A novel liposomal influenza vaccine (INFLUSOME-VAC) containing hemagglutinin–neuraminidase and IL-2 or GM-CSF induces protective anti-neuraminidase antibodies cross-reacting with a wide spectrum of influenza A viral strains

Babai, Ilan; Barenholz, Yechezkel; Zakay‐Rones, Zichria; Greenbaum, Evgenia; Samira, Sarit; Hayon, I; Rochman, Mark; Kedar, Eli

doi:10.1016/s0264-410x(01)00326-7

Cited by 59 publications

(22 citation statements)

References 35 publications

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“…IL-2 plays a crucial role in the stimulation and maturation of the immune system and is frequently used as a vaccine supplement or genetic adjuvant (1,4,9,16,34,37,38,52,62). For this reason, we compared the immunogenicities of the attenuated influenza ca Sing virus and a modified variant which expresses biologically active IL-2 in young adult and aged mice.…”

Section: Discussionmentioning

confidence: 99%

“…The previous investigation of a broad variety of adjuvants comprising immunomodulating cytokines as vaccine supplements has shown them to improve the immunogenicity of vaccines directed against various infectious diseases (1,8,47,49,53,65). Utilization of human interleukin-2 (IL-2) as a vaccine supplement resulted, for example, in enhanced immunogenicity and protection efficacy of the inactivated influenza vaccine not only in young but also in aged hosts (1,4,5,37).…”

mentioning

confidence: 99%

“…Utilization of human interleukin-2 (IL-2) as a vaccine supplement resulted, for example, in enhanced immunogenicity and protection efficacy of the inactivated influenza vaccine not only in young but also in aged hosts (1,4,5,37). The beneficial immunomodulating effect of IL-2 on the immune system could also be demonstrated when IL-2 was encoded by different viral vectors, virus-like particles, or DNA candidate vaccines in approaches aimed at combating infectious diseases or in antitumor therapy programs (9,16,34,38,62).…”

mentioning

confidence: 99%

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

Ferko

Kittel

Romanova

et al. 2006

J Virol

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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.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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

Ferko

Kittel

Romanova

et al. 2006

J Virol

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“…Several attempts have been made to apply inactivated vaccines intranasally. A combination of intranasally administered inactivated vaccine preparations with mucosal adjuvants, such as cholera toxin B or Escherichia coli heat-labile toxin B, could provide cross-protection in mice [26]–[29]. Promising results were obtained in mice with an influenza Virus-Like Particle (VLP) intranasal vaccine eliciting a cross-protective immune response without the addition of an adjuvant after two immunizations [30].…”

Section: Introductionmentioning

confidence: 99%

Preclinical Evaluation of a Replication-Deficient Intranasal ΔNS1 H5N1 Influenza Vaccine

Romanova¹,

Krenn²,

Wolschek

et al. 2009

PLoS ONE

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BackgroundWe developed a novel intranasal influenza vaccine approach that is based on the construction of replication-deficient vaccine viruses that lack the entire NS1 gene (ΔNS1 virus). We previously showed that these viruses undergo abortive replication in the respiratory tract of animals. The local release of type I interferons and other cytokines and chemokines in the upper respiratory tract may have a “self-adjuvant effect”, in turn increasing vaccine immunogenicity. As a result, ΔNS1 viruses elicit strong B- and T- cell mediated immune responses.Methodology/Principal FindingsWe applied this technology to the development of a pandemic H5N1 vaccine candidate. The vaccine virus was constructed by reverse genetics in Vero cells, as a 5∶3 reassortant, encoding four proteins HA, NA, M1, and M2 of the A/Vietnam/1203/04 virus while the remaining genes were derived from IVR-116. The HA cleavage site was modified in a trypsin dependent manner, serving as the second attenuation factor in addition to the deleted NS1 gene. The vaccine candidate was able to grow in the Vero cells that were cultivated in a serum free medium to titers exceeding 8 log10 TCID50/ml. The vaccine virus was replication deficient in interferon competent cells and did not lead to viral shedding in the vaccinated animals. The studies performed in three animal models confirmed the safety and immunogenicity of the vaccine. Intranasal immunization protected ferrets and mice from being infected with influenza H5 viruses of different clades. In a primate model (Macaca mulatta), one dose of vaccine delivered intranasally was sufficient for the induction of antibodies against homologous A/Vietnam/1203/04 and heterologous A/Indonesia/5/05 H5N1 strains.Conclusion/SignificanceOur findings show that intranasal immunization with the replication deficient H5N1 ΔNS1 vaccine candidate is sufficient to induce a protective immune response against H5N1 viruses. This approach might be attractive as an alternative to conventional influenza vaccines. Clinical evaluation of ΔNS1 pandemic and seasonal influenza vaccine candidates are currently in progress.

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“…It is also known that IL-2 acts as an immune adjuvant. Encouraging results were obtained with mice when IL-2 was coadministered with a liposome-based influenza vaccine, resulting in an increased antibody titer and the induction of better heterosubtypic protective immunity (1,2).…”

Section: Discussionmentioning

confidence: 99%

Generation of an Influenza A Virus Vector Expressing Biologically Active Human Interleukin-2 from the NS Gene Segment

Kittel¹,

Ferko

Kurz

et al. 2005

J Virol

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Engineering of the influenza A virus NS1 protein became an attractive approach to the development of influenza vaccine vectors since it can tolerate large inserts of foreign proteins. However, influenza virus vectors expressing long foreign sequences from the NS1 open reading frame (ORF) are usually replication deficient in animals due to the abrogation of their NS1 protein function. In this study, we describe a bicistronic expression strategy based on the insertion of an overlapping UAAUG stop-start codon cassette into the NS gene, allowing the reinitiation of translation of a foreign sequence. Although the expression level of green fluorescent protein (GFP) from the newly created reading frame was significantly lower than that obtained previously from an influenza virus vector expressing GFP from the NS1 ORF, the bicistronic vector appeared to be replication competent in mice and showed outstanding genetic stability. All viral isolates derived from mouse lungs at 10 days postinfection were still capable of expressing GFP in infected cells. Utilizing this bicistronic approach, we constructed another recombinant influenza virus, allowing the secretion of biologically active human interleukin-2 (IL-2). Although this virus also replicated to high titers in mouse lungs, it did not display any mortality rate in infected animals, in contrast to control viruses. Moreover, the IL-2-expressing virus showed an enhanced CD8 ؉ response to viral antigens in mice after a single intranasal immunization. These results indicate that influenza viruses could be engineered for the expression of biologically active molecules such as cytokines for immune modulation purposes.

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A novel liposomal influenza vaccine (INFLUSOME-VAC) containing hemagglutinin–neuraminidase and IL-2 or GM-CSF induces protective anti-neuraminidase antibodies cross-reacting with a wide spectrum of influenza A viral strains

Cited by 59 publications

References 35 publications

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

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

Preclinical Evaluation of a Replication-Deficient Intranasal ΔNS1 H5N1 Influenza Vaccine

Generation of an Influenza A Virus Vector Expressing Biologically Active Human Interleukin-2 from the NS Gene Segment

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