Novel Ricin Subunit Antigens With Enhanced Capacity to Elicit Toxin-Neutralizing Antibody Responses in Mice.


Abstract

RiVax is a candidate ricin toxin subunit vaccine antigen that has proven to be safe in human phase I clinical trials. In this study, we introduced double and triple cavity-filling point mutations into the RiVax antigen with the expectation that stability-enhancing modifications would have a beneficial effect on overall immunogenicity of the recombinant proteins. We demonstrate that 2 RiVax triple mutant derivatives, RB (V81L/C171L/V204I) and RC (V81I/C171L/V204I), when adsorbed to aluminum salts adjuvant and tested in a mouse prime-boost-boost regimen were 5- to 10-fold more effective than RiVax at eliciting toxin-neutralizing serum IgG antibody titers. Increased toxin neutralizing antibody values and seroconversion rates were evident at different antigen dosages and within 7 days after the first booster. Quantitative stability/flexibility relationships analysis revealed that the RB and RC mutations affect rigidification of regions spanning residues 98-103, which constitutes a known immunodominant neutralizing B-cell epitope. A more detailed understanding of the immunogenic nature of RB and RC may provide insight into the fundamental relationship between local protein stability and antibody reactivity.

Submission Details

ID: bxLcoWc64

Submitter: Shu-Ching Ou

Submission Date: Dec. 19, 2018, 10:31 a.m.

Version: 1

Publication Details
Wahome N;Sully E;Singer C;Thomas JC;Hu L;Joshi SB;Volkin DB;Fang J;Karanicolas J;Jacobs DJ;Mantis NJ;Middaugh CR,J Pharm Sci (2016) Novel Ricin Subunit Antigens With Enhanced Capacity to Elicit Toxin-Neutralizing Antibody Responses in Mice. PMID:26987947
Additional Information

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
1RZO 2003-12-26T00:00:00+0000 2.63 Agglutinin from Ricinus communis with galactoaza
1RZO 2003-12-26T00:00:00+0000 2.63 Agglutinin from Ricinus communis with galactoaza
1BR5 1998-08-26T00:00:00+0000 2.5 RICIN A CHAIN (RECOMBINANT) COMPLEX WITH NEOPTERIN
1BR6 1998-08-27T00:00:00+0000 2.3 RICIN A CHAIN (RECOMBINANT) COMPLEX WITH PTEROIC ACID
1IFS 1996-07-05T00:00:00+0000 2.0 RICIN A-CHAIN (RECOMBINANT) COMPLEX WITH ADENOSINE (ADENOSINE BECOMES ADENINE IN THE COMPLEX)
1IFT 1996-07-05T00:00:00+0000 1.8 RICIN A-CHAIN (RECOMBINANT)
1IFU 1996-07-05T00:00:00+0000 2.4 RICIN A-CHAIN (RECOMBINANT) COMPLEX WITH FORMYCIN
1IL3 2001-05-07T00:00:00+0000 2.8 STRUCTURE OF RICIN A CHAIN BOUND WITH INHIBITOR 7-DEAZAGUANINE
1IL4 2001-05-07T00:00:00+0000 2.6 STRUCTURE OF RICIN A CHAIN BOUND WITH INHIBITOR 9-DEAZAGUANINE
1IL5 2001-05-07T00:00:00+0000 2.8 STRUCTURE OF RICIN A CHAIN BOUND WITH INHIBITOR 2,5-DIAMINO-4,6-DIHYDROXYPYRIMIDINE (DDP)

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
92.9 Ricin P06750 AGGL_RICCO
99.3 Ricin P02879 RICI_RICCO