Incorporation of a GPI-anchored engineered cytokine as a molecular adjuvant enhances the immunogenicity of HIV VLPs

Feng, Hao; Zhang, Han; Deng, Jiusheng; Wang, Li; He, Yuan; Wang, Shelly; Seyedtabaei, Roheila; Wang, Qing; Liu, Laiting; Galipeau, Jacques; Compans, Richard W.; Wang, Bao‐Zhong

doi:10.1038/srep11856

Cited by 25 publications

(26 citation statements)

References 57 publications

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“…These fusokines have shown promise in prophylactic HIV vaccination studies in guinea pigs when anchored via glycolipids to virus-like particles (VLPs) [72]. These reports and our present findings suggest that the potency of GM-CSF as an adjuvant is dependent on administration route and formulation.…”

Section: Discussionsupporting

confidence: 59%

Stable incorporation of GM-CSF into dissolvable microneedle patch improves skin vaccination against influenza

Littauer

Mills

Brock

et al. 2018

Journal of Controlled Release

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The widely used influenza subunit vaccine would benefit from increased protection rates in vulnerable populations. Skin immunization by microneedle (MN) patch can increase vaccine immunogenicity, as well as increase vaccination coverage due to simplified administration. To further increase immunogenicity, we used granulocyte-macrophage colony stimulating factor (GM-CSF), an immunomodulatory cytokine already approved for skin cancer therapy and cancer support treatment. GM-CSF has been shown to be upregulated in skin following MN insertion. The GM-CSF-adjuvanted vaccine induced robust and long-lived antibody responses cross-reactive to homosubtypic and heterosubtypic influenza viruses. Addition of GM-CSF resulted in increased memory B cell persistence relative to groups given influenza vaccine alone and led to rapid lung viral clearance following lethal infection with homologous virus in the mouse model. Here we demonstrate that successful incorporation of the thermolabile cytokine GM-CSF into MN resulted in improved vaccine-induced protective immunity holding promise as a novel approach to improved influenza vaccination. To our knowledge, this is the first successful incorporation of a cytokine adjuvant into dissolvable MNs, thus advancing and diversifying the rapidly developing field of MN vaccination technology.

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Section: Discussionsupporting

confidence: 59%

Stable incorporation of GM-CSF into dissolvable microneedle patch improves skin vaccination against influenza

Littauer

Mills

Brock

et al. 2018

Journal of Controlled Release

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“…Thus, GPI-anchored CCL28 represents a promising candidate to act as a novel mucosal adjuvant/immunostimulator in influenza vaccine development. We have previously investigated the importance of various immunostimulators such as GMCSF, GIFT-4 (25), and flagellin (26, 27) into VLPs, and found that these adjuvants significantly promoted antigen-specific humoral and cellular immune responses, conferring cross-protection against lethal viral challenges. The above findings, along with the importance of mucosal immunity during influenza infection, prompted us to design the current study.…”

Section: Introductionmentioning

confidence: 99%

Co-delivery of GPI-anchored CCL28 and influenza HA in chimeric virus-like particles induces cross-protective immunity against H3N2 viruses

Mohan

Kim

Berman

et al. 2016

Journal of Controlled Release

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Influenza infection typically initiates at respiratory mucosal surfaces. Induction of immune responses at the sites where pathogens initiate replication is crucial for the prevention of infection. We studied the adjuvanticity of GPI-anchored CCL28 co-incorporated with influenza HA-antigens in chimeric virus-like particles (cVLPs), in boosting strong protective immune responses through an intranasal (i.n.) route in mice. We compared the immune responses to that from influenza VLPs without CCL28, or physically mixed with soluble CCL28 at systemic and various mucosal compartments. The cVLPs containing GPI-CCL28 showed in-vitro chemotactic activity towards spleen and lung cells expressing CCR3/CCR10 chemokine receptors. The cVLPs induced antigen specific endpoint titers and avidity indices of IgG in sera and IgA in tracheal, lung, and intestinal secretions, significantly higher (4–6 fold) than other formulations. Significantly higher (3–5 fold) hemagglutination inhibition titers and high serum neutralization against H3N2 viruses were also detected with CCL28-containing VLPs compared to other groups. The CCL28-containing VLPs showed complete and 80% protection, when vaccinated animals were challenged with A/Aichi/2/1968/H3N2 (homologous) and A/Philippines/2/1982/H3N2 (heterologous) viruses, respectively. Thus, GPI-anchored CCL28 in influenza VLPs act as a strong immunostimulator at both systemic and mucosal sites, boosting significant cross-protection in animals against heterologous viruses across a large distance.

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“…An effective HIV vaccine should not only induce systemic immune response to clear disseminated viruses, but also promote mucosal immune responses to block transmission. Our previous studies have shown that incorporation of cytokines as adjuvants promotes enhanced mucosal and systemic responses with improved quality [ 30 ]. The important roles that cytokines play in modulating immune responses induced by various vaccines have also been established [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

Membrane-anchored CCL20 augments HIV Env-specific mucosal immune responses

Sun

Zhang

et al. 2017

Virol J

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BackgroundInduction of broad immune responses at mucosal site remains a primary goal for most vaccines against mucosal pathogens. Abundance of evidence indicates that the co-delivery of mucosal adjuvants, including cytokines, is necessary to induce effective mucosal immunity. In the present study, we set out to evaluate the role of a chemokine, CCL20, as an effective mucosal adjuvant for HIV vaccine.MethodsTo evaluate the role of CCL20 as a potent adjuvant for HIV vaccine, we examined its effects on antigen-specific antibody responses, level of antibody-secreting cells, cytokine production and intestinal homing of plasma cells in vaccine immunized mice.ResultsCCL20-incorporated VLP administered by mucosal route (intranasal (n = 10, p = 0.0085) or intravaginal (n = 10, p = 0.0091)) showed much higher potency in inducing Env-specific IgA antibody response than those administered by intramuscular route (n = 10). For intranasal administration, the HIV Env-specific IFN-γ(751 pg/ml), IL-4 (566 pg/ml), IL-5 (811 pg/ml) production and IgA-secreting plasma cells (62 IgA-secreting plasma cells/106 cells) in mucosal lamina propria were significantly augmented in CCL20-incorporated VLP immunized mice as compared to those immunized with Env only VLPs (p = 0.0332, 0.0398, 0.033, 0.0302 for IFN-γ, IL-4, IL-5, and IgA-secreting plasma cells, respectively).Further, anti-CCL20 mAb partially suppressed homing of Env-specific IgA ASCs into small intestine in mice immunized with CCL20-incorporated VLP by intranasal (62 decreased to 16 IgA- secreting plasma cells/106 cells, p = 0.0341) or intravaginal (52 decreased to 13 IgA- secreting plasma cells/106 cells, p = 0.0332) routes.ConclusionOur data indicated that the VLP-incorporated CCL20 can enhance HIV Env-specific immune responses in mice, especially those occurring in the mucosal sites. We also found that i.m. prime followed by mucosal boost is critical and required for CCL20 to exert its full function as an effective mucosal adjuvant. Therefore, co-incorporation of CCL20 into Env VLPs when combined with mucosal administration could represent a novel and promising HIV vaccine candidate.

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Incorporation of a GPI-anchored engineered cytokine as a molecular adjuvant enhances the immunogenicity of HIV VLPs

Cited by 25 publications

References 57 publications

Stable incorporation of GM-CSF into dissolvable microneedle patch improves skin vaccination against influenza

Stable incorporation of GM-CSF into dissolvable microneedle patch improves skin vaccination against influenza

Co-delivery of GPI-anchored CCL28 and influenza HA in chimeric virus-like particles induces cross-protective immunity against H3N2 viruses

Membrane-anchored CCL20 augments HIV Env-specific mucosal immune responses

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