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Current and Emerging Threats from Arboviral Diseases: Existing Burden and Future Risk

The workshop opened with an overview from Eve Lackritz, the deputy director of the Center for Infectious Disease Research and Policy at the University of Minnesota, of efforts that have been dedicated to respond to Zika virus outbreaks, triggered by the 2014–2016 epidemic that emerged in Brazil. This was followed by a panel of speakers that discussed the threats, current and future, posed by arboviruses around the world.

ADVANCING GLOBAL RESEARCH PRIORITIES: LESSONS FROM ZIKA

Lackritz illustrated the range of challenges in mitigating arboviral threats by focusing on the experience with the Zika virus. Drawing from a recent international meeting on Zika and mosquito-borne arboviruses, her remarks reflect efforts over the past several years to develop strategic priorities to advance research and development of diagnostics, vaccines, and therapeutics to counter these pathogens.

Spread mainly by Aedes aegypti and Aedes albopictus mosquitoes, Zika rose to prominence for global health officials from the major 2015–2016 outbreak that emerged in Brazil and rapidly spread throughout the Americas (CDC, 2019). Although most cases are mild or asymptomatic, Zika can cause microcephaly, neurodevelopmental delay, and other severe congenital malformations in infants born to women who are infected during pregnancy. To date, locally acquired mosquito-borne transmission of Zika virus has been identified in more than 90 countries and territories worldwide (WHO, 2022). Lackritz observed a global sense of complacency about the

virus that seems to have developed since the end of the 2016 epidemic, noting that there are still currently no approved vaccines to prevent infection, no therapeutics to treat the disease, and no diagnostics for routine screening of pregnant women. Cautioning that there is a serious possibility of a large-scale Zika outbreak reemergence, she pointed out that it is “a critical time to develop countermeasures and to figure out how to be prepared for reemergence in the future.”

Research and development of medical countermeasures against Zika is particularly challenging compared with other arboviruses, Lackritz noted at the start. Main characteristics of Zika disease that contribute to its unique challenges in conducting research include: its frequency of co-circulation and co-infection with other arboviruses, its relatively low rate of transmission, uncertainty in its future transmission patterns, and the goal of preventing infection of the fetus while the disease is largely asymptomatic and undetected in adults.

First, Lackritz highlighted the need to prioritize the development of diagnostics in order to mitigate challenges in prevention and response efforts. Without diagnostics, it is difficult to carry out research, preparation, response efforts, disease forecasting, or the evaluation of public health interventions such as vector control, she said. The currently available diagnostic options each have trade-offs that preclude their broad use in outbreak settings. One diagnostic option, nucleic acid amplification tests (NAAT), have good specificity but only a very narrow window in which the viral ribonucleic acid (RNA) is detectable. NAATs thus have limited utility for identifying asymptomatic infections and for routine screenings and in antenatal care. By contrast, immunoglobulin M (IgM) may persist for up to 3 months, which provides a larger window for detection. This means that a positive IgM test might reflect an infection that occurred before pregnancy. IgM also has cross-reactivity with other flaviviruses,¹ so a positive result does not necessarily indicate a Zika infection. The plaque-reduction neutralization test is labor-intensive and limited to reference laboratories, and it often does not identify the etiologic agent due to cross-reactivity. There is also a lack of approved tests for other specimen types including urine, cerebrospinal fluid, and amniotic fluid. “There is clearly a need for rapid and simple tests,” Lackritz concluded. Clinicians facing a Zika outbreak need point-of-care diagnostics that work in settings with limited lab capacity. Lackritz shared that there were multiple NAAT and serologic assays

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¹ The genus Flavivirus was renamed to Orthoflavivirus in April 2023, though the majority of literature at this point still refer to the old nomenclature. See https://link.springer.com/article/10.1007/s00705-023-05835-1 (accessed June 30, 2024). This proceedings will use the term “flavivirus” for consistency with the speaker presentation material. For disambiguation, the proceedings will note where the speaker used “flavivirus” to refer to the family Flaviviridae instead of the genus Flavivirus.

approved under emergency use authorizations during the 2015 outbreak, but they were never validated by standardized evaluations.

On the current state and challenges of research and development for Zika vaccines, therapeutics, and prophylaxis, Lackritz conceded that understanding the immunology of Zika infections is difficult and further confounded by complex immunologic interactions with co-circulating flaviviruses. The potential cross-reactivity with co-circulating flaviviruses raises the concern for antibody-dependent enhancement from vaccination and underscore the need for better understanding of protective immunity. At the time of this workshop, the mechanisms by which the approved flavivirus vaccines create protective immunity remain poorly understood, so neutralizing antibodies are often used as correlates of protection. Lackritz highlighted a need to elucidate the roles of neutralizing and non-neutralizing antibodies as well as T cell–mediated immune responses in conferring protection from infection, disease development, and transmission. Another issue is that the prevention of congenital infection is an unrealistic endpoint of clinical trials as it is a relatively rare event on a population level, so it is impossible with a clinical trial to observe whether the vaccine is doing what it is designed to do. Finally, since most infections are asymptomatic, it is difficult to assess clinical endpoints and benefit for regulatory approval.

There are a number of Zika vaccine candidates based on different platforms and antigens in various stages of development at the time of the workshop, with some as far as in phase 2 clinical trials, Lackritz said.² However, this diversity also contributes to difficulties in interpreting clinical trial data due to a lack of standardization and points of comparison between the different methods, laboratory criteria, and trial endpoints. Another issue is the challenge of defining clinical trial endpoints. Despite its biological and epidemiological significance, prevention of congenital infection is a challenging endpoint for clinical trials as it is a relatively rare event on a population level, Lackritz said, and testing the prevention of congenital Zika infection will require a large sample size collected over many years. An additional and unique consideration in developing a Zika vaccine is the potential legal liabilities associated with its use in pregnant women or women who might become pregnant. She added that, since most infections are asymptomatic, it is also difficult to assess clinical endpoints and benefit for regulatory approval. This contributes to the uncertainty in market demand and unstable funding to developing Zika vaccines.

Several potential regulatory pathways exist to the approval of a Zika vaccine. For example, Lackritz pointed out, a chikungunya vaccine was

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² For more information on Zika vaccine candidate platforms and components see Figure 1 in https://doi.org/10.1080/21645515.2020.1730657 (accessed July 1, 2024).

just approved through a combination of efficacy testing in animal models and immunogenicity testing in humans. Acknowledging that regulatory pathways differ by country, Lackritz noted that the most likely path for a Zika vaccine to receive approval by the U.S. Food and Drug Administration (FDA) would be a stepwise approach with an accelerated pathway approval for adults combined with post-marketing studies to monitor for populational immunity and the impact on fetuses. Altogether, Lackritz said, it will be necessary to clearly identify the target populations in designing clinical trials as well as nontraditional regulatory pathways that a potential Zika vaccine could take to garner approval.

One challenge in developing a Zika vaccine that Lackritz highlighted is that any agent used in pregnant women or women who might become pregnant creates various potential legal liabilities for the company developing the vaccine. Testing the prevention of congenital Zika infection will require a large sample size collected over many years. Several potential regulatory pathways exist to the approval of a Zika vaccine. For example, Lackritz pointed out, a chikungunya vaccine was just approved through a combination of efficacy testing in animal models and immunogenicity testing in humans. Acknowledging that regulatory pathways differ by country, Lackritz noted that it seems the most likely path to approval of a Zika vaccine by the U.S. FDA would be a stepwise approach with an accelerated pathway approval for adults combined with post-marketing studies to monitor for populational immunity and the impact on fetuses.

Next, Lackritz described some systematic approaches that could accelerate research and development for Zika diagnostics, vaccines, and therapeutics. First, she focused on the use of biorepositories and specimen sharing. Researchers at the recent international meeting highlighted access to specimens as a major barrier to research and development, she said, and proposed a mitigation strategy of having regional specimen sharing guided by legal agreements and standards for how high-quality samples are collected, stored, and used.³ It is also possible for similar agreements to be set up between industry partners and individual countries if concerns of benefit sharing can be worked out among each side. Models of sample sharing agreements are already being developed in the Americas (through the Pan American Health Organization [PAHO]), Europe (through the European Union), and Africa (through the Africa Centres for Disease Con-

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³ Standardization considerations that Lackritz shared include specimen characterization and availability for research and development, assessment of diagnostic tests, and evaluation of laboratory proficiency programs; diversity of participant populations (pregnant women, adults, newborns); and specimen type (blood, saliva, urine, amniotic fluid, and cerebrospinal fluid).

trol and Prevention), in conjunction with viral repositories set up during the COVID-19 pandemic), Lackritz noted. One proposed strategy is to have regional specimen sharing guided by legal agreements and standards for how high-quality samples are collected, stored, and used. It is also possible that there may be agreements with industry partners if somehow countries could benefit from providing samples.

Lackritz suggested acting on other elements of a systematic preparedness for the next Zika outbreak, including:

• Developing animal models to recapitulate congenital Zika infection
• Exploring the use of controlled human infection models given the low transmission rate during non-outbreak periods, which would otherwise preclude carrying out necessary research studies
• Preparing geographically and epidemiologically diverse research sites
• Establishing global networks with standardized and pre-approved protocols to be ready for the next outbreak, including working with regulatory and public health agencies in different regions to develop plans for staffing, laboratories, and data management
• Engaging local communities and hearing from women who may participate in trials about how best to implement research in their settings

Conducting longitudinal cohort research would be ideal, said Lackritz, though this research is expensive and difficult to maintain. As a result, Lackritz asserted that strategies for maintaining long-term investment in integrated arbovirus research must be developed. Finally, Lackritz shared that it will be necessary to strengthen epidemiology and surveillance and build global laboratory capacity. Better systems are needed, she continued, for the early detection and monitoring of viral transmission, which in turn can feed into improved models that can be used for forecasting and evaluation. There is also an opportunity to develop a global mapping of reference laboratories, coordination among those laboratories, proficiency testing programs, and standardized protocols to evaluate diagnostics before the next outbreak.

In closing, Lackritz said that reaching these goals will depend on the proper funding. She shared that researchers at the recent international meeting believed it is important to advance Zika research as part of an integrated arbovirus strategy. Other strategies that this group discussed included developing a full public health value proposition with cost–benefit analyses of medical countermeasures and investigating the potential for advanced purchase agreements for vaccines and therapeutics.

OVERVIEW OF ARBOVIRAL DISEASE:
THE CURRENT STATUS AND FUTURE OF DISEASE CONTROL

The following session included presentation from four speakers. Marcos Espinal, former assistant director of PAHO, served as moderator and opened the session by commenting that while progress has been made in the control of arboviral diseases, much remains to be done. Duane Gubler, emeritus professor and founding director of the Emerging Infectious Diseases Signature Research Program at Duke-NUS Medical School, Singapore, provided an overview of the global burden of arboviral disease as well as opportunities for advancement in mitigation. The next three speakers focused on specific regions of the world. Laura Kramer, emeritus professor at the University at Albany School of Public Health discussed the threat of endemic and emerging arboviruses in the United States. Sylvain Aldighieri, director of Communicable Diseases Prevention, Control, and Elimination at PAHO, summarized the situation in the Americas, focusing mainly on Latin America. Finally, Raman Velayudhan, head of the Unit on Veterinary Public Health, Vector Control and Environment in the Neglected Tropical Disease Program at the World Health Organization (WHO), spoke about arboviral diseases in the rest of the world with a focus on Africa and Asia.

Gubler began with a comparison of arboviruses with other infectious disease agents. He pointed out that 8 of the 18 high-profile human infectious disease epidemics in the past 30 years were caused by arboviruses, such as dengue, West Nile, Zika, chikungunya, and yellow fever. Furthermore, of the seven pandemics that have occurred in the past 30 years, three have been caused by arboviruses: dengue, chikungunya, and Zika. The take-home message, he said, is that the biggest viral threats in terms of epidemic or pandemic potential are respiratory pathogens, such as SARSCoV-2, or those spread by urban mosquitoes—that is, arboviruses.

Indeed, he continued, arboviruses are a global threat and not limited to any particular geographic region. Globally, nearly two dozen different types of arbovirus outbreaks were reported in 2023, from dengue, Zika, and chikungunya to Murray Valley encephalitis and Crimean Congo hemorrhagic fever, he said. The three main groups of arboviruses—flaviviruses, alphaviruses, and bunyaviruses—are reflected in these recent outbreaks. He noted that, of the potential diseases caused by pathogens in these groups, those with highest severity and highest probability of occurring are yellow fever, Rift Valley fever, Venezuelan equine encephalitis, Ross River virus infection, and Japanese encephalitis.

Furthermore, Gubler noted that there has been a dramatic increase in epidemic arboviral diseases in the past 30 or 40 years, and attributes this to four major drivers of epidemic transmission. The first driver he cited is demographic changes, particularly population growth and migration

patterns. The second is environmental changes, which are closely tied to demographic changes and include unprecedented urban growth, changing lifestyles, and agricultural practices. The third driver is technology, particularly airplanes and shipping containers that have led to the rapid and far-flung movement of people, animals, and pathogens around the world. Finally, the public health infrastructure for handling vector-borne diseases has been allowed to deteriorate globally, he said. Gubler noted that, in combination, these four factors explain much of the increased transmission of arboviral diseases in recent decades.

Gubler highlighted several risk factors for arboviral disease epidemics specifically in urban areas. These include population growth, urbanization, modern modes of transportation, as well as environmental changes such as deforestation, climate, and weather patterns. While he noted that climate and weather are the most important factors in transmission of arboviral diseases, Gubler stressed that unplanned urban growth as a critical risk factor that must be controlled. He elaborated that urban growth and migration have led to the appearance of megacities of 10 to 20 million people, with many of the residents living in slum areas with inadequate housing, water, sewage, other waste management.⁴ These crowded conditions provide ideal ecological environments for the maintenance and transmission of viruses and vectors that cause arboviral diseases. These cities also have modern airports through which travelers can access endemic areas where they may be at increased risk of contracting arboviral diseases. Furthermore, Gubler continued, many of these travelers have the potential to introduce exotic viruses into urban areas, potentially amplifying transmission in urban settings.”

Gubler went on to share lessons learned from past epidemics. One observation is the cyclic nature of arboviral disease epidemics, and how sometimes long inter-epidemic periods can create a degree of complacency about the diseases, Gubler pointed out. Not only is it easy to forget the diseases when there is no active epidemic and there are no cases being diagnosed, various political and administrative changes can occur during these inter-epidemic periods that result in decreased readiness, such as staff turnover that leads to a loss in expertise and institutional memory. Another lesson, he continued, is that emergency response plans may be ineffective because of inadequate surveillance and because policy makers are often

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⁴ The United Nations defines slum households as dwellings where the inhabitants lack adequate housing or basic services such as access to an improved water source, access to improved sanitation facilities, sufficient living area, housing durability, or security of tenure in the dwelling. See the 2018 UN-Habitat SDG Indicator 11.1.1 Training Module: Adequate Housing and Slum Upgrading. https://unhabitat.org/tools-and-guides (accessed July 11, 2024).

hesitant to decide on implementation until there is an emergency. However, by the time the health emergency situation is certain, it is often too late to mount an effective response. Gubler noted that the general pattern in the current society seems to favor not doing anything until the crisis occurs, leading to outcomes that are far worse than if some preparations had been made.

Gubler noted there are tools to control arboviral diseases—some already available and others being developed—that, if used properly, could reverse the trend of emergent arboviral disease epidemics. However, Gubler believed that it will be necessary to apply these tools to prevention instead of relying on reactive control. Gubler believed that coordinated global funding aimed mainly at helping resource-poor countries develop operational and response plans will be a key factor of success. He went on to list several other requirements to complement the global funding support and disease control tools in reversing the arboviral disease epidemic trend. To ensure sustainability of these efforts, countries around the world will need to commit to the program. For example, he explained, countries in endemic areas will need to invest their own money into the prevention and control of these diseases and not rely on international public health agencies for their public health funding. These public health programs will need to be intersectoral, community partnerships that stay in communication with all segments of the society and not just the medical community. Laboratory-based proactive surveillance and urban renewal will also be important. He added that more research to develop better vaccines, therapeutics, diagnostics, insecticides, and surveillance tools will be critical. This in turn could benefit from the support of the community and of governments to develop and maintain these research programs.

In summary, Gubler said that the risk of epidemic arboviral diseases is now the highest in history. More than 500 viruses are known in animals, many of which have the potential to infect humans and domestic animals to cause major epidemics, and there are certainly many more that have yet to be discovered. More emergent epidemic diseases can be expected in the future, he said, but this trend can be reversed if the available tools are put to work in a synergistic way to prevent and control future outbreaks.

COUNTRY AND REGIONAL EXPERIENCE:
IMPACTS AND CHALLENGES OF ARBOVIRAL CONTROL

The remainder of the session was devoted to three presentations about experiences in regional arboviral control in the United States, the rest of the Americas, Asia, and Africa.

United States

Kramer began with an overview of medically important arboviruses that can be considered “established threats” to the United States, noting that some of these are endemic to the United States (including territories). There are three types of equine encephalitis caused by alphaviruses that are endemic in the United States: Western equine encephalitis, Eastern equine encephalitis, and Venezuelan equine encephalitis subtype II, also known as Everglades virus. Human cases are rare for these viruses, although there are regular cases in wildlife and domestic animals. There are several endemic mosquito-borne flaviviruses, including West Nile, St. Louis encephalitis, and dengue. West Nile virus, introduced into the United States in 1999, has since become the leading cause of domestic arboviral disease, Kramer pointed out, with an estimated 7 million infections having taken place in the country. Dengue virus poses a significant threat because it is frequently introduced into the United States, she said, in addition to lower levels of local transmission. Endemic Orthobunyaviruses, which cause neurological disease in humans, include La Crosse virus and Jamestown Canyon virus. Other viruses that are not currently endemic but can be considered as established threats to the United States include yellow fever virus, which caused several outbreaks in the 18th century, chikungunya, Zika, Venezuelan equine encephalitis subtype I-B, and the Mayaro viruses.⁵ Kramer also cautioned that there are risks for new arboviral threats to become introduced and established in the United States. There are multiple arboviruses that pose a threat to the United States in the future, such as Rift Valley fever virus, Japanese encephalitis virus, and Murray Valley encephalitis virus. There are also multiple mosquito species that can carry various arboviruses in the United States now, Kramer said. These include Aedes aegypti, Aedes albopictus, Culex pipiens, Culex quinquefasciatus, and Culex lactator.

Kramer suggested six areas to focus efforts on controlling potential introduction or reemergence of these medically important arboviruses: preparation, surveillance, diagnostics, epidemic countermeasures, research, and social science aspects. Preparation involves defining responsibilities, identifying gaps, organizing laboratory capacities, and localizing resources before the next outbreak occurs. Surveillance enables anticipation of the risk of an arboviral epidemic rather than being limited to responding to the outbreak retroactively. Rapid diagnostics enable tracking of an outbreak as it is progressing, and thus it is also important to train people on how to

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⁵ Kramer elaborated that, since 2014, there have been thousands of cases of chikungunya reported in U.S. travelers returning from affected areas in the Americas and a few cases of local transmission reported. There were large outbreaks of Zika in the United States in 2015 and 2016, but there have been no reports of Zika virus being transmitted by mosquitoes since 2018 in the United States.

perform these diagnostic tests before an outbreak appears. Basic epidemic countermeasures include vector control, personal protection, therapeutics, and vaccines. Intensive vector management programs have been effective in reducing the size of outbreaks, Kramer said, but they are costly and typically initiated only after many cases have already occurred. Personal protective measures can also be effective, but adherence to best practices, such as wearing long pants and using insect repellant, is often very low. Ongoing research can address these shortfalls, she said, by developing innovations in surveillance and epidemic countermeasures (e.g., insect control, diagnostics, and vaccines), while also conducting long-term studies on the epidemiology and ecology and geographic distribution of arboviruses in the world. Finally, she said, it is critical to have effective communication networks and commitment from local communities to partner in arboviral disease control. Kramer also noted that success will depend in part on building coalitions of national and global partners who can work together to identify changes in pathogen distribution and genomics, which can in turn provide early signals to public health officials.

To understand the cyclic nature and be able to predict arbovirus emergence, it is necessary to understand the drivers of disease emergence and establishment, Kramer said. This is a complex process that involves both biotic and abiotic factors. The biotic factors include the interactions among the virus, the vector, and the vertebrate host(s). These are shaped by the abiotic factors including the environment, landscape, ecology, agriculture, urbanization, and weather. Furthermore, climate change can affect the range, intensity, and seasonality of vector-borne diseases.

Kramer used West Nile virus as an example to illustrate the complex biotic factors affecting prediction and control in the United States. There are multiple different vectors, vertebrate hosts, and ecological niches associated with this one pathogen. In the southern region of the continental United States, the vector is Culex quinquefasciatus, a container breeding mosquito that feeds on both birds and mammals. In the west, the vector is Culex tarsalis, a floodwater breeding mosquito that feeds on mammals and birds. In the eastern region, the vector is Culex pipiens, a container breeder that feeds mainly on birds. Additionally, Culex pipiens has two forms, Culex pipiens pipiens and Culex pipiens molestus, that have different over-wintering, feeding, and egg laying patterns. Unsurprisingly, the patterns of West Nile infections vary tremendously between the Midwest, the Southwest, and the Northeast, Kramer said, complicating vector control and disease modeling.

In contrast, dengue and other viruses transmitted by Aedes aegypti do not require a zoonotic cycle, she noted. These viruses are rapidly transported to new locations because infected humans, a highly mobile vertebrate host, can directly infect the mosquito vectors Aedes aegypti and Aedes

albopictus. These mosquitoes have significantly expanded their ranges to the north and west because of climate change, further increasing the risk of population exposure to dengue and Zika, Kramer said. These arboviruses carried by Aedes mosquitoes are also challenging to diagnose, she continued, because early symptoms of diseases caused by these viruses tend to be similar and serologic assays for these viruses tend to cross-react. Distinguishing between the viruses requires specialized techniques such as plaque reduction neutralization, which is expensive, slow, and requires specific training.

Kramer also brought up tick-borne viruses, cautioning that while they are somewhat neglected in discussions so far, they have been expanding in range. Powassan virus is probably the most important tickborne virus in the United States, she said. It is carried by the Ixodes scapularis tick that is found across the eastern half of the United States, and the virus is now found across a significant portion of this range. Although there remains fewer than 50 reported cases each year, the incidence of disease has been increasing over the past couple of decades. Other tickborne viruses of concern in the United States are the Heartland virus and the Bourbon virus, Kramer said. The Heartland virus, first identified in Missouri in 2009, causes severe fever with thrombocytopenia; while rare in the U.S., thousands of clinical cases of this disease have been reported in China. The Bourbon virus, first found in 2014 in a sick patient in Bourbon County, Kansas, remains relatively rare.

In conclusion, Kramer noted that a strong public health infrastructure will be crucial, as will global surveillance with international cooperation and sharing of resources and data. Also, “we need to pay more attention to arboviruses on a global scale and viruses that are not as exotic as the Aedes-transmitted viruses,” she said. Other needs include early and rapid detection and reporting of human and zoonotic disease outbreaks and effective scientific communication, not just with the public but also among scientists and with funding agencies. She acknowledges the importance of taking a One Health approach in addressing arboviruses.⁶ Broad, multidisciplinary, long-term research programs will be vital, as will rapid technology transfer from the bench, Kramer stated.

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⁶ One Health is a collaborative, multilevel, transdisciplinary approach to preventing, detecting, preparing for, and responding to outbreaks of infectious disease that recognizes the health of humans, animals, plants, and the wider environment are closely linked and inter-dependent. See https://www.who.int/publications/m/item/one-health-definitions-and-principles (accessed July 4, 2024).

The Americas

Aldighieri discussed how dengue, chikungunya, Zika, and yellow fever have affected the Americas over the past couple of decades and the efforts that have been taken to control these diseases. These viruses are ubiquitous in the Americas year-round, he said. Dengue has caused epidemics in the Americas since the 1980s, while chikungunya was introduced in 2013, and Zika was first detected in 2015 (Espinal et al., 2019). Yellow fever is present in 13 countries, and there are also several emerging arboviruses in the Americas. Aldighieri highlighted two of these emerging viruses, Oropouche and Mayaro, which he said deserve special attention.

Aldighieri noted that the first line of defense against these arboviruses in the Americas are the virus reference laboratories. There are operational reference laboratories in the different subregions throughout the Americas, and there are several national labs, such as the one in Nicaragua, that have significant capacity for the detection and characterization of arboviruses. There is also a network of these laboratories, the Arbovirus Diagnosis Laboratory Network of the Americas (RELDA), that Aldighieri described as a major asset to arboviral preparedness and response. Nonetheless, Aldighieri believed this laboratory network could be strengthened in a few ways: by developing and standardizing laboratory diagnosis algorithms for arboviruses, improving the distribution of reagents for serological and molecular tests, strengthening the laboratory confirmation and identification of serotypes in the countries of the Americas, and further developing the complementary Genomic Surveillance of Dengue Virus in the Americas network (ViGenDA).

Aldighieri shared some lessons learned about patient care and about vector control. With endemic diseases, while the case burden may consistently increase over time, the proportion of severe cases and case fatality rate can be decreased by improving patient care at the primary health care level. This could be accomplished with updated training of health care workers in the management of severe cases, including training them regarding early predictors of when patients are likely to fare poorly. During epidemics, he said, it is key to be able to reorganize health care services and focus more on appropriate triage and preventing deaths. In recent years, investment has been made in virtual training for dengue and chikungunya management, but there is still room for improvement and reducing deaths related to inadequate clinical management.

Regarding vector control, he said, while Aedes aegypti has spread to colonize most of the intertropical areas of the Americas after the eradication program failed in the early 1970s, modernizing entomological surveillance methods and improving information systems could still make a major difference in country vector control efforts. In particular, he said it would be

valuable to implement integrated vector management, rationally incorporate new technologies and approaches, and strengthen capacities for monitoring and managing insecticide resistance. One challenge in vector control is the population growth and increase in the number of large cities that has taken place over the past several decades. Inhabitants in the Latin America and the Caribbean region increased from 168 million inhabitants in 1950 to over 660 million in 2022, and currently 80 percent of these people live in large cities (ECLAC, 2022). During the Zika response in 2016, Aldighieri said, “We estimated that more than 500 million people were at risk to be infected by the virus through Aedes aegypti.” In addition, climate change is leading to an expansion of the geographic areas with conditions suitable for vector reproduction.

Elaborating on the effects of climate change on the suitability of environments for disease vectors, Aldighieri cited the results of a recent study that found the world became more suitable for the development of Aedes aegypti at a rate of 1.5 percent per decade between 1950 and 2000, a trend that is expected to increase to 3.2–4.4 percent per decade by 2050 (Iwamura et al., 2020). As a result, the expansion of the vector into North America is expected to accelerate to around 2–6 kilometers per year by 2050. He noted an equity concern in this future scenario, stressing the unequal impacts of arboviral diseases across different groups. For example, Aldighieri noted that the incidence rates of dengue are, on average, much higher in people with low literacy levels than in people with high literacy levels. Similarly, Aldighieri explained that dengue rates are far higher among people with less access to basic health services.

To address this growing threat, Aldighieri described an integrated management strategy for the prevention and control of arboviral diseases that PAHO has been implementing on behalf of its member states for almost 20 years. This strategy was initiated to deal with dengue and later expanded to address chikungunya and Zika. The strategy draws from lessons of past arboviral epidemics, though Aldighieri noted that the strategy may need to be reassessed considering the recent changes in the region, including population growth and climate change.

To illustrate some of the concerns about the spread of arboviruses and strategies that could be used to resist that spread, Aldighieri described the reemergence of yellow fever in 2016–2017 in southeast Brazil that has led to more than 3,500 laboratory-confirmed cases and more than 900 deaths. The best way to predict where a yellow fever outbreak will occur, Aldighieri said, is to monitor for yellow fever epizootic episodes, or outbreaks among animal populations, and use information on those epizootic episodes to guide vaccination campaigns. Public health officials in southeast and south Brazil were able to dramatically reduce the number of human cases of yellow fever with this approach. Aldighieri detailed additional reasons behind

this successful outcome. In particular, this outbreak was transmitted by sylvatic vectors (i.e., via nonhuman primates and non-Aedes mosquitoes) and did not involve the Aedes aegypti vector in an urban setting. The context of the outbreak was deforestation and canopy loss, and much of the disease transmission took place along sylvatic corridors that sometimes run very close to urban areas, where epizootic spread can take place at a high velocity. Aldighieri also noted that it is best to take a One Health approach to addressing this type of outbreak, where it is critical to consider the integrated health of people, animals, and ecosystems. Given the important roles that deforestation, sylvatic corridors, and nonhuman primates play in the spread of the yellow fever virus and its ultimate threat to humans, the traditional approach of focusing narrowly on mosquitoes and human patients is not the best way to control and respond to outbreaks.

In his conclusion, Aldighieri emphasized several takeaway messages: The region of the Americas encompasses a constant circulation of emerging and reemerging arboviruses, many with high epidemic potential, and this presents a permanent risk to public health. Second, while the case number of diseases like dengue have consistently increased, countries have been able to reduce the proportion of cases that progress to severe disease and reduce the number of deaths from the disease through systematic capacity-building efforts. Finally, laboratory networks must be strengthened and used to detect the emergence of new viruses as well as monitoring existing viruses.

Worldwide

Almost 4 billion people in nearly 130 countries around the world are at risk of Aedes-borne arboviral infections, Velayudhan said, and the public health threat posed by these diseases is growing. For instance, the worldwide incidence of dengue increased tenfold over the past two decades, reaching a record high of 5.2 million cases reported in 129 countries in 2019 (WHO, 2023). Dengue outbreaks continued to be reported in many countries during the COVID-19 pandemic, leading WHO to create the Global Arbovirus Initiative. Metrics for 2023 have also been alarming, Velayudhan said, with reports of more than 5 million cases of dengue across 80 countries and in all WHO regions. While the overall case fatality rate is low, with at least 5,000 dengue-related deaths estimated for the year (WHO, 2023), Velayudhan reiterated that “any death is a matter of grave concern.” As of December 2023, WHO is actively monitoring dengue outbreaks in 23 countries, 17 of which are in the Americas.

Turning to Southeast Asia, he said, 10 out of the 11 countries in this region are dengue endemic. Recently there has been a significant increase in cases in Bangladesh, from a little over 62,000 in 2022 to over 310,000 in 2023, while the number of deaths there surpassed 1,600. Thailand also had

an unusually high number of cases—over 135,000—in 2023. Case fatality rates ranged from 0.04 percent in Nepal to 0.72 in Indonesia. Most of the data in this region come from hospitalized or severe cases. In the western Pacific regions, 2023 was a bad year as well. Eight countries in the region reported dengue cases, with the Philippines and Vietnam having particularly high numbers (WHO, 2024).

There are relatively little data for the eastern Mediterranean region, but there is growing interest in stepping up surveillance in the region, Velayudhan said. In 2023, eight countries reported a total of 10 dengue outbreaks in the Mediterranean region. It is a challenging area because of ongoing armed hostilities, which limit the amount and timeliness of information on infections, but the available data indicate a systematic increase in the number of cases. There has been an upsurge of dengue infections in Saudi Arabia, while Djibouti, Somalia, and Sudan have experienced outbreaks for the past several years. Afghanistan recorded its first outbreak in 2019. In Europe, dengue is not endemic and the recorded cases are mostly travel-related. Still, dengue has been reported constantly since 2000, and in 2011 there was a major outbreak on Madeira Island. In 2023 there were 81 cases in Italy, 43 in France, and 3 in Spain, which Velayudhan characterized as a “matter of concern” because it is very unusual to have three different countries report cases in the same year. Furthermore, there was local transmission in those countries. The mosquitoes that carry the virus hibernate in the winter, but the next summer’s potential for outbreaks is significant, Velayudhan said.

The African region is among the top four regions most affected by dengue and in 2020 recorded more than 200,000 cases, but it is not possible at this time to know the exact burden there. Some 30 countries in the region are dengue prone, and since the beginning of 2023, 11 countries in Africa have reported outbreaks of the disease. One of the countries of greatest concern is Burkina Faso, which had over 170,000 suspected cases of dengue, and 760 deaths (WHO, 2022). Velayudhan noted that the region is working to establish a surveillance system for arboviruses, and in 2022 a regional framework for combatting arboviruses and other vector-borne diseases was approved.

Velayudhan attributed the upsurge in dengue and other arboviruses in these regions to a combination of factors. Greater mobility and increased travel make it easier for the viruses to move from one area to another and increase the chances of outbreaks. The El Niño phenomenon brings higher temperatures, higher humidity, and greater rainfall to many areas, making the environments more suitable for mosquitoes. Environmental factors, such as urbanization, population growth, and the mass migration of populations also play a role, while complex humanitarian crises and armed conflicts weaken health systems and make access to health care facilities

more difficult. The co-circulation of the four serotypes of dengue may lead to an increased number of severe dengue cases and deaths because of the effects of antibody-dependent enhancement following secondary infection.⁷

Those who seek to monitor and control dengue and other arboviruses face many challenges, Velayudhan said. The biggest is insufficient multisectoral coordination for dengue responses at national and local levels. “Within a country it is becoming increasingly challenging to work across ministries and to implement the program and monitor it for a particular period,” he said. A second challenge is that there are relatively few effective tools for dealing with dengue. There are no sustainable vector control tools, vaccines have limited effectiveness, and there are no drugs to treat or prevent disease. The presence of multiple outbreaks—COVID-19, global cholera, and others—combined with other humanitarian crises all taking place simultaneously has greatly stretched resources, both financial and workforce. This is exacerbated by capacity issues, particularly a lack of trained clinical, entomological, and vector control staff.

Clinical diagnosis remains a priority issue, he continued, because most of the cases are asymptomatic. At the same time there is inadequate management of cases, and the triaging of cases is a particular challenge in many countries. A related issue is the limited capacities for laboratory testing, though Velayudhan noticed that COVID-19 seems to have spurred the development of new and easier-to-perform diagnostics, especially multiplex assays, so this may become less of a problem. Making further progress against arboviral diseases around the world will require thinking outside of the box, he continued. For instance, producers of water storage containers should be encouraged to develop ways to ensure that a lid is always covering the container except when it is in use. Along those lines, WHO is working with the United Nations to make sure that all refugee camps have their tanks well covered.

Looking to the future, Velayudhan anticipated that many cities will likely experience water stress and even water depletion, and this is likely to trigger more dengue as people hoard water in and around their houses. Building on experiences from the past, he added, during outbreaks public health authorities should make a concerted effort to address the periphery first, keeping mosquito populations low in the areas adjoining the hotspots as a way of preventing spread of the virus. Risk communication and community engagement efforts should focus on conveying a single important message, reinforcing it year after year, and the communication should be

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⁷ For an explanation on the phenomenon of antibody-dependent enhancement in dengue infections, see https://www.nature.com/scitable/topicpage/host-response-to-the-dengue-virus-22402106/ (accessed July 4, 2024).

done in the local language. Targeted interventions are needed to protect the most vulnerable populations.

In conclusion, Velayudhan offered several take-home messages:

• Vectors are continuing to expand into new countries.
• Enhancing real-time integrated surveillance will be essential to preventing outbreaks.
• Prevention should be prioritized, including vector population reduction wherever possible.
• Programmatic approaches can be more sustainable than outbreak response.

In particular, Velayudhan commented that a programmatic approach is needed for dengue because it is no longer an outbreak disease; it is endemic in more than 100 countries. Urban environments are hot spots for the rapid spread of diseases, and urbanization is only going to increase in the future, especially in continental Africa. Thus, a greater focus on urban environment and urban health could be beneficial. Finally, he said, tailored interventions along with infrastructure and capacity building will be essential in the effective control of arboviral diseases.

DISCUSSION

In the discussion session, one participant referred to the importance of taking a One Health approach to control arboviral diseases and asked the panelists to discuss how they would operationalize One Health in this context. Kramer stated that to control the spread of West Nile virus and other related viruses, it is important to study the virus, birds, mosquitoes, and human behavior. “We need to understand the migration patterns of the birds, the seasonality of them, the feeding patterns of mosquitoes on the birds, and of course the vector capacity of the birds, how infectious are they for how long.” For mosquitoes, she continued, one must think about how to control all the stages of the mosquito—the larva, the eggs, and the adults. Aldighieri added that it is also crucial to consider environmental factors, including wildlife. Surveillance systems used for different purposes must be harmonized, he said. Surveillance in farming systems, for instance, has different interests than surveillance for human public health. However, some new tools, such as genomic surveillance, can create a bridge between the different systems, Aldighieri said. There is a policy framework developed in the Americas for bridging the different sectors necessary for the One Health Approach, led by a permanent forum called RMSA after the Spanish acronym for the Conference of the Ministries of Health and Ministries of Agriculture of the Americas. It provides a place for various

stakeholders and decision makers to share opinions and make decisions. Gubler thought that One Health is a “buzz word” that is used liberally in scholarly publications as a solution without providing additional details; however, he recognized parallels between the One Health approach and the study of disease ecology, where disease transmission cycles, ecology, animal life cycles, and human-animal interactions are examined collectively.

Panelists were also asked about how they would prioritize making investments in the various unmet needs that had been mentioned, such as diagnostic capacity, surveillance systems, communication, and research and development. Kramer answered that those things are all high priority. However, she emphasized the importance of early-warning surveillance systems in moving from a reactive to a proactive approach. “With a zoonotic virus, once the virus is in the wildlife,” she said, “there’s no way of really controlling it, which we saw with West Nile.” Unfortunately, she continued, the current surveillance system is very inefficient and expensive. Additionally, Gubler noted that it would be useful to pay attention to surveillance and epidemiology news from other countries as part of understanding or predicting the threat that those outbreaks might pose in the United States.

Gubler agreed that preparation is a critical area where investment is needed and noted that existing early warning systems are not very effective. He focused on prevention, which requires applying principles of disease ecology to determine the best leverage points to intervene in the transmission cycle to prevent or reduce transmission. Since there is probably no single preventive approach that will fit all scenarios, he believed the best method will be to “develop an integrated approach with synergistic interventions that work to reduce transmission.” Gubler stated that to do that will require coming back to the One Health or disease ecology approaches to understand the complex interactions that go into epidemic transmission.

REFERENCES