The purpose of this Funding Opportunity Announcement (FOA) is to support the formation of Cooperative Research Centers (CRCs) to pursue vaccine development through multidisciplinary investigations into the host immune response to Clostridioides difficile infection (CDI). To this end, it will be critical to advance knowledge of immunity against CDI by leveraging clinical samples, identifying new protective antigens, and employing novel vaccine and adjuvant platforms. Information stemming from this research initiative will serve as a guide to develop the next generation of C. difficile vaccines to be tested in appropriately devised model systems.
CDI is the most common healthcare-associated infection in the U.S. and is listed as an Urgent Threat in the CDC’s 2019 Antibiotic Resistance Threat report. Recent estimates indicate that CDI rates have declined, although there are still approximately 223,900 infections and 12,800 deaths annually. CDI is a toxin-mediated disease, and the clinical manifestations range from asymptomatic colonization to severe fulminant CDI, which can progress to toxic megacolon, sepsis, and death. Antibiotic exposure is a primary risk factor for acquiring CDI; other factors include age (>65 yrs.) and prior hospitalization. Recent epidemiological data show a positive trend towards reduced hospital-associated infections, likely a reflection of improving antibiotic stewardship; however, this gain is seemingly offset by a rise in community acquired CDI.
The pathogenesis and clinical manifestations of CDI are mediated primarily through the activity of two large protein exotoxins, toxin A (TcdA) and toxin B (TcdB). C. difficile binary toxin (CDT) is a third toxin that is expressed by up to 30% of C. difficile strains and appears to contribute to disease pathogenesis. Nearly all clinically significant C. difficile strains express TcdB; some strains do not express TcdA; and epidemic BI/NAP1/027 strains can produce all three toxins. Regardless of the toxinotype, the host immune response to CDI is primarily directed towards TcdA and TcdB, and antibodies against these two toxins, particularly TcdB, have been shown to be an important predictor of disease outcome. Whilst many individuals have some detectable antitoxin antibodies, toxin-specific antibody levels tend to wane with advanced age, and low levels of antitoxin antibodies are associated with increased risk for recurrent CDI (rCDI). Conversely, elevated levels of circulating IgG antibodies against TcdA and TcdB are associated with asymptomatic colonization and protection from rCDI. Systemic antitoxin IgG has been studied extensively, but there has been less research on the role of local secretory IgA, and aspects of cellular immunity, including B-cell memory, are even less well defined.
Repeat infections with C. difficile are common and demonstrate that natural infection may not stimulate a protective immune response. The lack of protection following primary CDI could be due to insufficient antibody production, infection with an antigenically distinct strain or toxinotype, or other host related factors, such as waning immunity. Recent studies investigating TcdB identified critical sequence variations that contribute to differences in toxicity and may also influence the production of TcdB neutralizing antibodies. The two TcdB variants (TcdB1 and TcdB2) are associated with distinct C. difficile lineages, and adaptive immune responses to one lineage may not result in protective immunity against other lineages. The induction of a strong toxin-neutralizing antibody response likely plays a key role in protection from disease, whereas immunity to cell surface antigens and other polysaccharides are likely important for promoting pathogen clearance. Germination of C. difficile spores and colonization are critical steps in C. difficile pathogenesis, and adaptive immune responses that impact colonization have the potential to reduce transmission in healthcare facilities and community.
Research focused on C. difficile has increased substantially over the past two decades, leading to the availability of more therapeutics targeted to treat primary and rCDI. For example, fidaxomicin is a narrow-spectrum antibiotic approved in 2012 for the treatment of primary CDI and, more recently in 2016, the FDA approved bezlotoxumab, a monoclonal antibody against TcdB shown to reduce the rate of rCDI by up to 40%. Restoration of the gut microbiome using fecal microbiota transplantation or more defined consortia, appears highly effective against rCDI, but a more complete safety profile for this product class needs to be established in future prospective studies. Despite the promise of these new and innovative treatments, the disease burden still is not fully addressed, and licensed vaccines are needed for the primary prevention of CDI and as potential therapy for rCDI. Research on adaptive host immunity to CDI has been comparatively limited, and efforts to support research on the mechanistic aspects of protective immunity and vaccine development are warranted.
CDI vaccine development began several decades ago based on early data showing that prior exposure to C. difficile induces neutralizing antitoxin antibodies that can protect against disease. There are now several clinical stage CDI vaccines under development that use traditional vaccine technology (e.g., toxoids), and all have several common features, including a protein or subunit-based approach focused on generating systemic IgG anti-toxin immunity, with or without a traditional adjuvant. However, there are several lines of evidence suggesting that a highly efficacious CDI vaccine may be more elusive than originally thought. The unexpected termination of a large Phase 3 CDI vaccine trial due to futility in establishing efficacy was recently reported. The vaccine was safe and immunogenic, but it did not show efficacy in reducing the incidence of CDI. Additionally, there are tens of thousands of cases of rCDI reported each year. The basis for rCDI is multifactorial, and new cutting-edge research has highlighted a critical role for the gut microbiota, not only in providing resistance to C. difficile colonization, but also in generating a robust host immune response.
In 2018, NIAID hosted a programmatic workshop (Vaccines against Clostridium difficile infection: A Roadmap for the Future) that focused on C. difficile vaccine development. Experts in the field identified high-priority knowledge gaps, discussed high-quality benchmarks for CDI vaccine development, and considered the public health impact of introducing a licensed CDI vaccine. Bottlenecks and gaps identified during this workshop include the role of systemic vs. local (mucosal) immunity, the impact of the gut microbiome on host immunity, and the number and diversity of antigens needed to cover prevalent toxinotypes. The need to identify correlates of protection, to gain new insights in toxin antigenic variation, and to explore new vaccine targets that have the potential to impact bacterial colonization were identified as high priorities. Technical issues in CDI diagnostics, along with the difficulties of targeting an aging population with co-morbidities and waning immunity, were also identified as obstacles.
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