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Review 2: "Semi-synthetic Glycoconjugate Vaccine Candidate Against Cryptococcus Neoformans"

Overall, while reviewers enjoyed the approach, they caution further optimization of the vaccine such as improving the glycan-protein conjugation is needed before an efficient vaccine candidate is achieved.

Published onMar 25, 2024
Review 2: "Semi-synthetic Glycoconjugate Vaccine Candidate Against Cryptococcus Neoformans"
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key-enterThis Pub is a Review of
Semi-synthetic glycoconjugate vaccine candidate against Cryptococcus neoformans
Semi-synthetic glycoconjugate vaccine candidate against Cryptococcus neoformans

Abstract Cryptococcus neoformans is a fungus classified by the World Health Organization as a critically important pathogen, posing a significant threat to immunocompromised individuals. In this study, we present the chemical synthesis and evaluation of two semi-synthetic vaccine candidates targeting the capsular polysaccharide glucuronoxylomannan (GXM) of C. neoformans. These semi-synthetic glycoconjugate vaccines contain the identical synthetic decasaccharide (M2 motif) antigen. This motif is present in serotype A strains, which constitute 95% of clinical cryptococcosis cases. This synthetic oligosaccharide was conjugated to two proteins (CRM197 and Anthrax 63 kDa PA) and tested for immunogenicity in mice. The conjugates elicited a specific antibody response that bound to the M2 motif but also exhibited additional cross-reactivity towards M1 and M4 GXM motifs. Both glycoconjugates produced antibodies that bound to GXM in ELISA assays and to live fungal cells. Mice immunized with the CRM197 glycoconjugate produced opsonic antibodies and displayed trends toward increased median survival relative to mice given a mock PBS injection (18 vs 15 days, p = 0.06). While these findings indicate promise, achieving a successful vaccine demands further optimization of the glycoconjugate. It could serve as a component in a multi-valent GXM motif vaccine, enhancing both strength and breadth of immune responses.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.


Review: The authors evaluated two semi-synthetic vaccine candidates that target C. neoformans' capsular polysaccharide, glucuronoxylomannan (GXM). They synthesized decasaccharide 15, produced a conjugated derivative with two proteins (CRM197 and Anthrax 63 kDa PA), and investigated its immunogenicity in mice. They used ELISA, GXM microarray, and survival experiments with a murine infection model to characterize antibodies from immunized mice's serum. The studies are rationally designed and carried out with controls; the results are laid out clearly, and the conclusions are compatible with the findings. 

Given the heterogeneity of the conjugates of biologically extracted native polysaccharides, these studies are critical for identifying and understanding the complexity of the role of various glycol saccharides in the nature of the host antibody response and protective immunity to Cryptococcus infections. CRM-167 was discovered to have a more defined and thus more consistent effect in mice than the PA63 carrier protein. This study demonstrated that DECA-CRM197 combination elicited phagocytic antibodies, in contrast to their prior characterization of heptasaccaride-HSA conjugate, which did not. Even though DECA-CRM197 did not provide strong protective immunity in mice, the study's findings are important for rationalizing the components of potential future multivalent vaccines designed to prevent cryptococcosis.

Minor comment: On page 5, the last two sentences are redundant.

Overall, the capsule is crucial for Cryptococal pathogenicity. GXM, a significant component of the capsule, promotes antibody formation. However, it generates both protective and non-protective antibodies. As a result, understanding the link between capsule components and the nature of the antibody response in mice is critical for developing potential future cryptococcosis combination vaccines. This paper demonstrates the method to synthesize oligosachharides, conjugate them, and characterize the host antibody response.

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