by Fernanda Ferreira
figures by Daniel Utter

There are tens of thousands of buildings in São Paulo, the largest city in the Western hemisphere and Brazil’s financial center. From the sky, São Paulo looks like a fossilized forest of concrete trees. From the ground, it’s a pulsing behemoth, every avenue crammed with cars and people. The urban sprawl of Metropolitan São Paulo engulfs 39 municipalities and 21.4 million people: imagine the ramifications of a disease epidemic striking in a city of this size. With yellow fever circling São Paulo, these imagined ramifications have taken on a tangible veneer, and the fight to keep yellow fever out of Brazil’s large urban centers illustrates the importance of global vaccine stockpiles in preventing epidemics from taking hold.

Yellow fever in Brazil

Yellow fever disease is a viral hemorrhagic fever named after the jaundice (yellowing of the skin and eyes) that occurs in some of those infected. The disease is caused by the yellow fever virus, which is closely related to Dengue and Zika, and it is also transmitted by mosquitoes.

Brazil is not a novice when it comes to yellow fever. The first reported cases of yellow fever occurred in 1685, and the virus spread to most of the country in the mid 1800s. Mass vaccination and mosquito eradication efforts in the 1930s and 40s eliminated urban transmission of the virus and kept it out of most of the country’s coast, where large urban centers are located.

The December 2016 yellow fever outbreak in Brazil changed this pattern, with the disease re-emerging in parts of the country that do not conduct routine vaccination as shown in the map below. Yellow fever moved east and south, inching towards large coastal metropolitan areas including São Paulo and Rio de Janeiro, the two largest cities in Brazil.

Figure 1: Map showing the yellow fever distribution and areas of risk in Brazil, as of January 16th, 2018. Before December 2016, coastal areas in the southeast region of Brazil, extending from the states of São Paulo to Espirito Santo, were not considered at risk for yellow fever transmission. Since the outbreak, however, that has changed and yellow fever vaccination is now universally recommended in Brazil. Map created by the European Centre for Disease Prevention and Control (ECDC).

To stop the spread, Brazil increased its production of yellow fever vaccines and, in early 2017, also requested and received 3.5 million doses of the vaccine from the International Coordinating Group (ICG), which manages the global emergency stockpile of yellow fever vaccines.

An emergency vaccine stockpile is a supply of vaccines that are held by governments or international health organizations for use when an outbreak occurs or issues in vaccine manufacturing arise. Stockpiles like the one managed by the ICG, as well as national stockpiles, play an essential role in preventing outbreaks from spreading.

What is the ICG?

The ICG was established in 1997 to assist in the containment of outbreaks of bacterial meningitis, a vaccine-preventable inflammation of the brain and spinal cord. The ICG’s main role is to provide emergency vaccines to countries experiencing epidemics of meningitis, yellow fever (since 2001), and cholera (since 2013), though the organization also provides syringes, medication, and support in the design and planning of vaccination campaigns.

The ICG’s focus on emergency outbreak situations is intentional. “The ICG exists to make sure life-saving vaccines will not disappear during an outbreak,” says Dr. William Perea, the World Health Organization’s (WHO) Coordinator for Control of Epidemics and Mass Interventions. During disease outbreaks, there is often a rush for vaccines, and richer countries often get access to them more quickly. According to Dr. Perea, the ICG makes sure that even countries without financial funds or contact with the vaccine manufacturers get access to the vaccines in times of need.

In order to provide countries with this essential emergency service, the ICG is made up of four member agencies: the International Federation of Red Cross & Red Crescent Societies (IFRC); Medecíns sans Frontières (MSF); the United Nations Children’s Fund (UNICEF); and the WHO. The ICG also works closely with vaccine manufacturers: after vaccines are deployed from the stockpiles, UNICEF and WHO request that manufacturers increase vaccine production so that stockpiles can be replenished.

How does ICG decide who receives vaccines?

The ICG states that “vaccine security stocks can be accessed by ANY country facing an epidemic ANYWHERE in the world, as long as the country’s request fulfills the ICG’s criteria for release of vaccine stocks” (capitalization by WHO for emphasis). In the case of yellow fever, for instance, the ICG’s criteria consists of five conditions:

  1. At least one laboratory-confirmed case of yellow fever
  2. Analysis of the epidemic risk, demonstrating that cases are part of an outbreak with person-to-person transmission and not just an isolated case of sylvatic transmission (animal-to-human)
  3. A vaccination campaign plan
  4. Approval by the country’s national epidemic coordination body to ensure cooperation between various national agencies during the campaign
  5. Experience in conducting mass vaccination campaigns

Once a country suffering an epidemic has fulfilled all of the ICG’s conditions and the request has been fulfilled, vaccines arrive within 10 days. A breakdown of all the steps between confirmed case and vaccine arrival is shown below.

Figure 2: Framework for the ICG’s decision process for release of emergency vaccine stockpiles. After a country has at least one confirmed case of yellow fever, cholera, or bacterial meningitis, the country’s health ministry contacts the WHO and requests vaccine stocks. The ICG circulates the request among the four member organizations (IFRC, MSF, UNICEF and WHO) and together they approve the request within 48 hours. Once the request is approved, UNICEF delivers the vaccines within seven days. You can see what ICG’s request form looks like here.

Beyond the ICG vaccine stockpile

While the ICG manages the three large global stockpiles of vaccines for meningitis, cholera, and yellow fever and focuses its efforts on emergency situations, many countries have their own stockpiles. Furthermore, the WHO maintains a number of other vaccine stockpiles with different focuses and partners, such as a smallpox vaccine stockpile of 35 million doses in the case of an outbreak or bioterrorist attack.

National stockpiles are often established so that problems in the vaccine supply chain don’t lead to public health issues. For example, following vaccine shortages, the United States established a pediatric vaccine stockpile in 1983 to address supply shortages in vaccine production caused by high demand or manufacturing issues. The current stockpile is large enough to guarantee six months of access to vaccines recommended for routine pediatric immunization, which includes essential vaccines that protect against measles-mumps-rubella (MMR), poliovirus, and pertussis.

Developing a vaccine stockpile

As establishing a vaccine stockpile seems like a no-brainer from a public health perspective, it may come as a surprise that there are only four global stockpiles: the bacterial meningitis, cholera, and yellow fever vaccine stockpiles managed by the ICG, and the smallpox vaccine stockpile controlled by the WHO.

There are a number of factors that need to be weighed before a vaccine stockpile is established, ranging from disease and vaccine characteristics to funding and manufacturing, and not all vaccines are good candidates for a global stockpile. Though 290,000 to 650,000 people die annually from respiratory diseases linked to the flu, influenza virus varies too much from season to season for a vaccine stockpile to prove useful. Almost every year a new vaccine has to be developed to protect against the virus that is circulating that season, so establishing a stockpile that protects against last year’s flu would not be useful. In May 2007, a global vaccine stockpile  against the highly pathogenic H5N1 avian flu virus was actually recommended by the WHO. Six years later, however, WHO experts agreed to not establish such a stockpile given the potential for a lack of match between the stockpile vaccines and the circulating H5N1 virus.

On the other hand, yellow fever is a great candidate for a vaccine stockpile: the vaccine is highly effective, vaccination provides lifelong protection after even a single dose, and there is only one circulating form of yellow fever. Furthermore, given the long manufacturing time for the yellow fever vaccine (around 12 months) and essential production steps that make rapidly scaling up production difficult, a global emergency stockpile of the vaccine is imperative from a public health standpoint.

Vaccine stockpiles must also be flexible, able to adapt to current realities. The Ebola epidemic of 2014 and 2015, took over 11,000 lives and many experts agree that another outbreak is inevitable. A vaccine, even a yet unlicensed vaccine, would be a mighty ally in the fight to staunch a future Ebola outbreak. In early 2016, the WHO and the Global Alliance for Vaccines and Immunization (Gavi), announced the establishment of an Ebola vaccine stockpile.  In the agreement between Gavi and Merck (the vaccine’s manufacturer), Merck promised to  stockpile 300,000 doses of the unlicensed vaccine in case of an outbreak. On its end, Gavi pledged to buy five million dollars of the Ebola vaccine once it is licensed. This is the first time a stockpile of an unlicensed vaccine has been established, but it’s necessary in case an Ebola outbreak occurs while the Ebola vaccine goes through the licensing process.

Disease Never Sleeps

Between its ramped up production of yellow fever vaccine and the 3.5 million doses it received from the ICG, Brazil managed to end the yellow fever epidemic, keep the virus out of its urban centers, and, in September 2017, the Brazilian Ministry of Health declared that the yellow fever outbreak that had begun in December 2016 was over. A little over a month later, the death of five monkeys, which can also be infected by the virus, in the state of São Paulo signaled that the country was about to enter a new yellow fever cycle. Since then, yellow fever has caused 237 deaths and Brazil has started a new vaccination campaign, with a target of 23.8 million people vaccinated. Brazil has not requested more yellow fever vaccines from ICG’s global emergency stockpile since 2017, but as the ICG says, the stockpile is there for “any country facing an epidemic anywhere in the world,” and that is a necessary assurance as Brazil fights to keep yellow fever out of its large urban centers.

Fernanda Ferreira is a PhD student in the Virology program at Harvard University.

For more information:

To learn more about yellow fever, check out Apurva Govande’s piece from last year.

Cover image

Components of a smallpox vaccination kit including the diluent, a vial of Dryvax® smallpox vaccine, and a bifurcated needle. Credit: James Gathany Content Providers(s): CDC – This media comes from the Centers for Disease Control and Prevention‘s Public Health Image Library (PHIL), with identification number #2674.

 

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