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ImportanceData on the humoral and cellular immune response to primary and booster SARS-CoV-2 vaccination in immunosuppressed patients is limited. ObjectiveTo determine humoral and cellular response to primary and booster vaccination in immunosuppressed patients and identify variables associated with poor response. DesignRetrospective observational cohort study. SettingLarge healthcare system in Northern California. ParticipantsThis study included patients fully vaccinated against SARS-CoV-2 (mRNA-1273, BNT162b2, or Ad26.COV2.S) who underwent clinical testing for anti-SARS-SoV-2 S1 IgG ELISA (anti-S1 IgG) and SARS-CoV-2 interferon gamma release assay (IGRA) from January 1, 2021 through November 15, 2021. A cohort of 18 immunocompetent volunteer healthcare workers were included as reference. No participants had a prior diagnosis of SARS-CoV-2 infection. Exposure(s)Immunosuppressive diseases and therapies. Main Outcome(s) and Measure(s)Humoral and cellular SARS-CoV-2 vaccine response as measured by anti-S1 IgG and SARS-CoV-2 IGRA, respectively, after primary and booster vaccination. Results496 patients (54% female; median age 50 years) were included in this study. Among immunosuppressed patients after primary vaccination, 62% (261/419) had positive anti-S1 IgG and 71% (277/389) had positive IGRA. After booster, 69% (81/118) had positive anti-S1 IgG and 73% (91/124) had positive IGRA. Immunosuppressive factors associated with low rates of humoral response after primary vaccination included anti-CD20 monoclonal antibodies (P<.001), sphingosine 1-phsophate (S1P) receptor modulators (P<.001), mycophenolate (P=.002), and B cell lymphoma (P=.004); those associated with low rates of cellular response included S1P receptor modulators (P<.001) and mycophenolate (P<.001). Of patients who responded poorly to primary vaccination, 16% (4/25) with hematologic malignancy or primary immunodeficiency developed a significantly increased humoral response after the booster dose, while 52% (14/27) with solid malignancy, solid organ transplantation, or autoimmune disease developed an increased response (P=.009). Only 5% (2/42) of immunosuppressed patients developed a significantly increased cellular response following the booster dose. Conclusions and RelevanceCellular vaccine response rates were higher than humoral response rates in immunosuppressed individuals after primary vaccination, particularly among those undergoing B cell targeting therapies. However, humoral response can be increased with booster vaccination, even in patients on B cell targeting therapies.
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Multiple SARS-CoV-2 variants that possess mutations associated with increased transmission and antibody escape have arisen over the course of the current pandemic. While the current vaccines have largely been effective against past variants, the number of mutations found on the Omicron (B.1.529) spike appear to diminish the efficacy of pre-existing immunity. Using pseudoparticles expressing the spike of several SARS-CoV-2 variants, we evaluated the magnitude and breadth of the neutralizing antibody response over time in naturally infected and in mRNA-vaccinated individuals. We observed that while boosting increases the magnitude of the antibody response to wildtype (D614), Beta, Delta and Omicron variants, the Omicron variant was the most resistant to neutralization. We further observed that vaccinated healthy adults had robust and broad antibody responses while responses were relatively reduced in vaccinated pregnant women, underscoring the importance of learning how to maximize mRNA vaccine responses in pregnant populations. Findings from this study show substantial heterogeneity in the magnitude and breadth of responses after infection and mRNA vaccination and may support the addition of more conserved viral antigens to existing SARS-CoV-2 vaccines. One Sentence SummaryDiminished efficacy of pre-existing immunity to highly mutated SARS-CoV-2 variants.
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Different vaccines for SARS-CoV-2 are approved in various countries, but few direct comparisons of the antibody responses they stimulate have been reported. We collected plasma specimens in July 2021 from 196 Mongolian participants fully vaccinated with one of four Covid vaccines: Pfizer/BioNTech, AstraZeneca, Sputnik V and Sinopharm. Functional antibody testing with a panel of nine SARS-CoV-2 viral variant RBD proteins reveal marked differences in the vaccine responses, with low antibody levels and RBD-ACE2 blocking activity stimulated by the Sinopharm and Sputnik V vaccines in comparison to the AstraZeneca or Pfizer/BioNTech vaccines. The Alpha variant caused 97% of infections in Mongolia in June and early July 2021. Individuals who recover from SARS-CoV-2 infection after vaccination achieve high antibody titers in most cases. These data suggest that public health interventions such as vaccine boosting, potentially with more potent vaccine types, may be needed to control the COVID-19 pandemic in Mongolia and worldwide.
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Characterization of cell-mediated and humoral immune responses to SARS-CoV2 mRNA vaccine has implications for protective immunity in immunocompromised patients. However, studies have demonstrated poor humoral response to SARS-CoV2 mRNA vaccine in immunocompromised patients and data on cellular immune response are currently lacking. Here we compared immune response after 2-dose vaccination in 100 immunocompromised patients (solid organ transplant recipients, hematologic malignancy, autoimmune condition, and primary immunodeficiency) and 16 immunocompetent healthy healthcare workers. We find that 100% (CI=80.6-100%) of immunocompetent individuals show positive cell-mediated and humoral immune response post vaccination while only 50% (CI=40.4-59.6%) of immunocompromised patients show humoral immune response and 69% (CI=59.4-77.2%) have a positive cell-mediated immune response. 21% of immunocompromised patients have no humoral immune response or cell-mediated immune response and thus are likely vulnerable to SARS-CoV2 infection. Monitoring of immune response in immunocompromised populations, particularly in high-risk immunocompromised patients (solid organ transplant recipients, patients with severe autoimmunity, and those [≥]50 years), with clinical IGRA and serological assay after vaccination may identify patients who may benefit from revaccination or prophylactic monoclonal antibody therapy to prevent COVID-19 in this patient population
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BackgroundPatients receiving dialysis may mount impaired responses to COVID19 vaccination. MethodsWe report antibody response to vaccination from 1140 patients without, and 493 patients with pre-vaccination SARS-CoV-2 RBD antibody. We used commercially available assays (Siemens) to test remainder plasma monthly in association with vaccination date and type, and assess prevalence of absent total receptor binding antibody, and absent or attenuated (index value < 10) semiquantitative receptor binding domain IgG index values. We used Poisson regression to evaluate risk factors for absent or attenuated response to vaccination. ResultsAmong patients who were seronegative versus seropositive before vaccination, 62% and 56% were [≥]65 years old, 20% and 24% were Hispanic, and 22% and 23% were Black. Median IgG index values rose steadily over time, and were higher among the seropositive than in the seronegative patients after completing vaccination (150 [25th, 75th percentile 23.2, 150.0] versus 41.6 [11.3, 150.0]). Among 610 patients who completed vaccination (assessed [≥]14 days later, median 29 days later), the prevalence of absent total RBD response, and absent and attenuated semiquantitative IgG response was 4.4% (95% CI 3.1, 6.4%), 3.4% (2.4, 5.2%), and 14.3% (11.7, 17.3%) respectively. Risk factors for absent or attenuated response included longer vintage of end-stage kidney disease, and lower pre-vaccination serum albumin. ConclusionsMore than one in five patients receiving dialysis had evidence of an attenuated immune response to COVID19 vaccination. Significance statementPatients receiving dialysis face high likelihood of severe COVID19; at the same time, vaccination may be less efficacious, as prior data indicate impaired immune responses to influenza and Hepatitis B vaccination. We found that 22% of patients receiving dialysis had suboptimal responses to vaccination, irrespective of whether or not they had evidence of prior SARS-CoV-2 infection. Poorer health status and longer duration of end-stage kidney disease increased likelihood of suboptimal response. Ongoing vigilance for COVID19 in dialysis facilities and studies of modified vaccination dosing schedules will be critical to protecting patients receiving dialysis.
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During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, new vaccine strategies including lipid nanoparticle delivery of antigen encoding RNA have been deployed globally. The BioNTech/Pfizer mRNA vaccine BNT162b2 encoding SARS-CoV-2 spike protein shows 95% efficacy in preventing disease, but it is unclear how the antibody responses to vaccination differ from those generated by infection. Here we compare the magnitude and breadth of antibodies targeting SARS-CoV-2, SARS-CoV-2 variants of concern, and endemic coronaviruses, in vaccinees and infected patients. We find that vaccination differs from infection in the dominance of IgG over IgM and IgA responses, with IgG reaching levels similar to those of severely ill COVID-19 patients and shows decreased breadth of the antibody response targeting endemic coronaviruses. Viral variants of concern from B.1.1.7 to P.1 to B.1.351 form a remarkably consistent hierarchy of progressively decreasing antibody recognition by both vaccinees and infected patients exposed to Wuhan-Hu-1 antigens.
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The immunological picture of how different patients recover from COVID-19, and how those recovery trajectories are influenced by infection severity, remain unclear. We investigated 140 COVID-19 patients from diagnosis to convalescence using clinical data, viral load assessments, and multi-omic analyses of blood plasma and circulating immune cells. Immune-phenotype dynamics resolved four recovery trajectories. One trajectory signals a return to pre-infection healthy baseline, while the other three are characterized by differing fractions of persistent cytotoxic and proliferative T cells, distinct B cell maturation processes, and memory-like innate immunity. We resolve a small panel of plasma proteins that, when measured at diagnosis, can predict patient survival and recovery-trajectory commitment. Our study offers novel insights into post-acute immunological outcomes of COVID-19 that likely influence long-term adverse sequelae.
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BackgroundTo estimate seroprevalence of SARS-CoV-2 antibodies in the US, the country with the worlds largest absolute numbers of COVID19 cases and deaths, we conducted a cross-sectional assessment from a sample of patients receiving dialysis in January 2021. MethodsWe tested remainder plasma of 21,424 patients receiving dialysis through the third-largest US dialysis organization, with facilities located nationwide. We used the Siemens spike protein receptor binding domain total antibody assay to estimate crude SARS-CoV-2 seroprevalence, and then estimated seroprevalence for the US dialysis and adult population by standardizing by age, sex and region. We also compared January 2021 seroprevalence and case-detection rates to that from a similar subsample of patients receiving dialysis who had been tested in July 2020. ResultsPatients in the sample were disproportionately from older age and minority race/ethnic groups. Seroprevalence of SARS-CoV-2 was 18.9% (95% CI: 18.3-19.5%) in the sample, 18.7% (18.1-19.2%) standardized to the US dialysis population, and 21.3% (20.3-22.3%) standardized to the US adult population (range 15.3-20.8% in the Northeast and South respectively). Younger age groups (18-44 years), and persons self-identifying as Hispanic or living in Hispanic neighborhoods, and persons living in the poorest neighborhoods were among the subgroups with the highest seroprevalence (25.9% (24.1-27.8%), 25.1% (23.6-26.4%), 24.8% (23.2-26.5%) respectively). Compared to data from July 2020, we observed diminished variability in seroprevalence by geographic region and urban-rural status. Estimated case detection rate increased from 14% to 23% in July 2020 to January 2021. ConclusionsA year after the first case of SARS-CoV-2 infection was detected in the US, fewer than one in four adults have evidence of SARS-CoV-2 antibodies. Vaccine roll out to majority minority neighborhoods and poorer neighborhoods will be critical to disrupting the spread of infection. FundingAscend Clinical Laboratories funded remainder-plasma testing.
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BackgroundThere is increasing concern that persistent infection of SARS-CoV-2 within immunocompromised hosts could serve as a reservoir for mutation accumulation and subsequent emergence of novel strains with the potential to evade immune responses. MethodsWe describe three patients with acute lymphoblastic leukemia who were persistently positive for SARS-CoV-2 by real-time polymerase chain reaction. Viral viability from longitudinally-collected specimens was assessed. Whole-genome sequencing and serological studies were performed to measure viral evolution and evidence of immune escape. FindingsWe found compelling evidence of ongoing replication and infectivity for up to 162 days from initial positive by subgenomic RNA, single-stranded RNA, and viral culture analysis. Our results reveal a broad spectrum of infectivity, host immune responses, and accumulation of mutations, some with the potential for immune escape. InterpretationOur results highlight the need to reassess infection control precautions in the management and care of immunocompromised patients. Routine surveillance of mutations and evaluation of their potential impact on viral transmission and immune escape should be considered. FundingThe work was partially funded by The Saban Research Institute at Childrens Hospital Los Angeles intramural support for COVID-19 Directed Research (X.G. and J.D.B.), the Johns Hopkins Center of Excellence in Influenza Research and Surveillance HHSN272201400007C (A.P.), NIH/NIAID R01AI127877 (S.D.B.), NIH/NIAID R01AI130398 (S.D.B.), NIH 1U54CA260517 (S.D.B.), an endowment to S.D.B. from the Crown Family Foundation, an Early Postdoc.Mobility Fellowship Stipend to O.F.W. from the Swiss National Science Foundation (SNSF), and a Coulter COVID-19 Rapid Response Award to S.D.B. L.G. is a SHARE Research Fellow in Pediatric Hematology-Oncology.
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The biological determinants of the wide spectrum of COVID-19 clinical manifestations are not fully understood. Here, over 1400 plasma proteins and 2600 single-cell immune features comprising cell phenotype, basal signaling activity, and signaling responses to inflammatory ligands were assessed in peripheral blood from patients with mild, moderate, and severe COVID-19, at the time of diagnosis. Using an integrated computational approach to analyze the combined plasma and single-cell proteomic data, we identified and independently validated a multivariate model classifying COVID-19 severity (multi-class AUCtraining = 0.799, p-value = 4.2e-6; multi-class AUCvalidation = 0.773, p-value = 7.7e-6). Features of this high-dimensional model recapitulated recent COVID-19 related observations of immune perturbations, and revealed novel biological signatures of severity, including the mobilization of elements of the renin-angiotensin system and primary hemostasis, as well as dysregulation of JAK/STAT, MAPK/mTOR, and NF-{kappa}B immune signaling networks. These results provide a set of early determinants of COVID-19 severity that may point to therapeutic targets for the prevention of COVID-19 progression. SummaryFeyaerts et al. demonstrate that an integrated analysis of plasma and single-cell proteomics differentiates COVID-19 severity and reveals severity-specific biological signatures associated with the dysregulation of the JAK/STAT, MAPK/mTOR, and NF-{kappa}B immune signaling networks and the mobilization of the renin-angiotensin and hemostasis systems.
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The development of a portfolio of SARS-CoV-2 vaccines to vaccinate the global population remains an urgent public health imperative. Here, we demonstrate the capacity of a subunit vaccine under clinical development, comprising the SARS-CoV-2 Spike protein receptor binding domain displayed on a two-component protein nanoparticle (RBD-NP), to stimulate robust and durable neutralizing antibody (nAb) responses and protection against SARS-CoV-2 in non-human primates. We evaluated five different adjuvants combined with RBD-NP including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an alpha-tocopherol-containing squalene-based oil-in-water emulsion used in pandemic influenza vaccines; AS37, a TLR-7 agonist adsorbed to Alum; CpG 1018-Alum (CpG-Alum), a TLR-9 agonist formulated in Alum; or Alum, the most widely used adjuvant. All five adjuvants induced substantial nAb and CD4 T cell responses after two consecutive immunizations. Durable nAb responses were evaluated for RBD-NP/AS03 immunization and the live-virus nAb response was durably maintained up to 154 days post-vaccination. AS03, CpG-Alum, AS37 and Alum groups conferred significant protection against SARS-CoV-2 infection in the pharynges, nares and in the bronchoalveolar lavage. The nAb titers were highly correlated with protection against infection. Furthermore, RBD-NP when used in conjunction with AS03 was as potent as the prefusion stabilized Spike immunogen, HexaPro. Taken together, these data highlight the efficacy of the RBD-NP formulated with clinically relevant adjuvants in promoting robust immunity against SARS-CoV-2 in non-human primates.
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Vaccination and infection promote the formation, tissue distribution, and clonal evolution of B cells encoding humoral immune memory. We evaluated convergent antigen-specific antibody genes of similar sequences shared between individuals in pediatric and adult blood, and deceased organ donor tissues. B cell memory varied for different pathogens. Polysaccharide antigen-specific clones were not exclusive to the spleen. Adults convergent clones often express mutated IgM or IgD in blood and are class-switched in lymphoid tissues; in contrast, children have abundant class-switched convergent clones in blood. Consistent with serological reports, pre-pandemic children had class-switched convergent clones to SARS-CoV-2, enriched in cross-reactive clones for seasonal coronaviruses, while adults showed few such clones in blood or lymphoid tissues. These results extend age-related and anatomical mapping of human humoral pathogen-specific immunity. One Sentence SummaryChildren have elevated frequencies of pathogen-specific class-switched memory B cells, including SARS-CoV-2-binding clones.
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Recovery from COVID-19 is associated with production of anti-SARS-CoV-2 antibodies, but it is uncertain whether these confer immunity. We describe viral RNA shedding duration in hospitalized patients and identify patients with recurrent shedding. We sequenced viruses from two distinct episodes of symptomatic COVID-19 separated by 144 days in a single patient, to conclusively describe reinfection with a new strain harboring the spike variant D614G. With antibody and B cell analytics, we show correlates of adaptive immunity, including a differential response to D614G. Finally, we discuss implications for vaccine programs and begin to define benchmarks for protection against reinfection from SARS-CoV-2.
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SARS-CoV-2-specific antibodies, particularly those preventing viral spike receptor binding domain (RBD) interaction with host angiotensin-converting enzyme 2 (ACE2) receptor, could offer protective immunity, and may affect clinical outcomes of COVID-19 patients. We analyzed 625 serial plasma samples from 40 hospitalized COVID-19 patients and 170 SARS-CoV-2-infected outpatients and asymptomatic individuals. Severely ill patients developed significantly higher SARS-CoV-2-specific antibody responses than outpatients and asymptomatic individuals. The development of plasma antibodies was correlated with decreases in viral RNAemia, consistent with potential humoral immune clearance of virus. Using a novel competition ELISA, we detected antibodies blocking RBD-ACE2 interactions in 68% of inpatients and 40% of outpatients tested. Cross-reactive antibodies recognizing SARS-CoV RBD were found almost exclusively in hospitalized patients. Outpatient and asymptomatic individuals serological responses to SARS-CoV-2 decreased within 2 months, suggesting that humoral protection may be short-lived.
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During virus infection B cells are critical for the production of antibodies and protective immunity. Here we show that the human B cell compartment in patients with diagnostically confirmed SARS-CoV-2 and clinical COVID-19 is rapidly altered with the early recruitment of B cells expressing a limited subset of IGHV genes, progressing to a highly polyclonal response of B cells with broader IGHV gene usage and extensive class switching to IgG and IgA subclasses with limited somatic hypermutation in the initial weeks of infection. We identify extensive convergence of antibody sequences across SARS-CoV-2 patients, highlighting stereotyped naive responses to this virus. Notably, sequence-based detection in COVID-19 patients of convergent B cell clonotypes previously reported in SARS-CoV infection predicts the presence of SARS-CoV/SARS-CoV-2 cross-reactive antibody titers specific for the receptor-binding domain. These findings offer molecular insights into shared features of human B cell responses to SARS-CoV-2 and other zoonotic spillover coronaviruses.
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The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused a public health crisis that is exacerbated by our poor understanding of correlates of immunity. SARS-CoV-2 infection can cause Coronavirus Disease 2019 (COVID-19), with a spectrum of symptoms ranging from asymptomatic carriage to life threatening pneumonia and cytokine dysregulation [1-3]. Although antibodies have been shown in a variety of in vitro assays to promote coronavirus infections through mechanisms requiring interactions between IgG antibodies and Fc gamma receptors (Fc{gamma}Rs), the relevance of these observations to coronavirus infections in humans is not known [4-7]. In light of ongoing clinical trials examining convalescent serum therapy for COVID-19 patients and expedited SARS-CoV-2 vaccine testing in humans, it is essential to clarify the role of antibodies in the pathogenesis of COVID-19. Here we show that adults with PCR-diagnosed COVID-19 produce IgG antibodies with a specific Fc domain repertoire that is characterized by reduced fucosylation, a modification that enhances interactions with the activating Fc{gamma}R, Fc{gamma}RIIIa. Fc fucosylation was reduced when compared with SARS-CoV-2-seropositive children and relative to adults with symptomatic influenza virus infections. These results demonstrate an antibody correlate of symptomatic SARS-CoV-2 infections in adults and have implications for novel therapeutic strategies targeting Fc{gamma}RIIIa pathways.
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Pandemics originating from pathogen transmission between animals and humans highlight the broader need to understand how natural hosts have evolved in response to emerging human pathogens and which groups may be susceptible to infection. Here, we investigate angiotensin-converting enzyme 2 (ACE2), the host protein bound by SARS-CoV and SARS-CoV-2. We find that the ACE2 gene is under strong selection pressure in bats, the group in which the progenitors of SARS-CoV and SARS-CoV-2 are hypothesized to have evolved, particularly in residues that contact SARS-CoV and SARS-CoV-2. We detect positive selection in non-bat mammals in ACE2 but in a smaller proportion of branches than in bats, without enrichment of selection in residues that contact SARS-CoV or SARS-CoV-2. Additionally, we evaluate similarity between humans and other species in residues that contact SARS-CoV or SARS-CoV-2, revealing potential susceptible species but also highlighting the difficulties of predicting spillover events. This work increases our understanding of the relationship between mammals, particularly bats, and coronaviruses, and provides data that can be used in functional studies of how host proteins are bound by SARS-CoV and SARS-CoV-2 strains.