Impact of aging on immunity in the context of COVID-19, HIV, and tuberculosis.

Knowledge of aging biology needs to be expanded due to the continuously growing number of elderly people worldwide. Aging induces changes that affect all systems of the body. The risk of cardiovascular disease and cancer increases with age. In particular, the age-induced adaptation of the immune system causes a greater susceptibility to infections and contributes to the inability to control pathogen growth and immune-mediated tissue damage. Since the impact of aging on immune function, is still to be fully elucidated, this review addresses some of the recent understanding of age-related changes affecting key components of immunity. The emphasis is on immunosenescence and inflammaging that are impacted by common infectious diseases that are characterized by a high mortality, and includes COVID-19, HIV and tuberculosis.

Detection of SARS-CoV-2 antibodies after confirmed Omicron BA.1 and presumed BA.4/5 infections using Abbott ARCHITECT and Panbio assays.

Background: Commercial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody tests were developed before variants with spike protein mutations emerged, leading to concerns that these tests have reduced sensitivity for detecting antibody responses in individuals infected with Omicron subvariants. This study was performed to evaluate Abbott ARCHITECT serologic assays, AdviseDx SARS-CoV-2 IgG II, and SARS-CoV-2 IgG for the detection of spike (S) and nucleocapsid (N) IgG antibody increases in vaccinated healthcare workers infected with Omicron subvariants. Methods: During the BA.1/2 and BA.4/5 waves, 171 SARS-CoV-2-infected individuals (122 in the BA.1/2 wave, 49 in the BA.4/5 wave) were tested for S and N IgG post infection. Sequencing and SARS-CoV-2 variant confirmation were performed on nasal swab samples from individuals infected during the BA.1/2 wave. Results: Twenty-seven Omicron sequence confirmed individuals in the BA.1/2 wave and all 49 in the BA.4/5 wave had pre-infection antibody data. Compared to pre-infection levels, post-infection S IgG increased 6.6-fold from 1294 ± 302 BAU/ml (mean ± standard error measurement) to 9796 ± 1252 BAU/ml (P < 0.001) during the BA.1/2 wave, and 3.6-fold from 1771 ± 351 BAU/ml to 8224 ± 943 BAU/ml (P < 0.001) during the BA.4/5 wave. N IgG increased post infection 19.1-fold from 0.2 ± 0.1 to 3.7 ± 0.5 (P < 0.001) during the BA.1/2 wave and 13.5-fold from 0.22 ± 0.1 to 3.2 ± 0.3 (P < 0.001) during the BA.4/5 wave. Among 159 infection-naïve individuals, positive N IgG levels were detected with a sensitivity of 88% in the 87 individuals who were tested between 14 days and 60 days post infection. Conclusions: The large increases in post-infection S IgG along with the N IgG sensitivity that was comparable to previously reported N IgG sensitivity data in unvaccinated individuals after Omicron infection, support the use of Abbott SARS-CoV-2 assays for detecting increased S IgG and seroconversion of N IgG in vaccinated individuals post Omicron infection. Given that 68% of the United States population is fully vaccinated, these results are of current relevance.

Characterizing Symptoms and Identifying Biomarkers of Long COVID in People With and Without HIV: Protocol for a Remotely Conducted Prospective Observational Cohort Study.

BACKGROUND: Living with HIV is a risk factor for severe acute COVID-19, but it is unknown whether it is a risk factor for long COVID. OBJECTIVE: This study aims to characterize symptoms, sequelae, and cognition formally and prospectively 12 months following SARS-CoV-2 infection in people living with HIV compared with people without HIV. People with no history of SARS-CoV-2 infection, both with and without HIV, are enrolled as controls. The study also aims to identify blood-based biomarkers or patterns of immune dysregulation associated with long COVID. METHODS: This prospective observational cohort study enrolled participants into 1 of the following 4 study arms: people living with HIV who had SARS-CoV-2 infection for the first time <4 weeks before enrollment (HIV+COVID+ arm), people without HIV who had SARS-CoV-2 infection for the first time within 4 weeks of enrollment (HIV-COVID+ arm), people living with HIV who believed they never had SARS-CoV-2 infection (HIV+COVID- arm), and people without HIV who believed they never had SARS-CoV-2 infection (HIV-COVID- arm). At enrollment, participants in the COVID+ arms recalled their symptoms, mental health status, and quality of life in the month before having SARS-CoV-2 infection via a comprehensive survey administered by telephone or on the web. All participants completed the same comprehensive survey 1, 2, 4, 6, and 12 months after post-acute COVID-19 symptom onset or diagnosis, if asymptomatic, (COVID+ arms) or after enrollment (COVID- arms) on the web or by telephone. In total, 11 cognitive assessments were administered by telephone at 1 and 4 months after symptom onset (COVID+ arms) or after enrollment (COVID- arms). A mobile phlebotomist met the participants at a location of their choice for height and weight measurements, orthostatic vital signs, and a blood draw. Participants in the COVID+ arms donated blood 1 and 4 months after COVID-19, and participants in the COVID- arms donated blood once or none. Blood was then shipped overnight to the receiving study laboratory, processed, and stored. RESULTS: This project was funded in early 2021, and recruitment began in June 2021. Data analyses will be completed by summer 2023. As of February 2023, a total of 387 participants were enrolled in this study, with 345 participants having completed enrollment or baseline surveys together with at least one other completed study event. The 345 participants includes 76 (22%) HIV+COVID+, 121 (35.1%) HIV-COVID+, 78 (22.6%) HIV+COVID-, and 70 (20.3%) HIV-COVID- participants. CONCLUSIONS: This study will provide longitudinal data to characterize COVID-19 recovery over 12 months in people living with and without HIV. Additionally, this study will determine whether biomarkers or patterns of immune dsyregulation associate with decreased cognitive function or symptoms of long COVID. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47079.

Is France Once Again Looking for a Scapegoat?

On September 10, 2021, a special tribunal established by the French government launched an inquiry into the activities of former health minister Dr. Agnes Buzyn who was charged with "endangering the lives of others". It is surprising to learn of this accusation and inquiry into the actions of a public health official whose response to the epidemic was, to all appearances, exemplary.

Immune Dysregulation in Acute SARS-CoV-2 Infection.

Introduction: Neutralizing antibodies have been shown to develop rapidly following SARS-CoV-2 infection, specifically against spike (S) protein, where cytokine release and production is understood to drive the humoral immune response during acute infection. Thus, we evaluated the quantity and function of antibodies across disease severities and analyzed the associated inflammatory and coagulation pathways to identify acute markers that correlate with antibody response following infection. Methods: Blood samples were collected from patients at time of diagnostic SARS-CoV-2 PCR testing between March 2020-November 2020. Plasma samples were analyzed using the MesoScale Discovery (MSD) Platform using the COVID-19 Serology Kit and U-Plex 8 analyte multiplex plate to measure anti-alpha and beta coronavirus antibody concentration and ACE2 blocking function, as well as plasma cytokines. Results: A total of 230 (181 unique patients) samples were analyzed across the 5 COVID-19 disease severities. We found that antibody quantity directly correlated with functional ability to block virus binding to membrane-bound ACE2, where a lower SARS-CoV-2 anti-spike/anti-RBD response corresponded with a lower antibody blocking potential compared to higher antibody response (anti-S1 r = 0.884, P < 0.001; anti-RBD r = 0.75, P < 0.001). Across all the soluble proinflammatory markers we examined, ICAM, IL-1ß, IL-4, IL-6, TNFα, and Syndecan showed a statistically significant positive correlation between cytokine or epithelial marker and antibody quantity regardless of COVID-19 disease severity. Analysis of autoantibodies against type 1 interferon was not shown to be statistically significant between disease severity groups. Conclusion: Previous studies have shown that proinflammatory markers, including IL-6, IL-8, IL-1ß, and TNFα, are significant predictors of COVID-19 disease severity, regardless of demographics or comorbidities. Our study demonstrated that not only are these proinflammatory markers, as well as IL-4, ICAM, and Syndecan, correlative of disease severity, they are also correlative of antibody quantity and quality following SARS-CoV-2 exposure.

Siglec-9 Restrains Antibody-Dependent Natural Killer Cell Cytotoxicity against SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection alters the immunological profiles of natural killer (NK) cells. However, whether NK antiviral functions are impaired during severe coronavirus disease 2019 (COVID-19) and what host factors modulate these functions remain unclear. We found that NK cells from hospitalized COVID-19 patients degranulate less against SARS-CoV-2 antigen-expressing cells (in direct cytolytic and antibody-dependent cell cytotoxicity [ADCC] assays) than NK cells from mild COVID-19 patients or negative controls. The lower NK degranulation was associated with higher plasma levels of SARS-CoV-2 nucleocapsid antigen. Phenotypic and functional analyses showed that NK cells expressing the glyco-immune checkpoint Siglec-9 elicited higher ADCC than Siglec-9- NK cells. Consistently, Siglec-9+ NK cells exhibit an activated and mature phenotype with higher expression of CD16 (FcγRIII; mediator of ADCC), CD57 (maturation marker), and NKG2C (activating receptor), along with lower expression of the inhibitory receptor NKG2A, than Siglec-9- CD56dim NK cells. These data are consistent with the concept that the NK cell subpopulation expressing Siglec-9 is highly activated and cytotoxic. However, the Siglec-9 molecule itself is an inhibitory receptor that restrains NK cytotoxicity during cancer and other viral infections. Indeed, blocking Siglec-9 significantly enhanced the ADCC-mediated NK degranulation and lysis of SARS-CoV-2-antigen-positive target cells. These data support a model in which the Siglec-9+ CD56dim NK subpopulation is cytotoxic even while it is restrained by the inhibitory effects of Siglec-9. Alleviating the Siglec-9-mediated restriction on NK cytotoxicity may further improve NK immune surveillance and presents an opportunity to develop novel immunotherapeutic tools against SARS-CoV-2 infected cells. IMPORTANCE One mechanism that cancer cells use to evade natural killer cell immune surveillance is by expressing high levels of sialoglycans, which bind to Siglec-9, a glyco-immune checkpoint molecule on NK cells. This binding inhibits NK cell cytotoxicity. Several viruses, such as hepatitis B virus (HBV) and HIV, also use a similar mechanism to evade NK surveillance. We found that NK cells from SARS-CoV-2-hospitalized patients are less able to function against cells expressing SARS-CoV-2 Spike protein than NK cells from SARS-CoV-2 mild patients or uninfected controls. We also found that the cytotoxicity of the Siglec-9+ NK subpopulation is indeed restrained by the inhibitory nature of the Siglec-9 molecule and that blocking Siglec-9 can enhance the ability of NK cells to target cells expressing SARS-CoV-2 antigens. Our results suggest that a targetable glyco-immune checkpoint mechanism, Siglec-9/sialoglycan interaction, may contribute to the ability of SARS-CoV-2 to evade NK immune surveillance.

Effects of a booster dose of BNT162b2 on spike-binding antibodies to SARS-CoV-2 Omicron BA.2, BA.3, BA.4 and BA.5 subvariants in infection-naïve and previously-infected individuals.

It has been demonstrated that after two doses, SARS-CoV-2 mRNA vaccine-induced neutralizing antibodies against Omicron subvariants are much lower than against wild type virus and a booster dose greatly increases Omicron neutralization. We compared Spike-binding IgG responses against wild type virus and four SARS-CoV-2 Omicron subvariants in infection-naïve and previously-infected (hybrid immunity) individuals after the second and the third (booster) dose of BNT162b2. In both groups of individuals, antibodies for all four Omicron subvariants were lower than wild type antibodies. Compared to infection-naïve individuals, hybrid immunity resulted in higher antibodies levels after 2 doses of vaccine but not after the booster. In both groups, antibodies for wild type and all Omicron subvariants waned over an 8-month period post second dose but rebounded after the booster. These results underscore the importance of boosters to restore diminishing antibody levels for both infection-naïve and previously-infected individuals.

Longitudinal Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine Antibody Responses and Identification of Vaccine Breakthrough Infections Among Healthcare Workers Using Nucleocapsid Immunoglobulin G.

BACKGROUND: Long-term studies of vaccine recipients are necessary to understand severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody durability and assess the impact of booster doses on antibody levels and protection from infection. The identification of vaccine breakthrough infections among fully vaccinated populations will be important in understanding vaccine efficacy and SARS-CoV-2 vaccine escape capacity. METHODS: SARS-CoV-2 spike (S) receptor-binding domain and nucleocapsid (N) immunoglobulin (Ig) G levels were measured in a longitudinal study of 1000 Chicago healthcare workers who were infection naive or previously infected and then vaccinated. Changes in S and N IgG were followed up through 14 months, and vaccine breakthrough infections were identified by increasing levels of N IgG. RESULTS: SARS-CoV-2 S IgG antibody levels among previously infected and previously noninfected individuals decreased steadily for 11 months after vaccination. Administration of a booster 8-11 months after vaccination increased S IgG levels >2-fold beyond those observed after 2 doses, resulting in S IgG levels that were indistinguishable between previously infected and uninfected individuals. Increases in N IgG identified vaccine breakthrough infections and showed >15% breakthrough infection rates during the Omicron wave starting in December 2021. CONCLUSIONS: These results demonstrate SARS-CoV-2 antibody changes after vaccination and breakthrough infections and identify high levels of vaccine breakthrough infections during the Omicron wave, based on N IgG increases.

Correlation of Binding and Neutralizing Antibodies against SARS-CoV-2 Omicron Variant in Infection-Naïve and Convalescent BNT162b2 Recipients.

In vaccine clinical trials, both binding antibody (bAb) levels and neutralization antibody (nAb) titers have been shown to be correlates of SARS-CoV-2 vaccine efficacy. We report a strong correlation bAb and nAb responses against the SARS-CoV-2 Omicron (BA.1) variant in infection-naïve and previously infected (convalescent) individuals after one and two doses of BNT162b2 vaccination. The vaccine-induced bAb levels against Omicron were significantly lower compared to previous variants of concern in both infection-naive and convalescent individuals, with the convalescent individuals showing significantly higher bAb compared to the naïve individuals at all timepoints. The finding that bAb highly correlated with nAb provides evidence for utilizing binding antibody assays as a surrogate for neutralizing antibody assays. Our data also revealed that after full vaccination, a higher percentage of individuals had undetectable Omicron nAb (58.6% in naive individuals, 7.4% in convalescent individuals) compared to the percentage of individuals who had negative Omicron bAb (0% in naive individuals, 0% in convalescent individuals). The discordance between bAb and nAb activities and the high degree of immune escape by Omicron may explain the high frequency of Omicron infections after vaccination.

Neutralizing Antibody Activity to Severe Acute Respiratory Syndrome Coronavirus 2 Delta (B.1.617.2) and Omicron (B.1.1.529) After 1 or 2 Doses of BNT162b2 Vaccine in Infection-Naive and Previously Infected Individuals.

Previous reports demonstrated that severe acute respiratory syndrome coronavirus (SARS-CoV-2) binding immunoglobulin G levels did not increase significantly between the first and second doses of the BNT162b2 vaccine in previously infected individuals. We tested neutralizing antibodies (nAbs) against SARS-CoV-2 Delta and Omicron variants after the first and second doses of this vaccine in infection-naive and previously infected individuals. Delta, but not Omicron, nAb titers significantly increased from the first to the second dose in both groups of individuals. Importantly, we found that Omicron nAb titers were much lower than Delta nAb titers and that even after 2 doses of vaccine, 17 of 29 individuals in the infection-naive group and 2 of 27 in the previously infected group did not have detectable Omicron nAb titers. Infection history alone did not adequately predict whether a second dose resulted in adequate nAb. For future variants of concern, the discussion on the optimal number of vaccine doses should be based on studies testing for nAb against the specific variant.

Markers of fungal translocation are elevated during post-acute sequelae of SARS-CoV-2 and induce NF-κB signaling.

Long COVID, a type of post-acute sequelae of SARS-CoV-2 (PASC), has been associated with sustained elevated levels of immune activation and inflammation. However, the mechanisms that drive this inflammation remain unknown. Inflammation during acute coronavirus disease 2019 could be exacerbated by microbial translocation (from the gut and/or lung) to blood. Whether microbial translocation contributes to inflammation during PASC is unknown. We did not observe a significant elevation in plasma markers of bacterial translocation during PASC. However, we observed higher levels of fungal translocation - measured as ß-glucan, a fungal cell wall polysaccharide - in the plasma of individuals experiencing PASC compared with those without PASC or SARS-CoV-2-negative controls. The higher ß-glucan correlated with higher inflammation and elevated levels of host metabolites involved in activating N-methyl-d-aspartate receptors (such as metabolites within the tryptophan catabolism pathway) with established neurotoxic properties. Mechanistically, ß-glucan can directly induce inflammation by binding to myeloid cells (via Dectin-1) and activating Syk/NF-κB signaling. Using a Dectin-1/NF-κB reporter model, we found that plasma from individuals experiencing PASC induced higher NF-κB signaling compared with plasma from negative controls. This higher NF-κB signaling was abrogated by piceatannol (Syk inhibitor). These data suggest a potential targetable mechanism linking fungal translocation and inflammation during PASC.

The Abbott Pandemic Defense Coalition: a unique multisector approach adds to global pandemic preparedness efforts.

Detection and epidemiologic characterization of infectious disease outbreaks are key for early identification and response to potential pandemic threats. The rapid global spread of severe SARS-CoV-2 in 2020 highlighted the critical role of diagnostics in understanding the epidemiology of the virus early in the pandemic. As a natural extension of Abbott's work in diagnostics, virus discovery, and virus surveillance, the Abbott Pandemic Defense Coalition (APDC) was launched in early 2021. The APDC is a global multisector scientific and public health partnership whose primary objective is the early detection and mitigation of infectious disease threats of pandemic potential. As of January 2022, the APDC network has partners on 5 continents including academic institutions, governmental, and nongovernmental organizations. A novel element of the APDC is the capacity for early development and rapid deployment of scalable, quality diagnostics targeting newly identified pathogens of pandemic potential.

Network Topology of Biological Aging and Geroscience-Guided Approaches to COVID-19.

Aging has emerged as the greatest and most prevalent risk factor for the development of severe COVID-19 infection and death following exposure to the SARS-CoV-2 virus. The presence of multiple co-existing chronic diseases and conditions of aging further enhances this risk. Biological aging not only enhances the risk of chronic diseases, but the presence of such conditions further accelerates varied biological processes or "hallmarks" implicated in aging. Given growing evidence that it is possible to slow the rate of many biological aging processes using pharmacological compounds has led to the proposal that such geroscience-guided interventions may help enhance immune resilience and improve outcomes in the face of SARS-CoV-2 infection. Our review of the literature indicates that most, if not all, hallmarks of aging may contribute to the enhanced COVID-19 vulnerability seen in frail older adults. Moreover, varied biological mechanisms implicated in aging do not function in isolation from each other, and exhibit intricate effects on each other. With all of these considerations in mind, we highlight limitations of current strategies mostly focused on individual single mechanisms, and we propose an approach which is far more multidisciplinary and systems-based emphasizing network topology of biological aging and geroscience-guided approaches to COVID-19.

Corrigendum: Plasma Markers of Disrupted Gut Permeability in Severe COVID-19 Patients.

[This corrects the article DOI: 10.3389/fimmu.2021.686240.].

Plasma Markers of Disrupted Gut Permeability in Severe COVID-19 Patients.

A disruption of the crosstalk between the gut and the lung has been implicated as a driver of severity during respiratory-related diseases. Lung injury causes systemic inflammation, which disrupts gut barrier integrity, increasing the permeability to gut microbes and their products. This exacerbates inflammation, resulting in positive feedback. We aimed to test whether severe Coronavirus disease 2019 (COVID-19) is associated with markers of disrupted gut permeability. We applied a multi-omic systems biology approach to analyze plasma samples from COVID-19 patients with varying disease severity and SARS-CoV-2 negative controls. We investigated the potential links between plasma markers of gut barrier integrity, microbial translocation, systemic inflammation, metabolome, lipidome, and glycome, and COVID-19 severity. We found that severe COVID-19 is associated with high levels of markers of tight junction permeability and translocation of bacterial and fungal products into the blood. These markers of disrupted intestinal barrier integrity and microbial translocation correlate strongly with higher levels of markers of systemic inflammation and immune activation, lower levels of markers of intestinal function, disrupted plasma metabolome and glycome, and higher mortality rate. Our study highlights an underappreciated factor with significant clinical implications, disruption in gut functions, as a potential force that may contribute to COVID-19 severity.

Nasopharyngeal Microbiota in SARS-CoV-2 Positive and Negative Patients.

We investigated nasopharyngeal microbial community structure in COVID-19-positive and -negative patients. High-throughput 16S ribosomal RNA gene amplicon sequencing revealed significant microbial community structure differences between COVID-19-positive and -negative patients. This proof-of-concept study demonstrates that: (1) nasopharyngeal microbiome communities can be assessed using collection samples already collected for SARS-CoV-2 testing (viral transport media) and (2) SARS-CoV-2 infection is associated with altered dysbiotic microbial profiles which could be a biomarker for disease progression and prognosis in SARS-CoV-2.

COVID-19 Severity Is Associated with Differential Antibody Fc-Mediated Innate Immune Functions.

Beyond neutralization, antibodies binding to their Fc receptors elicit several innate immune functions including antibody-dependent complement deposition (ADCD), antibody-dependent cell-mediated phagocytosis (ADCP), and antibody-dependent cell-mediated cytotoxicity (ADCC). These functions are beneficial, as they contribute to pathogen clearance; however, they also can induce inflammation. We tested the possibility that qualitative differences in SARS-CoV-2-specific antibody-mediated innate immune functions contribute to coronavirus disease 2019 (COVID-19) severity. We found that anti-S1 and anti-RBD antibodies from hospitalized COVID-19 patients elicited higher ADCD but lower ADCP compared to antibodies from nonhospitalized COVID-19 patients. Consistently, higher ADCD was associated with higher systemic inflammation, whereas higher ADCP was associated with lower systemic inflammation during COVID-19. Our study points to qualitative, differential features of anti-SARS-CoV-2 specific antibodies as potential contributors to COVID-19 severity. Understanding these qualitative features of natural and vaccine-induced antibodies will be important in achieving optimal efficacy and safety of SARS-CoV-2 vaccines and/or COVID-19 therapeutics.IMPORTANCE A state of hyperinflammation and increased complement activation has been associated with coronavirus disease 2019 (COVID-19) severity. However, the pathophysiological mechanisms that contribute to this phenomenon remain mostly unknown. Our data point to a qualitative, rather than quantitative, difference in SARS-CoV-2-specific antibodies' ability to elicit Fc-mediated innate immune functions as a potential contributor to COVID-19 severity and associated inflammation. These data highlight the need for further studies to understand these qualitative features and their potential contribution to COVID-19 severity. This understanding could be essential to develop antibody-based COVID-19 therapeutics and SARS-CoV-2 vaccines with an optimal balance between efficacy and safety.