Le Infezioni in Medicina, n. 4, 434-450, 2024

doi: 10.53854/liim-3204-3

REVIEW

Yellow Fever: Global Impact, Epidemiology, Pathogenesis, and Integrated Prevention Approaches

Shriyansh Srivastava1,2, Shivang Dhoundiyal3, Sachin Kumar1, Awaneet Kaur2, Mahalaqua Nazli Khatib4, Shilpa Gaidhane5, Quazi Syed Zahiruddin6, Aroop Mohanty7, Andres F. Henao-Martinez8, Martin Krsak8, Alfonso J. Rodriguez-Morales9,10,11, Juan J. Montenegro-Idrogo9,12, D. Katterine Bonilla-Aldana13, Ranjit Sah14,15,16

1 Department of Pharmacology, Delhi Pharmaceutical Sciences and Research University (DPSRU), Sector 3 Pushp Vihar, New Delhi 110017, India;

2 Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida 203201, India;

3 Department of Pharmacy, Birla Institute of Technology and Sciences, Pilani, 333031 Rajasthan, India;

4 Division of Evidence Synthesis, Global Consortium of Public Health and Research, Datta Meghe Institute of Higher Education, Wardha, India;

5 One Health Centre (COHERD), Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education, Wardha, India;

6 Global Health Academy, Division of Evidence Synthesis, School of Epidemiology and Public Health and Research, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha. India;

7 Department of Microbiology, All India Institute of Medical Sciences, Gorakhpur, India;

8 Division of Infectious Diseases, University of Colorado Anschutz Medical Campus, Aurora, CO, USA;

9 Master of Clinical Epidemiology and Biostatistics Program, Faculty of Health Sciences, Universidad Científica del Sur, Lima, Peru;

10 Grupo de Investigación Biomedicina, Facultad de Medicina, Fundación Universitaria Autónoma de las Américas-Institución Universitaria Visión de las Américas, Pereira 660003, Risaralda, Colombia;

11 Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Beirut, Lebanon;

12 Infectious and Tropical Diseases Service, Hospital Nacional Dos de Mayo, Lima, Peru;

13 College of Medicine, Korea University, Seoul, Republic of Korea;

14 Department of Microbiology, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Dr. D. Y. Patil Vidyapeeth, Pune 411018, Maharashtra, India;

15 Department of Public Health Dentistry, Dr. D.Y. Patil Dental College and Hospital, Dr. D.Y. Patil Vidyapeeth,
Pune 411018, Maharashtra, India;

16 SR Sanjeevani Hospital, Kalyanpur-10, Siraha, Nepal

Article received 11 August 2024 and accepted 10 November 2024

Corresponding author

Alfonso J. Rodriguez-Morales

E-mail: arodriguezmo@cientifica.edu.pe

SummaRY

Yellow fever poses a substantial global health concern as one of the re-emerging diseases with pandemic potential in a scenario of the worldwide distribution of some vectors (such as Aedes aegypti); in the context of climatic change, an unclear knowledge about the immune behaviour of the virus, between other determinants. This review details the historical foundations, intricate evolution of geographical spread, and transmission mechanisms of the disease to understand the behaviour of outbreaks over time in a multifactorial context that could be difficult to understand. This article approaches to epidemiological, pathophysiological, immunological, social determinants, and climatic crisis by understanding possible control mechanisms and anticipating potential future epidemics. This article explores the evidence of yellow fever virus (YFV) pathogenesis and its complex interactions with the immune response in the host, the vector, and in the context of immunisation. These discussions contribute to a more comprehensive understanding of the disease’s progression. Despite the global presence of the vector and other factors that could facilitate an epidemic spread, yellow fever outbreaks have remained confined to specific endemic areas. This limited distribution is not entirely understood. However, it may be influenced by the complex immune interactions between the virus, the vector, and the host, preventing its spread to other regions.

Keywords: Societal consequences, transmission mechanisms, pathogenicity, immune response, virology.

INTRODUCTION

Yellow fever (YF), an acute and potentially fatal viral illness, is an enduring testament to the intricate interplay between viruses, mosquitoes, primates and human populations and their environment [1]. YF is a disease that has not only shaped history due to relevant outbreaks worldwide, the challenges in the limited medical management of severe cases, advances, and its impact on public health interventions, with several foci of research still in development. The yellow fever virus (YFV) is a single-stranded RNA genome virus, a member of the Flaviviridae family like other viruses transmitted by a vector in this family: dengue virus (DENV), Zika virus (ZIKV), Japanese Encephalitis fever virus (JEV), among others. Both DENV and ZIKV developed epidemics with worldwide distribution. In contrast, YFV has been located exclusively in African and South American regions but has not spread in Asia regions, in contrast to JEV, which has been located mainly in these Asian regions but has not spread to other American and African regions. Thus, despite belonging to the same viral family and having a common vector involved in all cases (Aedes mosquito), worldwide distribution is different between them; in YFV, it is still maintained in its historical distribution [2, 3]. From its initial emergence in the sylvatic cycle involving non-human primates and forest-dwelling mosquitoes to its recent urban outbreaks, probably explained by the change in the population dynamics in tropical regions cities, where the emergence of new towns/cities near or in the middle of the forest regions to the forays into the main cities of the Americas, yellow fever has exemplified one of the enigmas around of its ecological and epidemiological dynamics in the time, with a different understanding of the transmission dynamic and its impact in contrast with other viral-borne- diseases [4].

YFV immunisation in humans was one of the main advantages of vaccines due to their excellent performance worldwide. However, this prevention mechanism became available over eighty years ago; new outbreaks have been developed within the last ten years [5, 6]. The last outbreak in South America was considered an epidemic because it had a wide distribution across the east of the continent, where mainly all regions of Brazil were affected [6, 7].

This review was developed to understand the reasons for the YFV dynamic around the world and its potential scenarios in the context of the global distribution of some vectors like Aedes mosquitoes since the vision of immunological basis in the vector as in the host in the context of climatic change and other potential conditions at the global level. Additionally, we will summarise the current mechanisms proposed for the management, control, and prevention of YFV [8, 9]. We conducted a literature search to find relevant articles about epidemiology, clinical aspects, prevention and vaccination, and other aspects of yellow fever. Using a controlled vocabulary thesaurus, the following databases were searched: PubMed, Scopus, Web of Science, SciELO and LILACS, focusing on articles in English, Spanish and Portuguese, particularly from the last ten years.

GEOGRAPHICAL DISTRIBUTION AND TRANSMISSION

Geographical distribution

Yellow fever, a contagious illness propagated by mosquitoes feeding primarily during daylight hours, has re-emerged outbreaks in the Americas and Africa since 2016. By 2023, around 34 nations across Africa and 13 nations in the Central and South Americas, including the Caribbean, will be considered endemic for YFV, entirely or in specific regions. This global impact underscores the gravity of the situation and the need for your involvement. In both scenarios in the Americas and African regions, the presence of the vector and a susceptible non-human primate host is necessary. These conditions have been present since the first outbreaks were reported, contrasting with other regions, such as Asia or Europe, where YFV was unavailable. However, a susceptible vector (Ae. aegypti) has conditioned the worldwide distribution of similar viruses like DENV and ZIKV in these other regions, independent of the urban or rural settings. In these regions, the distribution of a similar Flaviviridae virus transmitted by Aedes is the Japanese encephalitis fever virus.

The spread of YFV near the classical distribution zones is significantly influenced by urbanisation and habitat loss. The development of emergent cities in these regions, with their proximity to wildlife, has led to persistent infections without disease in non-human local primates, maintaining the cycle in these zones and resulting in outbreaks. This is a serious issue that needs to be addressed [11-14]. African primate populations have not experienced significant loss, in contrast with the Americas, where there have been losses in some primate populations [13-15].

In Asia, other non-human primates could be potential hosts in an emergent YFV outbreak in this region. Nevertheless, Asia remains free of autochthonous YFV, and this behaviour was studied in a theoretical model of transmission risk based on assumptions attributed to vector availability, non-human primates’ susceptibility, and other ecological predictors in Asia. This model found that Malaysia, Singapore, Indonesia, Brunei, and portions of southern India were considered high-risk zones for YFV. Still, the percentage of suitability was lower than that of endemic YFV regions. Four primate species were distributed entirely in these zones, and 44 other species were included. Thus, Asia could be a potential scenario for emerging YFV if any condition could be available to introduce in this region [12, 13].

Within urban environments, the Aedes aegypti mosquito is the critical carrier, thriving in still water found in human-made receptacles like old tyres, flower pots, and cisterns [16]. In rural zones, the virus is propagated by other mosquito species that reproduce in natural reservoirs such as tree holes, leaf axils, and ground puddles [17]. In South America, yellow fever is found primarily in forested areas of the Amazon Basin. The virus is transmitted by mosquitoes that breed in tree holes and other natural containers [18]. The geographical arrangement of yellow fever is influenced by a confluence of factors, including mosquito vectors, non-human primate hosts, and vulnerable human populations. Environmental elements such as temperature, precipitation, and altitude significantly influence the disease’s distribution. Yellow fever correlates with altitude, precipitation, variety of non-human primate hosts, and temperature [20]. This information is crucial for understanding the distribution of yellow fever, which predominantly occurs in tropical and subtropical regions within Africa and South America [21]. The virus is propagated in these areas through mosquitoes that breed in urban and rural settings.

Yellow fever in non-human primates and vectors

Non-human primates related to the YFV outbreaks

YFV had origin in Africa in a sylvatic cycle that involved 11 non-human primates (NHP) genera: baboons (Papio spp.), colobus monkeys (Colobus spp.) green and vervet monkeys (Cercopithecus spp.) mangabeys (Cercocebus spp.) chimpanzees (Pan troglodites), bush babies (Galago spp.) and others: Erythrocebus, Otolemur, Perodicticus and Pilocolobus [11, 12].

In the Americas, YFV outbreaks were related to howler monkeys (Alouatta spp.), squirrel monkeys (Saimiri spp.), spider monkeys (Ateles spp.) and owl monkeys (Aotus spp.) In the latest YFV outbreaks in South America (2016-2019), urban titis (Callithrix) were identified in São Paulo, Brazil; in addition to these NHP reports, other specimens of genera Brachyteles, Callicebus, Leontopithecus, and Sapajus, all of them inhabiting the “Mata Atlantica” (Atlantic forest of Brazil) were identified [11, 12].

In contrast with Africa, where NHPs are adapted to the endemic of YFV, in the Americas, YFV was introduced in the black slave trade, which, coming from Africa, infected and developed spreads in the New World 400 years ago. In that scenario, some genera of NHP are susceptible and well-adapted to YFV infection, and others develop diseases related to YFV. One study with neotropical primates naturally infected with YFV showed that it could be high susceptibility to YFV infection, but the development of YFV-induced lesions could be different between each genus; thus, severe hepatic lesions were described in Alouatta sp. (howler monkey) in contrast with Callithrix spp. (titis or common marmosets) who did not present hepatic lesions, it suggests that primates like Callithrix spp. Could be efficient as a host in these regions of the Americas [14, 15]. Unlike the NHP in Africa, NHP in the Americas is susceptible to YFV developing clinical signs and outbreaks in these groups; in this way, NHP YFV outbreaks are expected new outbreaks of YFV in humans.

In this scenario, the NHP related to YFV differs between regions, and the susceptibility and immune response differ. This could be one of the reasons for understanding the specific distribution along the time of YFV in contrast with other Flavivirus transmissions by vectors that developed epidemic outbreaks in the last decades.

Vectors related and its role in YFV transmission

The forest-dwelling mosquitoes involved in the sylvatic cycle in Africa are Aedes species, mainly Ae. africanus (other Ae species: bromeliae, taylori, furcifer, luteocephalus, metallicus, opok, vittatus and simponi complex) [12, 22, 23]. In the Americas, this role was described on Haemagogus (leucocelaenus, albomaculatus, spegazzini, janthinomys) and Sabethes (chloropterus, albipivus, glaucodaemon, soperi and cyaneus) species [12, 22, 23]. In the urban cycle, the participation of Ae aegypti is described mainly.

YFV transmission is first made between mosquitoes by the transovarial transmission process (TOT). This step is relevant to maintain the cycle of transmission of YFV and, after that, transmission from mosquitoes to NHP in the sylvatic cycle. In Africa, during the rainy season, there is a “zone of emergence” if transmissions include humans; YFV transmission is amplified and sustainable to other humans by Ae aegypti in urban zones. In the Americas, humans are the eventual host who allows sustainable transmission in urban zones by Ae. aegypti, but in this case, without passing through a “zone of emergence”. Thus, the sylvatic cycle is affected by mosquitoes and NHP in both scenarios (Africa and South America); mosquitoes must generate TOT between them to continue the YFV transmission cycle. In Africa, only the “zone of emergence” of the Savannah cycle consists of the cycle of transmission of YFV from sylvatic vectors to humans, which could develop an urban transmission cycle by Ae. aegypti vector (Figure 1) [10-13]. A viraemic individual initially infected in a jungle or Savannah environment typically introduces the virus into urban settings. It is essential to recognise that individuals infected with the yellow fever virus become contagious to mosquitoes shortly before the onset of fever and for up to five days after its onset [24]. This signifies that within this timeframe, an infected person can transmit the virus to mosquitoes that bite them, which can further transmit it to other individuals.

Figure 1 - Transmission cycle of yellow fever virus.

About Ae. aegypti is the most relevant vector studied worldwide as a universal vector, which is also related to the transmission of other viruses of the Flaviviridae family, such as DENV, ZIKV, and EJV, that developed epidemics in the last decades.

Aedes spp. African subspecies in the beginning breed in plant axils and tree holes and are zoophilic; in contrast, the urban subspecies are domestic. With the changes in the populations of mosquitoes, it is theorised that Aedes mosquitoes evolved from tree holes to container breeding in human settings. It is described that the behaviour of this vector could change in decades; thus, in the Indian Ocean region, the interchange between endophilic Ae. aegypti and exophilic Ae. albopictus reversed their typical habitat (to exophilic and endophilic, respectively) over decades; when the outbreak of Chikungunya virus (CHIK), this mutant was adapted to this Ae. albopictus.

Another scenario is the Caribbean; the last reported YFV outbreak was in 1908 and was related to the Ae. Aegypti vector as the primary vector; after that, the following outbreaks related to this vector were due to other viruses such as DENV and ZIKV in the last decades; one report in Ae aegypti populations from the Caribbean zone was analysed with five YFV genotypes (Bolivia, Ghana, Nigeria, Sudan, and Uganda) where showed good susceptibility and higher transmission success (mainly with Uganda and Bolivia strains), these finding suggest vector transmission in this region is plausible, nevertheless, at current did not report any re-emergence in the zone [25-27].

It is known that mosquitoes need clean water in household containers, but in some places in Africa, subpopulations adapted to breeding in non-clear water [28]. In addition, the Aedes mosquito is disseminated worldwide. Still, the activity depends on the altitude, temperature (hot seasons increase the index of mosquitoes), rains, and different behaviours related to the change in the urbanisation of rural zones. Thus, climatic change probably plays a role in facilitating some determinants to help the spread of vectors, increase the transovarial transmission between vectors, and other similar cases.

EPIDEMIOLOGY

Yellow fever is a vector-borne disease with pandemic potential in current historical zones [5, 29, 30]. Two types of outbreaks and behaviours are well-defined: YFV in Africa and the Americas. In Africa, where YFV originated, the vectors and NHP are susceptible and tolerable to the immune response to YFV. It is possible that populations in the last decades showed less mortality in comparison to previous outbreaks due to the immune response at the people level developed by the persistent exposure to these vectors infected in these zones; for that reason, only in Africa are there the Savannah cycles, in emergent zones when is expected the YFV transmission [4, 8, 10].

In the Americas region, urban cycle development is due to the eventual infection of humans and the transmission by Aedes species. In this region, the NHP usually had an increased immune response to YFV. Therefore, epizootic outbreaks are expected to occur in outbreaks in contrast with African settings. In both scenarios, the implementation of the YFV vaccine was a relevant factor in immune tolerance at the people level. In both scenarios, it is relevant to discuss the role of the vector as a reservoir by the transovarial transmission to continue the cycle, the NHP as host in this process, and humans, for the first time, an occasional/casual host involved in this zone [17, 22, 31-33].

In Zika and Dengue, vector adaption, climatic change (warming and precipitation) and prevalence of heterotypic serotype infections were related to these distributions by Ae. Aegypti, which has spread worldwide. In YFV, the transition to endemic and epidemic urban YF is due to environmental changes, such as industrialisation and urbanisation, which mainly enhance contacts between sylvatic and urban cycles that could coexist after urbanisation in these areas [32-34].

Historical patterns of yellow fever outbreaks

Yellow fever holds a significant position in human history. Its evolutionary genesis can be traced back to Africa, which likely emerged from interactions between primates, mosquitoes and humans [35]. The virus and its mosquito carrier, Aedes aegypti, are thought to have been transported to the western hemisphere and the Americas via slave trade ships from Africa after the initial European exploration in 1492 [36]. The earliest exported disease outbreaks, likely associated with YFV, manifested in the Caribbean’s Windward Islands [36]. Notable occurrences transpired in Barbados in 1647 and Guadeloupe in 1648 (Table 1) [37]. Subsequently, a succession of significant outbreaks unfolded in North America. One such devastating event took place in 1793 in Philadelphia, where over 9% of the city’s total population perished, prompting even the American government, led by President George Washington, to evacuate the capital [38]. The year 1878 witnessed a devastating epidemic, claiming approximately 20,000 lives across settlements along the Mississippi River Valley and its tributaries. Notably, the final significant outbreak in the United States transpired in 1905, centred in New Orleans (Table 1). During 88 years, New Orleans was significantly affected by yellow fever, with more than 41,000 related deaths between the years 1817 (the first year that reliable statistics are available) and 1905 (the Crescent City’s last epidemic) (Figure 2) (https://nolacityarchives.org/2024/03/05/yellow-fever-deaths/). Europe also experienced yellow fever outbreaks in the 19th century, primarily linked to the arrival of sailing vessels from the Caribbean, often docking in Atlantic ports [39]. In Barcelona, Spain, outbreaks occurred in 1803, 1821, and 1870, with the latter resulting in 1,235 recorded fatalities among approximately 12,000 cases [40]. Smaller outbreaks extended to locales like Saint-Nazaire in France and Swansea in Wales, aligning with the arrivals of vessels carrying the mosquito vectors. Major yellow fever outbreaks have severely impacted North America and Europe [41]. However, since the considerable outbreak in New Orleans in 1905, the United States has managed to rein in yellow fever through vaccination campaigns and meticulous mosquito control measures [42]. Major outbreaks occurred in North America and Europe between the 18th and 20th centuries with devastating consequences [43]. In recent times, instances of yellow fever outbreaks have predominantly surfaced across Africa and South America. Angola confronted its most severe yellow fever outbreak in three decades in 2016, marked by over 4,000 suspected cases and 376 fatalities [44]. This outbreak subsequently extended its impact to the Democratic Republic of Congo, recording over 2,000 suspected cases and 95 deaths [45]. In 2018, Brazil faced a significant yellow fever outbreak, witnessing more than 1,500 confirmed cases and a toll of 500 deaths [46]. Addressing these outbreaks has entailed a multifaceted approach encompassing vaccination initiatives, strategies to curb mosquito populations, and widespread public awareness campaigns about the disease. The World Health Organization (WHO) has issued recommendations advocating vaccination for individuals residing in or travelling to regions where yellow fever is endemic [47]. A solitary administration of the yellow fever vaccine guarantees lifelong protection against the ailment. Controlling these outbreaks includes vaccination campaigns, mosquito control measures, and public education about the disease. Major yellow fever outbreaks are highlighted in Table 1.

Table 1 - Major yellow fever outbreaks.

Figure 2 - Deaths by yellow fever in New Orleans, USA, 1817-1905.

VIROLOGY AND GENETIC VARIABILITY

Viral structure and genome

YFV is classified as a single-stranded, positive-­sense RNA virus and is a member of the Flavivirus genus within the Flaviviridae family [54]. The virus adopts a spherical morphology and exhibits approximately 40-50 nm diameter. Its viral envelope is derived from the host cell membrane and comprises two vital glycoproteins, namely envelope (E) and membrane (M) proteins [55]. These glycoproteins hold responsibility for instigating viral attachment and facilitating the virus’s entry into host cells [56]. The genetic blueprint of YFV is about 11 kb long and codes for a singular polyprotein that is subsequently cleaved by both viral and host proteases [57]. This cleavage gives rise to three structural proteins (C, M/M, and E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). The structural proteins assemble to form the virion particle, while the non-structural proteins contribute to viral replication processes and evasion of host immune responses [58]. The C protein is the viral capsid protein, which envelops the viral RNA genome. The pre/M protein serves as a precursor, undergoing cleavage to become the M protein during the maturation of the virion [59]. The E protein is pivotal in mediating viral attachment to host cells and facilitating the fusion of the viral envelope with the host cell membrane during entry. Among the non-structural proteins, the NS1 protein functions as a glycoprotein, participating in viral replication and evading immune responses. The NS2A and NS2B proteins cooperate in RNA replication and the assembly of virions [60]. The NS3 protein showcases protease, helicase, and NTPase activities central to viral replication. Additionally, the NS4A and NS4B proteins take on roles in RNA replication and modulation of host immune reactions [61]. Lastly, the NS5 protein is responsible for the viral RNA synthesis due to their possessing RNA-dependent RNA polymerase and methyl-transferase activities.

Genetic variability

Like other RNA viruses, YFV showcases a marked genetic diversity that stems from the error-prone nature of its RNA-dependent RNA polymerase [62]. This inherent variability gives rise to novel viral strains characterized by modified antigenic attributes, levels of virulence, and transmissibility. Scientific investigations have substantiated that YFV demonstrates genetic divergence in multiple protein components, including the envelope (E) protein [63]. This protein is critical in viral attachment and facilitating the virus’s entry into host cells. Genetic alterations in the E protein can influence the virus’s capacity to evade the host’s immune response, potentially impacting in the immunity due to vaccine [64]. In contrast, variability in non-structural proteins such as NS1, NS3, and NS5 can affect the virus’s ability to replicate and evade host immune defenses [65]. These factors can influence the immune response and spread of YFV.

PATHOGENESIS AND IMMUNE RESPONSE

Immune response to YFV in host

Evidence about immune response in human in wild-type yellow fever is limited and reported in severe cases of YFV. In comparison with the non-­severe cases, severe cases have increase of chemoattractant cytokines MCP-1 and IP-10 and pro-­inflammatory cytokines TNF-a, IL-6 and IL-1 [66] In liver affected of severe cases were found high T cell infiltration and cell death with elevated cytokine expression at liver cells and endothelial cells. This finding suggest that immune response in severe cases of YF infection are related with increase of pro-inflammatory response innate and cellular, with the insufficient neutralizing antibody response. This could be explained in an ineffective control of YFV replication in the liver but a strongly cytolytic response that develop inflammation, damage and progression to severe disease [66-68].

Severe and hemorrhagic YF could compromise all systems, where the imbalance of the immune response with the expression of pro and anti-inflammatory cytokines developed in the tissue damage and increase destruction of resident cells in several organs such as liver, heart and kidney [68-70].

At lung level was shown in people with severe YF in comparison with people without YF the increase of the higher expression of E-selectin, P-selectin both involved in the cell migration and develop of inflammatory infiltrate; ICAM-1 and VCAM-1 both involved in the reinforce of tissue transmigration signaling; and other cytokines as TNF-a, IFN-g which participate in the process of cell injury and viral clearance; IL-4 and TGF-b which acting in synergism in the tissue regeneration and breakdown; thus IL-4, IL-10, and IL-13 develop anti-inflammatory effect and tissue repair. According to these findings, the activation of the endothelium increases the inflammatory response with the induction of adhesion molecules and cytokines that develop in the inflammatory process in the lung parenchyma with fatal outcome of the disease [70].

At myocardial level, there was no evidence of YF-antigens or viral particles within cardiomyocytes, that suggest absence of direct YF tropism to the cardiac cells, but the myocardial injury was related to the increase inflammatory cellular infiltrate (mainly by macrophages) located in the perivascular interstitium and presence of YF antigens within endothelial cells that suggest that direct YFV invasion in endothelial cells is a main mechanism of endothelial and myocardial damage due that activation of the inflammatory response in that tissue [71].

Thus, it was described high levels of multiple cytokines in the myocardial tissue of YF cases, one of them with statistical difference in YF than sepsis control cases were CXCL-10 chemokine (it is involved in the recruitment of lymphocytes, macrophages and NK cells). Also were described in YF cases frequent endothelial abnormalities (endothelial swelling, fibrinoid necrosis) with the increase of biomarkers associated with endothelial damage related with worse prognosis in sepsis patients (angiopoietin-2, endothelin-1, syndecan-1, VCAM-1 and PAI-1) [72-75]. Angiopoietin-2 is a vascular growth factor related with capillary leakage; endothelin-1 actives pathway of IL-1, IL-6 and TNF-α; and PAI-1 is a fibrinolysis inhibitor involved in the YF-coagulopathy and subsequent hemorrhages due to role in the disseminated intravascular coagulation. In contrast to other infectious diseases, evidence of arterial thrombosis or microthrombi were rarely seen [71-125].

Thus, the progression of diseases due to YFV in severe cases is related to two compounds: hepatic injury by YFV infiltrate with exacerbated local immune response and endothelial infiltration with exacerbation of immune response at this level in non-hepatic systems, which developed in damage and organic failure.

In 1951, Max Theiler of the Rockefeller Foundation received the Nobel Prize in Physiology or Medicine for developing an effective yellow fever vaccine-first reported in the JEM 70 years earlier. This remains the only Nobel Prize awarded for a virus vaccine. Recently released Nobel archives reveal how advancements in the yellow fever vaccine were assessed over 50 years ago, leading to Theiler’s recognition [126].

Immune response between YFV and vectors

At mosquito level, there are some mechanism of immune response potentially involved in Ae. Aegypti mosquitoes as the Thioester-containing proteins (TEPs), mainly TEP1, which was involved in the reduction of viral load when was overexpressed in contrast to TEP3; this suggest TEP1 could play a role in viral infection [76]. The Toll pathway by knockdown of the transcription factor Rel1 to attenuates the induction of Spaetzle 1A and Serpin-27A in the mosquito [77]. DENV infection of Ae. aegypti activates the transcription of Toll pathway-associated factors and putative effectors (Späetzle, Toll, Rel1A, and multiple AMPs) [78-80]. The Toll pathway begins to exert antiviral effects as early as 3 days after DENV infection, is able to protect against DENV infection in multiple serotypes, and remains active in different Ae. aegypti strains [81]. Furthermore, the symbiotic Wolbachia in mosquitoes can inhibit DENV replication by inducing mosquitoes to produce ROS to activate the Toll pathway and subsequently produce AMPs and DEFs [82]. The transcription of Dif, a Toll pathway transcription factor, is induced early in the infection of Ae. aegypti with Sindbis virus (SINV).

The JAK/STAT pathway is also important in immune response against DENV infection; thus the viral replication in the mosquito midgut was increased significantly with the inhibition by RNAi-­mediated silencing of transmembrane proteins or JAK immediate homologues, this effect was reduced with the silenced of the inhibitor of STAT activated [83].

RNAi pathway involve a process of production specific small RNA molecules with different characteristics: endogenous small interfering RNAs (siRNA 18-24 nt), microRNAs (miRNAs, 18-24 nt), and Piwi protein-interacting RNAs (piRNAs); siRNAs are the main molecules involved in the antiviral response [84, 85]. In YFV, siARN pathway is mainly triggered by Dicer2, R2D2, and Ago2, this last was involved in the inhibition of the iRNA pathway. Thus, siRNA pathway inhibits the YFV and DENV2 replication, and replication increase upon the knockdown or silencing of siRNA pathway-related genes [86-88]. Thus, siRNA modules infection pathogenesis due to human flavivirus in A. aegypti.

Immune response to yellow fever vaccination

The yellow fever vaccine (YF-17D) is a live attenuated vaccine that triggers an immune response in the body to protect against future infection with the yellow fever virus. It is one of the most effective vaccines ever made in more of 80 years [69, 89]. This has two substrains: 17DD (used in South America) and 17D-204 (used in most of the rest of world) both were developed in embryonated chicken eggs The immune mechanism of immune response and attenuation of YFV there are not clear. But it is probed the good performance in the immune response after vaccination [69].

Humoral immunity was a primary protective element in previous exposed individuals, and a single vaccine could offer protection to global strains of YFV by neutralizing antibodies [68]. Over 90% of 17D immunized individuals developed antibodies, and neutralizing antibodies were detected within two weeks after vaccination, since the sixth day following vaccination with evidence of neutralizing responses for up to 60 years after vaccination [90-95].

Innate immune response way after vaccination in plasma described interferon IFN-γ levels increased after two weeks of 17D vaccination. Re-stimulation of innate immune cell cultures of natural killer cells, neutrophils, and monocytes from 17D-vaccinated humans with YF antigen results in the increase of IFN-γ, IL-1b, IL-12, TNF-α, and IL-10 with the concomitant decrease of TNF-α, IL-10 and IL-4 [68]. After vaccination virus is detected by innate immune receptor, including RIG-I (retinoic acid-inducible gene I) and MDA5 (melanoma differentiation-associated gene 5), Toll-like receptors: TLR2, TLR7, TLR8 and TLR9; this last pathway stimulates a complex and robust antiviral response with TH1 and TH2 cell profile, and other ways to B cell response [69].

It is reported the earliest induction of cytokines by interactions with dendritic cells (DC) with multiple interactions with TLRs with a consequence downstream T cell response. However, 17D antigens are processed and presented by DCs which are most likely involved in eliciting downstream T cell responses. There is insufficient evidence about the understanding of the immune cellular response to YFV in humans, this topic is still uncertain. There is a strong immune response to 17D from T cells CD4+ and CD8+ within the first and second week after immunization, respectively; differentiated memory cells could maintain immune response for a long period of time (25 years) [68].

17D-specific CD4+ T cells develop TH1 and Th2 cytokines. TH1 T cells promote CD8+ responses due to T follicular helper (Tfh) cells (subtype of CD4+ T cell) which promote healthy B cell germinal centers, while TH2 cytokines promote B cell and neutralizing antibody response to virus. 17D-specific CD8+ T cells after re-stimulation developed a complex and multiple pro-inflammatory cytokine response, with a suggested capacity of degranulation and cytolytic effect [68, 69]. Evidence about exposure to 17D booster in comparison with individuals with only one vaccination, it did not find higher levels of memory T cell as was expected after re-exposure [69].

STRATEGIES OF PREVENTION AND CONTROL YFV SPREAD

Vector control

Vector control efforts in YFV could be limited because the dimension of the problem has been involved not only to urban vectors, but vector outdoor in the forest where mechanism to reduce populations of mosquitoes are difficult to manage despite the different interventions at local or inter-institutional level as Global Vector Control Response (GVCR) by the WHO [96]. There are common mechanisms of vector control in Aedes spp. in some regions of Africa due to the multiple risk of transmission of other virus (DENV, ZIKV, CHV, between others); nevertheless, insecticides mechanisms or similar are reduced to control of spread and dissemination of the forest vectors [96, 97]. This mechanism are effective in the reduction of urban mosquitos’ populations, but are insufficient to cut the YFV transmission chain [22, 96, 97]. At vector level biological alternatives could be emergent options in some regions identified, for example, there is evidence on vector control based on Wolbachia infections in mosquitoes infected by DENV. Additionally, this infection increases the mosquito resistance to DENV, CHIKV, and YFV infection [98]. As before was mentioned the immune response of Wolbachia at level of innate immune response, could induce and activation of the Toll pathway that interact with the viral immune response in the mosquito, in addition to the control vector populations [76].

Nonetheless, reliable efforts in Yellow fever to control and prevention of outbreaks and worse scenarios are reduced to the most effective mechanism: YFV immunization, follow of the common behaviors as continuing prevention of bites mosquitoes by repellents, or coverage clothes, which are less effective in hyper-endemic zones.

Vaccination strategies

YF immunization have been the best and effective method in YF-prevention since their creation and use. YF vaccine is one of the aged and effective vaccines again a vector-borne virus, made and maintained around the world with high effectiveness and safety along decades for long periods in users [69]. Other characteristics that position it are a single dose, and lifelong protection in individuals immunized, and long experience in the use. Nevertheless, the good characteristics of vaccine, the efforts to cover a massive immunization in endemic regions is still a challenge (typically recommended by at least 80% of the eligible population) of high-risk and endemic regions [69, 99, 100]. One of the recommendations is the vaccination since infants at 9-12 months and synchronizing it with the administration of measles vaccine in these regions [101].

The long action of YF vaccine was shown in specific series, nonetheless, the recommendation of additional reinforce in endemic zones is a practice recommended. Several analyses about the long-term immunity was made and showed good outcomes of protection in travelers, but in people from endemic regions where they are in continuing exposure is different, in Brazil was observed lower seroprotection rates in endemic regions but in this analysis was used a higher cut-off for seroprotection [99]. Also, in people living with HIV and children (younger than 2 years) booster doses might be an alternative because lower rates of vaccines were seroprotected 10 or more years post-­vaccination [102, 103]. A recommended practice involves administering the yellow fever vaccine to infants at 9-12 months and synchronizing it with the administration of the measles vaccine, which is particularly pertinent in regions where yellow fever prevails [101-125]. WHO-qualified vaccines for yellow fever are listed in Table 2.

Table 2 - Vaccines that WHO currently prequalifies against yellow fever.

The standard yellow fever vaccine dose provides long-lasting immunity, but using fractional or half doses can extend available resources in cases of limited supply. Research has shown that smaller doses (even as low as one-fifth of a total dose) can still provide adequate protection for a certain period, although possibly shorter than a total dose. The ring vaccination strategy is also worth mentioning, focusing on vaccinating people in close contact with an infected individual and their immediate contacts. It creates a “ring” of immunised people around the infected person, which helps to contain the spread of the disease [121].

Diagnosis and surveillance

YFV surveillance is necessary in endemic regions as a One Health mechanism, where the vector control would be integrated for several other endemic diseases (within acute febrile jaundiced conditions) and the surveillance would be made at vector level, at zoonotic level, and human level; the follow in the multiple actors of the transmission chain could predict outbreak emergency and take actions to reduce they develop in the zone. Surveillance in YFV needs are active, or sentinel depends on the type of populations monitoring. Thus, current information about spreads in vector, NHP and humans could predict some behaviors at local or regional level some seasons, and updated the previous information.

Availability and effectiveness of fast processing test could warranty the optimal surveillance in the region. Laboratory diagnosis of yellow fever typically involves the examination of serum samples to detect virus-specific IgM and neutralizing antibodies [5, 108, 109]. Sometimes, the virus can be traced in blood samples obtained early during the illness. The fundamental tests pivotal for confirming yellow fever in a laboratory setting amid an outbreak encompass the deployment of enzyme-linked immunosorbent assay (ELISA) to gauge yellow fever virus IgM [108]. Different diagnostics methods for detecting yellow fever are listed in Table 3.

Table 3 - Diagnostic methods for detecting yellow fever.

ROLE OF GLOBAL HEALTH ORGANIZATIONS IN YELLOW FEVER MANAGEMENT

Global health organizations play a crucial role in the management of yellow fever. The WHO is one of the key organizations involved in the global effort to control and prevent yellow fever outbreaks [114]. The WHO works with countries to strengthen their capacity to prevent, detect, and respond to yellow fever outbreaks [115]. This includes supporting vaccination campaigns, improving laboratory capacity, and enhancing surveillance systems. Also, it provides technical guidance on yellow fever prevention and control, including recommendations on vaccination, mosquito control measures, and outbreak response, and works with partners to ensure availability of yellow fever vaccines in countries with risk of outbreaks [116, 117]. In 2016, the WHO introduced the Eliminate Yellow Fever Epidemics (EYE) strategy, a comprehensive global initiative aimed at (1) protection of at risk populations, (2) preventing cross-border transmission, and (3) swiftly containing outbreaks [118]. In this case, the measures recommended depends on the risk level (a. high risk, b. moderate risk, and c. not considered at risk but potential for YF transmission). This risk level considered countries with background of outbreaks, mainly in South-America and Africa. Thus, in high risk zones the protection strategies are focused on the immunization and immunity monitoring at population level; in moderate risk zones are recommended sentinel surveillance, and it focused on fast laboratory testing, zones not considered at current risk is recommended the improvement in health services and screening/diagnostic services [119]. The inclusion of other international actors is a relevant condition to warranty more accessibility and improve in health services, immunization coverages and develop of technologies in health/One Health to improve the YF control, as the United Nations Children’s Fund (UNICEF) or the International Federation of Red Cross and Red Crescent Societies (IFRC) [118-120].

CONCLUSIONS

In conclusion, in contrast with other pandemic virus-borne diseases, yellow fever still maintains specific dissemination in endemic areas in the world, especially in countries lacking appropriate vaccination in risk areas, as is the case of Venezuela and probably in other countries of Latin America and Africa [121-125]. Nonetheless, multilevel conditions could develop during a potential pandemic worldwide. For these reasons, it is relevant to reinforce the measures of prevention and control in these specific areas and immunization monitoring at the population level in high-risk zones. Despite the Aedes spp. mosquito, as one of the main vectors in YF outbreaks, has not triggered worldwide dissemination like other viruses transmitted by this vector (DENV, CHIK, ZIKV), probably due to the interaction and role of YF in this vector as a reservoir and the interaction with other NHP.

Another relevant condition is the early diagnostic and algorithm of response at the beginning of outbreaks, mainly based on a surveillance sentinel and differential algorithm with other similar endemic diseases (acute febrile jaundiced diseases). It is pending in the research agenda effective strategies in vector control and management of wild host in the jungle scenarios.

The WHO has introduced the Global Vector Control Response, another important cornerstone initiative that promotes vector control efficiency, affordability, ecological harmony, and long-term sustainability. In the grand scheme, the path forward hinges upon a comprehensive approach; forecasting anticipated obstacles and proactive scientific exploration.

Conflict of interest

None

Funding

None

Acknowledgement

Dr Rodriguez-Morales would like to dedicate this publication to the memory of Prof. Eloy Maceira (1945-2024), from Venezuela, a great mentor and human being who passed away in Caracas, November 2024, R.I.P.

This article has been registered in the Research Proposal Registration of the Coordination of Scientific Integrity and Surveillance of Universidad Cientifica del Sur, Lima, Peru, under the number PI-50-2024-0765.

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