Candida antigens and immune responses: implications for a vaccine

Abstract

Superficial candidiasis of the oral cavity, vagina and the skin are common mild infections though they may be recalcitrant, as in the case of recurrent vaginitis or denture stomatitis. However, in debilitated people with immune deficiencies, Candida can cause serious invasive infections with high mortality. Both types of patients could benefit from the development of vaccines and monoclonal or polyclonal antibodies of utility for a passive immunization, according to their immune status. Several antigens as mannans, β-glucans, various adhesins, heat shock protein 90 and acid secreted proteinases can be very useful for the vaccines development. There is a broad and sound experience with many of these antigens in animal models, mainly in rabbits and mice. However, only two vaccines, based on recombinant antigens (rAls3p-N and rSap2t) are currently being tested in clinical trials.

Keywords::

• betaglucan
• Candida albicans
• candidiasis
• Hsp90
• mannan
• monoclonal antibody
• rAls3p-N
• rHyr1p
• rSap2t
• vaccine

Financial & competing interests disclosure

In the past five years, E Eraso has received grant support from Astellas Pharma and Pfizer SLU. In the past five years, G Quindós has received grant support from Astellas Pharma, Gilead Sciences, Pfizer SLU, Schering Plough and Merck Sharp and Dohme. He has been an advisor/consultant to Merck Sharp and Dohme, and has been paid for talks on behalf of Astellas Pharma, Esteve Hospital, Gilead Sciences, Merck Sharp and Dohme, Pfizer SLU and Schering Plough. A Rementeria has been supported by the Universidad del País Vasco-Euskal Herriko Unibertsitatea (UPV/EHU) (GIU12/44 and UFI11/25). G Quindós and E Eraso have received grant support from Consejería de Educación, Universidades e Investigación (GIC12 210-IT-696-13) and Departamento de Industria, Comercio y Turismo (S-PR12UN002, S-PE13UN121) of Gobierno Vasco-Eusko Jaurlaritza, Fondo de Investigación Sanitaria (FIS PI11/00203), and UPV/EHU (UFI 11/25). MD Moragues and MJ Sevilla have been funded by grants from the UPV/EHU (UFI11/25), Consejería de Educación, Universidades e Investigación (GIC12/184_IT-788-13) and Departamento de Industria, Comercio y Turismo (S-PC12UN010) of Gobierno Vasco-Eusko Jaurlaritza. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Candida albicans is a common cause of skin, and oral and vaginal mucosa infections in apparently healthy people.

• Superficial infections, such as denture stomatitis or recurrent vulvovaginal candidiasis, alter the quality of patients’ life and require antifungal treatment that could increase the risk of drug resistance.

• Invasive candidiasis is a severe infection that causes high morbidity and mortality. Candida is the fourth most common cause of bloodstream infections and incidence rates of 1.4–20 per 100,000 inhabitants have been reported. Cellular immunity is key to control candidiasis, while the role of humoral immunity is less well known but relevant in the case of mucosal candidiasis. The balance between Th1/Th2 responses (Th1-Th17 vs Th2-Treg) is a dynamic process that the resistance to candidiasis relies on.

• Patients who could benefit of an anti-Candida vaccine would be women suffering from recurrent episodes of vaginal candidiasis, people with repeated episodes of denture stomatitis and/or oral candidiasis, and those patients’ receptors for transplants or undergoing some kind of significant immunodeficiency.

• β-glucan (BG) is highly conserved in most fungi, so a BG-based vaccine would probably induce protection against different fungal pathogens (panfungal protection). Laminarin, a BG from the brown alga Laminaria digitata, is immunogenic and protective in a murine experimental model of candidiasis. Moreover, anti-BG antibodies confer cross-protection to mice challenged with Aspergillus fumigatus and Cryptococcus neoformans.

• NovaDigm is conducting a multicenter clinical trial of NDV-3 vaccine, based on the adhesin recombinant N terminal of Als3p, in patients diagnosed with recurrent vulvovaginal candidiasis, for studying the effect of a single-dose vaccine in preventing future episodes of vulvovaginal candidiasis, as well as its safety and tolerability. Preclinical studies in mice showed that this vaccine protects from oropharyngeal, vaginal and invasive candidiasis, and also protected mice against intravenous challenge and skin and soft tissues infection caused by S. aureus.

• PEV7 is a vaccine based on a truncated recombinant aspartyl proteinase-2 of C. albicans presented on the surface of influenza virosomes. A Phase I clinical trial has been designed to assess the safety and immunogenicity of this therapeutic vaccine candidate in healthy women. In animal models, PEV7 intravaginal or intramuscular administration conferred protection against vaginal candidiasis.

• Other antigens such as 1,6-β-poly-N-acetyl-d-glucosamine, Als1p, enolase, Hyr1p, Hwp1 or Mdh1p are promising candidates for anti-Candida vaccines.

Notes