**11. Conclusions**

may appear. We are currently working on establishing a safety assessment system based on the WPV as a toxicity indicator [60]. The WPV is an effective and excellent vaccine, but the frequency of adverse reactions is high, and currently, it is only rarely used, especially as a prepandemic vaccine. Therefore, we believe that the WPV can be a safety indicator. In other words, we think that there is a high probability that adjuvants and vaccines with innate-immunity– inducing activities that exceed the activity (toxicity) of WPVs will cause adverse reactions [60].

**9. Future perspectives of safety evaluation of vaccines and adjuvants**

development of novel adjuvants.

124 Influenza - Therapeutics and Challenges

that are safer than WPVs and more effective than the HAV.

**according to biomarkers' gene function**

it is necessary to interpret the results carefully.

**10. Extrapolation of the safety evaluation results to humans** 

According to the abovementioned concept, various evaluations of adjuvanted vaccines have been carried out. Furthermore, we have focused on the functions of biomarker genes. We have attempted to compile gene clusters based on the function of each gene. Such an assay is currently at the development stage, and further examination of the evaluation method and validation should be conducted in the future. Such an assay is considered applicable to the

For the development of low-molecular-weight synthetic drugs, a seed compound having a desired bioactivity is searched for by a screening system in compound libraries [61]. For promoting adjuvant development, to create as many prominent novel adjuvants as possible, finding seed compounds that are likely to become adjuvants is a crucial step in adjuvant development. Conventionally, to demonstrate whether a compound has adjuvant activities, animals are inoculated with one of the compounds, and the antibody titer and infection prevention rate are then assessed. This evaluation is not as efficient as the seed search and compound screening because the assessment process takes more than 1 month. In contrast, if we introduce an evaluation method involving a biomarker gene or genes, then prediction of safety and of the biological activity profile for compounds may be achieved in animals or cultured cells. Such an assessment may make it possible to search for effective adjuvant seeds

Given that the evaluation of the quality and safety of vaccines assumes a reaction with humans, the evaluation result must reflect the human biological response. Generally, there are species differences in immunological responses between humans and rodents. Therefore,

In case of safety evaluations based on genomic analyses, estimating the difference between experimental animals and humans with reference to the function of genes may be partially possible. For example, in the case of the WPV, leukopenic toxicity and body weight loss are observed in rodents, but these effects cannot be verified in humans. Nevertheless, at the gene level, if a gene is conserved among species, it is possible to estimate whether similar biological reactions can be observed between humans and animals. All our identified marker genes are homologous It has been established that information that could not be obtained by conventional phenotypic analyses can be obtained by genomic analyses. Research conducted on the safety of vaccines and adjuvants using toxicogenomics has been less likely to be reported, and such data about chemically synthesized drugs have mostly been limited. Since the late 2000s, we have been trying to apply the genomics technology to the safety assessment of vaccines, and to demonstrate its sensitivity, ability to yield abundant toxicological and mechanistic information, the possibility of extrapolating its results to humans, and its potential for application to *in vitro* evaluation systems. In addition, we have shown that the newly developed evaluation system may be employed in analyses involving a biomarker gene(s) as an indicator, instead of the conventional quality control or safety test. It can also be assumed that these technologies can be utilized for adjuvant development, and it is expected that a wide range of genomics technologies will be applied in the future to the development of quality control and safety testing.
