Novel Chimeric Protein Vaccines Against Clostridium difficile Infection

Wang, Shaohui; Wang, Yuanguo; Cai, Ying; Kelly, Ciarán P.; Sun, Xingmin

doi:10.3389/fimmu.2018.02440

Cited by 7 publications

(8 citation statements)

References 55 publications

(55 reference statements)

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“…The fact that this vaccine platform induced a robust humoral and cell-mediated immune response at a mucosal site makes it an attractive platform for mucosal vaccine development against other mucosal pathogens. Specifically, this platform can also be utilized for vaccines against pathogens such as influenza (antigens: Hemagglutinin, Neuraminidase) [76,77], Clostridium difficile (sntigens: TcdA, TcdB) [78], and enterotoxigenic Escherichia coli (antigens: colonization factor antigens, heat-stable toxin, heat-labile toxin) [79], which have well-defined protein antigens that can be readily fused with the APC-targeting component of Trivalent-FP. Importantly, most of these antigens (TcdA, TcdB, heat-stable toxin, and heat-labile toxin) are toxins, and are genetically modified to minimize their toxicity in order to utilize them in a vaccine.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Efficacy of a Trivalent Human FcγRI-Targeted Adjuvant-Free Subunit Mucosal Vaccine against Pulmonary Pneumococcal Infection

Kumar

Sunagar²,

Gosselin

2020

Vaccines

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Lack of safe and effective mucosal adjuvants has severely hampered the development of mucosal subunit vaccines. In this regard, we have previously shown that immunogenicity of vaccine antigens can be improved by targeting the antigens to the antigen-presenting cells. Specifically, groups of mice immunized intranasally with a fusion protein (Bivalent-FP) containing a fragment of pneumococcal-surface-protein-A (PspA) as antigen and a single-chain bivalent antibody raised against the anti-human Fc-gamma-receptor-I (hFcγRI) elicited protective immunity to pulmonary Streptococcus pneumoniae infection. In order to further enhance the immunogenicity, an additional hFcγRI-binding moiety of the single chain antibody was incorporated. The modified vaccine (Trivalent-FP) induced significantly improved protection against lethal pulmonary S. pneumoniae challenge compared to Bivalent-FP. In addition, the modified vaccine exhibited over 85% protection with only two immunizations. Trivalent-FP also induced S. pneumoniae-specific systemic and mucosal antibodies. Moreover, Trivalent-FP also induced IL-17-and IL-22-producing CD4 + T cells. Furthermore, it was found that the hFcγRI facilitated uptake and presentation of Trivalent-FP. In addition, Trivalent-FP also induced IL-1α, MIP-1α, and TNF-α; modulated recruitment of dendritic cells and macrophages; and induced CD80/86 and MHC-II expression on antigen presenting cells.With over 90 known serotypes, Streptococcus pneumoniae remains the leading cause of community acquired pneumoniae. In addition, younger and immunocompromised populations are more vulnerable to infection. Furthermore, S. pneumoniae causes over 1 million deaths per year in children aged less than 5 years [10]. To date, two polysaccharide-based subunit vaccines are available to combat select serotypes. However, use of these 13 and 23 serotype vaccines cause serotype replacement in the vaccinated population [11]. This results in a surge of non-vaccine serotypes within the vaccinated population. Thus, new approaches to pneumococcal vaccines are required, which can generate protection over multiple serotypes. The pneumococcal surface protein A (PspA) has been known to induce cross-serotype protection against S. pneumoniae [12]. Thus, not only is S. pneumoniae a significant global health problem, it also expresses a well-defined protective protein antigen, making it a particularly suitable model to test and optimize our mucosal subunit vaccine platform.Previously we have shown that targeting vaccine antigens to antigen-presenting cells (APCs) eliminates the need for adjuvants.By genetically fusing a bivalent single-chain variable fragment-based antibody (Bivalent anti-human-Fc-gamma-receptor-I (FcγRI)), which specifically recognizes human-FcγRI, to a pneumococcal antigen (PspA), a fusion protein named Bivalent-FP was obtained ( Figure 1A). Bivalent-FP induces systemic and mucosal antibodies and protection against pulmonary S. pneumoniae infection by intranasal immunization. However, this vaccine requires at least three i...

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Section: Discussionmentioning

confidence: 99%

Preclinical Efficacy of a Trivalent Human FcγRI-Targeted Adjuvant-Free Subunit Mucosal Vaccine against Pulmonary Pneumococcal Infection

Kumar

Sunagar²,

Gosselin

2020

Vaccines

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“…The following approaches will be discussed: active immunization strategies based on receptor-binding domain (RBD) and toxoid vaccines, and passive immunization strategies using anti-TcdA and anti-TcdB antibodies. Vaccination with a plasmid expressing the RBD of TcdA and TcdB has been wellstudied in cells and animal models (Zhang et al, 2016;Wang et al, 2018;Luo et al, 2019). Both model systems supported the expression of the proteins and animal models (mouse and hamster) demonstrated a B cell response as a result of immunization.…”

Section: Toxin-based Immunization Strategiesmentioning

confidence: 99%

Host Immune Responses to Clostridioides difficile: Toxins and Beyond

et al. 2021

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Clostridioides difficile is often resistant to the actions of antibiotics to treat other bacterial infections and the resulting C. difficile infection (CDI) is among the leading causes of nosocomial infectious diarrhea worldwide. The primary virulence mechanism contributing to CDI is the production of toxins. Treatment failures and recurrence of CDI have urged the medical community to search for novel treatment options. Strains that do not produce toxins, so called non-toxigenic C. difficile, have been known to colonize the colon and protect the host against CDI. In this review, a comprehensive description and comparison of the immune responses to toxigenic C. difficile and non-toxigenic adherence, and colonization factors, here called non-toxin proteins, is provided. This revealed a number of similarities between the host immune responses to toxigenic C. difficile and non-toxin proteins, such as the influx of granulocytes and the type of T-cell response. Differences may reflect genuine variation between the responses to toxigenic or non-toxigenic C. difficile or gaps in the current knowledge with respect to the immune response toward non-toxigenic C. difficile. Toxin-based and non-toxin-based immunization studies have been evaluated to further explore the role of B cells and reveal that plasma cells are important in protection against CDI. Since the success of toxin-based interventions in humans to date is limited, it is vital that future research will focus on the immune responses to non-toxin proteins and in particular non-toxigenic strains.

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“…To this end, we determined the cross-reactivities of anti-Tcd169, anti-mTcd138 and anti-Tcd169FI sera with FliCD by ELISAs. Sera were collected from mice after the 3rd immunizations in this work or previously ( 20 , 21 ). Tcd169FI was generated previously by fusing Tcd169 with S. typhimurium flagellin (sFliC) ( 20 ).…”

Section: Resultsmentioning

confidence: 99%