Challenges in assessing the immunization status of adults in Germany-lessons from a population-based VACCELERATE survey on polio vaccination.

PURPOSE: Considering the re-emergence of poliomyelitis (PM) in non-endemic regions, it becomes apparent that vaccine preventable diseases can rapidly develop epi- or even pandemic potential. Evaluation of the current vaccination status is required to inform patients, health care providers and policy makers about vaccination gaps. METHODS: Between October 28 2022 and November 23 2022, 5,989 adults from the VACCELEREATE Volunteer Registry completed an electronic case report form on their previous PM vaccine doses including number, types/-valencies and the time of administration based on their vaccination records. A uni-/multivariable regression analysis was performed to assess associations in participant characteristics and immunization status. RESULTS: Among German volunteers (n = 5,449), complete PM immunization schedule was found in 1,981 (36%) participants. Uncertain immunization, due to unknown previous PM vaccination (n = 313, 6%), number of doses (n = 497, 9%), types/-valencies (n = 1,233, 23%) or incoherent immunization schedule (n = 149, 3%) was found in 40% (n = 2,192). Out of 1,276 (23%) participants who reported an incomplete immunization schedule, 62 (1%) never received any PM vaccine. A total of 5,074 (93%) volunteers reported having been vaccinated at least once and 2,087 (38%) indicated that they received vaccination within the last ten years. Female sex, younger age, as well as availability of first vaccination record were characteristics significantly associated with complete immunization (p < 0.001). CONCLUSION: Full PM immunization schedule was low and status frequently classified as uncertain due to lack of details on administered doses. There is an obviousneed for improved recording to enable long-term access to detailed vaccination history in the absence of a centralized immunization register.

Antigen specific T cells in people with obesity at five months following ChAdOx1 COVID-19 vaccination.

BACKGROUND/OBJECTIVES: People with obesity (PWO) face an increased risk of severe outcomes from COVID-19, including hospitalisation, ICU admission and death. Obesity has been seen to impair immune memory following vaccination against influenza, hepatitis B, tetanus, and rabies. Little is known regarding immune memory in PWO following COVID-19 adenovirus vector vaccination. SUBJECTS/METHODS: We investigated SARS-CoV-2 specific T cell responses in 50 subjects, five months following a two-dose primary course of ChAdOx1 nCoV-19 (AZD1222) vaccination. We further divided our cohort into PWO (n = 30) and matched controls (n = 20). T cell (CD4+, CD8+) cytokine responses (IFNγ, TNFα) to SARS-CoV-2 spike peptide pools were determined using multicolour flow cytometry. RESULTS: Circulating T cells specific for SARS-CoV-2 were readily detected across our cohort, with robust responses to spike peptide stimulation across both T cell lines. PWO and controls had comparable levels of both CD4+ and CD8+ SARS-CoV-2 spike specific T cells. Polyfunctional T cells - associated with enhanced protection against viral infection - were detected at similar frequencies in both PWO and controls. CONCLUSIONS: These data indicate that PWO who have completed a primary course of ChAdOx1 COVID-19 vaccination have robust, durable, and functional antigen specific T cell immunity that is comparable to that seen in people without obesity.

Anticholinergic medications associated with falls and frailty in people with HIV.

BACKGROUND: Anticholinergic medications (ACMs) are associated with poorer age-related outcomes, including falls and frailty. We investigate associations between ACM use and recurrent falls and frailty among older (aged ≥50 years) people with HIV in the POPPY study. METHODS: Anticholinergic potential of co-medications at study entry was coded using the anticholinergic burden score, anticholinergic risk score, and Scottish Intercollegiate Guidelines Network score; drugs scoring ≥1 on any scale were defined as ACM. Associations with recurrent falls (two or more falls in the previous 28 days) and frailty (modified Fried's) were assessed using logistic regression adjusting for (1) possible demographic/lifestyle confounders and (2) clinical factors and depressive symptoms (Patient Health Questionnaire-9). RESULTS: ACM use was reported by 193 (28%) of 699 participants, with 64 (9%) receiving two or more ACM; commonly prescribed ACMs were codeine (12%), citalopram (12%), loperamide (9%), and amitriptyline (7%). Falls were reported in 63/673 (9%), and 126/609 (21%) met the frailty criteria. Both recurrent falls and frailty were more common in ACM users than in non-users (recurrent falls: 17% in users vs. 6% in non-users, p < 0.001; frailty: 32% vs. 17%, respectively, p < 0.001). Use of two or more ACMs was associated with increased odds of falls after adjustment for demographic/lifestyle factors (odds ratio [OR] 4.53; 95% confidence interval [CI] 2.06-9.98) and for clinical factors (OR 3.58; 95% CI 1.37-9.38). Similar albeit weaker associations were seen with frailty (OR 2.26; 95% CI 1.09-4.70 and OR 2.12; 95% CI 0.89-5.0, respectively). CONCLUSIONS: ACM are commonly prescribed for people living with HIV, and evidence exists for an association with recurrent falls and frailty. Clinicians should be alert to this and reduce ACM exposure where possible.

Impact of vaccination and variants of concern on long COVID clinical phenotypes.

BACKGROUND: Defining patterns of symptoms in long COVID is necessary to advance therapies for this heterogeneous condition. Here we aimed to describe clusters of symptoms in individuals with long COVID and explore the impact of the emergence of variants of concern (VOCs) and vaccination on these clusters. METHODS: In a prospective, multi centre cohort study, individuals with symptoms persisting > 4 weeks from acute COVID-19 were divided into two groups based on timing of acute infection; pre-Alpha VOC, denoted wild type (WT) group and post-Alpha VOC (incorporating alpha and delta dominant periods) denoted VOC group. We used multiple correspondence analysis (MCA) and hierarchical clustering in the WT and VOC groups to identify symptom clusters. We then used logistic regression to explore factors associated with individual symptoms. RESULTS: A total of 417 individuals were included in the analysis, 268 in WT and 149 in VOC groups respectively. In both groups MCA identified three similar clusters; a musculoskeletal (MSK) cluster characterised by joint pain and myalgia, a cardiorespiratory cluster and a less symptomatic cluster. Differences in characteristic symptoms were only seen in the cardiorespiratory cluster where a decrease in the frequency of palpitations (10% vs 34% p = 0.008) and an increase in cough (63% vs 17% p < 0.001) in the VOC compared to WT groups was observed. Analysis of the frequency of individual symptoms showed significantly lower frequency of both chest pain (25% vs 39% p = 0.004) and palpitations (12% vs 32% p < 0.001) in the VOC group compared to the WT group. In adjusted analysis being in the VOC group was significantly associated with a lower odds of both chest pain and palpitations, but vaccination was not associated with these symptoms. CONCLUSION: This study suggests changes in long COVID phenotype in individuals infected later in the pandemic, with less palpitations and chest pain reported. Adjusted analyses suggest that these effects are mediated through introduction of variants rather than an effect from vaccination.

Biomarkers to predict cardiovascular disease in people living with HIV.

PURPOSE OF REVIEW: Cardiovascular diseases (CVD) is one of the leading cause of morbidity and mortality in antiretroviral treated people living with HIV (PWH) with risk score algorithms based on traditional risk factors being shown to be consistently unreliable in estimating risk in this population. This review aims to examine recent data published in last 18-24 months exploring biomarkers that may be useful in identifying PWH at risk of developing CVD. RECENT FINDINGS: Ongoing research explores the association of inflammatory biomarkers with subclinical CVD with few studies examining their clinical utility in improving CVD risk prediction. Further mechanistic studies explore the role of monocyte/macrophages in CVD pathogenesis with some studies examining functional assays as better predictors of CVD risk. SUMMARY: Although persistent associations with inflammatory markers and CVD are demonstrated, few biomarkers have emerged as being clinically useful. Large population studies are needed to assess their utility in improving CVD risk prediction in PWH.

Major revision version 11.0 of the European AIDS Clinical Society Guidelines 2021.

BACKGROUND: The European AIDS Clinical Society (EACS) Guidelines were revised in 2021 for the 17th time with updates on all aspects of HIV care. KEY POINTS OF THE GUIDELINES UPDATE: Version 11.0 of the Guidelines recommend six first-line treatment options for antiretroviral treatment (ART)-naïve adults: tenofovir-based backbone plus an unboosted integrase inhibitor or plus doravirine; abacavir/lamivudine plus dolutegravir; or dual therapy with lamivudine or emtricitabine plus dolutegravir. Recommendations on preferred and alternative first-line combinations from birth to adolescence were included in the new paediatric section made with Penta. Long-acting cabotegravir plus rilpivirine was included as a switch option and, along with fostemsavir, was added to all drug-drug interaction (DDI) tables. Four new DDI tables for anti-tuberculosis drugs, anxiolytics, hormone replacement therapy and COVID-19 therapies were introduced, as well as guidance on screening and management of anxiety disorders, transgender health, sexual health for women and menopause. The sections on frailty, obesity and cancer were expanded, and recommendations for the management of people with diabetes and cardiovascular disease risk were revised extensively. Treatment of recently acquired hepatitis C is recommended with ongoing risk behaviour to reduce transmission. Bulevirtide was included as a treatment option for the hepatitis Delta virus. Drug-resistant tuberculosis guidance was adjusted in accordance with the 2020 World Health Organization recommendations. Finally, there is new guidance on COVID-19 management with a focus on continuance of HIV care. CONCLUSIONS: In 2021, the EACS Guidelines were updated extensively and broadened to include new sections. The recommendations are available as a free app, in interactive web format and as an online pdf.

Correlation between computerised and standard cognitive testing in people with HIV and HIV-negative individuals.

We investigated the correlations and agreement between cognitive assessments made using a computerised (CogState™, six domains) and a standard pen-and-paper battery (five domains) in PWH and lifestyle-similar HIV-negative individuals. Demographically adjusted domain and global T-scores were obtained and used to define cognitive impairment according to the multivariate normative comparison (MNC) criteria. Correlations between T-scores and the agreement between the classifications of cognitive impairment obtained from the two batteries were assessed using the Spearman's rank correlation and Cohen's κ, respectively. The correlation between global T-scores from the two batteries was 0.52 (95% CI 0.44-0.60) in PWH and 0.45 (0.29-0.59) in controls (p = 0.38 for their difference). Correlations were generally stronger between domains within the same battery than between those from different batteries. The agreement between the two batteries in classifying individuals as cognitively impaired or not impaired was fair in PWH (κ = 0.24) and poor in HIV-negative individuals (κ = -0.02). The moderate correlation between overall cognitive function and the modest agreement between binary classifications of cognitive impairment obtained from two different batteries indicate the two batteries may assess slightly different components of cognition.

Inflammatory Phenotypes Predict Changes in Arterial Stiffness Following Antiretroviral Therapy Initiation.

BACKGROUND: Inflammation drives vascular dysfunction in HIV, but in low-income settings causes of inflammation are multiple, and include infectious and environmental factors. We hypothesized that patients with advanced immunosuppression could be stratified into inflammatory phenotypes that predicted changes in vascular dysfunction on ART. METHODS: We recruited Malawian adults with CD4 <100 cells/µL 2 weeks after starting ART in the REALITY trial (NCT01825031). Carotid femoral pulse-wave velocity (cfPWV) measured arterial stiffness 2, 12, 24, and 42 weeks post-ART initiation. Plasma inflammation markers were measured by electrochemiluminescence at weeks 2 and 42. Hierarchical clustering on principal components identified inflammatory clusters. RESULTS: 211 participants with HIV grouped into 3 inflammatory clusters representing 51 (24%; cluster-1), 153 (73%; cluster-2), and 7 (3%; cluster-3) individuals. Cluster-1 showed markedly higher CD4 and CD8 T-cell expression of HLADR and PD-1 versus cluster-2 and cluster-3 (all P < .0001). Although small, cluster-3 had significantly higher levels of cytokines reflecting inflammation (IL-6, IFN-γ, IP-10, IL-1RA, IL-10), chemotaxis (IL-8), systemic and vascular inflammation (CRP, ICAM-1, VCAM-1), and SAA (all P < .001). In mixed-effects models, cfPWV changes over time were similar for cluster-2 versus cluster-1 (relative fold-change, 0.99; 95% CI, .86-1.14; P = .91), but greater in cluster-3 versus cluster-1 (relative fold-change, 1.45; 95% CI, 1.01-2.09; P = .045). CONCLUSIONS: Two inflammatory clusters were identified: one defined by high T-cell PD-1 expression and another by a hyperinflamed profile and increases in cfPWV on ART. Further clinical characterization of inflammatory phenotypes could help target vascular dysfunction interventions to those at highest risk. CLINICAL TRIALS NETWORK: NCT01825031.

Interferon lambda rs368234815 ΔG/ΔG is associated with higher CD4+:CD8+ T-cell ratio in treated HIV-1 infection.

BACKGROUND: The objectives of this study were to investigate the relationships between polymorphisms at the interferon lambda (IFNL) locus and CD4+:CD8+ ratio normalisation in people living with HIV (PLWH) on effective antiretroviral therapy (ART); and to examine whether these polymorphisms influence the composition of T lymphocyte compartments in long-term treated HIV-1 infection. METHODS: A cross-sectional study in PLWH enrolled into the Mater Immunology study. We performed IFNL genotyping on stored samples and evaluated the association of IFNL single-nucleotide polymorphisms (rs368234815 and rs12979860) with CD4+:CD8+ ratio normalization (> 1) and expanded CD4+ and CD8+ T-cell subsets; CD45RO+CD62L+ (central-memory), CD45RO+ CD62L-(effector-memory) and CD45RO-CD62L+ (naïve), using logistic and linear regression models, respectively. RESULTS: 190 ambulatory PLWH recruited to the main study, 143 were included in the analysis (38 had no stored DNA and 9 no T-lymphocyte subpopulation). Of 143 included, the median age (IQR) was 45(39-48) years, 64% were male and 66% were of Caucasian ethnicity. Heterosexual-contact (36%), injecting drug-use (33%) and men who have sex with men (24%) were the most presented HIV-transmission risk groups. The majority of subjects (90.2%) were on ART with 79% of the cohort having an undetectable HIV-RNA (< 40 copies/ml) and the time since ART initiation was 7.5 (3.7-10.4) year. rs368234815 and rs12979860 displayed similar allelic frequencies, with minor alleles ΔG and T representing 39% and 42%, respectively, of circulating alleles. rs368234815 ΔG/ΔG minor homozygotes were significantly associated with increased odds for attaining a normalised CD4+:CD8+ ratio compared to rs368234815 T/T major homozygotes in PLWH virologically suppressed on effective ART (OR = 3.11; 95% CI [1.01:9.56]). rs368234815 ΔG/ΔG homozygosity was also significantly associated with lower levels of CD4+ effector memory T-cells (regression coefficient: - 7.1%, p = 0.04) and CD8+ naïve T-cell subsets were significantly higher in HIV-1 mono-infected PLWH with rs368234815 ΔG/ΔG (regression coefficient: + 7.2%, p = 0.04). CONCLUSIONS: In virally-suppressed, long-term ART-treated PLWH, rs368234815 ΔG/ΔG homozygotes were more likely to have attained normalisation of their CD4+:CD8+ ratio, displayed lower CD4+ effector memory and higher naive CD8+ T-cells. Further studies are needed to replicate our findings in other, larger and more diverse cohorts and to determine the impact of IFNL genetic-variation on CD4+:CD8+ ratio normalisation and clinical outcomes in PLWH.

Improved adipose tissue function with initiation of protease inhibitor-only ART.

OBJECTIVES: Use of ART containing HIV PIs has previously been associated with toxicity in subcutaneous adipose tissue (SAT), potentially contributing to the development of lipodystrophy and insulin resistance. However, the effect of PIs on SAT function in ART-naive patients independent of other ART classes is unknown. This study aimed to elucidate the effect of initiating PI-only ART on SAT function in ART-naive subjects. METHODS: In the HIVNAT-019 study, 48 HIV-infected, ART-naive Thai adults commencing PI-only ART comprising lopinavir/ritonavir/saquinavir for 24 weeks underwent assessments of fasting metabolic parameters and body composition. In a molecular substudy, 20 subjects underwent SAT biopsies at weeks 0, 2 and 24 for transcriptional, protein, mitochondrial DNA (mtDNA) and histological analyses. ClinicalTrials.gov registration number: NCT00400738. RESULTS: Over 24 weeks, limb fat increased (+416.4 g, P = 0.023), coinciding with larger adipocytes as indicated by decreased adipocyte density in biopsies (-32.3 cells/mm2, P = 0.047) and increased mRNA expression of adipogenesis regulator PPARG at week 2 (+58.1%, P = 0.003). Increases in mtDNA over 24 weeks (+600 copies/cell, P = 0.041), decreased NRF1 mRNA expression at week 2 (-33.7%, P < 0.001) and increased COX2/COX4 protein ratio at week 24 (+288%, P = 0.038) indicated improved mitochondrial function. Despite decreased AKT2 mRNA at week 2 (-28.6%, P = 0.002) and increased PTPN1 mRNA at week 24 (+50.3%, P = 0.016) suggesting insulin resistance, clinical insulin sensitivity [by homeostasis model assessment (HOMA-IR)] was unchanged. CONCLUSIONS: Initiation of PI-only ART showed little evidence of SAT toxicity, the changes observed being consistent with a return to health rather than contributing to lipodystrophy.

Defining cognitive impairment in people-living-with-HIV: the POPPY study.

BACKGROUND: The reported prevalence of cognitive impairment (CI) varies widely in cohorts of people living with HIV (PLWH); this may partly be due to the use of different diagnostic criteria. Agreement between diagnostic criteria of CI, the optimal definition to use, and associations with patient-reported cognitive symptoms have not been fully investigated. METHODS: Two hundred ninety PLWH aged >50 years and 97 matched negative controls completed a detailed assessment of cognitive function and three questions regarding cognitive symptoms. Age- and education-adjusted test scores (T-scores) determined if subjects met the following definitions of CI: Frascati, global deficit score (GDS) and the multivariate normative comparison (MNC) method. RESULTS: PLWH were more likely than controls to meet each definition of CI (ORs were 2.17, 3.12 and 3.64 for Frascati, GDS and MNC, respectively). Agreement of MNC with Frascati and GDS was moderate (Cohen's k = 0.42 and 0.48, respectively), whereas that between Frascati and GDS was good (k = 0.74). A significant association was found between all the three criteria and reporting of memory loss but not with attention and reasoning problems. The 41 (14 %) PLWH meeting all the three criteria had the lowest median global T-score (36.9) and highest rate of symptom reporting (42 %). CONCLUSIONS: Different CI criteria show fair diagnostic agreement, likely reflecting their ability to exclude CI in the same group of individuals. Given the lower overall cognitive performance and higher rates of symptom reporting in those meeting all three criteria of CI, further work assessing this as a definition of CI in PLWH is justified.

Impact of nucleoside reverse transcriptase inhibitors on coronary heart disease.

The nucleoside and nucleotide reverse transcriptase inhibitor (N[t]RTI) drug class remains an integral component of effective antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection. However, these drugs are associated with toxicities, through their off-target effects, that may significantly contribute to a number of long-term comorbidities, including coronary artery disease (CAD) and myocardial infarction (MI), recognized to occur with increased frequency in those with HIV undergoing treatment with ART. The contribution of N(t)RTI to CAD and MI may arise either indirectly through induction of metabolic toxicities such as dyslipidemia and insulin resistance, or directly through impact on pathologic pathways involved in development of MI, such as altered platelet responsiveness or endothelial dysfunction. This review focuses on the available data relating to use of individual N(t)RTI drugs and the drug class as a whole and CAD, with a focus on MI.

The expression of cholesterol metabolism genes in monocytes from HIV-infected subjects suggests intracellular cholesterol accumulation.

BACKGROUND: Human immunodeficiency virus (HIV) infection is associated with increased cardiovascular risk and reduced high-density lipoprotein cholesterol (HDL-c). In vitro, HIV impairs monocyte-macrophage cholesterol efflux, a major determinant of circulating HDL-c, by increasing ABCA1 degradation, with compensatory upregulation of ABCA1 messenger RNA (mRNA). METHODS: We examined expression of genes involved in cholesterol uptake, metabolism, and efflux in monocytes from 22 HIV-positive subjects on antiretroviral therapy (ART-Treated), 30 untreated HIV-positive subjects (ART-Naive), and 22 HIV-negative controls (HIV-Neg). RESULTS: HDL-c was lower and expression of ABCA1 mRNA was higher in ART-Naive subjects than in both ART-Treated and HIV-Neg subjects (both P < .01), with HDL-c inversely correlated with HIV RNA (ρ = -0.52; P < .01). Expression of genes involved in cholesterol uptake (LDLR, CD36), synthesis (HMGCR), and regulation (SREBP2, LXRA) was significantly lower in both ART-Treated and ART-Naive subjects than in HIV-Neg controls. CONCLUSIONS: In vivo, increased monocyte ABCA1 expression in untreated HIV-infected patients and normalization of ABCA1 expression with virological suppression by ART supports direct HIV-induced impairment of cholesterol efflux previously demonstrated in vitro. However, decreased expression of cholesterol sensing, uptake, and synthesis genes in both untreated and treated HIV infection suggests that both HIV and ART affect monocyte cholesterol metabolism in a pattern consistent with accumulation of intramonocyte cholesterol.

Seroprevalence of Schistosomiasis and Strongyloides infection in HIV-infected patients from endemic areas attending a European infectious diseases clinic.

BACKGROUND: Although the Centres for disease Control and Prevention (CDC) recommends empiric treatment for schistosomiasis and strongyloidiasis (prevalent but treatable parasitic infections) in some refugee groups it is unclear if these guidelines should be extended to non-refugee immigrants from endemic areas. We aimed to assess seroprevalence of, and risk factors for, positive schistosomiasis and strongyloides serology in HIV-infected patients from endemic areas attending a European Infectious Diseases clinic. METHODS: In a prospective cohort study, HIV-infected patients from helminth endemic areas underwent clinical assessment and blood draw for schistosomiasis and strongyloides serology, routine haematology and inflammatory markers (ESR and CRP). Between-group differences were analyzed by Wilcoxin Signed Rank and Fisher's t tests as appropriate. RESULTS: Ninety HIV-infected patients (mean [standard deviation (SD)] age 34 [6] years, 29% male) were recruited from May 2008 to June 2009. Nine (10%) subjects tested positive for helminth infections. Seven tested positive for schistosomiasis (8%) while two tested positive for strongyloides (2%). Seropositive subjects were more likely to have higher eosinophil counts (mean [SD]) (0.3 [0.3] vs. 0.15 [0.2] x103cells/cm, P = 0.021) with a trend towards lower CD4+ T-cell counts (mean [SD]) (280 [218] vs. 395 [217] cells/mm3, P = 0.08). CONCLUSION: The high prevalence of helminth infections (10%) in asymptomatic HIV infected adults identified in this study supports routine screening of immigrants from helminth endemic areas or with exposure history.

HIV and comorbidities - the importance of gut inflammation and the kynurenine pathway.

PURPOSE OF REVIEW: The purpose of this article is to review alterations in microbiota composition, diversity, and functional features in the context of chronic inflammation and comorbidities associated with HIV infection. RECENT FINDINGS: The gut microbiome is an important mediator of host immunity, and disruption of gut homeostasis can contribute to both systemic inflammation and immune activation. Ageing and HIV share features of intestinal damage, microbial translocation and alterations in bacterial composition that contribute to a proinflammatory state and development of age-related comorbidities. One such inflammatory pathway reviewed is the nicotinamide adenine dinucleotide (NAD+) producing kynurenine pathway (KP). Kynurenine metabolites regulate many biological processes including host-microbiome communication, immunity and oxidative stress and the KP in turn is influenced by the microbiome environment. Age-associated decline in NAD+ is implicated as a driving factor in many age-associated diseases, including those seen in people with HIV (PWH). Recent studies have shown that KP can influence metabolic changes in PWH, including increased abdominal adiposity and cardiovascular disease. Furthermore, KP activity increases with age in the general population, but it is elevated in PWH at all ages compared to age-matched controls. Host or microbiome-mediated targeting of this pathway has merits to increase healthy longevity and has potential therapeutic applications in PWH. SUMMARY: As a growing proportion of PWH age, many face increased risks of developing age-related comorbidities. Chronic inflammation, a pillar of geroscience, the science of ageing and of age-related disease, is influenced by the gut microbiome and its metabolites. Combined, these contribute to a systemic inflammatory signature. Advances in geroscience-based approaches and therapeutics offer a novel paradigm for addressing age-related diseases and chronic inflammation in HIV infection. Whether targeted inhibition of KP activity alleviates pathological conditions or promotes successful ageing in PWH remains to be determined.

Long COVID: Clinical characteristics, proposed pathogenesis and potential therapeutic targets.

The emergence of persistent ill-health in the aftermath of SARS-CoV-2 infection has presented significant challenges to patients, healthcare workers and researchers. Termed long COVID, or post-acute sequelae of COVID-19 (PASC), the symptoms of this condition are highly variable and span multiple body systems. The underlying pathophysiology remains poorly understood, with no therapeutic agents proven to be effective. This narrative review describes predominant clinical features and phenotypes of long COVID alongside the data supporting potential pathogenesis of these phenotypes including ongoing immune dysregulation, viral persistence, endotheliopathy, gastrointestinal microbiome disturbance, autoimmunity, and dysautonomia. Finally, we describe current potential therapies under investigation, as well as future potential therapeutic options based on the proposed pathogenesis research.

Association between inflammatory biomarker profiles and cardiovascular risk in individuals with and without HIV.

BACKGROUND: People with HIV have an increased risk for cardiovascular morbidity and mortality. Inflammation and immune activation may contribute to this excess risk. METHODS: We assessed thirty-one biomarkers in a subset of POPPY participants and identified three distinct inflammatory profiles: 'gut/immune activation', 'neurovascular', and 'reference' (relatively low levels of inflammation). Ten-year cardiovascular disease (CVD) risk predictions were calculated using the QRISK, Framingham Risk Score (FRS) and the Data Collection on Adverse effects of anti-HIV Drugs (D:A:D) algorithms. The distributions of CVD risk scores across the different inflammatory profiles, stratified by HIV status, were compared using median quantile regression. RESULTS: Of the 312 participants included [70% living with HIV, median (interquartile range; IQR) age 55 (51-60) years; 82% male; 91% white], 36, 130, and 146 were in the 'gut/immune activation', 'neurovascular', and 'reference' cluster, respectively. The median (IQR) QRISK scores were 9.3% (4.5-14.5) and 10.2% (5.5-16.9) for people with and without HV, respectively, with similar scores obtained with the FRS and D:A:D. We observed statistically significant differences between the distributions of scores in the three clusters among people with HV. In particular, median QRISK [5.8% (1.0-10.7) and 3.1% (0.3-5.8)] scores were higher, respectively, for those in the 'gut/immune activation' and 'neurovascular' clusters compared to those in the reference cluster. CONCLUSIONS: People with HIV with increased gut/immune activation have a higher CVD risk compared to those with relatively low inflammation. Our findings highlight that clinically important inflammatory subgroups could be useful to differentiate risk and maximise prediction of CVD among people with HIV.

Development of a novel medium throughput flow-cytometry based micro-neutralisation test for SARS-CoV-2 with applications in clinical vaccine trials and antibody screening.

Quantifying neutralising capacity of circulating SARS-COV-2 antibodies is critical in evaluating protective humoral immune responses generated post-infection/post-vaccination. Here we describe a novel medium-throughput flow cytometry-based micro-neutralisation test to evaluate Neutralising Antibody (NAb) responses against live SARS-CoV-2 Wild Type and Variants of Concern (VOC) in convalescent/vaccinated populations. Flow Cytometry-Based Micro-Neutralisation Test (Micro-NT) was performed in 96-well plates using clinical isolates WT-B, WT-B.1.177.18 and/or VOCs Beta and Omicron. Plasma samples (All Ireland Infectious Diseases (AIID) Cohort) were serially diluted (8 points, half-log) from 1:20 and pre-incubated with SARS-CoV-2 (1h, 37°C). Virus-plasma mixture were added onto Vero E6 or Vero E6/TMPRSS2 cells for 18h. Percentage infected cells was analysed by automated flow cytometry following trypsinisation, fixation and SARS-CoV-2 Nucleoprotein intracellular staining. Half-maximal Neutralisation Titres (NT50) were determined using non-linear regression. Our assay was compared to Plaque Reduction Neutralisation Test (PRNT) and validated against the First WHO International Standard for anti-SARS-CoV-2 immunoglobulin. Both Micro-NT and PRNT achieved comparable NT50 values. Further validation showed adequate correlation with PRNT using a panel of secondary standards of clinical convalescent and vaccinated plasma samples. We found the assay to be reproducible through measuring both repeatability and intermediate precision. Screening 190 convalescent samples and 11 COVID-19 naive controls (AIID cohort) we demonstrated that Micro-NT has broad dynamic range differentiating NT50s <1/20 to >1/5000. We could also characterise immune-escape VOC Beta and Omicron BA.5, achieving fold-reductions in neutralising capacity similar to those published. Our flow cytometry-based Micro-NT is a robust and reliable assay to quantify NAb titres, and has been selected as an endpoint in clinical trials.

Distinct receptor binding domain IgG thresholds predict protective host immunity across SARS-CoV-2 variants and time.

SARS-CoV-2 neutralising antibodies provide protection against COVID-19. Evidence from early vaccine trials suggested binding antibody thresholds could serve as surrogate markers of neutralising capacity, but whether these thresholds predict sufficient neutralising capacity against variants of concern (VOCs), and whether this is impacted by vaccine or infection history remains unclear. Here we analyse individuals recovered from, vaccinated or with hybrid immunity against SARS-CoV-2. An NT50 ≥ 100 IU confers protection in vaccine trials, however, as VOC induce a reduction in NT50, we use NT50 ≥ 1000 IU as a cut off for WT NT50 that would retain neutralisation against VOC. In unvaccinated convalescent participants, a receptor binding domain (RBD) IgG of 456 BAU/mL predicts an NT50 against WT of 1000 IU with an accuracy of 80% (95%CI 73-86%). This threshold maintains accuracy in determining loss of protective immunity against VOC in two vaccinated cohorts. It predicts an NT50 < 100 IU against Beta with an accuracy of 80% (95%CI 67-89%) in 2 vaccine dose recipients. In booster vaccine recipients with a history of COVID-19 (hybrid immunity), accuracy is 87% (95%CI 77-94%) in determining an NT50 of <100 IU against BA.5. This analysis provides a discrete threshold that could be used in future clinical studies.

The Challenges of Vaccine Trial Participation among Underserved and Hard-to-Reach Communities: An Internal Expert Consultation of the VACCELERATE Consortium.

Underserved and hard-to-reach population groups are under-represented in vaccine trials. Thus, we aimed to identify the challenges of vaccine trial participation of these groups in member countries of the VACCELERATE network. Seventeen National Coordinators (NC), each representing their respective country (15 European countries, Israel, and Turkey), completed an online survey. From 15 eligible groups, those that were more frequently declared underserved/hard-to-reach in vaccine research were ethnic minorities (76.5%), persons experiencing homelessness (70.6%), illegal workers and refugees (64.7%, each). When prioritization for education on vaccine trials was considered, ethnic groups, migrants, and immigrants (5/17, 29.4%) were the groups most frequently identified by the NC as top targets. The most prominent barriers in vaccine trial participation affecting all groups were low levels of health literacy, reluctance to participate in trials due to engagement level, and low levels of trust in vaccines/vaccinations. This study highlighted population groups considered underserved/hard-to-reach in countries contained within the European region, and the respective barriers these groups face when participating in clinical studies. Our findings aid with the design of tailored interventions (within-and across-countries of the European region) and with the development of strategies to overcome major barriers in phase 2 and phase 3 vaccine trial participation.