and pathogens, and how these interactions shape pathogen transmission and virulence. Kathy graduated magna cum laude with a major in Biology from Amherst College, and she completed her Ph.D. in Biology at the University of California, San Diego. She conducted post-doctoral research at the University of California, Davis, the University of Maryland, and the National Institutes of Health, where she participated in the development of the NIH dengue virus vaccine. Since joining New Mexico State University in 2004, her lab has been at the forefront of research on the ecology and evolution of viruses transmitted by Aedes mosquitoes, including dengue, Zika, chikungunya and yellow fever virus. They have conducted groundbreaking field research on the ecology, spillover, and spillback of sylvatic arboviruses and their vectors around the world. They have also made significant advances via laboratory studies on arbovirus evolution and on the interaction between arboviruses and the mosquito RNA interference response. More recently they have launched a study of the ecology and emergence of vesicular stomatitis virus. Kathy is currently a Regents Professor of Biology at NMSU and a Visiting Scientist at the Cary Institute of Ecosystem Studies. She is a past President of the Rio Grande branch of the American Society for Microbiology and a past Chair of the American Committee on Arthropod-Borne viruses (ACAV). She is the recipient of the ACAV Dalrymple-Young award for research excellence and the NMSU College of Arts and Sciences award for excellence in graduate student mentorship. She is currently co-principal investigator of CREATE-NEO (Coordinating Research on Emerging Arboviral Disease Threats Encompassing the Neotropics), one of ten NIH-funded centers for research on emerging infectious diseases.

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Footnotes

Conflicts of Interest: The authors declare no conflict of interest.

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