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 to 227-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.

Impact of Preexisting Anti-Adenovirus 26 Humoral Immunity on Immunogenicity of the Ad26.COV2.S Coronavirus Disease 2019 Vaccine.

This secondary analysis of the phase 3 ENSEMBLE trial (NCT04505722) assessed the impact of preexisting humoral immunity to adenovirus 26 (Ad26) on the immunogenicity of Ad26.COV2.S-elicited severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody levels in 380 participants in Brazil, South Africa, and the United States. Among those vaccinated in Brazil and South Africa, 31% and 66%, respectively, had prevaccination serum-neutralizing activity against Ad26, with little preexisting immunity detected in the United States. Vaccine recipients in each country had similar postvaccination spike (S) protein-binding antibody levels, indicating that baseline immunity to Ad26 has no clear impact on vaccine-induced immune responses.

Age-Specific Transmissibility Change of COVID-19 and Associations With Breathing Air Volume, Preexisting Immunity, and Government Response.

Background: The comprehensive impacts of diverse breathing air volumes and preexisting immunity on the host susceptibility to and transmission of COVID-19 at various pandemic stages have not been investigated. Methods: We classified the US weekly COVID-19 data into 0-4, 5-11, 12-17, 18-64, and 65+ age groups and applied the odds ratio (OR) of incidence between one age group and the 18-64 age group to delineate the transmissibility change. Results: The changes of incidence ORs between May, 2020 and November, 2021 were 0.22-0.66 (0-4 years), 0.20-1.34 (5-11 years), 0.39-1.04 (12-17 years), and 0.82-0.73 (65+ years). The changes could be explained by age-specific preexisting immunity including previous infection and vaccination, as well as volumes of breathing air. At the early pandemic, the ratio that 0-4-year children exhaled one-fifth of air and discharge a similar ratio of viruses was closely associated with incidence OR between two age groups. While, after a rollout of pandemic and vaccination, the much less increased preexisting immunity in children resulted in rapidly increased OR of incidence. The ARIMA model predicted the largest increase of relative transmissibility in 6 coming months in 5-11-year children. Conclusions: The volume of breathing air may be a notable factor contributing to the infectivity of COVID-19 among different age groups of patients. This factor and the varied preexisting greatly shape the transmission of COVID-19 at different periods of pandemic among different age groups of people.

Profiling B cell immunodominance after SARS-CoV-2 infection reveals antibody evolution to non-neutralizing viral targets.

Dissecting the evolution of memory B cells (MBCs) against SARS-CoV-2 is critical for understanding antibody recall upon secondary exposure. Here, we used single-cell sequencing to profile SARS-CoV-2-reactive B cells in 38 COVID-19 patients. Using oligo-tagged antigen baits, we isolated B cells specific to the SARS-CoV-2 spike, nucleoprotein (NP), open reading frame 8 (ORF8), and endemic human coronavirus (HCoV) spike proteins. SARS-CoV-2 spike-specific cells were enriched in the memory compartment of acutely infected and convalescent patients several months post symptom onset. With severe acute infection, substantial populations of endemic HCoV-reactive antibody-secreting cells were identified and possessed highly mutated variable genes, signifying preexisting immunity. Finally, MBCs exhibited pronounced maturation to NP and ORF8 over time, especially in older patients. Monoclonal antibodies against these targets were non-neutralizing and non-protective in vivo. These findings reveal antibody adaptation to non-neutralizing intracellular antigens during infection, emphasizing the importance of vaccination for inducing neutralizing spike-specific MBCs.