Russian Journal of Infection and ImmunityRussian Journal of Infection and ImmunityИнфекция и иммунитет2220-76192313-7398SPb RAACI1769610.15789/2220-7619-IOC-17696REVIEWSОБЗОРЫReview ArticleImmunotherapy of Candida spp.-caused infections: myth or reality?Иммунотерапия инфекций, вызванных Candida spp.: миф или реальность?KhostelidiSofia N.ХостелидиСофья Николаевна
Russian Federation

DSc (Medicine), Associate Professor, Associate Professor of the Department of Clinical Mycology, Allergology and Immunology

д.м.н., доцент, доцент кафедры клинической микологии, аллергологии и иммунологии

Sofya.Khostelidi@szgmu.ruSerebryanayaN. B.СеребрянаяН. Б.
Russian Federation

DSc (Medicine), Professor, Professor of the Department of Clinical Mycology, Allergology and Immunology; Head of the Laboratory of General Immunology, Department of General Pathology and Pathophysiology; Professor of the Department of Cytology and Histology

д.м.н., профессор, профессор кафедры клинической микологии, аллергологии и иммунологии; зав. лабораторией общей иммунологии отдела общей патологии и патофизиологии; профессор кафедры цитологии и гистологии

Sofya.Khostelidi@szgmu.ruNorth-Western State Medical University named after I.I. MechnikovФБГБОУ ВО Северо-Западный государственный медицинский университет им. И.И. МечниковаInstitute of Experimental MedicineФГБНУ Институт экспериментальной медициныSt. Petersburg State UniversityФГБОУ ВО Санкт-Петербургский государственный университет160820243004202515127362406202413082024Copyright ©; 2025, Khostelidi S.N., Serebryanaya N.B.Copyright ©; 2025, Хостелиди С.Н., Серебряная Н.Б.2025Khostelidi S.N., Serebryanaya N.B.Хостелиди С.Н., Серебряная Н.Б.https://creativecommons.org/licenses/by/4.0https://iimmun.ru/iimm/article/view/17696

Candidiasis is a mycosis caused by opportunistic pathogenic Candida spp. fungi. The infectious process can manifest as superficial forms affecting the skin and mucous membranes, as well as invasive variants. Since Candida spp. are commensals, a related disease development implies an imbalance between the pathogenic fungal factors and human immune system. Research in the field of immunotherapy of fungal infections is particularly relevant due to the increasing resistance to antifungal drugs. Based on the analyzed publications investigating candidiasis immunotherapy retrieved from the databases PubMed, ClinicalKey, and e-library, we have assessed the main directions and achievements in immunotherapy of infections caused by Candida spp., described emerging issues, and outlined future prospects. The development of live vaccines based on attenuated, genetically modified, and mutant Candida strains began in the 1980s and continues to the present day. However, creating vaccines based on Candida recombinant proteins, adhesins, and enzymes represents a safer alternative to live vaccines. A promising direction is the development of conjugate vaccines, in which the fusion of weaker antigens (cell wall glycans) with carrier immunogenic proteins leads to the formation of immunogens capable of eliciting a robust immune response. In experiments, vaccines based on inactivated C. аlbicans along with a genetically Escherichia coli-derived modified heat-labile toxin as an adjuvant have also been studied. The experience of creating combination therapies aimed at combating recurrent bacterial and fungal urogenital tract infections is promising, e.g., the combination of sublingual inactivated polyvalent bacterial vaccine MV140 and sublingual preparation of inactivated Candida albicans V132. An interesting approach involves the use of inactivated S. cerevisiae yeasts, providing cross-protection against infections caused by C. аlbicans, Aspergillus fumigatus, and Coccidioides posadasii. A search for immunotherapy targets continues, with numerous studies aimed at a deeper understanding of crosstalk between C. аlbicans and human host. Currently, two recombinant vaccines (PEV7 and NDV-3) have successfully completed Phase I/II clinical trials, raising hopes for their clinical use in the near future.

Кандидоз — микоз, вызываемый условно-патогенными микромицетами Candida spp. Инфекционный процесс может протекать по типу поверхностных форм с поражением кожи и слизистых оболочек, а также инвазивных вариантов. Поскольку Candida spp. являются комменсалами, развитие заболевания предполагает дисбаланс между факторами патогенности микромицетов и иммунной системой человека. Исследования в области иммунотерапии микотических инфекций особенно актуальны в свете все возрастающей резистентности микромицетов к антифунгальным препаратам. На основании анализа публикаций, посвященных проблеме иммунотерапии кандидоза с использованием поисковых баз PubMed, ClinicalKey и e-library нами проведен анализ основных направлений и достижений иммунотерапии инфекций, вызванных Candida spp., описаны возникающие проблемы и дальнейшие перспективы. Создание живой вакцины на основе аттенуированных, генно-модифицированных и мутантных штаммов Candida было начато в 80-е гг. ХХ века и продолжается до настоящего времени. Однако создание вакцин на основе рекомбинантных белков, адгезинов и ферментов Candida, является более безопасной альтернативой живым вакцинам. Многообещающим направлением является и разработка конъюгированных вакцин, в которых слияние более слабых антигенов (гликанов клеточной стенки) с иммуногенными белками в качестве носителей приводит к формированию иммуногенов, способных вызывать стойкий иммунный ответ. В эксперименте изучены также вакцины на основе инактивированных C. аlbicans в сочетании с термолабильным генетически модифицированным токсином, полученным из Escherichia coli в качестве адъюванта. Интересен опыт создания комбинированных препаратов, направленные на совместную борьбу с рецидивирующими бактериальными и грибковыми инфекциями мочеполовых путей, например сочетание сублингвальной инактивированной поливалентной бактериальной вакцины MV140 и сублингвального препарата инактивированной Candida albicans V132. Интересным представляется подход и с использованием инактивированных дрожжей S. cerevisiae, их введение обеспечивает перекрестную защиту от инфекций, вызываемых C. аlbicans, Aspergillus fumigatus и Coccidioides posadasii. Поиски мишеней для иммунотерапии продолжаются, для чего проводятся многочисленные исследования, направленные на более глубокое понимание механизмов взаимодействия C. аlbicans с макроорганизмом человека. В настоящее время 2 рекомбинантные вакцины (PEV7 и NDV-3) успешно прошли I/II фазы клинических испытаний, что позволяет надеяться на их клиническое использование в недалеком будущем.

Candida spp.vaccineinvasive mycosisimmunotherapycandidiasissuperficial candidiasisantifungal vaccineCandida spp.вакцинаинвазивный микозиммунотерапиякандидозповерхностный кандидозпротивогрибковая вакцинаДанилова Е.Ю., Шабашова Н.В., Фролова Е.В., Учеваткина А.Е., Филиппова Л.В. Иммунопатогенез орофарингеального кандидоза у больных гемобластозами // Проблемы медицинской микологии. 2021. Т. 23, № 3. С. 38–45. [Danilova E.Yu., Shabashova N.V., Frolova E.V., Uchevatkina A.E., Filippova L.V. Immunopathogenesis of oropharyngeal candidiasis in patients with hemoblastosis. Problemy meditsinskoi mikologii = Problems of Medical Mycology, 2021, vol. 23, no. 3, pp. 38–45. (In Russ.)]Козлова О.П., Шаталова М.В., Сандгартен Л.М., Шадривова О.В., Шагдилеева Е.В., Хостелиди С.Н., Гусев Д.А., Завражнов А.А., Сатурнов А.В., Рысев А.В., Вашукова М.А., Пичугина Г.А., Митичкин М.С., Богомолова Т.С., Гордеева С.А., Оганесян Э.Г., Борзова Ю.В., Васильева Н.В., Климко Н.Н. Candida auris-ассоциированные инфекции у больных COVID-19 // Проблемы медицинской микологии. 2023. Т. 25, № 2. С. 32–38. [Kozlova O.P., Shatalova M.V., Sandgarten L.M. Shadrivova O.V., Shagdileeva E.V., Кhostelidi S.N., Gusev D.A., Zavrazhnov A.A., Saturnov A.V., Rysev A.V., Vashukova M.A., Pichugina G.A.A., Mitichkin M.S., Bogomolova T.S., Gordeeva S.A., Oganesyan E.G., Borzova Yu.V., Vasilyeva N.V., Klimko N.N. Candida auris-associated infections in patients with COVID-19. Problemy meditsinskoi mikologii = Problems of Medical Mycology, 2023, vol. 25, no. 2, pp. 32–38. (In Russ.)] doi: 10.24412/1999-6780-2023-2-32-38Abdelnaby M.A., Shoueir K.R., Ghazy A.A., Abdelhamid S.M., El Kemary M.A., Mahmoud H.E., Baraka K., Abozahra R.R. Synthesis and evaluation of metallic nanoparticles-based vaccines against Candida albicans infections. J. Drug Deliv. Sci. Technol., 2022, vol. 68: 102862.Akhtar N., Magdaleno J.S.L., Ranjan S., Wani A.K., Grewal R.K., Oliva R., Shaikh A.R., Cavallo L., Chawla M. Secreted aspartyl proteinases targeted multi-epitope vaccine design for Candida dubliniensis using immunoinformatics. Vaccines, 2023, vol. 11: 364.Allert S., Schulz D., Kämmer P., Großmann P., Wolf T., Schäuble S., Panagiotou G., Brunke S., Hube B. From environmental adaptation to host survival: attributes that mediate pathogenicity of Candida auris. Virulence, 2022, vol. 13, no. 1, pp. 191–214. doi:10.1080/21505594.2022.2026037Alqarihi A., Singh S., Edwards J.E. Jr., Ibrahim A.S., Uppuluri P. NDV-3A vaccination prevents C. albicans colonization of jugular vein catheters in mice. Sci. Rep., 2019, vol. 9: 6194.Bistoni F., Vecchiarelli A., Cenci E., Puccetti P., Marconi P., Cassone A. Evidence for macrophage-mediated protection against lethal Candida albicans infection. Infect. Immun., 1986, vol. 51, pp. 668–674.Butler G., Rasmussen M.D., Lin M.F., Santos M.A., Sakthikumar S., Munro C.A., Rheinbay E., Grabherr M., Forche A., Reedy J.L., Agrafioti I., Arnaud M.B., Bates S., Brown A.J., Brunke S., Costanzo M.C., Fitzpatrick D.A., de Groot P.W., Harris D., Hoyer L.L., Hube B., Klis F.M., Kodira C., Lennard N., Logue M.E., Martin R., Neiman A.M., Nikolaou E., Quail M.A., Quinn J., Santos M.C., Schmitzberger F.F., Sherlock G., Shah P., Silverstein K.A., Skrzypek M.S., Soll D., Staggs R., Stansfield I., Stumpf M.P., Sudbery P.E., Srikantha T., Zeng Q., Berman J., Berriman M., Heitman J., Gow N.A., Lorenz M.C., Birren B.W., Kellis M., Cuomo C.A. Evolution of pathogenicity and sexual reproduction in eight Candida genomes. Nature, 2009, vol. 459, no. 7247, pp. 657–662. doi: 10.1038/nature08064Cardenas-Freytag L., Cheng E., Mayeux P., Domer J.E., Clements J.D. Effectiveness of a vaccine composed of heat-killed candida albicans and a novel mucosal adjuvant, LT(R192G), against systemic candidiasis. Infect. Immun., 1999, vol. 67, pp. 826–833.Cassone A., Cauda R. Candida and candidiasis in HIV-infected patients: where commensalism, opportunistic behavior and frank pathogenicity lose their borders. AIDS, 2011, vol. 26, no. 12, pp. 1457–1472. doi: 10.1097/QAD.0b013e3283536ba8Cutler J.E., Deepe G.S. Jr., Klein B.S. Advances in combating fungal diseases: vaccines on the threshold. Nat. Rev. Microbiol., 2007, vol. 5, pp. 13–28.De Bernardis F., Boccanera M., Adriani D., Girolamo A., Cassone A. Intravaginal and intranasal immunizations are equally effective in inducing vaginal antibodies and conferring protection against vaginal candidiasis. Infect. Immun., 2002, vol. 70, pp. 2725–2729.Denning D.W. Global incidence and mortality of severe fungal disease — author’s reply. Lancet Infect. Dis., 2024, vol. 24, no. 5: e269. doi: 10.1016/S1473-3099(24)00103-8Feng Z., Lu H., Jiang Y. Promising immunotherapeutic targets for treating candidiasis. Front. Cell Infect. Microbiol., 2024, vol. 14: 1339501. doi: 10.3389/fcimb.2024.1339501Fernández-Arenas E., Molero G., Nombela C., Diez-Orejas R., Gil C. Low virulent strains of Candida albicans: unravelling the antigens for a future vaccine. Proteomics, 2004, vol. 4, pp. 3007–3020.Fungal Disease Frequency. Gaffi — Global Action For Fungal Infections. URL: https://gaffi.org/why/fungal-disease-frequencyHarpf V., Rambach G., Würzner R., Lass-Flörl C., Speth C. Candida and complement: new aspects in an old battle. Front. Immunol., 2014, vol. 11: 1471. doi: 10.3389/fimmu.2020.01471Hashash R., Younes S., Bahnan W., El Koussa J., Maalouf K., Dimassi H.I., Khalaf R.A. Characterisation of Pga1, a putative Candida albicans cell wall protein necessary for proper adhesion and biofilm formation. Mycoses, 2011, vol. 54, no. 6, pp. 491–500. doi: 10.1111/j.1439-0507.2010.01883.x.Hawksworth D.L., Lücking R. Fungal Diversity Revisited: 2.2 to 3.8 Million Species. Microbiol Spectr., 2017, vol. 5, no. 4. doi: 10.1128/microbiolspec.FUNK-0052-2016Hoyer L.L., Cota E. Candida albicans agglutinin-like sequence (Als) family vignettes: a review of als protein structure and function. Front. Microbiol., 2016, vol. 7: 280. doi: 10.3389/fmicb.2016.00280Ibrahim A.S., Spellberg B.J., Avanesian V., Fu Y., Edwards J.E. Jr. The anti-candida vaccine based on the recombinant n-terminal domain of Als1p is broadly active against disseminated candidiasis. Infect. Immun., 2006, vol. 74, pp. 3039–3304.Kozlova O., Burygina E., Khostelidi S., Shadrivova O., Saturnov A., Gusev D., Rysev A., Zavrazhnov A., Vashukova M., Pichugina G., Mitichkin M., Kovyrshin S., Bogomolova T., Borzova Y., Oganesyan E., Vasilyeva N., Klimko N. Working group. invasive candidiasis in adult patients with COVID-19: results of a multicenter study in St. Petersburg, Russia. J. Fungi (Basel), 2023, vol. 9, no. 9: 927. doi: 10.3390/jof9090927Lancaster K.Z., Pfeiffer J.K. Mechanisms controlling virulence thresholds of mixed viral populations. J. Virol., 2011, vol. 85, pp. 9778–9788.Leibovitch E.C., Jacobson S. Vaccinations for neuroinfectious disease: a global health priority. Neurotherapeutics, 2016, vol. 13, pp. 562–570.Li F., Svarovsky M.J., Karlsson A.J., Wagner J.P., Marchillo K., Oshel P., Andes D., Palecek S.P. Eap1p, an adhesin that mediates Candida albicans biofilm formation in vitro and in vivo. Eukaryot. Cell, 2017, vol. 6, pp. 931–939. doi: 10.1128/EC.00049-07Lionakis M.S. New insights into innate immune control of systemic candidiasis. Med. Mycol., 2014, vol. 52, no. 6, pp. 555–564. doi: 10.1093/mmy/myu029Lionakis M.S., Netea M.G. Candida and host determinants of susceptibility to invasive candidiasis. PLoS Pathog., 2013, vol. 9, no. 1: e1003079. doi: 10.1371/journal.ppat.1003079Lu H., Hong T., Jiang Y., Whiteway M., Zhang S. Candidiasis: from cutaneous to systemic, new perspectives of potential targets and therapeutic strategies. Adv. Drug Delivery Rev., 2023, vol. 199, pp. 1149–1160. doi: 10.1016/j.addr.2023.114960Luo G., Ibrahim A.S., French S.W., Edwards J.E. Jr., Fu Y. Active and passive immunization with rHyr1p-N protects mice against hematogenously disseminated candidiasis. PLoS One, 2011, vol. 6: e25909.Martin-Cruz L., Sevilla-Ortega C., Benito-Villalvilla C., Diez-Rivero C.M., Sanchez-Ramón S., Subiza J.L., Palomares O. A combination of polybacterial MV140 and Candida albicans V132 as a potential novel trained immunity-based vaccine for genitourinary tract infections. Front. Immunol., 2020, vol. 11, pp. 6122–6129.Martinez M., Clemons K.V., Stevens D.A. Heat-killed yeast as a pan-fungal vaccine. Methods Mol. Biol., 2017, vol. 1625, pp. 23–30.Matthews R.C., Rigg G., Hodgetts S., Carter T., Chapman C., Gregory C., Illidge C., Burnie J. Preclinical assessment of the efficacy of mycograb, a human recombinant antibody against fungal HSP90. Antimicrob. Agents Chemother., 2003, vol. 47, pp. 2208–2216.Mayer F.L., Wilson D., Hube B. Candida albicans pathogenicity mechanisms. Virulence, 2013, vol. 4, no. 2, pp. 119–128. doi: 10.4161/viru.22913Medici N.P., Del Poeta M. New insights on the development of fungal vaccines: from immunity to recent challenges. Mem. Inst. Oswaldo Cruz, 2015, vol. 110, no. 8, pp. 966–973. doi: 10.1590/0074-02760150335Mora C., Tittensor D.P., Adl S., Simpson A.G., Worm B. How many species are there on Earth and in the ocean? PLoS Biol., 2011, vol. 9, no. 8: e1001127. doi: 10.1371/journal.pbio.1001127Nami S., Mohammadi R., Vakili M., Khezripour K., Mirzaei H., Morovati H. Fungal vaccines, mechanism of actions and immunology: a comprehensive review. BioMed. Pharmacother., 2019, vol. 109, pp. 333–344. doi: 10.1016/j.biopha.2018.10.075Nami S., Aghebati-Maleki A., Morovati H., Aghebati-Maleki L. Current antifungal drugs and immunotherapeutic approaches as promising strategies to treatment of fungal diseases. BioMed. Pharmacother., 2019, vol. 110, pp. 857–868. doi: 10.1016/j.biopha.2018.12.009Ngo L.Y., Kasahara S., Kumasaka D.K., Knoblaugh S.E., Jhingran A., Hohl T.M. Inflammatory monocytes mediate early and organ-specific innate defense during systemic candidiasis. J. Infect. Dis., 2014, vol. 209, no. 1, pp. 109–119. doi: 10.1093/infdis/jit413Pappas P.G., Lionakis M.S., Arendrup M.C., Ostrosky-Zeichner L., Kullberg B.J. Invasive candidiasis. Nature Rev. Dis. Primers, 2018, vol. 4, pp. 1–20.Peroumal D., Sahu S.R., Kumari P., Utkalaja B., Acharya N. Commensal fungi candida albicans modulates dietary high-fat induced alterations in metabolism, immunity, and gut microbiota. bioRxiv, 2022, vol. 22, pp. 1–47.Phan Q.T., Myers C.L., Fu Y., Sheppard D.C., Yeaman M.R., Welch W.H., Ibrahim A.S., Edwards J.E. Jr., Filler S.G. Als3 is a Candida albicans invasin that binds to cadherins and induces endocytosis by host cells. PLoS Biol., 2007, vol. 5, no. 3: e64. doi: 10.1371/journal.pbio.0050064Piccione D., Mirabelli S., Minto N., Bouklas T. Difficult but not impossible: in search of an anti-Candida vaccine. Curr. Trop. Med. Rep., 2019, vol. 15, pp. 42–49.Qadri H., Shah A.H., Alkhanani M., Almilaibary A., Mir M.A. Immunotherapies against human bacterial and fungal infectious diseases: a review. Front. Med. (Lausanne), 2023, vol. 10: 10:1135541. doi: 10.3389/fmed.2023.1135541Richardson J.P., Moyes D.L. Adaptive immune responses to Candida albicans infection. Virulence, 2015, vol. 6, no. 4, pp. 327–337. doi: 10.1080/21505594.2015.1004977Sahu S.R., Bose S., Singh M., Kumari P., Dutta A., Utkalaja B.G., Patel S.K., Acharya N. Vaccines against candidiasis: status, challenges and emerging opportunity. Front. Cell. Infect. Microbiol., 2022, vol. 12, pp. 1002–1006.Saville S.P., Lazzell A.L., Chaturvedi A.K., Monteagudo C., Lopez-Ribot J.L. Efficacy of a genetically engineered Candida albicans tet-NRG1 strain as an experimental live attenuated vaccine against hematogenously disseminated candidiasis. Clin. Vaccine Immunol., 2009, vol. 16, pp. 430–432.Schmidt C.S., White C.J., Ibrahim A.S., Filler S.G., Fu Y., Yeaman M.R., Edwards J.E. Jr., Hennessey J.P. NDV-3, a recombinant alum-adjuvanted vaccine for Candida and Staphylococcus aureus, is safe and immunogenic in healthy adults. Vaccine, 2012, vol. 30, pp. 7594–7600.Shen H., Yu Y., Chen S.M., Sun J.J., Fang W., Guo S.Y., Hou W.T., Qiu X.R., Zhang Y., Chen Y.L., Wang Y.D., Hu X.Y., Lu L., Jiang Y.Y., Zou Z., An M.M. Dectin-1 facilitates IL-18 production for the generation of protective antibodies against Candida albicans. Front. Microbiol., 2020, vol. 11: 1648.Shibasaki S., Karasaki M., Tafuku S., Aoki W., Sewaki T., Ueda M. Oral immunization against candidiasis using Lactobacillus casei displaying enolase 1 from Candida albicans. Sci. Pharm., 2014, vol. 82, pp. 697–708.Tso G.H.W., Reales-Calderon J.A., Pavelka N. The elusive anti-Candida vaccine: lessons from the past and opportunities for the future. Front. Immunol., 2018, vol. 9: 897.Vilanova M., Teixeira L., Caramalho I., Torrado E., Marques A., Madureira P., Ribeiro A., Ferreira P., Gama M., Demengeot J. Protection against systemic candidiasis in mice immunized with secreted aspartic proteinase 2. Immunology, 2004, vol. 111, pp. 334–342.Voigt J., Hünniger K., Bouzani M., Jacobsen I.D., Barz D., Hube B., Löffler J., Kurzai O. Human natural killer cells acting as phagocytes against Candida albicans and mounting an inflammatory response that modulates neutrophil antifungal activity. J. Infect. Dis., 2014, vol. 209, no. 4, pp. 616–626. doi: 10.1093/infdis/jit574Wang X.J., Sui X., Yan L., Wang Y., Cao Y.B., Jiang Y.Y. Vaccines in the treatment of invasive candidiasis. Virulence, 2015, vol. 6, pp. 309–315.World Health Organization (WHO) Report. WHO fungal priority pathogens list to guide research, development and public health action. Oct 25, 2022. URL: https://www.who.int/publications/i/item/9789240060241Wüthrich M., Wang H., Li M., Lerksuthirat T., Hardison S.E., Brown G.D., Klein B. Fonsecaea pedrosoi-induced Th17-cell differentiation in mice is fostered by dectin-2 and suppressed by mincle recognition. Eur. J. Immunol., 2015, vol. 45, pp. 2542–2552. doi: 10.1002/eji.201545591Xin H. Active immunizations with peptide-DC vaccines and passive transfer with antibodies protect neutropenic mice against disseminated candidiasis. Vaccine, 2016, vol. 34, no. 2, pp. 245–251. doi: 10.1016/j.vaccine.2015.11.035Xin H., Glee P., Adams A., Mohiuddin F., Eberle K. Design of a mimotope-peptide based double epitope vaccine against disseminated candidiasis. Vaccine, 2019, vol. 37, pp. 2430–2438.