Overcoming scientific barriers in the transition from in vivo to non-animal batch testing of human and veterinary vaccines

References

• De Gregorio E, Rappuoli R. From empiricism to rational design: a personal perspective of the evolution of vaccine development. Nat Rev Immunol. 2014;14(7):505–514.
   PubMed Web of Science ®Google Scholar
• Milstien J, Dellepiane N, Lambert S, et al. Vaccine quality—can a single standard be defined? Vaccine. 2002;20(7–8):1000–1003.
   PubMed Web of Science ®Google Scholar
• Commission to the European Parliament and the Council. 2019 Report on the Statistics on the Use of Animals for Scientific Purposes in the Member States of the European Union in 2015-2017.; 2020.
   Google Scholar
• Hendriksen C, Spieser JM, Akkermans A, et al. Validation of alternative methods for the potency testing of vaccines. Altern Lab Anim. 1998;26(6):747–761.
   PubMed Web of Science ®Google Scholar
• Milne C, Buchheit KH. EDQM’s 3R activities in the field of quality control of vaccines. ALTEX. 2012;1/12.
   Google Scholar
• Walker A, Srinivas GB. Opportunities and strategies to further reduce animal use for Leptospira vaccine potency testing. Biologicals. 2013;41(5):332–337.
   PubMed Web of Science ®Google Scholar
• Schiffelers MJ, Blaauboer B, Bakker W, et al., Replacing the NIH test for rabies vaccine potency testing: a synopsis of drivers and barriers. Biologicals. 2014;42(4): 205–217.
   PubMed Web of Science ®Google Scholar
• Servat A, Kempff S, Labadie A, et al. In vivo potency tests of rabies inactivated vaccines for veterinary use. A 2-year retrospective analysis of data according to the criteria of the European Pharmacopoeia. Pharmeur Bio Sci Notes. 2008;20:655–664.
   Google Scholar
• Goris N, Merkelbach-Peters P, Diev VI, et al. European Pharmacopoeia foot-and-mouth disease vaccine potency testing in cattle: between test variability and its consequences. Vaccine. 2007;25(17):3373–3379.
   PubMed Web of Science ®Google Scholar
• Reed NE, Varney WC, Goddard RD, et al. The maintenance of challenge strains used in the potency test for canine leptospira vaccines. Biologicals. 2000;28(1):25–28.
   PubMed Web of Science ®Google Scholar
• EDQM. General chapter 5.2.14 Substitution of in vivo methods by in vitro methods for the quality control of vaccines. In: European Pharmacopoeia. 10th ed. (p. 679) Strasbourgh France: European Department for the Quality of Medicines; 2019.
   Google Scholar
• Xing D, Das RG, O’Neill T, et al. Laboratory testing of whole cell pertussis vaccine: a WHO proficiency study using the Kendrick test. Vaccine. 2001;20(3):342–351.
   PubMed Web of Science ®Google Scholar
• Hendriksen C, Arciniega JL, Bruckner L, et al., The consistency approach for the quality control of vaccines. Biologicals. 2008;36(1):73–77.
   PubMed Web of Science ®Google Scholar
• De Mattia F, Hendriksen C, Buchheit KH, et al. The vaccines consistency approach project: an EPAA initiative. Pharmeur Bio Sci Notes. 2015;(2015):30–56.
   PubMedGoogle Scholar
• Bruysters MWP, Schiffelers MJ, Hoonakker M, et al. Drivers and barriers in the consistency approach for vaccine batch release testing: report of an international workshop. Biologicals. 2017; 48:1–5.
   Google Scholar
• The European. Parliament and the Council of the European Union. DIRECTIVE 2010/63/EU on the protection of animals used for scientific purposes. Off J Eur Union. 2010;276:33–79.
   Google Scholar
• EDQM. European Pharmacopoeia. 10.5th ed. Strasbourgh France: European Department for the Quality of Medicines; 2020.
   Google Scholar
• Halder M, Depraetere H, Delannois F, et al. Recommendations of the VAC2VAC workshop on the design of multi-centre validation studies. Biologicals. 2018;52:78–82.
   Google Scholar
• Shank-Retzlaff M, Wang F, Morley T, et al., Correlation between Mouse Potency and In Vitro Relative Potency for Human Papillomavirus Type 16 Virus-Like Particles and Gardasil Vaccine Samples. Hum Vaccin. 2005;1(5):191–197.
   PubMed Web of Science ®Google Scholar
• Descamps J, Giffroy D, Remy E, et al. A case study of development, validation, and acceptance of a non-animal method for assessing human vaccine potency. Procedia Vaccinol. 2011;5:184–191.
   Google Scholar
• Rosenbruch M. [The sensitivity of chicken embryos in incubated eggs]. ALTEX. 1997;14(3):111–113.
   PubMedGoogle Scholar
• Settembre EC, Dormitzer PR, Rappuoli R. Bringing influenza vaccines into the 21st century. Hum Vaccin Immunother. 2014;10(3):600–604.
   PubMed Web of Science ®Google Scholar
• Zariri A, Beskers J, van de Waterbeemd B, et al. Meningococcal outer membrane vesicle composition-dependent activation of the innate immune response. Palmer GH, ed. Infect Immun. 2016;84(10): 3024LP - 3033.
   PubMed Web of Science ®Google Scholar
• Vrieling H, Kooijman S, de Ridder JW, et al. Activation of human monocytes by colloidal aluminum salts. J Pharm Sci. 2020;109(1):750–760.
   PubMed Web of Science ®Google Scholar
• Tukhvatulin AI, Dzharullaeva AS, Tukhvatulina NM, et al. Powerful complex immunoadjuvant based on synergistic effect of combined TLR4 and NOD2 activation significantly enhances magnitude of humoral and cellular adaptive immune responses. PLoS One. 2016;11(5):e0155650.
   PubMed Web of Science ®Google Scholar
• Maas RA, Komen M, Van Diepen M, et al. Correlation of haemagglutinin-neuraminidase and fusion protein content with protective antibody response after immunisation with inactivated Newcastle disease vaccines. Vaccine. 2003;21(23):3137–3142.
   PubMed Web of Science ®Google Scholar
• Pay TWF, Hingley PJ. Correlation of 140S antigen dose with the serum neutralizing antibody response and the level of protection induced in cattle by foot-and-mouth disease vaccines. Vaccine. 1987;5(1):60–64.
   PubMed Web of Science ®Google Scholar
• Poston R, Hill R, Allen C, et al. Achieving scientific and regulatory success in implementing non-animal approaches to human and veterinary rabies vaccine testing: a NICEATM and IABS workshop report. Biologicals. 2019;60:8-14.
   Google Scholar
• Poirier B, Morgeaux S, Variot P, et al. In vitro potency assay for hepatitis A vaccines: development of a unique economical test. Biologicals. 2000;28(4):247–256.
   PubMed Web of Science ®Google Scholar
• Maas PA, MPM DW, Venema S, et al. Antigen quantification as in vitro alternative for potency testing of inactivated viral poultry vaccines. Vet Q. 2000;22(4):223–227.
   Web of Science ®Google Scholar
• Romstad AB, Reitan LJ, Midtlyng P, et al. Antibody responses correlate with antigen dose and in vivo protection for oil-adjuvanted, experimental furunculosis (Aeromonas salmonicida subsp. salmonicida) vaccines in Atlantic salmon (Salmo salar L.) and can be used for batch potency testing of vaccin. Vaccine. 2013;31(5):791–796.
   PubMed Web of Science ®Google Scholar
• Coombes L, Tierney R, Rigsby P, et al. In vitro antigen ELISA for quality control of tetanus vaccines. Biologicals. 2012;40(6):466–472.
   PubMed Web of Science ®Google Scholar
• Riches-Duit R, Hassall L, Rigsby P, et al. Evaluation of a capture antigen ELISA for the characterisation of tetanus vaccines for veterinary use. Biologicals. 2019;61:8–14.
   PubMed Web of Science ®Google Scholar
• Coombes L, Stickings P, Tierney R, et al. Development and use of a novel in vitro assay for testing of diphtheria toxoid in combination vaccines. J Immunol Methods. 2009;350(1–2):142–149.
   PubMed Web of Science ®Google Scholar
• Westdijk J, Metz B, Spruit N, et al. Antigenic fingerprinting of diphtheria toxoid adsorbed to aluminium phosphate. Biologicals. 2017;47:69–75.
   PubMed Web of Science ®Google Scholar
• Minor PD. Assaying the potency of influenza vaccines. Vaccines (Basel). 2015;3(1):90–104.
   PubMed Web of Science ®Google Scholar
• Westdijk J, van den Ijssel J, Thalen M, et al. Quantification of cell-associated and free antigens in Bordetella pertussis suspensions by antigen binding ELISA. J Immunoassay. 1997;18(3):267–284.
   PubMedGoogle Scholar
• Agnolon V, Bruno C, Galletti B, et al. Multiplex immunoassay for in vitro characterization of acellular pertussis antigens in combination vaccines. Vaccine. 2016;34(8):1040–1046.
   PubMed Web of Science ®Google Scholar
• Hoonakker ME, Verhagen LM, Pupo E, et al., Vaccine-mediated activation of human TLR4 is affected by modulation of culture conditions during whole-cell pertussis vaccine preparation. PLoS One. 2016;11(8): e0161428.
   PubMed Web of Science ®Google Scholar
• Hoonakker ME, Verhagen LM, Hendriksen CFM, et al. In vitro innate immune cell based models to assess whole cell Bordetella pertussis vaccine quality: a proof of principle. Biologicals. 2015;43(2):100–109.
   PubMed Web of Science ®Google Scholar
• Metz B, Hoonakker M, Uittenbogaard JP, et al., Proteome analysis is a valuable tool to monitor antigen expression during upstream processing of whole-cell pertussis vaccines. J Proteome Res. 2017;16(2):528–537.
   PubMed Web of Science ®Google Scholar
• Maloney T, Phelan R, Simmons N. Saving the horseshoe crab: a synthetic alternative to horseshoe crab blood for endotoxin detection. PLoS Biol. 2018;16(10):e2006607.
   PubMed Web of Science ®Google Scholar
• Smith DR, Beekey MA, Brockmann HJ, et al. Limulus polyphemus. IUCN Red List Threatened Species. 2016;2016:e.T11987A80159830.
   Google Scholar
• Etna MP, Giacomini E, Rizzo F, et al. Optimization of the monocyte-activation-test for evaluating pyrogenicity of tick-borne encephalitis virus vaccine. ALTEX. 2020;37(4):532-544.
   PubMedGoogle Scholar
• Hasiwa N, Daneshian M, Bruegger P, et al. T4 Report evidence for the detection of non-endotoxin pyrogens by the whole blood monocyte activation test. ALTEX. 2013;30(2):169–208.
   PubMedGoogle Scholar
• Studholme L, Sutherland J, Desai T, et al. Evaluation of the monocyte activation test for the safety testing of meningococcal B vaccine Bexsero: a collaborative study. Vaccine. 2019;37(29):3761–3769.
   PubMed Web of Science ®Google Scholar
• Isbrucker R, Daas A, Wagner L, et al. Transferability study of CHO cell clustering assays for monitoring of pertussis toxin activity in acellular pertussis vaccines. Pharmeur Bio Sci Notes. 2016;2015:97–114.
   PubMedGoogle Scholar
• Sesardic D, Prior C, Daas A, et al. Collaborative study for establishment of the European Pharmacopoeia BRP batch 1 for diphtheria toxin. Pharmeuropa bio. (2003);2003(1):5–21
   PubMedGoogle Scholar
• Daas A, Behr-Gross ME, Bruckner L, et al. Collaborative study for the validation of cell line assays for in-process toxicity and antigenicity testing of Clostridium septicum vaccine antigens - Part 1. Pharmeur Bio Sci Notes. 2020;2020:53–124.
   PubMedGoogle Scholar
• Behrensdorf-Nicol HA, Weisser K, Krämer B. “BINACLE” assay for in vitro detection of active tetanus neurotoxin in toxoids. ALTEX. 2015;32(2):137–142.
   PubMedGoogle Scholar
• Committee for Human Medicinal Products - European Medicines Agency. ICH guideline Q8 (R2) on pharmaceutical development. 2017:1–24
   Google Scholar
• Clough NEC, Hauer PJ. Using polyclonal and monoclonal antibodies in regulatory testing of biological products. ILAR J. 2005;46(3):300–306.
   PubMed Web of Science ®Google Scholar
• Claassen I, Maas R, Daas A, et al. Feasibility study to evaluate the correlation between results of a candidate in vitro assay and established in vivo assays for potency determination of Newcastle disease vaccines. Pharmeuropa bio. 2003;2003(1):51–66
   PubMedGoogle Scholar
• Stokes W, McFarland R, Kulpa-Eddy J, et al. Report on the international workshop on alternative methods for human and veterinary rabies vaccine testing: state of the science and planning the way forward. Biologicals. 2012;40(5):369–381.
   PubMed Web of Science ®Google Scholar
• Geeraedts F, Ter Veer W, Wilschut J. ter Veer W, Wilschut J, et al. Effect of viral membrane fusion activity on antibody induction by influenza H5N1 whole inactivated virus vaccine. Vaccine. 2012;30(45):6501–6507.
   PubMed Web of Science ®Google Scholar
• Jagt HJM, Bekkers MLE, SAJT VB, et al., The influence of the inactivating agent on the antigen content of inactivated Newcastle disease vaccines assessed by the in vitro potency test. Biologicals;2010;38(1):128–134.
   PubMed Web of Science ®Google Scholar
• Metz B, Tilstra W, van der Put R, et al. Physicochemical and immunochemical assays for monitoring consistent production of tetanus toxoid. Biologicals. 2013;41(4):231–237.
   PubMed Web of Science ®Google Scholar
• Stalder J, Costanzo A, Daas A, et al. Establishment of a biological reference preparation for hepatitis A vaccine (inactivated, non-adsorbed). Pharmeur Bio Sci Notes. 2020;2010(1):15–29.
   Google Scholar
• van de Waterbeemd B, Streefland M, Pennings J, et al. Gene-expression-based quality scores indicate optimal harvest point in Bordetella pertussis cultivation for vaccine production. Biotechnol Bioeng. 2009;103(5):900–908.
   PubMed Web of Science ®Google Scholar
• Egger M, Jürets A, Wallner M, et al. Assessing protein immunogenicity with a dendritic cell line-derived endolysosomal degradome. PLoS One. 2011;6(2):e17278.
   PubMed Web of Science ®Google Scholar
• Michiels TJM, Meiring HD, Jiskoot W, et al. Formaldehyde treatment of proteins enhances proteolytic degradation by the endo-lysosomal protease cathepsin S. Sci Rep. 2020;10(1):11535.
   PubMed Web of Science ®Google Scholar
• Michiels TJM, Tilstra W, Hamzink MRJ, et al. Degradomics-based analysis of tetanus toxoids as a quality control assay. Vaccines (Basel). 2020;8(4):712.
   Web of Science ®Google Scholar
• Hagenaars N, Mastrobattista E, Glansbeek H, et al., Head-to-head comparison of four nonadjuvanted inactivated cell culture-derived influenza vaccines: effect of composition, spatial organization and immunization route on the immunogenicity in a murine challenge model. Vaccine.2008;26(51):6555–6563.
   PubMed Web of Science ®Google Scholar
• Geeraedts F, Goutagny N, Hornung V, et al. Superior immunogenicity of inactivated whole virus H5N1 influenza vaccine is primarily controlled by toll-like receptor signalling. Subbarao K, ed. PLoS Pathog. 2008;4(8):e1000138.
   PubMed Web of Science ®Google Scholar
• Bernstein DI, Zahradnik JM, DeAngelis CJ, et al. Clinical reactions and serologic responses after vaccination with whole-virus or split-virus influenza vaccines in children aged 6 to 36 months. Pediatrics. 1982;69:4.
   PubMed Web of Science ®Google Scholar
• Halbroth BR, Heil A, Distler E, et al. Superior in vitro stimulation of human CD8+ T-cells by whole virus versus split virus influenza vaccines. Stambas J, ed. PLoS One. 2014;9(7):e103392.
   PubMed Web of Science ®Google Scholar
• Hampson AW. Vaccines for pandemic influenza. The history of our current vaccines, their limitations and the requirements to deal with a pandemic threat. Ann Acad Med Singapore. 2008;37(6):510–517.
   PubMed Web of Science ®Google Scholar
• Bachmann MF, Jennings GT. Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns. Nat Rev Immunol. 2010;10(11):787–796.
   PubMed Web of Science ®Google Scholar
• Reynolds DL, Maraqa AD. Protective immunity against Newcastle disease: the role of cell-mediated immunity. Avian Dis. 2000;44(1):145–154.
   PubMed Web of Science ®Google Scholar
• Higgins SC, Jarnicki AG, Lavelle EC, et al. TLR4 mediates vaccine-induced protective cellular immunity to bordetella pertussis : role of IL-17-producing T cells. J Immunol. 2006;177(11):7980–7989.
   PubMed Web of Science ®Google Scholar
• Herrera-Rodriguez J, Signorazzi A, Holtrop M, et al. Inactivated or damaged? Comparing the effect of inactivation methods on influenza virions to optimize vaccine production. Vaccine. 2019;37(12):1630–1637.
   PubMed Web of Science ®Google Scholar
• Viviani L, Halder M, Gruber M, et al. Global harmonization of vaccine testing requirements: making elimination of the ATT and TABST a concrete global achievement. Biologicals. 2020;63:101-105.
   Google Scholar
• Garbe JHO, Ausborn S, Beggs C, et al. Historical data analyses and scientific knowledge suggest complete removal of the abnormal toxicity test as a quality control test. J Pharm Sci. 2014;103(11):3349–3355.
   PubMed Web of Science ®Google Scholar
• Spohr C, Kaufmann E, Battenfeld S, et al. A New Lymphocyte Proliferation Assay for Potency Determination of Bovine Tuberculin PPDs Supplementary Data. ALTEX. 2015;32(3):201–210.
   PubMedGoogle Scholar
• Neverov A, Chumakov K. Massively parallel sequencing for monitoring genetic consistency and quality control of live viral vaccines. Proc Natl Acad Sci. 2010;107(46): 20063LP - 20068.
   PubMed Web of Science ®Google Scholar
• Charlton B, Hockley J, Laassri M, et al. The use of next-generation sequencing for the quality control of live-attenuated polio vaccines. J Infect Dis. 2020;222(11):1920–1927.
   PubMed Web of Science ®Google Scholar
• Da Costa A, Prehaud C, Khou C, et al. Innovative in cellulo method as an alternative to in vivo neurovirulence test for the characterization and quality control of human live Yellow Fever virus vaccines: a pilot study. Biologicals. 2018;53:19–29.
   PubMed Web of Science ®Google Scholar
• Szymkowicz L, Wilson DJ, James DA. Development of a targeted nanoLC-MS/MS method for quantitation of residual toxins from Bordetella pertussis. J Pharm Biomed Anal. 2020;188:113395.
   PubMed Web of Science ®Google Scholar
• Akkermans A, Chapsal JM, Coccia EM, et al. Animal testing for vaccines. Implementing replacement, reduction and refinement: challenges and priorities. Biologicals. 2020;68:92–107.
   PubMed Web of Science ®Google Scholar
• Vandebriel R, Hoefnagel MMN. Dendritic cell-based in vitro assays for vaccine immunogenicity. Hum Vaccin Immunother. 2012;8(9):1323–1325.
   PubMed Web of Science ®Google Scholar
• Stoel M, Pool J, de Vries-Idema J, et al. Innate responses induced by whole inactivated virus or subunit influenza vaccines in cultured dendritic cells correlate with immune responses in vivo. PLoS One. 2015;10(5):e0125228.
   PubMed Web of Science ®Google Scholar
• Tapia-Calle G, Stoel M, de Vries-Idema J, et al. Distinctive responses in an in vitro human dendritic cell-based system upon stimulation with different influenza vaccine formulations. Vaccines (Basel). 2017;5(3):21.
   Web of Science ®Google Scholar
• Hoefnagel MHN, Vermeulen JP, Scheper RJ, et al. Response of MUTZ-3 dendritic cells to the different components of the Haemophilus influenzae type B conjugate vaccine: towards an in vitro assay for vaccine immunogenicity. Vaccine. 2011;29(32):5114–5121.
   PubMed Web of Science ®Google Scholar
• Querec T, Bennouna S, Alkan S, et al. Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity. J Exp Med. 2006;203(2):413–424.
   PubMed Web of Science ®Google Scholar
• Brummelman J, Veerman RE, Hamstra HJ, et al.Bordetella pertussis naturally occurring isolates with altered lipooligosaccharide structure fail to fully mature human dendritic cells.Ba M,editor.Infect Immun. 2015;83(1):227–238
   PubMed Web of Science ®Google Scholar
• Hovingh ES, Van Gent M, Hamstra H-J, et al. Emerging Bordetella pertussis strains induce enhanced signaling of human pattern recognition receptors TLR2, NOD2 and secretion of IL-10 by dendritic cells. Hozbor DF, ed. PLoS One. 2017;12(1):e0170027.
   PubMed Web of Science ®Google Scholar
• Hoffmann S, Peterbauer A, Schindler S, et al. International validation of novel pyrogen tests based on human monocytoid cells. J Immunol Methods. 2005;298(1–2):161–173.
   PubMed Web of Science ®Google Scholar
• Zaitseva M, Romantseva T, Blinova K, et al., Use of human MonoMac6 cells for development of in vitro assay predictive of adjuvant safety in vivo. Vaccine. 30(32): 4859–4865. 2012.
   PubMed Web of Science ®Google Scholar
• Zhu J, Yamane H, Paul WE. Differentiation of effector CD4+ T cell populations. Annu Rev Immunol. 2010;28(1):445–489.
   PubMed Web of Science ®Google Scholar
• Bent R, Moll L, Grabbe S, et al. Interleukin-1 beta—A friend or foe in malignancies. Int J Mol Sci. 2018;19(8):2155.
   PubMed Web of Science ®Google Scholar
• Hoonakker ME, Verhagen LM, van der Maas L, et al., Adaptive immune response to whole cell pertussis vaccine reflects vaccine quality: a possible complementation to the pertussis serological potency test. Vaccine. 2016;34(37): 4429–4436.
   PubMed Web of Science ®Google Scholar
• Joffret ML, Zanetti C, Morgeaux S, et al. Appraisal of rabies vaccine potency by determination of in vitro, specific interleukin-2 production. Biologicals. 1991;19(2):113–123.
   PubMed Web of Science ®Google Scholar
• Moser JM, Sassano ER, Leistritz DC, et al. Optimization of a dendritic cell-based assay for the in vitro priming of naïve human CD4+ T cells. J Immunol Methods. 2010;353(1–2):8–19.
   PubMed Web of Science ®Google Scholar
• Tapia-Calle G, Born PA, Koutsoumpli G, et al. A PBMC-based system to assess human T cell responses to influenza vaccine candidates in vitro. Vaccines (Basel). 2019;7(4):181.
   Web of Science ®Google Scholar
• Kangethe RT, Pichler R, Chuma FNJ, et al. Bovine monocyte derived dendritic cell based assay for measuring vaccine immunogenicity in vitro. Vet Immunol Immunopathol. 2018;197:39–48.
   PubMed Web of Science ®Google Scholar
• Yu SCT, Nag B. Application of murine T-T hybridoma cells to in vitro potency assay of human synthetic peptide vaccines. Vaccine. 1996;14(14):1313–1321.
   PubMed Web of Science ®Google Scholar
• Ise W, Inoue T, McLachlan JB, et al. Memory B cells contribute to rapid Bcl6 expression by memory follicular helper T cells. Proc Natl Acad Sci U S A. 2014;111(32):11792–11797.
   PubMed Web of Science ®Google Scholar
• Marrack P, McKee AS, Munks MW. Towards an understanding of the adjuvant action of aluminium. Nat Rev Immunol. 2009;9(4):287–293.
   PubMed Web of Science ®Google Scholar
• Spickler AR, Roth JA. Adjuvants in veterinary vaccines: modes of action and adverse effects. J Vet Intern Med. 2003;17(3):273–281.
   PubMed Web of Science ®Google Scholar
• Freund J, Casals J, Hosmer EP. Sensitization and antibody formation after injection of tubercle bacilli and paraffin oil. Proc Soc Exp Biol Med. 1937;37(3):509–513.
   Google Scholar
• Di Pasquale A, Preiss S, Da Silva FT, et al. Vaccine adjuvants: from 1920 to 2015 and beyond. Vaccines (Basel). 2015;3(2):320–343.
   PubMed Web of Science ®Google Scholar
• Van Doorn E, Liu H, Huckriede A, et al. Safety and tolerability evaluation of the use of Montanide ISA™51 as vaccine adjuvant: a systematic review. Hum Vaccines Immunother. 2016;12(1):159–169.
   PubMed Web of Science ®Google Scholar
• O’Hagan DT, Ott GS, Van Nest G, et al. The history of MF59 ® adjuvant: a phoenix that arose from the ashes. Expert Rev Vaccines. 2013;12(1):13–30.
   PubMed Web of Science ®Google Scholar
• Misquith A, Fung HWM, Dowling QM, et al. In vitro evaluation of TLR4 agonist activity: formulation effects. Colloids Surf B Biointerfaces. 2014;113:312–319.
   PubMed Web of Science ®Google Scholar
• Stokes W, Srinivas G, McFarland R, et al. Report on the international workshop on alternative methods for Leptospira vaccine potency testing: state of the science and the way forward. Biologicals. 2013;41(5):279–294.
   PubMed Web of Science ®Google Scholar
• Claassen I, Maas R, Oei H, et al. Validation study to evaluate the reproducibility of a candidate in vitro potency assay of newcastle disease vaccines and to establish the suitability of a candidate biological reference preparation. Pharmeuropa bio. 2004;2004(1):1–15
   PubMedGoogle Scholar
• van den Biggelaar RHGA, van Eden W, Rutten VPMG, et al. Macrophage activation assays to evaluate the immunostimulatory capacity of Avibacterium paragallinarum in a multivalent poultry vaccine. Vaccines (Basel). 2020;8(4):671.
   Web of Science ®Google Scholar
• Saravanan P, Iqbal Z, Selvaraj DPR, et al., Comparison of chemical extraction methods for determination of 146S content in foot-and-mouth disease oil-adjuvanted vaccine. J Appl Microbiol. 2020;128(1): 65–73.
   PubMed Web of Science ®Google Scholar
• Morgenroth A, Jakel V, Hanke-Robinson H, et al. A novel electrophoretic immunoblot as antigen desorption and quantification method for alum-adjuvanted veterinary rabies vaccines. Vaccine. 2020;38(27):4281–4287.
   PubMed Web of Science ®Google Scholar
• Rinella JV, Workman RF, Hermodson MA, et al. Elutability of proteins from aluminum-containing vaccine adjuvants by treatment with surfactants. J Colloid Interface Sci. 1998;197(1):48–56.
   PubMed Web of Science ®Google Scholar
• Wood D, Sands D, Heath A. Collaborative study for the establishment of three product specific European Pharmacopoeia biological reference preparations for inactivated adsorbed hepatitis A vaccines. Pharmeur Bio Sci Notes. 2000;2000(1):51–80.
   Google Scholar
• Byrne-Nash RT, Miller DF, Bueter KM, et al. VaxArray potency assay for rapid assessment of “pandemic” influenza vaccines. Npj Vaccines. 2018;3(1):43.
   PubMed Web of Science ®Google Scholar
• Song Y, Yang Y, Lin X, et al. In-situ and sensitive stability study of emulsion and aluminum adjuvanted inactivated foot-and-mouth disease virus vaccine by differential scanning fluorimetry analysis. Vaccine. 2020;38(14):2904–2912.
   PubMed Web of Science ®Google Scholar
• Nouchikian L, Roque C, Song JY, et al. An intrinsic fluorescence method for the determination of protein concentration in vaccines containing aluminum salt adjuvants. Vaccine. 2018;36(38):5738–5746.
   PubMed Web of Science ®Google Scholar
• Zhu D, Saul A, Huang S, et al. Use of o-phthalaldehyde assay to determine protein contents of Alhydrogel-based vaccines. Vaccine. 2009;27(43):6054–6059.
   PubMed Web of Science ®Google Scholar
• Amari JV, Levesque P, Lian Z, et al. Concentration determination of a recombinant vaccine antigen adsorbed onto an alum adjuvant by chemiluminescent nitrogen detection. Pharm Res. 2005;22(1):33–37.
   PubMed Web of Science ®Google Scholar
• van den Biggelaar RHGA, van Eden W, Rutten VPMG, et al. Nitric oxide production and Fc receptor-mediated phagocytosis as functional readouts of macrophage activity upon stimulation with inactivated poultry vaccines in vitro. Vaccines (Basel). 2020;8(2):332.
   Web of Science ®Google Scholar
• Da Silva M, Labas V, Nys Y, et al. Investigating proteins and proteases composing amniotic and allantoic fluids during chicken embryonic development. Poult Sci. 2017;96(8):2931–2941.
   PubMed Web of Science ®Google Scholar
• Katz JB, Hanson SK, Patterson PA, et al. In vitro assessment of viral antigen content in inactivated aluminum hydroxide adjuvanted vaccines. J Virol Methods. 1989;25(1):101–108.
   PubMed Web of Science ®Google Scholar
• Necchi F, Carducci M, Pisoni I, et al. Development of FAcE (Formulated Alhydrogel competitive ELISA) method for direct quantification of OAg present in Shigella sonnei GMMA-based vaccine and its optimization using Design of Experiments approach. J Immunol Methods. 2019;471:11–17.
   PubMed Web of Science ®Google Scholar
• Zhu D, Huang S, Gebregeorgis E, et al. Development of a direct alhydrogel formulation immunoassay (DAFIA). J Immunol Methods. 2009;344(1):73–78.
   PubMed Web of Science ®Google Scholar
• Li M, Wang X, Cao L, et al. Quantitative and epitope-specific antigenicity analysis of the human papillomavirus 6 capsid protein in aqueous solution or when adsorbed on particulate adjuvants. Vaccine. 2016;34(37):4422–4428.
   PubMed Web of Science ®Google Scholar
• Ugozzoli M, Laera D, Nuti S, et al. Flow cytometry: an alternative method for direct quantification of antigens adsorbed to aluminum hydroxide adjuvant. Anal Biochem. 2011;418(2):224–230.
   PubMed Web of Science ®Google Scholar
• Gibert R, Alberti M, Poirier B, et al. A relevant in vitro ELISA test in alternative to the in vivo NIH test for human rabies vaccine batch release. Vaccine. 2013;31(50):6022–6029.
   PubMed Web of Science ®Google Scholar
• Stalpers CAL, Retmana IA, Pennings JLA, et al. Variability of in vivo potency tests of Diphtheria, Tetanus and acellular Pertussis (DTaP) vaccines. Vaccine. 2021;39(18):2506–2516.
   PubMed Web of Science ®Google Scholar
• Chabaud-Riou M, Moreno N, Guinchard F, et al. G-protein based ELISA as a potency test for rabies vaccines. Biologicals. 2017;46:124–129.
   PubMed Web of Science ®Google Scholar
• Toinon A, Moreno N, Chausse H, et al. Potency test to discriminate between differentially over-inactivated rabies vaccines: agreement between the NIH assay and a G-protein based ELISA. Biologicals. 2019;60:49–54.
   PubMed Web of Science ®Google Scholar
• Vac2vac.eu [Internet]. London, UK: Manta Ray Media; [2021 August 03]. Available from: http://www.vac2vac.eu/
   Google Scholar
• Schiffelers MJWA, Blaauboer BJ, Bakker WE, et al. Regulatory acceptance and use of serology for inactivated veterinary rabies vaccines. ALTEX. 2015;32(3):211–221.
   PubMedGoogle Scholar