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Multiple (for 14 and 20 days) administrations of antibiotics, such as tetraolean, tetracycline and penicillin from the beginning of the animal immunization (rabbits and albino rats) with typhoid fever and candidosis vaccines inhibited activity of both the non-specific and the specific immunity.
The immunogenicity of a crude ribosomal fraction (CRF) extracted from Microsporum canis was tested by assessing protection of vaccinated guinea-pigs (GP) against a challenge with the dermatophyte. Stimulation of the humoral as well as the cellular immune systems of these animals was evaluated by ELISA and the lymphocyte stimulation tests, respectively. In addition, the immune response elicited by the M. canis CRF was examined for cross-reactivity towards Trichophyton verrucosum antigen. The duration of the infection induced by M. canis in GP was reduced to 8 days in vaccinated animals versus 37 days in the control GP. Both humoral and cellular immune systems were stimulated by the CRF. Sera of GP vaccinated with M. canis CRF revealed presence of anti-T. verrucosum antibodies, albeit at titres significantly lower than against M. canis.
Invasive pulmonary aspergillosis is an emerging devastating infection in the immunocompromised host that is treated with corticosteroids for neoplastic disease or for organ transplantation. By use of a model of invasive pulmonary aspergillosis in corticosteroid-treated CF-1 mice, prior infection and 2 Aspergillus fumigatus vaccine preparations (sonicate and filtrate) administered intranasally and subcutaneously were tested for efficacy in protecting against subsequent lethal A. fumigatus infection. The mortality rates were as follows: control subjects, 100%; prior infection, 12.5%; sonicate administered intranasally, 29%; sonicate given subcutaneously, 0%; filtrate given intranasally, 75%; and filtrate given subcutaneously, 50%. Prior infection and A. fumigatus sonicate vaccine administered by 2 routes protected corticosteroid-treated animals against subsequent lethal invasive pulmonary aspergillosis. The sonicate vaccine was more protective, but the subcutaneous route was more effective.
Trials were conducted with 262 one-month-old calves. Good immunity was found to have developed within the period of 21 to 28 days after the administration of the Czechoslovak live vaccine against bovine trichophytosis. After epicutaneous inoculation of a highly virulent culture of Trichophyton verrucosum, performed 28 and 35 days after re-vaccination, no clinical form of trichophytosis was observed to rise in the calves. The same doses of challenge inoculum induced profound trichophytic changes. In the groups of calves artificially infected on the day of re-vaccination and seven days after re-vaccination, the proportions of experimental animals that fell ill were 88.2% and 44.4%, respectively; in the majority of cases, the course of the disease was not so serious as in the controls. Calves challenged 11 to 21 days after the second administration of the vaccines were mostly resistant to experimental infection: slight changes occurred in 15.4 to 7.0% of the tested animals.
Cellular immunity mediated by T lymphocytes, in particular CD4(+) and CD8(+) type 1 (T1) cells, is the main defense against pathogenic fungi. IL-12 initiates T1 cell development and cell-mediated immunity, but it is unclear whether IL-12 contributes to the maintenance of an antifungal T1 response. In this study, we addressed the role of IL-12 for vaccine-induced memory T cell development against experimental pulmonary blastomycosis. CD4(+) T cells absolutely required IL-12 to control a live genetically engineered attenuated strain of Blastomyces dermatitidis given s.c. as a vaccine, whereas CD8(+) T cells were significantly less dependent on IL-12. Despite differential dependency of T cell subsets on IL-12 during vaccination, neither subset acquired memory immunity in the absence of IL-12. In contrast, adoptive transfer of immune CD4 T cells from wild-type mice into IL-12(-/-) mice showed that CD4(+) T1 memory cells sustained a T1 cytokine profile and remained protective over a period of 6 mo posttransfer. Similarly, memory CD8 cells elicited in IL-12(-/-) mice with killed yeast and transient rIL-12 treatment (during vaccination) remained durable and protective after animals were rested for 3 mo. In conclusion, these studies demonstrate that once CD4 and CD8 cells have acquired a protective T1 phenotype they no longer require the presence of IL-12 to maintain antifungal protective memory.
Human occupational diseases orginated from Trichophyton verrucosum infection of cattle belonged to the most frequent zooanthroponoses since 1960. Morbidity peaks of this human dermatophytosis could be observed in 1970 and 1971 with about 740 cases of occupational diseases per year. The ecological properties of Tr. verrucosum (compulsory monoxenic parasite), the pathogenetic development of bovine dermatophytosis (rising immunity with subsequent elimination of the agent), systematic medical therapy and prophylaxis with griseofulvin and other drugs as well as the application of Tr. verrucosum live vaccines were the preconditions for a successful control of this zooanthroponosis. Since then the number of human and animal diseases could be essentially reduced.
In earlier reports, it was shown that mice and monkeys could be immunized against otherwise lethal challenge doses of Coccidioides immitis arthrospores. The vaccine was composed of Formalin-killed, in vitro grown, endosporulating spherules of C. immitis strain Silveira. In this study, mice were immunized as in the earlier work and then challenged intranasally with arthrospores from seven heterologous strains of C. immitis. Two of these strains were typical of the species, and five were atypical with respect to their cultural characteristics and morphology of microscopic structures. The vaccinated animals were well protected against challenge doses that were lethal to a majority of the control animals, regardless of the strain of fungus employed. The infection ratios among surviving vaccinated and control animals were comparable, but demonstrable lesions were generally smaller and less numerous in the vaccinated groups. It is suggested that these strains are at least immunogenically similar, although not necessarily identical, and that a vaccine prepared from a single strain of C. immitis would be practical for an immunization program.
Human infection with Histoplasma capsulatum or Blastomyces dermatitidis is sufficiently frequent to warrant exploring the development of vaccines. This review examines the advancements that have been accomplished over the last few years. The availability of molecular tools to create recombinant antigens or mutant strains has produced a small number of useful vaccine candidates. More importantly, the studies summarized herein demonstrate that understanding the host response to a protein or mutant fungus is critical to creating a vaccine that may be useful for the immunocompromised patient.
Twenty-seven strains of Trichophyton verrucosum from 14 cattle herds in the Federal States of Thuringia and Mecklenburg-Vorpommern were examined by culture morphological and molecular biological (PCR fingerprinting, AFLP analysis sequencing of ITS region) methods. Six reference strains of the same species, among them the so-called album and ochraceum varieties, were also included. Despite great variability in terms of culture morphology, which suggested their possible classification into 4 different colony types, all T. verrucosum isolates were genotypically almost identical. Even the 2 field isolates growing with yellow pigment, which could possibly be regarded as belonging to the ochraceum variety, could not be differentiated using molecular biological methods. The results do not provide indications of a separate taxonomic position of the 3 T. verrucosum varieties. Furthermore, there is no evidence confirming the suspected infection of cattle herds with ochraceum strains as the cause of the failure of immune prophylaxis using various T. verrucosum vaccines. The frequent occurrence of animals not responding to vaccination could not be explained either. It should be assumed that the main factors responsible for this situation include poor handling of the vaccine strains and errors in application, especially the absence of continuous and systematic immune prophylaxis in the herds.
We investigated secondary immunity against coccidioidomycosis by using gene expression microarrays. Surprisingly, a high percentage of B-cell-related genes were associated with protective immunity. A functional confirmation of the importance of B cells against coccidioidomycosis was achieved by demonstrating that vaccination was not fully protective in B-cell-deficient MuMT mice.
Coccidioides posadasii and Coccidioides immitis are dimorphic, soil-dwelling pathogenic ascomycetes endemic to the southwestern United States. Infection can result from inhalation of a very few arthroconidia, but following natural infection, long-lived immunity is the norm. Previous work in the field has shown that spherule-derived vaccines afford more protection than those from mycelia. We have used two-dimensional differential in-gel electrophoresis coupled with nano-high-performance liquid chromatography-tandem mass spectrometry to directly assess both absolute abundance and differential expression of proteins in the spherule and the mycelial phases of C. posadasii with the intent to identify potential vaccine candidates. Peptides derived from 40 protein spots were analyzed and a probable identity was assigned to each. One spherule-abundant protein, identified as Pmp1, showed homology to allergens from Aspergillus fumigatus and other fungi, all of which exhibit similarity to yeast thiol peroxidases. Recombinant Pmp1 was reactive with serum from individuals with both acute and protracted disease, and evoked protection in two murine models of infection with C. posadasii. These results demonstrate the utility of proteomic analysis as a point of discovery for protective antigens for possible inclusion in a vaccine candidate to prevent coccidioidomycosis.
The investigations demonstrated that the inactivated vaccine against trichophytosis, elaborated by the authors, induced immune response in calves, aged 5-8 days. The state of immunity was assessed in vitro by the leukocyte migration inhibition test, and in vivo by the allergic test and the challenge test. In all vaccinated calves (10 animals) there occurred delayed hypersensitivity and in six cases also a significant leukocyte migration inhibition. Vaccinated animals exposed to challenge were to a large extent resistant to experimental infection with the virulent strain of T. verrucosum.
Previous work has shown that in hybrid (BALB/cCr x DBA/2Cr)F1 mice the development of a fatal disseminated disease by systemic infection with virulent Candida albicans is associated with the detection of strong Th2-like responses. However, a predominant Th1-like response and long-lived antifungal protection are induced by vaccinating these mice with live blastospores of attenuated C. albicans strains. When injected into DBA/2Cr mice, one such live vaccine strain was found in the present study to result in a progressive disease characterized by strong Th2 responses. Elevated serum IgG1, IgA, and IgE responses, weak or absent footpad reactions, sustained production in vitro of Th2 (IL-4 and IL-10) but not Th1 (IL-2 and IFN-gamma) cytokines by CD4+ cells, and eosinophilia were all detected in DBA/2 mice after infection with the attenuated vaccine. This was in marked contrast with the development of strong Th1 responses and persistent anticandidal protection in similarly infected, H-2-compatible BALB/cCr mice. Therefore, our data suggest that the type of Th response that predominates in mice after C. albicans infection correlates with genetically determined susceptibility or vaccine-induced resistance. Moreover, the genetic control of this resistance may not be associated with the H-2 complex.
Preventive vaccination by a hsp90-expressing DNA vaccine and recombinant hsp90 protein vaccine, both derived from the Candida albicans hsp90 using BALB-c mouse model of systemic candidiasis, was performed. Hsp90 mRNA was cloned from a clinical isolate of C. albicans, converted to cDNA and cloned into vaccination plasmid pVAX1. Two methods of DNA application were tested: intramuscular (i.m.) and intradermal (i.d.) injection. Recombinant protein was applied by i.d. injection with Freund's adjuvant; the control groups received PBS or Freund's adjuvant only. Mice were vaccinated and after 19 d re-vaccinated. After 3 weeks, the mice were challenged with the live C. albicans in a dose of 5 x 10(6) CFU per mouse. After the challenge, the mice vaccinated i.d. with DNA vaccine survived for 39 and 64% longer compared to those receiving Freund's adjuvant and/or PBS, respectively. The i.m. application of the DNA vaccine did not provide any significant protectivity. The serum level of anti-candida-hsp90 serum IgG antibodies correlated with the survival rate in both i.d. protein and DNA vaccination approaches. We stressed the importance of specific humoral immunity in the mouse model of systemic candidiasis.
Infections due to the encapsulated fungus Cryptococcus neoformans are a significant cause of morbidity and mortality in patients with impaired T-cell function, particularly those with AIDS. Presumably then, T-cell responses to cryptococcal antigens are critical for protection against this ubiquitous fungus. To test the protective efficacy of these antigens as vaccine candidates, secreted cryptococcal antigens were separated by concanavalin A affinity chromatography into adherent (mannoprotein [MP]) and nonadherent (flowthrough [FT]) fractions, and the fractions were tested in murine models of disseminated cryptococcosis. Compared with adjuvant alone, C57BL/6 mice that received two inoculations of MP and FT exhibited prolonged survival and reduced brain and kidney fungal loads following intravenous challenge with C. neoformans strain B3501. MP-immunized animals had increased brain levels of tumor necrosis factor alpha, gamma interferon, and interleukin-2. Histopathologic examination revealed that compared with organs from mice that received only adjuvant, MP-immunized mice were able to recruit a stronger cellular infiltrate in brain, kidney, and liver in response to cryptococcal infection. Conjugated O-linked glycans were necessary for optimal MP-mediated protection, because chemical O deglycosylation reduced the protective efficacy of MP immunization. FT and MP immunization protected B-cell-deficient, but not T-cell-deficient mice, suggesting that protection was T-cell mediated. CBA/J mice also benefited from immunization with FT and MP, although the benefits were more modest than those seen with C57BL/6 mice. Thus, both MP and FT fractions of C. neoformans contain components that protect mice from disseminated cryptococcosis, and this protection appears to be T-cell mediated.
An inactivated, broad-spectrum dermatophyte vaccine was used to produce an active immunity in guinea-pigs against Microsporum canis. None of the vaccinates developed infection from a contact exposure challenge that produced clinical infections in 70% of the unvaccinated controls. Infection with M. canis induced antibody titres (ELISA) and delayed cutaneous hypersensitivity (DCH) reactions to itself as well as cross-reacting titres to Trichophyton equinum and T. mentagrophytes and DCH reactions to T. mentagrophytes; however vaccinated animals developed significantly higher antibody titres and DCH responses to all of these antigens than did non-vaccinated animals which had been infected or exposed. Rabbits hyperimmunized with culture filtrate antigens to single dermatophyte agents (M. canis, M. gypseum, T. equinum, and T. mentagrophytes) developed positive inter-species and inter-generic DCH cross-reactions to a battery of six skin test antigens (M. canis, M. gypseum, M. equinum, T. equinum, T. mentagrophytes var. mentagrophytes and T. verrucosum). Guinea-pigs vaccinated with a T. equinum vaccine had increased resistance to M. canis infection than did non-vaccinated controls. These findings support clinical observations which suggest establishment of a broad-based immunity in animals following infection with a single dermatophyte.
Mice sublethally infected with viable Histoplasma capsulatum or immunized with merthiolate-killed yeast phase cells showed decreased mortality on subsequent challenge infection as compared to controls. Migration inhibition (MI) assays using peritoneal and spleen cells from immunized but unchallenged mice showed no parallel correlation with percent mortality. MI assay indices fluctuated without concomitant changes in resistance to challenge injection with live yeast phase cells. Viable vaccines induced greater resistance to challenge infection than killed cells, although both were comparable in sensitizing ability as measured by MI assay techniques with this mouse model.
The formaldehyde-killed, whole-spherule vaccine, which is protective against lethal challenge of laboratory animals with Coccidioides immitis, was fractionated. It yielded a soluble, multicomponent, subcellular fraction termed the 27K vaccine. This vaccine, when it was accompanied by adjuvant, protected mice against lethal intranasal and intravenous challenge with C. immitis.