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The NovaDigm research team has made critical discoveries toward enabling new vaccine technology to potentially protect against fungal and bacterial diseases. NovaDigm’s lead development candidate, NDV-3A, is the first vaccine to demonstrate preclinical efficacy in reducing the severity of disease caused by both fungal and bacterial pathogens. Additionally, results published from a Phase 1 clinical trial demonstrated that the NDV-3 vaccine was safe, well-tolerated and induced strong antibody and T-cell immune responses in healthy adults.1 The most recent Phase 1b/2a study also indicated that a single dose of NDV-3A was safe, well-tolerated, induced strong antibody and T-cell immune responses in patients with recurrent vulvovaginal candidiasis (RVVC). Statistically significant measures of efficacy were observed through the twelve month duration of the study in patients with RVVC.

Dr. John (Jack) E. Edwards, Jr., the lead scientific founder of NovaDigm Therapeutics, has led a team of internationally recognized scientists in groundbreaking mycological research, specifically focusing on infectious disease caused by fungal pathogens. He and his team, which includes NovaDigm's five other scientific founders, began testing the hypothesis that adhesion of Candida to human endothelial cells (the cells that line the inside of blood vessels) is necessary for Candida to become an infectious and pathogenic organism.

One aspect of this work was to develop a bank of endothelial cells, which were used in a variety of experiments culminating in the identification of the proteins that Candida albicans uses to adhere to and invade human tissues. These agglutinin-like sequence (Als) proteins had been previously identified by other researchers, but Dr. Edwards and his team were the first to specifically identify their role in pathogenesis. One of these proteins, Als3, was subsequently shown to be the most promising vaccine antigen, capable of inducing protection against both systemic and mucosal candidal infections.2 A recombinant form of the Als3 antigen is produced in Saccharomyces cerevisiae, also known as baker’s or brewer’s yeast, which is commonly used to produce vaccines. The antigen is then purified for subsequent use in the vaccine.

As part of these studies, the scientific founders began studying the three-dimensional shape of these proteins and discovered they shared a high degree of structural homology with a few Staphylococcus aureus (S. aureus) surface proteins.3 This, along with other anecdotal evidence, suggested to the team that an Als3-based vaccine may also protect against S. aureus, a bacterium.

As predicted, the vaccine proved effective in preclinical studies, reducing the mortality of an otherwise lethal S. aureus infection. This vaccine has also demonstrated efficacy against the more virulent and difficult to treat methicillin-resistant S. aureus (MRSA).4 This discovery was the first example of “cross-kingdom” protection by a single antigen (against both fungal and bacterial pathogens) and has been cited as an example of a “third-generation” vaccine for its breadth of protection.5

Interestingly, while the vaccine induces very high antibody levels, the mechanism-of-action in preclinical models for Candida and S. aureus bloodstream infections appears to be primarily mediated by Th1 and Th17 T-cells.6 Several recent publications involving studies of individuals with reduced Th17 T-cell function due to defined genetic mutations have shown increased susceptibilities to Candida and S. aureus infections.7,8,9 Recent review articles on S. aureus vaccines have also highlighted the potential importance of Th17 or Th1/17 cellular responses.10,11

Infectious diseases are and will always remain a moving target. Evolution has equipped bacteria, viruses and fungi with the incredible ability to rearrange their genetics—mutating and becoming resistant to the therapies that we have discovered to eliminate them. Nearly all available drugs put evolutionary pressure on microbes to become resistant. Antibiotics, antivirals and antifungals selectively kill those organisms that are not resistant and leave those that are resistant alone to multiply. Eventually, the drugs lose effectiveness as more and more of the surviving resistant microbes reproduce, further increasing the number of resistant strains.

NovaDigm is studying the bacteria and fungi responsible for several infectious diseases and identifying novel strategies to fight them. By teaching the immune system how to fight these microbes with novel vaccines and developing new strategies for antibiotic and antifungal therapies that are not as susceptible to resistance, we can begin to potentially combat the large and growing problem of drug-resistant infections.

References

  1. Schmidt CS, White CJ, Ibrahim AS, Filler SG, Fu Y, Yeaman MR, Edwards JE Jr., Hennessey JP Jr., NDV-3, a recombinant alum-adjuvanted vaccine for Candida and Staphylococcus aureus, is safe and immunogenic in healthy adults. Vaccine 2012; 30:7594-7600.
  2. Spellberg BJ, Ibrahim AS, Avanesian V, Fu Y, Myers C, Phan QT, Filler SG, Yeaman MR and Edwards JE Jr., Efficacy of the anti-Candida rAls3p-N or rAls1p-N vaccines against disseminated and mucosal candidiasis. J. Inf. Dis. 2006; 194:256-60.
  3. Sheppard DC, Yeaman MR, Welch HW, Phan QT, Fu Y, Ibrahim AS, Filler SG, Zhang M, Waring AJ and Edwards JE, Jr., Functional and structural diversity in the Als protein family of Candida alibicans. J. Biol. Chem. 2004; 279:30480-9.
  4. Spellberg BJ, Ibrahim AS, Yeaman MR, Lin L, Fu Y, Avanesian V, Bayer AS, Filler SG, Lipke P, Otoo H, and Edwards JE Jr., The antifungal vaccine derived from the recombinant N terminus of Als3 protects mice against the bacterium Staphylococcus aureus. Infect. Immun. 2008; 76:4574-580.
  5. Cassone A and Rappuoli R. 2010. Universal vaccines: shifting to one for many. mBio 1(1):e00042-10.
  6. Lin L, Ibrahim AS, Xu X, Farber JM, Avanesian V, Baquir B, Fu Y, French SM, Edwards JE Jr. and Spellberg BJ, Th1-Th17 cells mediate protective adaptive immunity against Staphylococcus aureus and Candida albicans infection in mice. PLoS Pathog 2009; 5:e1000703.
  7. Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, Kanno Y, Spalding C, Elloumi HZ, Paulson ML, David J, Hsu A, Asher AI, O'Shea J, Holland SM, Paul WE and Douek DC, Impaired Th17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 2008; 452: 773-776.
  8. Glocker E, Hennigs A, Nabavi M, Schaffer AA, Woellner C, Salzer U, Pfeifer D, Veelken H, Warnatz K, Tahami F, Jamal S, Manguiat A, Rezaei N, Amirzargar AA, Plebani A, Hannesschlager N, Gross O, Ruland J, and Grimbacher B, A homozygous CARD9 mutation in a family with susceptibility to fungal infections. NEJM 2009; 361: 1727-35.
  9. Ferwerda B, Ferwerda G, Plantinga TS, Willment JA, van Spriel AB, Venselaar H, Elbers CC, Johnson MD, Cambi A, Huysamen C, Jacobs L, Jansen T, Verheijen K, Masthoff L, Morre SA, Vriend G, Williams DL, Perfect JR, Joosten LAB, Wijmenga C, van der Meer JWM, Adema GJ, Kullberg BJ, Brown GD, and Netea MG, Human dectin-1 deficiency and mucocutaneous fungal infections. NEJM 2009; 361:1760-7.
  10. Kaslow DC and Shriver JW, Clostridium difficile and Methicillin-Resistant Staphylococcus aureus: Emerging Concepts in Vaccine Development. Annu. Rev. Med. 2010; 62: 6.1-6.15.
  11. Proctor, RA, Is there a future for a Staphylococcus aureus vaccine? Vaccine 2011; 30(19); 2921-2927.