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A more efficient flu vaccine
07-25-2017
by Kelsey Kaustinen  |  Email the author
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ATLANTA—Developing annual flu vaccines is a rather involved process. At present, the standard approach involves identifying the most common and virulent strains of influenza currently circulating, trying to determine which ones are most likely to feature in each flu season and then developing a composite vaccine that includes the selected strains. Most years, this approach works fairly well; in others where the most prominent strains aren't included in the vaccine, like this most recent flu season, it's less than effective.
 
Fortunately, there could be a new option in the works, courtesy of research out of Georgia State University. The research group of Dr. Baozhong Wang created a fusion protein—4M2e- tFliC—with four different sequences of M2e from four different influenza subtypes. The M2e peptide is a compound of two or more amino acids linked together and is found in all strains of influenza. This fusion protein contains flagellin (FliC) as well, a peptide that is present in nearly all bacteria with flagella. Flagellin serves as a powerful catalyst when administered with other antigens.
 
The team also sought to boost the effectiveness by changing up the delivery method as well. They condensed their fusion protein into a biodegradable microneedle patch, thanks to a collaboration with Dr. Mark R. Prausnitz of the Georgia Institute of Technology (Georgia Tech). The patch is developed from a biocompatible polymer, with tiny needles on the patch that dissolve and release vaccine into the skin. It is designed to deliver vaccines into the epidermis and dermis of the skin, which represents a promising site for vaccination given the abundance of blood vessels, lymphatic vessels and different immune cell types. Additionally, many skin cells express TLR5, a receptor for FliC that activates the innate immune system.
 
The researchers tested this new approach in combination with existing vaccines. Mice were administered a standard inactivated vaccine—in which pathogens are grown in culture, killed, then introduced to the immune system to allow it to recognize the threat and begin producing antigens—then administered a skin-applied dissolving 4M2e-tFliC microneedle patch. Specifically, the mouse models received the traditional flu vaccine, then four weeks later received either an intramuscular injection of 4M2e-tFliC fusion protein, a microneedle patch skin vaccination of 4M2e- tFliC or a placebo microneedle patch without the antigen.
 
The mice receiving the 4M2e-tFliC “boost” were further tested to see if it affected the immune responses triggered by inactivated influenza vaccines. H1N1 and H3N2 influenza viruses were introduced to the mice, who were then monitored for two weeks with an eye toward body weight and survival. The team then collected samples from the blood, spleens and bone marrow, as well as the lungs, to determine the immunological response. As noted in the study, which was published in the Journal of Controlled Release, “The results demonstrated that mice receiving a conventional inactivated vaccine followed by a skin-applied dissolving 4M2e-tFliC MNP boost could better maintain the humoral antibody response than that by the conventional vaccine-prime alone. Compared with an intramuscular injection boost, mice receiving the MNP boost showed significantly enhanced cellular immune responses, hemagglutination-inhibition (HAI) titers and neutralization titers. Increased frequency of antigen-specific plasma cells and long-lived bone marrow plasma cells was detected in the MNP boosted group as well, indicating that skin vaccination with 4M2e-tFliC facilitated a long- term antibody-mediated immunity.”
 
“Our study demonstrates that M2e-based vaccines greatly improve immune responses and strengthen protective functions against influenza virus infection,” said Wang, associate professor in the Institute for Biomedical Sciences at Georgia State. “We found that a skin-applied 4M2e-tFliC microneedle patch boosted immunization to seasonal vaccine recipients and may be a rapid approach to increasing the protective efficacy of seasonal vaccines in response to influenza virus challenges. Thus, the M2e antigen is a promising candidate for the development of universal influenza vaccines.”
 
And there's promise for this approach in humans as well. Georgia Tech announced on June 27 that in a Phase 1 clinical trial conducted by Emory University (in collaboration with Georgia Tech researchers), flu vaccination using the microneedle patches was safe and well tolerated and just as effective as the traditional intramuscular injection. It was also greatly preferred by trial participants, with more than 70 percent of the patients in the cohorts that received a microneedle patch reporting they would prefer it over other intramuscular or intranasal options. The first-in-human trial of the patches was initiated in June 2015 in 100 healthy individuals who had not been vaccinated during the 2014-2015 flu season. There were no adverse events, and skin reactions to the patches were generally limited to redness and itching that lasted two or three days.
 
Beyond ease of use and lack of discomfort, the patches also offer excellent storage life—while regular vaccines require refrigeration, the vaccines in the patches retained their potency without refrigeration for at least a year.
 
“It’s very gratifying and exciting to have these patches tested in a clinical trial, and with a result that turned out so well,” said Prausnitz in a press release. “We now need to follow this study with a Phase 2 clinical trial involving more people, and we hope that will happen soon.”
 
Code: E07261703

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