Serological Memory and Long-term Protection to Novel H1N1 Influenza Virus After Skin Vaccination

Department of Microbiology & Immunology and Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
The Journal of Infectious Diseases (Impact Factor: 6). 06/2011; 204(4):582-91. DOI: 10.1093/infdis/jir094
Source: PubMed


A major goal in influenza vaccine development is induction of serological memory and cellular responses to confer long-term protection and limit virus spread after infection. Here, we investigate induction of long-lived immunity against the 2009 H1N1 virus after skin vaccination.
BALB/c mice received a single dose of 5 μg inactivated A/California/04/09 virus via coated metal microneedles (MN) applied to skin or via subcutaneous injection.
MN or subcutaneous vaccination elicited similar serum IgG and hemagglutination inhibition titers and 100% protection against lethal viral challenge 6 weeks after vaccination. Six months after vaccination, the subcutaneous group exhibited a 60% decrease in functional antibody titers and extensive lung inflammation after challenge with 10 × LD(50) of homologous virus. In contrast, the MN group maintained high functional antibody titers and IFN-γ levels, inhibition of viral replication, and no signs of lung inflammation after challenge. MN vaccination conferred complete protection against lethal challenge, whereas subcutaneous vaccination induced only partial protection. These findings were further supported by high numbers of bone marrow plasma cells and spleen antibody-secreting cells detected in the MN group.
A single skin vaccination with MN induced potent long-lived immunity and improved protection against the 2009 H1N1 influenza virus, compared with subcutaneous injection.

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Available from: Ioanna Skountzou, Jul 16, 2014
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    • "vaccines or drugs into the epidermis and dermis of the skin (Fig. 1), rather than intramuscularly, the typical route. Intradermal delivery of influenza vaccine by microneedles can lead to longer-lasting and more-robust antibody responses than intramuscular vaccination in mice, suggesting the possibility of improved efficacy [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]. Clinical studies comparing intramuscular delivery of influenza vaccine to intradermal delivery in liquid form through hollow minineedles and microneedles have shown a superior immune response in the elderly when an equal dose is administered intradermally, and equivalent immune responses in younger adults with administration of a reduced dose [18] [19] [20] [21] [22] [23] [24]. "
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    ABSTRACT: Simple and efficacious delivery methods for influenza vaccines are needed to improve health outcomes and manage possible pandemics both in the United States and globally. One approach to meeting these needs is the microneedle patch (MNP), a small array of micron-scale needles that is applied to the skin like a bandage. To inform additional technical developments and the eventual introduction of MNPs for influenza vaccination, we interviewed key opinion leaders in the United States for insights into the opportunities and challenges associated with this technology, particularly its potential for self-administration. All interviewees expressed high support for administration of influenza vaccine in MNPs by health care providers and for self-administration in groups supervised by a provider. Self-administration via prescription and over-the-counter purchase of MNPs received lower levels of support. Interviewees also highlighted priorities that should be considered in the ongoing development of an influenza vaccine MNP, such as confirming it to be as efficacious as existing methods of influenza vaccine delivery and ensuring safety for self-administration. For patient and health care provider acceptability, important attributes are ease of use, short wear times, and an easily accessible application site. Stakeholders agreed that using MNPs can help increase coverage, facilitate easy and safe delivery, reduce the cost of vaccination, and decrease the global morbidity and mortality associated with influenza. Another opportunity for this delivery method is the potential for self-administration. The prospect of reduced provider training requirements, increased thermostability, and high patient and provider acceptability makes it an attractive option for use in remote and low-resource settings worldwide. However, in addition to the technological challenges associated with producing the patch, developers must be mindful of cost considerations and key product attributes or requirements, such as usability, wear time, and proper disposal, that can affect how the product will be received in the marketplace. Copyright © 2015. Published by Elsevier Ltd.
    Vaccine 04/2015; 368(37). DOI:10.1016/j.vaccine.2015.03.062 · 3.62 Impact Factor
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    • "Supernatants were collected after centrifugation at 14,000 rpm for 20 min at 4°C. To quantify vaccine contents in skin, lysates were analyzed using an ELISA60 with the following modifications. Immunoplates were coated overnight at 4°C with anti-A/California/07/09 HA (CBER, Kensington, MD) diluted 1:5000 in PBS-T followed by 1 h incubation with streptavidin-HRP (BD Biosciences, San Jose, CA) diluted 1:4000 in PBS-T. "
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    ABSTRACT: Cutaneous vaccination with microneedle patches offers several advantages over more frequently used approaches for vaccine delivery, including improved protective immunity. However, the involvement of specific APC subsets and their contribution to the induction of immunity following cutaneous vaccine delivery is not well understood. A better understanding of the functions of individual APC subsets in the skin will allow us to target specific skin cell populations in order to further enhance vaccine efficacy. Here we use a Langerin-EGFP-DTR knock-in mouse model to determine the contribution of langerin(+) subsets of skin APCs in the induction of adaptive immune responses following cutaneous microneedle delivery of influenza vaccine. Depletion of langerin(+) cells prior to vaccination resulted in substantial impairment of both Th1 and Th2 responses, and decreased post-challenge survival rates, in mice vaccinated cutaneously but not in those vaccinated via the intramuscular route or in non-depleted control mice. Our results indicate that langerin(+) cells contribute significantly to the induction of protective immune responses following cutaneous vaccination with a subunit influenza vaccine.
    Scientific Reports 08/2014; 4:6094. DOI:10.1038/srep06094 · 5.58 Impact Factor
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    • "Currently, most vaccines are administered by intramuscular injection. The muscle however only contains few macrophages, dendritic cells or lymphocytes and is therefore not considered as an optimal site for antigen presentation and T cell activation, which may lead to relatively weak humoral and cellular immune response [14], [15]. "
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    ABSTRACT: Annual outbreaks of influenza infections, caused by new influenza virus subtypes and high incidences of zoonosis, make seasonal influenza one of the most unpredictable and serious health threats worldwide. Currently available vaccines, though the main prevention strategy, can neither efficiently be adapted to new circulating virus subtypes nor provide high amounts to meet the global demand fast enough. New influenza vaccines quickly adapted to current virus strains are needed. In the present study we investigated the local toxicity and capacity of a new inhalable influenza vaccine to induce an antigen-specific recall response at the site of virus entry in human precision-cut lung slices (PCLS). This new vaccine combines recombinant H1N1 influenza hemagglutinin (HAC1), produced in tobacco plants, and a silica nanoparticle (NP)-based drug delivery system. We found no local cellular toxicity of the vaccine within applicable concentrations. However higher concentrations of NP (≥10(3) µg/ml) dose-dependently decreased viability of human PCLS. Furthermore NP, not the protein, provoked a dose-dependent induction of TNF-α and IL-1β, indicating adjuvant properties of silica. In contrast, we found an antigen-specific induction of the T cell proliferation and differentiation cytokine, IL-2, compared to baseline level (152±49 pg/mg vs. 22±5 pg/mg), which could not be seen for the NP alone. Additionally, treatment with 10 µg/ml HAC1 caused a 6-times higher secretion of IFN-γ compared to baseline (602±307 pg/mg vs. 97±51 pg/mg). This antigen-induced IFN-γ secretion was further boosted by the adjuvant effect of silica NP for the formulated vaccine to a 12-fold increase (97±51 pg/mg vs. 1226±535 pg/mg). Thus we were able to show that the plant-produced vaccine induced an adequate innate immune response and re-activated an established antigen-specific T cell response within a non-toxic range in human PCLS at the site of virus entry.
    PLoS ONE 08/2013; 8(8):e71728. DOI:10.1371/journal.pone.0071728 · 3.23 Impact Factor
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