Lung-Targeted Transgene Expression of Nanocomplexed Ad5 Enhances Immune Response in the Presence of Preexisting Immunity

Recombinant adenovirus serotype 5(Ad5)vector has been widely applied in vaccine development targeting infectious diseases,such as Ebola virus disease and coronavirus disease 2019(COVID-19).However,the high prevalence of preexisting anti-vector immunity compromises the immunogenicity of Ad5-based vaccines.Thus,there is a substantial unmet need to minimize preexisting immunity while improving the insert-induced immunity of Ad5 vectors.Herein,we address this need by utilizing biocompatible nanoparticles to modulate Ad5–host interactions.We show that positively charged human serum albumin nanoparticles((+)HSAnp),which are capable of forming a complex with Ad5,significantly increase the transgene expression of Ad5 in both coxsackievirus–adenovirus receptor-positive and-negative cells.Furthermore,in charge-and dose-dependent manners,Ad5/(+)HSAnp complexes achieve robust(up to227-fold higher)and long-term(up to 60 days)transgene expression in the lungs of mice following intranasal instillation.Importantly,in the presence of preexisting anti-Ad5 immunity,complexed Ad5-based Ebola and COVID-19 vaccines significantly enhance antigen-specific humoral response and mucosal immunity.These findings suggest that viral aggregation and charge modification could be leveraged to engineer enhanced viral vectors for vaccines and gene therapies.

Seasonal coronaviruses and SARS-CoV-2:effects of preexisting immunity during the COVID-19 pandemic

Although the coronavirus disease 2019(COVID-19)epidemic is still ongoing,vaccination rates are rising slowly and related treatments and drugs are being developed.At the same time,there is increasing evidence of preexisting immunity against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)in humans,mainly consisting of preexisting antibodies and immune cells(including T cells and B cells).The presence of these antibodies is mainly due to the seasonal prevalence of four common coronavirus types,especially OC43 and HKU1.The accumulated relevant evidence has suggested that the target of antibodies is mainly the S2 subunit of S protein,followed by evolutionary conservative regions such as the nucleocapsid(N)protein.Additionally,preexisting memory T and B cells are also present in the population.Preexisting antibodies can help the body protect against SARS-CoV-2 infection,reduce the severity of COVID-19,and rapidly increase the immune response post-infection.These multiple effects can directly affect disease progression and even the likelihood of death in certain individuals.Besides the positive effects,preexisting immunity may also have negative consequences,such as antibody-dependent enhancement(ADE)and original antigenic sin(OAS),the prevalence of which needs to be further established.In the future,more research should be focused on evaluating the role of preexisting immunity in COVID-19 outcomes,adopting appropriate policies and strategies for fighting the pandemic,and vaccine development that considers preexisting immunity.