Search Results (15)

As Valley fever (coccidioidomycosis) vaccine candidates progress towards human trials, a challenge to their eventual introduction is understanding vaccine demand and addressing vaccine hesitancy. We assessed intent to accept a Valley fever vaccine for humans and dogs in two populations living in highly endemic regions: employees at Kern Medical (KM) in Bakersfield, California (N = 103) and members of the public in West Texas (N = 230). We compared the weighted proportions of each population willing to vaccinate themselves and their dogs by demographic and coccidioidomycosis risk factors and assessed the importance of vaccine-related factors on vaccine uptake in each population. We found that 42% (95% confidence interval (CI): 34–49%) of West Texas residents and 76% (95% CI: 63–85%) of KM employees were willing to accept a coccidioidal vaccine, while 49% (95% CI: 41–58%) of West Texas residents and 74% (95% CI: 58–86%) of KM employees were willing to vaccinate their dogs. Among West Texas residents, vaccination willingness was significantly higher among those with prior awareness of Valley fever (adjusted odds ratio (aOR): 3.83, 95% CI: 1.73, 8.49). Across both study populations, absence of side effects was the most important condition that would increase vaccination willingness. Our results indicate substantial interest in a Valley fever vaccine while suggesting that increased Valley fever awareness and minimal vaccine side effects may be important for increased uptake. Full article

Coccidioidomycosis (CM) is a fungal infection caused by the inhalation of airborne arthroconidia released by Coccidioides spp. Endemic areas include the southwestern United States, Mexico, and parts of South America. The estimated CM cases exceed 300,000 per year. Current treatment for CM is limited and primarily relies on antifungals such as azoles and Amphotericin B. Moreover, concerns about drug cytotoxicity and rising of azole-resistance underscore the need for alternative or adjunctive immune-based prevention and therapies. This review presents recent advances in immune CM intervention and discusses the potential application of emerging antifungal immunotherapy to treat invasive CM. For preventive vaccination, we reviewed the recent development of subunit protein vaccines and mRNA-based vaccines. Prospects for formulating vaccines with potent adjuvants and delivery systems to enhance protective immunity against CM are also provided. For immunotherapy, we reviewed recent reports of antifungal treatment with immunomodulators, CAR-cells and checkpoint inhibitors. Finally, we discuss the application of experimental animal and in vitro models for advancing vaccine and immunotherapeutic development for CM. Full article

Emerging respiratory dimorphic fungi, including Coccidioides, pose a growing public health threat due to their ability to cause severe disease and the limited therapeutic options. A growing gap exists between rapidly expanding computational data and slower traditional experimental methods for virulence factor identification, limiting progress in fungal pathogenesis research and therapeutic development. This review presents a framework for integrating computational and experimental methodologies to accelerate virulence discovery in Coccidioides. We examine predictive tools for adhesins, transporters, secreted effectors, carbohydrate-active enzymes (CAZymes), and secondary metabolites, plus therapeutic target prioritization strategies based on druggability, selectivity, essentiality, and precedent. Examples from Coccidioides and other World Health Organization-designated emerging fungi highlight how computational pipelines clarify pathogenic mechanisms and guide experimental design. We also assess machine learning, structural prediction, and reverse vaccinology approaches for enhance target discovery. By applying computational advances to Coccidioides research with experimental validation, this integrated approach can guide future antifungal drug and vaccine development. Full article

Coccidioidomycosis is an important fungal disease that is found in many desert regions of the western hemisphere. The inhaled organisms are highly pathogenic, but only half of infected, immunologically intact people develop symptomatic pneumonia; most symptomatic infections resolve spontaneously, although some resolve very slowly. Furthermore, second infections are very rare and natural immunity after infection is robust. Therefore, the host response to this organism is very effective at resolving the infection in most cases and immunizing to prevent second infections. People who are immunocompromised are much more likely to develop disseminated infection. This is a comprehensive review of the innate and acquired immune responses to Coccidioides spp., the genetics of resistance to severe infection, and the search for an effective vaccine. Full article

Coccidioidomycosis is caused by Coccidioides posadasii (Cp) and Coccidioides immitis (Ci), which have a 4–5% difference in their genomic sequences. There is an urgent need to develop a human vaccine against both species. A previously created recombinant antigen (rCpa1) that contains multiple peptides derived from Cp isolate C735 is protective against the autologous isolate. The focus of this study is to evaluate cross-protective efficacy and immune correlates by the rCpa1-based vaccine against both species of Coccidioides. DNA sequence analyses of the homologous genes for the rCpa1 antigen were conducted for 39 and 17 clinical isolates of Cp and Ci, respectively. Protective efficacy and vaccine-induced immunity were evaluated for both C57BL/6 and human HLA-DR4 transgenic mice against five highly virulent isolates of Cp and Ci. There are total of seven amino acid substitutions in the rCpa1 antigen between Cp and Ci. Both C57BL/6 and HLA-DR4 mice that were vaccinated with an rCpa1 vaccine had a significant reduction of fungal burden and increased numbers of IFN-γ- and IL-17-producing CD4+ T cells in the first 2 weeks post challenge. These data suggest that rCpa1 has cross-protection activity against Cp and Ci pulmonary infection through activation of early Th1 and Th17 responses. Full article

Coccidioidomycosis is an endemic fungal infection that is reported in up to 20,000 persons per year and has an economic impact close to $1.5 billion. Natural infection virtually always confers protection from future exposure, and this suggests that a preventative vaccine strategy is likely to succeed. We here review progress toward that objective. There has been ongoing research to discover a coccidioidal vaccine over the past seven decades, including one phase III clinical trial, but for reasons of either efficacy or feasibility, a safe and effective vaccine has not yet been developed. This review first summarizes the past research to develop a coccidioidal vaccine. It then details the evidence that supports a live, gene-deletion vaccine candidate as suitable for further development as both a veterinary and a human clinical product. Finally, a plausible vaccine development plan is described which would be applicable to this vaccine candidate and also useful to other future candidates. The public health and economic impact of coccidioidomycosis fully justifies a public private partnership for vaccine development, and the development of a vaccine for this orphan disease will likely require some degree of public funding. Full article

Coccidioidomycosis is a fungal, respiratory disease caused by Coccidioides immitis and Coccidioides posadasii. The host immune responses that define disease outcome during infection are largely unknown, although T helper responses are required. Adaptive immunity is influenced by innate immunity as antigen-presenting cells activate and educate adaptive responses. Macrophage and dendritic cell (DC) recognition of pathogen surface molecules are critical for Coccidioides clearance. We characterize the broad innate immune responses to Coccidioides by analyzing macrophage and dendritic cell responses to Coccidioides arthroconidia using avirulent, vaccine Coccidioides strain NR-166 (Δcts2/Δard1/Δcts3), developed from parental virulent strain C735. We developed a novel flow cytometry-based method to analyze macrophage phagocytosis to complement traditional image-scoring methods. Our study found that macrophage polarization is blocked at M0 phase and activation reduced, while DCs polarize into proinflammatory DC1s, but not anti-inflammatory DC2, following interaction with Coccidioides. However, DCs exhibit a contact-dependent reduced activation to Coccidioides as defined by co-expression of MHC-II and CD86. In vivo, only modest DC1/DC2 recruitment and activation was observed with avirulent Coccidioides infection. In conclusion, the vaccine Coccidioides strain recruited a mixed DC population in vivo, while in vitro data suggest active innate immune cell inhibition by Coccidioides. Full article

Although first described more than 120 years ago, much remains unknown about coccidioidomycosis. In this review, new information that has led to changing concepts will be reviewed and remaining gaps in our knowledge will be discussed. In particular, new ideas regarding ecology and epidemiology, problems and promises of diagnosis, controversies over management, and the possibility of a vaccine will be covered. Full article

Vaccination is one of the greatest public health achievements in the past century, protecting and improving the quality of life of the population worldwide. However, a safe and effective vaccine for therapeutic or prophylactic treatment of fungal infections is not yet available. The lack of a vaccine for fungi is a problem of increasing importance as the incidence of diverse species, including Paracoccidioides, Aspergillus, Candida, Sporothrix, and Coccidioides, has increased in recent decades and new drug-resistant pathogenic fungi are emerging. In fact, our antifungal armamentarium too frequently fails to effectively control or cure mycoses, leading to high rates of mortality and morbidity. With this in mind, many groups are working towards identifying effective and safe vaccines for fungal pathogens, with a particular focus of generating vaccines that will work in individuals with compromised immunity who bear the major burden of infections from these microbes. In this review, we detail advances in the development of vaccines for pathogenic fungi, and highlight new methodologies using immunoproteomic techniques and bioinformatic tools that have led to new vaccine formulations, like peptide-based vaccines. Full article

Infectious diseases continue to be a significant cause of morbidity and mortality, and although efficacious vaccines are available for many diseases, some parenteral vaccines elicit little or no mucosal antibodies which can be a significant problem since mucosal tissue is the point of entry for 90% of pathogens. In order to provide protection for both serum and mucosal areas, we have tested a combinatorial approach of both parenteral and oral administration of antigens for diseases caused by a viral pathogen, Hepatitis B, and a fungal pathogen, Coccidioides. We demonstrate that co-administration by the parenteral and oral routes is a useful tool to increase the overall immune response. This can include achieving an immune response in tissues that are not elicited when using only one route of administration, providing a higher level of response that can lead to fewer required doses or possibly providing a better response for individuals that are considered poor or non-responders. Full article

The incidence of coccidioidomycosis, also known as Valley Fever, is increasing in the Southwestern United States and Mexico. Despite considerable efforts, a vaccine to protect humans from this disease is not forthcoming. The aim of this project was to isolate and phylogenetically compare bacterial species that could serve as biocontrol candidates to suppress the growth of Coccidioides immitis, the causative agent of coccidioidomycosis, in eroded soils or in areas close to human settlements that are being developed. Soil erosion in Coccidioides endemic areas is leading to substantial emissions of fugitive dust that can contain arthroconidia of the pathogen and thus it is becoming a health hazard. Natural microbial antagonists to C. immitis, that are adapted to arid desert soils could be used for biocontrol attempts to suppress the growth of the pathogen in situ to reduce the risk for humans and animals of contracting coccidioidomycosis. Bacteria were isolated from soil samples obtained near Bakersfield, California. Subsequently, pairwise challenge assays with bacterial pure cultures were initially performed against Uncinocarpus reesii, a non-pathogenic relative of C. immitis on media plates. Bacterial isolates that exhibited strongly antifungal properties were then re-challenged against C. immitis. Strongly anti-C. immitis bacterial isolates related to Bacillus subtilis and Streptomyces spp. were isolated, and their antifungal spectrum was investigated using a selection of environmental fungi. Full article

Antigenic fractions of 100, 50, 37, and 28 kDa obtained through the SDS-PAGE method that were more frequently recognized by anti-Coccidioides antibodies in the sera of coccidioidomycosis patients were selected using western blotting. Subsequently, these bands were sequenced, and the obtained proteins were analysed by BLAST to choose peptides specific for Coccidioides spp. from among the shared aligned sequences of related fungi. A peptide specific for C. immitis was selected from the “GPI anchored serine-threonine rich protein OS C. immitis”, while from the “uncharacterized protein of C. immitis”, we selected a peptide for C. immitis and C. posadasii. These proteins arose from the 100 kDa antigenic fraction. From the protein “fatty acid amide hydrolase 1 of C. posadasii” that was identified from the 50 kDa antigenic fraction, a peptide was selected that recognized C. immitis and C. posadasii. In addition, the analysis of all the peptides (353) of each of the assembled proteins showed that only 35 had 100% identity with proteins of C. immitis and C. posadasii, one had 100% identity with only C. immitis, and one had 100% identity with only C. posadasii. These peptides can be used as diagnostic reagents, vaccines, and antifungals. Full article

Coccidioidomycosis is a fungal infection caused by Coccidioides posadasii and Coccidioides immitis. It is estimated that 150,000 new infections occur in the United States each year. The incidence of this infection continues to rise in endemic regions. There is an urgent need for the development of better therapeutic drugs and a vaccine against coccidioidomycosis. This review discusses the features of host innate and adaptive immune responses to Coccidioides infection. The focus is on the recent advances in the immune response and host-pathogen interactions, including the recognition of spherules by the host and defining the signal pathways that guide the development of the adaptive T-cell response to Coccidioides infection. Also discussed is an update on progress in developing a vaccine against these fungal pathogens. Full article

Coccidioidomycosis (Valley Fever) is a disease caused by inhalation of Coccidioides spp. This neglected disease has substantial public health impact despite its geographic restriction to desert areas of the southwestern U.S., Mexico, Central and South America. The incidence of this infection in California and Arizona has been increasing over the past fifteen years. Several large cities are within the endemic region in the U.S. Coccidioidomycosis accounts for 25,000 hospital admissions per year in California. While most cases of coccidioidomycosis resolve spontaneously, up to 40% are severe enough to require anti-fungal treatment, and a significant number disseminate beyond the lungs. Disseminated infection involving the meninges is fatal without appropriate treatment. Infection with Coccidioides spp. is protective against a second infection, so vaccination seems biologically plausible. This review of efforts to develop a vaccine against coccidioidomycosis focuses on vaccine approaches and the difficulties in identifying protein antigen/adjuvant combinations that protect in experimental mouse models. Although the quest for a vaccine is still in the early stage, scientific efforts for vaccine development may pave the way for future success. Full article

We are presenting a quantitative proteomics tally of the most commonly expressed conserved fungal proteins of the cytosol, the cell wall, and the secretome. It was our goal to identify fungi-typical proteins that do not share significant homology with human proteins. Such fungal proteins are of interest to the development of vaccines or drug targets. Protein samples were derived from 13 fungal species, cultured in rich or in minimal media; these included clinical isolates of Aspergillus, Candida, Mucor, Cryptococcus, and Coccidioides species. Proteomes were analyzed by quantitative MS^E (Mass Spectrometry—Elevated Collision Energy). Several thousand proteins were identified and quantified in total across all fractions and culture conditions. The 42 most abundant proteins identified in fungal cell walls or supernatants shared no to very little homology with human proteins. In contrast, all but five of the 50 most abundant cytosolic proteins had human homologs with sequence identity averaging 59%. Proteomic comparisons of the secreted or surface localized fungal proteins highlighted conserved homologs of the Aspergillus fumigatus proteins 1,3-β-glucanosyltransferases (Bgt1, Gel1-4), Crf1, Ecm33, EglC, and others. The fact that Crf1 and Gel1 were previously shown to be promising vaccine candidates, underlines the value of the proteomics data presented here. Full article