3D rendering of a chikungunya virus-like particle. (Credit:NIAID)

new research Published in PNAS Rare cases of brain inflammation associated with live attenuated yellow fever and chikungunya vaccines suggest that they are due to autoantibodies carried by a small subset of the population, mostly the elderly.

The FDA suspended U.S. approval of a live attenuated chikungunya vaccine in August 2025 after reports of side effects. The only vaccine currently available in the United States does not replicate or cause infection. In other parts of the world where live virus vaccines are used, the authors suggest that doctors screen potentially vulnerable individuals before vaccination and direct those who test positive to alternative vaccines that do not rely on live viruses.

Chikungunya occurs in tropical and subtropical regions of Africa, the Americas, Asia, Europe, and the islands of the Indian and Pacific Oceans. The virus is spread by mosquito bites.

“We now know that this type of chikungunya vaccine can cause severe encephalitis in a small number of people with these autoantibodies,” said Shen Ying Zhang, associate professor of clinical research. Jean-Laurent Casanova‘s St Giles Institute of Human Genetics of Infectious Diseases at Rockefeller. “We therefore strongly recommend that people in countries that are still using this vaccine, especially those over 65 years old, undergo a screening test before administering it.”

From Reunion to Rockefeller

Live attenuated chikungunya vaccines prevent the disease by exposing the immune system to a weakened form of the virus, a mosquito-borne pathogen that causes fever and, in rare cases, life-threatening brain inflammation. The vaccine, launched in 2023, has been associated with several hospitalizations and deaths, and two participants in a Phase III clinical trial involving thousands of people had severe reactions.

Concerns intensified in early 2025 during a mass vaccination campaign on La Réunion island, a French overseas department in the Indian Ocean. In the United States, the Vaccine Adverse Event Reporting System warned of six serious adverse events, including brain inflammation, in people 65 and older, and news reports in both the United States and France reported on deaths after vaccination.

For Zhang, these reports were nostalgic. “When we read about these severe reactions in the news, we immediately suspected that they were due to the autoantibodies we were studying,” she says.

The suspicions are based on more than a decade of research by Casanova’s group. The lab showed that a small subset of the population carries autoantibodies that neutralize type I interferon molecules, which normally act as the immune system’s early antiviral alarm. Live attenuated vaccines take advantage of this antiviral alarm to keep weaker viruses under control long enough for the body to develop immunity. The presence of these autoantibodies means that even weakened viruses can be transmitted. In 2021, Casanova’s lab published research implicating autoantibodies in a third of life-threatening reactions to live attenuated yellow fever vaccines (about 10% of reported adverse reactions were considered life-threatening) and in severe illnesses caused by common viruses from the novel coronavirus to West Nile.

Concerned that a similar pattern might be emerging with the chikungunya vaccine, researchers in the Casanova lab contacted colleagues overseas and offered to test whether the same immune defects observed in yellow fever cases underpin these events.

Screening for autoantibodies

To track these rare reactions, the team focused on five adults aged 82 to 88 who developed serious complications after a vaccination campaign in La Réunion. Researchers confirmed that live vaccine virus was present in the bloodstream of all five patients, and in severe cases even in the cerebrospinal fluid, indicating that the virus had escaped the range of the vaccine.

To understand why the immune system was unable to contain the attenuated virus, which could have been easily controlled, the researchers tested blood and cerebrospinal fluid to see if interferon was still able to activate the first line of antiviral defense. In some patients, the samples completely blocked interferon signaling, but experiments determined that the effect was ultimately due to autoantibodies neutralizing type I interferon. Moreover, the presence of these autoantibodies several weeks after vaccination suggested that they were not a temporary reaction to the vaccine itself, but a persistent problem that had been quietly weakening the immune system for some time.

Of the five patients tested, all three who developed brain inflammation had high levels of autoantibodies, while two who had other severe outcomes had no autoantibodies, suggesting a link between this specific immune profile and encephalitis. Although based on a small number of cases, statistical analysis suggested a sharply elevated risk among individuals with these autoantibodies.

“This study suggests that severe disease caused by wild-type chikungunya virus, a rare outcome of infection, may be caused by the same autoantibodies,” Professor Casanova says.

It is estimated that people with antibodies are more than 100 times more likely to experience serious adverse events and more than 500 times more likely to develop vaccine-associated encephalitis. However, the risk was not absolute. An estimated 1.2 percent of people aged 80 to 85 have these high-risk antibodies, but only a small proportion of that population ever gets sick, and while antibodies clearly increase the risk of disease, they are by no means a guarantee.

This study points to a possible treatment option for people who get the disease. The authors write that some patients may benefit from recombinant interferon-beta therapy, which replaces front-line immune defenses. “As a first step, people who have a severe reaction to the vaccine should be tested for autoantibodies, and if we know they have this autoantibody, we can treat the patient with interferon, which is not neutralized by autoantibodies,” Zhang says.

However, it may also be possible to prevent it. In countries where live virus vaccines are still available, the authors recommend screening older adults for these autoantibodies before administering the vaccine and directing those who test positive to safer options such as inactivated virus, recombinant protein, or mRNA vaccines.

In the meantime, there are still many unknowns. The current study is based on only five adverse cases. The authors therefore call for larger studies. “More epidemiological data are needed to understand the global scope of severe reactions to this vaccine and other live vaccines,” Chan said. “These autoantibodies are not uncommon and increase the risk of severe viral illness.”