Cross-protective immunity against multiple influenza virus subtypes by a novel modified vaccinia Ankara (MVA) vectored vaccine in mice

Self Cite

A critical failure in our preparedness for an influenza pandemic is the lack of a universal vaccine. Influenza virus strains diverge by 1 to 2% per year, and commercially available vaccines often do not elicit protection from one year to the next, necessitating frequent formulation changes. This represents a major challenge to the development of a cross-protective vaccine that can protect against circulating viral antigenic diversity. We have constructed a recombinant modified vaccinia virus Ankara (MVA) that expresses an H5N1 mosaic hemagglutinin (H5M) (MVA-H5M). This mosaic was generated in silico using 2,145 field-sourced H5N1 isolates. A single dose of MVA-H5M provided 100% protection in mice against clade 0, 1, and 2 avian influenza viruses and also protected against seasonal H1N1 virus (A/Puerto Rico/8/34). It also provided short-term (10 days) and long-term (6 months) protection postvaccination. Both neutralizing antibodies and antigen-specific CD4 ؉ and CD8 ؉ T cells were still detected at 5 months postvaccination, suggesting that MVA-H5M provides long-lasting immunity. IMPORTANCEInfluenza viruses infect a billion people and cause up to 500,000 deaths every year. A major problem in combating influenza is the lack of broadly effective vaccines. One solution from the field of human immunodeficiency virus vaccinology involves a novel in silico mosaic approach that has been shown to provide broad and robust protection against highly variable viruses. Unlike a consensus algorithm which picks the most frequent residue at each position, the mosaic method chooses the most frequent Tcell epitopes and combines them to form a synthetic antigen. These studies demonstrated that a mosaic influenza virus H5 hemagglutinin expressed by a viral vector can elicit full protection against diverse H5N1 challenges as well as induce broader immunity than a wild-type hemagglutinin.

Section: Construction Of Pox-based H5n1 Mosaic Hemagglutinin Vaccinementioning

confidence: 89%

mentioning

confidence: 99%

Broad Protection against Avian Influenza Virus by Using a Modified Vaccinia Ankara Virus Expressing a Mosaic Hemagglutinin Gene

Kamlangdee

Kingstad-Bakke

Anderson

et al. 2014

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“…Groups of 5-week-old BALB/c female mice were used as an animal model for vaccine studies. For the MVA-based vaccine, mice were vaccinated with 1.25 ϫ 10 7 PFU of recombinant MVA expressing mosaic H5 (MVA-H5M) (12), MVA expressing native HA from influenza virus A/Vietnam/1203/04 (MVA-HA) (14), or MVA expressing green fluorescent protein (MVA-GFP) (12) via the intradermal (i.d.) route.…”

Section: Cellsmentioning

confidence: 99%

“…T cell responses were analyzed by using an intracellular cytokine staining (ICS) assay, as previously described (12,14). Briefly, vaccinated BALB/c mice were euthanized 6 weeks postpriming (n ϭ 6), and the spleens were aseptically removed.…”

Section: Cellsmentioning

confidence: 99%

Mosaic H5 Hemagglutinin Provides Broad Humoral and Cellular Immune Responses against Influenza Viruses

Kamlangdee

Kingstad-Bakke

Osorio

2016

Self Cite

The most effective way to prevent influenza virus infection is via vaccination. However, the constant mutation of influenza viruses due to antigenic drift and shift compromises vaccine efficacy. This represents a major challenge to the development of a cross-protective vaccine that can protect against circulating viral antigenic diversity. Using the modified vaccinia Ankara (MVA) virus, we had previously generated a recombinant vaccine against highly pathogenic avian influenza virus (H5N1) based on an in silico mosaic approach. This MVA-H5M construct protected mice against multiple clades of H5N1 and H1N1 viruses. We have now further characterized the immune responses using immunodepletion of T cells and passive serum transfer, and these studies indicate that antibodies are the main contributors in homosubtypic protection (H5N1 clades). Influenza viruses still pose a serious threat for both humans and animals. Every year, seasonal influenza infects an estimated one billion people around the globe, resulting in 3 to 5 million severe cases (1). Avian influenza viruses, especially highly pathogenic avian influenza (HPAI) H5N1 viruses, have also caused public health concerns and have the potential to cause the next influenza pandemic. The main intervention strategy against both seasonal and pandemic influenza viruses is vaccination.Conventional vaccination methods against influenza viruses include inactivated (whole virus, split, or subunit) and live-attenuated influenza vaccine (LAIV). These vaccines provide protection by inducing a hemagglutinin (HA)-specific neutralizing antibody. The efficacy of inactivated vaccines and LAIVs are strongly affected by antigenic mismatch between circulating and vaccine strains. Inactivated vaccine effectiveness is about 50 to 70% based on age and health condition but can be as low as 30% (2). LAIVs are, in general, more broadly protective than inactivated vaccines and can have up to 93% overall efficacy against matched strains (3). However, LAIVs are still significantly less effective against mismatched strains. In addition, seasonal vaccine strains need to be selected each year to match the circulating strain. Inactivated vaccines from specific strains of H5N1 virus have been generated and stockpiled, in case of a pandemic, but this vaccine is also less effective against heterologous H5N1 strains (4).Several vaccine approaches have attempted to address the high genetic variation of influenza viruses that can occur via antigenic drift and shift. One such strategy is based on choosing immunogens from conserved regions of the HA stalk domain (5, 6) or highly conserved proteins such as the M2 gene (7,8). Alternative approaches have attempted to centralize the virus antigenic sequences by using a consensus algorithm (9). Recently, a novel "mosaic" approach has been introduced in the field of human immunodeficiency virus (HIV) vaccinology and has been shown to provide broader protection against mismatched HIV strains than natural or consensus-derived antigens (10). The algorit...

“…For the efficient induction of CD8 ϩ T cell responses, proteins need to be processed endogenously for MHC class I-restricted antigen presentation, which requires the delivery of vaccine antigens to the cytosol of antigen-presenting cells (APCs). Modified vaccinia virus Ankara (MVA) is a vaccine vector that has been shown to efficiently induce T cell responses in various animal models and in humans (32)(33)(34)(35)(36)(37)(38)(39)(40)(41). Other advantages include the rapid production of an MVA-based vaccine, the easy and stable insertion of a transgene of interest, intrinsic adjuvant capacities, and an excellent safety record, even in immunosuppressed macaques and elderly people (41)(42)(43)(44).…”

mentioning

confidence: 99%

Increased Protein Degradation Improves Influenza Virus Nucleoprotein-Specific CD8⁺T Cell ActivationIn Vitrobut Not in C57BL/6 Mice

Altenburg

Sandt

Trierum

et al. 2016

Due to antigenic drift of influenza viruses, seasonal influenza vaccines need to be updated annually. These vaccines are based on predictions of strains likely to circulate in the next season. However, vaccine efficacy is greatly reduced in the case of a mismatch between circulating and vaccine strains. Furthermore, novel antigenically distinct influenza viruses are introduced into the human population from animal reservoirs occasionally and may cause pandemic outbreaks. To dampen the impact of seasonal and pandemic influenza, vaccines that induce broadly protective and long-lasting immunity are preferred. Because influenza virusspecific CD8؉ T cells are directed mainly against relatively conserved internal proteins, like nucleoprotein (NP), they are highly cross-reactive and afford protection against infection with antigenically distinct influenza virus strains, so-called heterosubtypic immunity. Here, we used modified vaccinia virus Ankara (MVA) as a vaccine vector for the induction of influenza virus NP-specific CD8 ؉ T cells. To optimize the induction of CD8 ؉ T cell responses, we made several modifications to NP, aiming at retaining the protein in the cytosol or targeting it to the proteasome. We hypothesized that these strategies would increase antigen processing and presentation and thus improve the induction of CD8 ؉ T cell responses. We showed that NP with increased degradation rates improved CD8 ؉ T cell activation in vitro if the amount of antigen was limited or if CD8 ؉ T cells were of low functional avidity. However, after immunization of C57BL/6 mice, no differences were detected between modified NP and wild-type NP (NPwt), since NPwt already induced optimal CD8 ؉ T cell responses. IMPORTANCEDue to the continuous antigenic drift of seasonal influenza viruses and the threat of a novel pandemic, there is a great need for the development of novel influenza vaccines that offer broadly protective immunity against multiple subtypes. CD8 ؉ T cells can provide immunity against multiple subtypes of influenza viruses by the recognition of relatively conserved internal antigens. In this study, we aimed at optimizing the CD8 ؉ T cell response to influenza A virus by making modifications to influenza A virus nucleoprotein (NP) expressed from the modified vaccinia virus Ankara (MVA) vaccine vector. These modifications resulted in increased antigen degradation, thereby producing elevated levels of peptides that can be presented on major histocompatibility complex (MHC) class I molecules to CD8 ؉ T cells. Although we were unable to increase the NP-specific immune response in the mouse strain used, this approach may have benefits for vaccine development using less-immunogenic proteins.