What Does the Future Hold for Yellow Fever Virus? (II)

Abstract

As revealed by the recent resurgence of yellow fever virus (YFV) activity in the tropical regions of Africa and South America, YFV control measures need urgent rethinking. Over the last decade, most reported outbreaks occurred in, or eventually reached, areas with low vaccination coverage but that are suitable for virus transmission, with an unprecedented risk of expansion to densely populated territories in Africa, South America and Asia. As reflected in the World Health Organization's initiative launched in 2017, it is high time to strengthen epidemiological surveillance to monitor accurately viral dissemination, and redefine vaccination recommendation areas. Vector-control and immunisation measures need to be adapted and vaccine manufacturing must be reconciled with an increasing demand. We will have to face more yellow fever (YF) cases in the upcoming years. Hence, improving disease management through the development of efficient treatments will prove most beneficial. Undoubtedly, these developments will require in-depth descriptions of YFV biology at molecular, physiological and ecological levels. This second section of a two-part review describes the current state of knowledge and gaps regarding the molecular biology of YFV, along with an overview of the tools that can be used to manage the disease at the individual, local and global levels.

Keywords: emergence; flavivirus; vector-borne transmission; yellow fever virus.

Figure 1

Functional sequences and secondary structures within Yellow fever virus (YFV) genome: diversity among genotypes (Modified from [57] and [87]). (Upper part) Functional sequences and secondary structures within YFV genome. Promoter and enhancer elements are highlighted in light blue and grey, respectively. At the 5′ end: Cap-1 and functional RNA structures SLA and SSL. The translation start (AUG) and stop (UGA) codons encompassing the complete coding sequence (CDS) are indicated in italics. Sequence motifs involved in viral genome cyclization are shown in blue: UAR, DAR and CYC sequences. The PN is shown in dark yellow. The 3′UTR is organized into three domains (I, II, and III). Domain I: functional RNA structures RYF1, 2 and 3 (RYFs). Domain II: functional RNA structures SL-E, SL-D, ΨDB and DB. The pseudoknot elements (PK1, PK2, and PK3) are indicated by dashed, maroon lines, and the corresponding interacting sequences, by solid lines. The 5′ end of YFV the subgenomic flavivirus RNA sequence is indicated by a triangle. Domain III: functional RNA structures sHP and 3′SL. The PN sequence “CACAG” is indicated by a dark yellow line. (Lower part) Schematic representation of the seven patterns described for the untranslated regions (UTRs) of YFV strains. (Ia) Full “native” sequence corresponding to pattern “I” corresponding to West African genotypes I and II. (Ib) Only two RYFs (1/3) are present in pattern “Ib”, which is associated with the Angolan, East and East/Central African genotypes. (II) Only one RYF (3) is present in pattern “III” (deletion YFVSADM1), it is associated with the South American II genotype. Patterns “III”, “IV”, “V” and “VI” correspond to sequences from South American I genotype. (III) Pattern “III” involves the deletion YFVSADM1 and 2 and the insertions YFVSACM1 and YFVSAUM. (IV) Pattern “IV” involves the deletions YFVSADM1 and 2 and the insertion YFVSACM1. (V) Pattern “V” involves the deletion YFVSADM1 and the insertion YFVSACM1. (VI) Pattern “VI” involves the deletion YFVSADM1 and the insertions YFVSACM1 and 2. Motifs: YFVSADM1: deletion of RYF1 and RYF2; YFVSADM2: partial deletion of 3′SL (incl. disruption of the PN); YFVSACM1: insertion disrupting the CYC sequence and including an imperfect cyclization sequence (imp-CYC); YFVSACM2: insertion upstream CYC sequence; YFVSAUM: insertion of a unique motif (YFVSAUM) disrupting the DAR sequence and the sHP structure, partly deleting the 3′SL (=YFVSADM2). Abbreviations: CS1/2: conserved sequences 1/2, CYC: cyclization motif, DAR: Downstream of AUG region motif, DB: dumbbell, imp-CYC: imperfect CYC, imp-DAR: imperfect DAR, PN: pentanucleotide sequence, RYF: imperfectly repeated sequences, YFVSAUM: South American unique motif, YFVSACM1/2: South American conserved motif, YFVSADM1/2: South American deleted motif, sHP: small hairpin structure, SL: stem-loop, SSL: side stem-loop, UAR: Upstream of AUG region.

Figure 2

Number of available complete coding sequences at GenBank for selected arboviruses. Sequences were accessed on 15 May 2018. Viruses are ordered by the number of available sequences. Chikungunya virus was included for comparison. CHIKV, Chikungunya virus; DENV, dengue virus; USUV, Usutu virus; WNV, West Nile virus; YFV, Yellow fever virus; ZIKV, Zika virus. YFV, n = 88; USUV, n = 142; ZIKV, n = 677; CHIKV, n = 684; WNV, n = 1778; DENV, n = 5145. For YFV, 49 sequences originate from the Americas (including 40 from Brazil), 28 from Africa and 11 from Asia (including five cases imported from Africa).

Figure 3

Yellow fever (YF) outbreaks since 2010 with regard to vaccination coverage at the time (modified from [299]). Estimated proportion of the population (across all ages, in %) to have ever received a YF vaccine at the beginning of 2010 for countries at risk of YFV transmission, based on the untargeted, unbiased vaccination-targeting scenario [299]. Countries where YFV outbreaks occurred since 2010 are indicated by a red dot. Outbreak time-span and total number of cases are detailed in grey boxes. Export cases are detailed when applicable. All country names’ abbreviations are defined according to international ISO country codes. * Presumptive positive cases ** reported cases.