Aspergillus vaccines: Hardly worth studying or worthy of hard study?

Vaccines rank among the greatest advances in the history of public health. Yet, despite the need, there are no licensed vaccines to protect humans against fungal diseases, including aspergillosis. In this focused review, some of the major scientific and logistical challenges to developing vaccines to protect at-risk individuals against aspergillosis are discussed. Approaches that have shown promise in animal models include vaccines that protect against multiple fungal genera and those that are specifically directed to Aspergillus Advances in proteomics and glycomics have facilitated identification of candidate antigens for use in subunit vaccines. Novel adjuvants and delivery systems are becoming available that can skew vaccine responses toward those associated with protection. Immunotherapy consisting of adoptive transfer of Aspergillus-specific T cells to allogeneic hematopoietic transplant recipients has advanced to human testing but is technically difficult and of unproven benefit. While progress has been impressive, much work still needs to be done if vaccines against aspergillosis are to become a reality.

Candidiasis: a fungal infection--current challenges and progress in prevention and treatment.

Despite therapeutic advances candidiasis remains a common fungal infection most frequently caused by C. albicans and may occur as vulvovaginal candidiasis or thrush, a mucocutaneous candidiasis. Candidiasis frequently occurs in newborns, in immune-deficient people like AIDS patients, and in people being treated with broad spectrum antibiotics. It is mainly due to C. albicans while other species such as C. tropicalis, C. glabrata, C. parapsilosis and C. krusei are increasingly isolated. OTC antifungal dosage forms such as creams and gels can be used for effective treatment of local candidiasis. Whereas, for preventing spread of the disease to deeper vital organs, candidiasis antifungal chemotherapy is preferred. Use of probiotics and development of novel vaccines is an advanced approach for the prevention of candidiasis. Present review summarizes the diagnosis, current status and challenges in the treatment and prevention of candidiasis with prime focus on host defense against candidiasis, advancements in diagnosis, probiotics role and recent progress in the development of vaccines against candidiasis.

Evaluation of Mdh1 protein as an antigenic candidate for a vaccine against candidiasis.

Candida albicans malate dehydrogenase (Mdh1p) has been screened by previous proteome studies as a candidate for a vaccine against candidiasis. In this study, recombinant Mdh1 protein with a His-tag was produced in Escherichia coli and evaluated as an immunogenic protein against candidiasis. Mdh1p was administrated to mice by two methods subcutaneous injection and intranasal administration before challenging them with a lethal dose of C. albicans. After vaccination of Mdh1p, antibody responses were observed. To evaluate the vaccination effect of Mdh1p, survival tests were performed after 35 d. Although all control mice died within 24 d or 25 d, 100% and 80% of mice survived with subcutaneous and intranasal administration, respectively. Therefore, our results indicate that, among C. albicans antigens examined thus far, Mdh1p is currently the most effective antigen for use as a vaccine for C. albicans.

Adjuvanticity of a recombinant calreticulin fragment in assisting anti-ß-glucan IgG responses in T cell-deficient mice.

Polysaccharide-encapsulated fungi are the chief source of diseases in immunocompromised hosts such as those infected with human immunodeficiency virus or neutropenia patients. Currently available polysaccharide-protein conjugate vaccines are mainly T cell dependent and are usually ineffective in weakened immune systems. In this study, laminarin, a well-characterized ß-1,3-glucan, was conjugated with a prokaryotically expressed recombinant fragment (amino acids [aa] 39 to 272) of calreticulin (rCRT/39-272), which exhibits extraordinarily potent immunogenicity and adjuvanticity in experimental animals. The resultant conjugate reserves the immunostimulatory effect of rCRT/39-272 on naïve murine B cells and is capable of eliciting anti-ß-glucan IgG (mostly IgG1) responses in not only BALB/c mice but also athymic nude mice. Laminarin-CRT-induced mouse antibodies (Abs) are able to bind with Candida albicans and inhibit its growth in vitro. In addition, vaccination with laminarin-CRT partially protects mice from lethal C. albicans challenge. These results imply that rCRT/39-272 could be used as an ideal carrier or adjuvant for carbohydrate vaccines aimed at inducing or boosting IgG responses to fungal infections in immunodeficient hosts.

Potential of anti-Candida antibodies in immunoprophylaxis.

The need for new options for the treatment of invasive candidiasis has fuelled the use of antibodies in combination with conventional antifungal therapy. After a long period of time in which antibodies were considered irrelevant in the resistance against invasive candidiasis, it was demonstrated that a number of antibodies or their engineered derivatives directed against Candida albicans cell-wall polysaccharides and glycopeptides, as well as against some protein epitopes, confer protection against invasive candidiasis. This has confirmed this approach as a new strategy for the prophylaxis of invasive candidiasis. Of particular interest is Mycograb, a human recombinant monoclonal antibody that inhibits heat shock protein 90, and has been administrated in combination with lipid-associated amphotericin B to patients with invasive candidiasis, and the fungicidal anti-beta-glucan antibodies induced by the glycoconjugate vaccine composed of a beta-glucan polysaccharide conjugated with the diphtheria toxoid CRM 197. However, despite the promising data obtained in vitro and in animal models, at present there is very little clinical experience on the use of antibodies in Candida immunoprophylaxis.

Attempts at a peptide vaccine against paracoccidioidomycosis, adjuvant to chemotherapy.

Chemotherapy is the basis of treatment of paracoccidioidomycosis in its various forms. Depending on the Paracoccidioides brasiliensis virulence, the status of host immunity, the degree of tissue involvement and fungal dissemination, treatment can be extended for long periods with an alarming frequency of relapses. Association of chemotherapy with a vaccine to boost the cellular immune response seemed a relevant project not only to reduce the time of treatment but also to prevent relapses and improve the prognosis of anergic cases. The candidate immunogen is the gp43 major diagnostic antigen of P. brasiliensis and more specifically its derived peptide P10, carrying the CD4+ T-cell epitope. Both gp43 and P10 protected Balb/c mice against intratracheal infections with virulent P. brasiliensis strain. P10 as single peptide or in a multiple-antigen-peptide (MAP) tetravalent construction was protective without adjuvant either by preimmunization and intratracheal challenge or as a therapeutic agent in mice with installed infection. P10 showed additive protective effects in drug-treated mice stimulating a Th-1 type immune response with high IFN-gamma and IL-12. P10 and few other peptides in the gp43 were selected by Tepitope algorithm and actually shown to promiscuously bind several prominent HLA-DR molecules suggesting that a peptide vaccine could be devised for a genetically heterogenous population. P10 was protective in animals turned anergic, was effective in a DNA minigene vaccine, and increased the protection by monoclonal antibodies in Balb/c mice. DNA vaccines and peptide vaccines are promising therapeutic tools to be explored in the control of systemic mycoses.

Peptide immunization as an adjuvant to chemotherapy in mice challenged intratracheally with virulent yeast cells of Paracoccidioides brasiliensis.

Immunization with peptide P10, derived from gp43, and chemotherapy were used together in an attempt to improve treatment of paracoccidioidomycosis and prevent relapses. The combined treatment showed an additive protective effect when administered at 48 h or 30 days after intratracheal challenge. Its use is recommended to improve regular chemotherapy and reduce the duration of treatment.

Synthesis and immunological studies of glycoconjugates of Cryptococcus neoformans capsular glucuronoxylomannan oligosaccharide structures.

Antibodies to the glucuronoxylomannan (GXM) component of the polysaccharide capsule of Cryptococcus neoformans are protective and GXM-protein conjugate vaccines can elicit protective immune responses. We report the synthesis of a heptasaccharide oligosaccharide representing the putative dominant motif of serotype A GXM and demonstrate that it is recognized by some monoclonal antibodies (mAbs) generated to GXM. Conjugation of the heptasaccharide to human serum albumin (HSA) resulted in an immunogenic compound that elicited high-titer IgG responses in mice when given with complete Freund's adjuvant. The antibody response elicited by the oligosaccharide conjugate vaccine had characteristics of a T-cell-dependent response. The availability of an immunogenic oligosaccharide representing a structural motif of GXM will prove useful in studies of antibody epitope specificity and represents a potential synthetic oligosaccharide vaccine against this fungal pathogen.

A vaccine against coccidioidomycosis is justified and attainable.

Coccidioides is a fungal pathogen of humans which can cause a life-threatening respiratory disease in immunocompetent individuals. Recurrent epidemics of coccidioidal infections in Southwestern United States has raised the specter of awareness of this soil-borne microbe, particularly among residents of Arizona and Southern California, and has galvanized research efforts to develop a human vaccine against coccidioidomycosis. In this review, we discuss the rationale for such a vaccine, examine the features of host innate and acquired immune response to Coccidioides infection, describe strategies used to identify and evaluate vaccine candidates, and provide an update on progress toward development of a vaccine against this endemic pathogen.

Liposomes containing Candida albicans ribosomes as a prophylactic vaccine against disseminated candidiasis in mice.

This study describes the development of prophylactic anti-Candida vaccine which combines the advantages of Candida albicans ribosomes as antigen(s) and of liposomes as carrier/adjuvant with minimal side-effects, which could be suitable for human use. The liposomal vaccine was composed of C. albicans ribosomes and the lipids dimyristoyl phosphatidyl choline (DMPC) and dimyristoyl phosphatidyl glycerol (DMPG) (9:1 molar ratio). Some of the vaccines contained Lipid-A (LA) as an additional adjuvant. The vaccine was prepared by two methods: (I) dehydration by lyophylization of small liposomes in the presence of the Candida ribosomes (DRV method); (II) colyophylization of DMPC/DMPG (9:1 mole ratio) in tertiary butanol with aqueous dispersion of Candida ribosomes. In both cases a dry powder was obtained which was rehydrated to form large multilamellar vesicles. The efficacy of the vaccines in mice was tested by their protectivity against a challenge with C. albicans, as assessed by survival rate, induction of cell mediated immunity (measured by delayed type hypersensitivity-DTH) and anti-Candida antibody titer. Unimmunized mice and mice vaccinated by ribosomes supplemented with incomplete Freund's adjuvant (IFA) were used as controls. The results indicated that the liposomal vaccines were effective at least as the IFA-based vaccine. The study indicates the feasibility of developing an efficacious anti-Candida vaccine for human use.

[The experimental efficacy of vaccination with a recombinant yeast vaccine against hepatitis B in combination with immunomodulators]. / Effektivnost' v éksperimente vaktsinatsii rekombinantnoi drozhzhevoi vaktsinoi protiv gepatita B v sochetanii s immunomoduliatorami.

Experiments in BALB/c mice were carried out to study a number of immunomodulators in combination with vaccination using a recombinant yeast hepatitis B vaccine. The use of poludan, ridostine, amixine, larifan, myekonide significantly enhanced specific antibody production and at least doubled cell-mediated immune response by 14 and 28 days postvaccination. The above-mentioned immunomodulators are planned to be used in vaccination with the recombinant yeast vaccine against hepatitis B.

An inactivated vaccine against ringworm.

A new vaccine against ringworm, containing the inactivated Trichophyton verrucosum strain, was assessed on guinea pigs and calves under experimental conditions and on three herds of cattle under natural conditions. The vaccine elicited a distinct immune response of the cellular type. This type of immunity assessed by the migration inhibition test of leukocytes corresponded to the immunity evaluated by the challenge. In herds in which there were from 30 to 67% of naturally infected animals with T. verrucosum, two doses of the vaccine resulted in after 4 weeks a decrease of the number of animals with clinical changes from 40.5 to 100% depending on the group of animals under study.

Protection against systemic infections with various Candida species elicited by vaccination with Candida albicans ribosomes.

This study investigated whether subcutaneous vaccination of mice with ribosomes from Candida albicans strain CBS 562 would also provide protection against infections by other isolates of Candida. Experiments with a total of 628 mice demonstrated that vaccination induced significant protection against heterologous C. albicans (serotypes A and B) and C. tropicalis isolates in terms of their 30 day survival rates. In all instances, however, protection was lower than that obtained against the homologous strain. In addition, a significant decrease in fungal colonization of the kidneys was found in immunized animals as compared to the non immunized controls. Cell-mediated immune responses against cytoplasmic extracts of the various fungi, as detected in vivo by the foot pad swelling test and in vitro by the lymphocyte transformation assay, were induced by the C. albicans ribosomal vaccination. The results show it is possible to induce cross protection to various Candida species by immunization with C. albicans ribosomes.