SBIR-STTR Award

Candida is a fungus that is among the most common causes of infections in hospitalized patients in the United States and worldwide. Candida spp. are one of the most common microbes that infect the blood and urine of hospitalized patients. The cost associated with Candida blood infections alone exceeds at least $1 billion per year in the US. Even with therapy, 40-50% of patients with Candida blood infections die from the infection. Furthermore, resistance to antifungal therapies is rising among Candida organisms. For these reasons, a vaccine to prevent life threatening Candida infections is particularly attractive. Such a vaccine could potentially be useful for large populations including nearly all patients who undergo surgery to the chest or abdomen, newborns in intensive care units, and other patients with weakened immune systems, including cancer patients receiving chemotherapy. We have isolated a protein that allows Candida to adhere to human cells. The gene that encodes this protein is called ALS1, and it is a member of a family of related genes that code for at least nine proteins, most of which are also adhesins. Active immunization with the recombinant N-terminus of Als1p (rAls1p-N) significantly protects mice from otherwise rapidly lethal bloodstream and deep organ Candida infection. More recently we have purified a related protein, rAls3p-N, that is also encoded by a member of the ALS gene family. We have discovered that rAls3p-N results in a broader immune response than rAls1p-N, raising the possibility that rAls3p-N might be more effective than rAls1p-N as a vaccine. We propose to define and optimize vaccine-mediated protection in preparation for future clinical studies in humans by identifying the optimally protective Als protein (Alsp) in murine models of infection. The efficacy of rAls1p-N vs. rAls3p-N vs. combination rAls1p-N + rAls3p-N vs. adjuvant alone will be compared in our murine models of bloodstream infection, oral thrush, or vaginal yeast infection. Although the current application is focused on the development of an anti-Candida vaccine, we have extremely novel data showing cross-protection of the rAls1p-N vaccine against S. aureus in the murine model. Therefore, we will also compare the efficacy of the vaccine immunogens in our murine model of S. aureus bloodstream infection. Finally, in other systems, activation of a host immune receptor called TLR5 has been shown to enhance the efficacy of vaccines. Therefore, to further enhance the immune response to the Alsp immunogens, we will create novel combination proteins by mixing the Alsp immunogens with special proteins that activate TLR5. Once we have optimized our immunogens, we intended to prepare the vaccine product for human trials in the future phases of this project. Due to modern therapeutic advances for sustained life support, patients undergoing a variety of medical procedures or with a variety of medical conditions have become at risk for developing life-threatening infections caused by the fungus Candida. Among these procedures and conditions are: being treated in an intensive care unit, having a plastic catheter in a large vein, undergoing surgery to the chest or abdomen, being the victim of trauma injuries (both domestic, such as motor vehicle accidents, and military), having extensive burn injuries, being a premature neonate, and having cancer and undergoing chemotherapy. Given how common these conditions are, the development of a vaccine that protects against Candida infections could save hundreds of thousands of lives as well as substantially reduce hospitalization costs in both the United States and other countries where highly effective medical advances have been made

Candida species are opportunistic fungal pathogens that have become among the most common causes of nosocomial infections in the United States and worldwide. Disseminated infections caused by Candida spp. have increased 15-fold in incidence in the last 15 years, and Candida is now the third most common cause of bloodstream infections. Even with modern antifungal therapy, disseminated candidiasis has an unacceptable attributable mortality of 40%- 50%. Furthermore, resistance to conventional antifungal therapies among Candida spp. is rising. For these reasons, a vaccine to prevent life threatening Candida infections in patients who are acutely at risk is particularly attractive. Estimates indicate that millions of high risk patients per year in the United States (U.S.) alone could benefit from such a vaccine. We have isolated Candidal protein adhesins that stimulate potent anti-Candida immune responses in mice. Through work completed as a result of our Phase I STTR grant, we confirmed that the recombinant N-terminus of Als3p (rAls3p-N) was the optimally effective immunogen, resulting in significant protection against hematogenously disseminated, vaginal, and oropharyngeal candidiasis. We have also determined that alum, the only vaccine adjuvant approved for use in humans by the US Food and Drug Administration (FDA), is an effective adjuvant in combination with rAls3p-N. To complete pre-clinical testing, the following aims will be accomplished in the current Phase II STTR application: 1) Establish Good Manufacturing Practice for the rAls3p-N vaccine; 2) Complete pre-clinical toxicity studies in support of an IND application; 3) Develop high throughput assays to measure immunogenicity as surrogate markers for efficacy to be used in future clinical trials; and 4) To develop a phase I clinical protocol and related documents to support an Investigational New Drug application. At the end of the funding period, an IND application will be submitted in support of a phase I clinical trial to determine the safety and immunogenicity of the rAls3p-N vaccine. In support of the IND application, a clinical protocol and investigator's brochure will be developed, and documents in support of a pre-IND meeting and the IND will be prepared. The IND will be submitted in the final year of funding. Completion of the proposed Phase II STTR plan will finalize pre-clinical testing of the rAls3p-N, anti-Candidal vaccine, and will allow subsequent initiation of a phase I clinical trial to test the safety and immunogenicity of the vaccine in humans. Finally, we will develop humoral and cell-mediated immunological surrogate efficacy markers to lay the groundwork for immunological testing in humans in a phase Ib clinical trial.

Public Health Relevance:
Due to modern therapeutic advances for sustained life support, patients undergoing a variety of medical procedures or with a variety of medical conditions have become at risk for developing life-threatening infections caused by the fungus Candida. Among these procedures and conditions are: being treated in an intensive care unit, having a plastic catheter in a large vein, undergoing surgery to the chest or abdomen, being the victim of trauma injuries (both domestic, such as motor vehicle accidents, and military), having extensive burn injuries, being a premature neonate, and having cancer and undergoing chemotherapy. Given how common these conditions are, the development of a vaccine that protects against Candida infections could save hundreds of thousands of lives as well as substantially reduce hospitalization costs in both the United States and other countries where highly effective medical advances have been made.

NIH Spending Category:
Biotechnology; Immunization; Infectious Diseases; Injury (total) Accidents/Adverse Effects; Vaccine Related

Project Terms:
Abdomen; Adjuvant; aluminum sulfate; Antifungal Therapy; Antigens; assay development; attributable mortality; Bacterial Adhesins; base; Biological Assay; Burn injury; Calendar; Candida; Catheters; CD4 Positive T Lymphocytes; cell bank; Cells; chemotherapy; Chest; Clinical Protocols; Clinical Trials; Competitive Bidding; Contracts; cost; Country; cytokine; Data; design; Disseminated candidiasis; experience; Funding; fungus; Future; Grant; Helper-Inducer T-Lymphocyte; high risk; high throughput screening; Hospitalization; Human; IgG3; Immune response; immunogenicity; Immunoglobulin G; Immunologic Tests; Incidence; Infection; Injury; Intensive Care Units; Investigational Drugs; Investigational New Drug Application; Lead; Life; Malignant Neoplasms; Measures; Mediating; Medical; meetings; Military Personnel; Mus; neonate; Nosocomial Infections; Operative Surgical Procedures; oropharyngeal thrush; Pamphlets; pathogen; Patients; Phase; Phase I Clinical Trials; Plastics; pre-clinical; premature; prevent; Procedures; Process; Production; Proteins; public health relevance; Qualifying; Ramp; Recombinants; Research Personnel; Resistance; response; Risk; Safety; safety study; safety testing; scale up; Sepsis; Small Business Technology Transfer Research; Surrogate Markers; Testing; Therapeutic; Toxic effect; Trauma; United States; United States Food and Drug Administration; Vaccine Adjuvant; vaccine candidate; vaccine development; Vaccines; Vagina; vehicular accident; Veins; Work