Fungal Vaccines Remain Out of Reach as Drug-Resistant Infections Spread Across Europe

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• Despite decades of promising research showing fungal vaccines are scientifically feasible, no licensed vaccine exists for any fungal disease—leaving millions of vulnerable patients unprotected

• The drug-resistant fungus Candidozyma auris is spreading rapidly through European hospitals, with cases jumping 67% in a single year and mortality rates reaching 29–62% in infected patients

• New research identifies a shared fungal protein that protects mice against three major fungal diseases, yet vaccine economics and the sporadic nature of fungal infections continue to stall development

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A paradox in vaccine science

Fungal diseases kill 3.8 million people worldwide each year—more than malaria, comparable to tuberculosis. They disproportionately strike patients whose immune systems are already compromised: organ transplant recipients, cancer patients undergoing chemotherapy, people living with HIV. For these vulnerable populations, invasive fungal infections carry mortality rates that can exceed 50%.

Yet despite this burden, and despite decades of research demonstrating that protective fungal vaccines are scientifically achievable, not a single licensed vaccine exists for any fungal disease. A commentary published in the Journal of Clinical Investigation by Arturo Casadevall of Johns Hopkins Bloomberg School of Public Health lays bare this troubling paradox: fungal vaccines are needed, feasible, and yet remain far from reality.

New research offers a path forward

The commentary accompanies research that represents a meaningful step toward a pan-fungal vaccine—one that could protect against multiple fungal diseases simultaneously. Scientists led by Bruce Klein at the University of Wisconsin-Madison identified endoglucanase 2 (Eng2), an enzyme found on the surface of three major pathogenic fungi: Blastomyces, Coccidioides, and Histoplasma. These organisms cause blastomycosis, coccidioidomycosis (Valley fever), and histoplasmosis—serious lung infections endemic to North America that can disseminate throughout the body.

Candidozyma auris—formerly known as Candida auris. Credits: Shutterstock

Vaccination with Eng2 protected mice against lethal infections from all three fungi. The research team also detected T cell responses to the enzyme in patients who had recovered from these mycoses, suggesting that the human immune system naturally recognises Eng2 during infection. This finding opens possibilities both for vaccine development and for diagnostic tools to identify past infections.

Sequence variation in Eng2 across the three fungal species means that immunisation with one version does not cross-protect against the others. However, vaccine design could overcome this limitation through a polyvalent approach—combining Eng2 from each species into a single preparation, similar to existing vaccines against Streptococcus pneumoniae and Neisseria meningitidis.

The curious ease of fungal vaccination

Eng2 joins a long list of fungal antigens shown to elicit protective immunity in animal models. Polysaccharides, enzymes, and cell wall proteins have all demonstrated effectiveness against various pathogenic fungi. Casadevall notes a striking paradox: whilst vaccines against highly virulent pathogens such as HIV, tuberculosis, and malaria have proven extraordinarily difficult to develop, experimental fungal vaccines show relatively consistent success.

One explanation may lie in the nature of fungal virulence itself. Most pathogenic fungi cause severe disease only in immunocompromised hosts—healthy individuals typically fight off infections without difficulty. Humans possess remarkable natural resistance to invasive fungal disease, maintained by high body temperatures that exclude most fungal species and sophisticated immune mechanisms. A vaccine need only provide incremental protection atop this existing defence—perhaps a lower bar than defeating pathogens capable of overwhelming intact immunity.

Why no vaccine exists

If fungal vaccines work so well in the laboratory, why has none reached the clinic? Several obstacles conspire against development.

First, the target population presents challenges. Because invasive fungal infections occur primarily in immunocompromised individuals—now comprising 6.6% of the US population—any vaccine must generate protective immunity in patients whose immune systems are already impaired. Experience with vaccines against varicella zoster virus and SARS-CoV-2 suggests this is achievable, but adds complexity to clinical trials.

Second, the sporadic nature of fungal disease complicates efficacy studies. Vaccines aim to prevent high-consequence but low-probability events. Demonstrating statistical significance requires either enormous trials or carefully targeted enrolment of high-risk cohorts—both expensive propositions.

Third, economics disfavour development. Vaccine development costs hundreds of millions of dollars. With fungal infections concentrated among immunocompromised individuals rather than the general population, the potential market is smaller than for vaccines targeting common infectious diseases.

An urgent threat emerges

These academic concerns take on new urgency as a dangerous fungal pathogen spreads through European hospitals. The European Centre for Disease Prevention and Control (ECDC) reports that Candidozyma auris—formerly known as Candida auris—is rapidly establishing itself across healthcare systems, posing what officials describe as a serious threat to patients.

First identified in Japan in 2009, C. auris has since spread worldwide. Between 2013 and 2023, EU/EEA countries reported over 4,000 cases, with a record 1,346 cases in 2023 alone—a 67% increase from the previous year. Spain, Greece, Italy, Romania, and Germany have recorded the highest case numbers. In some countries, the pathogen has become so widespread that health authorities can no longer distinguish individual outbreaks; it has effectively become endemic in hospital settings.

C. auris presents a perfect storm of dangerous characteristics. It spreads readily between patients in healthcare facilities, persisting on surfaces, bed rails, medical equipment, and healthcare workers' hands. Standard hospital disinfectants often prove ineffective against it. Most isolates resist fluconazole, the first-line antifungal drug, whilst increasing numbers show resistance to echinocandins and amphotericin B—the remaining treatment options. Mortality rates among infected patients range from 29% to 62%.

The fungus does not cause distinctive symptoms, making clinical detection impossible without laboratory testing. Yet only 17 of 36 European countries surveyed have national surveillance systems for C. auris, and just 15 have specific infection control guidelines. The true scale of the problem is likely significantly underreported.

A critical window closing

The ECDC data reveal a troubling pattern: once C. auris establishes itself in a country, it takes just five to seven years to achieve regional endemicity. This narrow window for intervention is rapidly closing in several European nations.

Recent outbreaks have occurred in Cyprus, France, and Germany. Greece, Italy, Romania, and Spain have indicated they can no longer distinguish specific outbreaks—the pathogen has spread too widely. Dr Diamantis Plachouras, Head of ECDC's Antimicrobial Resistance and Healthcare-Associated Infections Section, emphasised that this trajectory is not inevitable: early detection and coordinated infection control can still prevent further transmission.

But infection control measures are reactive, resource-intensive, and imperfect. A vaccine would offer proactive protection—particularly valuable for the immunocompromised patients most vulnerable to C. auris infection.

Therapeutic vaccines may offer a faster path

Casadevall suggests an alternative strategy that could accelerate development: therapeutic rather than preventive vaccines. Because invasive fungal infections tend to be chronic, with prolonged courses, there is time for vaccination to stimulate an immune response that assists antifungal drug therapy in clearing infection.

This approach has precedent. Both rabies and hepatitis A vaccines prove effective after exposure. Demonstrating therapeutic efficacy in patients already diagnosed with fungal infection could be considerably easier than proving prevention in at-risk populations—and success could ease the regulatory pathway toward preventive use.

The commentary notes that some fungal vaccines have reached clinical development. A vaccine using the Als3 protein reduced recurrent vaginal candidiasis in women during early trials. Although significant development work remains before potential licensure, these results encourage continued investment in antifungal vaccine research. Meanwhile, mRNA technology—proven during the COVID-19 pandemic—could substantially lower development costs for protein-based vaccines like Eng2.

The need for coordinated investment

The growing threat of antimicrobial-resistant pathogens demands new defensive strategies. Fungi have been largely neglected in the antimicrobial resistance conversation, yet they pose escalating risks. The World Health Organisation has designated C. auris as a critical priority fungal pathogen, recognising the urgency of the threat.

Vaccine development requires sustained investment over many years. The history of vaccinology, Casadevall notes, is one of committed individuals struggling against scepticism and limited resources to ultimately deliver enormous benefits to humanity. The scientific tools exist. The target antigens are identified. What remains is the collective will—and funding—to translate laboratory success into clinical reality.

For the 6.6% of patients whose compromised immune systems leave them vulnerable to invasive fungal disease, that translation cannot come soon enough.