A Report On Yellow Fever Virus
Yellow Fever Virus (YFV) is responsible for one of the deadliest mosquito-borne diseases in the tropics of sub-Saharan Africa and South America. Yellow fever (YF) is characteristically named for its primary clinical sign, yellow tinting of the skin and eyes caused by a liver malfunction known as jaundice. Despite having an effective live-attenuated vaccine available since the 1940s, YFV still remains a serious public health issue with recent outbreaks in the Democratic Republic of Congo, Angola, Brazil, and China all within the past three years. Consequently, there have been rising concerns of potential outbreaks being imported to North America. With a 3-70% mortality rate and lack of treatment options, new robust methods of effective prevention and therapy must be explored.
YFV’s primary mode of transmission in through arthropod vectors, particularly those in the Aedes (prevalent in Africa) and Haemagogus (in South America) mosquito species, during the rainy seasons. The virus has three epidemiological transmission cycles including: the sylvatic cycle (jungle), the intermediate cycle (African savannah), and the urban cycle. In the sylvatic cycle, infected non-human primates (NHPs) transmit the virus to mosquitoes, which then transmit it to humans. The intermediate cycle typically involves workers or residents along the jungle border region. In this cycle, both mosquito to human and monkey to human transmission are possible. Urban YFV transmission is normally introduced by a human who was infected either in the jungle or intermediate cycle, and then returned to the city. Thereafter, the infected human could potentially infect Aedes aegyptii mosquitos, which flourish in urban settings, and further perpetuate mosquito-human transmission leading to large epidemics.
During the dry seasons in YFV endemic regions, female YFV-carrying mosquitoes transmit the virus to their eggs, where the virus can maintain stability for extended periods and reactivate in more favorable conditions once the egg has hatched. The climate conditions in the tropics make an optimal breeding ground for mosquitoes, hence YFV’s prevalence in Africa and South America. So far, there have been no reported cases of human to human or NHP to human transmission that did not involve an arthropod vector.
Virulence Factors and Pathogenesis
YFV is an enveloped, positive sense, single-stranded RNA virus, prominent within the viral family Flaviviridae. With its wide cell tropism, YFV can undergo replication in the tissues of the heart, kidneys, liver, and lungs, resulting in a wide range of clinical symptoms. Symptoms can span from asymptomatic or mild to fatal hemorrhagic fever, followed by systemic organ failure. The virus gains entry and binds to the host cell using its structural E protein and capsid protein C, respectively. The nonstructural proteins NS1, NS2A, NS2B, NS3, and NS5 all play vital roles in its viral RNA replication.
The E protein is of particular interest in current research as it assumes multiple roles in YFV virulence. Apart from attachment and viral entry, the E protein is also instrumental in determining host ranges and tissue tropism, as well as initiating a host immune response or immunogenicity. Klitting et al. (2018) sought to genetically engineer YFV in hamster models. In their study, they found that sequence mutations introduced in the E protein significantly affected the virulence of the mutant strains. Their results led to the assumption that two specific E protein residues had integral roles in YFV’s virulence mechanism within hamsters. By manipulating the virus’s genome, they were able to alter its replication cycle and consequently impact its virulence. Klitting et al.’s (2018) findings suggest that if YFV was able to jump species, only a few mutations in its E protein sequence would be sufficient to affect its virulence and replicative success.
In another study, Barros et al., (2011) produced a variant of the baculovirus vSynYFE that possessed the E protein gene of YFV’s 17D vaccine strain to evaluate mutant protein immunogenicity in insect cells. Their constructed recombinant YFV E protein was successfully recognized by the same monoclonal and polyclonal antibodies found in human sera that identify YFV infections. Their findings provide salient insight into the impact of the E protein and could lead to substantial improvements in disease diagnosis and the potential development of a subunit vaccine development for patients that cannot receive the existing YFV 17D live-attenuated virus vaccine.
Typically, most infected YFV patients are asymptomatic, but some will exhibit general initial symptoms such as fever, chills, severe headaches, fatigue, nausea, and vomiting. Most of these conditions improve within a week. Approximately 15% of these patients who show these symptoms will experience a brief remission period but develop more severe YF symptoms including high fever, abdominal pain, jaundice, bleeding, cardiovascular complications, shock, and even organ failure. Of these conditions, YFV has the potential to cause the most damage on the liver and the kidneys. Hepatocellular damage can lead to necrosis and apoptotic bodies. In advanced cases, acute tubular necrosis and hemorrhaging are possible. If the gastric mucosa is damaged, this can lead to hematemesis or black vomit. Cardiovascular complications caused by myocardial infiltration and inflammation can develop into arrhythmias and myocarditis.
Prevention Methods & Current Advances
Widespread resurgence of YF infections has been associated with insufficient vaccine coverage, increased urbanization and human migration, as well as re-infestation of A. aegyptii due to shifting climate patterns. The World Health Organization (WHO) recommends that populations reach at least 80% vaccination coverage, which would require an estimated 400 million people in at risk YSV areas to receive their vaccines (Klitting et al., 2018). Currently, the only prevention methods available are the 17D YFV vaccine and taking general precautions to avoid mosquito bites (McGuinness et al., 2018). However, recent advances in YFV genomic sequencing has allowed for researchers to model YFV activity. Novel information gathered from these new studies could vastly broaden the scope of knowledge surrounding YFV movement, which would allow for early identification of potential outbreak areas.
The WHO has also recently launched a massive global campaign to eliminate epidemics by 2026, known as Eliminate Yellow Fever Epidemics (EYE). Their main objectives are to protect populations in endemic areas, prevent global transmission, and control outbreaks rapidly. To achieve this goal, expanded international vaccination coverage and supplies are required, along with building resilient urban centers, improving urban preparedness, and consolidating adherence to international health standards. A part of this campaign is also dedicated to improving YFV surveillance, enforcing childhood vaccinations in at risk areas, and improving diagnostic capabilities.
Although there are mounting concerns surrounding yellow fever epidemics worldwide, there is reason for hope. Further research utilizing these novel YFV surveillance techniques will enable early anticipation and prevention of YFV epidemics. Global strategic cooperation is crucial to executing EYE, along with developing a better understanding of YFV through viral modeling and sequencing, elimination of yellow fever epidemics by 2026 seems like an achievable feat.