Despite the existence of an effective yellow fever vaccine, outbreaks can occur suddenly and spread rapidly in densely populated urban areas in countries where the disease is endemic. But new findings from a clinical trial show that existing vaccine stores can be stretched in an emergency, by administering just one-fifth a standard dose, to slow transmission. The study was recently published in The Lancet.
The results will help public health experts to coordinate quick and effective responses to yellow fever outbreaks within the constraints of a limited global supply of vaccine. The trial was conducted by Epicentre, a division of Doctors Without Borders, with contributions from UF preeminence professor Derek Cummings and his Infectious Disease Dynamics lab.
“There is only a certain amount of this vaccine made every year, and it’s very hard to ramp up production quickly enough to address an emerging outbreak,” says Cummings, who is a biologist in UF’s College of Liberal Arts and Sciences. “Our findings will help optimize the existing supply for emergency responses by stretching vaccine supplies to five times as many people.”
Cummings studies population-level immune responses to infectious diseases, and he is a faculty member of UF’s Emerging Pathogens Institute. He contributed to the design of the clinical trial, and the analysis of its data. Kyra Grantz, who was a research assistant in Cummings’ lab at the time of this research, helped support the data management and statistical analysis at Epicentre in Paris. She also assisted in preparations at the trial field sites in Mbarara, Uganda and Kilifi, Kenya in 2017-2018. Grantz is now a PhD candidate in infectious disease epidemiology at Johns Hopkins University.
Yellow fever is endemic to 44 countries, and it is caused by a virus transmitted by the same Aedes aegypti mosquito that also spreads dengue and Zika virus. Outbreaks are fueled by introductions of infections into dense urban areas from forested areas where Ae. aegypti dwell and feed on non-human primates — apes and monkeys — allowing this mosquito-borne virus to spill over into people.
Yellow fever has a higher rate of severe illness and mortality compared with dengue and Zika virus, which makes outbreak responses in human populations critically important.
During a large yellow fever epidemic in Angola and Democratic Republic of Congo in 2016, the World Health Organization reviewed available studies and recommended using fractional doses to mitigate acute vaccine shortages. This approach was used in the Democratic Republic of Congo to rapidly vaccinate the at-risk population. It was tried again in 2017-2018 in Brazil, where a vaccine manufacturer suggested administering one-fifth the standard dose, with apparent success. Though these experiences suggested that fractional doses could be used effectively, the WHO recognized that more data was needed to formally evaluate the effectiveness of this approach.
Though studies hinted that a fractional dose could be effective in stemming transmission during outbreaks, the yellow fever vaccine formula is about 80 years old and data is limited on the minimum amount of antigen necessary to elicit a robust immune response.
“This is a very old vaccine, and studies looking at dosing and titer levels are relatively rare,” Grantz says. “The first versions were developed and put in use long before there were FDA regulations on what kinds of clinical trials to do, and what kind of dose-finding data are needed.”
The new work used a clinical non-inferiority trial to test the immune response of people vaccinated with a standard yellow fever vaccine dose to those who received a one-fifth fractional dose. These types of trials are designed to test if the alternative dose is not inferior to the standard dose.
In this study, the researchers directly compared antibody levels of participants who received a standard versus fractional vaccine dose. They found that the participants’ immune response 28 days after vaccination was virtually identical between the standard and fractional dose groups; this held true across all four manufacturers’ formulas.
“This is the first time that all four widely available yellow fever vaccines have been tested for the efficacy of a fractional dose,” Cummings says. “It’s a very comprehensive approach.”
The researchers also had the potency of all four vaccine formulas tested independently. When designing the fractional dose, they purposefully used vaccine lots found to have low concentrations.
“It was a very conservative and conscious decision to do it this way,” Grantz says. “Because we know that the manufacturing process is not entirely uniform and there is variation in potency between lots. So by intentionally selecting the least potent lots, we ensured that even some of the weakest possible fractional doses could still be effective.”
Cummings and Grantz caution that the results apply only to outbreak responses and emergency use, and that they do not imply a change is warranted for standard or routine yellow fever vaccination doses for people who live in, or are traveling to, endemic areas.
Optimizing existing vaccines and therapies is a large focus of Cummings’ lab. “This study gives us another tool for dealing with yellow fever,” he says.
Researchers expect the suitable ranges for Ae. aegypti to expand in the future, which means that the geographic range of yellow fever will likely expand.
“A big issue looking forward is urbanization,” Grantz says. “With the extension of the urban-wildlife interface, spillovers and interactions between humans and the sylvatic cycle of yellow fever will be more common.”
While the current study looked at adults, Grantz says that future work will refine data on fractional dosing for children and people living with HIV.
“But the new study gives us critically valuable information,” Grantz says. “Because in future outbreaks, we will know it is effective to use fractional dosing for most adults.”
Written by: DeLene Beeland