Live Attenuated Influenza Virus Expressing Human Interleukin-2 Reveals Increased Immunogenic Potential in Young and Aged Hosts

Abstract

Despite the reported efficacy of commercially available influenza virus vaccines, a considerable proportion of the human population does not respond well to vaccination. In an attempt to improve the immunogenicity of live influenza vaccines, an attenuated, cold-adapted (ca) influenza A virus expressing human interleukin-2 (IL-2) from the NS gene was generated. Intranasal immunization of young adult and aged mice with the IL-2-expressing virus resulted in markedly enhanced mucosal and cellular immune responses compared to those of mice immunized with the nonrecombinant ca parent strain. Interestingly, the mucosal immunoglobulin A (IgA) and CD8؉ T-cell responses in the respiratory compartment could be restored in aged mice primed with the IL-2-expressing virus to magnitudes similar to those in young adult mice. The immunomodulating effect of locally expressed IL-2 also gave rise to a systemic CD8 ؉ T-cell and distant urogenital IgA response in young adult mice, but this effect was less distinct in aged mice. Importantly, only mice immunized with the recombinant IL-2 virus were completely protected from a pathogenic wild-type virus challenge and revealed a stronger onset of virus-specific CD8 ؉ T-cell recall response. Our findings emphasize the potential of reverse genetics to improve the efficacy of live influenza vaccines, thus rendering them more suitable for high-risk age groups.

Evaluation of Recombinant Influenza Virus-Simian Immunodeficiency Virus Vaccines in Macaques

“…Although we show proof of principle that at least three SIV-specific CD8 T-cell responses (one Gag response and two Tat responses, all presented by Mane-A*10) can be boosted simultaneously by this recombinant influenza virus strategy, it could be cumbersome to construct sufficient numbers of influenza virus vectors to broadly cover relevant HIV/SIV T-cell epitopes in outbred populations. Expression of whole heterologous proteins from influenza virus proteins is technically possible and has been achieved with expression of the enhanced green fluorescence protein, interleukin-2, and tuberculosis proteins (21,37,56); however, the stability of such vectors will require careful study. We are currently constructing influenza virus vectors expressing whole SIV proteins.…”

Intranasal co-delivery of IL-6 gene enhances the immunogenicity of anti-caries DNA vaccine

“…Recently, studies have focused on the use of cytokines as intranasal vaccine adjuvants to enhance the immunogenicity of the DNA vaccine because of their potent effects on innate and adaptive immunity as well as functional diversity of immune responses. Studies have shown that cytokines, such as IL-12 [13,14] , IL-2 [15] , IL-15 [16] , type I interferon (IFN) [17,18] , IL-1 [19] , IL-6 [20] , and granulocyte-macrophage colony-stimulating factor (GM-CSF) [21] , enhanced antigen-specific immunity following delivery with different antigens.…”

A genetically adjuvanted influenza B virus vector increases immunogenicity and protective efficacy in mice

“…In this group, cytokines, especially interleukin 2 (IL2), have proved to enhance the immunogenicity and protective efficacy of inactivated influenza vaccines [1,4]. In a previous study, we demonstrated that a cold-adapted (ca) influenza A virus vector co-expressing human IL2 (hIL2) boosted the mucosal IgA and cellular immune response as well as the protection rate after wildtype (wt) influenza virus challenge of aged mice to levels of young mice immunized with a non-IL2-expressing control virus [9].…”