Human papilloma virus-like particles (HPV VLP) serve as the basis of the current licensed vaccines for HPV. We have previously shown that encapsidation of DNA expressing the model antigen M/M2 from ...respiratory syncytial virus (RSV) in HPV pseudovirions (PsV) is immunogenic when delivered intravaginally. Because the HPV capsids confer tropism for basal epithelium, they represent attractive carriers for vaccination targeted to the skin using microneedles. In this study we asked: 1) whether HPV16 VLP administered by microneedles could induce protective immune responses to HPV16 and 2) whether HPV16 PsV-encapsidated plasmids delivered by microneedles could elicit immune responses to both HPV and the antigen delivered by the transgene. Mice immunized with HPV16 VLP coated microneedles generated robust neutralizing antibody responses and were protected from HPV16 challenge. Microneedle arrays coated with HPV16-M/M2 or HPV16-F protein (genes of RSV) were then tested and dose-dependent HPV and F-specific antibody responses were detected post-immunization, and M/M2-specific T-cell responses were detected post RSV challenge, respectively. HPV16 PsV-F immunized mice were fully protected from challenge with HPV16 PsV and had reduced RSV viral load in lung and nose upon intranasal RSV challenge. In summary, HPV16 PsV-encapsidated DNA delivered by microneedles induced neutralizing antibody responses against HPV and primed for antibody and T-cell responses to RSV antigens encoded by the encapsidated plasmids. Although the immunogenicity of the DNA component was just above the dose response threshold, the HPV-specific immunity was robust. Taken together, these data suggest microneedle delivery of lyophilized HPV PsV could provide a practical, thermostable combined vaccine approach that could be developed for clinical evaluation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mucosal immunization may be important for protection against pathogens whose transmission and pathogenesis target the mucosal tissue. The capsid proteins of human papillomavirus (HPV) confer tropism ...for the basal epithelium and can encapsidate DNA during self-assembly to form pseudovirions (PsVs). Therefore, we produced mucosal vaccine vectors by HPV PsV encapsidation of DNA plasmids expressing an experimental antigen derived from the M and M2 proteins of respiratory syncytial virus (RSV). Intravaginal (IVag) delivery elicited local and systemic M-M2-specific CD8+ T-cell and antibody responses in mice that were comparable to an approximately 10,000-fold higher dose of naked DNA. A single HPV PsV IVag immunization primed for M-M2-specific-IgA in nasal and vaginal secretions. Based on light emission and immunofluorescent microscopy, immunization with HPV PsV-encapsidated luciferase- and red fluorescent protein (RFP)-expressing plasmids resulted in transient antigen expression (<5 days), which was restricted to the vaginal epithelium. HPV PsV encapsidation of plasmid DNA is a novel strategy for mucosal immunization that could provide new vaccine options for selected mucosal pathogens.
Human papilloma virus-like particles (HPV VLP) serve as the basis of the current licensed vaccines for HPV. We have previously shown that encapsidation of DNA expressing the model antigen M/M2 from ...respiratory syncytial virus (RSV) in HPV pseudovirions (PsV) is immunogenic when delivered intravaginally. Because the HPV capsids confer tropism for basal epithelium, they represent attractive carriers for vaccination targeted to the skin using microneedles. In this study we asked: 1) whether HPV16 VLP administered by microneedles could induce protective immune responses to HPV16 and 2) whether HPV16 PsV-encapsidated plasmids delivered by microneedles could elicit immune responses to both HPV and the antigen delivered by the transgene. Mice immunized with HPV16 VLP coated microneedles generated robust neutralizing antibody responses and were protected from HPV16 challenge. Microneedle arrays coated with HPV16-M/M2 or HPV16-F protein (genes of RSV) were then tested and dose-dependent HPV and F-specific antibody responses were detected post-immunization, and M/M2-specific T-cell responses were detected post RSV challenge, respectively. HPV16 PsV-F immunized mice were fully protected from challenge with HPV16 PsV and had reduced RSV viral load in lung and nose upon intranasal RSV challenge. In summary, HPV16 PsV-encapsidated DNA delivered by microneedles induced neutralizing antibody responses against HPV and primed for antibody and T-cell responses to RSV antigens encoded by the encapsidated plasmids. Although the immunogenicity of the DNA component was just above the dose response threshold, the HPV-specific immunity was robust. Taken together, these data suggest microneedle delivery of lyophilized HPV PsV could provide a practical, thermostable combined vaccine approach that could be developed for clinical evaluation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The South Pole Ice Core (SPICEcore) was drilled in 2014–2016 to provide a detailed multi-proxy archive of paleoclimate conditions in East Antarctica during the Holocene and late Pleistocene. ...Interpretation of these records requires an accurate depth–age relationship. Here, we present the SPICEcore (SP19) timescale for the age of the ice of SPICEcore. SP19 is synchronized to the WD2014 chronology from the West Antarctic Ice Sheet Divide (WAIS Divide) ice core using stratigraphic matching of 251 volcanic events. These events indicate an age of 54 302±519 BP (years before 1950) at the bottom of SPICEcore. Annual layers identified in sodium and magnesium ions to 11 341 BP were used to interpolate between stratigraphic volcanic tie points, yielding an annually resolved chronology through the Holocene. Estimated timescale uncertainty during the Holocene is less than 18 years relative to WD2014, with the exception of the interval between 1800 to 3100 BP when uncertainty estimates reach ±25 years due to widely spaced volcanic tie points. Prior to the Holocene, uncertainties remain within 124 years relative to WD2014. Results show an average Holocene accumulation rate of 7.4 cm yr−1 (water equivalent). The time variability of accumulation rate is consistent with expectations for steady-state ice flow through the modern spatial pattern of accumulation rate. Time variations in nitrate concentration, nitrate seasonal amplitude and δ15N of N2 in turn are as expected for the accumulation rate variations. The highly variable yet well-constrained Holocene accumulation history at the site can help improve scientific understanding of deposition-sensitive climate proxies such as δ15N of N2 and photolyzed chemical compounds.
An intermediate-depth (1751 m) ice core was drilled at the South Pole between 2014 and 2016 using the newly designed US Intermediate Depth Drill. The South Pole ice core is the highest-resolution ...interior East Antarctic ice core record that extends into the glacial period. The methods used at the South Pole to handle and log the drilled ice, the procedures used to safely retrograde the ice back to the National Science Foundation Ice Core Facility (NSF-ICF), and the methods used to process and sample the ice at the NSF-ICF are described. The South Pole ice core exhibited minimal brittle ice, which was likely due to site characteristics and, to a lesser extent, to drill technology and core handling procedures.
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