Characterizing and Minimizing Aggregation and Particle Formation of Three Recombinant Fusion-Protein Bulk Antigens for Use in a Candidate Trivalent Rotavirus Vaccine.
aggregation
formulation
recombinant protein
rotavirus
stability
subunit vaccine
Journal
Journal of pharmaceutical sciences
ISSN: 1520-6017
Titre abrégé: J Pharm Sci
Pays: United States
ID NLM: 2985195R
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
30
04
2019
revised:
26
07
2019
accepted:
01
08
2019
pubmed:
11
8
2019
medline:
23
3
2021
entrez:
11
8
2019
Statut:
ppublish
Résumé
In a companion paper, the structural integrity, conformational stability, and degradation mechanisms of 3 recombinant fusion-protein antigens comprising a non-replicating rotavirus (NRRV) vaccine candidate (currently being evaluated in early-stage clinical trials) are described. In this work, we focus on the aggregation propensity of the 3 NRRV antigens coupled to formulation development studies to identify common frozen bulk candidate formulations. The P2-VP8-P[8] antigen was most susceptible to shaking and freeze-thaw-induced aggregation and particle formation. Each NRRV antigen formed aggregates with structurally altered protein (with exposed apolar regions and intermolecular β-sheet) and dimers containing a non-native disulfide bond. From excipient screening studies with P2-VP8-P[8], sugars or polyols (e.g., sucrose, trehalose, mannitol, sorbitol) and various detergents (e.g., Pluronic F-68, polysorbate 20 and 80, PEG-3350) were identified as stabilizers against aggregation. By combining promising additives, candidate bulk formulations were optimized to not only minimize agitation-induced aggregation, but also particle formation due to freeze-thaw stress of P2-VP8-P[8] antigen. Owing to limited material availability, stabilization of the P2-VP8-P[4] and P2-VP8-P[6] was confirmed with the lead candidate P2-VP8-P[8] formulations. The optimization of these bulk NRRV candidate formulations is discussed in the context of subsequent drug product formulations in the presence of aluminum adjuvants.
Identifiants
pubmed: 31400346
pii: S0022-3549(19)30494-0
doi: 10.1016/j.xphs.2019.08.001
pmc: PMC6941221
pii:
doi:
Substances chimiques
Antigens, Viral
0
Drugs, Investigational
0
Excipients
0
Protein Aggregates
0
Recombinant Fusion Proteins
0
Rotavirus Vaccines
0
Vaccines, Subunit
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
394-406Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Références
Vaccine. 2015 May 21;33(22):2606-13
pubmed: 25882173
Pharm Res. 2013 May;30(5):1263-80
pubmed: 23319172
J Biol Chem. 2012 Jul 20;287(30):25266-79
pubmed: 22584577
Pharm Res. 2007 Jan;24(1):136-46
pubmed: 17109212
Vaccine. 2015 Jul 17;33(31):3766-72
pubmed: 26065919
Vaccine. 2018 Apr 12;36(16):2086-2092
pubmed: 29555220
FEBS Open Bio. 2016 Jan 04;6(2):126-34
pubmed: 27239434
Vaccine. 2018 Jun 7;36(24):3427-3433
pubmed: 29752022
J Infect Dis. 2017 Jan 1;215(1):34-41
pubmed: 27803175
Biologicals. 2014 Sep;42(5):237-59
pubmed: 24996452
Lancet Infect Dis. 2017 Aug;17(8):786-787
pubmed: 28483417
Vaccine. 2008 Dec 9;26(52):6754-8
pubmed: 18951937
J Pharm Sci. 2012 Jul;101(7):2534-44
pubmed: 22535541
J Pharm Sci. 2013 Feb;102(2):387-400
pubmed: 23161162
J Pharm Sci. 2011 Mar;100(3):1009-21
pubmed: 21280052
J Pharm Sci. 2018 Apr;107(4):999-1008
pubmed: 29269269
J Pharm Sci. 2020 Jan;109(1):380-393
pubmed: 31400347
Arch Virol. 2015 Aug;160(8):2075-8
pubmed: 26016444
J Pharm Sci. 2012 Mar;101(3):895-913
pubmed: 22083792
Dev Biol (Basel). 2003;112:81-97
pubmed: 12762507
Vaccine. 2017 Oct 4;35(41):5471-5480
pubmed: 28551040
J Pharm Sci. 2012 Aug;101(8):2720-32
pubmed: 22648863
Expert Rev Vaccines. 2014 Jul;13(7):843-54
pubmed: 24865112
Hum Vaccin Immunother. 2018 Feb 1;14(2):495-499
pubmed: 29135339
J Pharm Sci. 2015 Feb;104(2):686-97
pubmed: 25219372
J Pharm Sci. 2009 Sep;98(9):3239-46
pubmed: 19544369
J Pharm Sci. 2013 Apr;102(4):1194-208
pubmed: 23400717
Adv Drug Deliv Rev. 2011 Oct;63(13):1160-71
pubmed: 21763375
Vaccine. 2018 Jan 4;36(2):273-279
pubmed: 28874323
J Biol Chem. 1981 Jul 25;256(14):7193-201
pubmed: 7251592
Expert Rev Vaccines. 2014 May;13(5):671-85
pubmed: 24702271
J Pharm Sci. 2016 Aug;105(8):2319-27
pubmed: 27368120
J Pharm Sci. 2013 Dec;102(12):4256-67
pubmed: 24122556
Biotechnol J. 2015 Mar;10(3):367-78
pubmed: 25772395
Vaccine. 2018 Jan 4;36(2):264-272
pubmed: 29217369
Trends Biotechnol. 2018 Oct;36(10):1068-1084
pubmed: 29908714
Nat Rev Drug Discov. 2005 Apr;4(4):298-306
pubmed: 15803194
J Pharm Sci. 2014 Jul;103(7):1979-1986
pubmed: 24832730
Expert Rev Vaccines. 2010 Jul;9(7):689-91
pubmed: 20624039
Vaccine. 2014 Jul 31;32(35):4420-7
pubmed: 24962749
J Immunotoxicol. 2014 Apr-Jun;11(2):99-109
pubmed: 23919460
J Pharm Sci. 2008 May;97(5):1801-12
pubmed: 17823949
Paediatr Drugs. 2018 Jun;20(3):223-233
pubmed: 29388076
J Pharm Sci. 2013 Dec;102(12):4305-14
pubmed: 24129946
Virol Sin. 2015 Oct;30(5):363-70
pubmed: 26459269
Virus Res. 2015 Dec 2;210:298-307
pubmed: 26368053
J Pharm Sci. 2014 Mar;103(3):796-809
pubmed: 24452866
Vaccine. 2012 Sep 21;30(43):6121-6
pubmed: 22885016
Lancet Infect Dis. 2017 Aug;17(8):843-853
pubmed: 28483414
Biophys J. 2007 Mar 15;92(6):2131-8
pubmed: 17189314
Vaccine. 2019 Nov 28;37(50):7328-7335
pubmed: 28396207