Co-Delivery of M2e Virus-Like Particles with Influenza Split Vaccine to the Skin Using Microneedles Enhances the Efficacy of Cross Protection

It is a high priority to develop a simple and effective delivery method for a cross-protective influenza vaccine. We investigated skin immunization by microneedle (MN) patch with human influenza split vaccine and virus-like particles containing heterologous M2 extracellular (M2e) domains (M2e5x virus-like particles (VLP)) as a cross-protective influenza vaccine candidate. Co-delivery of influenza split vaccine and M2e5x VLP to the skin by MN patch was found to confer effective protection against heterosubtypic influenza virus by preventing weight loss and reducing lung viral loads. Compared to intramuscular immunization, MN-based delivery of combined split vaccine and M2e5x VLPs shaped cellular immune responses toward T helper type 1 responses increasing IgG2a isotype antibodies as well as IFN-γ producing cells in mucosal and systemic sites. This study provides evidence that potential immunological and logistic benefits of M2e5x VLP with human influenza split vaccine delivered by MN patch can be used to develop an easy-to-administer cross-protective influenza vaccine.

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Human Immunodeficiency Virus Type 1-Hepatitis C Virus Coinfection: Intraindividual Comparison of Cellular Immune Responses against Two Persistent Viruses

Journal of Virology ◽

10.1128/jvi.76.6.2817-2826.2002 ◽

2002 ◽

Vol 76 (6) ◽

pp. 2817-2826 ◽

Cited By ~ 69

Author(s):

Georg M. Lauer ◽

Tam N. Nguyen ◽

Cheryl L. Day ◽

Gregory K. Robbins ◽

Theresa Flynn ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Immune Responses ◽

T Lymphocyte ◽

Viral Loads ◽

Cellular Immune Responses ◽

Immunodeficiency Virus ◽

Cellular Immune ◽

Lymphocyte Responses ◽

Hiv 1

ABSTRACT Both human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) lead to chronic infection in a high percentage of persons, and an expanding epidemic of HIV-1-HCV coinfection has recently been identified. These individuals provide an opportunity for simultaneous assessment of immune responses to two viral infections associated with chronic plasma viremia. In this study we analyzed the breadth and magnitude of the CD8+- and CD4+-T-lymphocyte responses in 22 individuals infected with both HIV-1 and HCV. A CD8+-T-lymphocyte response against HIV-1 was readily detected in all subjects over a broad range of viral loads. In marked contrast, HCV-specific CD8+-T-lymphocyte responses were rarely detected, despite viral loads in plasma that were on average 1,000-fold higher. The few HCV-specific responses that were observed were relatively weak and limited in breadth. CD4-proliferative responses against HIV-1 were detected in about half of the coinfected subjects tested, but no proliferative response against any HCV protein was found in these coinfected persons. These data demonstrate a major discordance in immune responses to two persistent RNA viruses. In addition, they show a consistent and profound impairment in cellular immune responses to HCV compared to HIV-1 in HIV-1-HCV-coinfected persons.

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Induction of Neutralizing Antibodies and Gag-Specific Cellular Immune Responses to an R5 Primary Isolate of Human Immunodeficiency Virus Type 1 in Rhesus Macaques

Journal of Virology ◽

10.1128/jvi.75.13.5879-5890.2001 ◽

2001 ◽

Vol 75 (13) ◽

pp. 5879-5890 ◽

Cited By ~ 52

Author(s):

David C. Montefiori ◽

Jeffrey T. Safrit ◽

Shari L. Lydy ◽

Ashley P. Barry ◽

Miroslawa Bilska ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Immune Responses ◽

Neutralizing Antibodies ◽

Rhesus Macaques ◽

Cellular Immune Responses ◽

Immunodeficiency Virus ◽

Ifn Γ ◽

Cellular Immune ◽

Hiv 1

ABSTRACT The ability to generate antibodies that cross-neutralize diverse primary isolates is an important goal for human immunodeficiency virus type 1 (HIV-1) vaccine development. Most of the candidate HIV-1 vaccines tested in humans and nonhuman primates have failed in this regard. Past efforts have focused almost entirely on the envelope glycoproteins of a small number of T-cell line-adapted strains of the virus as immunogens. Here we assessed the immunogenicity of noninfectious virus-like particles (VLP) consisting of Gag, Pro (protease), and Env from R5 primary isolate HIV-1Bx08. Immunogens were delivered to rhesus macaques in the form of either purified VLP, recombinant DNA and canarypox (ALVAC) vectors engineered to express VLP, or a combination of these products. Seroconversion to Gag and Pro was detected in all of the immunized animals. Antibodies that could neutralize HIV-1Bx08 were detected in animals that received (i) coinoculations with DNABx08 and VLPBx08, (ii) DNABx08 followed by ALVACBx08 boosting, and (iii) VLPBx08 alone. The neutralizing antibodies were highly strain specific despite the fact that they did not appear to be directed to linear epitopes in the V3 loop. Virus-specific cellular immune responses also were generated, as judged by the presence of Gag-specific gamma interferon (IFN-γ)-producing cells. These cellular immune responses required the inclusion of DNABx08 in the immunization modality, since few or no IFN-γ-producing cells were detected in animals that received either VLPBx08 or ALVACBx08 alone. The results demonstrate the feasibility of generating neutralizing antibodies and cellular immune responses that target an R5 primary HIV-1 isolate by vaccination in primates.

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Immunization with Hepatitis C Virus-Like Particles Induces Humoral and Cellular Immune Responses in Nonhuman Primates

Journal of Virology ◽

10.1128/jvi.78.13.6995-7003.2004 ◽

2004 ◽

Vol 78 (13) ◽

pp. 6995-7003 ◽

Cited By ~ 84

Author(s):

Sook-Hyang Jeong ◽

Ming Qiao ◽

Michelina Nascimbeni ◽

Zongyi Hu ◽

Barbara Rehermann ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Immune Responses ◽

Structural Proteins ◽

Virus Like Particles ◽

Cellular Immune Responses ◽

Monophosphoryl Lipid A ◽

Ifn Γ ◽

Cellular Immune ◽

Hcv Structural Proteins

ABSTRACT We have previously reported the production of hepatitis C virus-like particles (HCV-LP) using a recombinant baculovirus containing the cDNA of the HCV structural proteins (core, E1, and E2). These particles resemble the putative HCV virions and are capable of inducing strong and broad humoral and cellular immune responses in mice. Here we present evidence on the immunogenicity of HCV-LP and the effects of novel adjuvant systems in a nonhuman primate model, the baboon. Three groups of four baboons were immunized with HCV-LP, HCV-LP and adjuvant AS01B (monophosphoryl lipid A and QS21), or HCV-LP and the combination of AS01B and CpG oligodeoxynucleotides 10105. After four immunizations over an 8-month period, all animals developed HCV-specific humoral and cellular immune responses including antibodies to HCV structural proteins and gamma interferon+ (IFN-γ+)CD4+ and IFN-γ+CD8+ T-cell responses. The immunogenicity of HCV-LP was only marginally enhanced by the use of adjuvants. The overall HCV-specific immune responses were broad and long lasting. Our results suggest that HCV-LP is a potent immunogen to induce HCV-specific humoral and cellular immune responses in primates and may be a promising approach to develop novel preventive and therapeutic modalities.

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Cellular Immune Responses in Children and Adults Receiving Inactivated or Live Attenuated Influenza Vaccines

Journal of Virology ◽

10.1128/jvi.01460-06 ◽

2006 ◽

Vol 80 (23) ◽

pp. 11756-11766 ◽

Cited By ~ 231

Author(s):

Xiao-Song He ◽

Tyson H. Holmes ◽

Caiqiu Zhang ◽

Kutubuddin Mahmood ◽

George W. Kemble ◽

...

Keyword(s):

T Cells ◽

Immune Responses ◽

Influenza Vaccine ◽

Influenza A Virus ◽

Influenza A ◽

Influenza Vaccines ◽

Cellular Immune Responses ◽

Ifn Γ ◽

The Mean ◽

Cellular Immune

ABSTRACT The patterns of cellular immune responses induced by live attenuated influenza vaccine (LAIV) versus those of the trivalent inactivated influenza vaccine (TIV) have not been studied extensively, especially in children. The goals of this study were to evaluate the effects of TIV and LAIV immunization on cellular immunity to live influenza A virus in children and adults and to explore factors associated with variations in responses to influenza vaccines among individuals. A gamma interferon (IFN-γ) flow cytometry assay was used to measure IFN-γ-producing (IFN-γ+) NK and T cells in peripheral blood mononuclear cell cultures stimulated with a live influenza A virus strain before and after LAIV or TIV immunization of children and adults. The mean percentages of influenza A virus-specific IFN-γ+ CD4 and CD8 T cells increased significantly after LAIV, but not TIV, immunization in children aged 5 to 9 years. No increases in the mean levels of influenza A virus-reactive IFN-γ+ T cells and NK cells were observed in adults given LAIV or TIV. TIV induced a significant increase in influenza A virus-reactive T cells in 6-month- to 4-year-old children; LAIV was not evaluated in this age group. The postvaccination changes (n-fold) in the percentages of influenza A virus-reactive IFN-γ+ T and NK cells in adults were highly variable and correlated inversely with the prevaccination percentages, in particular with that of the CD56dim NK cell subset. In conclusion, our findings identify age, type of vaccine, and prevaccination levels of immune reactivity to influenza A virus as factors significantly associated with the magnitude of cellular immune responses to influenza vaccines.

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Comprehensive Epitope Analysis of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific T-Cell Responses Directed against the Entire Expressed HIV-1 Genome Demonstrate Broadly Directed Responses, but No Correlation to Viral Load

Journal of Virology ◽

10.1128/jvi.77.3.2081-2092.2003 ◽

2003 ◽

Vol 77 (3) ◽

pp. 2081-2092 ◽

Cited By ~ 513

Author(s):

M. M. Addo ◽

X. G. Yu ◽

A. Rathod ◽

D. Cohen ◽

R. L. Eldridge ◽

...

Keyword(s):

T Cell ◽

T Cell Responses ◽

Protein Subunits ◽

Cell Responses ◽

Cellular Immune Responses ◽

Immunodeficiency Virus ◽

Total Magnitude ◽

Cellular Immune ◽

Hiv 1

ABSTRACT Cellular immune responses play a critical role in the control of human immunodeficiency virus type 1 (HIV-1); however, the breadth of these responses at the single-epitope level has not been comprehensively assessed. We therefore screened peripheral blood mononuclear cells (PBMC) from 57 individuals at different stages of HIV-1 infection for virus-specific T-cell responses using a matrix of 504 overlapping peptides spanning all expressed HIV-1 proteins in a gamma interferon-enzyme-linked immunospot (Elispot) assay. HIV-1-specific T-cell responses were detectable in all study subjects, with a median of 14 individual epitopic regions targeted per person (range, 2 to 42), and all 14 HIV-1 protein subunits were recognized. HIV-1 p24-Gag and Nef contained the highest epitope density and were also the most frequently recognized HIV-1 proteins. The total magnitude of the HIV-1-specific response ranged from 280 to 25,860 spot-forming cells (SFC)/106 PBMC (median, 4,245) among all study participants. However, the number of epitopic regions targeted, the protein subunits recognized, and the total magnitude of HIV-1-specific responses varied significantly among the tested individuals, with the strongest and broadest responses detectable in individuals with untreated chronic HIV-1 infection. Neither the breadth nor the magnitude of the total HIV-1-specific CD8+-T-cell responses correlated with plasma viral load. We conclude that a peptide matrix-based Elispot assay allows for rapid, sensitive, specific, and efficient assessment of cellular immune responses directed against the entire expressed HIV-1 genome. These data also suggest that the impact of T-cell responses on control of viral replication cannot be explained by the mere quantification of the magnitude and breadth of the CD8+-T-cell response, even if a comprehensive pan-genome screening approach is applied.

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Evaluation of the cellular immune responses induced by a non-adjuvanted inactivated whole virus A/H5N1/VN/1203 pandemic influenza vaccine in humans

Vaccine ◽

10.1016/j.vaccine.2010.10.065 ◽

2010 ◽

Vol 29 (2) ◽

pp. 166-173 ◽

Cited By ~ 24

Author(s):

Brian A. Crowe ◽

Peter Brühl ◽

Marijan Gerencer ◽

Michael G. Schwendinger ◽

Andreas Pilz ◽

...

Keyword(s):

Immune Responses ◽

Influenza Vaccine ◽

Pandemic Influenza ◽

Cellular Immune Responses ◽

Cellular Immune

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Humoral and cellular immune responses to airway immunization of mice with human papillomavirus type 16 virus-like particles and mucosal adjuvants

Antiviral Research ◽

10.1016/j.antiviral.2007.05.005 ◽

2007 ◽

Vol 76 (1) ◽

pp. 75-85 ◽

Cited By ~ 19

Author(s):

V REVAZ ◽

R ZURBRIGGEN ◽

C MOSER ◽

J SCHILLER ◽

F PONCI ◽

...

Keyword(s):

Human Papillomavirus ◽

Immune Responses ◽

Virus Like Particles ◽

Human Papillomavirus Type 16 ◽

Cellular Immune Responses ◽

Cellular Immune

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Simultaneous Administration of Recombinant Measles Viruses Expressing Respiratory Syncytial Virus Fusion (F) and Nucleo (N) Proteins Induced Humoral and Cellular Immune Responses in Cotton Rats

Vaccines ◽

10.3390/vaccines7010027 ◽

2019 ◽

Vol 7 (1) ◽

pp. 27 ◽

Cited By ~ 2

Author(s):

Yoshiaki Yamaji ◽

Akihito Sawada ◽

Yosuke Yasui ◽

Takashi Ito ◽

Tetsuo Nakayama

Keyword(s):

Respiratory Syncytial Virus ◽

Immune Responses ◽

Neutralizing Antibodies ◽

Simultaneous Administration ◽

Cellular Immune Responses ◽

Immunization Group ◽

Cotton Rats ◽

Ifn Γ ◽

Syncytial Virus ◽

Cellular Immune

We previously reported that recombinant measles virus expressing the respiratory syncytial virus (RSV) fusion protein (F), MVAIK/RSV/F, induced neutralizing antibodies against RSV, and those expressing RSV-NP (MVAIK/RSV/NP) and M2-1 (MVAIK/RSV/M2-1) induced RSV-specific CD8+/IFN-γ+ cells, but not neutralizing antibodies. In the present study, MVAIK/RSV/F and MVAIK/RSV/NP were simultaneously administered to cotton rats and immune responses and protective effects were compared with MVAIK/RSV/F alone. Sufficient neutralizing antibodies against RSV and RSV-specific CD8+/IFN-γ+ cells were observed after re-immunization with simultaneous administration. After the RSV challenge, CD8+/IFN-γ+ increased in spleen cells obtained from the simultaneous immunization group in response to F and NP peptides. Higher numbers of CD8+/IFN-γ+ and CD4+/IFN-γ+ cells were detected in lung tissues from the simultaneous immunization group after the RSV challenge. No detectable RSV was recovered from lung homogenates in the immunized groups. Mild inflammatory reactions with the thickening of broncho-epithelial cells and the infiltration of inflammatory cells were observed in lung tissues obtained from cotton rats immunized with MVAIK/RSV/F alone after the RSV challenge. No inflammatory responses were observed after the RSV challenge in the simultaneous immunization groups. The present results indicate that combined administration with MVAIK/RSV/F and MVAIK/RSV/NP induces humoral and cellular immune responses and shows effective protection against RSV, suggesting the importance of cellular immunity.

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