Scientists at the University of Wisconsin (UW)-Madison say they have some new insights into an alternative vaccine approach that provides broader protection against seasonal influenza.

In a study, “Programming Multifaceted Pulmonary T Cell Immunity by Combination Adjuvants,” published in Cell Reports Medicine, researchers described a T-cell-based vaccine strategy that reportedly is effective against multiple strains of influenza virus. The experimental vaccine, administered through the nose, delivered long-lasting, multi-pronged protection in the lungs of mice by rallying T cells that eliminate viral invaders through an immune response.

“Induction of protective mucosal T-cell memory remains a formidable challenge to vaccinologists. Using a combination adjuvant strategy that elicits potent CD8 and CD4 T-cell responses, we define the tenets of vaccine-induced pulmonary T-cell immunity. An acrylic-acid-based adjuvant (ADJ), in combination with Toll-like receptor (TLR) agonists glucopyranosyl lipid adjuvant (GLA) or CpG, promotes mucosal imprinting but engages distinct transcription programs to drive different degrees of terminal differentiation and disparate polarization of TH1/TC1/TH17/TC17 effector/memory T cells,” the investigators wrote.

“Combination of ADJ with GLA, but not CpG, dampens T-cell receptor (TCR) signaling, mitigates terminal differentiation of effectors, and enhances the development of CD4 and CD8 TRM cells that protect against H1N1 and H5N1 influenza viruses. Mechanistically, vaccine-elicited CD4 T cells play a vital role in optimal programming of CD8 TRM and viral control. Taken together, these findings provide further insights into vaccine-induced multifaceted mucosal T-cell immunity with implications in the development of vaccines against respiratory pathogens, including influenza virus and SARS-CoV-2.”

The research suggests a potential strategy for developing a universal flu vaccine, “so you don’t have to make a new vaccine every year,” explained Marulasiddappa Suresh, DVM, a professor of immunology in the School of Veterinary Medicine who led the research. The findings also aid understanding of how to induce and maintain T-cell immunity in the respiratory tract, a knowledge gap that has constrained the development of immunization strategies. The researchers believe the same approach could apply to several other respiratory pathogens, including the novel coronavirus that causes COVID-19.

“We don’t currently have any vaccine for humans on the market that can be given into the mucosa and stimulate T-cell immunity like this,” said Suresh, who is also a veterinarian with specialty training in studying T-cell responses to viral infections.

The strategy addresses the Achilles’ heel of flu vaccines, which is to achieve specific antibody responses to different circulating influenza strains annually, by harnessing T-cell immunity against multiple strains. In particular, the new approach calls into action tissue-resident memory T-cells, or TRM cells, which reside in the airways and lining of lung epithelial cells and combat invading pathogens. Like elite soldiers, TRM cells serve as front line defense against infection.

“We didn’t previously know how to elicit these tissue-resident memory cells with a safe protein vaccine, but we now have a strategy to stimulate them in the lungs that will protect against influenza,” explained Suresh. “As soon as a cell gets infected, these memory cells will kill the infected cells and the infection will be stopped in its tracks before it goes further.”

Flu vaccines work by arming the immune system with an enhanced ability to recognize and fight off the flu virus. Vaccines introduce proteins found on the surface of flu viruses, prompting the immune system to produce antibodies that are primed to react should the virus attack.

However, because strains must be predicted ahead of flu season in order to produce vaccines, the vaccine in any given year may not completely match the viral strains in circulation that season. Flu viruses frequently mutate and can differ across time and from region to region. In addition, protection is neither long-lasting nor universal.

“Even though current vaccines that people get annually stimulate antibody responses, these antibodies don’t cross-protect,” noted Suresh. “If there is a new flu strain not found in that year’s vaccine, the antibodies that we generated last year won’t be able to protect. That’s when pandemics happen because there is a completely new strain for which we have no antibodies. That is a really big problem in the field.”

The vaccine developed by Suresh and his team is directed against an internal protein of influenza, specifically nucleoprotein. This protein is conserved between flu strains, meaning its genetic sequences are similar across different strains of flu.

The vaccine also utilizes a special combination of adjuvants, that enhance an immune response, which the researchers developed to stimulate protective T cells in the lungs. These adjuvants spur T cells to form into different subtypes—in the case of the experimental flu vaccine, memory helper T cells and killer T cells. By doing so, the vaccine leverages multiple modes of immunity.

Researchers demonstrated in a mouse model of influenza that the vaccine provides long-lasting immunity—at least 400 days after vaccination—against multiple flu strains. They will next test the vaccine in ferrets and nonhuman primates, two animal models of influenza research more biologically similar to human infection and transmission.

The vaccine’s combination of adjuvants makes it adaptable to other pathogens and “expands the toolbox” for vaccine research, noted Suresh. He and his team have devised ways to program immunity to target multiple respiratory viruses. They are currently testing the same vaccine strategy against tuberculosis, which infects more than 10 million people globally each year, and human respiratory syncytial virus, or RSV, a major cause of lower respiratory tract infections during infancy and childhood.

The researchers believe the same vaccine technology can be applied against SARS-CoV-2, the coronavirus that causes COVID-19. “Based on the COVID-19 immunology, we know this vaccine strategy would most likely work,” said Suresh.

The team is now developing an experimental vaccine against COVID-19 and conducting laboratory tests to measure its effectiveness in mice and hamsters, animal models for COVID-19. Initial unpublished studies in mice show that the vaccine stimulates strong T-cell immunity against COVID-19 in the lungs.

Along with its adaptability, this vaccine approach may harbor important safety benefits, continued Suresh. Typically, long-lasting T-cell immune responses are stimulated by live vaccines. For instance, the measles, mumps, and chickenpox vaccines administered worldwide are live, replicating vaccines, essentially benign versions of the pathogenic organism. These live vaccines stimulate strong, almost lifelong immunity. However, they can’t typically be given to pregnant or immunocompromised individuals due to health risks.

In the case of the UW-Madison team’s vaccine, because it is a protein vaccine and not a live vaccine, it should be safe for delivery to those who are pregnant or immunocompromised—an advantage in delivering protection to a wider patient population. Suresh added that in recent years, vaccine development efforts have shifted away from live vaccines toward protein vaccines because an increasing number of people are living with compromised immune systems due to chemotherapy, radiation treatments, or conditions such as HIV/AIDS.

“Previously, we didn’t know how to induce T-cell immunity in the lung without live viruses,” explained Suresh. “If we cleverly use a combination adjuvant, which we have developed, you can induce T-cell immunity that should stay in the lungs and protect longer.”

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