BACKGROUND:Antiretroviral therapies with long dosing intervals have the potential to improve virological outcomes and treatment satisfaction for people with HIV-1. We report the primary endpoint results from week 48 of ISLEND-2, a phase 3 trial evaluating the efficacy and safety of switching to once-weekly oral islatravir-lenacapavir from daily oral standard of care in virologically suppressed adults with HIV-1. METHODS:This randomised, open-label, active-controlled, phase 3 non-inferiority trial was conducted at 100 sites in 14 countries and territories. Eligible participants were adults (aged ≥18 years) with HIV-1 who had been virologically suppressed on daily oral standard-of-care treatment for at least 6 months and had no previous virological failure. Participants were randomly assigned (1:1), using interactive response technology and stratified by geographical region, antiretroviral class, and CD4+ T-cell count, to switch to the once-weekly, single-tablet oral regimen of islatravir (2 mg)-lenacapavir (300 mg) or to continue daily oral standard of care for at least 96 weeks. The primary endpoint was the proportion of participants with an HIV-1 RNA viral load of 50 copies per mL or higher at week 48 (as per the US Food and Drug Administration-defined Snapshot algorithm), with a non-inferiority margin of 4%, assessed in all randomly assigned participants who received any dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT06630299, and is active but closed to new participants. FINDINGS:From Oct 8, 2024, to April 30, 2025, 727 participants were screened, of whom 647 were eligible for the study, 634 were randomly assigned, and 626 received treatment: 314 with islatravir-lenacapavir and 312 with standard of care. Of 626 participants, 211 (34%) were female, 193 (31%) were Black, 119 (19%) were Asian, 123 (20%) were Hispanic or Latine, and 89 (14%) were aged 65 years or older. At baseline, 552 (88%) were on a single-tablet antiretroviral regimen and 478 (76%) were receiving regimens containing integrase strand transfer inhibitors. At week 48, one (0·3%) of 314 participants in the islatravir-lenacapavir group and four (1·3%) of 312 participants in the standard-of-care group had an HIV-1 RNA viral load of 50 copies per mL or higher (difference -1·0% [95·002% CI -3·0 to 1·1]), meeting the non-inferiority criteria. Treatment-related adverse events occurred in 58 (18%) of 314 participants in the islatravir-lenacapavir group and one (<1%) of 312 participants in the standard-of-care group. Two (1%) of 314 participants in the islatravir-lenacapavir group and one (<1%) of 312 participants in the standard-of-care group discontinued the study owing to adverse events, with adverse events of grade 3 or higher occurring in 24 (8%) and 28 (9%) participants and serious adverse events in 22 (7%) and 27 (9%) participants in the islatravir-lenacapavir group and standard-of-care group, respectively. There were three deaths: one in the islatravir-lenacapavir group and two in the standard-of-care group, none of which were considered treatment-related. INTERPRETATION:Once-weekly islatravir-lenacapavir showed non-inferior efficacy to the standard of care and was generally well tolerated. Longer-term safety data will provide further valuable insights beyond the week 48 data presented here. Islatravir-lenacapavir has potential to be the first once-weekly complete oral single-tablet regimen for HIV-1 treatment. FUNDING:Gilead Sciences and Merck Sharp & Dohme.

Since the introduction of the Post-COVID-19 Functional Status (PCFS) scale early in the COVID-19 pandemic, the scale has been incorporated in research and clinical guidelines to assess and monitor functional status. In this explorative study, we aimed to evaluate characteristics of the PCFS scale based on its use during a 12-month follow-up of COVID-19 survivors to increase understanding of the scale over a longer period of time. Adult COVID-19 patients who were evaluated by multidisciplinary measures at 6 weeks and 12 months post-discharge at the Leiden University Medical Center (The Netherlands) were included. The distribution of PCFS scale grades, as well as descriptive patterns between PCFS grades and patient-reported outcome measures (PROMs), pulmonary function and physical function were evaluated with descriptive analyses; no statistical tests were performed due to data availability. Of the 79 included patients, 62% had a change in PCFS grade between the 6-week and 12-month follow-ups, of whom 63% improved over time. At 12 months, abnormal PROMs regarding psychological symptoms (according to clinical cut-offs), relatively lower quality of life (EQ VAS) scores, and MRC dyspnea grades >= 2 were observed in patients scoring PCFS grade >= 2. With increasing PCFS grade, a decrease in pulmonary function and physical function outcomes was observed. Higher PCFS grades (worse functional status) seemed related to worse outcomes at 12-month follow-up. Future studies are needed to investigate whether changes in PCFS grade reflect clinically relevant changes in patients' self-perceived functioning.

Despite highly effective antiretroviral therapy, people living with HIV (PLWH) remain at elevated risk for invasive pneumococcal disease. Clinical studies show that, even with high CD4+ counts, PLWH exhibit diminished serological responses and rapid antibody decline following pneumococcal vaccination, plausibly due to underlying immune dysfunction. Germinal centers (GCs), located within lymph nodes, are essential for generating high-affinity antibodies, but are structurally and functionally disrupted in PLWH. These local impairments, combined with systemic immune dysregulation, contribute to vaccine hyporesponsiveness in PLWH. This narrative review links immunological findings from experimental and in vivo studies to clinical pneumococcal vaccine trials, to investigate mechanisms that may be leveraged to strengthen vaccine-induced immunity in PLWH. We also highlight the application of fine needle aspiration (FNA) of the lymph node as a way to study pneumococcal vaccine hyporesponsiveness in the GC and provide potential direction to improve responses for next-generation pneumococcal conjugate vaccines in PLWH.

OBJECTIVE:Develop and validate a strategy to improve HIV testing rates using HIV teams. DESIGN:A prospective clinical trial was conducted from January 2020 to July 2023 in two Dutch university hospitals. METHODS:The intervention involved implementing HIV teams to provide peer awareness, education, and feedback to physicians treating patients ≥18 years newly diagnosed with HIV indicator conditions. The primary outcome was the HIV testing rate. Secondary outcomes included testing rates by specialty, HIV prevalence, and reasons for withholding testing. RESULTS:Of the 313 666 newly registered diagnoses, 2395 involved indicator conditions. The overall HIV testing rate of newly diagnosed HIV indicator conditions increased from 50.1% (222/443) preimplementation to 80.7% (1575/1952) postimplementation of HIV teams ( P  < 0.001) with sustained improvement during the observation period (range 72.4-90.4%). The intervention was effective across physicians from all medical specialties. HIV prevalence among those tested was 0.6% [95% confidence interval (CI) 0.3-1.1]. Peer feedback for 411 untested indicator conditions, resulted in 69 (16.3%) additional HIV tests. Failure to test frequently remained without reason (50.6%) or due to patient loss of follow-up (18.4%). Multivariate analysis indicated that women with indicator conditions were tested less often [adjusted odds ratio (aOR) 0.59, 95% CI 0.45-0.79, P  < 0.01], and indicator conditions without HIV testing recommendations in national guidelines were also less likely to be tested for HIV (aOR 0.36, 95% CI 0.27-0.48, P  < 0.01). For external validation, we implemented this intervention in a second hospital, where it also significantly increased the testing rate postimplementation of HIV teams. CONCLUSION:Implementing HIV teams in hospitals is feasible, effective and leads to a sustained increase in HIV indicator condition-guided testing, supporting its broader adoption.

BACKGROUND:Aging coincides with a decline in immune functioning, whereby elderly become less responsive to vaccination. Alternative vaccination strategies, including administration into the skin, may improve immunogenicity and efficacy. Here, we investigated the immunogenicity of intradermal (ID) administration of a fractional dose of a COVID-19 vaccine in elderly (75 years and older) compared to standard intramuscular (IM) administration of an equivalent dose. METHODS:Between November and December 2023, 48 adults aged 75-86 were randomized (1:1:1, n = 16/group) to receive either 20 μg of the BNT162b2 XBB.1.5 vaccine via ID injection, using a microneedle, or 20 μg via IM injection, or the standard 30 μg dose via IM injection (NCT05977127). The primary endpoint was the geometric mean concentration (GMC) of SARS-CoV-2 Spike-specific IgG at day 28 post-vaccination. Secondary endpoints included the serum ACE2 binding inhibition at day 28, as well as incidence of local and systemic adverse events (AEs), recorded during the first 28 days post-vaccination. Exploratory outcomes included longitudinal immunogenicity assessments in serum and nasal mucosal lining fluid, on days 0, 28 and 122 and whole blood transcriptome profiling on day 0 and 1. RESULTS:At day 28 post-vaccination, no differences were found in serum anti-Spike IgG and ACE2 binding inhibition capacity between all three groups. Longitudinal analysis revealed parallel trends across groups in serum and mucosal IgG, IgA and ACE2 inhibition response. While ID vaccination induced a distinct blood transcriptomic profile compared to IM administration, no specific pathways were found that were differentially regulated. Mild and self-limiting local AEs were observed in all ID vaccinated participants, in contrast to IM vaccinated participants. CONCLUSION:No differences were found in antibody level and functionality following ID and IM administration of 20 μg BNT162b2 XBB.1.5 vaccine in elderly, while IM administration was less reactogenic than ID administration.

The innate immune system plays a pivotal role in pathogen defense via pattern recognition receptor sensing, initiating responses upon infection or vaccination. Understanding its functional capacity is crucial for deciphering correlates of vaccine efficacy and understanding responses to infection. Here, we developed a holistic approach to study immune function, generating >3,100 readouts across 16 cell types, 18 pattern recognition receptors, and 11 produced cytokines using spectral flow cytometry. To explore geographical variation, we compared Europeans and urban and rural Indonesians. We observed different immune responses, such as increased interleukin (IL)-1β production in rural Indonesians and impaired interferon (IFN) γ production by innate lymphocytes after Toll-like receptor (TLR) 8 stimulation. In Europeans vaccinated with mRNA-1273, baseline IFNγ production by innate lymphocytes correlated with SARS-CoV-2 spike-specific immune responses. In vitro mRNA vaccine stimulation also induced IFNγ production, which was TLR8 dependent and reduced in rural Indonesians. This study highlights functional immune diversity and TLR8’s potential role in mRNA vaccine responses.

BACKGROUND:Although guidelines for COVID-19 additional vaccination strategies generally prioritise people with advanced HIV infection, recommendations vary globally, with some countries recommending an annual vaccination for all people with HIV (PWH), while others restrict this to PWH with a CD4+ T-cell count < 200 cells per µL. METHODS:We conducted a prospective cohort study in 448 adult PWH. The primary outcome was the SARS-CoV-2 spike (S1)-specific IgG antibody level at 1, 6, 12, 18, and 24 months after completing a primary COVID-19 vaccination series (two doses of BNT162b2, mRNA-1273, or ChAdOx1-S, or one dose of Ad26.COV2.S). We compared the antibody kinetics over two years between PWH with a baseline CD4+ T-cell count < 200 cells per µL (n = 16) vs. ≥ 200 cells per µL (n = 432) with a mixed-effects model. Secondary outcomes included variables associated with the kinetics of S1-specific antibody levels and the incidence of breakthrough infections. RESULTS:The median most recent CD4+ T-cell count prior to primary vaccination was 140 (IQR 80-165) in the < 200 cells per µL group, and 688 (IQR 520-899) in the ≥ 200 cells per µL group at the time of primary vaccination. S1-specific antibodies were lower in PWH with a CD4+ T-cell count < 200 vs. ≥ 200 cells per µL during the two-year follow-up, with predicted S1-specific antibody levels of 514 (95% CI 456-578) vs. 2758 (95% CI 1488-5110) BAU per mL at 12 months (p < 0.001) and 839 (95% CI 732-959) vs. 3505 (95% CI 1712-7175) BAU per mL at 24 months (p < 0.001). The overall incidence of SARS-CoV-2 infections was 55% and comparable between groups. A CD4+ T-cell count < 200 cells per µL, higher age, and a vector-based primary vaccination series were negatively associated with S1-specific antibody levels over time. CONCLUSION:Long-term humoral responses were lower in PWH with a CD4+ T-cell count < 200 cells per µL compared to those with a CD4+ T-cell count ≥ 200 cells per µL. National COVID-19 vaccine guidelines recommending booster vaccines for all PWH, should therefore specifically emphasise the need for booster vaccines in those with a CD4+ T-cell count < 200 cells per µL. Trial registration: The trial was registered on the International Clinical Trials Platform (registration number: EUCTR2021-001054-57-N).

Background:COVID-19 patients frequently experience pulmonary embolism (PE), but its long-term consequences remain uncertain. Objectives:To assess the impact of PE in COVID-19 patients on health outcomes at 3 months after hospitalization. Methods:In this multicenter cross-sectional study, we aggregated data from existing databases to evaluate the impact of PE on health outcomes at 3 months after hospitalization. We assessed 1) questionnaires on health-related quality of life (5-level EuroQol 5-dimensional questionnaire [EQ-5D-5L] questionnaire), anxiety, depression, cognitive failure, and posttraumatic stress disorder; 2) pulmonary function tests (diffusing capacity of the lungs for carbon monoxide [DLCO] and spirometry); and 3) radiological abnormalities. We developed 3 models to assess the association between PE and the EQ-5D-5L index and the percentage of predicted DLCO (DLCO%): a crude model (model 1), adjusted for age, sex, and presence of comorbidities (model 2), and model 2 additionally adjusted for intensive care unit admission (model 3). Results:We included 465 patients who had been hospitalized for COVID-19, of whom 102 (21.9%) had developed a PE during admission. Patients with PE had poorer EQ-5D-5L index values, more impairment in pulmonary functions, and more frequent radiological abnormalities than patients without PE. Symptoms of anxiety, depression, cognitive failure, and posttraumatic stress disorder did not differ between the 2 groups. In model 2, PE was associated with lower EQ-5D-5L index and lower DLCO%. After additionally adjusting for intensive care unit admission, the association between PE and lower EQ-5D-5L index (mean difference = -0.069, [95% CI, -0.12 to -0.017]) remained but not between PE and DLCO%. Conclusion:Our findings suggest that PE in COVID-19 patients is associated with reduced health-related quality of life at 3 months after hospitalization. While PE may be a marker of COVID-19 severity, its presence during hospitalization could indicate potential long-term health issues, which may be considered during follow-up care.

Fractional dosing can be a cost-effective vaccination strategy to accelerate individual and herd immunity in a pandemic. We assessed the immunogenicity and safety of primary intradermal (ID) vaccination, with a 1/5th dose compared with the standard intramuscular (IM) dose of mRNA-1273 in SARS-CoV-2 naïve persons. We conducted an open-label, non-inferiority, randomized controlled trial in the Netherlands between June and December 2021. One hundred and fifty healthy and SARS-CoV-2 naïve participants, aged 18–30 years, were randomized (1:1:1) to receive either two doses of 20 µg mRNA-1273 ID with a standard needle (SN) or the Bella-mu® needle (BM), or two doses of 100 µg IM, 28 days apart. The primary outcome was non-inferiority in seroconversion rates at day 43 (D43), defined as a neutralizing antibody concentration threshold of 465 IU/mL, the lowest response in the IM group. The non-inferiority margin was set at −15%. Neutralizing antibody concentrations at D43 were 1789 (95% CI: 1488–2150) in the IM and 1263 (951–1676) and 1295 (1020–1645) in the ID-SN and ID-BM groups, respectively. The absolute difference in seroconversion proportion between fractional and standard-dose groups was −13.95% (−24.31 to −3.60) for the ID-SN and −13.04% (−22.78 to −3.31) for the ID-BM group and exceeded the predefined non-inferiority margin. Although ID vaccination with 1/5th dose of mRNA-1273 did not meet the predefined non-inferior criteria, the neutralizing antibody concentrations in these groups are far above the proposed proxy for protection against severe disease (100 IU/mL), justifying this strategy in times of vaccine scarcity to accelerate mass protection against severe disease.

Background:Confirming the efficacy of dolutegravir/lamivudine in clinical practice solidifies recommendations on its use.Methods:Prospective cohort study (DUALING) in 24 human immunodeficiency virus (HIV) treatment centers in the Netherlands. HIV RNA-suppressed cases were on triple-drug antiretroviral regimens without prior virological failure or resistance and started dolutegravir/lamivudine. Cases were 1:2 matched to controls on triple-drug antiretroviral regimens by the use of dolutegravir-based regimens, age, sex, transmission route, CD4+ T-cell nadir, and HIV RNA zenith. The primary endpoint was the treatment failure rate in cases versus controls at 1 year by intention-to-treat and on-treatment analyses with 5% noninferiority margin.Results:The 2040 participants were 680 cases and 1380 controls. Treatment failure in the 390 dolutegravir-based cases versus controls occurred in 8.72% and 12.50% (difference: -3.78% [95% confidence interval {CI}, -7.49% to .08%]) by intention-to-treat and 1.39% and 0.80% (difference: 0.59% [95% CI, -.80% to 1.98%]) by on-treatment analyses. The treatment failure risk in 290 non-dolutegravir-based cases was also noninferior to controls. Antiretroviral regimen modifications unrelated to virological failure explained the higher treatment failure rate by intention-to-treat. A shorter time on triple-drug antiretroviral therapy and being of non-Western origin was associated with treatment failure. Treatment failure, defined as 2 consecutive HIV RNA >50 copies/mL, occurred in 4 cases and 5 controls but without genotypic resistance detected. Viral blips occured comparable in cases and controls but cases gained more weight, especially when tenofovir-based regimens were discontinued.Conclusions:In routine care, dolutegravir/lamivudine was noninferior to continuing triple-drug antiretroviral regimens after 1 year, supporting the use of dolutegravir/lamivudine in clinical practice.Clinical Trials Registration:NCT04707326.

Total plasma protein N-glycosylation (TPNG) changes are a hallmark of many diseases. Here, we analyzed the TPNG of 169 COVID-19 patients and 12 healthy controls, using mass spectrometry, resulting in the relative quantification of 85 N-glycans. We found a COVID-19 N-glycomic signature, with 59 glycans differing between patients and controls, many of them additionally differentiating between severe and mild COVID-19. Tri- and tetra-antennary N-glycans were increased in patients, showing additionally elevated levels of antennary α2,6-sialylation. Conversely, bisection of di-antennary, core-fucosylated, nonsialylated glycans was low in COVID-19, particularly in severe cases, potentially driven by the previously observed low levels of bisection on antibodies of severely diseased COVID-19 patients. These glycomic changes point toward systemic changes in the blood glycoproteome, particularly involvement of acute-phase proteins, immunoglobulins and the complement cascade. Further research is needed to dissect glycosylation changes in a protein- and site-specific way to obtain specific functional leads.

Background SARS-CoV-2 has been associated with a higher proportion of asymptomatic infections and lower mortality in sub-Saharan Africa than high-income countries. However, there is currently a lack of data on cellular immune responses to SARS-CoV-2 in people living in Africa compared with people in high-income regions of the world. We aimed to assess geographical variation in peripheral and mucosal immune responses. Methods In this retrospective, population-based, cross-sectional study, we analysed peripheral blood and nasal curettage samples from seven clinical studies involving individuals from Senegal (Senegalese cohort), the Netherlands, and Germany (European cohort). Samples were collected between Nov 1, 2018, and Dec 20, 2021. We included samples from individuals with no, mild, or severe COVID-19. A validation cohort of individuals from Senegal and Gabon (n=64) was used to validate key findings from the main cohort. Matching of individuals between geographical regions by age, sex, viral load, and infection severity and duration was used to address confounding factors. We examined the cellular, humoral, and cytokine immune responses using cytometry by time of flight, spectral flow cytometry, ELISA, and Luminex. Findings We included 133 individuals (59 from the Senegalese cohort and 74 from the European cohort). In contrast to the European cohort, mild COVID-19 in the Senegalese cohort was not associated with any statistically significant perturbations in blood or nasal immune cell profiles, nor with increased pro-inflammatory cytokines, although SARS-CoV-2-specific adaptive immunity was readily induced, as seen in Europeans. In severe COVID-19, both the Senegalese and European cohorts showed lymphopenia (Senegal: 2·9-times decrease, p=0·0010 vs Europe: 1·6-times decrease, p=0·0046) and increased neutrophil frequencies in blood (Senegal: 2·0-times increase, p=0·0044 vs Europe: 1·3-times increase, p=0·026) and the nasal mucosa CD66b+CD16low neutrophils (Senegal: 9·9-times increase, p=0·045 vs Europe: 392-times increase, p<0·0001). However, in contrast to Europeans, the Senegalese cohort had no significant expansion of immature immune populations, inflammasome activation, or monocyte recruitment to the nasal mucosa. Interpretation The observed divergent immunological trajectories during SARS-CoV-2 infection offer a potential explanation for the reported attenuated disease course in sub-Saharan Africa and highlight the need to further investigate immune responses to SARS-CoV-2 in understudied populations. Funding European and Developing Countries Clinical Trials Partnership 2 programme (AIDCO), LUMC Gisela Thier Fellowship, Dutch Research Council (NWO), European Research Council, and Leids Universitair Fonds.

Background:Fractional-dosed intradermal (i.d.) vaccination produces antibody concentrations above the proposed proxy for protection against severe disease as compared with intramuscular (i.m.) vaccination and may be associated with a decreased prothrombotic effect.Objectives:To assess changes in coagulation following standard dosed i.m. or fractional-dosed i.d. (one-fifth of i.m.) mRNA-1273 SARS-CoV-2 vaccine and to determine the association between the inflammatory response and coagulation.Methods:This study was embedded in a randomized controlled trial assessing the immunogenicity of an i.d. fractional-dosed mRNA-1273 vaccine. Healthy participants, aged 18 to 30 years, were randomized (2:1) to receive either 2 doses of i.d. or i.m. vaccine. Blood was drawn prior to first and second vaccination doses and 1 and 2 weeks after the second dose. The outcomes were changes in coagulation parameters (primary endpoint peak height of the thrombin generation curve) and inflammation (high-sensitivity C-reactive protein [hs-CRP]).Results:One hundred twenty-three participants were included (81 i.d.; 42 i.m.). Peak height increased after vaccination (i.m., 28.8 nmol; 95% CI, 6.3-63.8; i.d., 17.3 nmol; 95% CI, 12.5-47.2) and recovered back to baseline within 2 weeks. I.m. vaccination showed a higher inflammatory response compared with i.d. vaccination (extra increase hs-CRP, 0.92 mg/L; 95% CI, 0.2-1.7). Change in endogenous thrombin potential was associated with change in hs-CRP (beta, 28.0; 95% CI, 7.6-48.3).Conclusion:A transient increase in coagulability after mRNA-1273 SARS-CoV-2 vaccination occurred, which was associated with the inflammatory response. While i.d. administration showed antibody concentrations above the proposed proxy for protection against severe disease, it was associated with less systemic inflammation. Hence, i.d. vaccination may be safer.

Objectives: The aim of this study was to assess the safety and immunogenicity of a dose -sparing fractional intradermal (ID) booster strategy with the mRNA-1273 COVID-19 vaccine. Methods: COVID-19 naive adults aged 18-30 years were recruited from a previous study on primary vaccination regimens that compared 20 mu g ID vaccinations with 100 mu g intramuscular (IM) vaccinations with mRNA-1273 as the primary vaccination series. Participants previously immunized with ID regimens were randomly assigned (1:1) to receive a fractional ID booster dose (20 mu g) or the standard-of-care intramuscular (IM) booster dose (50 mu g) of the mRNA-1273 vaccine, 6 months after completing their primary series (ID -ID and ID-IM group, respectively). Participants that had received a full dose IM regimen as the primary series, received the IM standard-of-care booster dose (IM-IM group). In addition, COVID-19 naive individuals aged 18-40 years who had received an IM mRNA vaccine as the primary series were recruited from the general population to receive a fractional ID booster dose (IM-ID group). Immunogenicity was assessed using IgG anti -spike antibody responses and neutralizing capacity against SARS-CoV-2. Cellular immune responses were measured in a sub-group. Safety and tolerability were monitored. Results: In January 2022,129 participants were included in the study. Fractional ID boosting was safe and well tolerated, with fewer systemic adverse events compared with IM boosting. At day 28 post -booster, anti -spike S1 IgG geometric mean concentrations were 9106 (95% CI, 7150-11 597) binding antibody units (BAU)/mL in the IM-IM group and 4357 (3003-6322) BAU/mL; 6629 (4913-8946) BAU/mL; and 5264 (4032-6873) BAU/mL in the ID-IM, ID -ID, and IM-ID groups, respectively. Discussion: Intradermal boosting provides robust immune responses and is a viable dose -sparing strategy for mRNA COVID-19 vaccines. The favourable side-effect pro file supports its potential to reduce vaccine hesitancy. Fractional dosing strategies should be considered early in the clinical development of future mRNA vaccines to enhance vaccine availability and pandemic preparedness. Geert V.T. Roozen, dlin Microbiol Infect 2024;30:930 (c) 2024 The Authors. Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/).

SARS-CoV2 infection results in a range of disease severities, but the underlying differential pathogenesis is still not completely understood. At presentation it remains difficult to estimate and predict severity, in particular, identify individuals at greatest risk of progression towards the most severe disease-states. Here we used advanced models with circulating serum analytes as variables in combination with daily assessment of disease severity using the SCODA-score, not only at single time points but also during the course of disease, to correlate analyte levels and disease severity. We identified a remarkably strong pro-inflammatory cytokine/chemokine profile with high levels for sCD163, CCL20, HGF, CHintinase3like1 and Pentraxin3 in serum which correlated with COVID-19 disease severity and overall outcome. Although precise analyte levels differed, resulting biomarker profiles were highly similar at early and late disease stages, and even during convalescence similar biomarkers were elevated and further included CXCL3, CXCL6 and Osteopontin. Taken together, strong pro-inflammatory marker profiles were identified in patients with COVID-19 disease which correlated with overall outcome and disease severity.

Suspected allergic reactions after mRNA COVID-19 vaccination withheld multiple individuals from getting fully vaccinated during the pandemic. We vaccinated adults who had experienced possible allergic symptoms after their first intramuscular dose of a COVID-19 mRNA vaccine with a 1/5th fractional intradermal test dose of the mRNA-1273 (Moderna) COVID-19 vaccine. No anaphylactic reactions were observed after intradermal vaccination (n = 56). Serum anti-S1 IgG concentrations were measured using a bead-based multiplex assay four weeks after vaccinations. Antibody concentrations were compared with a previously collected nationwide cohort that had received two intramuscular doses of mRNA-1273. Antibody responses in all subjects tested (n = 47) were comparable to standard of care intramuscular dosing. Fractional intradermal dosing of mRNA COVID-19 vaccines may provide a pragmatic solution that is safe, time efficient compared to skin prick testing, dose sparing and immunogenic in individuals with suspected vaccine allergy.

Objective:We evaluated the immunogenicity of a bivalent BA.1 COVID-19 booster vaccine in people with HIV (PWH).Design:Prospective observational cohort study.Methods:PWH aged ≥45 years received Wuhan-BA.1 mRNA-1273.214 and those <45 years Wuhan-BA.1 BNT162b2. Participants were propensity score-matched 1 : 2 to people without HIV (non-PWH) by age, primary vaccine platform (mRNA-based or vector-based), number of prior COVID-19 boosters and SARS-CoV-2 infections, and spike (S1)-specific antibodies on the day of booster administration. The primary endpoint was the geometric mean ratio (GMR) of ancestral S1-specific antibodies from day 0 to 28 in PWH compared to non-PWH. Secondary endpoints included humoral responses, T-cell responses and cytokine responses up to 180 days post-vaccination.Results:Forty PWH received mRNA-1273.214 (N = 35) or BNT162b2 (N = 5) following mRNA-based (N = 29) or vector-based (N = 11) primary vaccination. PWH were predominantly male (87% vs. 26% of non-PWH) and median 57 years [interquartile range (IQR) 53–59]. Their median CD4+T-cell count was 775 (IQR 511–965) and the plasma HIV-RNA load was <50 copies/ml in 39/40. The GMR of S1-specific antibodies by 28 days post-vaccination was comparable between PWH [4.48, 95% confidence interval (CI) 3.24–6.19] and non-PWH (4.07, 95% CI 3.42–4.83). S1-specific antibody responses were comparable between PWH and non-PWH up to 180 days, and T-cell responses up to 90 days post-vaccination. Interferon-γ, interleukin (IL)-2, and IL-4 cytokine concentrations increased 28 days post-vaccination in PWH.Conclusion:A bivalent BA.1 booster vaccine was immunogenic in well treated PWH, eliciting comparable humoral responses to non-PWH. However, T-cell responses waned faster after 90 days in PWH compared to non-PWH.

Diagnostic services for tuberculosis (TB) are not sufficiently accessible in low-resource settings, where most cases occur, which was aggravated by the COVID-19 pandemic. Early diagnosis of pulmonary TB can reduce transmission. Current TB-diagnostics rely on detection of Mycobacterium tuberculosis (Mtb) in sputum requiring costly, time-consuming methods, and trained staff. In this study, quantitative lateral flow (LF) assays were used to measure levels of seven host proteins in sera from pre-COVID-19 TB patients diagnosed in Europe and latently Mtb-infected individuals (LTBI), and from COVID-19 patients and healthy controls. Analysis of host proteins showed significantly lower levels in LTBI versus TB (AUC:0 · 94) and discriminated healthy individuals from COVID-19 patients (0 · 99) and severe COVID-19 from TB. Importantly, these host proteins allowed treatment monitoring of both respiratory diseases. This study demonstrates the potential of non-sputum LF assays as adjunct diagnostics and treatment monitoring for COVID-19 and TB based on quantitative detection of multiple host biomarkers.

Abstract Background The COVIH study is a prospective coronavirus disease 2019 (COVID-19) vaccination study in 1154 people with HIV (PWH), of whom 14% showed reduced antibody levels after primary vaccination. We evaluated whether an additional vaccination boosts immune responses in these hyporesponders. Methods The primary end point was the increase in antibodies 28 days after additional mRNA-1273 vaccination. Secondary end points included neutralizing antibodies, S-specific T-cell and B-cell responses, and reactogenicity. Results Of the 66 participants, 40 previously received 2 doses ChAdOx1-S, 22 received 2 doses BNT162b2, and 4 received a single dose Ad26.COV2.S. The median age was 63 years (interquartile range [IQR], 60–66), 86% were male, and median CD4+ T-cell count was 650/μL (IQR, 423–941). The mean S1-specific antibody level increased from 35 binding antibody units (BAU)/mL (95% confidence interval [CI], 24–46) to 4317 BAU/mL (95% CI, 3275–5360) (P < .0001). Of all participants, 97% showed an adequate response and the 45 antibody-negative participants all seroconverted. A significant increase in the proportion of PWH with ancestral S-specific CD4+ T cells (P = .04) and S-specific B cells (P = .02) was observed. Conclusions An additional mRNA-1273 vaccination induced a robust serological response in 97% of PWH with a hyporesponse after primary vaccination. Clinical Trials Registration. EUCTR2021-001054-57-N.