Infectious Disease 2: Yellow Fever

Yellow Fever is caused by

a virus in the family Flaviviridae

What does the virus look like?

* enveloped, spherical, \~50nm in diameter
* \*mature virion contains two virus-encoded membrane proteins (immune sys can recognize)
* genome is one ‘piece’ of single-stranded RNA, 10-11 kb in size
* host proteases cut the RNA-encoded polypeptide into 3 structural proteins and seven nonstructural proteins

How does yellow fever virus replicate?

multistep process that uses host machinery in order to be successful

What are the steps to replication of the virus?

* initial steps - attachment, fusion to endososome, and uncoating into cytoplasm (orange enters cell, orange peel comes off)
* polypeptide syth occurs at ER men and immature visions localize to the ER
* processing in Golgi → culminates in mature visions being releasded into the extracellular envir

which of these steps are vulnerable to therapeutic intervention?

what is the yellow fever virus pathogenesis (dev of disease)?

* inhibits type 1 interferon-mediated response which is impt for antiviral immunity
* YFV infection → cytokine dysreg and lymphopenia in spleen, lymph nodes, tonsils, Peyer’s patches
* endothelial damage
* intravascular coagulation
* prolonged clotting times
* shock

signs and symptoms of YF

\*most ppl do not exp symptomatic disease

symptomatic disease includes:

* sudden onset of fever and chills
* severer headache and body aches
* nausea
* vomiting
* fatigue and weakness

small fraction of ppl progress to more severe symptoms

sever symptoms of YFV

* high fever
* yellow skin (jaundice - hence, yellow fever)
* shock
* bleeding
* organ failure

treatment options for YFV?

\*there is no approved therapeutics for yellow fever virus infection

* supportive care to maintain electrolyte \[\]s , hydration, and bp
* avoid meds that may lead to bleeding (ex: aspirin, ibuprofen, others)
* anti-convulsive drugs and proton pump inhibitors to reduce gastric bleeding
* Galidesivir and Sofosbuvir nucleoside analogs been used as antivirals in hep C
* have been used as promising treatments
* req intravenous admin
* monoclonal antibodies are in trials

Where did YFV originate and how did it spread to the Americas?

originated in Africa, spread into the Americas w/slave trade

YF epidemics in the Americas

* brought to Americas w enslaved ppl after first Europeans arrived
* early outbreaks are likely to have happened in 1647 on sugar cane and logging industry islands where Europeans used enslaved ppl
* ‘Africans were immune to YF’ was misinfo used to promote slavery
* ppl of all backgrounds and heritages suffered from YF
* Mayans referred to YF as ‘blood vomit’, others as ‘American Plague’\*
* first use of term ‘yellow fever’ was in 1744

NAmerica and its sig YF outbreaks are?

* YF epidemics have occurred t/o the ECoast
* \*outbreak in Philly (5,000+ deaths) in 1793 contributed to the decision to move the US capital to D.C.
* in 1878, the ‘great epidemic’ led to 16,000-20,000 deaths along the Mississippi River
* Between 1693-1905, 100,000+ deaths in the US were attributed to YF

Who found that mosquitoes vectored YF?

Carlos Juan Finlay

* t/o much of its history, YF was thought to be transmitted b/w ppl by contact or t/miasmas
* tissue studies of YF victims, Finlay noted YF must be ‘deposited w/n vessels’ and that mosquitoes were well suited to do this
* exposed 20 human volunteers to A. aegypti , and some of them dev YF symptoms → suggesting link
* 1881 - presented paper, was ridiculed
* 1901 - US Army physician confirmed Finlay’s findings that Aedes mosquitoes vectored YF (credited Finlay)
* premier military hospital is named after Walter Reed for this!

What is the vector of YF?

the mosquito - aedes aegypti

aedes aegypti backstory

* can vector several flaviviruses including YFV, Zika, and dengue
* also non-flaviviruses
* originally from Africa, thought to be brought to Americas in water barrels

What are the three forms of aedes aegypti?

* sylvan - breeds in treeholes
* peri-domestic - lives in disturbed natural environments (ex: farms, plantations)
* domestic form lives and breeds in urban areas

YFV cycles between ______?

cycles b/w sylvan and urban cycles

* in most cases, YFV persists in NHPs that are infected by ‘local’ mosquitoes
* YFV epidemics occur when a human becomes involved in the sylvatic cycle and this can start an urban cycle
* A. aegypti is the primary vectors in the urban cycle

why is the A. aegypti’s life history important?

bc it contributes to the vectors competence

A. aegypti life history

* females live 2 weeks-1 month
* take mult blood meals → mult opps to take up virus-infected blood or transmit the virus!
* YFV can be passed on t/eggs
* females can lay upto 5 batches
* each batch = 100-200 eggs
* eggs laid singly in damp areas
* can survive desiccation
* hatch whenever water is available
* rapid larval and pupal dev can occur in containers and temp pools
* mult generations per year

what was YFs impact on the Panama Canal?

* YF-rel deaths were a maj obstacle for construction of the Panama Canala
* over 22,000 workers died, French gave up
* Col William Gorgas was tapped by Teddy Roosevelt to control mosquitoes
* Gorgas implemented prgs draining swamps and cisterns, put oil in standing water to kill mosquitoes, fumigated areas where mosquitoes rested, and added screens to reduce mosquitoes bites
* by 1905, there was no more deaths in the Panama Canal construction area

is A. aegypti still present?

A. aegypti (or a v similar species is present t/o much go the world)

What is vector control and is it impt?

yes, vector control is critical in YF prevention and mitigation

* eliminate A. aegypti breeding sites → remember, larval and pupal mosquitoes live in standing water
* minimize places for vectors to ‘hide out’ during the day
* bed nets to min mosquito bites at night
* Insect repellents containing DEET to prevent bites
* appropriate use of pesticides and mosquito larvicides

What else is impt for YF prevention and mitigation?

* vector control is critical
* surveillance and epidemics preparedness is important (PH matters!)
* prevent currently- or previously-symptomatic ppl from being bitten by mosquitos (prevent intro of YFV into the local mosquito pop in a non-endemic area)
* vaccination efforts are critical - need to reach herd immunity levels of vaccination other than NHPs and mosquitoes, there isn’t an envir reservoir of YFV
* limit intro or reintro of YFV into areas w competent vectors or sylvatic hosts
* hence, the rational behind vaccine passports

Is YF still a concern?

YF is a sig PH prob in endemic regions and an ongoing threat to non-endemic regions

* 90% of deaths in Africa
* 20%-50% of infected ppl who dev severe disease die
* ppl infected w YF are infectious to mosquitoes until onset of fever and up to 5 days after
* outbreaks of YF, which often occur when disease is introduced to densely pop urban areas, can have disruptive effects on Econs and health care systems
* bc of poor diagnostics, delays in symtom dev, and access to rapid routes of travel, transport of YFV by infected ppl to non=endemic regions is a concern
* climate change is expanding range of vector A. aegypti

vaccination???

live attenuated vaccine (LAV) - passaged t/embryonated chicken eggs, originally dev in 1938

* one dose and is safe, highly effective, and affordable (impt!)
* 95% of vaccines are seropositive (producing antibodies vs YFV) within 30 days of vaccination
* bc it is a LAV, admin to immunosuppressed indivs is a concern, but HIV+ indivs on ART mount protective immune responses
* formerly, boosters were req , not anymore

What’re vaccine passports

req YFV vaccination to enter a country (usually YFV-endemic country)

what does distb of A. aegypti have w risk

the distb of A. aegypti puts much of the world at risk of becoming endemic for YF

What is WHO’s E.Y.E strategy?

* EYE - eliminate YF epidemics
* eliminate and eradicate YFV
* built on 3 objs
* protect at-risk pops: no epidemic
* prevent int spread: no exportation
* contain outbreaks rapidly: no sustained transmission
* long-term strategy leveraging local and int groups

summary - YF

* YF is caused by a virus in the family Flavivirdae and is transmitted by mosquitoes
* endemic to Africa, S and Central America = YF maintained t/sylan and urban cycles
* most YFV = asymptomatic but YFV can cause epidemics of hemorrhagic disease that caused many (!) hundreds of thousands of deaths in the Americas
* YFV has had a sig info on US history, and historic dev in the Americas
* safe, highly effective, and affordable vaccine for YFV is available
* combo of vector control, herb immunity level vaccination, and PH measures have critical roles in preventing YFV epidemics