Mechanistic Studies On Protective Effects Against Lethal Virus Challenge Conferred By Particulate Adjuvants

Innate immunity and adaptive immune system are playing critical roles to resist external pathogen invasion.The duration of innate immunity is relatively short and non-specific,while adaptive immunity has significant specificity and relatively longer immune duration.Based on the above characteristics of innate immunity and adaptive immunity,vaccination can prevent related pathogens.However,for pathogens with high mutagenicity,as long as their key epitopes are changed,the antibodies produced by adaptive immunity will lose their neutralization ability.Thus,vaccinations for these highly mutated viruses are relatively inefficient.Influenza virus is one of the viruses with high mutation ability.Every year,the World Health Organization recommends influenza vaccine components based on the worldwide influenza virus epidemic,resulting in a relatively cumbersome and tense process for the production of influenza vaccines.It may even lead to a "off-target effect"due to misprediction.Therefore,to explore the preventive preparations and preventive means of new influenza vaccines has become a very important and practical work.In contrast,although the respiratory syncytial virus,which also causes respiratory diseases,is not relatively mutated,its vaccine development has gone through a painful experience,which has led to a significant increase in the hospitalization rate of vaccinators.Two babies even died of respiratory syncytial virus after vaccination of RSV vaccine.Until now,there is still no respiratory syncytial virus vaccine on the market around the world,and there is no specific drug treatment.At present,the harm caused by respiratory syncytial virus has not been paid enough attention in China,many people are not familiar with the respiratory syncytial virus,and even hospitals sometimes misdiagnose respiratory syncytial virus infection as influenza virus infection.Due to the harm of influenza virus and respiratory syncytial virus and the relatively limited means of prevention and treatment,this thesis is focused on the development of prophylactic preparation(namely FH-001 and Al-001)of influenza virus and respiratory syncytial virus based on innate immune activation,and demonstrated the mechanism of action of the prophylactic effect of FH-001.The results showed that the FH-001 and Al-001 both have the ability to induce a protective effect against the challenge of influenza virus and respiratory syncytial virus in mouse model.Further studies revealed that the prophylactic effect of FH-001 is related to alveolar macrophage and type I interferon pathway.These results suggested that the activation of innate immune response is a potential way to provide a prophylactic effect in mouse,probably in human too.In summary,we found that the activation of the innate immune system has a good protective effect on the prevention of influenza A virus,influenza B virus and respiratory syncytial virus.With the use of influenza B virus as an example,the protective effect of FH-001 and Al-001 could be evoked within three days after intranasal administration in mouse,while the vaccination of inleunza virus vaccine generally take fifteen days to produce neutralizing antibodies.Furthermore,the results from mouse model showed that the protective effect of these two aluminum-based imunopotentiators was lasted at least half a month.These results suggested that,with the use of these immune enhancers alone can broadly prevent the challenge of multiple pathogens.In addition,the aluminum adjuvant(namely Al-001)has been widely used in the vaccine field for more than 90 years around the world,and the chimeric adjuvant that improved based on aluminum adjuvant(codenamed FH-001)has a stronger immune enhancement effect.The preparation process of FH-001 is the same as that of aluminum adjuvant,and the cost is relatively low when compared to biologics.As an"old medicine/adjuvant",these aluminum-based immunopotentiators showed a "new use" They could be used as a strategic reserve of preventive agents in response to new outbreaks of influenza or respiratory syncytial virus outbreaks,and furthermore,has the potential to be further developed into a commonly used influenza preventive agent with wide application prospects.