It’s an unprecedented emergency measure, but one that could become the norm: In a bid to stop an outbreak of yellow fever, more than 8 million people in Kinshasa, the capital of the Democratic Republic of the Congo (DRC), will be vaccinated using just one-fifth the normal dose. The campaign, scheduled to start next week, comes as yellow fever continues to spread in the DRC and vaccine demand outstrips supply.
Scientists feel confident that the lower doses will offer protection, at least for the short term, but they are urging studies accompanying the campaign to assess whether routine use of the lower dose is an option.
The current outbreak started in neighboring Angola in December of last year and later spread to the DRC. According to the World Health Organization (WHO), more than 16 million people in the two countries have already been vaccinated, and Angola has reported no new cases for more than 6 weeks. But new cases are still emerging in the DRC, which has reported more than 2000 suspected cases so far and 95 deaths.
WHO's emergency stockpile of yellow fever vaccine, which was depleted earlier this year, has been restocked and is now back to 5 million doses. But the Congolese government, worried that the virus could spread rapidly among Kinshasa's 10 million residents, has decided to stretch the 1.7 million doses it has received by giving people 0.1 milliliters of the vaccine each instead of the standard 0.5 milliliters.
The yellow fever virus is primarily transmitted by Aedes aegypti, the mosquito species that also spreads Zika and dengue. Most people who are infected have no symptoms, but about 15% develop serious disease, and about half these patients die. There is no cure, but the vaccine, although cumbersome to produce, is highly effective: A single dose confers lifelong protection.
Fearing that the disease could spread to Asia, which has never seen a yellow fever outbreak, some experts had urged governments and WHO to adopt the vaccine-saving strategy. In June, WHO's Strategic Advisory Group of Experts (SAGE) on Immunization concluded that the lower dose would still offer protection for at least 12 months. (The recommendation was made in an emergency session, but the group has planned a formal evaluation for October.) “We felt very comfortable with the data that was presented to go ahead and make the recommendation,” says SAGE chair Jon Abramson, a pediatrician at Wake Forest School of Medicine in Winston-Salem, North Carolina. “We feel the benefit of vaccinating as many people as we can far outweighs the small risk that somebody won’t respond who could have responded to a larger dose.”
SAGE advised that children under 2 years of age should receive the full dose, however, and it pointed out some practical problems as well, such as the need for millions of smaller syringes. A WHO spokesperson says that problem has been solved by using syringes stored in China and Denmark for polio vaccination programs.
Abramson and other experts argue that the effects of the campaign need to be studied. One important question is safety. The yellow fever vaccine is itself a living virus that can replicate inside the body and, in very rare cases, cause a disease in which the vaccine virus proliferates in multiple organs, often leading to death. Although a lower dose would be expected to lead to fewer side effects, that may not be the case. Some researchers have argued that lower doses may be slower to kick the immune system into gear, which could cause the vaccine virus to linger in the body for longer and actually increase the risk of some side effects. A few studies have found no such effect, but because severe side effects are very rare (about one in 2 million), small trials cannot provide definitive answers.
The other question is efficacy. A recent study on 749 men in Brazil showed that a 46-fold diluted vaccine triggered the same antibody response as a full dose. A study in the Netherlands found that a fifth of a normal dose injected intradermally was just as effective as a normal dose injected subcutaneously (the usual route).
But more data on the efficacy of the lower dose need to be collected, especially because an African population may react differently to those studied in the trials. Ideally, scientists would set up a randomized, controlled clinical trial to assess the immune response to the lower dose, says Tom Monath, a virologist who has studied yellow fever for decades and currently works at NewLink Genetics, a biotech company in Ames, Iowa. But Monath concedes that that is unlikely given the time pressure and the logistical problems. At the very least, researchers should collect blood samples and compare the antibody responses from people who received the full and the lower dose, he argues. “It wouldn't be a formal study but it would give you some confidence that people have responded appropriately,” Monath says. "I think that really should be done.”
Another important question is whether 0.1 milliliters of the vaccine also offers lifelong protection. If not, the population will have to be revaccinated in the future. It’s also not clear whether lower doses will be protective in young children.
In a paper advocating the dose-sparing strategy that Monath and eight other scientists just submitted, they go one step further. "If the worst-case scenario were to come to pass and yellow fever spread in Asia, serious consideration should be given to using a one-tenth dose,” the authors write. "Although it would probably protect any age group for only a few months, a one-tenth dose should mitigate the severity of a yellow fever infection, preventing some deaths.“