Score: 354.8, Published: 2024-02-13
DOI: 10.1101/2024.02.11.24302636
During the COVID-19 pandemic it was widely described that certain individuals infected by SARS-CoV-2 experience persistent disease signs and symptoms, Long COVID, which in some cases is very severe with life changing consequences. To maximize our chances of identifying the underpinnings of this illness, we have focused on 121 of the most severe cases from >1000 patients screened in specialized clinics in Sweden and Belgium. We restricted this study to subjects with objective measures of organ damage or dysfunction, >3 months following a verified, but mild-to-moderate SARS-CoV-2 infection. By performing systems-level immunological testing and comparisons to controls fully convalescent following a similar mild/moderate COVID-19 episode, we identify elevated serological responses to SARS-CoV-2 in severe Long COVID suggestive of chronic antigen stimulation. Persistent viral reservoirs have been proposed in Long COVID and using multiple orthogonal methods for detection of SARS-CoV-2 RNA and protein in plasma we identify a subset of patients with detectable antigens, but with minimal overlap across assays, and no correlation to symptoms or immune measurements. Elevated serologic responses to SARS-CoV-2 on the other hand were inversely correlated with clonally expanded memory CD8+ T cells, indicating that restrained clonal expansion enables viral persistence, chronic antigen exposure and elevated IgG responses, even if antigen-detection in blood is not universally possible.
Score: 257.9, Published: 2024-02-14
DOI: 10.1101/2024.02.11.24302530
BackgroundThe urgent need for safe, effective, and economical coronavirus disease 2019 (COVID-19) vaccines, especially for booster campaigns targeting vulnerable populations, prompted the development of the AVX/COVID-12 vaccine candidate. AVX/COVD-12 is based in a Newcastle disease virus La Sota (NDV-LaSota) recombinant viral vector. This vaccine expresses a stabilized version of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), specifically the ancestral Wuhan strain. The study aimed to assess its safety, immunogenicity, and potential efficacy as an anti-COVID-19 booster vaccine. MethodsIn a phase II/III clinical trial conducted from November 9, 2022, to September 11, 2023, a total of 4,056 volunteers were enrolled. Participants received an intramuscular booster dose of either AVX/COVID-12 or AZ/ChAdOx-1-S vaccines. Safety, immunogenicity, and potential efficacy were assessed through various measures, including neutralizing antibody titers, interferon (IFN)-{gamma}-producing CD4+ T cells, and CD8+ T cells. The evaluation also involved immunobridging, utilizing the AZ/ChAdOx-1-S vaccine as an active comparator, and monitoring the incidence of COVID-19 cases. FindingsThe AVX/COVID-12 vaccine induced neutralizing antibodies against both the ancestral SARS-CoV-2 and the BA.2 and BA.5 Omicron variants. The geometric mean ratio of neutralizing antibody titers between individuals immunized with the AVX/COVID-12 vaccine and those with the AZ/ChAdOx-1-S vaccine at 14 days is 0.96, with a confidence interval (CI) of 0.85-1.06. The outcome aligns with the non-inferiority criterion recommended by the World Health Organization (WHO), indicating a lower limit of the CI greater than or equal to 0.67. Induction of IFN-{gamma}-producing CD8+ T cells at day 14 post-immunization was exclusively observed in the AVX/COVID-12 group. Finally, a trend suggested a potentially lower incidence of COVID-19 cases in AVX/COVID-12 boosted volunteers compared to AZ/ChAdOx-1-S recipients. ConclusionThe AVX/COVID-12 vaccine proved safe, well-tolerated, and immunogenic. AVX/COVID-12 meets the WHO non-inferiority standard compared to AZ/ChAdOx-1-S. These results strongly advocate for AVX/COVID-12 as a viable booster dose, supporting its utilization in the population.
Score: 212.4, Published: 2024-02-15
DOI: 10.1101/2024.02.15.24302857
Autoantibodies have been shown to be implied in COVID-19 but the emerging autoantibody repertoire remains largely unexplored. We investigated the new-onset autoantibody repertoire in 525 healthcare workers and hospitalized COVID-19 patients in five time points over 16 months using proteome-wide and targeted protein and peptide arrays. Our results show that prevalent new-onset autoantibodies against a wide range of antigens emerged following SARS-CoV-2 infection in relation to pre-infectious baseline samples and remained elevated for at least 12 months. We demonstrated associations between distinct new-onset autoantibodies and neuropsychiatric symptoms post-COVID-19. Using epitope mapping, we determined the main epitopes of selected new-onset autoantibodies, validated them in independent cohorts of neuro-COVID and pre-pandemic healthy controls, and identified molecular mimicry between main epitopes and the conserved fusion peptide of the SARS-CoV-2 Spike glycoprotein. Our work describes the complexity and dynamics of the autoantibody repertoire emerging with COVID-19 and supports the need for continued analysis of the new-onset autoantibody repertoire to elucidate the mechanisms of the post-COVID-19 condition.
Score: 118.6, Published: 2024-02-13
DOI: 10.1101/2024.02.11.24302594
BackgroundThe global inequity in coronavirus disease 2019 (COVID-19) vaccine distribution, primarily affecting low- and middle-income countries (LMICs), highlights the urgent need for innovative and cost-effective vaccine technologies to address availability disparities. This is crucial for achieving and sustaining widespread immunity and protecting vulnerable populations during future booster campaigns. MethodsTo address this need, we conducted a phase II clinical trial evaluating the safety and immunogenicity of the AVX/COVID-12 "Patria" vaccine as a booster dose. The vaccine was administered through both intramuscular (IM) and intranasal (IN) routes to participants who had previously received severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines based on adenoviral technology, inactivated virus, or mRNA technology. The inclusion criterion involved individuals with initial anti-spike IgG titers below 1,200 U/mL, allowing observation of the booster effect induced by vaccination. ResultsImmunization with AVX/COVID-12 resulted in a significant (>2.5 times) increase in neutralizing antibodies against the original Wuhan strain and variants of concern (VOCs) such as Alpha, Beta, Delta, and Omicron (BA.2 and BA.5). This immune response was accompanied by cellular interferon-gamma (IFN-{gamma}) production, indicating a robust and multifaceted reaction. ConclusionsThe administration of AVX/COVID-12 as a booster dose, whether through IM or IN routes, was safe and well-tolerated. The vaccine extended immune responses not only against the original Wuhan-1 strain but also against various VOCs. Its ability to enhance preexisting immune responses suggests a potential contribution to expanding and sustaining herd immunity within the population.
Score: 31.2, Published: 2024-02-14
DOI: 10.1101/2024.02.13.24302781
RATIONALEPersistent cough and dyspnea are prominent features of post-acute sequelae of SARS-CoV-2 (termed Long COVID); however, physiologic measures and clinical features associated with these pulmonary symptoms remain poorly defined. OBJECTIVESUsing longitudinal pulmonary function testing (PFTs) and CT imaging, this study aimed to identify the characteristics and determinants of pulmonary Long COVID. METHODSThe University of Alabama at Birmingham Pulmonary Long COVID cohort was utilized to characterize lung defects in patients with persistent pulmonary symptoms after resolution primary COVID infection. Longitudinal PFTs including total lung capacity (TLC) and diffusion limitation of carbon monoxide (DLCO) were used to evaluate restriction and diffusion impairment over time in this cohort. Analysis of chest CT imaging was used to phenotype the pulmonary Long COVID pathology. Risk factors linked to development of pulmonary Long COVID were estimated using univariate and multivariate logistic regression models. MEASUREMENTS AND MAIN RESULTSLongitudinal evaluation 929 patients with post-COVID pulmonary symptoms revealed diffusion impairment (DLCO [≤]80%) and restriction (TLC [≤]80%) in 51% of the cohort (n=479). In multivariable logistic regression analysis (adjusted odds ratio; aOR, 95% confidence interval [CI]), invasive mechanical ventilation during primary infection conferred the greatest increased odds of developing pulmonary Long COVID with diffusion impaired restriction (aOR=10.9 [4.09-28.6]). Finally, a sub-analysis of CT imaging identified evidence of fibrosis in this population. CONCLUSIONSPersistent diffusion impaired restriction was identified as a key feature of pulmonary Long COVID. Subsequent clinical trials should leverage combined symptomatic and quantitative PFT measurements for more targeted enrollment of pulmonary Long COVID patients.
Score: 33.3, Published: 2024-02-08
DOI: 10.1101/2024.02.08.24302516
BackgroundMultiple studies have shown that Long COVID (LC) disease is associated with heightened immune activation, as evidenced by elevated levels of inflammatory mediators. However, there is no comprehensive meta-analysis focusing on activation of the immune inflammatory response system (IRS) and the compensatory immunoregulatory system (CIRS) along with other immune phenotypes in LC patients. ObjectivesThis meta-analysis is designed to explore the IRS and CIRS profiles in LC patients, the individual cytokines, chemokines, growth factors, along with C-reactive protein (CRP) and immune-associated neurotoxicity. MethodsTo gather relevant studies for our research, we conducted a thorough search using databases such as PubMed, Google Scholar, and SciFinder, covering all available literature up to December 20th, 2023. ResultsThe current meta-analysis encompassed 82 studies that examined multiple immune profiles, C-reactive protein, and 58 cytokines/chemokines/growth factors in 3836 LC patients versus 4537 normal controls (NC). LC patients showed significant increases in IRS/CIRS ratio (standardized mean difference (SMD:0.156, confidence interval (CI): 0.051;0.261), IRS (SMD: 0.345, CI: 0.222;0.468), M1 macrophage (SMD: 0.421, CI: 0.290;0.551), T helper (Th)1 (SMD: 0.353, CI: 0.189;0.517), Th17 (SMD: 0.492, CI: 0.332;0.651) and immune-associated neurotoxicity (SMD: 0.327 CI: 0.205;0.448). In addition, CRP and 19 different cytokines displayed significantly elevated levels in LC patients compared to NC. ConclusionLC disease is characterized by IRS activation and increased immune-associated neurotoxicity.
Score: 27.3, Published: 2024-02-14
DOI: 10.1101/2024.02.13.24302758
It has been postulated from a combination of evidence that a sudden increase in COVID-19 cases among pediatric patients after onset of the Omicron wave was attributed to a reduced requirement for TMPRSS2-mediated entry in pediatric airways with lower expression levels of TMPRSS2. Epidemic strains were isolated from the indigenous population in an area, and the levels of TMPRSS2 required for Delta and Omicron variants were assessed. As a result, Delta variants proliferated fully in cultures of TMPRSS2-positive Vero cells but not in TMPRSS2-negative Vero cell culture (350-fold, Delta vs 9.6-fold, Omicron). There was no obvious age-dependent selection of Omicron strains affected by the TMPRSS2 (9.6-fold, Adults vs. 12-fold, Children). A phylogenetic tree was generated and Blast searches (up to 100 references) for the spread of strains in the study area showed that each strain had almost identical homology (>99.5%) with foreign isolates, although indigenous strains had obvious differences from each other. This suggested that the differences had been present abroad for a long period. Therefore, the lower requirement for TMPRSS2 by Omicron strains might be applicable to epidemic strains globally. In conclusion, the property of TMPRSS2-independent cleavage makes Omicron proliferate with ease and allows epidemics among children with fewer TMPRSS2 on epithelial surfaces of the respiratory organs.
Score: 69.3, Published: 2024-02-09
DOI: 10.1101/2024.02.08.24302032
The ongoing evolution of the SARS-CoV-2 virus has led to a move to update vaccine antigens in 2022 and 2023. These updated antigens were chosen and approved based on in vitro neutralisation titres against recent SARS-CoV-2 variants. However, unavoidable delays in viral manufacture and distribution meant that the updated booster vaccine was no longer well matched to the circulating SARS-CoV-2 variant by the time of its deployment. Understanding whether the updating of booster vaccine antigens improves immune responses to subsequent SARS-CoV-2 circulating variants is a major priority in justifying future vaccine updates. Here we analyse all available data on the immunogenicity of variant containing SARS-CoV-2 vaccines and their ability to neutralise later circulating SARS-CoV-2 variants. We find that updated booster antigens give a 1.4-fold [95%CI 1.07-1.82] greater increase in neutralising antibody levels when compared with a historical vaccine immunogen. We then use this to predict the relative protection that can be expected from an updated vaccine even when the circulating variant has evolved away from the updated vaccine immunogen. These findings help inform the roll out of future booster vaccination programs.
Score: 14.5, Published: 2024-02-12
DOI: 10.1101/2024.02.06.24302387
BackgroundThe incidence of respiratory syncytial virus (RSV) dropped markedly early in the COVID-19 pandemic, followed by a resurgence with heightened case counts. The "immunity debt" hypothesis proposes that the RSV-naive pediatric population increased during the period of low transmission, resulting in a subsequent increased risk of infection. However, the evidence supporting this hypothesis is limited, and no studies have comprehensively evaluated the role of changing respiratory viral testing practices in the perceived surge. MethodsWe conducted a multicenter, retrospective analysis of 342,530 RSV encounters and 980,546 RSV diagnostic tests occurring at 32 United States pediatric hospitals between 2013 and 2023. We used interrupted time series analysis to estimate pandemic-associated changes in RSV patient and testing volume, and to quantify changes in the proportions of patients admitted from the emergency department (ED), admitted to the intensive care unit (ICU), and receiving mechanical ventilation. We quantified the fraction of the observed shifts in case counts and in the age of diagnosed patients attributable to changes in RSV testing practices. Finally, we analyzed 524,404 influenza virus encounters and 1,768,526 influenza diagnostic tests to address the specificity of the findings to RSV. FindingsRSV patient volume increased 2.4-fold (95% CI: 1.7, 3.5) in 2021-2023 relative to the pre-pandemic phase, and was accompanied by an 18.9-fold increase (95% CI: 15.0, 23.9) in RSV test volume. Over two-thirds of the apparent shifts in patient volume and in patient age were attributable to increased testing, which was concentrated among older pediatric patients. The proportions of patients with RSV requiring hospitalization, intensive care, or mechanical ventilation declined significantly across all patient age groups. These declines were not observed for patients with influenza virus. InterpretationA surge in RSV testing, rather than in viral circulation, likely underlies the increased case counts observed in 2021-2023. We identify expected consequences of increased testing, including the diagnosis of less severe cases and a shift in the patient age distribution. These findings warrant a critical assessment of the immunity debt hypothesis, while highlighting the importance of considering the testing denominator when surveillance strategies are dynamic. FundingNational Institutes of Health & Howard Hughes Medical Institute Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSGoogle Scholar was used to identify studies describing the epidemiology or clinical severity of RSV after the emergence of SARS-CoV-2. On 2 February 2024, a search was conducted for articles published since 2021 whose titles contain the term "respiratory syncytial virus" as well as one or more of the following terms: "clinical", "COVID-19", "debt", "epidemiology", "immunity", "severity", or "outcome." Prior to the study, it was clear that RSV circulation was limited during the first year of the COVID-19 pandemic, and that its return was documented as large, off-season epidemics. An increase in the age of pediatric patients diagnosed with RSV has also been well characterized. Multiple studies include discussions of an RSV immunity debt as the cause of elevated case counts, though no studies have provided causal evidence that a decline in population immunity underlies the large epidemics. Moreover, no studies have examined the role of shifting respiratory viral testing practices in epidemic sizes. Added value of this studyHere, we provide the first comprehensive assessment of the role of increased diagnostic testing in the incidence of RSV before and after the emergence of SARS-CoV-2. We find that testing for RSV increased nearly 20-fold, and that the majority of the increase in patient volume can be attributed to increased testing, primarily of older children. Implications of all the available evidenceChanging diagnostic testing practices can explain the bulk of the increased detection of RSV over multiple annual epidemics following the emergence of SARS-CoV-2. Additional factors, including increased tendency to seek healthcare and a decline in population-level immunity to RSV may be a role in the observed dynamics.
Score: 80.4, Published: 2024-01-30
DOI: 10.1101/2024.01.29.24301882
PurposeThere have been large geographical differences in the infection and death rates of COVID-19. Foods and beverages containing high amounts of phytochemicals with bioactive properties were suggested to prevent contracting, to limit the severity of, and to facilitate recovery from COVID-19. The goal of our study was to determine the correlation of the type of foods/beverages people consumed and the risk reduction of contracting COVID-19 and the recovery from COVID-19. MethodsWe developed an online survey that asked the participants whether they contracted COVID-19, their symptoms, time to recover, and their frequency of eating various types of foods/beverages. The survey was first developed in English and then translated into 10 different languages. ResultsThe participants who did not contract COVID-19 consumed vegetables, herbs/spices, and fermented foods/beverages significantly more than the participants who contracted COVID-19 and those who were not tested but became sick most likely from COVID-19. The geographic location of participants corresponded with the language of the survey, except for the English version, thus, nine out of the 10 language versions represented a country. Among the six countries (India, Iran, Italy, Japan, Russia, Spain) with over one hundred participants, we found that in India and Japan the people who contracted COVID-19 showed significantly shorter recovery time, and greater daily intake of vegetables, herbs/spices, and fermented foods/beverages was associated with faster recovery. ConclusionOur results suggest that phytochemical compounds included in the vegetables may have contributed in not only preventing contraction of COVID-19, but also accelerating their recovery. (249 words; EJN limit is 250 words)