Adeno‐associated virus‐vectored influenza vaccine elicits neutralizing and Fcγ receptor‐activating antibodies

Abstract

The current seasonal inactivated influenza vaccine protects only against a narrow range of virus strains as it triggers a dominant antibody response toward the hypervariable hemagglutinin (HA) head region. The discovery of rare broadly protective antibodies against conserved regions in influenza virus proteins has propelled research on distinct antigens and delivery methods to efficiently induce broad immunity toward drifted or shifted virus strains.Here, we report that adeno-associated virus (AAV) vectors expressing influenza virus HA or chimeric HA protected mice against homologous and heterologous virus challenges. Unexpectedly, immunization even with wild-type HA induced antibodies recognizing the HA-stalk and activating FccR-dependent responses indicating that AAV-vectored expression balances HA head-and HA stalk-specific humoral responses. Immunization with AAV-HA partially protected also ferrets against a harsh virus challenge. Results from this study provide a rationale for further clinical development of AAV vectors as influenza vaccine platform, which could benefit from their approved use in human gene therapy.

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“…[ 31 ] In fact, Demminger et al used a recombinant AAV vector carrying an influenza hemagglutinin expression cassette to show that broadly reactive neutralizing antibodies were induced and protected against influenza viruses with different mutations. [ 34 ] In addition, Yusuf et al have demonstrated that recombinant AAV‐based immunization after adenovirus priming was able to induce a long‐lasting antibody response in a mouse model. [ 32 ] Recombinant AAV technology has been considered for SARS‐CoV‐1 with promising results.…”

“…[30] Therefore, it has been mainly used as a delivery system for either gene therapy or antigens for immunogenicity. [28][29][30][31][32][33][34] Gene therapy has focused on cancer and neurodegenerative diseases, using recombinant AAV, in which the viral genetic code is replaced with a gene of interest. [31,35] However, the replacement gene must be similar or smaller than the 4.7 kb AAV genes or the stability of the recombinant AAV will suffer.…”

“…[61] It has been suggested that using multistructural VLPs as vaccines, instead of the classic influenza vaccine method using embryonated chicken eggs, could produce immune responses that would defend against the different forms of influenza. [34,60,62,63] More investigation is necessary, but influenza VLPs have the potential to save time and labor spent continuously developing subtype-and strain-specific influenza vaccines. Even as VLPs are used to address challenges that plagued for centuries, they are also being considered as novel infectious diseases emerge.…”

“…(2016) [31] Leber congenital amaurosis FDA approved Wang et al (2019) [29] HIV-1 Preclinical Lin et al (2018) [28] Influenza Preclinical Demminger et al (2020) [34] SARS-CoV-1 Preclinical Du et al (2008) [33] SARS-CoV-2 Phase III Logunev et al (2020) [36] Folegatti et al (2020) [37] VLPs HPV FDA approved Wang et al (2013) [45]…”

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“…The use of adeno‐associated virus (AAV) vectors as vaccine platforms have also been studied for infectious diseases including HIV‐1, HPV, influenza (H1N1), and hepatitis C (ClinicalTrials.gov, 2020a; Demminger et al, 2020; Naso, Tomkowicz, Perry 3rd, & Strohl, 2017; Nieto & Salvetti, 2014; Ramezanpour et al, 2016; Ura et al, 2014; Vardas et al, 2010; Zhu et al, 2019). The rarity of AAV‐based vaccines in clinical trials is due to its relatively weak ability to induce humoral and cellular immune response when compared to other viral vectors (Ura et al, 2014).…”