A DNA Vaccine That Targets Hemagglutinin to Antigen-Presenting Cells Protects Mice against H7 Influenza

Abstract

Zoonotic influenza H7 viral infections have a case fatality rate of about 40%. Currently, no or limited human to human spread has occurred, but we may be facing a severe pandemic threat if the virus acquires the ability to transmit between humans. Novel vaccines that can be rapidly produced for global distribution are urgently needed, and DNA vaccines may be the only type of vaccine that allows for the speed necessary to quench an emerging pandemic. Here, we constructed DNA vaccines encoding the hemagglutinin (HA) from influenza A/chicken/Italy/13474/99 (H7N1). In order to increase the efficacy of DNA vaccination, HA was targeted to either major histocompatibility complex class II molecules or chemokine receptors 1, 3, and 5 (CCR1/3/5) that are expressed on antigen-presenting cells (APC). A single DNA vaccination with APC-targeted HA significantly increased antibody levels in sera compared to nontargeted control vaccines. The antibodies were confirmed neutralizing in an H7 pseudotype-based neutralization assay. Furthermore, the APC-targeted vaccines increased the levels of antigen-specific cytotoxic T cells, and a single DNA vaccination could confer protection against a lethal challenge with influenza A/turkey/Italy/3889/1999 (H7N1) in mice. In conclusion, we have developed a vaccine that rapidly could contribute protection against a pandemic threat from avian influenza.IMPORTANCE Highly pathogenic avian influenza H7 constitute a pandemic threat that can cause severe illness and death in infected individuals. Vaccination is the main method of prophylaxis against influenza, but current vaccine strategies fall short in a pandemic situation due to a prolonged production time and insufficient production capabilities. In contrast, a DNA vaccine can be rapidly produced and deployed to prevent the potential escalation of a highly pathogenic influenza pandemic. We here demonstrate that a single DNA delivery of hemagglutinin from an H7 influenza could mediate full protection against a lethal challenge with H7N1 influenza in mice. Vaccine efficacy was contingent on targeting of the secreted vaccine protein to antigen-presenting cells.

The Magnitude and IgG Subclass of Antibodies Elicited by Targeted DNA Vaccines Are Influenced by Specificity for APC Surface Molecules

“…DNA vaccines are attractive because they are safe, and can be rapidly constructed and produced in large amounts. This is important in situations of pandemic threats, e.g., with avian influenza virus (52). Another advantage of DNA vaccines is their relative independence of a cold chain, due to the high resistance of DNA to degradation.…”

A Review of DNA Vaccines Against Influenza

“…Ferrets and pigs vaccinated with plasmids expressing the targeted H1 fusion protein generated significant antibody titres, whereas H1 DNA alone failed to cause seroconversion. A similar DNA vaccine strategy expressing APC-targeted H7 fusion proteins was found to improve anti-HA serum antibody and cytotoxic T cell responses to highly pathogenic avian influenza ( 56 ).…”

Potential Role of Rainbow Trout Erythrocytes as Mediators in the Immune Response Induced by a DNA Vaccine in Fish

“…Regarding RBCs, in recent decades, mammalian RBCs, which are not nucleated, have been proposed as possible drug and vaccine carriers [15,16,17,18] because of their capacity to induce effective immune responses comparable to traditional vaccination [15]. Additionally, DNA vaccines directed to antigen-presenting cells (APCs) have demonstrated improved humoral and cellular responses compared to non-targeted vaccines in mammalian models [19,20,21]. Considering that fish RBCs have been proposed to behave as atypical APCs [22], the strategy of targeting DNA vaccines or immunostimulants to RBCs represents a new approach in the field of fish prophylaxis.…”