Yellow Fever Vaccine study reveals link between immunity and cells' starvation response

One of the most effective vaccines in history has been the yellow fever vaccine, which was developed in the 1930s and has been administered to more than 500 million people.

Scientists at Emory Vaccine Center studying immune responses to the yellow fever vaccine have identified a gene whose activation in key immune cells is a sign of a robust response. The gene, called GCN2, encodes a protein involved in sensing amino acid starvation and regulates the process of autophagy, a response to starvation or stress within cells.

The findings highlight a link between antiviral defenses and an ancient way that cells adapt to scarcity, and could help researchers develop vaccines against challenging viruses such as HIV or dengue. The results suggest that vaccine additives (called adjuvants) that are effective in stimulating GCN2 and autophagy would be especially potent in stimulating long-lasting immunity.

The results are scheduled for publication Thursday by the journal Science.

"This is an example of taking a system-wide approach to studying vaccine responses, and how it can reveal new insights about the functioning of the immune system," says senior author Bali Pulendran, PhD. "We were not thinking about the stress response pathway and immunity until our analysis pointed us in that direction."

Pulendran is Charles Howard Candler professor of pathology and laboratory medicine at Emory University School of Medicine and a researcher at Yerkes National Primate Research Center. The co-first authors of the paper are postdoctoral fellows Ravesh Ravindran, PhD and Noor Khan, PhD.

A single dose of the live attenuated viral yellow fever vaccine can protect against disease-causing forms of the virus for decades. Investigators led by Pulendran have been dissecting immune responses to the yellow fever vaccine, taking a genome-wide "systems biology" approach.

They started by looking at all the genes that are turned on a few days after human volunteers were vaccinated against yellow fever and asked: which genes' activations are the signatures of especially strong immune responses later? In particular, Pulendran and his colleagues looked for responses by CD8 "killer" T cells, which are important for eliminating virally-infected cells from the body.

One gene that stuck out was GCN2, because it was induced quickly after vaccination and was a sign that the immune system would later respond with lots of CD8 T cells.

GCN2 was known to be a sensor inside cells that detects low levels of amino acids, the building blocks for proteins. GCN2 regulates the process of autophagy, in which cells respond to starvation or stress by ceasing growth and beginning to digest themselves.

In the Science paper, Pulendran and his colleagues show that GCN2's function is especially critical in dendritic cells, whose job is to "present" information about viruses and other pathogens to the rest of the immune system. Dendritic cells lacking GCN2 are less able to activate CD8 T cells, they found.

Mice that lacked GCN2 had impaired responses to yellow fever vaccine and to inhaled influenza vaccine, the researchers found.

They also found that infection with yellow fever leads to a depletion of amino acids within dendritic cells. When viruses infect dendritic cells, it appears that the viruses start using up the building materials on hand. This tips the dendritic cells into autophagy and raising an alarm with the rest of the immune system, Pulendran says.

"This may have evolved as a mechanism of pathogen sensing that is capable of detecting the footprints of a pathogen, such as depleted amino acids in a local microenvironment," he says.

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Could Yellow Fever Return to the United States?

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In the summer-fall of 1878 an epidemic of yellow fever destroyed the city of Memphis, Tennessee.  Likely introduced into the Caribbean by trade from the West Coast of Africa and later brought up the Mississippi River by a steamer ship (the Emily B. Souder) with sick and dying sailors, yellow fever killed an estimated 5,000 Memphis residents, almost one-third of its population who did not flee the city that August [1].   According to Molly Caldwell Crosby in her detailed account, the summer-fall 1878 yellow fever epidemic in the Mississippi Valley was possibly “the worst urban disaster in American history” [1].

Among the factors responsible for the 1878 tragedy were an unusually warm winter and spring that year, which helped Aedes aegypti mosquitoes  to flourish in the Mississippi Valley, together with a lack of adequate urban drainage and a functioning sewer system, and a susceptible (non-immunized) population – the yellow fever vaccine would not be developed for another 50 years.

Today, the world’s yellow fever-endemic areas are restricted to Sub-Saharan Africa (figure image) and tropical regions of South America, but there are a few red flags suggesting the possibility that the “yellow jack” (a historical term used to once describe yellow fever) could return to the US.  The Ae. aegypti mosquitocan now be found in many areas of the southern United States.  This is an area where US poverty rates are at their highest, along with its fellow travelers poor urban housing and neglected foci of standing water.  The area has also experienced unusually warm winters and springs over the past few years.  Indeed, dengue fever, another arbovirus infection transmitted by Ae. aegyptimosquitoes, was recently shown to have emerged in Houston, Texas in 2003.  Although Max Theiler received the Nobel Prize for developing the yellow fever vaccine in 1951, vaccination rates in the US are practically non-existent except among travelers to endemic areas.

There are several examples of US vulnerability to yellow fever, including our home city of Houston, which has recently emerged as a true gateway city and globalization hub. For instance, today, Houston hosts the world’s largest number of Nigerians expats (who provide important and skilled expertise for our city’s oil and energy industry), and there are direct flights to and from Lagos, the largest Nigerian city.  A recent study from the Division of Global Migration and Quarantine of the CDC (Centers for Disease Control and Prevention) found thatUS travelers to Nigeria are especially likely to decline vaccination, despite the fact that its urban areas are at especially high risk for yellow fever outbreaks. The culmination of travelers returning to Houston from endemic areas, subtropical climate, high prevalence of Ae. aegypti mosquitoes, and areas of dense housing overlapped with poverty place Houston at risk for yellow fever emergence.

We need to seriously evaluate the risks of the major southern cities of the US, including Houston, but also New Orleans, Tampa, and Miami for their vulnerability to Aedes-transmitted arbovirus infections, such as yellow fever. As we have pointed out, cities such as Houston have emerged as important endemic zones for neglected tropical diseases. While we are aware that US urban areas may not be as vulnerable to yellow fever as Memphis was more than a century ago, there is still an important risk that needs to be considered as part of our national emergency preparedness, particularly in light of an emerging dengue problem (i.e., another Ae. Aegypti mosquito transmitted virus infection) in Houston and other southern coastal US areas.

Sudan Reports Widespread Yellow Fever Outbreak, 14 Dead

December 4, 2013

Sudan’s Federal Ministry of Health (FMOH) has notified the World Health Organization (WHO) of an outbreak ofyellow fever that is affecting 12 localities in West and South Kordofan states.

A total of 44 suspected cases and 14 deaths have been reported from October 3 to November 24, 2013 in the localities of Lagawa, Kailak, Muglad and Abyei in West Kordofan and Elreef Alshargi, Abu Gibaiha, Ghadir, Habila, Kadugli, Altadamon, Talodi and Aliri in South Kordofan.

Field investigations carried out by the FMOH revealed that the initial suspected cases were reported among seasonal workers coming from the eastern states of Sudan who had traveled to West Kordofan for work in October. Subsequent cases were reported among locals in both West and South Kordofan states, following the arrival of the workers.

Blood samples that were collected during the field investigation tested positive for Yellow Fever by IgM ELISA Assay at the National Public Health Laboratory of the FMOH in Khartoum. The samples were retested at theInstitute of Pasteur in Senegal and were confirmed to be that of Yellow Fever. Subsequent seroneutralizing (PRNT) testing by WHO researchers also confirmed presence of yellow fever.

The field investigation also found evidence of Aedes aegepty mosquitoes in the areas where the infected persons were found. A. aegepty is one vector that can sustain transmission of yellow fever.

WHO is assisting the FMOH to strengthen surveillance efforts and to conduct active case searches in and around the region. So far no suspected cases have been reported from any of the areas outside of where the initial outbreak occurred. The FMOH is now organizing a massive vaccination program against yellow fever in the affected areas to prevent further infection.

According to a WHO report, it is estimated that yellow fever infects between 840,000 and 1.7 million people in Africa each year, resulting in about 29,000 to 60,000 deaths.

An outbreak last year in the Darfur region of Sudan resulted in 849 suspected cases and 171 deaths. Around five million people were vaccinated against yellow fever in the five states of Darfur following the outbreak. In 2005, a yellow fever outbreak was also reported from the South Kordofan state, resulting in 615 suspected cases and 183 deaths. A vaccination campaign followed targeting about 1.6 million people in the region.

Yellow fever, also known as Yellow Jack, is an acute viral hemorrhagic virus that affects 20 percent of an area’s population where it is commonly found. Most cases only cause a mild infection with fever, headache, chills, back pain, loss of appetite, nausea and vomiting. In these cases, the infection generally lasts three or four days.

In about 15 percent of cases, sufferers can enter a toxic phase of the disease with recurring fever accompanied by jaundice due to liver damage and abdominal pain. Bleeding in the mouth, eyes and gastrointestinal tract is also common at this stage and vomit may contain blood. This toxic phase is lethal in about 20 percent of cases, making the overall mortality rate for the disease about three percent. In severe epidemic outbreaks, mortality may rise to 50 percent or more.

For those who survive their infection, they usually do so without any organ damage and they are provided with a lifelong immunity to the virus.

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