Comparative pharmacokinetic and biodistribution study of two distinct squalene-containing oil-in-water emulsion adjuvants in H5N1 influenza vaccines

Million A Tegenge; Linda S Von Tungeln; Steven A Anderson; Robert J Mitkus; Michelle M Vanlandingham; Richard A Forshee; Frederick A Beland

doi:10.1016/j.yrtph.2019.104436

Comparative pharmacokinetic and biodistribution study of two distinct squalene-containing oil-in-water emulsion adjuvants in H5N1 influenza vaccines

Regul Toxicol Pharmacol. 2019 Nov:108:104436. doi: 10.1016/j.yrtph.2019.104436. Epub 2019 Aug 2.

Authors

Million A Tegenge¹, Linda S Von Tungeln², Steven A Anderson³, Robert J Mitkus⁴, Michelle M Vanlandingham², Richard A Forshee³, Frederick A Beland²

Affiliations

¹ Office of Biostatistics & Epidemiology, Center for Biologics Evaluation and Research, FDA, Silver Spring, MD, 20993, USA. Electronic address: million.tegenge@fda.hhs.gov.
² Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, Jefferson, AR, 72079, USA.
³ Office of Biostatistics & Epidemiology, Center for Biologics Evaluation and Research, FDA, Silver Spring, MD, 20993, USA.
⁴ Office of Biostatistics & Epidemiology, Center for Biologics Evaluation and Research, FDA, Silver Spring, MD, 20993, USA; Current Address: BASF Corporation, 26 Davis Drive, Durham, NC, 27709, USA.

PMID: 31381939
DOI: 10.1016/j.yrtph.2019.104436

Abstract

Background: In recent years, there has been great interest from academia, industry and government scientists for an increased understanding of the mode of action of vaccine adjuvants to characterize the safety and efficacy of vaccines. In this context, pharmacokinetic (PK) and biodistribution studies are useful for quantifying the concentration of vaccine adjuvants in mechanistically or toxicologically relevant target tissues.

Methods: In this study, we conducted a comparative analysis of the PK and biodistribution profile of radiolabeled squalene for up to 336 h (14 days) after intramuscular injection of mice with adjuvanted H5N1 influenza vaccines. The evaluated adjuvants included an experimental-grade squalene-in-water (SQ/W) emulsion (AddaVax®) and an adjuvant system (AS03®) that contained squalene and α-tocopherol in the oil phase of the emulsion.

Results: The half-life of the initial exponential decay from quadriceps muscle was 1.5 h for AS03 versus 12.9 h for AddaVax. At early time points (1-6 h), there was about a 10-fold higher concentration of labeled squalene in draining lymph nodes following AS03 injection compared to AddaVax. The area-under-concentration curve up to 336 h (AUC_0-336hr) and peak concentration of squalene in spleen (immune organ) was about 1.7-fold higher following injection of AS03 than AddaVax. The peak systemic tissue concentration of squalene from the two adjuvants, with or without antigen, remained below 1% of injected dose for toxicologically relevant target tissues, such as spinal cord, brain, and kidney. The pharmacokinetics of AS03 was unaffected by the presence of H5N1 antigen.

Conclusions: This study demonstrates a rapid decline of AS03 from the quadriceps muscles of mice as compared to conventional SQ/W emulsion adjuvant, with an increased transfer to mechanistically relevant tissues such as local lymph nodes. Systemic tissue exposure to potential toxicological target tissues was very low.

Keywords: AS03; Lymphatics; MF59; Pharmacokinetics; Pre-pandemic; Safety.

Publication types

Comparative Study

MeSH terms

Adjuvants, Immunologic / pharmacokinetics*
Animals
Antigens / immunology
Drug Combinations
Emulsions
Female
Influenza A Virus, H5N1 Subtype / immunology*
Influenza Vaccines / pharmacokinetics*
Injections, Intramuscular
Lymph Nodes / metabolism
Male
Mice, Inbred BALB C
Polysorbates / pharmacokinetics*
Quadriceps Muscle / metabolism
Squalene / pharmacokinetics*
Tissue Distribution
alpha-Tocopherol / pharmacokinetics*

Substances

Addavax
Adjuvants, Immunologic
Antigens
Drug Combinations
Emulsions
Influenza Vaccines
Polysorbates
Squalene
AS03 adjuvant
alpha-Tocopherol