Young-Ho Byun

Yonsei University, Sŏul, Seoul, South Korea

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Publications (12)43.33 Total impact

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    ABSTRACT: Influenza vaccines aimed at inducing antibody (Ab) responses against viral surface hemagglutinin (HA) and neuraminidase (NA) provide sterile immunity to infection with the same subtypes. Vaccines targeting viral conserved determinants shared by the influenza A viruses (IAV) offer heterosubtypic immunity (HSI), a broad protection against different subtypes. We proposed that vaccines targeting both HA and the conserved ectodomain of matrix protein 2 (M2e) would provide protection against infection with the same subtype and also HSI against other subtypes. Here we report that single intranasal (i.n.) immunization with a recombinant adenovirus (rAd) vector encoding both HA of H5 virus and M2e (rAdH5/M2e) induced significant HA and M2e specific Ab responses along with protection against heterosubtypic challenge in mice. The protection is superior as compared to that induced by rAd vector encoding either HA (rAdH5), or M2e (rAdM2e). While protection against homotypic H5 virus is primarily mediated by virus neutralizing (VN) antibodies (Abs), the cross-protection is associated with Abs directed to conserved stalk HA and M2e that seem to have additive effect. Consistently, adoptive transfer of antisera induced by rAdH5/M2e provided the best protection against heterosubtypic challenge as compared to that provided by antisera derived from mice immunized with rAdH5 or rAdM2e. These results support the development of rAd vectored vaccines encoding both H5 and M2e as universal vaccines against different IAV subtypes.
    Journal of virology. 06/2014;
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    ABSTRACT: BACKGROUND: Hemodialysis (HD) patients have multiple causes of immune dysfunction and poor immune response to influenza vaccination. We investigated the antibody response rate to a pandemic H1N1/2009 influenza vaccination and clinical parameters influencing the induction of antibody responses in HD patients. METHODS: A total of 114 HD patients were vaccinated with a monovalent adjuvanted H1N1 inactivated influenza vaccine. Titers of neutralizing antibodies were evaluated by hemagglutination inhibition (HI) assay at pre- and 4 weeks after vaccination. Seroconversion was defined as either a pre-vaccination HI titer < 1:10 and a post vaccination HI titer > 1:40 or a pre-vaccination HI titer >= 1:10 and a minimum four-fold rise in post-vaccination HI antibody titer. Seventeen out of 114 HD patients (14.9%) tested positive for antibodies against influenza A/H1N1/2009 before vaccination. The remaining 97 baseline sero-negative patients were included in the analysis. RESULTS: Only 30 (30.9%) HD patients had seroconversion 4 weeks after vaccination. The elderly patients, those over 65 years of age, showed significantly lower seroconversion rate compared to younger HD patients (20.5% vs. 39.6%, p = 0.042). Furthermore, patients with hemoglobin values less than 10 g/dL had a significantly lower seroconversion rate compared to those with higher hemoglobin values (20.0 vs. 38.6%, p = 0.049). By multivariate logistic regression analysis, only age >=65 years (OR = 0.336, 95% confidence interval (CI) 0.116-0.971, p = 0.044) and hemoglobin levels <10 g/dL (OR = 0.315, 95% CI 0.106-0.932, p = 0.037) were independently associated with seroconversion after vaccination. CONCLUSIONS: Our data show that HD patients, especially who are elderly with low hemoglobin levels, are at increased risk for lower seroconversion rate after influenza A/H1N1 vaccination. Further studies are needed to improve the efficacy of vaccination in these high risk patients.
    BMC Nephrology 12/2012; 13(1):165. · 1.64 Impact Factor
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    ABSTRACT: The nonstructural protein 1 (NS1) of influenza A virus (IAV) enables the virus to disarm the host cell type 1 IFN defense system. Mutation or deletion of the NS1 gene leads to attenuation of the virus and enhances host antiviral response making such live-attenuated influenza viruses attractive vaccine candidates. Sublingual (SL) immunization with live influenza virus has been found to be safe and effective for inducing protective immune responses in mucosal and systemic compartments. Here we demonstrate that SL immunization with NS1 deleted IAV (DeltaNS1 H1N1 or DeltaNS1 H5N1) induced protection against challenge with homologous as well as heterosubtypic influenza viruses. Protection was comparable with that induced by intranasal (IN) immunization and was associated with high levels of virus-specific antibodies (Abs). SL immunization with DeltaNS1 virus induced broad Ab responses in mucosal and systemic compartments and stimulated immune cells in mucosa-associated and systemic lymphoid organs. Thus, SL immunization with DeltaNS1 offers a novel potential vaccination strategy for the control of influenza outbreaks including pandemics.
    PLoS ONE 01/2012; 7(6):e39921. · 3.53 Impact Factor
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    ABSTRACT: The influenza virus, a mucosal pathogen that infects the respiratory tract, is a major global health issue. There have been attempts to mucosally administer inactivated influenza vaccines to induce both mucosal and systemic immune responses. However, mucosally administered inactivated influenza vaccine has low immunogenicity, which is partially due to the lack of an effective mucosal adjuvant. The development of a safe and effective mucosal adjuvant is a prerequisite to the practical use of a mucosal inactivated influenza vaccine. We have previously demonstrated that a bacterial flagellin, Vibrio vulnificus FlaB, when mixed with antigen and administered intranasally, exerts a strong mucosal adjuvant activity by stimulating the Toll-like receptor 5 (TLR5). In this study, we tested whether the FlaB protein could serve as an effective mucosal adjuvant for an inactivated trivalent influenza vaccine (TIV) manufactured for humans; in a murine vaccination model, this vaccine consists of A/Brisbane/59/07 (H1N1 subtype), A/Uruguay/716/07 (H3N2 subtype), and B/Florida/4/06 (B type). Intranasal co-administration of the TIV with FlaB induced prominent humoral responses as demonstrated by high influenza-specific IgA levels in both the mucosal secretions and serum and significant specific IgG induction in the systemic compartment. The FlaB protein significantly potentiated influenza-specific cytokine production by draining lymph node cells and splenocytes. The FlaB mucosal adjuvant conferred excellent protection against a lethal challenge with a live virulent virus with high hemagglutination inhibition (HAI) antibody (Ab) titers. The FlaB did not accumulate in the olfactory nerve and epithelium, guaranteeing against a retrograde uptake into the central nervous system. These results suggest that FlaB can be used as a promising mucosal adjuvant for nasal inactivated influenza vaccine development.
    Vaccine 10/2011; 30(2):466-74. · 3.77 Impact Factor
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    ABSTRACT: Type I interferon (IFN-I) plays a critical role in the homeostasis of hematopoietic stem cells and influences neutrophil influx to the site of inflammation. IFN-I receptor knockout (Ifnar1⁻/⁻) mice develop significant defects in the infiltration of Ly6C(hi) monocytes in the lung after influenza infection (A/PR/8/34, H1N1). Ly6C(hi) monocytes of wild-type (WT) mice are the main producers of MCP-1 while the alternatively generated Ly6C(int) monocytes of Ifnar1⁻/⁻ mice mainly produce KC for neutrophil influx. As a consequence, Ifnar1⁻/⁻ mice recruit more neutrophils after influenza infection than do WT mice. Treatment of IFNAR1 blocking antibody on the WT bone marrow (BM) cells in vitro failed to differentiate into Ly6C(hi) monocytes. By using BM chimeric mice (WT BM into Ifnar1⁻/⁻ and vice versa), we confirmed that IFN-I signaling in hematopoietic cells is required for the generation of Ly6C(hi) monocytes. Of note, WT BM reconstituted Ifnar1⁻/⁻ chimeric mice with increased numbers of Ly6C(hi) monocytes survived longer than influenza-infected Ifnar1⁻/⁻ mice. In contrast, WT mice that received Ifnar1⁻/⁻ BM cells with alternative Ly6C(int) monocytes and increased numbers of neutrophils exhibited higher mortality rates than WT mice given WT BM cells. Collectively, these data suggest that IFN-I contributes to resistance of influenza infection by control of monocytes and neutrophils in the lung.
    PLoS Pathogens 02/2011; 7(2):e1001304. · 8.14 Impact Factor
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    ABSTRACT: The ectodomain of matrix protein 2 (M2e) of influenza A virus is a rationale target antigen candidate for the development of a universal vaccine against influenza as M2e undergoes little sequence variation amongst human influenza A strains. Vaccine-induced M2e-specific antibodies (Abs) have been shown to display significant cross-protective activity in animal models. M2e-based vaccine constructs have been shown to be more protective when administered by the intranasal (i.n.) route than after parenteral injection. However, i.n. administration of vaccines poses rare but serious safety issues associated with retrograde passage of inhaled antigens and adjuvants through the olfactory epithelium. In this study, we examined whether the sublingual (s.l.) route could serve as a safe and effective alternative mucosal delivery route for administering a prototype M2e-based vaccine. The mechanism whereby s.l. immunization with M2e vaccine candidate induces broad protection against infection with different influenza virus subtypes was explored. A recombinant M2 protein with three tandem copies of the M2e (3M2eC) was expressed in Escherichia coli. Parenteral immunizations of mice with 3M2eC induced high levels of M2e-specific serum Abs but failed to provide complete protection against lethal challenge with influenza virus. In contrast, s.l. immunization with 3M2eC was superior for inducing protection in mice. In the latter animals, protection was associated with specific Ab responses in the lungs. The results demonstrate that s.l. immunization with 3M2eC vaccine induced airway mucosal immune responses along with broad cross-protective immunity to influenza. These findings may contribute to the understanding of the M2-based vaccine approach to control epidemic and pandemic influenza infections.
    PLoS ONE 01/2011; 6(11):e27953. · 3.53 Impact Factor
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    ABSTRACT: Recent studies have revealed that innate immunity is involved in the development of adaptive immune responses; however, its role in protection is not clear. In order to elucidate the exact role of Toll-like receptor (TLR) or RIG-I-like receptor (RLR) signaling on immunogenicity and protective efficacy against influenza A virus infection (A/PR/8/34 [PR8]; H1N1), we adapted several innate signal-deficient mice (e.g., TRIF(-/-), MyD88(-/-), MyD88(-/-) TRIF(-/-), TLR3(-/-) TLR7(-/-), and IPS-1(-/-)). In this study, we found that MyD88 signaling was required for recruitment of CD11b(+) granulocytes, production of early inflammatory cytokines, optimal proliferation of CD4 T cells, and production of Th1 cytokines by T cells. However, PR8 virus-specific IgG and IgA antibody levels in both systemic and mucosal compartments were normal in TLR- and RLR-deficient mice. To further assess the susceptibility of these mice to influenza virus infection, protective efficacy was determined after primary or secondary lethal challenge. We found that MyD88(-/-) and MyD88(-/-) TRIF(-/-) mice were more susceptible to primary influenza virus infection than the B6 mice but were fully protected against homologous (H1N1) and heterosubtypic (H5N2) secondary infection when primed with a nonlethal dose of PR8 virus. Taken together, these results show that MyD88 signaling plays an important role for resisting primary influenza virus infection but is dispensable for protection against a secondary lethal challenge.
    Journal of Virology 10/2010; 84(24):12713-22. · 5.08 Impact Factor
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    ABSTRACT: A randomized, double-blind, controlled clinical trial was conducted to evaluate the efficacy and safety of CJ-50300, a newly developed cell culture-derived smallpox vaccine, and to determine its minimum effective dose. The overall rates of cutaneous "take" reaction and humoral and cellular immunogenicity in CJ-50300 vaccinees were 100% (123/123), 99.2% (122/123), and 90.8% (109/120), respectively, and these rates did not differ significantly between the conventional-dose and the low-dose CJ-50300 (1.0x10(8) and 1.0x10(7) plaque-forming units/mL, respectively) (P>0.05 for each). No serious adverse reaction was observed. However, one case of possible generalized vaccinia occurred in the conventionally dosed group [ClinicalTrials.gov Identifier: NCT00607243].
    Vaccine 08/2010; 28(36):5845-9. · 3.77 Impact Factor
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    ABSTRACT: Pandemic influenza poses a serious threat to global health and the world economy. While vaccines are currently under development, passive immunization could offer an alternative strategy to prevent and treat influenza virus infection. Attempts to develop monoclonal antibodies (mAbs) have been made. However, passive immunization based on mAbs may require a cocktail of mAbs with broader specificity in order to provide full protection since mAbs are generally specific for single epitopes. Chicken immunoglobulins (IgY) found in egg yolk have been used mainly for treatment of infectious diseases of the gastrointestinal tract. Because the recent epidemic of highly pathogenic avian influenza virus (HPAIV) strain H5N1 has resulted in serious economic losses to the poultry industry, many countries including Vietnam have introduced mass vaccination of poultry with H5N1 virus vaccines. We reasoned that IgY from consumable eggs available in supermarkets in Vietnam could provide protection against infections with HPAIV H5N1. We found that H5N1-specific IgY that are prepared from eggs available in supermarkets in Vietnam by a rapid and simple water dilution method cross-protect against infections with HPAIV H5N1 and related H5N2 strains in mice. When administered intranasally before or after lethal infection, the IgY prevent the infection or significantly reduce viral replication resulting in complete recovery from the disease, respectively. We further generated H1N1 virus-specific IgY by immunization of hens with inactivated H1N1 A/PR/8/34 as a model virus for the current pandemic H1N1/09 and found that such H1N1-specific IgY protect mice from lethal influenza virus infection. The findings suggest that readily available H5N1-specific IgY offer an enormous source of valuable biological material to combat a potential H5N1 pandemic. In addition, our study provides a proof-of-concept for the approach using virus-specific IgY as affordable, safe, and effective alternative for the control of influenza outbreaks, including the current H1N1 pandemic.
    PLoS ONE 04/2010; 5(4):e10152. · 3.53 Impact Factor
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    ABSTRACT: Development of effective vaccines against highly pathogenic avian influenza (HPAI) H5N1 viruses is a global public health priority. Considering the difficulty in predicting HPAI H5N1 pandemic strains, one strategy used in their design includes the development of formulations with the capacity of eliciting broad cross-protective immunity against multiple viral antigens. To this end we constructed a replication-defective recombinant adenovirus-based avian influenza virus vaccine (rAdv-AI) expressing the codon-optimized M2eX-HA-hCD40L and the M1-M2 fusion genes from HPAI H5N1 human isolate. Although there were no significant differences in the systemic immune responses observed between the intramuscular prime-intramuscular boost regimen (IM/IM) and the intranasal prime-intramuscular boost regimen (IN/IM), IN/IM induced more potent CD8(+) T cell and antibody responses at mucosal sites than the IM/IM vaccination, resulting in more effective protection against lethal H5N2 avian influenza (AI) virus challenge. These findings suggest that the strategies used to induce multi-antigen-targeted mucosal immunity, such as IN/IM delivery of rAdv-AI, may be a promising approach for developing broad protective vaccines that may be more effective against the new HPAI pandemic strains.
    Virology 10/2009; 395(2):182-9. · 3.35 Impact Factor
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    ABSTRACT: A human influenza B/Lee/40 virus was cold-adapted by serial passages in embryonated chicken eggs, at progressively lower temperatures, for possible use as a future influenza B vaccine donor strain. Temperature sensitive and cold-adapted phenotypes were achieved as a consequence of the adaptation process. It was determined that the virus was attenuated in mice since the replication of the viral genome was significantly reduced in the lung. Despite decreased viral replication, the attenuated infection effectively induced a virus-specific immune response. We next developed a reassortant virus carrying two major surface proteins, hemagglutinin and neuraminidase from virulent B/Shangdong/7/97 and six internal genes from the cold-adapted B/Lee/40. The reassortant virus was also attenuated and protected mice from lethal challenge with wild type B/Shangdong/7/97. In addition, vaccination with the reassortant virus resulted in a specific antibody response and inhibited the replication of wild type virus in mice. We conclude that the cold-adapted B/Lee/40 donor strain merits further investigation as potential live vaccine carrier as an alternative means for protection from influenza B virus epidemics.
    Vaccine 03/2008; 26(7):874-81. · 3.49 Impact Factor
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    ABSTRACT: In this study, we evaluated a live attenuated influenza vaccine (X-31 ca, H3N2) as a fast-acting prophylaxis against both heterologous (A/New Caledonia/99, H1N1) and heterotypic (B/Shangdong/97, influenza B) infection. An immediate and broad-spectrum protection was achieved in the absence of specific antibody responses. Vaccination immediately prior to challenge resulted in the generation of a significant pool of reassortant virus between the vaccine and virulent strains suggesting that the acquisition of attenuating gene(s) from the live vaccine contributes to the attenuation of virulence. Vaccination resulted in an immediate release of the antiviral IFN-alpha response and pro-inflammatory cytokines. In addition, it was determined that agonists for TLR 3 and TLR 7 provided early protection. Thus, our results suggest that innate immune responses and genetic interference may play a role, independently and synergistically, in early protection by live influenza vaccination. The broad-spectrum and immediate protection provided by live attenuated influenza vaccine may offer a prompt measure for minimizing the initial spread of virus and mitigating the impact of unexpected influenza outbreaks.
    Vaccine 12/2007; 25(47):8067-76. · 3.49 Impact Factor

Publication Stats

144 Citations
43.33 Total Impact Points

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Institutions

  • 2009–2014
    • Yonsei University
      • • Translational Research Center for Protein Function Control
      • • Department of Biotechnology
      Sŏul, Seoul, South Korea
  • 2010
    • Osaka University
      • Department of Host Defense
      Suika, Ōsaka, Japan