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A 2016 emergency yellow fever vaccination campaign that had to resort to using smaller than standard doses because of a global vaccine shortage appears to have protected the people who were vaccinated, a new study suggests.

People who received a fractional dose — one-fifth the standard size — showed strong immune responses a month after they received the single dose of vaccine, the authors reported in the New England Journal of Medicine.


While the study — conducted during a mass vaccination campaign in Kinshasa, capital of the Democratic Republic of Congo — is not the first to provide hints that fractional doses of yellow fever vaccine are effective, it was the first such study undertaken outside the artificial confines of a laboratory.

“This is really the first evidence for a fractional dose coming from a vaccination campaign setting and in the context of an outbreak,” said Dr. Rebecca Casey, first author of the study and a scientist with the Center for Disease Control and Prevention’s global immunization division.

Yellow fever is a serious, and sometimes fatal, disease. People who contract the virus, which spread through the bite of infected mosquitoes, can experience an array of symptoms — fever, headache, backache, and muscle pains, loss of appetite, and nausea or vomiting.


Those symptoms typically go away after three or four days. But about 15 percent of people then suffer a relapse, going on to develop jaundice and more severe illness. And in roughly half of that group of severe cases, the infection is fatal.

There is limited annual production of yellow fever vaccine. And while an international stockpile of 6 million doses is maintained, the events of the past few years have raised fears about the capacity to respond when yellow fever threatens large populations of people.

The problem in 2016 began with a large, rolling outbreak in Angola that eventually spread to Kinshasa, a city of 11.6 million people. When the DRC government decided to preemptively vaccinate in Kinshasa, there was not enough vaccine in the international stockpile to undertake the job.

(Brazil, which has recorded an alarming number of cases of yellow fever in people and in monkeys near Sao Paolo and Rio de Janeiro in recent months, is using fractional doses to vaccinate in and around those cities.)

The World Health Organization, based on expert advice, recommended using a fractional dose. The plan was to follow up a year later with a second fractional dose to ensure long-term protection. Joachim Hombach, head of immunization policy for WHO, said the recommendation for a followup shot may be waived if study participants show they retain good antibody responses a year after vaccination.

Casey said the researchers went back to the people they studied to assess antibody levels at the one-year point. They are still analyzing the data, and expect to be able to publish findings in the next few months.

The study monitored 716 people who were vaccinated during the Kinshasa campaign, looking for antibodies in their blood after vaccination as a measure of whether the vaccine worked. The study could not actually assess whether the vaccine was protective because the outbreak was waning by the time the vaccination campaign got underway.

Nearly 500 of the people enrolled had no antibodies to yellow fever when the trial started and 98 percent of them “sero-converted” — meaning they developed what is thought to be protective levels of antibodies when they were checked a month after vaccination.

The other people had some antibodies at the start, suggesting they had either been previously vaccinated against yellow fever or they had contracted it at some point. Only 66 percent of them recorded an antibody rise after vaccination, but the lack of response in some isn’t alarming. A full dose of vaccine and infection with yellow fever are both thought to confer life-long immunity to the virus.

Experts consider these results very promising, but warned this doesn’t mean the vaccine dose can be lowered for everyone. Duane Gubler, a world expert in yellow fever, suggested there aren’t data to indicate how long the protection from a fractional dose lasts.

Dr. Erin Staples, senior author of the paper and a yellow fever expert in CDC’s vectorborne diseases operation at Fort Collins, Colo., said the early results are fueling questions about whether the vaccine dose could be lowered and whether using a lower dose would reduce the rate of adverse reactions to the vaccine. Yellow fever vaccine is one of the more reactogenic vaccines, meaning it can cause discomfort. And in rare cases, it can trigger serious illness.

“It’s a theoretical potential benefit. But until we have data, we can’t say for sure if it will or won’t improve it — but that’s something that we hope to get data on,” Staples said.

The WHO’s Hombach said fractional dosing should be used as a last resort only until it is known how long protection from a fractional dose lasts, whether smaller doses work as well in young children, and whether vaccines from other manufacturers work as well as the one used in the study.

“It’s a way of having some surge capacity,” he told STAT. “I think we need to really confine it to emergency situations…. Because I think it is one of the few tools that we have, indeed, if we need to counter an outbreak and we are running short of vaccine supplies.”