A Fungal Immunotherapeutic Vaccine (NDV-3A) for Treatment of Recurrent Vulvovaginal Candidiasis-A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial.

Background: Recurrent vulvovaginal candidiasis (RVVC) is a problematic form of mucosal Candida infection, characterized by repeated episodes per year. Candida albicans is the most common cause of RVVC. Currently, there are no immunotherapeutic treatments for RVVC. Methods: This exploratory randomized, double-blind, placebo-controlled trial evaluated an immunotherapeutic vaccine (NDV-3A) containing a recombinant C. albicans adhesin/invasin protein for prevention of RVVC. Results: The study in 188 women with RVVC (n = 178 evaluable) showed that 1 intramuscular dose of NDV-3A was safe and generated rapid and robust B- and T-cell immune responses. Post hoc exploratory analyses revealed a statistically significant increase in the percentage of symptom-free patients at 12 months after vaccination (42% vaccinated vs 22% placebo; P = .03) and a doubling in median time to first symptomatic episode (210 days vaccinated vs 105 days placebo) for the subset of patients aged <40 years (n = 137). The analysis of evaluable patients, which combined patients aged <40 years (77%) and ≥40 years (23%), trended toward a positive impact of NDV-3A versus placebo (P = .099). Conclusions: In this unprecedented study of the effectiveness of a fungal vaccine in humans, NDV-3A administered to women with RVVC was safe and highly immunogenic and reduced the frequency of symptomatic episodes of vulvovaginal candidiasis for up to 12 months in women aged <40 years. These results support further development of NDV-3A vaccine and provide guidance for meaningful clinical endpoints for immunotherapeutic management of RVVC. Clinical Trials Registration: NCT01926028.

Comparative efficacy and toxicity of two vaccine candidates against Sporothrix schenckii using either Montanide™ Pet Gel A or aluminum hydroxide adjuvants in mice.

Sporotrichosis is an important zoonosis in Brazil and the most frequent subcutaneous mycosis in Latin America, caused by different Sporothrix species. Currently, there is no effective vaccine available to prevent this disease. In this study, the efficacy and toxicity of the adjuvant Montanide™ Pet Gel A (PGA) formulated with S. schenckii cell wall proteins (ssCWP) was evaluated and compared with that of aluminum hydroxide (AH). Balb/c mice received two subcutaneous doses (1st and 14th days) of either the unadjuvanted or adjuvanted vaccine candidates. On the 21st day, anti-ssCWP antibody levels (ELISA), the phagocytic index, as well as the ex vivo release of IFN-γ, IL-4, and IL-17 by splenocytes and IL-12 by peritoneal macrophages were assessed. Cytotoxicity of the vaccine formulations was evaluated in vitro and by histopathological analysis of the inoculation site. Both adjuvanted vaccine formulations increased anti-ssCWP IgG, IgG1, IgG2a, and IgG3 levels, although IgG2a levels were higher in response to PGA+CWP100, probably contributing to the increase in S. schenckii yeast phagocytosis by macrophages in the opsonophagocytosis assay when using serum from PGA+CWP100-immunized mice. Immunization with AH+CWP100 led to a mixed Th1/Th2/Th17 ex vivo cytokine release profile, while PGA+CWP100 stimulated a preferential Th1/Th2 profile. Moreover, PGA+CWP100 was less cytotoxic in vitro, caused less local toxicity and led to a similar reduction in fungal load in the liver and spleen of S. schenckii- or S. brasiliensis-challenged mice as compared with AH+CWP100. These results suggest that PGA may be an effective and safe adjuvant for a future sporotrichosis vaccine.

NDV-3, a recombinant alum-adjuvanted vaccine for Candida and Staphylococcus aureus, is safe and immunogenic in healthy adults.

The investigational vaccine, NDV-3, contains the N-terminal portion of the Candida albicans agglutinin-like sequence 3 protein (Als3p) formulated with an aluminum hydroxide adjuvant in phosphate-buffered saline. Preclinical studies demonstrated that the Als3p vaccine antigen protects mice from oropharyngeal, vaginal and intravenous challenge with C. albicans and other selected species of Candida as well as both intravenous challenge and skin and soft tissue infection with Staphylococcus aureus. The objectives of this first-in-human Phase I clinical trial were to evaluate the safety, tolerability and immunogenicity of NDV-3 at two different antigen levels compared to a saline placebo. Forty healthy, adult subjects were randomized to receive one dose of NDV-3 containing either 30 or 300 µg of Als3p, or placebo. NDV-3 at both dose levels was safe and generally well-tolerated. Anti-Als3p total IgG and IgA1 levels for both doses reached peak levels by day 14 post vaccination, with 100% seroconversion of all vaccinated subjects. On average, NDV-3 stimulated peripheral blood mononuclear cell (PBMC) production of both IFN-γ and IL-17A, which peaked at day 7 for subjects receiving the 300 µg dose and at day 28 for those receiving the 30 µg dose. Six months after receiving the first dose of NDV-3, nineteen subjects received a second dose of NDV-3 identical to their first dose to evaluate memory B- and T-cell immune responses. The second dose resulted in a significant boost of IgG and IgA1 titers in >70% of subjects, with the biggest impact in those receiving the 30 µg dose. A memory T-cell response was also noted for IFN-γ in almost all subjects and for IL-17A in the majority of subjects. These data support the continued investigation of NDV-3 as a vaccine candidate against Candida and S. aureus infections.

Safety, tolerability, and immunogenicity of a recombinant, genetically engineered, live-attenuated vaccine against canine blastomycosis.

Blastomycosis is a severe, commonly fatal infection caused by the dimorphic fungus Blastomyces dermatitidis in dogs that live in the United States, Canada, and parts of Africa. The cost of treating an infection can be expensive, and no vaccine against this infection is commercially available. A genetically engineered live-attenuated strain of B. dermatitidis lacking the major virulence factor BAD-1 successfully vaccinates against lethal experimental infection in mice. Here we studied the safety, toxicity, and immunogenicity of this strain as a vaccine in dogs, using 25 beagles at a teaching laboratory and 78 foxhounds in a field trial. In the beagles, escalating doses of live vaccine ranging from 2 × 104 to 2 × 107 yeast cells given subcutaneously were safe and did not disseminate to the lung or induce systemic illness, but a dose of < 2 × 106 yeast cells induced less fever and local inflammation. A vaccine dose of 105 yeast cells was also well tolerated in vaccinated foxhounds who had never had blastomycosis; however, vaccinated dogs with prior infection had more local reactions at the vaccine site. The draining lymph node cells and peripheral blood lymphocytes from vaccinated dogs demonstrated gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and granulocyte-macrophage colony-stimulating factor (GM-CSF) specifically in response to stimulation with Blastomyces antigens. Thus, the live-attenuated vaccine against blastomycosis studied here proved safe, well tolerated, and immunogenic in dogs and merits further studies of vaccine efficacy.

Safety of a non-adjuvanted therapeutic vaccine for the treatment of feline dermatophytosis.

The safety of a non-adjuvanted inactivated fungal vaccine for the treatment of dermatophytosis in cats was investigated in two studies: a controlled laboratory study, and a placebo-controlled double-blind field study with a cross-over design in Europe. In the laboratory study, two groups of 10 cats each were administered an intramuscular twofold overdose, followed by five single 1 ml doses, of either vaccine or control product at 14-day intervals. In the field study, cats were treated with three intramuscular injections of 1 ml vaccine administered at 14-day intervals, as recommended by the manufacturer. A total of 89 cats were enrolled in the field study and divided into two groups to receive either vaccine or placebo for the first three treatments, followed by the opposite product for the final three treatments. The cats enrolled in the two studies were 12 weeks of age or older, as recommended by the manufacturer. All the cats were monitored closely for possible injection site reactions, systemic reactions (including changes in rectal body temperature) and adverse events. The results from both studies showed no significant differences between the vaccinated cats and the control or placebo-treated cats with regard to local or systemic reactions. A few mild to moderate local reactions were noted, but these were evenly distributed between the vaccinated and placebo-treated cats and resolved within a few days. No severe or serious adverse events related to the vaccinations were observed.

Safety and immunologic effects after inoculation of inactivated and combined live-inactivated dermatophytosis vaccines in cats.

OBJECTIVE: To determine antidermatophyte immunologic effects of an experimental combined live-inactivated dermatophytosis vaccine (CLIDV) and a commercial inactivated dermatophytosis vaccine (IDV) in cats and to evaluate adverse effects associated with administration of these vaccines. ANIMALS: 20 healthy juvenile domestic shorthair cats. PROCEDURE: Cats were injected with 2 doses of CLIDV at the standard dosage or 1 dose of CLIDV at 10 times the standard dosage; IDV was administered at the manufacturer-recommended dosage. Cats were observed for illness and reactions at inoculation sites. Periodically, samples were obtained for fungal culture, lymphocyte blastogenesis test (LBT) as an indicator of cell-mediated immunity against dermatophyte antigens, and antidermatophyte IgG titers. Following vaccination, cats were challenge-exposed by topical application of Microsporum canis macroconidia and examined weekly for clinical signs of dermatophytosis. RESULTS: of 10 cats given CLIDV developed focal crusts at the injection site that resolved without treatment; these were areas of dermatophyte infection with the vaccine strain. Antidermatophyte IgG titers increased significantly with all vaccination protocols. Cellular immunity against M canis increased slightly and variably during the vaccination period and did not differ significantly between vaccinated and control cats. All cats developed dermatophyte infection after challenge exposure. Vaccination with CLIDV or IDV was associated with slightly reduced severity of initial infection. CONCLUSIONS AND CLINICAL RELEVANCE: Noculation with IDV or CLIDV did not provide prophylactic immunity against topical challenge exposure with M canis. Inoculation with either vaccine did not provide a more rapid cure of an established infection.

Discontinuation of Pneumocystis carinii prophylaxis in patients infected with human immunodeficiency virus: a meta-analysis and decision analysis.

We performed a meta-analysis and a decision analysis on the discontinuation of prophylaxis for Pneumocystis carinii pneumonia (PCP) in patients infected with human immunodeficiency virus who had adequate immune recovery while receiving highly active antiretroviral therapy. In the meta-analysis (14 studies with 3584 subjects who had discontinued prophylaxis), 8 cases of PCP occurred during 3449 person-years (0.23 cases per 100 person-years [95% confidence interval, 0.10-0.46]). In the decision analysis, mortality and time spent alive without immunodeficiency in the modeled discontinuation strategy were similar to those in the continuation strategy. For patients who received primary prophylaxis, the discontinuation strategy led to slightly fewer episodes of PCP and fewer toxicity-related prophylaxis withdrawals (e.g., 8.6 vs. 34.5 cases per 100 patients during a 10-year period). Patients on the discontinuation strategy were more likely to be receiving trimethoprim-sulfamethoxazole when they became immunodeficient. Comparative results were similar for patients with prior PCP. Discontinuation of PCP prophylaxis in patients with adequate immune recovery is a useful strategy that should be widely considered.

Fungemia with Saccharomyces cerevisiae in two newborns, only one of whom had been treated with ultra-levura.

Ultra-Levura (Upsamedica, Spain) is a yeast (Saccharomyces boulardii) widely used as a biotherapeutic agent. To date, few adverse effects have been reported, although fungemia with Saccharomyces cerevisiae can occur in weak and immunosuppressed patients. Reported here are two cases of fungemia with Saccharomyces cerevisiae. One patient had been treated with Ultra-Levura and the other contracted the infection from the first. This is the first report of infection with Saccharomyces boulardii (Saccharomyces cerevisiae) in a patient who was not being treated with the agent.

Evaluation of the protective efficacy of the killed Coccidioides immitis spherule vaccine in humans. The Valley Fever Vaccine Study Group.

A vaccine consisting of formaldehyde-killed spherules of Coccidioides immitis, previously shown to provide protection against development of lethal coccidioidomycosis in laboratory animals, was evaluated in humans. This double blind "Phase 3" study, conducted during the period 1980 to 1985, involved 2,867 healthy subjects with no history of coccidioidomycosis and negative skin tests. Randomized into vaccine (n = 1,436) or placebo (n = 1,431) groups, the former received three intramuscular injections of 1.75 mg (dry weight) of spherules, the latter received three injections of sterile 0.85% NaCl solution. Compatible clinical presentation with cultural or serologic findings permitted detection of coccidioidomycosis. Of those receiving vaccine, nine developed coccidioidomycosis and nine additional were suspected of having the disease. Of the group receiving placebo, 12 developed coccidioidomycosis, and 13 additional were suspected of having the disease. All cases and suspected cases were mild. Under the conditions of this study, a slight but statistically insignificant reduction in the incidence of coccidioidomycosis was noted in the vaccinated group compared with that in the placebo group, and there was no discernible difference in severity of disease between these groups.

Evaluation of two vaccines for the treatment of pythiosis insidiosi in horses.

Two vaccines to treat phythiosis insidiosi in horses were evaluated in 71 Costa Rican horses between 1982 to 1988. One vaccine used a cell-mass (CMV) as antigen and the other a soluble concentrated antigen (SCAV). Both vaccines cured horses infected with Pythium insidiosum (p value approximately 14%). The age of lesions prior to vaccination was important in the response of the horses to immunotherapy. All horses with lesions 0.5 months or less in duration were cured regardless of the vaccine used. Horses with lesions two or more months old did not respond to either vaccine. The age of the horses did not have any influence on their response to the vaccinations. The CMV produced a prominent inflammatory reaction at the side of injection, while the SCAV gave a low inflammatory reaction. In addition, the CMV lost its effectiveness two to three weeks after its preparation. By contrast, the SCAV maintained its ability to cure horses even after 18 months. Immunotherapy using SCAV can thus be used as the vaccine of choice in early cases of equine cutaneous pythiosis insidiosi.

Immunisation against ringworm in cattle.

Immunisation against dermatomycoses in cattle was introduced in Gausdal, Norway, in 1979. A programme was implemented in which a six-year period of mandatory vaccination of all cattle was followed by vaccination on a voluntary basis. The prevalence of infected herds fell from 70 per cent in 1979 to 0 per cent in 1987. During the last five years, no newly infected herds have been registered in Gausdal. Proper disinfection of premises, the isolation of infected animals and other hygienic measures contributed to the successful result.