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Nanoporous Microneedle Arrays Effectively Induce Antibody Responses against Diphtheria and Tetanus Toxoid.

ABSTRACT: The skin is immunologically very potent because of the high number of antigen-presenting cells in the dermis and epidermis, and is therefore considered to be very suitable for vaccination. However, the skin's physical barrier, the stratum corneum, prevents foreign substances, including vaccines, from entering the skin. Microneedles, which are needle-like structures with dimensions in the micrometer range, form a relatively new approach to circumvent the stratum corneum, allowing for minimally invasive and pain-free vaccination. In this study, we tested ceramic nanoporous microneedle arrays (npMNAs), representing a novel microneedle-based drug delivery technology, for their ability to deliver the subunit vaccines diphtheria toxoid (DT) and tetanus toxoid (TT) intradermally. First, the piercing ability of the ceramic (alumina) npMNAs, which contained over 100 microneedles per array, a length of 475?µm, and an average pore size of 80?nm, was evaluated in mouse skin. Then, the hydrodynamic diameters of DT and TT and the loading of DT, TT, and imiquimod into, and subsequent release from the npMNAs were assessed in vitro. It was shown that DT and TT were successfully loaded into the tips of the ceramic nanoporous microneedles, and by using near-infrared fluorescently labeled antigens, we found that DT and TT were released following piercing of the antigen-loaded npMNAs into ex vivo murine skin. Finally, the application of DT- and TT-loaded npMNAs onto mouse skin in vivo led to the induction of antigen-specific antibodies, with titers similar to those obtained upon subcutaneous immunization with a similar dose. In conclusion, we show for the first time, the potential of npMNAs for intradermal (ID) immunization with subunit vaccines, which opens possibilities for future ID vaccination designs.

SUBMITTER: de Groot AM

PROVIDER: S-EPMC5770646 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Nanoporous Microneedle Arrays Effectively Induce Antibody Responses against Diphtheria and Tetanus Toxoid.

de Groot Anne Marit AM Platteel Anouk C M ACM Kuijt Nico N van Kooten Peter J S PJS Vos Pieter Jan PJ Sijts Alice J A M AJAM van der Maaden Koen K

Frontiers in immunology 20171213

The skin is immunologically very potent because of the high number of antigen-presenting cells in the dermis and epidermis, and is therefore considered to be very suitable for vaccination. However, the skin's physical barrier, the stratum corneum, prevents foreign substances, including vaccines, from entering the skin. Microneedles, which are needle-like structures with dimensions in the micrometer range, form a relatively new approach to circumvent the stratum corneum, allowing for minimally in ...[more]

PMID: 29375544

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Project description:ObjectiveTetanus toxoid, reduced diphtheria toxoid, and acellular pertusiss (Tdap) vaccine is recommended during each pregnancy, regardless of prior receipt. Data on reactogenicity and immunogenicity, particularly after repeated Tdap, are limited. We compared local injection-site and systemic reactions and serologic response following Tdap in (1) pregnant and nonpregnant women and (2) pregnant women by self-reported prior Tdap receipt.Study designPregnant women (gestational age 20-34 weeks) and nonpregnant women receiving Tdap were enrolled in this observational study. Injection-site and systemic reactions were assessed for one week post-vaccination. Pertussis toxin, filamentous hemagglutinin, pertactin, fimbriae, tetanus and diphtheria specific IgG antibody titers were determined by standardized enzyme-linked immunosorbent assay at baseline and 28 days post-vaccination. Reactogenicity and serologic responses were compared by pregnancy status, and within pregnant women by self-reported prior Tdap receipt.Results374 pregnant and 225 nonpregnant women were vaccinated. Severe local or systemic reactions or "any" fever were uncommon (≤3% for both groups). Moderate/severe injection-site pain was significantly higher in pregnant (17.9%) versus nonpregnant (11.1%) women, but did not prompt a healthcare visit. Proportions of other moderate/severe or any severe reactions were not significantly higher in pregnant compared to nonpregnant women. Moderate/severe (including pain) and severe reactions were not significantly higher in pregnant women receiving repeat versus first-time Tdap. Antibody titers increased from baseline to post-vaccination for all vaccine antigens in pregnant and nonpregnant women; post-vaccination titers against pertussis toxin and filamentous hemagglutinin were significantly higher in nonpregnant versus pregnant women (p < 0.01).ConclusionTdap was well-tolerated in pregnant and nonpregnant women. Pregnant women were more likely to report moderate/severe pain at the Tdap injection-site compared with nonpregnant women, but did not necessitate medical visits. Prior Tdap receipt did not increase occurrence of moderate/severe local or systemic reactions in pregnant women. Serologic responses to all vaccine antigens were robust. Clinical Trial Registration@ClinicalTrials.gov. NCT02209623. https://clinicaltrials.gov/ct2/show/NCT02209623.

Project description:BackgroundArsenic can impair immune function. Timing of exposure can influence potential immunotoxicity of arsenic exposure. We examined the association between drinking water arsenic concentrations (W-As) measured repeatedly during different exposure windows in early life and serum concentrations of IgG antibodies against diphtheria and tetanus toxoids (diphtheria and tetanus antibody).MethodsA prospective cohort of pregnant women was recruited in Bangladesh (2008-2011). Averaged W-As levels were calculated for: pregnancy (W-Aspregnancy): ≤16 weeks gestation and <1 month; toddlerhood (W-Astoddlerhood): 12 and 20-40 months; and early childhood (W-Aschildhood): 4-5 years. Serum was collected from 502 vaccinated children at age 5 and concentrations of diphtheria and tetanus toxoid IgG (i.e. antibody) were quantified. Antibody concentrations >0.1 IU/mL were considered clinically sufficient for protection. Associations were estimated using linear and logistic regression models.ResultsInverse associations were observed between W-Aspregnancy and serum diphtheria antibody levels, while null associations were observed between W-As and tetanus antibody. Children within the highest versus lowest tertile of W-Aspregnancy had 91% greater odds of having clinically insufficient concentrations of diphtheria antibody (Odds ratio:1.91, 95% confidence interval (CI): 1.03, 3.56). Among females, a doubling in W-Aspregnancy was associated with 12.3% (95%CI: -20.1%, -4.5%) lower median concentrations of diphtheria antibody. Tetanus antibody was only associated with W-Aspregnancy among females (percent change in median: -9.5%, 95%CI: -17.6%, -1.3%). Among children who were stunted or underweight, a doubling in W-Aspregnancy was associated with decreased diphtheria antibody of 19.8% (95%CI: -32%, -7.5%) and 14.3% (95%CI: -26.7%, -2%), respectively.ConclusionsAmong vaccinated children, W-As measured during pregnancy was associated with decreased diphtheria antibody levels, but not tetanus antibody. However, W-As measured during toddlerhood and early childhood were not associated with either antibody outcome. Children's sex and malnutrition status were important effect modifiers of W-As for both diphtheria and tetanus antibody levels, highlighting the importance of these factors and the timing of the exposure when evaluating the effect of arsenic on humoral immunity.

Project description:BackgroundImmunization with tetanus-diphtheria-acellular pertussis (Tdap) vaccine in pregnancy is increasingly recommended. We determined the effect of Tdap immunization in pregnancy on infants' vaccine responses.MethodsIndividual-participant data meta-analysis of ten studies (n=1884) investigating infants' antibody response to routine immunizations following Tdap immunization in pregnancy was performed. Geometric mean ratios (GMRs) of antigen-specific immunoglobulin G (IgG) levels were calculated using mixed-effects models. Seroprotection rates were compared using chi-squared tests.ResultsInfants of Tdap-immunized women had significantly lower IgG against pertussis toxin (GMR 0.65; 95%CI 0.57-0.74), filamentous haemagglutinin (FHA) (0.68; 0.53-0.87), pertactin (0.65; 0.58-0.72) and fimbria 2/3 (FIM2/3) (0.41; 0.32-0.52) after primary immunization, compared with infants of unimmunized women. These lower levels persisted after booster immunization for FHA (0.72; 0.61-0.84) and FIM2/3 (0.53; 0.29-0.96). After primary immunization, infants of Tdap-immunized women had lower seroprotection rates against diphtheria (90% [843/973] vs 98% [566/579]; p<0.001) and invasive pneumococcal disease (IPD) caused by 5 Streptococcus pneumoniae (SPN) serotypes (SPN5, SPN6B, SPN9V, SPN19A, SPN23F), and higher seroprotection rates against Haemophilus influenzae type b (short-term and long-term seroprotection rates, 86%[471/547] vs 76%[188/247] and 62%[337/547] vs 49%(121/247), respectively, all p=0.001). After booster immunization, seroprotection rates against diphtheria and tetanus were 99% (286/288) and (618/619) in infants of Tdap-immunized women, respectively.ConclusionsInfants of Tdap-immunized women in pregnancy had lower IgG levels against pertussis, diphtheria and some SPN serotypes after their immunization compared with infants of unimmunized women. Enhanced surveillance of pertussis, diphtheria and IPD in infants is needed to determine the clinical significance of these findings.Systematic review registrationCRD42017079171.

Dataset Information

Nanoporous Microneedle Arrays Effectively Induce Antibody Responses against Diphtheria and Tetanus Toxoid.

Publications

Nanoporous Microneedle Arrays Effectively Induce Antibody Responses against Diphtheria and Tetanus Toxoid.

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