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Drug delivery to the skin is highly constrained by the stratum corneum barrier layer.sup.1. Here, we developed star-shaped particles, termed STAR particles, to dramatically increase skin permeability. STAR particles are millimeter-scale particles made of aluminum oxide or stainless steel with micron-scale projections designed to create microscopic pores across the stratum corneum. After gentle topical application for 10 s to porcine skin ex vivo, delivery of dermatological drugs and macromolecules, including those that cannot be given topically, was increased by 1 to 2 orders of magnitude. In mice treated with topical 5-fluorouracil, use of STAR particles increased the efficacy of the drug in suppressing the growth of subcutaneous melanoma tumors and prolonging survival. Moreover, topical delivery of tetanus toxoid vaccine to mice using STAR particles generated immune responses that were at least as strong as delivery of the vaccine by intramuscular injection, albeit at a higher dose for topical than intramuscular vaccine administration. STAR particles were well tolerated and effective at creating micropores when applied to the skin of human participants. Use of STAR particles provides a simple, low-cost and well-tolerated method for increasing drug and vaccine delivery to the skin and could widen the range of compounds that can be topically administered. Star-shaped, approximately 1-mm-wide ceramic particles, termed STAR particles, create micropores in the skin and, when added to topical formulations, enhance drug and vaccine delivery through the skin in mice., Author(s): Andrew R. Tadros [sup.1] , Andrey Romanyuk [sup.1] , Ian C. Miller [sup.2] , Andrea Santiago [sup.2] , Richard K. Noel [sup.3] , Laura O'Farrell [sup.3] , Gabriel A. [...]

Byline: Gajendra. Choudhary#, Manisha. Prajapat#, J. Kumaravel, Praisy. Prabha, Phulen. Sarma, Vrishbhanu. Handa, Harminder. Kaur, Ajay. Patel, Bikash. Medhi The new omicron variant of severe acute respiratory syndrome coronavirus 2 [...]

Antibodies are the primary correlate of protection for most licensed vaccines; however, their mechanisms of protection may vary, ranging from physical blockade to clearance via the recruitment of innate immunity. Here, we uncover striking functional diversity in vaccine-induced antibodies that is driven by immunization site and is associated with reduced risk of SIV infection in nonhuman primates. While equivalent levels of protection were observed following intramuscular (IM) and aerosol (AE) immunization with an otherwise identical DNA prime-Ad5 boost regimen, reduced risk of infection was associated with IgG-driven antibody-dependent monocyte-mediated phagocytosis in the IM vaccinees, but with vaccine-elicited IgA-driven neutrophil-mediated phagocytosis in AE-immunized animals. Thus, although route-independent correlates indicate a critical role for phagocytic Fc-effector activity in protection from SIV, the site of immunization may drive this Fc activity via distinct innate effector cells and antibody isotypes. Moreover, the same correlates predicted protection from SHIV infection in a second nonhuman primate vaccine trial using a disparate IM canarypox prime-protein boost strategy, analogous to that used in the first moderately protective human HIV vaccine trial. These data identify orthogonal functional humoral mechanisms, initiated by distinct vaccination routes and immunization strategies, pointing to multiple, potentially complementary correlates of immunity that may support the rational design of a protective vaccine against HIV. Distinct routes of immunization elicit different antibody isotypes and functions associated with protection against SIV infection that converge on phagocytosis as a candidate protective mechanism of independent SIV vaccines., Author(s): Margaret E. Ackerman [sup.1] , Jishnu Das [sup.2] , Srivamshi Pittala [sup.3] , Thomas Broge [sup.2] , Caitlyn Linde [sup.2] , Todd J. Suscovich [sup.2] , Eric P. Brown [...]

BACKGROUND: Lyme borreliosis (LB) is the most prevalent arthropod-borne infectious disease in North America. Currently, no vaccine is available to prevent LB in humans, although monovalent and multivalent vaccines have been developed in the past. OBJECTIVE: The aim of the current study is to conduct a systematic review and meta-analysis to evaluate and compare the findings from these two classes of vaccines for their reactogenicity, immunogenicity and efficacy, in the hope this may assist in the development of future vaccines. METHODS: A search strategy was developed for online databases (PubMed, Ovid MEDLINE, and Embase). Search terms used were 'vaccine/vaccination', 'Lyme disease/Borreliosis', 'clinical trial(s)' and 'efficacy'. Only seven clinical trials were included to compare the results of the monovalent vaccines to those of the multivalent one. Meta-analyses were conducted to evaluate the reactogenicity and immunogenicity of the two vaccine classes. Odds ratio (OR) for LB (and 95% confidence intervals; 95% CI) were calculated for the efficacy of the monovalent vaccine from three different clinical trials at different dose schedules. RESULTS: Incidence of redness (local adverse effect) and fever (systemic side effect) were, respectively, 6.8- and 2.9-fold significantly lower (p < 0.05) in individuals who received multivalent vaccines compared to those receiving the monovalent one. Incidences of all other local and systemic adverse effects were non-significantly lower in the multivalent vaccine compared to the monovalent vaccines. Seroprotection was comparable among individuals who received the two vaccine classes at the 30 [micro]g dose level. Efficacy in the prevention of LB was only evaluated for the monovalent vaccines. OR of LB ranged from 0.49 (95% CI: 0.14-0.70; p < 0.005, vs. placebo) to 0.31 (95% CI: 0.26-0.63; p < 0.005) for the initial and final doses respectively, with an overall OR of 0.4 (95% CI: 0.26-0.63, p < 0.001). CONCLUSION: The current study further validates that the monovalent and multivalent LB vaccines result in mild local side effects and self-limiting systemic adverse effects, with the multivalent vaccine slightly more tolerable than the monovalent one. Both vaccine classes were similarly highly immunogenic. A new vaccine with high safety standards, better efficacy, low cost, and public acceptance is yet to be developed. Meanwhile, personal protection limiting exposure to ticks is recommended. KEY WORDS: Lyme disease; vaccine; clinical trial; efficacy; systematic review CONTEXTE: La borreliose de Lyme (BL) est la plus prevalente des maladies infectieuses transmises par les arthropodes en Amerique du Nord. Il n'existe actuellement aucun vaccin pour prevenir la BL chez les humains, mais deux vaccins monovalents et un vaccin multivalent ont ete mis au point par le passe. OBJECTIF: Notre etude vise a mener une revue systematique et des meta-analyses pour evaluer et comparer les constatations sur la reactogenicite, l'immunogenicite et l'efficacite potentielle de ces deux classes de vaccins, dans l'espoir que cela aidera a mettre au point de futurs vaccins. METHODE: Nous avons elabore une strategie de consultation de bases de donnees en ligne (PubMed, Ovid MEDLINE et Embase). Les termes de recherche utilises ont ete ' vaccine/vaccination ' (vaccin/vaccination), ' Lyme disease/Borreliosis ' (maladie de Lyme/borreliose), ' clinical trial (s) ' (essai(s) clinique(s)) et ' efficacy ' (efficacite potentielle). Nous n'avons inclus que sept essais cliniques pour comparer les resultats des vaccins monovalents a ceux du vaccin multivalent. Nous avons mene des meta-analyses pour evaluer la reactogenicite et l'immunogenicite des deux classes de vaccins. Des rapports de cotes (RC) pour la BL (et des intervalles de confiance de 95%; IC de 95%) ont ete calcules pour determiner l'efficacite potentielle des vaccins monovalents administres durant trois essais cliniques menes selon des schemas posologiques differents. RESULTATS: L'incidence de rougeurs (un effet indesirable local) et de fievre (un effet indesirable general) a ete, respectivement, de 6,8 et de 2,9 fois significativement inferieure (p < 0,05) chez les sujets ayant recu le vaccin multivalent que chez ceux ayant recu les vaccins monovalents. Les incidences de tous les autres effets indesirables locaux et generaux ont ete non significativement inferieures pour le vaccin multivalent que pour les vaccins monovalents. La seroprotection etait comparable chez les sujets ayant recu les deux classes de vaccins en doses de 30 [micro]g. L'efficacite potentielle des vaccins pour prevenir la BL n'a ete evaluee que pour les vaccins monovalents. Le RC de la BL variait entre 0,49 (IC de 95%: 0,14-0,70; p< 0,005, contre un placebo) et 0,31 (IC de 95%: 0,26-0,63; p < 0,005) pour les doses initiale et finale, respectivement, avec un RC global de 0,4 (IC de 95%: 0,26-0,63, p < 0,001). CONCLUSION: L'etude actuelle confirme que les vaccins monovalents et multivalent contre la BL entrainent de legers effets secondaires locaux et des effets indesirables generaux spontanement resolutifs, et que le vaccin multivalent est legerement mieux tolere que les vaccins monovalents. Les deux classes de vaccins ont la meme immunogenicite elevee. Un nouveau vaccin avec des normes de securite elevees, une efficacite potentielle accrue, un prix abordable et une bonne acceptation par le public n'est pas encore au point. Entre-temps, il est recommande de prendre des mesures de protection individuelles pour limiter l'exposition aux tiques. MOTS CLES: maladie de Lyme; vaccin; essai clinique; efficacite potentielle; revue systematique, Lyme disease or Lyme borreliosis (LB) is the most prevalent arthropod-borne disease in North America. (1) It is caused by Borrelia burgdorferi sensu stricto (B. burgdorferi) in North America, which [...]

Recombinant adenoviral vectors (rAds) are lead vaccine candidates for protection against a variety of pathogens, including Ebola, HIV, tuberculosis, and malaria, due to their ability to potently induce T cell immunity in humans. However, the ability to induce protective cellular immunity varies among rAds. Here, we assessed the mechanisms that control the potency of CD8 T cell responses in murine models following vaccination with human-, chimpanzee-, and simian-derived rAds encoding SIV-Gag antigen (Ag). After rAd vaccination, we quantified Ag expression and performed expression profiling of innate immune response genes in the draining lymph node. Human-derived rAd5 and chimpanzee- derived chAd3 were the most potent rAds and induced high and persistent Ag expression with low innate gene activation, while less potent rAds induced less Ag expression and robustly induced innate immunity genes that were primarily associated with IFN signaling. Abrogation of type I IFN or stimulator of IFN genes (STING) signaling increased Ag expression and accelerated CD8 T cell response kinetics but did not alter memory responses or protection. These findings reveal that the magnitude of rAd-induced memory CD8 T cell immune responses correlates with Ag expression but is independent of IFN and STING and provide criteria for optimizing protective CD8 T cell immunity with rAd vaccines., Introduction CD8 T cells play a critical role in mediating protection to a variety of intracellular pathogens, including Ebola, HIV, tuberculosis, and malaria. Replication-defective recombinant adenoviral vectors (rAds) are promising [...]

Immunizations combined with antibiotics could be our best shot at combating drug-resistant microbes, argue Rino Rappuoli, David E. Bloom and Steve Black. Immunizations combined with antibiotics could be our best shot at combating drug-resistant microbes, argue Rino Rappuoli, David E. Bloom and Steve Black., Author(s): Rino Rappuoli, David E. Bloom, Steve Black Author Affiliations: Deploy vaccines to fight superbugs Vaccines can have an effect on antimicrobial resistance by reducing the number of ill people [...]

Author(s): Carrie Arnold [1] [illus. 1] In a forest in southern India in January of last year, Samil George took a cotton swab and carefully swiped the clear goo off [...]

Background. Defining the parameters that modulate vaccine responses in African populations will be imperative to design effective vaccines for protection against HIV, malaria, tuberculosis, and dengue virus infections. This study aimed to evaluate the contribution of the patient-specific immune microenvironment to the response to the licensed yellow fever vaccine 17D (YF-17D) in an African cohort. Methods. We compared responses to YF-17D in 50 volunteers in Entebbe, Uganda, and 50 volunteers in Lausanne, Switzerland. We measured the [CD8.sup.+] T cell and B cell responses induced by YF-17D and correlated them with immune parameters analyzed by flow cytometry prior to vaccination. Results. We showed that YF-17D-induced [CD8.sup.+] T cell and B cell responses were substantially lower in immunized individuals from Entebbe compared with immunized individuals from Lausanne. The impaired vaccine response in the Entebbe cohort associated with reduced YF-17D replication. Prior to vaccination, we observed higher frequencies of exhausted and activated NK cells, differentiated T and B cell subsets and proinflammatory monocytes, suggesting an activated immune microenvironment in the Entebbe volunteers. Interestingly, activation of [CD8.sup.+] T cells and B cells as well as proinflammatory monocytes at baseline negatively correlated with YF-17D-neutralizing antibody titers after vaccination. Additionally, memory T and B cell responses in preimmunized volunteers exhibited reduced persistence in the Entebbe cohort but were boosted by a second vaccination. Conclusion. Together, these results demonstrate that an activated immune microenvironment prior to vaccination impedes efficacy of the YF-17D vaccine in an African cohort and suggest that vaccine regimens may need to be boosted in African populations to achieve efficient immunity. Trial registration. Registration is not required for observational studies. Funding. This study was funded by Canada's Global Health Research Initiative, Defense Threat Reduction Agency, National Institute of Allergy and Infectious Diseases, Bill & Melinda Gates Foundation, and United States Agency for International Development., Introduction The yellow fever vaccine 17D (YF-17D) induces an efficient immune protection against infection. The protective effect of the vaccine is thought to occur within 10 days after vaccination in [...]

In cancer patients, visual identification of sentinel lymph nodes (LNs) is achieved by the injection of dyes that bind avidly to endogenous albumin, targeting these compounds to LNs, where they are efficiently filtered by resident phagocytes (1,2). Here we translate this 'albumin hitchhiking' approach to molecular vaccines, through the synthesis of amphiphiles (amph-vaccines) comprising an antigen or adjuvant cargo linked to a lipophilic albumin-binding tail by a solubility-promoting polar polymer chain. Administration of structurally optimized CpG-DNA/peptide amph-vaccines in mice resulted in marked increases in LN accumulation and decreased systemic dissemination relative to their parent compounds, leading to 30-fold increases in T-cell priming and enhanced anti-tumour efficacy while greatly reducing systemic toxicity. Amph-vaccines provide a simple, broadly applicable strategy to simultaneously increase the potency and safety of subunit vaccines., A major challenge in the development of subunit vaccines is the efficient delivery of antigen/adjuvant to secondary lymphoid organs, where immune responses are orchestrated (3,4). Attempts to enhance vaccine delivery [...]

To improve coverage against vaccine-preventable diseases for children and adults, and to aid caretakers and providers in making appropriate and timely vaccination decisions, Georgia Institute of Technology collaborated with the [...]