In 1793 the US capital of Philadelphia was in a state of crisis. A deadly virus gripped the city forcing the President, George Washington, and other members of his administration to flee, bringing the government to a standstill. By the time the disease had run its course, one tenth of the city’s population had lost their lives. The cause was not smallpox, plague or Spanish flu, but Yellow Fever — a tropical virus which in the 21st century is more often viewed as an exotic disease, and usually confined to Africa and parts of South America. But now that could all change.
As the largest Yellow Fever outbreak in 30 years continues to spread in and around the capital city of Luanda, Angola, and now to the Democratic Republic of Congo’s (DRC) capital, Kinshasa, there is a growing concern that we could start to see a re-emergence of urban epidemics like the one in Philadelphia. Declining efforts to control Aedes aegypti, the mosquito that usually transmits the disease, have led to its spread, prompting fears that Yellow Fever will return to regions where it was once banished, or even take hold in new parts of the world like Asia. Globalization and recent exports of cases from Angola to DRC, Kenya and China only emphasize the risk. Furthermore, the surge in demand has already placed global vaccine stocks under serious pressure, leaving us potentially even more vulnerable.
We have faced similar epidemic threats recently with Ebola and Zika, but with Yellow Fever the big difference is that a highly effective and safe vaccine already exists and has done so for more than half a century, requiring just one dose for lifetime protection. This begs the question how we ended up in this situation.
The fact that we have four manufacturers of a vaccine first produced in the 1930s and are still having to resort to the use of fractional doses — where one fifth of the normal dose will be used per person — because we don’t have an adequate supply, means that something is not working.
This gets to some of the biggest challenges we face with modern vaccine production.
For now, despite the scale of the Angola outbreak, vaccine demand is currently mostly still being met. The problem is that of roughly 90 million doses of Yellow Fever vaccine produced globally this year, nearly 13 million have already gone towards dealing with this one situation and now in August, in what is arguably one of the biggest vaccination campaigns ever, we are preparing to vaccinate a further 15.5 million people in Angola and DRC, and all in the space of just one month. That has meant diverting doses away from preventative campaigns, increasing the risk of further outbreaks elsewhere and leaving emergency stocks dangerously thin. One more significant flare up and we could be in trouble. Given the speed with which Yellow Fever can spread and given its high mortality rate, which is even higher among those from non-endemic areas, the consequences could be horrific.
Stepping up mosquito control is clearly one priority, but the increasing spread of Dengue, Zika and Chikungunya which are transmitted by the same species show how this is not working. So we also desperately need to increase vaccine production too. The trouble is we already have and it’s not enough. In Gavi/UNICEF-supported countries, demand surged from around 5 million doses a year in 2000 to 55 million today. Manufacturers have tried to keep pace, but the egg-based production of Yellow Fever vaccine is relatively slow and difficult to scale-up. As a result, today’s demand still outstrips existing supplies by around 10%.
Beyond shortfalls in production against current estimates of demand, another important driver for the inability to respond most effectively to today’s outbreak in Angola is that our risk assessment is out-of-date. Because of climate change, human and animal migration and increasing urbanization, the behavior and spread of Yellow Fever has shifted over time and may be threatening many more areas. This makes it probable that current estimates for required supply underestimate true need. The challenge now is finding ways to make up this shortfall and get ahead on production.
In such situations, the global health community normally has an effective tool to help boost global production. It can hike up prices to either stimulate investment from existing suppliers, or to try to encourage new manufacturers to enter the market. However, Yellow Fever appears to defy conventions. We already have four suppliers, making it a relatively competitive market and prices have already increased by close to 100% over the last decade-and-a-half.
Acting as a counter force, there is the rising cost of manufacturing vaccines. Compared to when the Yellow Fever vaccine was first developed at the Rockefeller Institute in the 1930s, modern manufacturing practices are more stringent, requiring a much higher level of production, quality and safety control. This is as it should be, but it comes at a cost. So the big question is what incentives do we need to put in place to encourage manufacturers to make the significant investments necessary to boost vaccine production?
While some critics argue that the price of new, state-of-the-art vaccines should be brought down to match older ones, which cost just tens of cents per dose, Yellow Fever is the chilling example that suggests the trend may need to sometimes go the other way. For older vaccines that have fairly predictable demand forecasts and established supply capacity is adequate to meet demand, it may well be feasible to continue selling them for the same price as three decades ago. But when it comes to investing for wider-scale use, where it can cost hundreds of millions of dollars to set up a new production facility, those economic-models go out the window.
The point is that we desperately need a reboot.
Our risk assessment of Yellow Fever has to be brought up-to-date and our strategies adapted accordingly. This could mean entering into discussions with manufacturers to determine what further incentives are necessary to meet demand, and that could result in anything from different price structures to multi-year demand forecasts or subsidies for new production lines. Such solutions may not sit well with everyone, but in the current market place the rules of economics clearly aren’t giving us what we need. We also need to be sure that coverage of Yellow Fever is high in countries that have it in their routine immunization programs. So, given that there is no cure or treatment for Yellow Fever, if we want to avoid a return of the kind of urban epidemics that afflicted cities two centuries ago and prevent Yellow Fever from re-establishing itself, then we need to be prepared to do what it takes to achieve vaccine security.