Guidelines on stability evaluation of vaccines

Dobbelaer, R.; Pfleiderer, Michael; Haase, M.; Griffiths, Elwyn; Knežević, Ivana; Merkle, Antje; Hongzhang, Y; Candrian, U.; Castillo, M.; Wood, David D.; Daviaud, Joelle; Dellepiane, Nora; Hernandez, Cynthia; Lambert, Samuel W.; Shin, Jin-Ho; Fournier-Caruna, J; Kopp, Sabrina; Zhou, Tong; Zaffran, Michel; Bektimirov, T. A.; Cooper, G L; Silveira, Sophia Calábria da; Egan, William; Medveczky, N E; Morris, Tina S.; Nuñez, Yesenia; Horiuchi, Yoshinobu; Jivapaisarnpong, Teeranart; Krause, Philip R.; Martín, Juan José Díaz; Southern, James F.; Utami, Asih; Jadhav, Suresh; Susanti, Ida; Yamaguchi, Isuke; Duchêne, Michel; Laschi, Alda; Schofield, Timothy L.

doi:10.1016/j.biologicals.2009.08.017

Cited by 26 publications

(6 citation statements)

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“…As little as 5 mM phosphate, 0.9% NaCl, pH 7.4 has been observed to reduce adsorption of proteins to aluminum adjuvants [46] . Similar inhibition has been observed for diphtheria and tetanus toxoids in combination vaccines [48] and with a monovalent MenC-TT [50] or MenA-TT vaccine (Tiengwe, Mattick & Bolgiano, unpublished). With a higher strength PBS buffer, containing 10 times more phosphate ion, negligible binding to the adjuvants was found irrespective of the aluminum salt used.…”

Section: Discussionsupporting

confidence: 71%

“…Because of the differences observed in the binding of the CRM 197 conjugates to the adjuvants in a low ionic strength phosphate buffer, the influence of the phosphate ion was studied in an adequately buffered solution at a physiological saline concentration. Phosphate ions have been found to have a number of different effects on adjuvant, such as promoting Ag-adjuvant adsorption, competing with Ag adsorption by binding, or exchanging ligands with adjuvant [8,13,14,21,28,46–48] .…”

Section: Resultsmentioning

confidence: 99%

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Patterns of binding of aluminum-containing adjuvants to Haemophilus influenzae type b and meningococcal group C conjugate vaccines and components

et al. 2015

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The basis of Haemophilus influenzae type b (Hib) and Neisseria meningitidis serogroup C (MenC) glycoconjugates binding to aluminum-containing adjuvants was studied. By measuring the amount of polysaccharide and protein in the non-adsorbed supernatant, the adjuvant, aluminum phosphate, AlPO4, was found to be less efficient than aluminum hydroxide, Al(OH)3 at binding to the conjugates, at concentrations relevant to licensed vaccine formulations and when equimolar. At neutral pH, binding of TT conjugates to AlPO4 was facilitated through the carrier protein, with only weak binding of AlPO4 to CRM197 being observed. There was slightly higher binding of either adjuvant to tetanus toxoid conjugates, than to CRM197 conjugates. This was verified in AlPO4 formulations containing DTwP–Hib, where the adsorption of TT-conjugated Hib was higher than CRM197-conjugated Hib. At neutral pH, the anionic Hib and MenC polysaccharides did not appreciably bind to AlPO4, but did bind to Al(OH)3, due to electrostatic interactions. Phosphate ions reduced the binding of the conjugates to the adjuvants. These patterns of adjuvant adsorption can form the basis for future formulation studies with individual and combination vaccines containing saccharide-protein conjugates.

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Section: Discussionsupporting

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Patterns of binding of aluminum-containing adjuvants to Haemophilus influenzae type b and meningococcal group C conjugate vaccines and components

et al. 2015

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“…Stresses such as pH changes, temperature fluctuations, agitation, or light exposure can affect the stability and potency of vaccines. 28 , 29 Forced physical and chemical degradation studies are employed during the development of vaccines to elucidate potential causes and molecular mechanisms of degradation, develop stability-indicating methods, 28 and design stable formulations including pharmaceutical excipients 30 to minimize degradation. The major physical instability pathways of a vaccine constitute structural/conformational changes and aggregation of either the antigen or adjuvant.…”

Section: Discussionmentioning

confidence: 99%

Structural Characterization and Physicochemical Stability Profile of a Double Mutant Heat Labile Toxin Protein Based Adjuvant

Toprani

Hickey

Sahni

et al. 2017

Journal of Pharmaceutical Sciences

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A novel protein adjuvant double-mutant Escherichia coli heat-labile toxin, LT (R192G/L211A) or dmLT, is in preclinical and early clinical development with various vaccine candidates. Structural characterization and formulation development of dmLT will play a key role in its successful process development, scale-up/transfer, and commercial manufacturing. This work describes extensive analytical characterization of structural integrity and physicochemical stability profile of dmLT from a lyophilized clinical formulation. Reconstituted dmLT contained a heterogeneous mixture of intact holotoxin (AB5, ∼75%) and free B5 subunit (∼25%) as assessed by analytical ultracentrifugation and hydrophobic interaction chromatography. Intact mass spectrometry (MS) analysis revealed presence of Lys84 glycation near the native sugar-binding site in dmLT, and forced degradation studies using liquid chromatography-MS peptide mapping demonstrated specific Asn deamidation and Met oxidation sites. Using multiple biophysical measurements, dmLT was found most stable between pH 6.5 and 7.5 and at temperatures ≤50°C. In addition, soluble aggregates and particle formation were observed upon shaking stress. By identifying the physicochemical degradation pathways of dmLT using newly developed stability-indicating analytical methods from this study, we aim at developing more stable candidate formulations of dmLT that will minimize the formation of degradants and improve storage stability, as both a frozen bulk substance and eventually as a liquid final dosage form.

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“…While batches with a low titer need to be tested to safeguard efficacy of the vaccine at the end of shelf-life, it is equally important to assess the safety of batches with a titer as high as what may be expected when the batch is released. [17][18][19][20] As higher viral titers in a vaccine lot may theoretically lead to increased reactogenicity and safety concerns, the current study aimed to evaluate whether the safety profile of the MMR-RIT vaccine at an upper-range release titer (not tested thus far) was clinically acceptable. We therefore compared this upper-range release titer MMR-RIT lot with commercial lots of MMR II vaccine both administered in children 12-15 months of age together with varicella, hepatitis A, and pneumococcal conjugate vaccines, reflecting the standard of care in the US.…”

Section: Introductionmentioning

confidence: 99%

Safety and immunogenicity of an upper-range release titer measles-mumps-rubella vaccine in children vaccinated at 12 to 15 months of age: a phase III, randomized study

2018

Human Vaccines & Immunotherapeutics

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The titer of live attenuated viral vaccines, such as MMR vaccines, varies between batches and over the shelf-life of a batch, with the highest titer expected at batch release. As higher titers may theoretically lead to increased reactogenicity, we compared the safety profile of an upper-range release titer MMR-RIT lot with commercial MMR II lots in a phase III, randomized, controlled study (NCT02184572). We vaccinated 1736 children with MMR-RIT (N = 1164) or MMR II (N = 572), both administered as first doses with varicella, hepatitis A, and pneumococcal conjugate vaccines at 12-15 months of age. The incidence of fever 5-12 days post-vaccination was comparable following MMR-RIT and MMR II vaccination: 4.2% vs 3.1% (difference: 1.1%) for fever > 39.0°C and 18.2% vs 17.1% (difference: 1.1%) for fever ≥ 38.0°C, which met the primary objective. Two cases of febrile convulsions (one considered vaccination-related) were reported within 43 days post-MMR-RIT. During Days 0-42, rashes were reported for 24.4% (MMR-RIT) and 27.4% (MMR II) of children; measles/rubella-like rashes for 5.8% and 4.7%, respectively. Measles-like illnesses were reported for 1.5% (MMR-RIT) and 0.9% (MMR II) of children 5-12 days post-vaccination. One serious adverse event, immune thrombocytopenic purpura following MMR II vaccination, was considered vaccination-related. Immune responses were similar in both groups. In summary, the safety profile of an upper-range release titer MMR-RIT lot was in line with that of commercial MMR II lots, with similar rates of fever and other MMR-specific symptoms and low rates of measles-like illnesses reported with both vaccines.

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Guidelines on stability evaluation of vaccines

Cited by 26 publications

References 0 publications

Patterns of binding of aluminum-containing adjuvants to Haemophilus influenzae type b and meningococcal group C conjugate vaccines and components

Patterns of binding of aluminum-containing adjuvants to Haemophilus influenzae type b and meningococcal group C conjugate vaccines and components

Structural Characterization and Physicochemical Stability Profile of a Double Mutant Heat Labile Toxin Protein Based Adjuvant

Safety and immunogenicity of an upper-range release titer measles-mumps-rubella vaccine in children vaccinated at 12 to 15 months of age: a phase III, randomized study

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