Efficient vaccine against pandemic influenza: combining DNA vaccination and targeted delivery to MHC class II molecules

Grødeland, Gunnveig; Bogen, Bjarne

doi:10.1586/14760584.2015.1029919

Cited by 19 publications

(21 citation statements)

References 87 publications

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“…For targeted DNA vaccines to induce Abs, it is important that the included Ags express conformation-dependent antigenic determinants recognized by the BCR of B cells (10). Moreover, induction of Abs appears to be enhanced if plasmids encode dimeric (rather than monomeric) APC-targeting fusion proteins, presumably due to a need for cross-linking of BCRs (11).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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Upon APC-targeted DNA vaccination, transfected cells secrete fusion proteins with targeting units specific for surface molecules on APC. In this study, we have tested several different targeting units for their ability to influence the magnitude and subclass of Ab responses to hemagglutinin from influenza A virus. The experiments employed bivalent homodimeric Ig-based molecules (vaccibodies). The overall efficiency in BALB/c mice depended on the targeting units in the following order: αMHC class II > αCD11c > αCD40 > Xcl-1 = MIP-1α > FliC > GM-CSF > Flt-3L > αDEC205. GM-CSF induced mainly IgG1, whereas Xcl1, MIP-1α, αCD40, and αDEC205 induced predominantly IgG2a. A more balanced mixture of IgG1 and IgG2a was observed with αCD11c, αMHC class II, Flt-3L, and FliC. Similar results of IgG subclass–skewing were obtained in Th1-prone C57BL/6 mice with a more limited panel of vaccines. IgG1 responses in BALB/c occurred early after immunization but declined relatively rapidly over time. IgG2a responses appeared later but lasted longer (>252 d) than IgG1 responses. The most efficient targeting units elicited short- and long-term protection against PR8 influenza (H1N1) virus in BALB/c mice. The results suggest that targeting of Xcr1+ conventional type 1 dendritic cells preferentially induces IgG2a responses, whereas simultaneous targeting of several dendritic cell subtypes also induces IgG1 responses. The induction of distinct subclass profiles by different surface molecules supports the APC–B cell synapse hypothesis. The results may contribute to generation of more potent DNA vaccines that elicit high levels of Abs with desired biologic effector functions.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…To this end, in this study we have used a DNA vaccine format that encodes secreted bivalent vaccine proteins composed of targeting units, dimerization units, and full-length Ags (14,16,17,22,23). Because human MHC-II (HLA class II [HLA-II]) molecules are highly polymorphic, and because a vaccine should be deployable in all humans, we generated two different scFv targeting units that should bind HLA-II molecules in humans.…”

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confidence: 99%

Antigen Targeting to Human HLA Class II Molecules Increases Efficacy of DNA Vaccination

Grødeland

Fredriksen²,

Løset

et al. 2016

The Journal of Immunology

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It has been difficult to translate promising results from DNA vaccination in mice to larger animals and humans. Previously, DNA vaccines encoding proteins that target Ag to MHC class II (MHC-II) molecules on APCs have been shown to induce rapid, enhanced, and long-lasting Ag-specific Ab titers in mice. In this study, we describe two novel DNA vaccines that as proteins target HLA class II (HLA-II) molecules. These vaccine proteins cross-react with MHC-II molecules in several species of larger mammals. When tested in ferrets and pigs, a single DNA delivery with low doses of the HLA-II–targeted vaccines resulted in rapid and increased Ab responses. Importantly, painless intradermal jet delivery of DNA was as effective as delivery by needle injection followed by electroporation. As an indication that the vaccines could also be useful for human application, HLA-II–targeted vaccine proteins were found to increase human CD4+ T cell responses by a factor of ×103 in vitro. Thus, targeting of Ag to MHC-II molecules may represent an attractive strategy for increasing efficacy of DNA vaccines in larger animals and humans.

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“…We have previously demonstrated that targeting of HA from H1N1 influenza viruses to MHCII molecules rapidly induced protective levels of neutralizing Abs in mice (18) and larger animals (21) and that APC-targeted DNA vaccines could be produced within 1 mo after identification of the viral sequence (28). In this article, we have demonstrated that this versatile and flexible format also contributed to improved Ab responses when extended to a mixture of six subtypes of influenza (H5, H6, H8, H9, H11, and H13).…”

Section: Discussionmentioning

confidence: 99%

“…We have hypothesized that this may be due to the formation of APC-B cell synapses in which MHCII-targeted vaccine proteins bridge the two cell types (16,27,28). Indeed, APC-B cell synapses have been demonstrated in vitro (33); however, in vivo evidence is lacking.…”

Section: Discussionmentioning

confidence: 99%

“…The increased efficacy conferred by MHCII targeting of Ag has recently been translated to influenza vaccination of ferrets and pigs (21). As a mechanism for enhanced Ab induction, it has been suggested that the DNA-encoded anti-MHCII-HA vaccine proteins bridge B cells and APCs in an APC-B cell synapse (16,27,28). In this article, we show that the same MHCII-targeted DNA vaccine format can induce strong Ab responses against H5, H6, H8, H9, H11, and H13 subtypes of group 1 influenza viruses.…”

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confidence: 99%

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Simultaneous Targeting of Multiple Hemagglutinins to APCs for Induction of Broad Immunity against Influenza

Anderson

Baranowska-Hustad

Braathen

et al. 2018

The Journal of Immunology

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There is a need for vaccines that can confer broad immunity against highly diverse pathogens, such as influenza. The efficacy of conventional influenza vaccines is dependent on accurate matching of vaccines to circulating strains, but slow and limited production capacities increase the probability of vaccine mismatches. In contrast, DNA vaccination allows for rapid production of vaccines encoding novel influenza Ags. The efficacy of DNA vaccination is greatly improved if the DNA-encoded vaccine proteins target APCs. In this study, we have used hemagglutinin (HA) genes from each of six group 1 influenza viruses (H5, H6, H8, H9, H11, and H13), and inserted these into a DNA vaccine format that induces delivery of the HA protein Ags to MHC class II molecules on APCs. Each of the targeted DNA vaccines induced high titers of strain-specific anti-HA Abs. Importantly, when the six HA vaccines were mixed and injected simultaneously, the strain-specific Ab titers were maintained. In addition, the vaccine mixture induced Abs that cross-reacted with strains not included in the vaccine mixture (H1) and could protect mice against a heterosubtypic challenge with the H1 viruses A/Puerto Rico/8/1934 (H1N1) and A/California/07/2009 (H1N1). The data suggest that vaccination with a mixture of HAs could be useful for induction of strain-specific immunity against strains represented in the mixture and, in addition, confer some degree of cross-protection against unrelated influenza strains.

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Efficient vaccine against pandemic influenza: combining DNA vaccination and targeted delivery to MHC class II molecules

Cited by 19 publications

References 87 publications

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

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

Antigen Targeting to Human HLA Class II Molecules Increases Efficacy of DNA Vaccination

Simultaneous Targeting of Multiple Hemagglutinins to APCs for Induction of Broad Immunity against Influenza

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