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Sound Off Science: Yellow Fever

*This post is an assignment for BLG 451: Medical Microbiology (Ryerson University, W17).

If you’re planning a trip to Africa or South America anytime soon (and you’ve done your homework), you’ve likely come across notices urging you to get the yellow fever vaccine. Typically, an African or South American government will require you to have received the vaccine if you are travelling from another country where the disease is endemic (ie. where it historically occurs). If this applies to your itinerary, it’s important to understand why this disease is important, and how it can drastically affect the lives of the people you will encounter during your trip.

Yellow fever is a serious infectious disease with major impacts on public health in certain regions of Africa and South America. The disease is caused by a virus: a molecular parasite that – while possessing its own genetic material – depends on the synthetic machinery of a host cell to produce the proteins required to continue its lifecycle (above (CDC, 2017)). The yellow fever virus (YFV) belongs to the Flavivirus genus, a group of over 70 viruses that are transmitted by insects – most commonly, mosquitos.[1]

At its best, yellow fever may present without symptoms, as is the case in an estimated 90% of all infections.[2] At its worst, yellow fever causes systemic infection, leading to liver (jaundice) and kidney failure, and internal bleeding.[1] The virus’s name comes from the yellow skin colour caused by jaundice.[1] During the initial stage of infection, a symptomatic patient typically experiences fever, fatigue, nausea, vomiting, and muscle tenderness.[1] Improvement follows in the second phase, with some recovering completely. In the third stage, YFV-fighting antibodies appear in the blood.[1] However, in 15% of third-stage cases, condition declines with the return of previous symptoms, in addition to jaundice and kidney failure.[1] Mortality rates following this stage vary between 20-60%, depending on location of the epidemic, the infecting YFV strain, and genetic factors of the population.[2] The mortality rate in South America is higher than in Africa, as the disease is relatively new to the continent, brought by slave traders only a few hundred years ago.[2] Severity of clinical presentation is dependent on the infecting strain, and can be reduced if preexisting immunity to a related virus exists, such as West Nile or Dengue Fever.[2]

Epidemiology YFV appeared approximately 1,500 years ago in the tropical and subtropical regions of central Africa, and for centuries was maintained in nature through non-human primate populations.[2] However, at some point prior to the 17th century, human migration led to a jump of the virus into a new ecological niche – us. With the rise of the slave trade in the 17th century, YFV radiated from central Africa to the western and eastern slave ports, killing negligently recorded numbers of Africans who possessed no immune barrier against the virus.[2] Yellow fever only became a major public health issue in the 18th century, when epidemics occurred in Europe, and the North American and Caribbean colonies.[2] Efforts to control mosquito populations began in 1900, following the identification of the mosquito as the primary vector for the disease.[2] The creation of a vaccine effective against all YFV strains in 1927 led to further reduction in disease prevalence; however, as organized vaccination campaigns in Africa and South America were not sustained, the disease has resurged since the 1980s.[1]

Today, an estimated 200,000 symptomatic cases of yellow fever occur annually, with over 90% in Africa.[1] The mortality rate is an estimated 20-50%.[3] Both the African and South American endemic zones can be seen in above.[2] Historically, the severest epidemics have occurred in West Africa, and at a higher frequency than in East Africa.[2] Yellow fever events experience a high degree of variability, arising every 5-20 years in West Africa, and 40-50 years in East Africa.[2] Intensity of an epidemic is highly dependent on weather, peaking at the end of the wet season or beginning of the dry season. Increased precipitation and temperature during this period is associated with greater severity and longevity of the epidemic.[2] The primary life cycle of yellow fever still occurs within non-human primate populations, especially in South America, where deaths in nearby monkey populations due to YFV often precede a human epidemic.2 South American epidemics have been associated with deforestation and settlement activity by an unvaccinated human population in regions where the virus previously only circulated in monkeys.[1,2] Following significant outbreaks in rural Peru, Bolivia, Colombia, Ecuador, and Brazil in the mid-90s, aggressive mass-vaccination campaigns have successfully reduced the rate and severity of epidemics in South America.[2]

In Africa, increased urbanization has created environments in which mosquitos thrive, making humans the primary viral reservoir.[1,2] Passive surveillance has led to severe underreporting of disease incidence, meaning that a yellow fever case is only recorded when a patient seeks care of a doctor who actively reports to their national public health organization; many individuals living in regions affected by yellow fever are unable to access healthcare when ill.[2] For this reason, most African countries require documentation of yellow fever vaccination within the past 10 years for all travellers. To improve surveillance across Africa, a network of national laboratories and a case investigation system was established in 2002; now, when more than two yellow fever cases are confirmed by a blood test in the same region, the WHO initiates a mass-vaccination campaign in the region.[2]

The Biology of Yellow Fever 

Often, cells infected with YFV are targeted by effectors of the immune system that cause the cell to die. Typically, cell death in yellow fever occurs through a process called apoptosis, where a cell dies by fragmenting into small pieces. At the organ level, this is what produces liver and kidney failure. Immune activation products are responsible for inducing fever and nausea. There are 5 identified strains of YFV, roughly representing the geographic regions discussed above, with overlaps. Strains are distinguished by slight differences in two types of protein molecules projecting from the surface of the viral membrane. Certain strains can infect host cells more effectively than others, and therefore cause more severe disease.[2]

At a cellular level, yellow fever infection begins with attachment of virions (ie. viral particles) to the surface of a host cell. These particles are then internalized by the cell in a process called endocytosis. The compartment the virions are contained within becomes acidic; the acidic environment typically kills bacteria, but in flaviviruses, it results in release of the viral genome into the cell. Flaviviruses possess a positive-strand ribonucleic acid (RNA) genome, instead of deoxyribonucleic acid DNA. Positive-strand RNA can be directly translated into viral proteins following successful infection of a host cell, whereas a DNA genome requires additional steps before viral proteins can be made. Following YFV protein translation and virion assembly in the endoplasmic reticulum, the host cell’s protein processing machine, called the golgi apparatus, processes the new virions. These virions are then transported in another compartment to the cell surface, where they are released to infect more host cells. This process repeats itself until an effective immune response can mount.[4] 

Vaccination and Treatment The best treatment for yellow fever is a prophylactic one – vaccination. Mosquito bite prevention is the next closest option, if a vaccine is not available.[2] Yellow fever vaccines are produced using the 17D strain isolated in 1927, and protect against all YFV strains.[2] The solution injected during vaccination contains a live attenuated version of the YFV, meaning the strain is incapable of causing disease (usually – more on that later). Introduction of this “neutralized” virus into the body triggers the immune system to produce antibodies that specifically bind yellow fever virions (ie. viral particles) if a person is infected by the in the future. Antibody binding targets virions for destruction, and mobilizes other cells in the immune system to fend off a viral attack, protecting you from becoming sick.

All administered vaccines are produced according to established World Health Organization manufacturing standards, and are tested for adverse effects before distribution.[1] Mild elevation in virus levels occurs 3-7 days following vaccination, potentially manifesting as a low-grade fever, headache, or muscle tenderness.[1] These symptoms disappear as neutralizing antibodies develop, and do not occur with revaccination.[1] Ten days following vaccination, more than 99% of all recipients will have generated protective levels of antibody, with immunity lasting more than 10 years, although revaccination every decade is recommended.[1]

Risks of Vaccination In rare cases, the 17D vaccine can cause a disease similar to infection with the wild-type virus, an understanding only established by the public health community in the past 20 years.[1] Risk of this disease is 1 in 200,000-300,000 for the general population, but increases to 1 in 40,000-50,000 for adults over the age of 60.[1] The cause for these adverse events is unclear, as no mutations in the 17D strain have been identified in any confirmed cases.[2] However, pre-existing medical conditions that suppress the immune system are associated with increased risk.[1] The vaccine should also not be taken by any individuals with an egg allergy, as it is manufactured in chicken eggs, and has been known to cause anaphylactic reactions in individuals with an egg allergy.[2] Those with sensitivity to gelatin should also avoid the vaccine, unless the risk of infection is high.[2] Pregnant women should avoid the vaccine unless there is unavoidable risk of infection, is it may increase the risk of miscarriage, and is not as effective as stimulating antibody generation.[1] Children under 9 months should not receive the vaccine, as temporary but severe neurological inflammation as been reported in 23 infants between 1945 and 2002.[1] Children younger than 12 months should not receive the vaccines unless exposure to yellow fever is unavoidable.[1] Travellers should only take the vaccine if they are travelling to a region where yellow fever is endemic. Two previously immunocompromised travellers were reported to have suffered multi-organ system failure following yellow fever vaccination, when they were not planning to travel to an endemic region.[1]

The risk of a severe reaction to the 17D vaccine is extremely rare, and vaccination has proven essential in reducing the incidence of yellow fever across both continents. Superior surveillance has provided supportive data for the reductive impacts of mass-vaccination campaigns in South America.[2] Recently, a team of statisticians provided an estimate of the impact of recently undertaken WHO mass-vaccination campaigns across Africa, finding that these campaigns reduced YF cases by 57% in the 12 most-vulnerable countries, with a 27% reduction in cases across the entire continent.[3] Despite these encouraging results, there is serious concern within the international public health committee regarding the spread of yellow fever by air travel.[1] Regions such as India and Southeast Asia provide the ideal stage for a massive YFV epidemic, having the same ecology and social structures conducive to the virus in its endemic zone, but with a human reservoir without any existing immunity.[1] An epidemic in either of these regions could potentially deplete world YFV vaccine stocks.[1] So, while it is important for you, personally, to receive the YFV vaccine if you are travelling to the endemic zone (unvaccinated travellers have the highest rates of mortality), vaccination also ensures your responsible engagement with these nations and their people, by preventing the spread of a potentially devastating disease.  

Good luck, and happy travels! 

REFERENCES

[1] Barnett, E. D. Yellow fever: Epidemiology and prevention. Clin. Infect. Dis. 44, 850–856 (2007). [2] Monath, T. P. & Vasconcelos, P. F. C. Yellow fever. J. Clin. Virol. 64, 160–173 (2015). [3] Garske, T. et al. Yellow fever in Africa: Estimating the burden of disease and impact of mass vaccination from outbreak and serological data. PLoS Med. 11, e1001638 (2014). [4] Kaufmann, B. & Rossman, M. G. Molecular mechanisms involved in the early steps of flavivirus cell entry. Infect. Microbes 13, 1–9 (2011).