Tuesday, 12 July 2011

A vaccine for aspergillosis?

Successful vaccines have been created to protect against pathogenic bacteria and viruses. Why aren't there any for combating fungal infections? A recent article in The Scientist by Brad Spellberg discusses the possibilities.

"Invasive fungal diseases often take hold when a person’s natural defenses are weakened. These infections frequently occur in hospital settings, after a patient’s normal bacterial flora is wiped out by antibiotics, or the skin and gut mucosa are breached by surgery or central venous catheters including for intravenous nutrition. In fact, candidiasis, an infection caused by one of several species of the yeast Candida, is now the fourth most common bloodstream infection in hospitalized patients both in the United States and in many European countries. And the death rate from such Candida infections remains about 30 to 40 percent, even after treatment with antifungal therapy. Given their increasing frequency and unacceptably high morbidity and mortality rates, prevention of invasive fungal infections has become of paramount importance. Vaccination is a promising strategy for prevention, since it has the potential to permanently protect individuals from fungal infection."

The premise that all patients who develop life-threatening fungal infections have profound defects in their immune system -implying that their immune systems would be too weak to respond to vaccination - has led to incorrect assumptions that would limit the usefulness of an anti-fungal vaccine.
However if you consider patients who develop serious candida infections of the bloodstream- only 10-20% are seriously immunocompromised- the remainder have developed infection because their susceptibility has increased whilst in hospital -due to broad spectrum antibiotic usage, surgery, IV catheters etc. Such patients have relatively intact immune systems - besides there is significant evidence in the literature that even patients with very weakened immunity - can generate adequate immune responses to vaccination - for example - to the influenza or pneumonia vaccines - which are often given to leukaemic patients, HIV and those on corticosteroids.
A candida vaccine is currently entering phase I trials - based on the agglutinin-like group of proteins expressed on the cell surface of candida albicans. When injected into mice it prevented widespread lethal candidiasis. Moreover this vaccine targeted TH1 and Th17 CD4+ T helper cells which recruit and activate phagocytic cells that can engulf and destroy the fungus in tissue.

The author points out that vaccination against fungal pathogens very likely requires enhancement of phagocytic host defences whether via antibody mediated or non antibody methods. Also vaccine responsive T cells can provide phagocytic enhancement in the absence of protective antibodies, and contrary to widely held assumption - it is not necessary to develop antibodies that neutralize virulence factors- ie the toxins or disease causing proteins expressed by the pathogen- in order to achieve protection with a vaccine.

So where does that leave us with respect to Aspergillus infection - the second most common cause of hospital acquired invasive fungal infection ? It is more of a challenge to develop a vaccine for Aspergillosis since virtually all patients with invasive illness are highly immunocompromised. The risk factors for aspergillosis include white cell depletion from chemotherapy, leukaemia or bone marrow transplant and long term corticosteroid or immunosuppressant treatment. Since the infections tend to set in after multiple weeks of an at - risk situation - the suggestion that clinicians could vaccinate before infection sets in - is promising.
Early studies using crude extracts of Aspergillus fumigatus as vaccines in mice have shown protection against subsequent infection- however these have now been refined to identify a fungal surface antigen Asp f3 which appears to be the active antigen at least in mice. If this antigen can be produced according to good manufacturing practice it is a potential candidate for a development of a specific Aspergillus vaccine.

Another approach would be to develop a pan fungal vaccine which targets most serious fungal infections. Evidence recently published (Stevens et al) suggests that a combination of glycan (cell wall component) with an immunogenic protein - based on studies from heat killed Saccharomyces (yeast), may lead to developing such a pan fungal vaccine.

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