What Constitutes Protective Immunity Following Yellow Fever Vaccination? Part 2

3. Diversity and Transmission of YFV

Molecular phylogenetic studies have described YFV diversity based on nucleotide sequence analysis of the whole genome as well as different sub-genomic regions [16]. 

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It has been reported that the evolutionary rate of YFV, which is estimated at 2-5 x 10 substitutions/site/year, is generally consistent across different sub-genomic regions and therefore a representation of that of the entire genome 16,17]. 

While the mode of replication fidelity of the polymerase enzyme, ecology, epidemiology, and immune response could play a role in the evolution of YFV, the specific drivers/mechanisms are yet to be determined [18] seven major genotypes of YFV have been described: five African (AngolaEast Africa, East/Central Africa, West Africa I and West Africa ll) and two South AmericanSouth America I and South America ll)[16](Figure 2). 

Based on complete genome sequences or sub-genomic sequences (M-E junction), the nucleotide difference betweenAfrican and South American genotypes is up to 16%, whereas the nucleotide difference betweenAfrican genotypes is approximately 8% and approximately 5% between South American genotypes l16,19]. 

There are no studies that have investigated the relationship between strains to specific phenotypes such as disease severity, possibly due to the availability of a vaccine that is effective across all strains resulting in limited interest in experimental investigations 16. 

Nevertheless, the difference in the geographical distribution of these genotypes can be attributed to a difference in the modes of maintenance and transmission however, insufficient data are available to ascertain this [16].

YFV is transmitted to humans and non-human primates in tropical areas of Africa and the Americas, via the bite of an infected mosquito [21]. 

Transmission to humans occurs in three cycles: sylvatic, intermediate, and urban [2,21] (Figure 3). In sylvatic transmission, infection to humans occurs when they enter forests where the virus is enzootically transmitted between non-human primates and mosquitoes. 

This sylvatic reservoir makes it challenging to eliminate YF [2,21]. 

In intermediate (savannah) transmission, humans residing in rural areas become infected when bitten by infected semi-domestic mosquitoes that feed on both humans and non-human primates, and in urban transmission, urban-infected mosquitoes (Aedes aegypti) transmit the virus from human to human in densely populated areas [2].

4. Clinical Presentation, Diagnosis and Treatment of YF

Most acute febrile infections are often self-limiting with viral replication occurring in regional lymph nodes [16]. However, approximately 20–50% of infected individuals develop pan-systemic sepsis characterized by viremia, fever, injury to the liver, kidney, and heart, and hemorrhage [2,16]. 

Diagnosis of YF remains challenging given the differences in disease severity and symptom presentation in different infected individuals, the similarity of clinical symptoms with other endemic diseases, and laboratory diagnosis which requires specialized resources that may not be accessible in areas where YF is endemic [2]. 

Furthermore, the protein similarity of YFV to other flaviviruses (DENV, WNV, and ZIKV) often results in the production of cross-reactive antibodies thus making serological tests inconclusive [14,15,22]. 

Nevertheless, diagnosis can be made based using reverse transcriptase polymerase chain reaction to assess for YFV genomic RNA in body fluids, and/or using serologic tests which involve evaluating for the presence of YFV specific Immunoglobulin M (IgM) or Immunoglobulin G (IgG), with a differential diagnosis of DENV, WNV and ZIKV to rule out these viruses [2,22] (Figure 4). 

In addition, plaque reduction neutralization antibody tests (PRNT) add specificity to the serological distinction by using a higher titer threshold (typically a fourfold difference in PRNT titers) when comparing responses between flaviviruses [22]. 

There is no specific antiviral treatment for YF. However, early supportive clinical management of specific symptoms or complications (such as treatment for dehydration, fever, organ failure, and antibiotics for associated bacterial infections) could improve the outcome [2,17].

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