Blocking a frontline response to infection could increase the effectiveness of viral vaccines, such as those against coronaviruses, according to a Northwestern Medicine study published in the Journal of Experimental Medicine.
Mice injected with a low dose of an immunoglobulin type-I interferon (IFN) blocker alongside viral vaccines generated superior immune responses and disease resistance. Pablo Penaloza-MacMaster, PhD, assistant professor of Microbiology-Immunology and senior author of the study, believes that’s because the IFN blocker increased vaccine replication during the first 96 hours after vaccination, which allowed the body to better study the virus and develop enhanced immune defenses.
Nicole Palacio, a fourth-year student in the Driskill Graduate Program in Life Sciences (DGP), was the lead author of the study.
Viral vaccines work by introducing weakened or inactivated pieces of a virus into the body. The immune system learns how to fight off the virus by studying its proteins, and then producing T-cells and antibodies that remember these proteins upon infection with the real virus.
According to the authors, the IFN pathway evolved in animals to rapidly eliminate viral infections within minutes or hours. While this helps organisms respond to infection, the authors hypothesized that IFN may reduce the effectiveness of viral vaccines, as the immune system has less time to learn about the virus.
“Six decades of research have shown that IFN is essential for clearing infections and to generate protective immunity following vaccination,” Penaloza said. “Researchers have tested the ‘all-or-none’ effects of IFN, and it is known that people with genetic defects in IFN exhibit immune dysfunctions. However, the effects of a short-term absence of IFN are not well-studied.”
The investigators tested the short-term IFN blockade in mouse vaccination models, intramuscularly administering vaccines alongside a small amount of IFN blocker. The IFN blocker was calculated to block IFN for only 96 hours.
Whether it was for clinically approved vaccines, or experimental HIV or coronavirus vaccines — not SARS CoV-2, but a close cousin called MHV— the IFN blockade generated more potent immune responses following vaccination. In addition, IFN modulated vaccines generated cross-reactive immune responses that better recognized mutant viruses. This may be especially important for SARS CoV-2 and other RNA viruses that constantly mutate.
Interestingly, once the transient IFN blockade was over, the mice seemed to compensate, producing more IFN than usual, according to Penaloza.
“Since the IFN blockade was very short in duration, mice appeared healthy and most vaccine replication stayed localized following intramuscular vaccination, but future studies are needed to evaluate safety more rigorously in large animal models,” Penaloza said.
“We think that these studies are potentially translatable, since IFN blockers have shown acceptable safety profiles in humans, but one needs to be extra careful when testing new vaccines in people. Most importantly, these findings highlight the tug of war between frontline immune responses and adaptive immune responses, providing a framework for rational vaccine design.”
IFN modulated vaccines may be potent against human coronaviruses such as SARS Cov-2, the virus that causes COVID-19, especially because there are concerns about the durability of immune responses to coronaviruses. Studies of recovered patients have suggested that antibodies may drastically decrease over time, which may indicate a fading protection from the virus. This has raised the question of immune durability for the first generation of SARS CoV-2 vaccines, and whether the vaccines that are being tested could protect long-term, according to Penaloza.
“Our data provides a proof-of-concept that short-term IFN blockade can increase not only the magnitude and cross-reactivity of antiviral responses, but also their durability,” Penaloza said. “Short-term IFN modulation could be useful in second generation SARS CoV-2 vaccines aimed at conferring potent, broad and durable protection against different coronavirus strains, but further testing in SARS CoV-2 animal models would be needed before this type of vaccines can be tested in humans.”
Penaloza is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
This work was funded by Third Coast Center for AIDS Research grant P30 AI117943, National Institutes of Health grants 1R21AI132848-01A1 and DP2DA051912, and the National Science Foundation Graduate Research Fellowship Program grant DGE-1842165.
