Document text
Principal Investigator: Lothar Hennighausen
Organization: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
Fiscal Year: 2021
Award: $3,036,975
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Objective 1
SARS-CoV-2 infection ranges from asymptomatic to severe with lingering symptomatology in some. We have conducted three clinical studies addressing newly emerging questions and problems as the pandemic progressed. Although a large percentage of infected individuals are asymptomatic, the response of their immune systems and prevalence of unrecognized ongoing inflammation to SARS-CoV-2 was not understood at the time the pandemic started in the spring of 2020. We addressed this question and investigated immune transcriptomes in individuals from one of the original super spreading events in Europe (PMID: 33608566). Over the past few months, several variants of concern (VOC) carrying specific mutations thought to enhance viral fitness have emerged. We investigated the immune response of hospitalized patients infected with the Alpha (PMID: 34100027) and Beta (PMID: 34013280) variants and the benefits of prior vaccination with the mRNA vaccine BNT162b.
Immune response in individuals asymptomatically infected with the original SARS-CoV-2 strain
This study was specifically designed to fill a gap in the understanding of immunological outcomes in asymptomatic individuals following a community super-spreading event. Using blood transcriptomes from the Ischgl community that had experienced a super spreading event, we provide evidence that asymptomatic infection can resolve without evidence of immunological activation four to six weeks following infection (PMID: 33608566). Immune activation following asymptomatic SARS-CoV-2 infection was characterized through a comparative investigation of the immune cell transcriptomes from 43 asymptomatic seropositive and 52 highly exposed seronegative individuals from the same community four to six weeks following a superspreading event. Few of the 95 individuals had underlying health issues. There were no statistically significant differences in immune transcriptomes between asymptomatic seropositive and highly exposed seronegative individuals. All individuals remained in their usual state of health through a five-month follow-up after sample collection.
With the pandemic extending itself into populations with underlying genetic disease, there is also an urgent need to understand their immune response and immunity to SARS-CoV-2 infections. Here our community-based study also included one asymptomatic seropositive patient with Cystic Fibrosis (CF) and one individual reported Incontinentia pigmenti. No evidence of immune activation was found in asymptomatic seropositive individuals with exception of the Cystic Fibrosis patient.
In summary, whole blood transcriptomes identified individual immune profiles within a community population and showed that asymptomatic infection within a super-spreading event was not associated with enduring immunological activation.
Immune response in patients infected with the Alpha and Beta variants carrying escape mutations
Fast-spreading variants of SARS-CoV-2 energize the COVID-19 pandemic. Over the past few months, several variants of concern (VOC) carrying specific mutations thought to enhance viral fitness have emerged. Specifically, the Beta variant was of particular concern because it carries the mutation E484K within the receptor binding domain (RBD), which has been demonstrated to enhance escape from neutralizing antibody inhibition in vitro and may be linked with reduced vaccination efficacy. In February 2021 it was reported that the Alpha variant had also acquired the E484K spike mutation.
The Alpha+E484K variant is fast spreading, prompting interest in the response of both unvaccinated and vaccinated individuals to disease from this variant. Recent in vitro data demonstrated that this mutation led to a more-substantial loss of neutralizing activity by vaccine-elicited antibodies, suggesting that this variant represents a threat to the efficacy of the BNT162b2 vaccine. However, it had remained unclear whether these variants elicit a modified immune response in patients. To fill this knowledge gap, we investigated differences in the immune transcriptome in hospitalized patients infected with either the native Alpha variant or the Alpha+E484K variant. RNA-seq conducted on PBMCs isolated within five days after the onset of COVID symptoms demonstrated elevated activation of specific immune pathways, including JAK-STAT signaling, in Alpha+E484K patients. Longitudinal transcriptome studies demonstrated a delayed dampening of interferon-activated pathways in Alpha+E484K patients. Prior vaccination with BNT162b vaccine reduced the transcriptome inflammatory response to Alpha+E484K infection relative to unvaccinated patients. Acquisition of the single amino acid change E484K in the Alpha background elicits an altered immune response, which could impact disease progression.
The Beta variant carrying the escape mutation E484K in the receptor binding domain was of particular concern due to reduced immunological protection following vaccination. Protection can manifest as early as 10 days following immunization with full protection two weeks following the second dose, but the course is not well-characterized for variants. Here, we investigated the immune transcriptome of six elderly individuals (average age 82 yr.) from an old peoples home, who contracted Beta, with four having received the first dose of BNT162b eight to 11 days prior to the onset of COVID-19 symptoms (PMID: 34013280). The patients were hospitalized and received dexamethasone treatment. Immune transcriptomes were established from PBMCs approximately 10 and 35 days after the onset of COVID-19 symptomology. RNA-seq revealed a more intensive immune response in vaccinated patients as compared to unvaccinated ones. Specifically, transcription factors linked to the JAK/STAT pathway, interferon stimulated genes, and genes associated with innate antiviral immunity and COVID-19 were highly enriched in vaccinated patients. This rendered the transcriptomes of the older vaccinated group significantly different than older unvaccinated individuals infected at the same institution and more similar to the immune response of younger unvaccinated individuals (age range 48-62) following Beta infection. All individuals in this study whether vaccinated or not were hospitalized due to Beta infection and one vaccinated patient died illustrating that although an enhanced immune response was documented infection it was insufficient to protect from disease. This highlights the need for maintaining physical distancing and prevention measures throughout the time course of vaccination in older adults. In summary, our clinical data contributes to ongoing large-scale efforts by many labs to understand the spectrum of immune response elicited by SARS-CoV-2 infection, the contribution of variants and effects of prior vaccination.
Objective 2
In December 2020, the U.S. Food and Drug Administration issued the first emergency use authorization (EUA) for a vaccine for the prevention of COVID-19 caused by SARS-CoV-2). Although highly effective against the original SARS-CoV-2 strain, efficacy against variants of concerns can be substantially lower. As 100s of millions of citizens world-wide receive mRNA-based as well as vector-based vaccines, the innate immune responses are unclear and are only beginning to be investigated. There is an urgent need to understand the immune response mounted in different population groups. Among those are the response of young versus old and the response of individuals that had been previously infected. Equally, and maybe even more critical, is an understanding of the immune response in immunocompromised individuals, such as cancer patients as well as those with organ transplants.
We are currently addressing some of these questions with clinical collaborators in Austria, Germany and South Korea.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><ACE2><Active Follow-up><Address><Age><Amino Acids><Antibodies><Asboe-Hansen disease><Austria><BNT162b2><Basal Transcription Factor><Basal transcription factor genes><Bloch Sulzberger syndrome><Bloch-Siemens syndrome><Bloch-Sulzberger melanoblastoma><Blood><Blood Reticuloendothelial System><CF patients><COVID><COVID crisis><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID-19><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 immune response><COVID-19 immunity><COVID-19 infected patient><COVID-19 infection><COVID-19 pandemic><COVID-19 patient><COVID-19 positive patient><COVID-19 prevention><COVID-19 public health crisis><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID19><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 immune response><COVID19 immunity><COVID19 infection><COVID19 pandemic><COVID19 patient><COVID19 positive patient><COVID19 prevention><COVID19 public health crisis><COVID19 virus><CV-19><CV19><Cancer Patient><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Clinical><Clinical Data><Clinical Research><Clinical Study><CoV disease><CoV-2><CoV2><Communities><Contracting Opportunities><Contracts><Data><Dexamethasone><Disease><Disease Progression><Disorder><Dose><Elderly><Europe><Event><FDA EUA><FDA Emergency Use Authorization><Food and Drug Administration><Food and Drug Administration EUA><Food and Drug Administration Emergency Use Authorization><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Alteration><Genetic Change><Genetic Diseases><Genetic defect><Germany><Grafting Procedure><Health><Home><Human><IFN><Immune><Immune Cell Activation><Immune response><Immune system><Immunes><Immunization><Immunochemical Immunologic><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunologic><Immunologic Sensitization><Immunologic Stimulation><Immunological><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunologically><Immunologics><Immunostimulation><Immunosuppressed Host><In Vitro><Incontinentia Pigmenti><Individual><Infection><Inflammation><Inflammatory Response><Innate Immune Response><Institution><Interferons><International><Intracellular Communication and Signaling><Investigation><JAK kinase><Janus kinase><Kidney><Kidney Urinary System><Knowledge><Link><Logistics><Lung><Lung Respiratory System><Messenger RNA><Mice><Mice Mammals><Modern Man><Murine><Mus><Mutation><Organ Transplantation><Organ Transplants><Outcome><PBMC><Pathway interactions><Patients><Peripheral Blood Mononuclear Cell><Pfizer-BioNTech COVID-19 vaccine><Pfizer-BioNTech coronavirus disease 2019 vaccine><Population><Population Group><Prevalence><Prevention Measures><RNA Seq><RNA sequencing><RNA vaccine><RNA-based vaccine><RNAseq><Receptor Protein><Reporting><Republic of Korea><Research><SARS corona virus 2><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 immune response><SARS-CoV-2 immunity><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 pandemic><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><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 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><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 corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 immune response><Severe acute respiratory syndrome coronavirus 2 immunity><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Siemens-Bloch pigmented dermatosis><Signal Transduction><Signal Transduction Systems><Signaling><South Korea><Symptoms><System><Therapeutic Uses><Time><Transcription Factor Proto-Oncogene><Transcription factor genes><USFDA><United States Food and Drug Administration><Vaccinated><Vaccination><Vaccines><Variant><Variation><Whole Blood><Wuhan coronavirus><active followup><advanced age><ages><allergic/immunologic body system><allergic/immunologic organ system><aminoacid><angiotensin converting enzyme 2><angiotensin converting enzyme II><anti-viral immunity><antiviral immunity><base><biological signal transduction><comparative><corona virus disease><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease><coronavirus disease 2019><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 immune response><coronavirus disease 2019 immunity><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 prevention><coronavirus disease 2019 public health crisis><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease infected patient><coronavirus disease pandemic><coronavirus disease patient><coronavirus disease positive patient><coronavirus patient><cystic fibrosis patients><cytokine release syndrome><cytokine storm><design><designing><elders><emergency use authorization><experience><experiment><experimental research><experimental study><follow up><follow-up><followed up><followup><genetic condition><genetic disorder><genome mutation><genome scale><genome-wide><genomewide><geriatric><global gene expression><global transcription profile><hCoV19><host response><immune activation><immune system response><immunity against COVID-19><immunity against COVID19><immunity against SARS-CoV-2><immunity against Severe acute respiratory syndrome coronavirus 2><immunity against coronavirus disease 2019><immunity to COVID-19><immunity to COVID19><immunity to SARS-CoV-2><immunity to Severe acute respiratory syndrome coronavirus 2><immunity to coronavirus disease 2019><immunoresponse><immunosuppressed patient><incontinentia pigmenti 1><individual response><individualized response><individuals with CF><individuals with cystic fibrosis><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><interest><international partnership><international research partnership><kinase inhibitor><late life><later life><mRNA><mRNA vaccine><mRNA-based vaccine><melanoblastosis cutis linearis sive systematisata><melanosis corii degenerativa><nCoV2><neutralizing antibody><nevus pigmentosus systematicus><older adult><older person><organ allograft><organ graft><organ xenograft><pandemic><pandemic disease><pathway><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><patients with CF><patients with cystic fibrosis><prevent COVID-19><prevent COVID19><prevent coronavirus disease 2019><pulmonary><receptor><receptor binding><receptor bound><renal><response><sample collection><senior citizen><seropositive><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 variant><severe acute respiratory syndrome coronavirus 2 variant forms><severe acute respiratory syndrome coronavirus 2 variant strains><specimen collection><symptomatology><transcription factor><transcriptome><transcriptome sequencing><vaccinology><variants of concern><vector-based vaccine><viral fitness>