Primary SARS-CoV-2 variant of concern infections elicit broad antibody Fc-mediated effector functions and memory B cell responses.

Neutralization of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by human sera is a strong correlate of protection against symptomatic and severe Coronavirus Disease 2019 (COVID-19). The emergence of antigenically distinct SARS-CoV-2 variants of concern (VOCs) and the relatively rapid waning of serum antibody titers, however, raises questions about the sustainability of serum protection. In addition to serum neutralization, other antibody functionalities and the memory B cell (MBC) response are suggested to help maintaining this protection. In this study, we investigate the breadth of spike (S) protein-specific serum antibodies that mediate effector functions by interacting with Fc-gamma receptor IIa (FcγRIIa) and FcγRIIIa, and of the receptor binding domain (RBD)-specific MBCs, following a primary SARS-CoV-2 infection with the D614G, Alpha, Beta, Gamma, Delta, Omicron BA.1 or BA.2 variant. Irrespectively of the variant causing the infection, the breadth of S protein-specific serum antibodies that interact with FcγRIIa and FcγRIIIa and the RBD-specific MBC responses exceeded the breadth of serum neutralization, although the Alpha-induced B cell response seemed more strain-specific. Between VOC groups, both quantitative and qualitative differences in the immune responses were observed, suggesting differences in immunogenicity. Overall, this study contributes to the understanding of protective humoral and B cell responses in the light of emerging antigenically distinct VOCs, and highlights the need to study the immune system beyond serum neutralization to gain a better understanding of the protection against emerging variants.

Inflammatory profiles are associated with long COVID up to 6 months after COVID-19 onset: A prospective cohort study of individuals with mild to critical COVID-19.

BACKGROUND: After initial COVID-19, immune dysregulation may persist and drive post-acute sequelae of COVID-19 (PASC). We described longitudinal trajectories of cytokines in adults up to 6 months following SARS-CoV-2 infection and explored early predictors of PASC. METHODS: RECoVERED is a prospective cohort of individuals with laboratory-confirmed SARS-CoV-2 infection between May 2020 and June 2021 in Amsterdam, the Netherlands. Serum was collected at weeks 4, 12 and 24 of follow-up. Monthly symptom questionnaires were completed from month 2 after COVID-19 onset onwards; lung diffusion capacity (DLCO) was tested at 6 months. Cytokine concentrations were analysed by human magnetic Luminex screening assay. We used a linear mixed-effects model to study log-concentrations of cytokines over time, assessing their association with socio-demographic and clinical characteristics that were included in the model as fixed effects. RESULTS: 186/349 (53%) participants had ≥2 serum samples and were included in current analyses. Of these, 101/186 (54%: 45/101[45%] female, median age 55 years [IQR = 45-64]) reported PASC at 12 and 24 weeks after COVID-19 onset. We included 37 reference samples (17/37[46%] female, median age 49 years [IQR = 40-56]). In a multivariate model, PASC was associated with raised CRP and abnormal diffusion capacity with raised IL10, IL17, IL6, IP10 and TNFα at 24 weeks. Early (0-4 week) IL-1ß and BMI at COVID-19 onset were predictive of PASC at 24 weeks. CONCLUSIONS: Our findings indicate that immune dysregulation plays an important role in PASC pathogenesis, especially among individuals with reduced pulmonary function. Early IL-1ß shows promise as a predictor of PASC.

Sources of Human Immunodeficiency Virus Infections Among Men Who Have Sex With Men With a Migration Background: A Viral Phylogenetic Case Study in Amsterdam, The Netherlands.

BACKGROUND: Men and women with a migration background comprise an increasing proportion of incident human immunodeficiency virus (HIV) cases across Western Europe. METHODS: To characterize sources of transmission in local transmission chains, we used partial HIV consensus sequences with linked demographic and clinical data from the opt-out AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort of people with HIV in the Netherlands and identified phylogenetically and epidemiologically possible HIV transmission pairs in Amsterdam. We interpreted these in the context of estimated infection dates, and quantified population-level sources of transmission to foreign-born and Dutch-born Amsterdam men who have sex with men (MSM) within Amsterdam transmission chains. RESULTS: We estimate that Dutch-born MSM were the predominant sources of infections among all Amsterdam MSM who acquired their infection locally in 2010-2021, and among almost all foreign-born Amsterdam MSM subpopulations. Stratifying by 2-year intervals indicated time trends in transmission dynamics, with a majority of infections originating from foreign-born MSM since 2016, although uncertainty ranges remained wide. CONCLUSIONS: Native-born MSM have predominantly driven HIV transmissions in Amsterdam in 2010-2021. However, in the context of rapidly declining incidence in Amsterdam, the contribution from foreign-born MSM living in Amsterdam is increasing, with some evidence that most local transmissions have been from foreign-born Amsterdam MSM since 2016.

A Robust SARS-CoV-2-specific T and B Cell Response is Associated with Early Viral Clearance in SARS-CoV-2 Omicron-Infected Immunocompromised Individuals.

BACKGROUND: The immunological determinants of delayed viral clearance and intra-host viral evolution that drive the development of new pathogenic virus strains in immunocompromised individuals are unknown. Therefore, we longitudinally studied SARS-CoV-2-specific immune responses in relation to viral-clearance and evolution in immunocompromised individuals. METHODS: Among Omicron-infected immunocompromised individuals, we determined SARS-CoV-2-specific T- and B-cell responses, anti-spike IgG(3) titers, neutralization titers, and monoclonal antibody (mAb)-resistance-associated mutations. The 28-day post-enrollment nasopharyngeal specimen defined early (RT-PCR negative ≤28 days) or late (RT-PCR- positive >28 days) viral-clearance. RESULTS: Of 30 patients included (median age 61.9 years [IQR 47.4-72.3], 50% females), 20 (66.7%) received mAb-therapy. Thirteen (43.3%) demonstrated early and 17 (56.7%) late viral-clearance. Early viral-clearance patients and patients without resistance-associated mutations had significantly higher baseline IFN-γ release and early viral-clearance patients had a higher frequency of SARS-CoV-2-specific B-cells at baseline. In non-mAb-treated patients, day 7 IgG and neutralization titers were significantly higher in those with early versus late viral-clearance. CONCLUSION: An early robust adaptive immune response is vital for efficient viral-clearance and associated with less emergence of mAb-resistance-associated mutations in Omicron-infected immunocompromised patients. This emphasizes the importance of early SARS-CoV-2-specific T- and B-cell responses and thereby provides a rationale for development of novel therapeutic approaches.

Immunogenicity of COVID-19 booster vaccination in IEI patients and their one year clinical follow-up after start of the COVID-19 vaccination program.

Purpose: Previous studies have demonstrated that the majority of patients with an inborn error of immunity (IEI) develop a spike (S)-specific IgG antibody and T-cell response after two doses of the mRNA-1273 COVID-19 vaccine, but little is known about the response to a booster vaccination. We studied the immune responses 8 weeks after booster vaccination with mRNA-based COVID-19 vaccines in 171 IEI patients. Moreover, we evaluated the clinical outcomes in these patients one year after the start of the Dutch COVID-19 vaccination campaign. Methods: This study was embedded in a large prospective multicenter study investigating the immunogenicity of COVID-19 mRNA-based vaccines in IEI (VACOPID study). Blood samples were taken from 244 participants 8 weeks after booster vaccination. These participants included 171 IEI patients (X-linked agammaglobulinemia (XLA;N=11), combined immunodeficiency (CID;N=4), common variable immunodeficiency (CVID;N=45), isolated or undefined antibody deficiencies (N=108) and phagocyte defects (N=3)) and 73 controls. SARS-CoV-2-specific IgG titers, neutralizing antibodies, and T-cell responses were evaluated. One year after the start of the COVID-19 vaccination program, 334 study participants (239 IEI patients and 95 controls) completed a questionnaire to supplement their clinical data focusing on SARS-CoV-2 infections. Results: After booster vaccination, S-specific IgG titers increased in all COVID-19 naive IEI cohorts and controls, when compared to titers at 6 months after the priming regimen. The fold-increases did not differ between controls and IEI cohorts. SARS-CoV-2-specific T-cell responses also increased equally in all cohorts after booster vaccination compared to 6 months after the priming regimen. Most SARS-CoV-2 infections during the study period occurred in the period when the Omicron variant had become dominant. The clinical course of these infections was mild, although IEI patients experienced more frequent fever and dyspnea compared to controls and their symptoms persisted longer. Conclusion: Our study demonstrates that mRNA-based booster vaccination induces robust recall of memory B-cell and T-cell responses in most IEI patients. One-year clinical follow-up demonstrated that SARS-CoV-2 infections in IEI patients were mild. Given our results, we support booster campaigns with newer variant-specific COVID-19 booster vaccines to IEI patients with milder phenotypes.

Control of complement-induced inflammatory responses to SARS-CoV-2 infection by anti-SARS-CoV-2 antibodies.

Dysregulated immune responses contribute to the excessive and uncontrolled inflammation observed in severe COVID-19. However, how immunity to SARS-CoV-2 is induced and regulated remains unclear. Here, we uncover the role of the complement system in the induction of innate and adaptive immunity to SARS-CoV-2. Complement rapidly opsonizes SARS-CoV-2 particles via the lectin pathway. Complement-opsonized SARS-CoV-2 efficiently induces type-I interferon and pro-inflammatory cytokine responses via activation of dendritic cells, which are inhibited by antibodies against the complement receptors (CR) 3 and 4. Serum from COVID-19 patients, or monoclonal antibodies against SARS-CoV-2, attenuate innate and adaptive immunity induced by complement-opsonized SARS-CoV-2. Blocking of CD32, the FcγRII antibody receptor of dendritic cells, restores complement-induced immunity. These results suggest that opsonization of SARS-CoV-2 by complement is involved in the induction of innate and adaptive immunity to SARS-CoV-2 in the acute phase of infection. Subsequent antibody responses limit inflammation and restore immune homeostasis. These findings suggest that dysregulation of the complement system and FcγRII signaling may contribute to severe COVID-19.

Determinants of epidemic size and the impacts of lulls in seasonal influenza virus circulation.

During the COVID-19 pandemic, levels of seasonal influenza virus circulation were unprecedentedly low, leading to concerns that a lack of exposure to influenza viruses, combined with waning antibody titres, could result in larger and/or more severe post-pandemic seasonal influenza epidemics. However, in most countries the first post-pandemic influenza season was not unusually large and/or severe. Here, based on an analysis of historical influenza virus epidemic patterns from 2002 to 2019, we show that historic lulls in influenza virus circulation had relatively minor impacts on subsequent epidemic size and that epidemic size was more substantially impacted by season-specific effects unrelated to the magnitude of circulation in prior seasons. From measurements of antibody levels from serum samples collected each year from 2017 to 2021, we show that the rate of waning of antibody titres against influenza virus during the pandemic was smaller than assumed in predictive models. Taken together, these results partially explain why the re-emergence of seasonal influenza virus epidemics was less dramatic than anticipated and suggest that influenza virus epidemic dynamics are not currently amenable to multi-season prediction.

Aberrant neutrophil degranulation in hospitalized patients with COVID-19 partially remains for 6 months.

Neutrophils are important players in COVID-19, contributing to tissue damage by release of inflammatory mediators, including ROS and neutrophil elastase. Longitudinal studies on the effects of COVID-19 on neutrophil phenotype and function are scarce. Here, we longitudinally investigated the phenotype and degranulation of neutrophils in COVID-19 patients (28 nonhospitalized and 35 hospitalized patients) compared with 17 healthy donors (HDs). We assessed phenotype, degranulation, CXCL8 (IL-8) release, and ROS generation within 8 days, at one or 6 month(s) after COVID-19 diagnosis. For degranulation and ROS production, we stimulated neutrophils, either with ssRNA and TNF or granulocyte-macrophage colony-stimulating factor and N-Formylmethionyl-leucyl-phenylalanine. During active COVID-19, neutrophils from hospitalized patients were more immature than from HDs and were impaired in degranulation and ROS generation, while neutrophils from nonhospitalized patients only demonstrated reduced CD66b+ granule release and ROS production. Baseline CD63 expression, indicative of primary granule release, and CXCL8 production by neutrophils from hospitalized patients were elevated for up to 6 months. These findings show that patients hospitalized due to COVID-19, but not nonhospitalized patients, demonstrated an aberrant neutrophil phenotype, degranulation, CXCL8 release, and ROS generation that partially persists up to 6 months after infection.

Case report: XMEN disease: a patient with recurrent Hodgkin lymphoma and immune thrombocytopenia.

Here we present the case of a 28-year-old man with X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection and neoplasia (XMEN) disease. He presented with immune thrombocytopenia within 1 year after successful autologous hematopoietic stem cell transplantation for recurrent EBV-associated classical Hodgkin lymphoma (CHL). The combination of EBV- associated malignancy, autoimmunity, recurrent airway infections at young age and bronchiectasis, prompted immunological investigation for an inborn error of immunity (IEI). Genetic testing revealed XMEN disease. XMEN disease is characterized by a glycosylation defect due to mutations in the MAGT1 gene. Germline mutations in the MAGT1 gene disrupt glycosylation of the NKG2D receptor in immune cells, including natural killer and CD8-positive T cells, vital for immune surveillance, especially against EBV. Consequently, individuals with XMEN disease, are prone to EBV-associated lymphoproliferative disorders in addition to auto-immunity. Early recognition of adult onset IEI-related B-lymphoproliferative disorders, including CHL is of vital importance for treatment decisions, including (allogeneic) haematopoietic stem cell transplantation and family screening.

Two-year trajectories of COVID-19 symptoms and their association with illness perception: A prospective cohort study in Amsterdam, the Netherlands.

Background: We used data from a prospective cohort to explore 2-year trajectories of 'long COVID' (persistent symptoms after SARS-CoV-2 infection) and their association with illness perception. Methods: RECoVERED participants (adults; prospectively enrolled following laboratory-confirmed SARS-CoV-2 infection, May 2020-June 2021) completed symptom questionnaires at months 2-12, 18 and 24, and the Brief Illness Perception Questionnaire (B-IPQ) at months 1, 6 and 12. Using group-based trajectory models (GBTM), we modelled symptoms (mean total numbers and proportion with four specific complaints), including age, sex, BMI and timing of infection as covariates. In a multivariable linear mixed-effects model, we assessed the association between symptom trajectories and repeated B-IPQ scores. Results: Among 292 participants (42% female; median age 51 [IQR = 36-62]), four trajectories were identified, ranging from Trajectory 4 (8.9%; 6 + symptoms) to Trajectory 1 (24.8%; no symptoms). The occurrence of fatigue and myalgia increased among 23% and 12% of participants, respectively. Individuals in Trajectory 4 experienced more negative adjusted B-IPQ scores over time than those in Trajectories 1-3. Conclusions: We observed little fluctuation in the total number of symptoms, but individual symptoms may develop as others resolve. Reporting a greater number of symptoms was congruent with more negative illness perception over time.

Perceptions of Rapid Antiretroviral Therapy Initiation Among Participants of The Netherlands Cohort Study on Acute HIV Infection.

Starting antiretroviral therapy (ART) same-day, or as soon as possible after HIV diagnosis is advised in guidelines worldwide. Especially during acute HIV infection (AHI), rapid ART start may be more urgent because of a higher risk of transmission or symptoms of acute retroviral syndrome. During this phase, rapid ART start may have additional benefits for viral reservoir size and host immunity. We explored perceptions of rapid ART start among participants of The Netherlands Cohort Study on Acute HIV infection (NOVA study), who started ART rapidly after diagnosis of AHI. We conducted 20 in-depth qualitative interviews with NOVA study participants between October and December 2018. Data were analyzed thematically, using inductive and iterative coding techniques. Roughly half of the participants stated they felt well-informed about the importance of (rapid) ART. Starting ART rapidly was perceived positively by almost all participants, mostly because of the expected benefits on their health, and to prevent HIV transmission. Rapid ART start was seen as a way to cope with the diagnosis. However, a more negative perception was that rapid ART start confronted participants with their diagnosis, when they were still adjusting to a new situation. Our results show that among people diagnosed during AHI, rapid ART is well-accepted. These results should be encouraging to HIV care providers who encounter people with AHI in their clinical practice and to researchers who carry out cure-related studies, in which early ART is often included. The Clinical Trial Registration number is NCT05728996.

Broad SARS-CoV-2 neutralization by monoclonal and bispecific antibodies derived from a Gamma-infected individual.

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has remained a medical threat due to the evolution of multiple variants that acquire resistance to vaccines and prior infection. Therefore, it is imperative to discover monoclonal antibodies (mAbs) that neutralize a broad range of SARS-CoV-2 variants. A stabilized spike glycoprotein was used to enrich antigen-specific B cells from an individual with a primary Gamma variant infection. Five mAbs selected from those B cells showed considerable neutralizing potency against multiple variants, with COVA309-35 being the most potent against the autologous virus, as well as Omicron BA.1 and BA.2, and COVA309-22 having binding and neutralization activity against Omicron BA.4/5, BQ.1.1, and XBB.1. When combining the COVA309 mAbs as cocktails or bispecific antibodies, the breadth and potency were improved. In addition, the mechanism of cross-neutralization of the COVA309 mAbs was elucidated by structural analysis. Altogether these data indicate that a Gamma-infected individual can develop broadly neutralizing antibodies.

Mental health up to 12 months following SARS-CoV-2 infection: A prospective cohort study.

OBJECTIVE: To investigate to what extent individuals report clinically relevant levels of depression, anxiety, post-traumatic stress disorder (PTSD) symptoms and concentration problems up to 12 months following COVID-19 symptom onset, using validated questionnaires. METHODS: RECoVERED, a prospective cohort study in Amsterdam, the Netherlands, enrolled both hospitalized and community-dwelling adult participants diagnosed with SARS-CoV-2. Symptoms of depression and anxiety were assessed with the Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7 1, 3, 6 and 12 months following illness onset. The DSM-V PTSD checklist was administered at month 3 and 9. Concentration problems were assessed using the Checklist Individual Strength concentration subscale at month 1 and 12. Generalized Estimating Equations were used to determine factors related with clinically relevant levels of depression-, anxiety- and PTSD-symptoms and concentration problems over time. RESULTS: In 303 individuals, the prevalence of clinically relevant symptoms of depression, anxiety and concentration problems was 10.6% (95%CI = 7.2-15.4), 7.0% (95%CI = 4.4-11.2) and 33.6% (95%CI = 27.7-40.1), respectively, twelve months after infection. Nine months after illness onset, 4.2% (95%CI = 2.3-7.7) scored within the clinical range of PTSD. Risk factors for an increased likelihood of reporting mental health problems during follow up included initial severe/critical COVID-19, non-Dutch origin, psychological problems prior to COVID-19 and being infected during the first COVID-19 wave. CONCLUSION: Our findings highlight that a minority of patients with COVID-19 face clinically relevant symptoms of depression, anxiety or PTSD up to 12 months after infection. The prevalence of concentration problems was high. This study contributes to the identification of specific groups for which support after initial illness is indicated.

One-fourth of COVID-19 patients have an impaired pulmonary function after 12 months of disease onset.

BACKGROUND: There is increasing data that show a persistently impaired pulmonary function upon recovery after severe infection. Little is known however about the extent, recovery and determinants of pulmonary impairment across the full spectrum of COVID-19 severity over time. METHODS: In a well characterized, prospective cohort of both hospitalised and non-hospitalised individuals with SARS-CoV-2 infection, the RECoVERED study, pulmonary function (diffusing capacity for carbon monoxide (DLCO)) and spirometry) was measured until one year after disease onset. Additionally, data on sociodemographics, clinical characteristics, symptoms, and health-related quality of life (HRQL) were collected. Pulmonary function and these determinants were modelled over time using mixed-effect linear regression. Determinants of pulmonary function impairment at 12 months after disease onset were identified using logistic regression. FINDINGS: Between May 2020 and December 2021, 301 of 349 participants underwent at least one pulmonary function test. After one year of follow-up, 25% of the participants had an impaired pulmonary function which translates in 11%, 22%, and 48% of the participants with mild, moderate and severe/critical COVID-19. Improvement in DLCO among the participants continued over the period across one, six and twelve months. Being older, having more than three comorbidities (p<0·001) and initial severe/critical disease (p<0·001) were associated with slower improvement of pulmonary function over time, adjusted for age and sex. HRQL improved over time and at 12 months was comparable to individuals without impaired pulmonary function. INTERPRETATION: The prevalence of impaired pulmonary function after twelve months of follow-up, was still significant among those with initially moderate or severe/critical COVID-19. Pulmonary function increased over time in most of the severity groups. These data imply that guidelines regarding revalidation after COVID-19 should target individuals with moderate and severe/critical disease severities.

Virological and immunological correlates of HIV posttreatment control after temporal antiretroviral therapy during acute HIV infection.

OBJECTIVE: People with HIV rarely control viral replication after cessation of antiretroviral therapy (ART). We present a person with HIV with extraordinary posttreatment control (PTC) for over 23 years after temporary ART during acute HIV infection (AHI) leading to a new insight in factors contributing to PTC. DESIGN/METHODS: Viral reservoir was determined by HIV qPCR, Intact Proviral DNA Assay, and quantitative viral outgrowth assay. Viral replication kinetics were determined in autologous and donor PBMC. IgG levels directed against HIV envelope and neutralizing antibodies were measured. Immune phenotyping of T cells and HIV-specific T-cell responses were analyzed by flow cytometry. RESULTS: The case presented with AHI and a plasma viral load of 2.7 million copies/ml. ART was initiated 2 weeks after diagnosis and interrupted after 26 months. Replicating virus was isolated shortly after start ART. At 18 years after treatment interruption, HIV-DNA in CD4 + T cells and low levels of HIV-RNA in plasma (<5 copies/ml) were detectable. Stable HIV envelope glycoprotein-directed IgG was present during follow-up, but lacked neutralizing activity. Strong antiviral CD8 + T-cell responses, in particular targeting HIV-gag, were detected during 25 years follow-up. Moreover, we found a P255A mutation in an HLA-B∗44 : 02 restricted gag-epitope, which was associated with decreased replication. CONCLUSION: We describe an exceptional case of PTC, which is likely associated with sustained potent gag-specific CD8 + T-cell responses in combination with a replication attenuating escape mutation in gag. Understanding the initiation and preservation of the HIV-specific T-cell responses could guide the development of strategies to induce HIV control.

Health Outcomes and Cost-effectiveness of Monoclonal SARS-CoV-2 Antibodies as Pre-exposure Prophylaxis.

Importance: Pre-exposure prophylaxis with neutralizing SARS-CoV-2 monoclonal antibodies (mAbs PrEP) prevents infection and reduces hospitalizations and the duration thereof for COVID-19 and death among high-risk individuals. However, reduced effectiveness due to a changing SARS-CoV-2 viral landscape and high drug prices remain substantial implementation barriers. Objective: To assess the cost-effectiveness of mAbs PrEP as COVID-19 PrEP. Design, Setting, and Participants: For this economic evaluation, a decision analytic model was developed and parameterized with health care outcome and utilization data from individuals with high risk for COVID-19. The SARS-CoV-2 infection probability, mAbs PrEP effectiveness, and drug pricing were varied. All costs were collected from a third-party payer perspective. Data were analyzed from September 2021 to December 2022. Main Outcomes and Measures: Health care outcomes including new SARS-CoV-2 infections, hospitalization, and deaths. The cost per death averted and cost-effectiveness ratios using a threshold for prevention interventions of $22 000 or less per quality-adjusted life year (QALY) gained. Results: The clinical cohort consisted of 636 individuals with COVID-19 (mean [SD] age 63 [18] years; 341 [54%] male). Most individuals were at high risk for severe COVID-19, including 137 (21%) with a body mass index of 30 or higher, 60 (9.4%) with hematological malignant neoplasm, 108 (17%) post-transplantation, and 152 (23.9%) who used immunosuppressive medication before COVID-19. Within the context of a high (18%) SARS-CoV-2 infection probability and low (25%) effectiveness the model calculated a short-term reduction of 42% ward admissions, 31% intensive care unit (ICU) admissions, and 34% deaths. Cost-saving scenarios were obtained with drug prices of $275 and 75% or higher effectiveness. With a 100% effectiveness mAbs PrEP can reduce ward admissions by 70%, ICU admissions by 97%, and deaths by 92%. Drug prices, however, need to reduce to $550 for cost-effectiveness ratios less than $22 000 per QALY gained per death averted and to $2200 for ratios between $22 000 and $88 000. Conclusions and Relevance: In this study, use of mAbs PrEP for preventing SARS-CoV-2 infections was cost-saving at the beginning of an epidemic wave (high infection probability) with 75% or higher effectiveness and drug price of $275. These results are timely and relevant for decision-makers involved in mAbs PrEP implementation. When newer mAbs PrEP combinations become available, guidance on implementation should be formulated ensuring a fast rollout. Nevertheless, advocacy for mAbs PrEP use and critical discussion on drug prices are necessary to ensuring cost-effectiveness for different epidemic settings.

Neurobiological basis and risk factors of persistent fatigue and concentration problems after COVID-19: study protocol for a prospective case-control study (VeCosCO).

INTRODUCTION: The risk factors for persistent fatigue and cognitive complaints after infection with SARS-CoV-2 and the underlying pathophysiology are largely unknown. Both clinical factors and cognitive-behavioural factors have been suggested to play a role in the perpetuation of complaints. A neurobiological aetiology, such as neuroinflammation, could be the underlying pathophysiological mechanism for persisting complaints.To unravel factors associated with persisting complaints, VeCosCO will compare individuals with and without persistent fatigue and cognitive complaints >3 months after infection with SARS-CoV-2. The study consists of two work packages. The first work package aims to (1) investigate the relation between persisting complaints and neuropsychological functioning; (2) determine risk factors and at-risk phenotypes for the development of persistent fatigue and cognitive complaints, including the presence of postexertional malaise and (3) describe consequences of persistent complaints on quality of life, healthcare consumption and physical functioning. The second work package aims to (1) determine the presence of neuroinflammation with [18F]DPA-714 whole-body positron emission tomography (PET) scans in patients with persisting complaints and (2) explore the relationship between (neuro)inflammation and brain structure and functioning measured with MRI. METHODS AND ANALYSIS: This is a prospective case-control study in participants with and without persistent fatigue and cognitive complaints, >3 months after laboratory-confirmed SARS-CoV-2 infection. Participants will be mainly included from existing COVID-19 cohorts in the Netherlands covering the full spectrum of COVID-19 acute disease severity. Primary outcomes are neuropsychological functioning, postexertional malaise, neuroinflammation measured using [18F]DPA-714 PET, and brain functioning and structure using (f)MRI. ETHICS AND DISSEMINATION: Work package 1 (NL79575.018.21) and 2 (NL77033.029.21) were approved by the medical ethical review board of the Amsterdam University Medical Centers (The Netherlands). Informed consent is required prior to participation in the study. Results of this study will be submitted for publication in peer-reviewed journals and shared with the key population.

Crosstalk between TLR8 and RIG-I-like receptors enhances antiviral immune responses.

Background: Toll-like receptor (TLR) agonists have been investigated due to their potential dual effects as latency reverting agents and immune modulatory compounds in people living with HIV (PLWH). Here, we investigated whether co-stimulation of TLR7/8 agonists with RIG-I-like receptor (RLR) agonists enhances antiviral immunity. Methods: Peripheral blood mononuclear cells (PBMCs) and monocyte-derived dendritic cells (DCs) were incubated with TLR and RLR-agonists for 24 h and innate and adaptive immune responses were determined (maturation markers, cytokines in supernatant, ISG expression). Results: Both TLR7 and TLR8 agonists induced pro-inflammatory cytokines in DCs as well as PBMCs. TLR8 agonists were more potent in inducing cytokine responses and had a stronger effect on DC-induced immunity. Notably, while all compounds induced IL-12p70, co-stimulation with TLR8 agonists and RLR agonist polyI: C induced significantly higher levels of IL-12p70 in PBMCs. Moreover, crosstalk between TLR8 and RLR agonists induced a strong type I Interferon (IFN) response as different antiviral IFN-stimulated genes were upregulated by the combination compared to the agonists alone. Conclusion: Our data strongly suggest that TLR crosstalk with RLRs leads to strong antiviral immunity as shown by induction of IL-12 and type I IFN responses in contrast to TLRs alone. Thus, co-stimulation of TLRs and RLRs might be a powerful strategy to induce reactivation of latent reservoir as well as antiviral immunity that eliminates the reactivated cells.

Immune Responses 6 Months After mRNA-1273 COVID-19 Vaccination and the Effect of a Third Vaccination in Patients with Inborn Errors of Immunity.

PURPOSE: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective long-term protection against COVID-19 is therefore of great importance in these patients, but little is known about the decay of the immune response after primary vaccination. We studied the immune responses 6 months after two mRNA-1273 COVID-19 vaccines in 473 IEI patients and subsequently the response to a third mRNA COVID-19 vaccine in 50 patients with common variable immunodeficiency (CVID). METHODS: In a prospective multicenter study, 473 IEI patients (including X-linked agammaglobulinemia (XLA) (N = 18), combined immunodeficiency (CID) (N = 22), CVID (N = 203), isolated or undefined antibody deficiencies (N = 204), and phagocyte defects (N = 16)), and 179 controls were included and followed up to 6 months after two doses of the mRNA-1273 COVID-19 vaccine. Additionally, samples were collected from 50 CVID patients who received a third vaccine 6 months after primary vaccination through the national vaccination program. SARS-CoV-2-specific IgG titers, neutralizing antibodies, and T cell responses were assessed. RESULTS: At 6 months after vaccination, the geometric mean antibody titers (GMT) declined in both IEI patients and healthy controls, when compared to GMT 28 days after vaccination. The trajectory of this decline did not differ between controls and most IEI cohorts; however, antibody titers in CID, CVID, and isolated antibody deficiency patients more often dropped to below the responder cut-off compared to controls. Specific T cell responses were still detectable in 77% of controls and 68% of IEI patients at 6 months post vaccination. A third mRNA vaccine resulted in an antibody response in only two out of 30 CVID patients that did not seroconvert after two mRNA vaccines. CONCLUSION: A similar decline in IgG titers and T cell responses was observed in patients with IEI when compared to healthy controls 6 months after mRNA-1273 COVID-19 vaccination. The limited beneficial benefit of a third mRNA COVID-19 vaccine in previous non-responder CVID patients implicates that other protective strategies are needed for these vulnerable patients.

Age-related changes in plasma biomarkers and their association with mortality in COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19)-induced mortality occurs predominantly in older patients. Several immunomodulating therapies seem less beneficial in these patients. The biological substrate behind these observations is unknown. The aim of this study was to obtain insight into the association between ageing, the host response and mortality in patients with COVID-19. METHODS: We determined 43 biomarkers reflective of alterations in four pathophysiological domains: endothelial cell and coagulation activation, inflammation and organ damage, and cytokine and chemokine release. We used mediation analysis to associate ageing-driven alterations in the host response with 30-day mortality. Biomarkers associated with both ageing and mortality were validated in an intensive care unit and external cohort. RESULTS: 464 general ward patients with COVID-19 were stratified according to age decades. Increasing age was an independent risk factor for 30-day mortality. Ageing was associated with alterations in each of the host response domains, characterised by greater activation of the endothelium and coagulation system and stronger elevation of inflammation and organ damage markers, which was independent of an increase in age-related comorbidities. Soluble tumour necrosis factor receptor 1, soluble triggering receptor expressed on myeloid cells 1 and soluble thrombomodulin showed the strongest correlation with ageing and explained part of the ageing-driven increase in 30-day mortality (proportion mediated: 13.0%, 12.9% and 12.6%, respectively). CONCLUSIONS: Ageing is associated with a strong and broad modification of the host response to COVID-19, and specific immune changes likely contribute to increased mortality in older patients. These results may provide insight into potential age-specific immunomodulatory targets in COVID-19.