Discoveries show that natural cross-protection between viruses is mediated by T cells, paving the way for more effective and long-lasting vaccines.
A new vaccine approach could offer simultaneous protection against two of the greatest threats to public health in tropical regions: Dengue and Zika. This strategy was presented by Professor Sujan Shresta in a seminar at the Institut Pasteur de São Paulo, held on April 25, in the city of São Paulo.
This approach stands out because it stimulates not only the production of antibodies, but also the activation of T cells — a type of defense cell essential for eliminating infections and offering long-lasting protection. By combining these two aspects of the immune system, the vaccine is aimed at achieving a more robust and long-lasting response than traditional approaches based solely on antibodies. “For a long time, we focused only on neutralizing antibodies. Now we know that we also need T cells to ensure a more complete and sustainable protection,” said Sujan Shresta.
Conducted at the Center for Vaccine Innovation in the La Jolla Institute for Immunology (USA), the research seeks to overcome historical obstacles controlling these diseases, such as the great viral diversity and individual variability of immune responses. The project is also aimed at ensuring that vaccines are accessible to countries that have historically been excluded from immunization campaigns.
Persistent threats – Among infectious diseases, Dengue and Zika continue to be the ones with the greatest impact in tropical regions. Despite belonging to the same viral family and sharing approximately 65% of their genes, the viruses interact in different ways with the human immune system.
Dengue causes strong immune activation, leading to intense inflammation. Zika, on the other hand, adopts a stealthy tactic: it inhibits the activation of dendritic cells — essential for activating the immune response —, allowing the virus to spread silently in sensitive areas such as the placenta, the brain and the eyes. This difference helps explain why Zika is especially dangerous during pregnancy, and can cause congenital Zika syndrome, including microcephaly.
“When we consider how Zika interacts with the immune system, it becomes clear why it can reach the brain and placenta so efficiently. It simply deactivates the initial alarms that the body would use to defend itself,” the researcher highlighted.
Cross-protection – During her presentation, Sujan Shresta explained in detail how previous exposure to the Dengue virus can provide protection against Zika infection. Epidemiological studies had already observed that individuals previously exposed to Dengue had a lower risk of developing serious complications from Zika. However, the immunological mechanism involved remained unexplained.
Sujan Shresta’s group managed to better understand this mechanism demonstrating, in experimental studies, that this protection does not depend on antibodies, but rather on the activation of T cells, especially CD8+ cells, which recognize and eliminate infected cells, and, to a lesser extent, CD4+ cells. Studies with animal models showed that when these T cells were eliminated, the protection disappeared, an evidence that immunological memory mediated by T cells is the main factor in the cross-defense between Dengue and Zika.
“We discovered that the immune system has a functional memory that can be reactivated against related viruses, which completely changes the way we think about combined vaccines,” she said.
Innovative strategies – Based on these discoveries, Sujan Shresta’s team is developing new-generation vaccines based on replicating RNA encapsulated in lipid nanoparticles, aimed at simultaneously stimulating the production of neutralizing antibodies and activating specific T cells (CD4+ and CD8+), to promote a more complete and balanced immune response.
The leader of the “Genomic Surveillance and Vaccine Innovation” group at IPSP, Researcher Rúbens Alves, contributed to this stage of the project. During his postdoctoral studies in Sujan Shresta’s laboratory, he created and designed the self-replicating RNA platform, produced the vaccines and generated the presented results.
In the preclinical tests, the combination of structural antigens, such as the E envelope protein, and non-structural antigens, such as the NS3 protein, resulted in high levels of protection against both viruses. In addition, the researchers are exploring strategies to prolong the immune response, such as the use of immune memory-stimulating molecules, including OX40 and 4-1BB, aiming to reduce the need for multiple booster doses.
The inspiration for this approach comes from the epidemiological and experimental observations of natural cross-protection, which indicate that a balanced response involving both antibodies and T cells can provide a more robust and safer response. “Nature has already shown us that prior exposure to a virus can prepare the immune system to effectively fight the next one. Our goal is to mimic this strategy with safe and affordable vaccines,” explained the researcher.