The reemergence of yellow fever

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Since 2016, yellow fever has become a major public health concern

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Out of Africa: A Molecular Perspective on the Introduction of Yellow Fever Virus into the Americas

Juliet E. Bryant, Edward C Holmes, Alan Barrett (2007)

Introduction Few diseases have attracted more attention from medical historians than yellow fever (YF). It was one of the most feared of epidemic diseases from the 15th to 19th centuries, when large scale outbreaks in port cities of North and South America, Africa, and Europe caused devastating mortality and helped to shape the expansion of settlements and colonial powers. The landmark studies of Walter Reed in 1900–1901 established that the disease was transmissible among humans via Aedes aegypti mosquitoes [1]. Within one year of Reed's discovery, the disease was successfully controlled in Cuba as a result of vigilant mosquito control campaigns [2]. Twenty-eight years later, yellow fever virus (YFV) became the first mosquito-borne virus to be identified [3]. Despite this legacy, YF is currently classified as a reemerging disease and remains a significant cause of morbidity and mortality, with an estimated 200,000 cases each year and 30,000 deaths [4,5]. Indeed, although a highly effective vaccine is available, epidemiological data suggest an alarming resurgence of virus circulation in West Africa over the last 20 years [6,7]. The failure to implement sustained vaccination programs reflects larger problems of poverty, civil war, and the inaccessibility of rural areas where outbreaks of the disease occur [8]. The agent of the disease, YFV, is a single-stranded, positive-sense RNA virus with a genome of approximately 11 kb. The virus is a member of the genus Flavivirus (family Flaviviridae), which contains a number of important vector-borne human pathogens, such as the dengue, Japanese encephalitis, and West Nile viruses. Previous evolutionary studies suggest that YFV originated in Africa, as the deepest phylogenetic split among viral genotypes is between those isolates sampled from East and West Africa [9–11]. What is less clear, however, is the timing and mechanism by which YFV was introduced to the Americas and whether the descendants of the earliest imported viruses still circulate today. The most commonly cited hypothesis of the origin of YFV in the Americas is that the virus was introduced from Africa, along with A. aegypti, in the bilges of sailing vessels during the slave trade. Subsequent to devastating urban outbreaks within port cities on both the east and west coasts of South America, the virus established a sylvatic enzootic cycle within the Amazon, Araguaia, and Orinoco river basins vectored by Haemagogus and Sabethes mosquitoes [12,13]. Although the hypothesis of a slave trade introduction is often repeated, it has not been subject to rigorous examination using gene sequence data and modern phylogenetic techniques for estimating divergence times [14]. Determining the age of American sylvan YFV is of particular interest given the virtual disappearance of urban (human) YFV transmission in South America in the 20th century. Although a small number of sporadic cases have been reported from residents of urban areas (three cases in 1942 in Sena Madureira, Acra, Brazil [15], 15 cases in 1954 in Trinidad [16], six cases in 1999 in Santa Cruz de la Sierra, Bolivia [17]), there was no evidence for inter-human transmission during these outbreaks. The last documented Aedes-vectored epidemic occurred in 1928 in Rio de Janeiro [12]. However, the reinfestation of many densely populated coastal cities with A. aegypti and the emergence of dengue in the Americas indicates that surveillance and monitoring of YF endemic/epidemic viral activity remains a critical public health objective. To provide an insight on the factors that influence the emergence of YF in the two hemispheres and to determine the time-scale of these events, we have performed an extensive analysis of the evolutionary relationships and dynamics of YFV. To achieve this, we assembled the largest data set of viral isolates compiled to date, including samples taken from a wide range of geographical localities and over an extensive time-span. The fragment analyzed comprised half of premembrane (prM) (containing an important cleavage site for pr→M), and extended through the first 112 amino acids of envelope (E). This region was chosen because of the relatively large data set available from previous studies [9–11,18–21]. Further, the prM and E genes are of interest because of their critical role in immunity and infectivity, and because they form the structural proteins of the virion surface and are the primary antigens that induce protective immunity. From these data we were able to infer the time-scale and evolutionary history of YFV, and provide the first direct evidence to our knowledge that YFV was introduced to the Americas during the slave trade. Results/Discussion We examined YFV isolates representing the global diversity of the disease from the World Reference Center for Emerging Viruses and Arboviruses at the University of Texas Medical Branch, Galveston, Texas, United States. Novel sequence data from 37 human isolates, 21 mosquito isolates, and four vertebrate isolates was obtained for the prM/E gene region (670 nucleotides [nt], genomic positions 641-1310). Inclusion of an additional 71 prM/E sequences from GenBank resulted in an alignment of 133 wild-type isolates representing 22 countries (14 African, eight South American). Table 1 provides summary details on the YFV isolates included in this study (more details are available in Table S1). Table 1 Summary of Yellow Fever Virus prM/E Gene Sequences Used in This Study Our phylogenetic analysis shows that YFV can be divided into two geographic groups, with distinct viral lineages observed in Africa and the Americas (Figure 1). The prM/E phylogeny supports the major genotype and subclade distinctions observed previously in phylogenies based on full genome sequences [22], the complete E gene [9], and the 3′ non-coding region [23]. Four key observations can be drawn from the structure of the YFV phylogeny. (1) The American isolates are monophyletic, (2) the American isolates are divided into those from the east and west of the continent, (3) the isolates from West Africa are most closely related to those from the Americas, and (4) the isolates from East Africa are the most divergent. Such a phylogenetic pattern is compatible with the hypothesis that YFV arose in Africa, most likely in the east of that continent, and was imported into the Americas from West Africa, and then spread westwards across the Americas. To further test this hypothesis, we constructed a model tree in which both the African and American lineages were monophyletic, which is compatible with the theory that the viruses from these two continents have evolved separately for a far longer period of time (an “ancient origin” model). However, the likelihood of this phylogeny was significantly lower (p 1) was only observed at a single codon, E100, in some data sets, most notably Peru. Table 2 Evolutionary Rates and Divergence Times of Yellow Fever Viruses From the substitution rates estimated above, the deepest node on the YFV phylogeny, corresponding to the time of origin of viral strains sampled here, has a mean age of 723 years (95% highest probability density [HPD] of 288–1,304 years). A similar time-scale was observed under models of both constant population size (the best-fit to the data in hand) and a Bayesian skyline plot, indicating that these age estimates are robust to the demographic model (unpublished data). More importantly, the estimated mean divergence time of the West African and South American clades was approximately 470 years ago (95% HPD of 186 and 869 years, respectively), while the mean time of origin of both South American genotypes was 306 years ago (95% HPD of 120 and 590 years). Taken together, these analyses suggest that genetic diversity in the available sample of South American YFV arose within the last three to four centuries and provide compelling support for an initial introduction during the period of the slave trade and first contact between the two continents. Furthermore, it appears that the divergence of the two South American lineages occurred shortly after their initial introduction and that they have been maintained in the Americas ever since. Of equal significance, and no doubt a tribute to effective public health measures, is the lack of evidence for subsequent traffic of viruses between the hemispheres since the advent of the post-vaccine era. An outstanding issue, however, is why the newly established sylvatic South American viruses have failed to cause urban epidemics like those caused by their sylvatic counterparts in West Africa. In West Africa, outbreaks are reported on a nearly annual basis, and five large West African cities have faced YF epidemics since 2001 alone [7]. However, our analyses revealed no major difference in evolutionary dynamics among viruses circulating in South America or Africa, and neither population exhibited the increases in virus diversity expected of epidemic expansion. Indeed, for both regions, the sequence data supported either a constant population size or a population growth rate with an extremely low epidemic doubling time (e.g., ~26 years in the case of YFV from Brazil). This suggests that viral epidemiology in both regions is still dominated by sylvatic transmission. It is also likely that population subdivision has played a significant role in maintaining the relatively constant levels of genetic diversity within YFV, as reflected in the clear geographic structure of the phylogeny clades, which generally consist of sequences from neighboring countries with little mixing among them. Previous studies of the spatiotemporal distribution of the two South American genotypes [25] indicated that Peruvian YFV may persist in discrete enzootic foci due to biogeographic barriers that inhibit movement of both vectors and hosts. In contrast, YFV isolates obtained during recent Brazilian epizootics exhibit more rapid dispersal over larger distances, suggesting higher rates of virus traffic within the YF endemic zone that can most likely be attributed to human-aided transportation of virus-infected vectors or hosts [26]. Interestingly, these higher rates of virus traffic and population mixing within Brazil appear to correspond to marginally higher rates of population growth (Table 2). YF provides a powerful historical demonstration of how the establishment of travel and trade routes between countries has been accompanied by the spread of microbes and their vectors. Global trade and transportation in the modern era continues to facilitate the movement of pathogens and vectors farther and faster than ever before, thus altering the potential geographic distribution of infectious diseases. During recent decades there have been several documented cases of the human importation of YFV to non-endemic areas. Since 1964, such episodes have included at least nine documented cases of European and North American tourists who have died as a result of YFV infection after returning home from visits to the Congo, Senegal, Mauritania, Gambia, Côte d'Ivoire, Brazil, and Venezuela [27–30]. These examples demonstrate that although YFV continues to be exported outside of endemic regions, conditions have not been favorable to support secondary transmission. Why YFV has not successfully dispersed to new regions infested with A. aegypti, in particular Asia, remains uncertain, although it is clear that previous geographic barriers that prevented spread of YF in the past are quickly eroding. Materials and Methods Viruses used in this study. All virus isolates were available from the World Reference Center for Emerging Viruses and Arboviruses at the University of Texas Medical Branch, Galveston, Texas, United States (see Table S1). The majority of isolates were obtained through primary isolation in suckling mouse brain, followed by a single passage in C6/36 cells. A smaller number of isolates had uncertain (undocumented) passage histories, or as many as two to ten passages in suckling mouse brain. The viruses used covered a sampling period of 76 years: 16 isolates from 1927–1959, 19 isolates from 1960–1969, 25 isolates from 1970–1979, 21 isolates from 1980–1989, 46 isolates from 1990–1999, and 6 isolates from 2000–2003. Importantly, all of the South American isolates represented sylvatic transmission cycles, as no YFV isolates representing human-mosquito-human transmission in South America are available in historical or contemporary archives. Sequence analysis. Maximum likelihood phylogenetic trees were inferred for the YFV prM/E sequence data (670 nt) set under a variety of nucleotide substitution models in PAUP* [31], including (a) codon-specific substitution rates and (b) the GTR+I+Γ4 model, with the rate of each substitution type under the general reversible model (GTR), the proportion of invariant sites (I), and shape parameter of a gamma distribution with four rate categories (Γ4) estimated from the data. The GTR+I+Γ4 substitution model was also used as the basis to estimate trees using Bayesian Markov chain Monte Carlo approaches implemented in MrBayes [32] and BEAST [33]. The final tree presented is the MAP tree estimated in BEAST (chain length of 25 million, sampling every 1,000), with tip times corresponding to the year of virus sampling. To test the competing hypotheses of the “recent” and “ancient” origin of YFV in the Americas, we compared the likelihood of the maximum likelihood tree (“recent origin”) with that of a model tree in which both the African and American lineages were monophyletic (“ancient origin”) using a Shimodaira–Hasegawa test [34]. Rates of nucleotide substitution, the age of the most recent common ancestor (MRCA), and demographic histories were estimated for the whole data set and each geographic subset using models that allow for rate variation among lineages under a relaxed (uncorrelated exponential) molecular clock [14] implemented in BEAST [33]. Four population dynamic models were investigated: constant population size, exponential population growth, logistic growth, and expansion growth. To confirm the age of the MRCA of all the YFV sequences analyzed, we also used the piecewise Bayesian skyline plot [35], as this possesses the least constrained coalescent prior. Akaike's information criterion was used to determine the best-fit model, with uncertainty in parameter estimates reflected in the 95% HPD values, and all chains were run for sufficient time to ensure convergence. All estimates were again based on the GTR+I+Γ4 model of nucleotide substitution. Mean and site-specific selection pressures acting on YFV were measured as the ratio of nonsynonymous (dN) to synonymous substitutions (dS) per site estimated using the single likelihood ancestor counting (all sequences) and random effects likelihood (maximum of 50 sequences) methods, both incorporating the GTR model with phylogenetic trees inferred using the neighbor-joining method available at the Datamonkey facility [36]. Supporting Information Table S1 Click here for additional data file.

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Immunogenicity of Fractional-Dose Vaccine during a Yellow Fever Outbreak — Preliminary Report

Steve Ahuka-Mundeke, Rebecca Casey, Jennifer B. Harris … (2018)

In 2016, the response to a yellow fever outbreak in Angola and the Democratic Republic of Congo led to a global shortage of yellow fever vaccine. As a result, a fractional dose of the 17DD yellow fever vaccine (containing one fifth [0.1 ml] of the standard dose) was offered to 7.6 million children 2 years of age or older and nonpregnant adults in a preemptive campaign in Kinshasa. The goal of this study was to assess the immune response to the fractional dose in a large-scale campaign.

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Fatal Yellow Fever in Travelers to Brazil, 2018

Davidson H. Hamer, Kristina M Angelo, Eric Caumes … (2018)

Yellow fever virus is a mosquito-borne flavivirus that causes yellow fever, an acute infectious disease that occurs in South America and sub-Saharan Africa. Most patients with yellow fever are asymptomatic, but among the 15% who develop severe illness, the case fatality rate is 20%–60%. Effective live-attenuated virus vaccines are available that protect against yellow fever ( 1 ). An outbreak of yellow fever began in Brazil in December 2016; since July 2017, cases in both humans and nonhuman primates have been reported from the states of São Paulo, Minas Gerais, and Rio de Janeiro, including cases occurring near large urban centers in these states ( 2 ). On January 16, 2018, the World Health Organization updated yellow fever vaccination recommendations for Brazil to include all persons traveling to or living in Espírito Santo, São Paulo, and Rio de Janeiro states, and certain cities in Bahia state, in addition to areas where vaccination had been recommended before the recent outbreak ( 3 ). Since January 2018, 10 travel-related cases of yellow fever, including four deaths, have been reported in international travelers returning from Brazil. None of the 10 travelers had received yellow fever vaccination. Five of the 10 cases were reported by ProMED since January 15, including two from Argentina and three from Chile; two of the travelers from Chile died. In addition, during January 1–March 15, 2018, five confirmed cases of yellow fever in unvaccinated travelers returning from Brazil were reported by GeoSentinel (http://www.istm.org/geosentinel), the global clinician-based sentinel surveillance system for travel-related illness among international travelers and migrants ( 4 ). These five yellow fever cases represent the first such cases identified by GeoSentinel (Table), which was initiated in 1995 by the International Society of Travel Medicine with support from CDC and now consists of 70 specialized travel and tropical medicine clinical sites around the world. The first of the GeoSentinel-reported cases occurred in a Dutch man aged 46 years who traveled to São Paulo state for 3 weeks during December 2017–January 2018. The second case occurred in a French woman, aged 42 years, who traveled to Minas Gerais state in Brazil for 4 weeks during December 2017–January 2018. She received a diagnosis of yellow fever in Brazil and was examined at a GeoSentinel site after returning to France to convalesce. The third and fourth cases occurred in a Romanian man, aged 34 years, and a Swiss man, aged 44 years, each of whom visited Brazil for approximately 2 weeks in February 2018. The fifth case was in a German man, aged 33 years, who spent a week in Brazil in late February. The Swiss and German travelers died from their illness (Table). TABLE Characteristics of five travelers to Brazil with yellow fever reported by GeoSentinel sites, January–March 2018* Characteristic Patient 1 (man) Patient 2 (woman) Patient 3 (man) Patient 4 (man) Patient 5 (man) Age (yrs) 46 42 34 44 33 Nationality Dutch French Romanian Swiss German Reporting site Netherlands France Romania Switzerland United Kingdom Area (state) of presumed yellow fever acquisition Mairiporã (São Paulo) (Minas Gerais) Ilha Grande (Rio de Janeiro) Ilha Grande (Rio de Janeiro) Ilha Grande (Rio de Janeiro) Signs/Symptoms Fever, headache, myalgia, nausea, vomiting, diarrhea Fever Fever, rash, myalgia, encephalopathy Fever, petechial rash, arthralgia, vomiting, diarrhea Fever, malaise, nausea, jaundice, hepatomegaly Clinical/Laboratory findings Hepatitis Hepatitis, thrombocytopenia, neutropenia Renal and hepatic failure Renal and hepatic failure Thrombocytopenia, renal and hepatic failure Yellow fever diagnostic testing Positive RT-PCR for YFV (urine, whole blood, plasma) Positive RT-PCR (blood); positive IgM (initial diagnosis made in Brazil) Positive PCR (serum, urine); YF IgM positive; IgG titers rising days 4–8 Positive PCR (blood) Positive RT-PCR (serum, urine) Yellow fever vaccination status No No No No No Outcome Recovered Recovered Condition improving as of March 15, 2018 Died Died Abbreviations: IgG = Immunoglobulin G; IgM = Immunoglobulin M; PCR = polymerase chain reaction; RT-PCR = reverse transcription–PCR; YF = yellow fever; YFV = YF virus. * In addition to the five patients reported by GeoSentinel sites, five additional cases of yellow fever have been reported by ProMED among persons who traveled to Brazil from Argentina (two) and Chile (three) since January 2018. Two of the patients from Chile died. Among the 10 international travelers reported with yellow fever acquired in Brazil, eight acquired the disease on Ilha Grande, a forested island off the Rio de Janeiro coast, where one human and one nonhuman primate yellow fever case were reported in early February 2018 ( 5 ); of the eight patients who acquired the disease on Ilha Grande, four died. Another travel-related case of yellow fever was reported recently outside of Brazil ( 6 ). Yellow fever is a potentially fatal illness that is preventable by vaccination. Yellow fever vaccination is recommended for all eligible persons aged ≥9 months, traveling to many areas in Brazil, including the states of São Paulo and Rio de Janeiro (especially Ilha Grande). Unvaccinated travelers should avoid traveling to areas where vaccination is recommended (https://wwwnc.cdc.gov/travel/notices). Travelers planning to visit areas in Brazil or elsewhere where yellow fever transmission is occurring should receive yellow fever vaccine at least 10 days before travel and follow recommendations for avoiding mosquito bites (https://www.cdc.gov/yellowfever/prevention/index.html). The Food and Drug Administration–approved yellow fever vaccine, YF-VAX, is currently unavailable in the United States because of manufacturing difficulties ( 7 ). An alternative yellow fever vaccine, Stamaril, is available through a limited number of U.S. yellow fever vaccination clinics. U.S. travelers should therefore plan ahead to obtain Stamaril because it might take more time to access one of these clinics. Clinicians assessing returned travelers should be aware of yellow fever signs and symptoms and maintain vigilance regarding the possibility of yellow fever exposure in travelers returning from Brazil or other areas with ongoing transmission of yellow fever.