After recently writing an article titled "History of Yellow Fever in the United States," I spoke with Dr. Derick Kimathi, a clinical researcher at the Kenya Medical Research Institute-Wellcome Trust Research Programme (KEMRI-Wellcome Trust) who is investigating the safety and efficacy of using smaller doses of yellow fever vaccine to induce similar immunologic protection as standard doses (also known as fractional dosing). There is a limited global supply of yellow fever vaccine, as only a handful of manufacturers produce it, making the availability of vaccine during outbreaks a major challenge. Recent yellow fever outbreaks have pushed the World Health Organization (WHO) to consider fractional doses to increase vaccine access and lower the potential of yellow fever to spread.

An Epidemic Comes to Angola

To understand the significance of the yellow fever outbreak that started in Angola in Dec. 2015, one must first understand the capital city of Luanda. An industrial center with a bustling seaport, Luanda is Angola's largest city, with over 2 million people. While yellow fever is endemic in tropical and subtropical areas of Africa and South America, the virus had not significantly impacted Luanda since the last major outbreak in 1971. On Dec. 5, 2015, that changed.

The first suspected cases of yellow fever were reported in individuals visiting Luanda from Eritrea. In a little over a month, 23 additional cases of yellow fever were reported among Eritrean and Congolese citizens living in Luanda, 7 of whom died from their illness. By 2016, Angola reported more than 4,000 suspected infections (884 confirmed) and 376 suspected deaths (121 confirmed) from yellow fever. Additionally, the disease spread into the bordering country of the Democratic Republic of Congo (DRC), where nearly 3,000 suspected cases (81 confirmed) and 16 deaths were reported.

The spread of yellow fever through large cities like Luanda and Kinshasa demonstrates precisely why the urban spread of yellow fever is so frightening. Once the virus is imported into a metropolis that harbors the Aedes aegypti mosquito, it is a recipe for disaster. One (or several) mosquitoes can feed off a viremic individual, spreading the virus to one (or several) susceptible individuals with their next bite. Areas with greater population densities and higher numbers of man-made habitats where mosquitoes can lay their eggs increase the risk of yellow fever transmission in the urban setting. Due to the amount of international travel in and out of Luanda, WHO deemed the outbreak in Angola of global concern in April 2016. It was estimated that given the widespread distribution of the Aedes aegypti mosquito to every continent, nearly 3 billion people were at risk of acquiring yellow fever infection.

The Excellent but Unavailable Yellow Fever Vaccine

There is no specific treatment for yellow fever, but there is a vaccine that is highly effective and offers lifelong protection after just one dose. While this may seem like a simple and obvious solution for outbreaks like the one in Angola, there is a significant challenge: a yellow fever vaccine shortage. The shortage was so severe during the 2015-2017 outbreak that the allotted global stockpile of yellow fever vaccine (6 million doses) was depleted numerous times. Various factors contribute to the limited availability of the vaccine, but the most significant one is the time it takes to produce. Yellow fever vaccine is still produced by the original methods used by Dr. Max Theiler and his team when they developed the vaccine in the 1930s—growing the virus in eggs repeatedly until a viral load is reached that is considered acceptable for administration. This is a slow, tedious process yielding 100-300 doses per egg, and there are only 4 major yellow fever vaccine manufacturers in the world.

Interestingly, while WHO recommends a potency of 1,000 International Units (IUs) for a full dose of yellow fever vaccine, the actual potency is variable and ranges from about 13,000 to nearly 44,000 IUs per dose. In part, this is to ensure that the minimum potency is met after extended periods on the shelf or in transport. During the 2016 outbreak in Africa, when the yellow fever vaccine was in extremely short supply, WHO saw an opportunity to stretch doses further. Data from a study of 900 healthy men in the military in Brazil demonstrated immunity after fractional dosing was used to immunize them. This study, which involved the use of a series of de-escalating doses that ranged from 27,476 IUs to 31 IUs, led WHO to approve fractional doses of yellow fever vaccine in the summer of 2016.

Studying Fractional Dosing During a Yellow Fever Epidemic

As yellow fever moved into the DRC, the country urgently needed a massive vaccination campaign. Initially, the DRC government planned on executing a campaign to vaccinate over 7 million people in 10 days, but the dwindling global supply of vaccines could not support that goal. Based on a review of data from previous fractional dosing studies, the DRC and WHO opted to administer yellow fever vaccines at 1/5 the dose regularly administered. This vaccine strategy had yet to be used in a real-world setting. This strategy also posed ample opportunity to study the efficacy of fractional dosing of yellow fever vaccine in various participants, not just healthy males.

The study of immunogenicity from fractional doses of yellow fever vaccine was led by Dr. Rebecca Casey and enrolled 764 participants older than 2 years of age and who were not pregnant. Protective immunity against the yellow fever virus (a neutralizing antibody titer of >1:10), developed within a month of vaccination in 98% of participants, and 97% were seropositive 1 year after vaccination. While this study did not determine immunogenicity longer than 1 year after immunization, prior studies demonstrated high rates of detectable antibodies up to 10 years after receiving a 1/5 dose, suggesting that immunity can last for years after receiving a fractional dose. However, it is essential to note that while this study was a brilliant success that contributed valuable knowledge to the field, the researchers did not include a control group (primarily for ethical reasons) and therefore were unable to directly compare the immune response of individuals who received fractional doses to those who received full doses.

The Eliminating Yellow Fever Epidemics (EYE) Initiative Is Born

The 2015-2017 yellow fever outbreak in Africa was a stark warning of the potential destruction from unpredictable urban outbreaks of the disease. Not only is the threat of urban yellow fever outbreaks dangerous for people living in Africa and South America, but for anywhere in the world where the Aedes aegypti mosquito resides and where there is a population immunologically naive to yellow fever disease. In recognizing the urgency of the matter, a collaborative initiative called The Eliminating Yellow Fever Epidemics Initiative (EYE) was born in 2017. This initiative, a collaboration between WHO, Gavi and UNICEF, aims to detect, prevent and appropriately respond to yellow fever outbreaks in 40 at-risk countries in Africa and South America, with improvements in strategy and safety by 2026. One of the most significant components is risk assessment and evaluating how best to ensure that everyone who needs a life-saving vaccine can get one. Members of the EYE initiative knew that to fully demonstrate that fractional dosing of yellow fever vaccine is safe and offers appropriate protection, randomized controlled trials would need to be performed. They called upon African researchers to complete this work—enter Kimathi and his team. Kimathi works with a consortium of investigators from the University of Oxford, MSF/Epicenter, Insitut Pasteur de Dakar, Uganda Virus Research Institute and the KEMRI-Wellcome Trust.

Expanding Evidence for the use of Fractional Dosing of Yellow Fever Vaccine

Kimathi is one of many medical scientists working within the Kenya Medical Research Institute-Wellcome Trust Research program, a partnership between the Research Institute in Kenya, Oxford University and the Wellcome Trust that conducts novel research matching global and national needs, as well as building a strong research capacity in Kenya. As a clinical researcher with interest in emerging and neglected tropical diseases, Kimathi was the perfect candidate to lead a large clinical trial assessing the immunogenicity of fractional yellow fever doses. Alongside lead scientist Aitana Juan-Giner (Doctors Without Borders' Epicentre), Kimathi and team performed a double-blind, randomized non-inferiority trial at Epicentre Mbarara Research Centre in Mbarara, Uganda, and the Kenya Medical Research Institute-Wellcome Trust Research Programme clinical trials facility in Kilifi, Kenya.

Using local recruitment strategies, the researchers recruited participants between 18-59 years old from surrounding communities who had no contraindications for vaccination, were not pregnant or lactating and did not have a history of previous yellow fever infection or vaccination. Overall, the study team was able to enroll 960 participants. Each participant was then randomized to 1 of 4 vaccine manufacturer groups (240 assigned to Bio-Manguinhos-Fiocruz, 240 assigned to Chumakov Institute of Poliomyelitis and Viral Encephalitides, 240 assigned to Institute Pasteur Dakar, 240 assigned to Sanofi Pasteur). Once participants were randomized to a specific vaccine manufacturer group, they were randomized to either receive a fractional dose or a full dose of yellow fever vaccine (120 people in each group). After vaccination, participants were followed up at 10 days, 28 days and a year. At each follow-up appointment, clinical staff performed a medical exam and collected blood to measure and track the body's response to the vaccine.

While various clinical and laboratory characteristics were assessed about vaccination, the primary outcome of interest was to see if participants who received fractional doses of yellow fever vaccine achieved at least the same level of seroconversion (immunity) as participants who received a full dose 28 days after vaccination. Seroconversion was determined by plaque reduction neutralization (PRNT), which measures the amount of neutralizing antibodies against the yellow fever virus present in the blood.

Amazingly, 96.7% of patients were retained throughout the study and followed up a year after vaccination. Additionally, the results of the study were outstanding. All results demonstrate that the fractional doses were non-inferior to full doses. At 28 days after immunization, nearly all participants showed neutralizing antibodies at levels far higher than the minimum protective threshold of 1:10. These levels remained high a year after vaccination. The researchers reported no safety concerns. The only adverse finding in this study was low seroconversion rates at 10 days post-vaccination in the fractional dose groups, although the study was not appropriately powered to assess this fully. This suggests further studies to determine the earliest timepoint when patients achieve protection with fractional doses, which will determine the logistics of vaccination campaigns during outbreaks.

Routine Use of Fractional Yellow Fever Vaccine

Currently, the recommendation from WHO is to use fractional dosing only during times of crisis, such as large epidemics or times of shortage. But if the data look so good, why can't fractional doses be administered all the time? There are several challenges to consider:

Yellow Fever Vaccines Are Not Profitable

Over the years, several manufacturers have stopped making yellow fever vaccines. Overall, the process is laborious and time-consuming, and while it costs a great deal to make the vaccines, they don’t turn a profit. In addition, each person usually needs only one immunization for their entire life, and the areas where the vaccines are required most often lack the funds to pay for them. The incentive to produce yellow fever vaccines is low.

Lack of Infrastructure and Strategy

If manufacturers aren't willing to change the doses that go into a vial of yellow fever vaccine, then changes to the way vaccines are administered may be required. During both routine vaccination schedules and epidemics, changing the process of administration may be challenging. The process has remained virtually unchanged since the vaccine was developed. Additionally, it still isn't clear how long fractional dose immunity lasts. If fractional dosing does not offer lifelong protection, booster programs might be necessary.

Why Change a Good Thing?

In my discussion with Kimathi, he brought up a fascinating point. The vaccine development process for yellow fever has not changed in decades; why change it now? Most manufacturers are reluctant to modify the process for a vaccine that is already highly effective, particularly since trying to get smaller doses into vials could compromise viral particle quantity and will require a change to well-established practices. Creative strategies are needed to communicate the science and policy for the use of fractional doses to both policymakers and communities in need of the vaccine.

Why Non-Endemic Areas Should Invest in Yellow Fever Prevention and Control

Those reading this article who are not living in an endemic yellow fever area are likely reading because of an interest in tropical diseases, viruses or immunization. It is less likely due to worry about the yellow fever virus's impact on everyday life. This is reasonable, as the last outbreak of yellow fever in the United States occurred in 1905. However, with the increased distribution of the Aedes aegypti mosquito worldwide, increases in population density, extensive travel and impactful changes to the climate, it is time to start paying more attention to this deadly disease.

One additional, terrifying component of the 2016-2017 yellow fever epidemic in Africa was that 11 cases were imported into China, where the population is entirely non-immune to the disease. The challenge with vector-borne diseases is that preventing disease spread is not as straightforward as with a disease that spreads person-to-person, like SARS-CoV-2. If the mosquito that spreads the disease is present in an area where people have the virus in their blood, there will be more infections and could even be an epidemic. The Aedes aegypti mosquito is already distributed across several areas in China, where it carries and spreads dengue fever. Imported cases of yellow fever increase the risk that mosquitoes will take infected blood and spread the virus to a population of people with no immunity. The results of this situation could be catastrophic.

Given that there is already a significant vaccine shortage, it is unlikely that China could use emergency vaccination campaigns successfully in such a large population. This scenario may seem like a scene from a disaster movie, but it is not unrealistic. Gavi reports that it would take only a few introductions of imported cases from Africa or South America for the virus to spread rapidly, since the mosquito vector already inhabits numerous non-endemic yellow fever areas with high population densities and continues to move into new areas as well.

What's Next for Yellow Fever Research and The EYE Initiative

As the COVID-19 pandemic has shown, being one step ahead of infectious diseases proves to be both a life-saving and cost-saving practice. Kimathi and fellow experts suggest that, in order to prevent and control future outbreaks of yellow fever, the following steps should be taken:

• The burden of yellow fever should be brought to the agenda at global-level discussions of public health and policy.
• Science communication and education should focus on the use of fractional doses as a life-saving strategy in endemic regions to ensure optimal vaccine coverage.
• Non-endemic areas should understand their risk: these areas are still at risk of yellow fever as long as the vectors that transmit the virus are in these regions.
• Support for further studies, particularly in children, are needed in endemic regions to ascertain immunization longevity based on current vaccine guidance.
• Fractional dosing should be used in the context of the EYE framework to achieve the main aims of the initiative by 2026.