Yellow Fever’s Re-Emergence: Preventing The Next Pandemic

Abstract

Yellow fever kills 30,000 annually. Yet large outbreaks are entirely preventable as vaccines have been available for decades. Through complacency there is now a risk of it spreading to Asia. The WHO has a new strategy to eliminate future outbreaks.

Introduction

The scourge of yellow fever (YF) was introduced to the New World from West Africa through the slave trade and caused major outbreaks in port cities throughout the 1600-1800’s, killing hundreds of thousands. (Cdc.gov, 2019). Effective control of its main vector, the Aedes aegypti mosquito, and subsequent mass vaccination campaigns meant that yellow fever was effectively controlled by the mid-1900’s. Sadly, this recent period of optimism has come to an end. Between 2016 and 2018 there were large outbreaks in Angola/DR Congo, Nigeria and Brazil. Environmental risk is creating conditions that contribute to the spread of the Yellow Fever virus (YFV) beyond current endemic zones in tropical Africa and Latin America and the Caribbean (LAC). These include deforestation, rampant urbanisation, increased air travel, labour mobility and climate change. The risk of a YF pandemic is exacerbated by complacency in vector control, poor enforcement of International Health Regulations (IHR), waning vaccination coverage, historically low vaccine stock piles and limited production capacity (Gubler, 2018). Against this backdrop of YF’s changing epidemiology, a resurgence in abundance of mosquito vectors and the risk of intercontinental spread, the World Health Organization (WHO) in 2017 formulated a Global Strategy to eliminate Yellow Fever Epidemics (EYE) 2017-2026 (WHO, 2018). In this report we evaluate the main features of the EYE strategy.

Causative Agent and Clinical Presentation

YFV is an arbovirus, i.e. a virus transmitted by arthropod vectors, in this case female mosquitoes that requires a vertebrate blood meal for their eggs to develop. It is a single-stranded Group IV RNA virus that belongs to the genus Flavivirus which also includes dengue, Japanese encephalitis and West Nile viruses (Gardner and Ryman, 2010). Asymptomatic infection occurs in the majority of patients infected with YFV. For patients who do develop symptoms, the incubation period is 3 to 6 days. The initial illness presents with various non-specific influenza-like symptoms after which most patients recover. About 15% of patients progress to a more serious form of the disease, characterized by jaundice, haemorrhagic symptoms, and multisystem organ failure. The fatality ratio for severe cases is 20%–50% (Gardner and Ryman, 2018). There are no medications to treat YFV infections; treatment is limited to symptomatic care.

Ecology and Transmission Cycles

YF pathogen range and vector abundance are complex and not geographically uniform, as shown in Table 1. Transmission events are determined by the complexity of the vegetational zones, temperature, rainfall patterns, abundance and distribution of vectors and vertebrate hosts as well as human interaction shaped by commerce and colonization. YF is endemic and intermittently epidemic to tropical and subtropical areas of Africa (“Old World”) and LAC (“New World”) and is transmitted by infected mosquito vectors of various genera.

The YFV Has Three Distinct Transmission Cycles:

The sylvatic cycle involves transmission between NHP’s and wild mosquitoes found in the jungle canopy. Humans, like loggers or miners, are infected sporadically through mosquito bites when encroaching into the jungle. This the typical outbreak pattern in LAC but it also occurs in Africa. During the unusually large 2016/18 outbreaks in Brazil, YFV broke out of its usual pattern and encircled the country’s largest cities, highlighting the increasing proximity between the urban and wild environments. (Possas et al., 2018). Wild mosquitoes that are infected for life and can transmit vertically serve as the reservoirs for the YFV while NHP’s function as amplifying hosts. The intermediate cycle occurs only in the African savannah and involves humans who live or work in areas surrounding the jungle. Transmission takes place between NHP and human or human to human via semi-domestic mosquito vectors. This can cause small epidemics in villages. This is a common type of outbreak in Africa. The urban cycle involves infected humans who contracted the virus in either the jungle or intermediate cycle and then “spillover” YFV into urban areas. They infect domestic Aedes aegypti mosquitoes, which can then transmit the virus to other humans in urban areas. After Aedes aegypti control campaigns were stopped in the 1960’s, the species has re-infested cities across Africa and LAC. High vector concentration and abundance in urban areas can quickly cause explosive epidemics as YFV is introduced into dense unvaccinated populations (Gardner and Ryman, 2010). Urban YF occurs periodically in Africa and sporadically in LAC and is the most likely launching pad for exporting the virus.

Extending Pathogen Range: Coming to A Place Near You

Since the last outbreak in the USA in 1905 (Cdc.gov, 2019), YFV has infected humans and NHP’s within a relatively static geographical range confined to the tropical regions of Africa and LAC. Recent outbreaks through sylvatic transmission in Brazil have tested the limits of this range. Other trends may expand these limits further: Tiger mosquito: new research has demonstrated that YFV can be transmitted, at least under laboratory conditions, via tiger mosquitoes, Aedes albopictus (Amraoui et al., 2018). This is an opportunistic species that, unlike Aedes aegypti, can colonise forests as well as rural and urban areas and can also survive in cool climates. Aedes albopictus emerged in Brazil in 1986 where it could serve as a link between the sylvatic cycle and future urban cycles of yellow fever. Aedes albopictus is a competent vector for a range of arboviruses, including dengue, chikungunya and Zika (Ryan et al., 2019). Having originated in SE-Asia, it has been reported as far North as the UK (Metelmann et al., 2019).

Asian expansion: Eleven cases of YF imported into China from Angola in 2016 did not result in secondary cases but set off fears that it might gain a foothold in the Asia-Pacific region, where 2 billion people without immunity could be at risk. The restriction of YF to Africa and LAC is not well understood (Wasserman, Tambyah and Lim, 2016). The related Flavivirus dengue occurs across Asia, but the two diseases do not co-occur, despite an abundance of people, NHP’s and the vectors Aedes albopictus and Aedes aegypti. Several hypotheses have sought to explain the failure of YF to become established in Asia, none of them conclusively (Wasserman, Tambyah and Lim, 2016). Just because it hasn’t happened yet doesn’t mean that it won’t. An YF epidemic in a region without any prior exposure and immunity remains an alarming possibility.

Climate change: A recent study used modelling to estimate how the geographical range of the vectors Aedes albopictus and Aedes aegypti is likely to change under various scenarios of climate change (Ryan et al., 2019). The results show that, under the most extreme scenario of climate change, one billion additional people, mostly in Europe, North America and Northern Asia could become exposed to Aedes-borne diseases like YF by 2080.

The EYE Strategy

The persistence of sylvatic pathogen reservoirs in jungles across two continents means that YF can never be eradicated as natural breeding sites are inaccessible for vector control. The WHO has therefore sensibly concentrated its efforts on prevention of urban epidemics and has formulated a number of primary and secondary prevention strategies to eliminate YF epidemics by 2026 (WHO, 2018):

• Primary: Prevent news cases of infection by:
• Routine childhood vaccination to reach long-term population immunity.
• Preventative and “catch up” campaigns in high risk areas (based on revised risk classifications), needcase through fractional dosing.
• Maintaining a stockpile for reactive campaigns.
• A renewed emphasis on vector surveillance and control in cities.
• Secondary: detect new cases and reduce risk of spreading internationally by:
• Improving early detection of outbreaks by investing in additional surveillance and diagnostic laboratory capacity.
• Stricter traveler compliance to IHR by implementing a unique registration system.
• Support for outbreak preparedness in the most at-risk countries.

For a disease that kills 30,000 per year (WHO, 2010) with potential to expose billions more, any interventions would surely be considered cost effective. However, endemic regions are resource-poor and cost effectiveness is a key consideration for any successful intervention. Perhaps for this reason, the WHO has prioritized resources on low-cost vaccination and vector control campaigns, rather than on higher-cost strategies involving anti-viral drug development. Designing anti-viral drugs is challenging as treatment would need to be inexpensive, safe and have efficacy when administered at the onset of symptoms to reduce further transmission. Several compounds have been identified for further research (Julander, 2013). Previous WHO campaigns like the “Yellow Fever Initiative” (WHO, 2010) failed to reach objectives. For EYE to succeed where earlier initiatives have failed, the following concerns should be addressed:

1. Endemic countries often lack the most basic health care delivery systems. However, outbreak management relies on rapid diagnosis to kick-off mitigation. Unless logistical challenges are tackled and basic health care infrastructure is built, massive under-reporting will continue. This require a heavy investment.
2. A lack of appreciation of the full impact of YF, resulting in insufficient political commitment to YF control by Governments of endemic countries and a lack of robust governance all conspire to undermine the EYE objectives.
3. Vaccine availability is a limiting factor in the prevention and control of swiftly moving outbreaks. WHO-preapproved vaccines are produced by only four companies. Rapid increases in vaccine production are not possible with existing production techniques. The stockpiles will not cope with large, successive outbreaks.
4. Vector control is limited by emerging vector resistance to common insecticides and by environmental restrictions on their widespread application.

Conclusion

Eradication of YF is not feasible. However, outbreak prevention is multifaceted but achievable, primarily because of the availability of a low cost, effective vaccine. WHO’s EYE strategy calls on endemic countries to improve IHR compliance, improve surveillance by building laboratory capacity and develop more effective urban vector control. EYE also recommends that childhood immunization programmes are expanded to include YF vaccination. However, such expansion will not be possible until the vaccine shortage is solved. Given the political, logistical, technical and financial challenges associated with implementing EYE, additional funding should be made available to develop YF antiviral therapies. Preventing the next pandemic is a global issue that requires commitment and investment, not just from resource-poor endemic countries but from the global community.