Abstract
Keywords
As the first half of 2025 progresses, yellow fever (YF) has again made a concerning resurgence in the Americas. On March 31, 2025, the Pan American Health Organization (PAHO) issued an epidemiological alert warning of a notable increase in YF cases across several countries. 1 As of April 26, 2025, 212 confirmed human cases had been reported, with 85 deaths, corresponding to an estimated case fatality rate of approximately 40%. Brazil alone has documented 110 cases and 44 deaths; Colombia follows with 60 cases and 24 deaths; Peru has confirmed 35 cases with 12 deaths; and Bolivia reported 3 cases and one fatal case (Figure 1). The red dots in Figure 1 represent confirmed YF cases, with the size of each dot proportional to the number of cases in each location, scaled relative to the total case count across the region. These numbers have since increased, suggesting an urgent and evolving public health crisis.
Confirmed human cases of yellow fever in the Americas Region in 2025. The red dots represent confirmed yellow fever cases, with the size of each dot proportional to the number of cases in each location, scaled relative to the total case count across the region.
What is particularly troubling in this resurgence is the pattern of geographic spread. While YF cases in 2024 were primarily clustered in the Amazonian regions of Bolivia, Brazil, Colombia, Guyana, and Peru, 2025 has seen the virus spread beyond these traditionally endemic zones. New cases have emerged in São Paulo (Brazil) and the Tolima and Caldas departments (Colombia)—outside the Amazonian basin. This geographic shift signals potential changes in viral ecology and transmission dynamics. While no large urban outbreaks of YF have been reported in the Americas since 1942, with the exception of some inconclusive origin human cases. Most of the cases reported from recent outbreaks, as those occurring in Brazil, in 2016–2018 and Colombia in 2024–2025, have been successfully attributed to exposure to the sylvatic cycle, with analyses tracing the virus’s spread to peri-urban areas leading to sporadic human spillovers. 2 In the last decade, YF cases from Brazil have been concentrated in men, racialized and marginalized groups, and rural workers, underscoring the role of sociodemographic and occupational risk factors. 3 The case fatality rate in the most recent outbreaks remains high, between 40% and 50%, urging active surveillance and targeted prevention measures.
Orthoflavivirus flavi, formerly known as Yellow fever virus (YFV), is a mosquito-borne flavivirus that has historically maintained an enzootic cycle involving nonhuman primates and sylvatic mosquitoes, particularly species of the genus Haemagogus and Sabethes. Human infections typically occur as spillovers when individuals enter or live near forested areas. However, in the past, urban outbreaks—driven by Aedes aegypti mosquitoes—caused devastating epidemics, particularly before the development and widespread use of vaccines. Although no sustained urban transmission has occurred in recent decades, the conditions for such a scenario remain dangerously present.
Urban centers across South America are densely populated and support large populations of A aegypti mosquitoes. Environmental and social changes—driven by macro-determinants such as economic activity, land use, climate change, and human migration—can, as observed in the past, alter the geographic distribution of mosquito vectors and their vectorial capacity. 4 Vector presence in non-endemic regions alone is not enough to cause YF outbreaks or sustained transmission. Such a spread requires a combination of favorable environmental and social factors. Sylvatic transmission depends on reservoir hosts such as nonhuman primates, while urban cycles can persist through human-mosquito-human transmission. Though cities at high altitudes like Bogotá or La Paz are unlikely to see urban transmission, many areas in the region have climate conditions—such as suitable temperature, altitude, and rainfall—that could support the virus’s expansion into new urban and peri-urban zones.
Viral dynamics and human risk lie in the complex entanglement of vector biology, population immunity, viral adaptation, and ecological isolation. Understanding this interplay is not only a scientific endeavor—it is now a public health imperative. A critical gap in our preparedness is the limited understanding of the current vector competence of urban A. aegypti populations for YFV. Earlier laboratory studies demonstrated that A. aegypti are competent vectors, 5 yet ongoing genetic and environmental changes may have altered their susceptibility and transmission efficiency. Given the dynamic nature of arboviral evolution and mosquito adaptation, comprehensive studies assessing the vector competence of urban mosquito populations to YFV must be prioritized. These studies should evaluate YFV infection and dissemination rates in mosquitoes and how climate change, insecticide resistance, and urbanization could reshape vectorial capacity. Without such data, predictions about urban YF outbreaks remain largely speculative. Another potential surveillance tool is to conduct virological surveillance of primate populations and use satellite imagery to monitor deforestation in endemic areas. This enables targeted identification of high-risk zones for YF outbreaks.
The concept of “bridge vectors”—mosquito species that inhabit both sylvatic and urban environments and feed on multiple host species—is particularly relevant. Haemagogus leucocelaenus, H. equinus, H. janthinomys, H. lucifer, and Sabethes chloropterus are efficient YFV transmitters in forested environments. However, their potential role as intermediaries in peri-urban and rural settings remains underexplored. The emergence of cases in São Paulo and Tolima—regions characterized by complex mosaics of fragmented forests, agricultural zones, and expanding urban sprawl—suggests these species may play a more prominent role as bridge vectors than previously recognized. Mapping their geographic distributions, host-feeding behavior, and population dynamics could provide critical insights into how YFV expands its territory without igniting full-scale urban outbreaks.
Another underappreciated factor is the role of ecological isolation in shaping the evolutionary trajectory of YFV. Within distinct forest patches, isolated primate and mosquito populations may create micro-environments that foster viral diversification. 6 This diversification can affect virulence, transmissibility, and antigenic properties, potentially impacting diagnostic accuracy and vaccine effectiveness. 7 Monitoring YFV genetic diversity across enzootic regions is, therefore, essential. It enables the early detection of emerging lineages that may evade immune responses in previously vaccinated individuals or exhibit altered vector compatibility. These insights can inform vaccine strain selection and help anticipate future outbreak potential.
The current epidemiological picture underscores the need for robust sentinel surveillance, particularly in areas where natural ecosystems intersect with human settlements—ecotones. Zoonotic spillovers from epizootic foci are most likely to occur in these transitional zones, and early detection could prevent urban amplification. 8 Implementing real-time surveillance systems in such high-risk zones could involve monitoring nonhuman primate morbidity and mortality, strategically deploying mosquito traps across ecological gradients, engaging local communities in syndromic reporting, and tracking viral evolution through genomic surveillance using publicly available data-sharing platforms, such as GISAID EpiArbo. 9 A sentinel system focused on these emergence zones could function as an early warning beacon, allowing health authorities to preemptively deploy vaccines and vector control measures. Timely detection of cases can help identify areas of active transmission, allowing for more effective and targeted vaccination campaigns. Other effective strategies, such as sterile male releases or genetically engineered transgenic mosquitoes, may also hold promise.10,11
Despite the effectiveness of the YF vaccine, coverage remains patchy in many at-risk regions, partly due to logistical challenges, political instability, and vaccine hesitancy. The World Health Organization’s Eliminate Yellow Fever Epidemiology (2017–2026) includes vaccination rate targets for 2026 that may be insufficient in regions where R > 0.5. 12 Nonetheless, the YF vaccine remains the most crucial and effective tool for countries to combat transmission, particularly in endemic sylvatic cycles. As long as YFV persists in forest ecosystems—sustained by nonhuman primate hosts and competent sylvatic vectors—there will always be a risk of human infection, especially as deforestation and encroachment increase human-wildlife contact. Routine immunization must remain a cornerstone of public health policy in all at-risk countries and should ideally be integrated into broader zoonotic disease prevention programs. While mass vaccination campaigns are effective during outbreaks, they remain reactive measures. Sustained immunization—particularly for children, migrants, and travelers—is the only proactive shield against the urbanization of the disease. 13 A 2024 phase I clinical trial evaluated the safety and immunogenicity of a next-generation live-attenuated YF vaccine produced in a Vero cell line. Results showed comparable performance to the licensed YF-VAX vaccine, offering a promising option for future scalability. 14
Governments across the region must recognize that the response to YF requires sustained, long-term efforts grounded in a comprehensive approach that addresses the full range of biological, environmental, social, and structural disease determinants. While reactive measures may sometimes be warranted, they must be based on sound scientific evidence. For example, the recent announcement by Colombia’s Ministry of Health to impose mobility restrictions on unvaccinated individuals could disproportionately impact vulnerable populations and would be difficult to enforce in practice. Yellow fever’s resurgence in 2025 is not merely a regional public health problem but a global warning. It reminds us that zoonotic diseases remain a persistent threat, our surveillance systems are often reactive, and ecological changes erode the natural buffers that once contained these pathogens. We must update and expand vaccination campaigns in endemic and peripheral areas to respond adequately. We must invest in ecological and entomological research to understand the evolving dynamics of vector competence and emergence zones. Health teams must be trained to conduct effective entomological surveillance of both sylvatic and urban vectors. We must establish surveillance systems integrating human, animal, and environmental health data—a proper One Health approach. 15 We must engage local communities and train health workers to recognize early signs of YF and other arboviral illnesses. It is also essential to communicate that primates do not transmit YF to avoid the sacrifices of these emblematic animals. Finally, we must strengthen regional collaboration to share data, coordinate responses, and ensure equitable access to vaccines and diagnostic tools.
More broadly, the COVID-19 pandemic left behind critical lessons that some governments are now beginning to overlook. These include the importance of sustaining the public health workforce, recognizing vaccination as a universal public good, strengthening health surveillance systems, and maintaining the operational capacity of public health laboratories. These capacities must be preserved and strengthened at the national and local levels to ensure timely and effective responses. Unfortunately, signs of regression in these priorities are on the public agenda in several countries. The current situation with YF is just one of many public health alerts emerging across the Americas—alongside measles, pertussis, and other re-emerging threats—that underscore the urgent need to reinforce regional preparedness and response systems.
The 2025 YF outbreak reminds us that YF is not a disease of the past. Like the forests it inhabits, it remains deeply entangled with the present—and dangerously poised to shape the future.
