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Front Immunol ; 12: 776933, 2021.
Article in English | MEDLINE | ID: covidwho-1581333


The efficacy of COVID-19 vaccines appears to depend in complex ways on the vaccine dosage and the interval between the prime and boost doses. Unexpectedly, lower dose prime and longer prime-boost intervals have yielded higher efficacies in clinical trials. To elucidate the origins of these effects, we developed a stochastic simulation model of the germinal center (GC) reaction and predicted the antibody responses elicited by different vaccination protocols. The simulations predicted that a lower dose prime could increase the selection stringency in GCs due to reduced antigen availability, resulting in the selection of GC B cells with higher affinities for the target antigen. The boost could relax this selection stringency and allow the expansion of the higher affinity GC B cells selected, improving the overall response. With a longer dosing interval, the decay in the antigen with time following the prime could further increase the selection stringency, amplifying this effect. The effect remained in our simulations even when new GCs following the boost had to be seeded by memory B cells formed following the prime. These predictions offer a plausible explanation of the observed paradoxical effects of dosage and dosing interval on vaccine efficacy. Tuning the selection stringency in the GCs using prime-boost dosages and dosing intervals as handles may help improve vaccine efficacies.

B-Lymphocytes/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , Clonal Selection, Antigen-Mediated/immunology , Germinal Center/immunology , Host-Pathogen Interactions/immunology , SARS-CoV-2/immunology , Antigens/immunology , B-Lymphocytes/metabolism , COVID-19/virology , COVID-19 Vaccines/administration & dosage , Dose-Response Relationship, Immunologic , Germinal Center/metabolism , Humans , Immunization, Secondary , Models, Theoretical , Vaccination
Sci Immunol ; 5(49)2020 07 15.
Article in English | MEDLINE | ID: covidwho-646575


Although critical illness has been associated with SARS-CoV-2-induced hyperinflammation, the immune correlates of severe COVID-19 remain unclear. Here, we comprehensively analyzed peripheral blood immune perturbations in 42 SARS-CoV-2 infected and recovered individuals. We identified extensive induction and activation of multiple immune lineages, including T cell activation, oligoclonal plasmablast expansion, and Fc and trafficking receptor modulation on innate lymphocytes and granulocytes, that distinguished severe COVID-19 cases from healthy donors or SARS-CoV-2-recovered or moderate severity patients. We found the neutrophil to lymphocyte ratio to be a prognostic biomarker of disease severity and organ failure. Our findings demonstrate broad innate and adaptive leukocyte perturbations that distinguish dysregulated host responses in severe SARS-CoV-2 infection and warrant therapeutic investigation.

B-Lymphocyte Subsets/immunology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Neutrophils/immunology , Pneumonia, Viral/immunology , T-Lymphocytes/immunology , Aged , COVID-19 , Clonal Selection, Antigen-Mediated/immunology , Coronavirus Infections/pathology , Cytokines/metabolism , Female , Humans , Immunity, Innate/immunology , Immunologic Memory/immunology , Lymphocyte Activation/immunology , Lymphocyte Count , Male , Middle Aged , Pandemics , Pneumonia, Viral/pathology , SARS-CoV-2
Int J Immunogenet ; 47(4): 329-331, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-591799


We provide evidence for a linear correlation between the frequency of clonal haematopoiesis and COVID-19 mortality rate. We discuss the mechanistic explanations for this association mediated by a pathological inflammatory response. Our hypothesis can be tested in COVID-19-infected patients and eventually lead to new approaches to risk stratification and therapy.

Aging/immunology , Clonal Selection, Antigen-Mediated/immunology , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Hematopoiesis/immunology , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Age Factors , Aged, 80 and over , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/mortality , Humans , Pandemics , Pneumonia, Viral/mortality , SARS-CoV-2