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Aedes mosquito.
This species can transmit pathogens such as Zika, Chikungunya, and dengue virus.
Photo Credit: NIAID
Scientific Frontline: Extended "At a Glance" Summary: Zika Virus Vaccine Development
The Core Concept: Researchers evaluated two experimental Zika virus vaccines to understand the roles of antibodies and T cells, discovering that long-term viral protection requires a coordinated immune response from both components rather than relying on T cells alone.
Key Distinction/Mechanism: Traditional vaccines generate neutralizing antibodies, which carry the risk of triggering antibody-dependent enhancement (ADE) upon exposure to closely related orthoflaviviruses, such as dengue. To circumvent this, a modified vaccine mutated the viral fusion loop to avoid ADE; however, this vaccine relied entirely on CD8\(^+\) T cells and lost its efficacy after 12 weeks, demonstrating that durable immunity requires both targeted antibodies and T cells.
Origin/History: The Zika virus caused a major global public health emergency in 2016 following an outbreak across the Americas that led to severe birth defects. This recent study, published in Nature Microbiology, addresses the ongoing lack of licensed Zika treatments.
Major Frameworks/Components:
- CD8+ T Cells: Specialized immune cells that actively locate, target, and destroy virus-infected cells.
- Neutralizing Antibodies: Immune proteins that bind to a pathogen's outer surface, disabling the virus before it can cause an infection.
- Antibody-Dependent Enhancement (ADE): A phenomenon where sub-optimal or cross-reactive antibodies inadvertently help a closely related virus enter host immune cells, resulting in a significantly more severe infection.
- Orthoflaviviruses: A family of mosquito-borne viruses that includes Zika, dengue, and Japanese encephalitis, primarily transmitted by Aedes mosquitoes.
- Fusion Loop: A specific patch on the virus's outer envelope protein that generates the cross-reactive antibodies largely responsible for ADE.
Branch of Science: Immunology, Virology, and Epidemiology.
Future Application: These immunological insights aim to guide the engineering of a durable "pan-orthoflavivirus vaccine." Such a vaccine would safely leverage cross-reactive T cell immunity alongside safe neutralizing antibodies to protect against multiple related viruses simultaneously without triggering ADE.
Why It Matters: As warming climates expand the habitats of insecticide-resistant Aedes mosquitoes, populations face a growing risk of overlapping Zika and dengue outbreaks. Developing a safe, long-lasting vaccine is essential to preventing severe adult infections and congenital Zika syndrome in newborns.
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| LJI Professor Sujan Shresta, Ph.D. Photo Credit: Courtesy of La Jolla Institute |
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 that lasted until that November. An estimated 1 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. Consequently, 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 problems, 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. A warming climate and the spread of insecticide-resistant Aedes mosquitoes continue to widen the map of those at risk. Currently, there are no specific Zika virus treatments or vaccines.
Researchers at the La Jolla Institute for Immunology (LJI) aim to change this by investigating how to design vaccines that provide long-lasting, effective protection against severe Zika virus infection.
LJI professor Sujan Shresta, PhD, recently published a study in Nature Microbiology showing that an experimental Zika virus vaccine can protect mice through T cells alone, without assistance from virus-fighting antibodies. The catch: On their own, those T cells do not maintain the protection.
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,” says Shresta.
Why do we not have Zika virus vaccines?
Most vaccines work by prompting the body to produce antibodies, which bind to part of a pathogen—the outside of a virus, for example—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.
However, in the case of Zika virus vaccines, antibodies pose a significant problem. Zika belongs to a family of mosquito-borne viruses—the orthoflaviviruses—that also includes the dengue and Japanese encephalitis viruses, 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 to 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 produce 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 antibodies cannot be relied upon.
Vaccine yields surprising results
For the new study, Shresta worked with LJI research instructor Annie Elong Ngono, PhD, and visiting scientist Kantinan Chuensirikulchai, PhD, 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 exact site that generates most of the cross-reactive antibodies responsible for ADE. The researchers wanted to know whether removing that liability would also change how T cells respond.
In their tests, the unmodified vaccine prompted the immune system to fight Zika virus infection with a dual response of antibodies and T cells. Transferring CD8\(^+\) T cells from those mice into unvaccinated animals reduced Zika levels independently, demonstrating that T cells were highly effective even in the vaccine where antibodies worked as intended.
The fusion-loop mutant vaccine came with an even bigger surprise. Its antibodies shared many characteristics in cell cultures and test tubes with those from the unmodified vaccine, but they did not protect unvaccinated animals at all. Depleting the CD8+ T cells, by contrast, eliminated the protection entirely. “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 did not 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 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 is next for life-saving vaccines?
This work does not 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 the Zika and dengue viruses, simultaneously.
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 highly valuable in the many regions where people are exposed to more than one related virus.
As Chuensirikulchai explains, the new findings reinforce the idea that effective vaccines against orthoflaviviruses should prompt the body to produce virus-specific and cross-reactive T cells in addition to antibodies that neutralize the virus 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.”
Funding: This study was supported by the National Institutes of Health (grants R01AI153500, R01AI163188, R01AI180196, and U19AI181960) and the Prebys Foundation Research Heroes program.
Published in journal: Nature Microbiology
Title: A Zika virus vaccine with E protein fusion loop mutations protects via CD8\(^+\) T cells
Authors: Kantinan Chuensirikulchai, Qin Hui Li, Hsueh-han Lu, Julia Timis, Manuel Montano, Luke Eder, Pradip Bhandari, Dawid Zyla, Maximilian Bunz, Henry Madany, Rubens Prince Dos Santos Alves, Paolla Beatriz Almeida Pinto, Erin Maule, Michael Nguyen, Erica Ollmann Saphire, Lakshmanane Premkumar, Annie Elong Ngono, and Sujan Shresta
Source/Credit: La Jolla Institute | Madeline McCurry-Schmidt
Edited by: Scientific Frontline
Reference Number: imgy082626_01