Severe respiratory viral infections: T-cell functions diverging from immunity to inflammation.

Respiratory viral infections such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (IAV) trigger distinct clinical outcomes defined by immunity-based viral clearance or disease associated with exaggerated and prolonged inflammation. The important role of T cells in shaping both antiviral immunity and inflammation has revived interest in understanding the host-pathogen interactions that lead to the diverse functions of T cells in respiratory viral infections. Inborn deficiencies and acquired insufficiency in immunity can prolong infection and shift the immune response towards exacerbated inflammation, which results from persistent innate immune activation and bystander T-cell activation that is nonspecific to the pathogen but is often driven by cytokines. This review discusses how virus variants, exposure doses, routes of infection, host genetics, and immune history can modulate the activation and function of T cells, thus influencing clinical outcomes. Knowledge of virus-host interaction can inform strategies to prevent immune dysfunction in respiratory viral infection and help in the treatment of associated diseases.

Longevity of vaccine protection: Immunological mechanism, assessment methods, and improving strategy

Vaccination represents one of the most important achievements in modern medicine. During the era of COVID‐19 pandemic, the successful vaccination for SARS‐COV‐2 is the major hope to bring the society back to normal. However, although vaccines, such as for smallpox and poliomyelitis, can trigger life‐long protection in individuals and help to generate the herd immunity resulting in the eradication of pathogens, other vaccines, with seasonal influenza vaccine as a case in point, are unable to induce sustained immunity so that repeated vaccination is required. As most vaccines were developed empirically, the immunological mechanism underlying the longevity of vaccine‐induced protection remains only partially understood. In this review, we first describe vaccine‐induced humoral immune response in which long‐lived plasma cells and memory B cells are produced. We then summarise methods using immunological correlates of protection to assess the longevity of vaccine efficacy and provide the evidence and knowledge for the duration of protection by current vaccines. Last, we discuss rationale and strategies to improve the duration of vaccine protection by targeting vaccine immunogenicity, antibody affinity, avidity and prime‐boost scheme.

Separable Microneedle Patch to Protect and Deliver DNA Nanovaccines Against COVID-19.

The successful control of coronavirus disease 2019 (COVID-19) pandemic is not only relying on the development of vaccines, but also depending on the storage, transportation, and administration of vaccines. Ideally, nucleic acid vaccine should be directly delivered to proper immune cells or tissue (such as lymph nodes). However, current developed vaccines are normally treated through intramuscular injection, where immune cells do not normally reside. Meanwhile, current nucleic acid vaccines must be stored in a frozen state that may hinder their application in developing countries. Here, we report a separable microneedle (SMN) patch to deliver polymer encapsulated spike (or nucleocapsid) protein encoding DNA vaccines and immune adjuvant for efficient immunization. Compared with intramuscular injection, SMN patch can deliver nanovaccines into intradermal for inducing potent and durable adaptive immunity. IFN-γ+CD4/8+ and IL-2+CD4/8+ T cells or virus specific IgG are significantly increased after vaccination. Moreover, in vivo results show the SMN patches can be stored at room temperature for at least 30 days without decreases in immune responses. These features of nanovaccines-laden SMN patch are important for developing advanced COVID-19 vaccines with global accessibility.

High levels of soluble CD25 in COVID-19 severity suggest a divergence between anti-viral and pro-inflammatory T-cell responses.

OBJECTIVES: We aimed to gain an understanding of the paradox of the immunity in COVID-19 patients with T cells showing both functional defects and hyperactivation and enhanced proliferation. METHODS: A total of 280 hospitalised patients with COVID-19 were evaluated for cytokine profiles and clinical features including viral shedding. A mouse model of acute infection by lymphocytic choriomeningitis virus (LCMV) was applied to dissect the relationship between immunological, virological and pathological features. The results from the mouse model were validated by published data set of single-cell RNA sequencing (scRNA-seq) of immune cells in bronchoalveolar lavage fluid (BALF) of COVID-19 patients. RESULTS: The levels of soluble CD25 (sCD25), IL-6, IL-8, IL-10 and TNF-α were higher in severe COVID-19 patients than non-severe cases, but only sCD25 was identified as an independent risk factor for disease severity by multivariable binary logistic regression analysis and showed a positive association with the duration of viral shedding. In agreement with the clinical observation, LCMV-infected mice with high levels of sCD25 demonstrated insufficient anti-viral response and delayed viral clearance. The elevation of sCD25 in mice was mainly contributed by the expansion of CD25+CD8+ T cells that also expressed the highest level of PD-1 with pro-inflammatory potential. The counterpart human CD25+PD-1+ T cells were expanded in BALF of COVID-19 patients with severe disease compared to those with modest disease. CONCLUSION: These results suggest that high levels of sCD25 in COVID-19 patients probably result from insufficient anti-viral immunity and indicate an expansion of pro-inflammatory T cells that contribute to disease severity.

Peripheral CD4⁺ T cell subsets and antibody response in COVID-19 convalescent individuals

BACKGROUND. Marked progress is achieved in understanding the physiopathology of coronavirus disease 2019 (COVID-19), which caused a global pandemic. However, the CD4· T cell population critical for antibody response in COVID-19 is poorly understood. METHODS. In this study, we provided a comprehensive analysis of peripheral CD4· T cells from 13 COVID-19 convalescent patients, defined as confirmed free of SARS-CoV-2 for 2 to 4 weeks, using flow cytometry and magnetic chemiluminescence enzyme antibody immunoassay. The data were correlated with clinical characteristics. RESULTS. We observed that, relative to healthy individuals, convalescent patients displayed an altered peripheral CD4· T cell spectrum. Specifically, consistent with other viral infections, cTfh1 cells associated with SARS-CoV-2-targeting antibodies were found in COVID-19 covalescent patients. Individuals with severe disease showed higher frequencies of Tem and Tfh-em cells but lower frequencies of Tcm, Tfh-cm, Tfr, and Tnaive cells, compared with healthy individuals and patients with mild and moderate disease. Interestingly, a higher frequency of cTfh-em cells correlated with a lower blood oxygen level, recorded at the time of admission, in convalescent patients. These observations might constitute residual effects by which COVID-19 can impact the homeostasis of CD4· T cells in the long-term and explain the highest ratio of class-switched virus-specific antibody producing individuals found in our severe COVID-19 cohort. CONCLUSION. Our study demonstrated a close connection between CD4· T cells and antibody production in COVID-19 convalescent patients. FUNDING. Six Talent Peaks Project in Jiangsu Province and the National Natural Science Foundation of China (NSFC).

Peripheral CD4+ T cell subsets and antibody response in COVID-19 convalescent individuals.

BACKGROUNDMarked progress is achieved in understanding the physiopathology of coronavirus disease 2019 (COVID-19), which caused a global pandemic. However, the CD4+ T cell population critical for antibody response in COVID-19 is poorly understood.METHODSIn this study, we provided a comprehensive analysis of peripheral CD4+ T cells from 13 COVID-19 convalescent patients, defined as confirmed free of SARS-CoV-2 for 2 to 4 weeks, using flow cytometry and magnetic chemiluminescence enzyme antibody immunoassay. The data were correlated with clinical characteristics.RESULTSWe observed that, relative to healthy individuals, convalescent patients displayed an altered peripheral CD4+ T cell spectrum. Specifically, consistent with other viral infections, cTfh1 cells associated with SARS-CoV-2-targeting antibodies were found in COVID-19 covalescent patients. Individuals with severe disease showed higher frequencies of Tem and Tfh-em cells but lower frequencies of Tcm, Tfh-cm, Tfr, and Tnaive cells, compared with healthy individuals and patients with mild and moderate disease. Interestingly, a higher frequency of cTfh-em cells correlated with a lower blood oxygen level, recorded at the time of admission, in convalescent patients. These observations might constitute residual effects by which COVID-19 can impact the homeostasis of CD4+ T cells in the long-term and explain the highest ratio of class-switched virus-specific antibody producing individuals found in our severe COVID-19 cohort.CONCLUSIONOur study demonstrated a close connection between CD4+ T cells and antibody production in COVID-19 convalescent patients.FUNDINGSix Talent Peaks Project in Jiangsu Province and the National Natural Science Foundation of China (NSFC).