Baseline innate and T cell populations are correlates of protection against symptomatic influenza virus infection independent of serology.

Evidence suggests that innate and adaptive cellular responses mediate resistance to the influenza virus and confer protection after vaccination. However, few studies have resolved the contribution of cellular responses within the context of preexisting antibody titers. Here, we measured the peripheral immune profiles of 206 vaccinated or unvaccinated adults to determine how baseline variations in the cellular and humoral immune compartments contribute independently or synergistically to the risk of developing symptomatic influenza. Protection correlated with diverse and polyfunctional CD4+ and CD8+ T, circulating T follicular helper, T helper type 17, myeloid dendritic and CD16+ natural killer (NK) cell subsets. Conversely, increased susceptibility was predominantly attributed to nonspecific inflammatory populations, including γδ T cells and activated CD16- NK cells, as well as TNFα+ single-cytokine-producing CD8+ T cells. Multivariate and predictive modeling indicated that cellular subsets (1) work synergistically with humoral immunity to confer protection, (2) improve model performance over demographic and serologic factors alone and (3) comprise the most important predictive covariates. Together, these results demonstrate that preinfection peripheral cell composition improves the prediction of symptomatic influenza susceptibility over vaccination, demographics or serology alone.

SARS-CoV-2 antigen exposure history shapes phenotypes and specificity of memory CD8+ T cells.

Although mRNA vaccine efficacy against severe coronavirus disease 2019 remains high, variant emergence has prompted booster immunizations. However, the effects of repeated exposures to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens on memory T cells are poorly understood. Here, we utilize major histocompatibility complex multimers with single-cell RNA sequencing to profile SARS-CoV-2-responsive T cells ex vivo from humans with one, two or three antigen exposures, including vaccination, primary infection and breakthrough infection. Exposure order determined the distribution between spike-specific and non-spike-specific responses, with vaccination after infection leading to expansion of spike-specific T cells and differentiation to CCR7-CD45RA+ effectors. In contrast, individuals after breakthrough infection mount vigorous non-spike-specific responses. Analysis of over 4,000 epitope-specific T cell antigen receptor (TCR) sequences demonstrates that all exposures elicit diverse repertoires characterized by shared TCR motifs, confirmed by monoclonal TCR characterization, with no evidence for repertoire narrowing from repeated exposure. Our findings suggest that breakthrough infections diversify the T cell memory repertoire and current vaccination protocols continue to expand and differentiate spike-specific memory.

Human CD8+ T cell cross-reactivity across influenza A, B and C viruses.

Influenza A, B and C viruses (IAV, IBV and ICV, respectively) circulate globally and infect humans, with IAV and IBV causing the most severe disease. CD8+ T cells confer cross-protection against IAV strains, however the responses of CD8+ T cells to IBV and ICV are understudied. We investigated the breadth of CD8+ T cell cross-recognition and provide evidence of CD8+ T cell cross-reactivity across IAV, IBV and ICV. We identified immunodominant CD8+ T cell epitopes from IBVs that were protective in mice and found memory CD8+ T cells directed against universal and influenza-virus-type-specific epitopes in the blood and lungs of healthy humans. Lung-derived CD8+ T cells displayed tissue-resident memory phenotypes. Notably, CD38+Ki67+CD8+ effector T cells directed against novel epitopes were readily detected in IAV- or IBV-infected pediatric and adult subjects. Our study introduces a new paradigm whereby CD8+ T cells confer unprecedented cross-reactivity across all influenza viruses, a key finding for the design of universal vaccines.

Mucosal immune responses to infection and vaccination in the respiratory tract.

The lungs are constantly exposed to inhaled debris, allergens, pollutants, commensal or pathogenic microorganisms, and respiratory viruses. As a result, innate and adaptive immune responses in the respiratory tract are tightly regulated and are in continual flux between states of enhanced pathogen clearance, immune-modulation, and tissue repair. New single-cell-sequencing techniques are expanding our knowledge of airway cellular complexity and the nuanced connections between structural and immune cell compartments. Understanding these varied interactions is critical in treatment of human pulmonary disease and infections and in next-generation vaccine design. Here, we review the innate and adaptive immune responses in the lung and airways following infection and vaccination, with particular focus on influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The ongoing SARS-CoV-2 pandemic has put pulmonary research firmly into the global spotlight, challenging previously held notions of respiratory immunity and helping identify new populations at high risk for respiratory distress.

SARS-CoV-2-specific T cell memory with common TCRαß motifs is established in unvaccinated children who seroconvert after infection.

As the establishment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell memory in children remains largely unexplored, we recruited convalescent COVID-19 children and adults to define their circulating memory SARS-CoV-2-specific CD4+ and CD8+ T cells prior to vaccination. We analyzed epitope-specific T cells directly ex vivo using seven HLA class I and class II tetramers presenting SARS-CoV-2 epitopes, together with Spike-specific B cells. Unvaccinated children who seroconverted had comparable Spike-specific but lower ORF1a- and N-specific memory T cell responses compared with adults. This agreed with our TCR sequencing data showing reduced clonal expansion in children. A strong stem cell memory phenotype and common T cell receptor motifs were detected within tetramer-specific T cells in seroconverted children. Conversely, children who did not seroconvert had tetramer-specific T cells of predominantly naive phenotypes and diverse TCRαß repertoires. Our study demonstrates the generation of SARS-CoV-2-specific T cell memory with common TCRαß motifs in unvaccinated seroconverted children after their first virus encounter.

Lung γδ T Cells Mediate Protective Responses during Neonatal Influenza Infection that Are Associated with Type 2 Immunity.

Compared to adults, infants suffer higher rates of hospitalization, severe clinical complications, and mortality due to influenza infection. We found that γδ T cells protected neonatal mice against mortality during influenza infection. γδ T cell deficiency did not alter viral clearance or interferon-γ production. Instead, neonatal influenza infection induced the accumulation of interleukin-17A (IL-17A)-producing γδ T cells, which was associated with IL-33 production by lung epithelial cells. Neonates lacking IL-17A-expressing γδ T cells or Il33 had higher mortality upon influenza infection. γδ T cells and IL-33 promoted lung infiltration of group 2 innate lymphoid cells and regulatory T cells, resulting in increased amphiregulin secretion and tissue repair. In influenza-infected children, IL-17A, IL-33, and amphiregulin expression were correlated, and increased IL-17A levels in nasal aspirates were associated with better clinical outcomes. Our results indicate that γδ T cells are required in influenza-infected neonates to initiate protective immunity and mediate lung homeostasis.

Publisher Correction: Exuberant fibroblast activity compromises lung function via ADAMTS4.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Exuberant fibroblast activity compromises lung function via ADAMTS4.

Severe respiratory infections can result in acute respiratory distress syndrome (ARDS)1. There are no effective pharmacological therapies that have been shown to improve outcomes for patients with ARDS. Although the host inflammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS1,2. Here we demonstrate that respiratory viral infection induces distinct fibroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive and interferon-responsive states. We provide evidence that excess activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing ECM-remodelling enzymes-in particular the ECM protease ADAMTS4-and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. In three cohorts of human participants, the levels of ADAMTS4 in the lower respiratory tract were associated with the severity of infection with seasonal or avian influenza virus. A therapeutic agent that targets the ECM protease activity of damage-responsive lung fibroblasts could provide a promising approach to preserving lung function and improving clinical outcomes following severe respiratory infections.

The dynamics of SARS-CoV-2 infectivity with changes in aerosol microenvironment.

Understanding the factors that influence the airborne survival of viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in aerosols is important for identifying routes of transmission and the value of various mitigation strategies for preventing transmission. We present measurements of the stability of SARS-CoV-2 in aerosol droplets (∼5 to 10 µm equilibrated radius) over timescales spanning 5 s to 20 min using an instrument to probe survival in a small population of droplets (typically 5 to 10) containing ∼1 virus/droplet. Measurements of airborne infectivity change are coupled with a detailed physicochemical analysis of the airborne droplets containing the virus. A decrease in infectivity to ∼10% of the starting value was observable for SARS-CoV-2 over 20 min, with a large proportion of the loss occurring within the first 5 min after aerosolization. The initial rate of infectivity loss was found to correlate with physical transformation of the equilibrating droplet; salts within the droplets crystallize at relative humidities (RHs) below 50%, leading to a near-instant loss of infectivity in 50 to 60% of the virus. However, at 90% RH, the droplet remains homogenous and aqueous, and the viral stability is sustained for the first 2 min, beyond which it decays to only 10% remaining infectious after 10 min. The loss of infectivity at high RH is consistent with an elevation in the pH of the droplets, caused by volatilization of CO2 from bicarbonate buffer within the droplet. Four different variants of SARS-CoV-2 were compared and found to have a similar degree of airborne stability at both high and low RH.

An assessment of the airborne longevity of group A Streptococcus.

Group A streptococcus (GAS) infections result in more than 500 000 deaths annually. Despite mounting evidence for airborne transmission of GAS, little is known about its stability in aerosol. Measurements of GAS airborne stability were carried out using the Controlled Electrodynamic Levitation and Extraction of Bioaerosols onto a Substrate (CELEBS) instrument. CELEBS measurements with two different isolates of GAS suggest that it is aerostable, with approximately 70 % of bacteria remaining viable after 20 min of levitation at 50 % relative humidity (RH), with lower survival as RH was reduced. GAS airborne viability loss was driven primarily by desiccation and efflorescence (i.e. salt crystallization), with high pH also potentially playing a role, given reduced survival in bicarbonate containing droplet compositions. At low enough RH for efflorescence to occur, a greater proportion of organic components in the droplet appeared to protect the bacteria from efflorescence. These first insights into the aerosol stability of GAS indicate that airborne transmission of these respiratory tract bacteria may occur, and that both the composition of the droplet containing the bacteria, and the RH of the air affect the duration of bacterial survival in this environment. Future studies will explore a broader range of droplet and air compositions and include a larger selection of GAS strains.

Toward Standardized Aerovirology: A Critical Review of Existing Results and Methodologies.

Understanding the airborne survival of viruses is important for public health and epidemiological modeling and potentially to develop mitigation strategies to minimize the transmission of airborne pathogens. Laboratory experiments typically involve investigating the effects of environmental parameters on the viability or infectivity of a target airborne virus. However, conflicting results among studies are common. Herein, the results of 34 aerovirology studies were compared to identify links between environmental and compositional effects on the viability of airborne viruses. While the specific experimental apparatus was not a factor in variability between reported results, it was determined that the experimental procedure was a major factor that contributed to discrepancies in results. The most significant contributor to variability between studies was poorly defined initial viable virus concentration in the aerosol phase, causing many studies to not measure the rapid inactivation, which occurs quickly after particle generation, leading to conflicting results. Consistently, studies that measured their reference airborne viability minutes after aerosolization reported higher viability at subsequent times, which indicates that there is an initial loss of viability which is not captured in these studies. The composition of the particles which carry the viruses was also found to be important in the viability of airborne viruses; however, the mechanisms for this effect are unknown. Temperature was found to be important for aerosol-phase viability, but there is a lack of experiments that directly compare the effects of temperature in the aerosol phase and the bulk phase. There is a need for repeated measurements between different research groups under identical conditions both to assess the degree of variability between studies and also to attempt to better understand already published data. Lack of experimental standardization has hindered the ability to quantify the differences between studies, for which we provide recommendations for future studies. These recommendations are as follows: measuring the reference airborne viability using the "direct method"; use equipment which maximizes time resolution; quantify all losses appropriately; perform, at least, a 5- and 10-min sample, if possible; report clearly the composition of the virus suspension; measure the composition of the gas throughout the experiment. Implementing these recommendations will address the most significant oversights in the existing literature and produce data which can more easily be quantitatively compared.

Studies of the Crystallization and Dissolution of Individual Suspended Sodium Chloride Aerosol Particles.

Aerosols transform between physical phases, as they respond to variations in environmental conditions. There are many industries that depend on these dynamic processes of crystallization and dissolution. Here, a single particle technique (an electrodynamic balance) is used to explore the crystallization and dissolution dynamics of a model system, sodium chloride. The physical and environmental factors that influence the dynamics of crystal formation from a saline droplet (whose initial radius is ∼25 µm) and the kinetics of water adsorption onto dried particles are examined. The drying relative humidity (RH) is shown to impact the physical properties of the dried particle. When a saline droplet is injected into an airflow at an RH close to the efflorescence RH (ERH, 45%), an individual single crystal forms. By contrast, when a compositionally equivalent saline droplet is injected into dry air (RH ∼ 0%), a salt crystal made of multiple crystalline particles is formed. Subsequent to crystallization, the crystal shape, morphology, and surface area were all found to affect the dissolution dynamics of the dried particle. Additionally, we report that the difference between the deliquesce RH and environmental RH significantly impacts the dissolution time scale.

Multilayer depressive symptom networks in adults with bodily pain living in precarious housing or homelessness.

Housing insecurity is associated with co-occurring depression and pain interfering with daily activities. Network analysis of depressive symptoms along with associated risk or protective exposures may identify potential targets for intervention in patients with co-occurring bodily pain. In a community-based sample of adults (n = 408) living in precarious housing or homelessness in Vancouver, Canada, depressive symptoms were measured by the Beck Depression Inventory; bodily pain and impact were assessed with the 36-item Short Form Health Survey. Network and bootstrap permutation analyses were used to compare depressive symptoms endorsed by Low versus Moderate-to-Severe (Mod + Pain) groups. Multilayer networks estimated the effects of risk and protective factors. The overall sample was comprised of 78% men, mean age 40.7 years, with 53% opioid use disorder and 14% major depressive disorder. The Mod + Pain group was characterized by multiple types of pain, more persistent pain, more severe depressive symptoms and a higher rate of suicidal ideation. Global network connectivity did not differ between the two pain groups. Suicidal ideation was a network hub only in the Mod + Pain group, with high centrality and a direct association with exposure to lifetime trauma. Antidepressant medications had limited impact on suicidal ideation. Guilt and increased feelings of failure represented symptoms from two other communities of network nodes, and completed the shortest pathway from trauma exposure through suicidal ideation, to the non-prescribed opioid exposure node. Interventions targeting these risk factors and symptoms could affect the progression of depression among precariously housed patients.

A qualitative study of barriers and facilitators for health behavior change in low-income men with prostate cancer.

PURPOSE: Low-income prostate cancer survivors, who typically have worse outcomes and greater all-cause mortality, often have poor health-promoting behaviors. Our objective was to assess perceived facilitators of and barriers to healthy behavior change by interviewing low-income men with prostate cancer who received no-cost treatment through a state-funded program. METHODS: Between September 2021 and April 2022, we conducted semi-structured interviews with 19 men (ages 60-75). Purposive sampling was utilized from participants of a cohort of men with prostate cancer from low-income backgrounds. Interviews were recorded, transcribed, and then coded by the authors to generate salient themes via thematic analysis. RESULTS: We found internal characteristics and structural characteristics that functioned independently and in concert to promote and/or hinder healthy behavior change. Internal characteristics such as motivations (prostate cancer diagnosis, self-perceptions, support system, and preferences) and determination, defined as level of motivation, drove behavior actualization. Structural characteristics that influenced behavior change included resources (access to food and opportunities for exercise) and social support. CONCLUSIONS: These outcomes suggest that motivation and determination can serve as protective facilitators encouraging healthy behaviors despite structural barriers low-income prostate cancer survivors may face. However, motivations challenged by financial constraints were not sufficient to guide healthy behavior change. With this in mind, we recommend that interventions promoting healthy behavior change among this population should focus on identifying and strengthening internal assets such as motivations, self-perceptions, preferences, and support systems.

Hepatology Genome Rounds: An interdisciplinary approach to integrate genomic data into clinical practice.

In the last decade, the utility of whole-exome sequencing in uncovering genetic aetiologies of a variety of liver diseases has been demonstrated. These new diagnoses have guided the management, treatment, and prognostication of previously undiagnosed patients, largely thanks to improved insight into the underlying pathogenesis of their conditions. Despite its clear benefits, the uptake of genetic testing by hepatologists has been limited, in part due to limited prior genetic training and/or opportunities for continuing education. Herein, we show that Hepatology Genome Rounds, an interdisciplinary forum highlighting hepatology cases of clinical interest and educational value, are an important venue for integrating genotypic and phenotypic information to enable accurate diagnosis and appropriate management, dissemination of genomic knowledge within the field of hepatology, and ongoing education to providers and trainees in genomic medicine. We describe our single-centre experience and discuss practical considerations for clinicians interested in launching such a series. We foresee that this format will be adopted at other institutions and by additional specialties, with the aim of further incorporating genomic information into clinical medicine.

Molecular markers of metastatic disease in KRAS-mutant lung adenocarcinoma.

BACKGROUND: Prior studies characterized the association of molecular alterations with treatment-specific outcomes in KRAS-mutant (KRASMUT) lung adenocarcinoma (LUAD). Less is known about the prognostic role of molecular alterations and their associations with metastatic disease. PATIENTS AND METHODS: We analyzed clinicogenomic data from 1817 patients with KRASMUT LUAD sequenced at the Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering Cancer Center (MSKCC). Patients with metastatic (M1) and nonmetastatic (M0) disease were compared. Transcriptomic data from The Cancer Genome Atlas (TCGA) were investigated to characterize the biology of differential associations with clinical outcomes. Organ-specific metastasis was associated with overall survival (OS). RESULTS: KEAP1 (DFCI: OR = 2.3, q = 0.04; MSKCC: OR = 2.2, q = 0.00027) and SMARCA4 mutations (DFCI: OR = 2.5, q = 0.06; MSKCC: OR = 2.6, q = 0.0021) were enriched in M1 versus M0 tumors. On integrative modeling, NRF2 activation was the genomic feature most associated with OS. KEAP1 mutations were enriched in M1 versus M0 tumors independent of STK11 status (KEAP1MUT/STK11WT: DFCI OR = 3.0, P = 0.0064; MSKCC OR = 2.0, P = 0.041; KEAP1MUT/STK11MUT: DFCI OR = 2.3, P = 0.0063; MSKCC OR = 2.5, P = 3.6 × 10-05); STK11 mutations without KEAP1 loss were not associated with stage (KEAP1WT/STK11MUT: DFCI OR = 0.97, P = 1.0; MSKCC OR = 1.2, P = 0.33) or outcome. KEAP1/KRAS-mutated tumors with and without STK11 mutations exhibited high functional STK11 loss. The negative effects of KEAP1 were compounded in the presence of bone (HR = 2.3, P = 4.4 × 10-14) and negated in the presence of lymph node metastasis (HR = 1.0, P = 0.91). CONCLUSIONS: Mutations in KEAP1 and SMARCA4, but not STK11, were associated with metastatic disease and poor OS. Functional STK11 loss, however, may contribute to poor outcomes in KEAP1MUT tumors. Integrating molecular data with clinical and metastatic-site annotations can more accurately risk stratify patients.

Relationship between pelvic sensations and lifetime exposure to receptive anal intercourse among people with prostates.

BACKGROUND: Despite the negative stigma on receptive anal intercourse (RAI), this behavior has a positive influence on individuals' sexual and relationship health. No large studies have previously looked at specific sensations experienced during RAI and how these sensations may change with experience. AIM: In this study we aimed to quantify commonly reported pelvic sensations during RAI and determine whether their presentation changes with increasing experience of RAI. METHODS: An internet survey was conducted on sensations felt during RAI among people with prostates from July 2022-January 2023. The survey content was developed based on a mixed-methods qualitative study and inquired about demographic and sexual histories as well as sensations (pleasure, pain, urinary, and bowel) experienced during RAI. We used descriptive statistics to describe demographic and sexual histories. All data were stratified by lifetime exposure to RAI. OUTCOMES: The primary outcomes assessed included the quantification of both the primary sensations experienced during RAI and the associated bother. RESULTS: In total, 975 participants completed the survey. The median age was 32 (range 18-78) years. The average age of first participation in RAI was 21 ± 6.6 years. Most respondents were having sex at least once a week (65%). Nine percent of respondents reported fewer than 10 experiences with RAI, 26% reported 11-50 RAI experiences, 32% reported 51-200 experiences, 16% reported 201-500 experiences, and 18% reported >500 experiences. As the number of experiences with RAI increased (from <10 to >500 exposures), the reported frequency of pleasurable sensation increased from 41% to 92% (P < .0001), whereas severe insertional pain and symptoms of bowel urgency decreased from 39% to 13% and from 21% to 6%, respectively (P < .0001). Urinary urgency sensation did not differ by lifetime RAI experience. CLINICAL IMPLICATIONS: Lifetime RAI exposure can be readily assessed and correlates not only with pelvic sensation but also many other aspects of sexual health. These results imply that the etiology of dissatisfaction with pleasure or anodyspareunia during RAI may differ by lifetime RAI exposure. STRENGTHS AND LIMITATIONS: This is the first study to our knowledge to assess pelvic sensations experienced during RAI among a large sample of individuals. This is a cross-sectional study, and we cannot conclude how pelvic sensations change over time among individuals. Internet-based participants may not be representative of clinical populations. CONCLUSION: Lifetime exposure to RAI is positively associated with pleasure and is negatively associated with pain and bowel urgency. Pelvic sensations experienced during RAI appear to be dependent on lifetime RAI exposure history regardless of age.

Massively parallel variant characterization identifies NUDT15 alleles associated with thiopurine toxicity.

As a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. Recently, NUDT15 deficiency was identified as a genetic cause of thiopurine toxicity, and NUDT15-informed preemptive dose reduction was quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine the variants' effect on protein abundance and thiopurine cytotoxicity. Of the 3,097 possible missense variants, we characterized the abundance of 2,922 variants and found 54 hotspot residues at which variants resulted in complete loss of protein stability. Analyzing 2,935 variants in the thiopurine cytotoxicity-based assay, we identified 17 additional residues where variants altered NUDT15 activity without affecting protein stability. We identified structural elements key to NUDT15 stability and/or catalytical activity with single amino acid resolution. Functional effects for NUDT15 variants accurately predicted toxicity risk alleles in patients treated with thiopurines with far superior sensitivity and specificity compared to bioinformatic prediction algorithms. In conclusion, our massively parallel variant function assays identified 1,152 deleterious NUDT15 variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization.

Anxiety symptoms and theory of mind in older and younger adults: curvilinearity moderated by age group.

OBJECTIVES: Theory of mind (ToM), the ability to reason about mental states, declines in later life. While anxiety symptoms may predict ToM abilities, the nature of associations requires more elucidation. Further, it is unknown whether age group moderates associational patterns. We examined associations between anxiety symptoms (linear and curvilinear) and cognitive ToM (C-ToM) and affective ToM (A-ToM); and moderation by age group (older vs. younger adults). METHODS: In a sample of healthy younger (n = 90, Mage = 20.17 years) and older adults (n = 87, Mage = 71.52), we used hierarchical regressions with polynomial and interaction terms to assess the association between anxiety symptoms and ToM in younger and older adults. RESULTS: Anxiety symptoms were associated with C-ToM but not A-ToM. Age group interacted linearly with anxiety (ß = -1.64, p = .02), and with anxiety's quadratic polynomial (ß = .84, p = .04). The inverted-U shaped association in younger adults (highest C-ToM at moderate anxiety) contrasted with older adults' linear decline in C-ToM with increasing anxiety. CONCLUSION: We highlight the importance of anxiety symptoms for predicting ToM, and clarify that associations vary by age. Elucidating associations may be critical to developing interventions that improve social wellbeing.

Host Predictors of Broadly Cross-Reactive Antibodies Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Variants of Concern Differ Between Infection and Vaccination.

BACKGROUND: Following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination there is significant variability between individuals in protective antibody levels against SARS-CoV-2, and within individuals against different virus variants. However, host demographic or clinical characteristics that predict variability in cross-reactive antibody levels are not well-described. These data could inform clinicians, researchers, and policymakers on the populations most likely to require vaccine booster shots. METHODS: In an institutional review board-approved prospective observational cohort study of staff at St. Jude Children's Research Hospital, we identified participants with plasma samples collected after SARS-CoV-2 infection, after mRNA vaccination, and after vaccination following infection, and quantitated immunoglobulin G (IgG) levels by enzyme-linked immunosorbent assay to the spike receptor binding domain (RBD) from 5 important SARS-CoV-2 variants (Wuhan Hu-1, B.1.1.7, B.1.351, P.1, and B.1.617.2). We used regression models to identify factors that contributed to cross-reactive IgG against 1 or multiple viral variants. RESULTS: Following infection, a minority of the cohort generated cross-reactive antibodies, IgG antibodies that bound all tested variants. Those who did had increased disease severity, poor metabolic health, and were of a particular ancestry. Vaccination increased the levels of cross-reactive IgG levels in all populations, including immunocompromised, elderly, and persons with poor metabolic health. Younger people with a healthy weight mounted the highest responses. CONCLUSIONS: Our findings provide important new information on individual antibody responses to infection/vaccination that could inform clinicians on populations that may require follow-on immunization.