Changes of urine metabolite profiles are induced by inactivated influenza vaccine inoculations in mice

Eita Sasaki,Kazuo Hosoda,Isao Hamaguchi,Takuo Mizukami,Kaori Wakamatsu,Haruka Momose,Keiko Furuhata,Hideki Kusunoki

doi:10.1038/s41598-019-52686-5

Eita Sasaki, Kazuo Hosoda + Show 6 more

Open Access

https://doi.org/10.1038/s41598-019-52686-5

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Abstract

The safety evaluation of vaccines is critical to avoid the development of side effects in humans. To increase the sensitivity of detection for toxicity tests, it is important to capture not only pathological changes but also physiological changes. 1H nuclear magnetic resonance (NMR) spectroscopy analysis of biofluids produces profiles that show characteristic responses to changes in physiological status. In this study, mouse urine metabolomics analysis with 1H NMR was performed using different influenza vaccines of varying toxicity to assess the usefulness of 1H NMR in evaluating vaccine toxicity. Two types of influenza vaccines were used as model vaccines: a toxicity reference vaccine (RE) and a hemagglutinin split vaccine. According to the blood biochemical analyses, the plasma alanine transaminase levels were increased in RE-treated mice. Changes in metabolite levels between mice administered different types of influenza vaccines were observed in the 1H NMR spectra of urine, and a tendency toward dosage-dependent responses for some spectra was observed. Hierarchical clustering analyses and principal component analyses showed that the changes in various urine metabolite levels allowed for the classification of different types of vaccines. Among them, two liver-derived metabolites were shown to largely contribute to the formation of the cluster. These results demonstrate the possibility that urine metabolomics analysis could provide information about vaccine-induced toxicity and physiological changes.

Highlights

The safety evaluation of vaccines is critical to avoid the development of side effects in humans
The results showed that significant WBC reductions were observed at all doses in the reference vaccine (RE)-treated groups compared with the SA-treated group (Fig. 1b)
While no dose in HAV-treated animals produced any significant changes in WBCs (Fig. 1b) and body weight compared with the SA group (Fig. 1c), at a dose of 15 μg HA, the HAV-treated group showed a tendency towards decreased body weight compared with the SA-treated group

Summary

Introduction

The safety evaluation of vaccines is critical to avoid the development of side effects in humans. Mouse urine metabolomics analysis with 1H NMR was performed using different influenza vaccines of varying toxicity to assess the usefulness of 1H NMR in evaluating vaccine toxicity. Two liver-derived metabolites were shown to largely contribute to the formation of the cluster These results demonstrate the possibility that urine metabolomics analysis could provide information about vaccine-induced toxicity and physiological changes. LTT has been employed for safety testing for inactivated influenza vaccines in Japan[1] These methods mainly evaluate pathological and immunotoxicological changes. The aim of this study was to analyze urine metabolite changes by using a mouse body weight loss test and LTT with 1H NMR analysis for different types of influenza vaccines. The acquired metabolomics data were assessed to determine whether urine could be used to evaluate toxicity-related physiological changes

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