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Novel vaccine regimen elicits strong airway immune responses and control of respiratory syncytial virus in nonhuman primates.

ABSTRACT: Induction of long-lasting immunity against viral respiratory tract infections remains an elusive goal. Using a nonhuman primate model of human respiratory syncytial virus (hRSV) infection, we compared mucosal and systemic immune responses induced by different DNA delivery approaches to a novel parenteral DNA prime-tonsillar adenoviral vector booster immunization regimen. Intramuscular (i.m.) electroporation (EP) of a DNA vaccine encoding the fusion protein of hRSV induced stronger systemic immune responses than intradermal EP, tattoo immunization, and conventional i.m. DNA injection. A single EP i.m., followed by two atraumatic tonsillar immunizations with the adenoviral vector, elicited strong systemic immune responses, an unique persistent CD4(+) and CD8(+) T cell response in the lower respiratory tract and protection from intranasal hRSV challenge. Thus, parenteral DNA priming followed by booster immunization targeted to a mucosal inductive site constitutes an effective vaccine regimen for eliciting protective immune responses at mucosal effector sites.The human respiratory syncytial virus (hRSV) is the most common cause of severe respiratory tract disease in infancy and leads to substantial morbidity and morality in the elderly. In this study, we compared the immunogenicity and efficacy of several gene-based immunization protocols in rhesus macaques. Thereby, we found that the combination of an initially parenterally delivered DNA vaccine with a subsequent atraumatic tonsillar adenoviral vector immunization results in a strong systemic immune response accompanied by an exceptional high T-cell response in the mucosa. Strikingly, these animals were protected against a RSV challenge infection controlling the viral replication indicated by a 1,000-fold-lower viral load in the lower respiratory tract. Since mucosal cellular responses of this strength had not been described in earlier RSV vaccine studies, this heterologous DNA prime-tonsillar boost vaccine strategy is very promising and should be pursued for further preclinical and clinical testing.

SUBMITTER: Grunwald T

PROVIDER: S-EPMC3993754 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Novel vaccine regimen elicits strong airway immune responses and control of respiratory syncytial virus in nonhuman primates.

Grunwald Thomas T Tenbusch Matthias M Schulte Reiner R Raue Katharina K Wolf Hans H Hannaman Drew D de Swart Rik L RL Uberla Klaus K Stahl-Hennig Christiane C

Journal of virology 20140122 8

<h4>Unlabelled</h4>Induction of long-lasting immunity against viral respiratory tract infections remains an elusive goal. Using a nonhuman primate model of human respiratory syncytial virus (hRSV) infection, we compared mucosal and systemic immune responses induced by different DNA delivery approaches to a novel parenteral DNA prime-tonsillar adenoviral vector booster immunization regimen. Intramuscular (i.m.) electroporation (EP) of a DNA vaccine encoding the fusion protein of hRSV induced stro ...[more]

PMID: 24453366

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Project description:Mucosal immune responses are crucial in protecting against pathogens entering through mucosal surfaces. However, due to poor T-cell responsiveness upon mucosal antigenic stimulation, mucosal immunity remains difficult to obtain through vaccines and requires appropriate adjuvants. We previously demonstrated that administered systemically to healthy macaques or locally expressed in the intestinal mucosa of acutely SIV-infected macaques, interleukin-7 (IL-7) triggers chemokine expression and immune cell homing into mucosae, suggesting its important role in the development of mucosal immune responses. We therefore examined whether local delivery of recombinant glycosylated simian IL-7 (rs-IL-7gly) to the vaginal mucosa of rhesus macaques could prepare the lower female genital tract (FGT) for subsequent immunization and act as an efficient mucosal adjuvant. First, we showed that local administration of rs-IL-7gly triggers vaginal overexpression of chemokines and infiltration of mDCs, macrophages, NKs, B- and T-cells in the lamina propria while MamuLa-DR+ APCs accumulated in the epithelium. Subsequent mucosal anti-DT immunization in macaques resulted in a faster, stronger, and more persistent mucosal antibody response compared to DT-immunization alone. Indeed, we detected robust productions of DT-specific IgAs and IgGs in their vaginal secretions and identified cells secreting DT-specific IgAs in their vaginal mucosa and IgGs in draining lymph nodes. Finally, the expression of chemokines involved in the organization of tertiary lymphoid structures (TLS) was only increased in the vaginal mucosa of IL-7-adjuvanted immunized macaques. Interestingly, TLSs developed around PNAd+ high endothelial venules in their lower FGT sampled 2 weeks after the last immunization. Non-traumatic vaginal administration of rs-IL-7gly prepares the mucosa to respond to subsequent local immunization and allows the development of a strong mucosal immune response in macaques, through the chemokine-dependent recruitment of immune cells, the activation of mDCs and the formation of TLSs. The localization of DT-specific IgA+ plasma cells in the upper vaginal mucosa argues for their contribution to the production of specific immunoglobulins in the vaginal secretions. Our results highlight the potential of IL-7 as a potent mucosal adjuvant to stimulate the FGT immune system and elicit vaginal antibody responses to local immunization, which is the most promising way to confer protection against many sexually transmitted diseases.

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Novel vaccine regimen elicits strong airway immune responses and control of respiratory syncytial virus in nonhuman primates.

Publications

Novel vaccine regimen elicits strong airway immune responses and control of respiratory syncytial virus in nonhuman primates.

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