Candida infections are frequent and major causes of septicemia in neonatal intensive care units, and neonatal candidiasis is associated with high morbidity and mortality rates. Low birth weight preterm infants (LBWI) are especially vulnerable to these infections, despite advances in current antifungal drug regimen. The high morbidity related to invasive candidiasis demands consideration of novel strategies for curtailing the incidence of these infections. We are at the crossroads of harnessing novel immunotherapeutic approaches for treatment of candidiasis in neonates. Our group has developed the very first vaccines against Candida, based on the cell wall antigens of C. albicans (Als3, Hyr1, Sap2). Vaccination with any of the three antigens elicits a robust immune response that protects from disseminated as well as mucosal Candida infections, in pre-clinical animal studies. Two of these vaccines (rAls3p or NDV-3A and rSap2p) have already been adjudged safe and well tolerated in humans in Phase I clinical trials, and NDV-3A vaccination has proven efficacious in protecting women against recurrent vulvovaginal candidiasis in Phase 1B/2A trials. Further, passive immunization using antibodies raised against the antigens Hyr1 and Sap2, protect mice from hematogenously disseminated candidiasis, by neutralizing antigens? virulence functions and inhibiting inflammatory responses. We now propose to use these vaccines to cover the spectrum of Candida infections in pre-term infants. We will use both active maternal vaccination as well as passive antibody transfusion in pregnant mice, with the ultimate goal to obtain potentially protective, vertically transferred antibodies in neonates. In addition, the potency of anti-Candida antibodies to protect from disseminated candidiasis, will also be evaluated after passive transfer in new born mice. Our overreaching goal is to develop a robust immunization-based approach that can potentially be used independently, or augment antifungal prophylaxis for ultimately defending low-birthweight infants from candidiasis. The outcomes of this proposal will be a first foray in the direction of understanding the immune response against Candida infections during pregnancy, and in neonates. The lessons learnt from our studies will result in reducing morbidity, mortality and healthcare costs, associated with these difficult to treat infections.
Development of immunotherapeutics for prevention of diseases in infants is a rapidly developing field, which can be harnessed for protecting neonates from Candida infections. The current study will first identify the hitherto unexplored immune response during pregnancy, and in neonates, after infection with Candida. Next, a multipronged approach will be used to identify the best strategy (active/passive vaccination) for prevention of VLBWI from acquiring candidiasis.
