The influenza virus is complicated and constantly evolving. It’s a cunning opponent that has kept scientists who work to prevent and treat it playing a guessing game for more than a century.
Year after year, scientists try to predict which strains of the virus will circulate during the next flu season, then work to create vaccines to target them. They don’t always forecast correctly, and efforts to develop drugs to treat the symptoms have even been thwarted by the virus’ ability to develop resistance.
But researchers in the Institute for Biomedical Sciences are developing innovative ways to battle and cure the flu, from universal vaccines to antiviral treatments. Some of their ground-breaking, federally funded research is now contributing to clinical trials and commercialization projects.
Breakthroughs can’t come soon enough as the virus continues to wreak havoc on human health each flu season. The past two flu seasons resulted in record numbers of hospitalizations and deaths in the United States, especially among the elderly and very young. During the 2018-19 flu season, the Centers for Disease Control and Prevention estimates there were more than 35.5 million illnesses, 490,600 hospitalizations and 34,200 deaths, including 136 deaths of children.
The 2019-20 flu season got off to a rocky, unusual start. There was an early rise of influenza B, a strain of the virus that usually emerges toward the end of the season, leading to a seasonal vaccine mismatch. The number of visits to healthcare providers for flu-like illnesses was also above the national baseline at the earliest point in the season in a decade. Other than the 2009 H1N1 epidemic, the last time this happened was the 2003-04 flu season when a menacing strain of influenza A hit the U.S.
While taking slightly different approaches, two researchers in the Institute for Biomedical Sciences are working toward a common goal — developing a universal flu vaccine.
“A novel approach to fighting the flu is needed because there are several disadvantages to seasonal flu vaccines, including the need to produce new vaccines every season, uncertainty in selecting virus strains and compromised vaccine efficacy when viruses are mismatched,” said Baozhong Wang, an associate professor in the Institute for Biomedical Sciences. “Universal flu vaccines will overcome these challenges.”
Last year, Wang received two federal grants from the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (NIH-NIAID) to fund his work for five years. He received a $3.86 million grant to develop a universal flu vaccine with a microneedle patch and a $3.26 million grant to develop a universal flu vaccine that induces broad cross-protection against influenza A and B viruses.
In his latest work, Wang and his team developed a universal flu vaccine with nanoparticles that effectively offers broad, long-lasting protection against six different influenza viruses in mice. The double-layered nanoparticle vaccine combines two major influenza proteins — matrix protein 2 ectodomain (M2e) and neuraminidase (NA). Mice that were immunized with the nanoparticle vaccine before being exposed to influenza were protected against six different strains of the virus.
The researchers were strategic in choosing the proteins for the vaccine. A similar version of M2e is found in all influenza strains. This protein has also mutated very slowly over time. NA is found on the surface of influenza virus and has also mutated much slower than other surface proteins. The vaccine uses M2e as its core, with a surface coating of NA.
The researchers plan to load this double-layered nanoparticle vaccine onto microneedle patches for skin vaccination. The dry, thermostable formulation and painless, self-manageable skin application would simplify distribution because it wouldn’t need to be kept cold during transport and would allow inoculation without the assistance of a healthcare provider.
Sang-Moo Kang, a professor in the Institute for Biomedical Sciences, was recently awarded a $537,222 contract from the Metaclipse Therapeutics Corp. to improve the efficacy of flu vaccines in young and older mice. The funding, issued by the National Institutes of Health, will be used to evaluate the dose and dosing schedule for an influenza vaccine (CytoFlu) with cytokine-modified virus-like particles. Kang will make comparisons to current vaccines that are in use for the elderly.
The work is significant because elderly adults are extremely vulnerable to the flu, and the research could help to better protect this high-risk population.
In addition, Kang has been developing a universal flu vaccine with the M2 protein, creating tiny, nanometer-sized particles that mimic the size, structure and shape of the virus. In a study published in Frontiers in Immunology, Kang and his colleagues demonstrated their vaccine worked better than seasonal flu vaccines to induce effective cross-protection against several influenza viruses, including H1N1, H3N2 and H5N1.
His work also involves hemagglutinin (HA), the exterior head of influenza virus’ surface protein, which is different for each virus. Using reverse genetics methods, Kang’s laboratory has developed recombinant influenza virus vaccines that are decorated with chimeric HA-M2e conjugate molecules from different influenza viruses. The vaccines use both virus-neutralizing full-length HA and extra conserved M2e epitopes that offer the opportunity for universal protection. This new approach has been reported in the journal Antiviral Research.
“This technology of engineering recombinant influenza viruses has enabled the generation of more effective flu vaccines that are highly compatible with current vaccine platforms and confer effective protection against seasonal viruses as well as cross protection against drifted pandemic viruses,” Kang said.
"A novel approach to fighting the flu is needed because there are several disadvantages to seasonal flu vaccines, including the need to produce new vaccines every season, uncertainty in selecting virus strains and compromised vaccine efficacy when viruses are mismatched."
In another study published in the journal Virology, Kang found that NA, the second major surface antigen (a foreign substance that induces an immune response in the body) on flu viruses, can provide cross-protective immunity against antigenically different influenza viruses when delivered via a virus-like particle carrier. In addition to the strain-specific neutralizing target of HA, vaccine approaches effectively generating immunity against the conserved parts of antigens such as M2e, NA and the stalk region of HA are expected to provide a new applicable, translational and effective universal flu vaccine in the near future.
Institute for Biomedical Sciences professor Richard Plemper wants to help treat those who have already become sick with the flu.
Medical professionals depend on antiviral drugs to prevent serious complications, alleviate flu symptoms and shorten the length of illness, but new drugs are urgently needed because the virus has outsmarted existing treatments.
Tamiflu is increasingly compromised by resistance in circulating strains and the recently approved drug Xofluza has induced viral resistance in 10 percent of patients in clinical trials.
Last year, Plemper received a five-year $5 million grant from the NIH-NIAID to develop a new antiviral flu treatment. The funding is designed to advance translational research projects that have already met critical milestones toward development and have a high likelihood of advancing to clinical testing. Plemper, the principal investigator, has been collaborating with colleagues from the Emory Institute for Drug Development, the University of Georgia and Drug Innovation Ventures at Emory (DRIVE) to advance a novel compound toward an investigational study.
Plemper established an automated drug screening facility at Georgia State and determined dosing requirements for effective antiviral therapy against seasonal and highly pathogenic flu viruses in ferrets and human respiratory epithelial cell cultures. This information will provide insight for clinical trials and human therapy.
In a recent study published in the journal Science Translational Medicine, Plemper and his colleagues demonstrated that this new antiviral drug compound was highly effective in treating influenza infection in ferrets and human airway tissue. The drug blocks RNA polymerase, the enzyme that plays a central role in replicating the genome of the virus, causing mutations in its genetic material. If enough mutations occur, the genome becomes nonfunctional and the virus cannot replicate.
“The compound is highly efficacious against influenza,” Plemper said. “It’s orally available, it’s broad-spectrum against all influenza virus strains tested and, most important, it establishes a high barrier against viral escape from inhibition. We have not identified specific resistance mutations yet and are confident to say that the genetic barrier against viral resistance is high. We believe that this compound has high clinical potential as a next-generation influenza drug that combines key antiviral features.”
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