A century after early warnings, researchers now fear that yellow fever could erupt beyond its historical strongholds, posing an unprecedented threat to billions in the Asia-Pacific and beyond. Study: Yellow Jack: a modern threat to Asia-Pacific countries? Image Credit: nechaevkon / Shutterstock Early 20th-century quarantine efforts in Hawai’i successfully halted YFV outbreaks after infected ships arrived from South America, demonstrating the effectiveness of preemptive public health measures. A recent study published in the journal npj Viruses proposed that global trends, including unprecedented urbanization, increased international travel, and the expansion of mosquito habitats, increase the odds of the geographic spread of the yellow fever (YF) virus (YFV). YF, caused by YFV, is an acute viral illness in humans and several nonhuman primates. Unlike other mosquito-borne diseases, humans infected with YFV exhibit heightened viremia and are efficient amplifying hosts, allowing for inter-human transmission by mosquitoes. This makes YFV particularly capable of sparking urban epidemics, as infected people can efficiently infect mosquitoes that bite them. The YF mosquito (Aedes aegypti) is the primary urban vector, being anthropophilic and adapted to the human environment. Both YFV and YF mosquitoes originated in African forests and were introduced into the Americas via the transatlantic slave trade before or in the 1600s. During the colonial era in North America, Caribbean trading vessels imported yellow fever (YF) mosquitoes to coastal port cities in the eastern United States (US). Onboard YFV transmission could ensue, leading to quarantine. Once an area was infested with YF mosquitoes, YFV infection followed soon, resulting in epidemics over the past three centuries. An effective YFV vaccine, developed in the 1930s, and the eradication of YF mosquitoes in the Western Hemisphere eventually led to the cessation of YFV transmission in the Americas. Nevertheless, enzootic cycles in nonhuman primates and sylvatic mosquitoes continued in the forest canopies of the American tropics and Sub-Saharan Africa. Further, human-amplified urban YF epidemics have occurred recently in Africa. The reasons for the reemergence of YF epidemics are unclear but are believed to be due to various factors, including human population expansion, inadequate vaccine coverage, and a lack of effective mosquito control. The study notes that, for example, recent years (2016–2023) have seen an increase in YF spillover from sylvatic cycles in both Africa and the Americas, raising alarms about further geographic spread. Historic U.S. epidemics, such as Philadelphia’s 1793 outbreak that claimed 10% of the population, permanently altered societal behaviors, influencing urban planning and disease response strategies. The paper is published on the 100th anniversary of epidemiologist H.R. Carter’s original warning about yellow fever’s potential to invade the Asia-Pacific region, and the authors stress that many of Carter’s concerns are now more pressing than ever. Notably, YFV has not been transmitted in Asia so far. However, studies suggest a possibility of YFV expansion to the Asia Pacific region. The paper emphasizes that over two billion susceptible people in the Asia-Pacific region live in areas infested by Aedes aegypti mosquitoes, with no natural herd immunity to YFV. This was recognized in the 18th and 19th centuries but deemed unlikely due to logistical barriers. Nevertheless, the threat of YFV spread to Asia was underscored once Aedes aegypti was identified as a YFV vector in 1903. The present study reviewed the YF threat to the Asia Pacific. Current YF risk The YF mosquito eradication program was initiated in the United States in 1962 and was abandoned seven years later due to repeated importations from countries without similar policies. Meanwhile, the persistence of YF mosquitoes in limited refugia has gradually led to reinfestation across the Americas, which continues to this day. Yellow fever’s “extrinsic incubation” period, the 10-day delay between a mosquito biting an infected host and transmitting the virus, was first documented in 1898, reshaping outbreak containment protocols. Global trends have facilitated the resurgence and spread of YF, including population growth, urbanization, the emergence of megacities, rapid transportation, trade globalization, and the expansion of YF-carrying mosquitoes. For instance, it was estimated that over four billion people traveled internationally by airplane in 2019, and a 2016 study found that 60 million unvaccinated people traveled to or from YF-endemic countries to areas infested with yellow fever mosquitoes. Travel by unvaccinated individuals from or to YF-endemic areas increases the probability of the introduction of YFV to non-endemic countries infested with Aedes aegypti. Besides, if YFV is introduced in a permissive country, the disease could first be misdiagnosed as dengue. This risk is heightened because early or mild YF cases can closely resemble other flavivirus infections, and cross-reactive immunity complicates laboratory diagnosis. However, some mitigating factors reduce the risk of YFV transmission, such as the World Health Organization's (WHO) “Eliminate Yellow Fever Epidemics” program, which aims to increase YF vaccine access and coverage. Another factor is that the severe form of YF is remarkable and easily diagnosed. Besides, travel history raises suspicion about YF, and imported cases are likely to be recognized early. Nonetheless, the study warns that most countries infested with YF mosquitoes lack the public health infrastructure to effectively control mosquitoes, rapidly distribute vaccines, or manage a surge of clinical cases. As such, a large YF epidemic could cause chaos in a non-endemic country. The paper warns explicitly that the combination of high case–fatality ratio, hemorrhagic symptoms, and inadequate vaccine supply could rapidly overwhelm public health systems. Epidemic spread The fundamental question is why no YF epidemic has occurred in permissive urban centers of Asia-Pacific or tropical America. Moreover, recent pandemics of chikungunya, Zika virus disease, and dengue suggest ideal epidemiological conditions for the global and regional transmission of YFV. The article frames this as an “enigma,” noting that unraveling why YF has not yet spread in these regions can help in designing effective preventive measures. Possible explanations for the lack of YF spread include cross-protective immunity from Zika, dengue, and other orthoflavivirus, demographic and geographic obstacles, non-adaptation of YFV lineages to the YF mosquito-human urban cycle, effective mosquito control in at-risk areas, good surveillance and rapid response containment, variable YF mosquito densities, variable host-vector competence, and plain old luck, among others. In particular, the article highlights that areas endemic for dengue and other flaviviruses may have populations with cross-reactive immunity, which could either reduce disease severity or suppress transmission, though this remains to be confirmed in humans. Measures to prevent the YF pandemic Brazil’s 1938 eradication of Aedes aegypti, achieved through door-to-door insecticide campaigns, collapsed by the 1970s due to funding cuts, allowing the mosquito to resurge globally. Effective control and prevention of YF will require more information on the epidemiology, biology, and genetic diversity of YFV, as well as enhanced surveillance and improved tools to prevent, identify, and contain transmission. Although a highly effective and safe YF vaccine is available, its supply is limited, and significant upscaling will be necessary for widespread use. The study notes that current egg-based vaccine production is difficult to rapidly scale up in emergencies, contributing to shortages during outbreaks. Further, while new mosquito control tools in the pipeline appear promising, none provide effective emergency and long-term control at the required scale. Moreover, public health infrastructure should be built to address Aedes-linked viral diseases. The article emphasizes the urgent need for research into new vaccine platforms, sustainable mosquito control strategies, antivirals, improved surveillance, and integration of vaccination with vector control. Thus, successful YF containment requires extensive capacity-building and research in most tropical urban centers. Concluding remarks In summary, the concern that YFV will spread to the Asia Pacific region, which was raised a century ago, remains equally pressing today, and the odds of such a catastrophe may be even higher now. The authors explicitly warn that if a yellow fever pandemic were to occur in today’s world, its much higher lethality could make the COVID-19 pandemic pale by comparison, resulting in a devastating global public health crisis. Further, the risk in 2025 is amplified by ideal social, epidemiological, and ecological conditions for spreading and transmitting YFV and its mosquito vector. Moreover, it is unlikely that the global trends responsible for the elevated risk will abate.