Experimental vaccine protects against Zika virus through T cells alone

Zika virus has been spreading for decades, but it first grabbed worldwide headlines in 2016. That February, with an outbreak sweeping the Americas, the World Health Organization (WHO) declared the surge in Zika-linked birth defects a "public health emergency of international concern"-a designation which lasted until that November. An estimated one million people or more were infected before the wave subsided.

Zika virus is carried by different species of Aedes mosquitoes. These mosquitoes had spread into new regions and found new victims. More people were getting sick, including pregnant women.

Doctors realized that the increased cases of microcephaly (significantly smaller brain and head development) in newborns across the Americas were caused by Zika virus infection. Women who contracted Zika virus during pregnancy were also much more likely to miscarry. Babies who survived could be born with eye and ear problems and joint issues, a pattern of birth defects doctors now group together as congenital Zika syndrome.

Today, at least 97 countries and territories have reported evidence of Zika virus transmission, according to the WHO. Reported cases have fallen sharply since 2017, but researchers expect the pool of susceptible people to rebuild over the coming decade, and a warming climate and the spread of insecticide-resistant Aedes mosquitoes keep widening the map of who is at risk. We still do not have any specific Zika virus treatments or vaccines.

Researchers at La Jolla Institute for Immunology (LJI) aim to change that by investigating how we can design vaccines that provide long-lasting, effective protection against severe Zika virus infection.

LJI Professor Sujan Shresta, Ph.D., recently published a study in Nature Microbiology showing that an experimental Zika virus vaccine can protect mice through T cells alone, without help from virus-fighting antibodies. The catch: on their own, those T cells do not keep the protection going.

This discovery is a critical step in the fight against Zika virus and its close viral relatives, including the life-threatening dengue virus.

The long-term goal of our lab is to develop a vaccine that provides long-term protection against all of these viruses."

Sujan Shresta, Ph.D., LJI Professor 

Why don't we have Zika virus vaccines?

Most vaccines work by prompting the body to make antibodies, which bind to part of a pathogen-the outside of a virus, say-and neutralize it before it can cause infection. Antibodies and the B cells that produce them can then linger in the blood for years, lying in wait for their targets.

But in the case of Zika virus vaccines, antibodies pose a big problem. Zika belongs to a family of mosquito-borne viruses-the orthoflaviviruses-that also includes dengue and Japanese encephalitis virus, and these viruses overlap across much of the world. Zika and dengue are especially close cousins: the envelope proteins that coat them are so similar that antibodies raised against one routinely latch onto the other.

Shresta has studied a phenomenon called antibody-dependent enhancement (ADE). When antibodies bind a virus without disabling it-because they were raised against a relative, or because their levels have waned-they can end up ferrying the virus into immune cells instead of blocking it, driving a more severe infection. Because of ADE, a person who receives a vaccine that prompts the body to make antibodies against Zika virus could be vulnerable to a severe case of Zika or dengue infection later on.

The risk of ADE means vaccine researchers need to find innovative ways of protecting the body from orthoflaviviruses.

In past studies, Shresta uncovered the potential power of T cells in fighting orthoflaviviruses. T cells patrol the body for signs of disease and adapt over time to recognize specific threats, and vaccines can train them just as they train antibodies. Shresta has shown that T cells offer a chance to fight these viruses when you can't depend on antibodies.

Vaccine yields surprising results

For the new study, Shresta worked with LJI Research Instructor Annie Elong Ngono, Ph.D., and Visiting Scientist Kantinan Chuensirikulchai, Ph.D., to compare two experimental Zika vaccines in mice bred to be susceptible to the virus. 

Like most Zika vaccine candidates, both were built around the virus's outer coat proteins to elicit neutralizing antibodies. In one, those proteins were left as they occur in nature. In the other, the team mutated a small patch called the fusion loop, the very site that generates most of the cross-reactive antibodies behind ADE. The researchers wanted to know whether removing that liability would also change how T cells respond.

In their tests, the unmodified vaccine got the immune system to fight Zika virus infection with a double-whammy of antibodies and T cells. Transferring CD8+ T cells from those mice into unvaccinated animals cut Zika levels on its own-so T cells were pulling real weight even in the vaccine whose antibodies worked as intended.

The fusion-loop mutant vaccine came with an even bigger surprise. Its antibodies shared many features in cell cultures and test tubes as those from the unmodified vaccine, but they did not protect unvaccinated animals at all. Stripping out the CD8+ T cells, by contrast, wiped the protection away. "This vaccine wasn't protecting via antibodies," says Shresta. "It was protecting via T cells."

"The protection came from CD8+ T cells, a type of immune cell that finds and destroys virus-infected cells," adds Chuensirikulchai.

This protection was effective, but it didn't last. Twelve weeks after the final dose, mice given the fusion-loop mutant vaccine were no better off than unvaccinated animals, while those given the unmodified vaccine were still protected. The lesson is a cautionary one: a change made to reduce ADE risk quietly cost the vaccine its staying power. 

Shresta and her colleagues are now investigating how to build up a "durable" army of T cells that can respond to Zika virus infection for years after vaccination. "We need innovative vaccines," says Elong Ngono. "And now we know what to focus on."

What's next for life-saving vaccines?

This work doesn't stop with a Zika virus vaccine, says Shresta. She has found that T cells have the power to "cross-react" and respond to several related viruses, such as Zika and dengue, at the same time.

The new study brings Shresta's team closer to a "pan-orthoflavivirus vaccine" that could teach T cells to fight many of these viruses at once-an approach that would be worth a great deal in the many places where people meet more than one related virus.

As Chuensirikulchai explains, the new findings reinforce the idea that effective vaccines against orthoflaviviruses should prompt the body to make virus-specific and cross-reactive T cells in addition to antibodies that neutralize and avoid ADE.

"Our study highlights the importance of considering T cell-mediated immunity alongside neutralizing antibodies," says Chuensirikulchai. "This concept may inspire new vaccine strategies for other orthoflaviviruses, particularly in situations where antibody responses alone are insufficient or may contribute to unwanted immune effects."