Invasive fungal diseases are uncommon but almost always severe and frequently fatal. It is estimated that fungal infections claim approximately 3.8 million lives worldwide each year. Their prevalence is increasing due to the growing number of immunocompromised individuals and people living with HIV. Diagnosis and treatment of these infections are challenging: therapy usually requires prolonged courses of antifungal drugs and depends heavily on underlying conditions and the degree of immunosuppression. To date, no licensed vaccines against fungal infections are available.
A recent study demonstrated that endoglucanase 2 (Eng2) – an enzyme present in Blastomyces, Coccidioides, and Histoplasma species – can trigger a protective immune response. In experiments using mice with a humanized immune system, Eng2 administration protected against fungal infection. Moreover, CD4 T cells responsive to Eng2 were detected in individuals who had recovered from these mycoses, indicating that during fungal infection, the immune system recognizes this enzyme and forms cellular immune memory against it. Thus, Eng2 is of interest not only as a candidate antigen for antifungal vaccines but also as a potential diagnostic tool and epidemiological marker in endemic regions.
However, Eng2 is not a universal antigen. Although this enzyme is present in all three fungi, differences in its amino acid sequence eliminate cross-protection. Immunization with Eng2 from one fungal species did not protect mice against infection with other species. At the same time, administration of the species-specific Eng2 variant reliably protected against the corresponding fungus, indicating that a vaccine based on a single Eng2 variant would not prevent all three mycoses.
Nevertheless, this limitation is not fundamental. It could be overcome by developing a multivalent vaccine containing Eng2 from each fungal species, analogous to vaccines already developed against antigenically variable bacterial pathogens.
Antifungal Vaccines and Natural Immunity Form Multilayered Protection
Eng2 adds to an extensive list of fungal antigens already shown to elicit protective immune responses. Experimental vaccines have successfully used polysaccharides, enzymes, and cell wall proteins from various pathogenic fungi. Overall, numerous fungal antigens have been shown to induce protective immunity, and dozens of vaccine candidates have demonstrated efficacy in animal models.
One paradox in medical mycology is that fungal infections are difficult to treat but relatively easy to prevent. Acquired immunity to fungi is multilayered and engages both arms of adaptive immunity – humoral and cellular – providing redundancy of protection. For example, in cryptococcosis models, protective effects were achieved with both vaccines that stimulate antibody-only responses and those that activate T cell–mediated immunity alone.
The relative success of experimental antifungal vaccines contrasts sharply with the difficulties encountered in developing vaccines against other pathogens, such as HIV, herpes simplex viruses, Mycobacterium tuberculosis, or Plasmodium falciparum. Although the relationship between pathogen virulence and vaccine success remains insufficiently studied, one difference stands out. Vaccines are hardest to develop for pathogens that cause disease in immunocompetent individuals. In contrast, for most pathogenic fungi that cause severe, invasive infections primarily in immunocompromised patients, promising vaccine candidates already exist.
In this context, vaccines can be viewed as an additional layer of protection superimposed on natural immunity. In immunocompetent individuals, even exposure to highly pathogenic microbes does not always result in disease, indicating the presence of intrinsically effective antimicrobial defenses. Consequently, pathogens capable of overcoming intact immunity may be less susceptible to vaccine prevention. Conversely, microbes that cause severe disease mainly in immunocompromised individuals, including pathogenic fungi, may be more amenable to vaccine control.
Antifungal Vaccines Would Benefit Immunocompromised Individuals
Humans are generally well protected against invasive fungal infections. This resistance is attributed, first, to the high body temperature of mammals, which creates unfavorable conditions for the growth of most fungi, and second, to an effective immune system that includes both innate and adaptive defense mechanisms. As a result, invasive fungal infections develop mainly in immunocompromised individuals, who currently constitute approximately 6.6% of the population in the United States.
This creates an additional challenge for vaccine prevention. A vaccine must provide protection specifically for immunocompromised individuals, that is, under conditions where immune responses are inherently weakened. However, experience with vaccines against varicella-zoster virus, coronavirus, and other infections shows that even in such patients, immune responses sufficient for partial protection or disease mitigation can be induced. For pathogenic fungi, which rarely cause disease in immunocompetent individuals, the level of immune stimulation provided by vaccination may be sufficient to prevent infection.
Even assuming that effective antifungal vaccines can be developed and function in immunocompromised individuals, the next major obstacle will be demonstrating their efficacy. Most immunocompromised individuals never develop invasive fungal infections, meaning that vaccination would aim to prevent rare but extremely severe events, requiring targeted clinical trials in high-risk groups. Such trials are feasible because the epidemiology of invasive fungal infections is well characterized, but they will be costly. Additional challenges include patient heterogeneity and the widespread use of prophylactic antifungal drugs.
Vaccine development itself is expensive, and the target population for antifungal vaccines is smaller than that for vaccines intended for the general population. Nevertheless, the high morbidity and mortality associated with invasive fungal infections mean that vaccines could be economically justified even for limited groups. For example, a vaccine to prevent aspergillosis in organ transplant recipients or coccidioidomycosis in pregnant women could be applied to clearly defined risk groups.
mRNA vaccine technology has the potential to substantially reduce the cost of developing protein antigen vaccines. The Eng2 protein described in the recent study is well-suited for the development of an mRNA vaccine against invasive fungal infections.
Conclusion
Their rare and unpredictable occurrence hampers the development of prophylactic vaccines against invasive fungal diseases in immunocompromised individuals. A more realistic direction may be therapeutic vaccines, as fungal infections often have a prolonged course, allowing time for vaccination to enhance immune responses and improve the efficacy of antifungal therapy. This approach has already been implemented for specific viral infections – such as rabies and hepatitis A – and may be simpler for assessing clinical efficacy.
Despite these challenges, several antifungal vaccines have already entered clinical trials and shown encouraging efficacy, including in therapeutic vaccination formats. The protective potential of the Eng2 antigen points to the possibility of simplifying the development of an effective pan-fungal vaccine.
Reference
Fungal vaccines: so needed, so feasible, and yet so far off
