New research led by Oregon Health & Science University (OHSU) has revealed a promising approach to developing a universal influenza vaccine—a “one and done” vaccine—that confers lifetime immunity against an evolving virus.

The researchers reported that the cytomegalovirus (CMV)-vectored vaccine generated a robust immune response in Mauritian cynomolgus macaques (MCM) that were exposed to the avian H5N1 influenza virus. However, the new vaccine wasn’t based on the contemporary H5N1 virus. Instead, it expressed conserved antigens from the influenza virus of 1918 that killed millions of people worldwide, and was designed to induce a specific T-cell response.

The results confirmed that six of 11 nonhuman primates inoculated against the 1918 flu virus antigens survived exposure to the H5N1 strain, one of the deadliest viruses in the world today. In contrast, a control group of six unvaccinated primates exposed to the H5N1 virus succumbed to the infection.

“It’s exciting because in most cases, this kind of basic science research advances the science very gradually; in 20 years, it might become something,” said research lead Jonah Sacha, PhD, professor and chief of the division of pathobiology at OHSU’s Oregon National Primate Research Center. “This could actually become a vaccine in five years or less,” Sacha said. He believes the platform “absolutely” could be useful against other mutating viruses, including SARS-CoV-2. “It’s a very viable approach,” he said. “For viruses of pandemic potential, it’s critical to have something like this. We set out to test influenza, but we don’t know what’s going to come next.”

Sacha and colleagues reported their study findings in Nature Communications, in a paper titled, “Cytomegalovirus vaccine vector-induced effector memory CD4+ T cells protect cynomolgus macaques from lethal aerosolized heterologous avian influenza challenge.”

The world remains at risk of another influenza pandemic, the authors wrote. “The four influenza pandemics of the past 100 years killed tens of millions of people, yet a universal influenza vaccine capable of protecting against future pandemic influenza viruses still does not exist.”

Of particular concern are highly pathogenic avian influenza (HPAI) viruses such as H5N1, which has a fatality rate of 52% in humans, the investigators noted. “… new vaccine approaches capable of protecting against all influenza strains, and particularly against HPAI with pandemic potential, are urgently needed.” Commented co-corresponding author Douglas Reed, PhD, associate professor of immunology at the University of Pittsburgh Center for Vaccine Research, “Should a deadly virus such as H5N1 infect a human and ignite a pandemic, we need to quickly validate and deploy a new vaccine.”

The researchers’ newly reported approach harnesses a vaccine platform previously developed by scientists at OHSU to fight HIV and tuberculosis, and is already being used in a clinical trial against HIV. The method involves inserting small pieces of target pathogens into the common herpes virus cytomegalovirus, or CMV, which infects most people in their lifetimes and typically produces mild or no symptoms. The virus acts as a vector specifically designed to induce an immune response from the body’s own T cells.

This approach differs from common vaccines—including the existing flu vaccines—which are designed to induce an antibody response that targets the most recent evolution of the virus that is distinguished by the arrangement of proteins covering the exterior surface. “Current antibody-mediated influenza vaccines are strain-specific due to targeting of the highly variable hemagglutinin (HA) and neuraminidase (NA) glycoproteins,” the team continued.

Jonah Sacha, PhD, senior co-author of a study published today in the journal Nature Communications, says the research could lead to a universal influenza vaccine within five years. [OHSU/Christine Torres Hicks]
Jonah Sacha, PhD, senior co-author of a study published in Nature Communications, said the research could lead to a universal influenza vaccine within five years. [OHSU/Christine Torres Hicks]
“The problem with influenza is that it’s not just one virus,” Sacha said. “Like the SARS-CoV-2 virus, it’s always evolving the next variant and we’re always left to chase where the virus was, not where it’s going to be.”

The spike proteins on the virus exterior surface evolve to elude antibodies. In the case of flu, vaccines are updated regularly using a best estimate of the next evolution of the virus. Sometimes it’s accurate, sometimes less so. “… given the continual sequence evolution of HA and NA through antigenic drift and ability of the segmented virus to recombine two or more different strains through antigenic shift, seasonal influenza vaccine effectiveness ranges from 30% to 60% depending on matching of the vaccine sequence to influenza viruses subsequently circulating that year,” the investigators stated.

In contrast, effector memory T cells (TEM cells) in the lung target the internal structural proteins of the virus, rather than its continually mutating outer envelope. This internal structure doesn’t change much over time—presenting a stationary target for T cells to search out and destroy any cells infected by an old or newly evolved influenza virus.

To test their T cell theory, the researchers designed a cynomolgus CMV (cyCMV)-based vaccine using the 1918 influenza virus as a template. The vaccines expressed H1N1 1918 influenza M1, NP, and PB1 antigens (CyCMV/Flu). They exposed CyCMV/flu-vaccinated nonhuman primates to small particle aerosols containing the avian H5N1 influenza virus—a severe virus that is currently circulating among dairy cows in the United States. The team found that, remarkably, six of the 11 vaccinated primates survived the exposure, despite the century-long period of virus evolution. The authors further noted, “Overall, we demonstrate that CyCMV vaccine vector-induced, influenza-specific CD4+ TEM protect MCM from an otherwise lethal HPAI infection … Survival correlates with the magnitude of lung-resident influenza-specific CD4 + T cells prior to challenge.”

Sacha added, “It worked because the interior protein of the virus was so well preserved. So much so, that even after almost 100 years of evolution, the virus can’t change those critically important parts of itself.”

The scientists noted that while it’s likely that a universal influenza vaccine will have to activate both humoral and cellular immune responses, the CMV vaccine vector platform is “unique” given its ability to elicit and maintain long-lived TEM, and this could be paired with a separate platform to stimulate both arms of the immune system. With CMV vectors now in clinical trials for HIV, there’s also a direct pathway forward for testing influenza-specific vectors in humans. “Further such studies are required to determine if CMV-induced TEM can contribute to the development of a universal influenza vaccine,” the authors pointed out.

“Inhalation of aerosolized H5N1 influenza virus causes a cascade of events that can trigger respiratory failure,” added co-senior author Simon Barratt-Boyes, PhD, professor of infectious diseases, microbiology and immunology at Pitt. “The immunity induced by the vaccine was sufficient to limit virus infection and lung damage, protecting the monkeys from this very serious infection.” By synthesizing more up-to-date virus templates, the new study suggests CMV vaccines may be able to generate an effective, long-lasting immune response against a wide suite of new variants. “I think it means within five to 10 years, a one-and-done shot for influenza is realistic,” Sacha said.

The same CMV platform developed by OHSU researchers has advanced to a clinical trial to protect against HIV, and a recent publication by those scientists suggests it may even be useful targeting specific cancer cells. Sacha sees the development as the latest in the rapid advance of medical research to treat or prevent disease. “It’s a massive sea change within our lifetimes,” Sacha said. “There is no question we are on the cusp of the next generation of how we address infectious disease.”

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