The WHO has issued a yellow fever warning over an outbreak emerging from Angola that has killed 258 people and resulted in 1,975 suspected cases since December. The global health community needs more doses of the yellow fever vaccine, both to address the current epidemic and for regular preventative vaccination programs. But stepping up production is easier said than done for the four facilities that manufacture the vaccine. Leo Visser conducts yellow fever vaccine research at the Leiden University Medical Centre. We asked him to explain the limits production facilities face and offer suggestions for alleviating the shortage.

What is the state of the yellow fever outbreak in Angola?

Leo Visser: The outbreak in Angola started in the capital city Luanda in December, and although the number of cases seem to be going down in Luanda, the outbreak has spread to 16 out of Angola's 18 provinces. The WHO is particularly concerned about the situation in Angola, because of the risk the disease will cross the country's borders and spread internationally. Several cases have already been reported in the Democratic Republic of the Congo, which borders an affected Angolan province. This is a particularly worrying situation, since the risk of the outbreak spreading to urban areas in Africa is higher than ever. Many large West-African cities are especially at risk because they have high densities of both non-immune populations and Aedes aegyptii mosquitoes.

How did there come to be a worldwide vaccine shortage?

Visser: According to a 2015 UNICEF report, the forecasted demand for the yellow fever vaccine for preventive campaigns exceeds current availability by 42 percent. The limited global production capacity can hardly meet the demand because routine immunization programs, preventive mass vaccination campaigns, and emergency response stockpiling are all becoming more prevalent. Emergency stockpiles in Angola are completely depleted, and the WHO is negotiating for shipments of vaccines for routine vaccination programs to be diverted in order to replenish these stockpiles.

How is the yellow fever vaccine made?

Visser: Currently, the yellow fever vaccine is produced by four manufacturers. The bulk production of the yellow fever strain used in vaccines (YFV-17D) depends on a sufficient supply of specific pathogen-free eggs with primary chick embryos. The seven- to nine-day-old chick embryos in these eggs are infected with the virus, it's allowed to incubate for three to four days, and then the infected embryos are harvested under aseptic conditions. A process involving homogenization and centrifugation produces a surface liquid that is then diluted, mixed with stabilizers, and preserved for use in vaccines. Each embryo can produce 100-300 vaccine doses. Because the eggs used in the process must come from special pathogen-free chicken flocks, their availability is limited, making it difficult to rapidly scale up vaccine production.

Has the price of vaccines risen significantly? How do you see that developing?

Visser: The weighted average price per dose of the yellow fever vaccine, as recorded by UNICEF, has increased by 30 percent per year on average since 2000, when a dose cost $0.20. By 2014, a single dose cost $0.98.



What can be done to prevent shortages like the current one? Do you see this outbreak impacting future approaches to vaccine production?

Visser: One possibility is to vaccinate more people with the same vaccine stockpile. Vaccination with a fractional dose (1/5 of the typical dose) has been shown to protect against yellow fever just as well. With proper investment, the production of the yellow fever could be scaled up further. This of course would help as well.

There's been increasing interest in automated vaccine production. Would that be an option for the yellow fever vaccine?

Visser: The use of cell cultures to produce a yellow fever vaccine would eliminate the need for specific pathogen-free eggs. An inactivated yellow fever vaccine, grown on Vero cells rather than in eggs, has been developed and shown to be effective in a phase-1 study. However, it hasn't yet been commercialized.

Beyond the vaccine shortage, are there other obstacles to controlling the outbreak?



Visser: As with the Zika outbreak in the Americas, the high density of the vector Aedes aegyptii in the affected area contributes to the high risk of transmission. Because of this, travelers should only be allowed to leave or enter Angola if they have been adequately immunized against yellow fever.

This interview originally appeared on ResearchGate News.