Tuning Subunit Vaccines with Novel TLR Triagonist Adjuvants to Generate Protective Immune Responses against Coxiella burnetii.

Coxiella burnetii is an obligate intracellular bacterium and the causative agent of Q fever. C. burnetii is considered a potential bioterrorism agent because of its low infectious dose; resistance to heat, drying, and common disinfectants; and lack of prophylactic therapies. Q-Vax, a formalin-inactivated whole-bacteria vaccine, is currently the only prophylactic measure that is protective against C. burnetii infections but is not U.S. Food and Drug Administration approved. To overcome the safety concerns associated with the whole-bacteria vaccine, we sought to generate and evaluate recombinant protein subunit vaccines against C. burnetii To accomplish this, we formulated C. burnetii Ags with a novel TLR triagonist adjuvant platform, which used combinatorial chemistry to link three different TLR agonists together to form one adjuvanting complex. We evaluated the immunomodulatory activity of a panel of TLR triagonist adjuvants and found that they elicited unique Ag-specific immune responses both in vitro and in vivo. We evaluated our top candidates in a live C. burnetii aerosol challenge model in C56BL/6 mice and found that several of our novel vaccine formulations conferred varying levels of protection to the challenged animals compared with sham immunized mice, although none of our candidates were as protective as the commercial vaccine across all protection criteria that were analyzed. Our findings characterize a novel adjuvant platform and offer an alternative approach to generating protective and effective vaccines against C. burnetii.

The dangers of human papillomavirus (HPV) laser plume and best safety practices.

Human papillomavirus (HPV) remains to be one of the most common viruses that afflicts the skin and mucosa. Direct contact with cutaneous lesions facilitates a majority of viral transmission. However, the development of laser therapy as treatment for HPV brought to attention the concern of infectious laser plume and the risk it poses to those inhaling it. We conducted a literature review using English articles in PubMed to validate this risk and propose the best safety practices dermatologists can apply when using laser therapy as treatment for HPV. Our investigation identified smoke evacuators as primary modes of mitigation, and we suggest further studies will aid in the refinement of best practice recommendations.

Redesigning Sentinel Lymph Node Biopsy Guidelines in Melanoma Cases.

Background: Accurately staging and prognosticating melanoma classically depends on a sentinel lymph node biopsy (SLNB). The mainstay predictors of SLNB positivity according to the American Joint Committee on Cancer (AJCC) are Breslow depth and ulceration. Nevertheless, even with these predictors, negative SLNBs, even in deep melanomas, are a common occurrence and may result in unnecessary invasive procedures for patients. This suggests that the parameters for determining SLNB candidates are a potential area for improvement in surgical dermatology (surgical oncology and plastic surgery). Methods: The authors conducted a systemic review to assess current AJCC guidelines on when a SLNB in melanoma is indicated. We also investigated how age, mitotic rate, lymphovascular invasion, satellitosis, melanoma subtype, anatomical location, and an immunocompromised state affected positivity rates in sentinel lymph node biopsies in melanoma. Results: These variables significantly impacted SLNB positivity rates and serve as evidence to support the proposal of redesigning SLNB guidelines in melanoma. Conclusions: Integrating the current AJCC guidelines with the newly examined variables will create patient-specific recommendations centered on the aim of reducing the number of invasive procedures while increasing SLNB positivity rates and prognostication.

Linked Toll-Like Receptor Triagonists Stimulate Distinct, Combination-Dependent Innate Immune Responses.

Traditional vaccination strategies have failed to generate effective vaccines for many infections like tuberculosis and HIV. New approaches are needed for each type of disease. The protective immunity and distinct responses of many successful vaccines come from activating multiple Toll-like receptors (TLRs). Vaccines with multiple TLRs as adjuvants have proven effective in preclinical studies, but current research has not explored two important elements. First, few multi-TLR systems explore spatial organization-a critical feature of whole-cell vaccines. Second, no multi-TLR systems to date provide systematic analysis of the combinatorial space of three TLR agonists. Here, we present the first examination of the combinatorial space of several spatially defined triple-TLR adjuvants, by synthesizing a series of five triple-TLR agonists and testing their innate activity both in vitro and in vivo. The combinations were evaluated by measuring activation of immune stimulatory genes (Nf-κB, ISGs), cytokine profiles (IL12-p70, TNF-α, IL-6, IL-10, CCL2, IFN-α, IFN-ß, IFN-γ), and in vivo cytokine serum levels (IL-6, TNF-α, IL12-p40, IFN-α, IFN-ß). We demonstrate that linking TLR agonists substantially alters the resulting immune response compared to their unlinked counterparts and that each combination results in a distinct immune response, particularly between linked combinations. We show that combinations containing a TLR9 agonist produce more Th1 biasing immune response profiles, and that the effect is amplified upon conjugation. However, combinations containing TLR2/6 agonist are skewed toward TH2 biasing profiles despite the presence of TLR9. These results demonstrate the profound effects that conjugation and combinatorial administration of TLR agonists can have on immune responses, a critical element of vaccine development.