Vaccines to prevent systemic mycoses: holy grails meet translational realities.

In this issue of the Journal, Spellberg et al. [1] report that immunization with a recombinant protein (rAls3p-N) mixed with aluminum hydroxide gel (Alhydrogel) can protect mice from a lethal candidal infection. This is an extension of their original finding of protection resulting from this and related Als recombinant proteins when used with Freund’s adjuvant. From a purely immunologic perspective, their finding that protection can also be achieved using Alhydrogel in place of Freund’s adjuvant might be viewed as a modest advance. However, because Alhydrogel has been widely used as an adjuvant in US Food and Drug Administration (FDA)-approved vaccines, these studies represent a milestone in the movement of the vaccine toward clinical testing. Thus, on the occasion of this report, it may be useful to review the potential value of vaccines for systemic mycoses in general, using vaccines for coccidioidomycosis as a specific example, and to review the challenges these vaccine candidates will face before becoming realities in the marketplace. There is substantial reason to believe in the possibility of using vaccines to prevent systemic fungal infections [2–9]. In the case of coccidioidomycosis, untreated infection, regardless of whether it produces clinical illness, results in life-long immunity from future infection [10]. This is likely true for histoplasmosis and blastomycosis as well. Attempts to mimic the protection afforded by coccidioidal infection with a vaccine have been ongoing for over half a century. Indeed, a formalinkilled whole-cell (spherule) vaccine, shown to be highly effective in mice [11; 12], was submitted to a clinical trial and was found not to be effective [13]. The failure of the whole-cell vaccine may have been the result of an exaggerated doserelated irritation that it engendered at the injection site, which, in human subjects, limited the vaccine dose and the immunogens that it contained in to quantities thousands of times less than those used for mice, relative to body mass. Were that the case, then the development of a subcellular vaccine composed of specific immunoprotective spherule proteins might be more effective. This approach has been taken for the past decade by a collaboration between 5 laboratories, coordinated through the University of California at San Francisco, and largely underwritten with approximately $15 million of funding from the state of California and the California Health Care Foundation [14]. As a result of this effort, several recombinant antigens have shown promise [15– 19]. One chimeric antigen, composed of sequences from 2 independently protective antigens, has shown sufficient immunogenicity in mice to protect 95% of immunized animals from an infection that would otherwise be lethal [20]. Corroborating evidence for the efficacy of vaccination with this chimeric antigen has also been demonstrated in studies involving nonhuman primates [21]. Although it is possible that further exploration would improve the results obtained thus far, the current vaccine candidate is arguably sufficiently promising to recommend its extension into clinical trials. Other fungal vaccines also have compelling rationales supporting their continued development. As Spellberg et al. have detailed [22], candidemia has a high attributable mortality. Furthermore, because the onset of candidemia usually occurs only after weeks of hospitalization [23], a vaccination strategy for at-risk patients at the time of admission is plausible. One of the challenges of translating vaccine discovery into clinical trials is expanded vaccine production. Vaccines developed for early testing in experimental infections are prepared in relatively small quantities. The process of scaling up vaccine production typically requires extensive changes in approach, specialized Received 6 December 2007; accepted 6 December 2007; electronically published 29 February 2008. Potential conflicts of interest: none declared. Financial support: Valley Fever Vaccine Project; US Department of Veterans Affairs; National Institutes of Health, National Institute of Allergy and Infectious Diseases (1P01AI061310-01). Reprints or correspondence: John N.Galgiani, MD, Valley Fever Center for Excellence, University of Arizona, PO Box 205215, Tucson, Arizona 85724 ([email protected]). The Journal of Infectious Diseases 2008; 197:938–40 © 2008 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2008/19707-0002$15.00 DOI: 10.1086/529205 E D I T O R I A L C O M M E N T A R Y