Dose finding for new vaccines: The role for immunostimulation/immunodynamic modelling

Sophie J Rhodes, Gwenan M Knight, Denise E Kirschner, Richard G White, Thomas G Evans, Sophie J Rhodes, Gwenan M Knight, Denise E Kirschner, Richard G White, Thomas G Evans

Abstract

Current methods to optimize vaccine dose are purely empirically based, whereas in the drug development field, dosing determinations use far more advanced quantitative methodology to accelerate decision-making. Applying these established methods in the field of vaccine development may reduce the currently large clinical trial sample sizes, long time frames, high costs, and ultimately have a better potential to save lives. We propose the field of immunostimulation/immunodynamic (IS/ID) modelling, which aims to translate mathematical frameworks used for drug dosing towards optimizing vaccine dose decision-making. Analogous to Pharmacokinetic/Pharmacodynamic (PK/PD) modelling, the mathematical description of drug distribution (PK) and effect (PD) in host, IS/ID modelling approaches apply mathematical models to describe the underlying mechanisms by which the immune response is stimulated by vaccination (IS) and the resulting measured immune response dynamics (ID). To move IS/ID modelling forward, existing datasets and further data on vaccine allometry and dose-dependent dynamics need to be generated and collate, requiring a collaborative environment with input from academia, industry, regulators, governmental and non-governmental agencies to share modelling expertise, and connect modellers to vaccine data.

Keywords: Immune response; Mathematical modelling; Vaccine development; Vaccine dose optimization.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Figures

Fig. 1.
Fig. 1.
Schema depicting the steps required to incorporate immunostimulation (IS) /immunodynamic (ID) modeling into vaccine development.

References

    1. Aagaard C, Hoang T, Dietrich J, Cardona PJ, Izzo A, Dolganov G, Andersen P, 2011. A multistage tuberculosis vaccine that confers efficient protection before and after exposure. Nat. Med. 17 (2), 189–194. doi:10.1038/nm.2285.
    1. Aagaard C, Hoang TT, Izzo A, Billeskov R, Troudt J, Arnett K, Dietrich J, 2009. Protection and polyfunctional T cells induced by Ag85B-TB10.4/IC31 against Mycobacterium tuberculosis is highly dependent on the antigen dose. PLoS One 4 (6), e5930. doi:10.1371/journal.pone.0005930.
    1. Aarons L, Ogungbenro K, 2010. Optimal design of pharmacokinetic studies. Basic Clin. Pharmacol. Toxicol. 106 (3), 250–255. doi:10.1111/j.1742-7843.2009.00533.x.
    1. Baldi E, Bucherelli C, 2005. The inverted “u-shaped” dose-effect relationships in learning and memory: modulation of arousal and consolidation. Nonlinearity Biol. Toxicol. Med. 3 (1), 9–21. doi:10.2201/nonlin.003.01.002.
    1. Billeskov R, Lindenstrom T, Woodworth J, Vilaplana C, Cardona PJ, Cassidy JP, Andersen P, 2017. High antigen dose is detrimental to post-exposure vaccine protection against tuberculosis. Front Immunol. 8, 1973. doi:10.3389/fimmu.2017.01973.
    1. Campi-Azevedo AC, de Almeida Estevam P, Coelho-Dos-Reis JG, Peruhype-Magalhaes V, Villela-Rezende G, Quaresma PF, Martins-Filho OA, 2014. Subdoses of 17DD yellow fever vaccine elicit equivalent virological/immunological kinetics timeline. BMC Infect. Dis. 14 (391), 1–12. doi:10.1186/1471-2334-14-391.
    1. Darrah PA, Patel DT, De Luca PM, Lindsay RW, Davey DF, Flynn BJ, Seder RA, 2007. Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major. Nat. Med. 13 (7), 843–850. doi:10.1038/nm1592.
    1. Dickson M, Gagnon JP, 2004. The cost of new drug discovery and development. Discov. Med. 4 (22), 172–179.
    1. Evans TG. McElrath MJ. Matthews T. Montefiori D. Weinhold K. Wolff M, Group NAVE. 2001. QS-21 promotes an adjuvant effect allowing for reduced antigen dose during HIV-1 envelope subunit immunization in humans. Vaccine 19 (15–16), 2080–2091.
    1. Fletcher HA, Tanner R, Wallis RS, Meyer J, Manjaly ZR, Harris S, McShane H, 2013. Inhibition of mycobacterial growth in vitro following primary but not secondary vaccination with Mycobacterium bovis BCG. Clin. Vaccine Immunol. 20 (11), 1683–1689. doi:10.1128/CV1.00427-13.
    1. Guerin PJ, Naess LM, Fogg C, Rosenqvist E, Pinoges L, Bajunirwe F, Caugant DA, 2008. Immunogenicity of fractional doses of tetravalent a/c/y/w135 meningococcal polysaccharide vaccine: results from a randomized non-inferiority controlled trial in Uganda. PLoS Negl. Trop. Dis. 2 (12), e342. doi:10.1371/journal.pntd.0000342.
    1. Han JE, Kim HK, Park SA, Lee SJ, Kim HJ, Son GH, Lee NG, 2010. A non-toxic derivative of lipopolysaccharide increases immune responses to Gardasil HPV vaccine in mice. Int. Immunopharmacol. 10 (2), 169–176. doi:10.1016/j.intimp.2009.10.012.
    1. Han S, 2015. Clinical vaccine development. Clin. Exp. Vaccine Res. 4 (1), 46–53. doi:10.7774/cevr.2015.4.1.46.
    1. Hassett KJ, Meinerz NM, Semmelmann F, Cousins MC, Garcea RL, Randolph TW, 2015. Development of a highly thermostable, adjuvanted human papillomavirus vaccine. Eur. J. Pharm. Biopharm. 94, 220–228. doi:10.1016/j.ejpb.2015.05.009.
    1. Joslyn LR, Pienaar E, DiFazio RM, Suliman S, Kagina BM, Flynn JL, Kirschner DE, 2018. Integrating non-human primate, human, and mathematical studies to determine the influence of BCG timing on H56 vaccine outcomes. Front. Microbiol. 9, 1–6. ARTN 1734. doi:10.3389/fmicb.2018.01734.
    1. Kimko H, Pinheiro J, 2014. Model-based clinical drug development in the past, present & future: a commentary. Br. J. Clin. Pharmacol. doi:10.1111/bcp.12341.
    1. Lenz N, Schindler T, Kagina BM, Zhang JD, Lukindo T, Mpina M, Daubenberger CA, 2015. Antiviral innate immune activation in H1V-infected adults negatively affects H1/1C31-induced vaccine-specific memory CD4+ T cells. Clin. Vaccine 1mmunol. 22 (7), 688–696. doi:10.1128/CVI.00092-15.
    1. Loxton AG, Knaul JK, Grode L, Gutschmidt A, Meller C, Eisele B, Group VPMS, 2017. Safety and immunogenicity of the recombinant mycobacterium bovis BCG vaccine VPM1002 in HIV-unexposed newborn infants in South Africa. Clin. Vaccine 1mmunol. 24 (2). doi:10.1128/CVI.00439-16.
    1. Luabeya AK, Kagina BM, Tameris MD, Geldenhuys H, Hoff ST, Shi Z, Hussey GD, 2015. First-in-human trial of the post-exposure tuberculosis vaccine H56:IC31 in Mycobacterium tuberculosis infected and non-infected healthy adults. Vaccine 33 (33), 4130–4140. doi:10.1016/j.vaccine.2015.06.051.
    1. Martins RM, Mde, Maia L, Farias H,R, Camacho LA, Freire MS, Galler R, Homma A, 2013. 17DD yellow fever vaccine: a double blind, randomized clinical trial of immunogenicity and safety on a dose-response study. Hum. Vaccin Immunother. 9 (4), 879–888. doi:10.4161/hv.22982.
    1. Nassim C, Christensen S, Henry D, Holmes S, Hohenboken M, Kanesa-Thasan N, 2012. Identification of antigen and adjuvant doses resulting in optimal immunogenicity and antibody persistence up to one year after immunization with a pandemic A/H1N1 influenza vaccine in children 3 to <9 years of age. Pediatr. Infect. Dis. J. doi:10.1097/INF.0b013e3180343104.
    1. Norrby M, Vesikari T, Lindqvist L, Maeurer M, Ahmed R, Mahdavifar S, Brighenti S, 2017. Safety and immunogenicity of the novel H4:IC31 tuberculosis vaccine candidate in BCG-vaccinated adults: two phase I dose escalation trials. Vaccine 35 (12), 1652–1661. doi:10.1016/j.vaccine.2017.01.055.
    1. Ophorst OJ, Radosevic K, Havenga MJ, Pau MG, Holterman L, Berkhout B, Tsuji M, 2006. Immunogenicity and protection of a recombinant human adenovirus serotype 35-based malaria vaccine against Plasmodium yoelii in mice. Infect. Immun. 74 (1), 313–320. doi:10.1128/IAI.74.1.313-320.2006.
    1. Pienaar E, Dartois V, Linderman JJ, Kirschner DE, 2015. In silico evaluation and exploration of antibiotic tuberculosis treatment regimens. BMC Syst. Biol. 9, 79. doi:10.1186/s12918-015-0221-8.
    1. Plotkin SA, 2008. Vaccines: correlates of vaccine-induced immunity. Clin. Infect. Dis. 47 (3), 401–409. doi:10.1086/589862.
    1. Plotkin SA, Orenstein WA, Offit PA, 2013. Vaccines, 6 ed. Saunders.
    1. Regules JA, Cicatelli SB, Bennett JW, Paolino KM, Twomey PS, Moon JE, Vekemans J, 2016. Fractional third and fourth dose of RTS,S/AS01 malaria candidate vaccine: a phase 2a controlled human malaria parasite infection and immunogenicity study. J. Infect. Dis. 214 (5), 762–771. doi:10.1093/infdis/jiw237.
    1. Reither K, Katsoulis L, Beattie T, Gardiner N, Lenz N, Said K, Churchyard GJ, 2014. Safety and immunogenicity of H1/IC31(R), an adjuvanted TB subunit vaccine, in HIV-infected adults with CD4+ Lymphocyte counts greater than 350 cells/mm3: a phase II, multi-centre, double-blind, randomized, placebo-controlled trial. PLoS One 9 (12), e114602. doi:10.1371/journal.pone.0114602.
    1. Rhodes SJ, Guedj J, Fletcher HA, Lindenstrom T, Scriba TJ, Evans TG, White RG, 2018. Using vaccine Immunostimulation/Immunodynamic modelling methods to inform vaccine dose decision-making. NPJ Vaccines 3, 36. doi:10.1038/s41541-018-0075-3.
    1. Rhodes SJ, Zelmer A, Knight GM, Prabowo SA, Stockdale L, Evans TG, Fletcher H, 2016. The TB vaccine H56+IC31 dose-response curve is peaked not saturating: data generation for new mathematical modelling methods to inform vaccine dose decisions. Vaccine 34 (50), 6285–6291. doi:10.1016/j.vaccine.2016.10.060.
    1. Segovia-Juarez JL, Ganguli S, Kirschner D, 2004. Identifying control mechanisms of granuloma formation during M. tuberculosis infection using an agent-based model. J. Theor. Biol. 231 (3), 357–376. doi:10.1016/j.jtbi.2004.06.031.
    1. Semenova VA, Schiffer J, Steward-Clark E, Soroka S, Schmidt DS, Brawner MM, Quinn C, 2012. Validation and long term performance characteristics of a quantitative enzyme linked immunosorbent assay (ELISA) for human anti-PA IgG. J. Immunol. Methods 376 (1–2), 97–107. doi:10.1016/j.jim.2011.12.002.
    1. Sherwin CM, Zobell JT, Stockmann C, McCrory BE, Wisdom M, Young DC, Spigarelli MG, 2014. Pharmacokinetic and pharmacodynamic optimisation of intravenous tobramycin dosing among children with cystic fibrosis. J. Pharmacokinet. Pharmacodyn. 41 (1), 71–79. doi:10.1007/s10928-013-9348-7.
    1. Suliman S, Luabeya AKK, Geldenhuys H, Tameris M, Hoff ST, Shi Z, Group HT, 2018. Dose optimization of H56:IC31 vaccine for TB endemic populations: a double-blind, placebo-controlled, dose-selection trial. Am. J. Respir. Crit. Care Med. doi:10.1164/rccm.201802-03660C.
    1. Tameris MD, Hatherill M, Landry BS, Scriba TJ, Snowden MA, Lockhart S, Team MATS, 2013. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet 381 (9871), 1021–1028. doi:10.1016/S0140-6736(13)60177-4.
    1. Tanner R, McShane H, 2016. Replacing, reducing and refining the use of animals in tuberculosis vaccine research. ALTEX doi:10.14573/altex.1607281.
    1. Tchilian EZ, Desel C, Forbes EK, Bandermann S, Sander CR, Hill AV, Kaufmann SH, 2009. Immunogenicity and protective efficacy of prime-boost regimens with recombinant (delta)ureC hly+ Mycobacterium bovis BCG and modified vaccinia virus ankara expressing M. tuberculosis antigen 85A against murine tuberculosis. Infect. Immun. 77 (2), 622–631. doi:10.1128/IAI.00685-08.
    1. Upton RN, Mould DR, 2014. Basic concepts in population modeling, simulation, and model-based drug development: part 3-introduction to pharmacodynamic modeling methods. CPT Pharmacomet. Syst. Pharmacol. 3, e88. doi:10.1038/psp.2013.71.
    1. van Dissel JT, Joosten SA, Hoff ST, Soonawala D, Prins C, Hokey DA, Andersen P, 2014. A novel liposomal adjuvant system, CAF01, promotes long-lived Mycobacterium tuberculosis-specific T-cell responses in human. Vaccine 32 (52), 7098–7107. doi:10.1016/j.vaccine.2014.10.036.
    1. WHO, 2016. Meeting of the Strategic Advisory Group of Experts on Immunization. October 2016 - conclusions and recommendations. . Accessed May 2018.
    1. WHO, 2018. Yellow fever - Brazil Disease outbreak news - 9 March 2018. . Accessed May 2018.
    1. Wilkins JJ, Langdon G, McIlleron H, Pillai G, Smith PJ, Simonsson US, 2011. Variability in the population pharmacokinetics of isoniazid in South African tuberculosis patients. Br. J. Clin. Pharmacol. 72 (1), 51–62. doi:10.1111/j.1365-2125.2011.03940.x.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere