Document text
Principal Investigator: BARBARA K FELBER
Organization: DIVISION OF BASIC SCIENCES - NCI
Fiscal Year: 2024
Award: $510,540
Funding agency: National Cancer Institute
We have been studying the immune response of COVID-19 cohorts longitudinally to characterize the nature and longevity of immune response (Rosati M, Am J Hematol: 97:E3, 2022; Rosati Front Immunol 12: 793953, 2021; Thomopoulos, Viruses 1:1844; 2021; Terpos, Eur J Intern Med, 89:87,2021; Pappa, Microorganisms 9, 806, 2021; Terpos, Microorganisms. 8:1885, 2020). The analysis of natural infection is providing important information for the design of vaccine strategies. To characterize adaptive and innate immune responses in SARS-CoV2 vaccinated persons, we identified early responses to vaccination that are important in shaping both humoral and cellular protective immunity (Bergamaschi, Cell Rep 36:109504; 2021; Bergamaschi, Front Immunol 3:899972, 2022). We characterized the cytokine and chemokine responses to BNT162b2 mRNA (Pfizer/BioNtech) vaccinations in antigen-naive and in previously COVID-19-infected individuals and in patients with hematological malignancies (NCT04743388). We identified a systemic signature including IL-15, IFN-gamma, IP-10/CXCL10, TNF-alpha and IL-6 (Bergamaschi, Cell Rep 36:109504; 2021). Transient increases in IL-15 and IFN-gamma levels early after boost correlated with Spike antibody levels, supporting their use as biomarkers of effective humoral immunity development in response to vaccination. We expanded our studies to immunocompromised individuals including patients with hematological malignancies, a population at high risk of developing severe disease upon SARS-CoV-2 infection (Bergamaschi, Front Immunol 3:899972, 2022). Protection afforded by vaccination is frequently low and the biology leading to altered vaccine efficacy is not fully understood. Overall, the patients showed heterogeneous adaptive immune responses with lower humoral (binding and neutralizing antibodies) levels. In contrast to vaccination of a cohort of healthy participants, patients with hematological malignancies who had a lower anti-Spike response, also had a diminished systemic cytokine response (IFN-gamma, IL-15 and CXCL10/IP-10), and this correlated with the lower anti-Spike antibody levels. On the other hand, in patients who failed to develop antibodies, the innate systemic response showed a lack of the IL-15/IFN-gamma signature with responses dominated by CCL8/IL-8 and CCL3/MIP-1alpha. Thus, we concluded that successful development of an anti-Spike immune response was associated with a robust transient activation of the IL-15 signature, serving as a novel, prognostic approaches for potentiating the effectiveness of COVID-19 vaccination. We have been expanding our research of the development of adaptive and innate immune responses upon the third COVID-19 mRNA vaccination. In addition to the previously identified cytokine/chemokine responses, we detected induction of CXCL13, a biomarker for germinal center activation and a key regulator of B cells, found only after the 3rd vaccination. In contrast to the transient increase of the IL-15 signature cytokines, a set of pro-inflammatory cytokines (CCL3/MIP-1alpha, CCL4/MIP-1beta, MCP-1, CCL22/MDC, CXCL8/IL-8, IL-16) and the anti-inflammatory factor IL-1Ra remained at higher levels for up to one month post the 2nd and the 3rd vaccination, indicative of a state of longer-lasting innate immune change. Importantly, changes of the IL-15 signature and the inflammatory/anti-inflammatory cytokine profile correlated with neutralizing antibody levels also after the 3rd vaccination supporting their role as immune biomarkers for effective development of vaccine-induced humoral responses. Together, these data revealed that repeated BNT162b2 mRNA vaccination induced both rapid/transient as well as longer-lasting cytokine/chemokine changes. These results highlight the important role of innate responses to the BNT162b2 mRNA vaccination in shaping adaptive immunity. Together, our results show coordinated responses to the BNT162b2 mRNA vaccine and highlight the important role of a network of innate responses, centering on IL-15, in shaping adaptive immunity after vaccination. This study suggests that understanding the role of these biomarkers could also help the refinement of regimens to increase efficacy of other vaccine platforms including HIV vaccines. We are building on this knowledge to develop novel vaccines described in project 2.
Terms: <(TNF)-α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV vaccine><3-10C><A-152E5.1><ABCD-1><ACT2><AMCF-I><AT744.1><Act-2><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antibodies><Antigens><B blood cells><B cell><B cell differentiation factor><B cell stimulating factor 2><B cells><B-Cell Attracting Chemokine 1><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><B-Cells><B-Lymphocyte Chemoattractant><B-Lymphocytes><B-cell><BCA1><BCDF><BLC gene><BLC protein><BNT 162b2><BNT162b2><BSF-2><BSF2><Binding><Biological Markers><Biology><CCL2><CCL2 gene><CCL22><CCL22 gene><CCL3><CCL3 gene><CCL4><CCL4 gene><CCL8><CCL8 gene><CD183><CKR-L2><CMKAR3><COVID-19><COVID-19 immune response><COVID-19 infection><COVID-19 vaccination><COVID-19 vaccine><COVID-19 virus><COVID-19 virus infection><COVID19 infection><COVID19 virus><CRG-2><CV-19><CXCL10><CXCL10 gene><CXCL13><CXCL13 gene><CXCL8><CXCR3><CXCR3 gene><Cachectin><Cancer Patient><Cell Body><Cells><Chemokine (C-C Motif) Ligand 4><Chemokine (C-C motif) Ligand 3><Chemokine (C-X-C Motif) Receptor 3><Chemokine, CC Motif, Ligand 2><Chemokine, CC Motif, Ligand 4><Chemokine, CXC Motif, Ligand 13><Chemotactic Cytokines><CoV-2><CoV2><Coronavirus Infectious Disease 2019><DC/B-CK><Data><Development><Development and Research><Disease><Disorder><Early identification><Effectiveness><G Protein-Coupled Receptor 9><G0S19-1><GCP1><GPR9><Germinal Center><Goals><HC14><HIV vaccine><HIV/AIDS Vaccines><HPGF><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic Cancer><Hepatocyte-Stimulating Factor><Homologous Chemotactic Cytokines><Humoral Immunities><Hybridoma Growth Factor><IFI10><IFN-Gamma><IFN-beta 2><IFN-g><IFN-γ><IFNB2><IFNG><IFNγ><IL-15><IL-16><IL-16 Gene><IL-1ra><IL-6><IL-8><IL1 febrile inhibitor><IL15><IL15 Protein><IL16><IL16 Protein><IL16 gene><IL1RN><IL6 Protein><IL8><IL8 gene><INP10><IP-10><IP10><IP10 Receptor><IP10-Mig receptor><IP10-R><Immune><Immune Activation 2><Immune Interferon><Immune Markers><Immune response><Immunes><Immunity><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunologic Markers><Immunological response><Immunosuppressed Host><Individual><Infection><Inflammatory><Innate Immune Response><Intercrines><Interferon Gamma><Interferon Type II><Interleukin 16 (Lymphocyte Chemoattractant Factor) Gene><Interleukin 16 Precursor Gene><Interleukin-1 Receptor Antagonist><Interleukin-15><Interleukin-15 Precursor><Interleukin-16><Interleukin-16 Gene><Interleukin-6><Internships><K60><Knowledge><LCF Factor><LCF Gene><LD78ALPHA><Length of Life><Long-term cohort><Longevity><Longitudinal cohort><Longterm cohort><Lymphocyte Chemoattractant Factor><Lymphocyte Chemoattractant Factor Gene><MCAF><MCP-1><MCP-2><MCP1><MCP2><MGC34554><MGC9721><MGI-2><MIP 1alpha><MIP-1-alpha><MIP-1a><MIP1A><MIP1B><MIP1B1><MOB-1><Macrophage Inflammatory Protein 1-Beta><Macrophage-Derived TNF><Malignant Hematologic Neoplasm><Messenger RNA><Mig Receptor><Mig-R><MigR><Molecular Interaction><Monitor><Monocyte Chemoattractant Protein-1><Monocyte Chemotactic Protein-1><Monocyte Chemotactic and Activating Factor><Monocyte Chemotactic and Activating Protein><Monocyte Chemotactive and Activating Factor><Monocyte Secretory Protein JE><Monocyte-Derived TNF><Myeloid Differentiation-Inducing Protein><Nature><Participant><Patients><Persons><Pfizer covid19 vaccine><Pfizer-BioNTech COVID-19 vaccine><Pfizer-BioNTech coronavirus disease 2019 vaccine><Pfizer/BioNTech vaccine><Plasmacytoma Growth Factor><Population><R & D><R&D><RNA immunization><RNA vaccination><RNA vaccine><RNA-based vaccine><Regimen><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 immune response><SARS-CoV-2 infection><SARS-CoV-2 vaccination><SARS-CoV-2 vaccine><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SCYA10><SCYA2><SCYA22><SCYA3><SCYA4><SCYA8><SCYB10><SCYB13><SCYB8><SIS cytokines><STCP-1><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 immune response><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 vaccination><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Shapes><Small Inducible Cytokine A2><Small Inducible Cytokine A3><Small Inducible Cytokine A4><Small Inducible Cytokine Subfamily B, Member 13><Stem Cell Inhibitor><Structure of germinal center of lymph node><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><TSG-1><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Vaccinated><Vaccination><Vaccine Design><Vaccinee><Virus><Wuhan coronavirus><adaptive immune response><adaptive immunity><anakinra><antibody-based immunity><b-ENAP><bio-markers><biologic marker><biomarker><chemoattractant cytokine><chemokine><cohort><coronavirus disease 2019><coronavirus disease 2019 immune response><coronavirus disease 2019 infection><coronavirus disease 2019 vaccination><coronavirus disease 2019 vaccine><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 vaccine><coronavirus disease-19 virus><coronavirus infectious disease-19><cytokine><develop a vaccine><develop vaccines><development of a vaccine><developmental><gIP-10><hCoV19><high risk><host response><human immunodeficiency virus vaccine><immune system response><immune-based biomarkers><immunogen><immunological biomarkers><immunological markers><immunoresponse><immunosuppressed patient><individual patient><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><interferon beta 2><interleukin 1 receptor antagonist protein><intern><lFN-Gamma><mRNA><mRNA immunization><mRNA vaccination><mRNA vaccine><mRNA-based vaccine><microorganism><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><nCoV2><neutralizing antibody><new vaccines><next generation vaccines><novel><novel vaccines><prIL-16><prIL-16 Gene><prognostic><research and development><response><social role><urine IL-1 inhibitor><urine interleukin 1 inhibitor><urine-derived IL1 inhibitor><vaccinate against COVID-19><vaccinate against SARS-CoV-2><vaccinate against coronavirus disease 2019><vaccinate against severe acute respiratory syndrome coronavirus 2><vaccinated individual><vaccinated participant><vaccinated patient><vaccinated person><vaccinated subject><vaccination against COVID-19><vaccination against SARS-CoV-2><vaccination against Severe acute respiratory syndrome coronavirus 2><vaccination against coronavirus disease 2019><vaccine against 2019-nCov><vaccine against COVID-19><vaccine against SARS-CoV-2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine candidates against SARS-CoV-2><vaccine development><vaccine efficacy><vaccine for novel coronavirus><vaccine platform><vaccine strategy><vaccines preventing COVID><vaccines to prevent COVID><volunteer>