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Correlates of protection, thresholds of protection, and immunobridging in SARS-CoV-2 infection
Correlates of protection, thresholds of protection, and immunobridging in SARS-CoV-2 infection
Several studies show neutralizing antibody levels are an important correlate of immune protection from COVID-19 and have estimated the relationship between neutralizing antibodies and protection. However, a number of these studies appear to yield quite different estimates of the level of neutralizing antibodies required for protection. Here we show that after normalization of antibody titers current studies converge on a consistent relationship between antibody levels and protection from COVID-19. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work is supported by an Australian government Medical Research Future Fund awards GNT2002073 (to MPD, SJK, AKW), MRF2005544 (to SJK, AKW, JAJ and MPD), MRF2005760 (to MPD), MRF2007221 (to JAT and MS), an NHMRC program grant GNT1149990 (SJK and MPD), and the Victorian Government (SJK, AKW, JAJ). JAJ, DSK and SJK are supported by NHMRC fellowships. AKW, DC and MPD are supported by NHMRC Investigator grants. The Melbourne WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health. The funding source had no role in the writing of the manuscript or the decision to submit it for publication, nor in data collection, analysis, or interpretation; or any aspect pertinent to the study. Authors were not precluded from accessing data in the study, and they accept responsibility to submit for publication. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All data were publicly available and the raw data use was either extracted from publications (Feng et al. Nature Medicine 2021, Gilbert et al. Science 2021) or provided by the authors on request (Bergwerk et al. New England Journal of Medicine 2021). Analysis of this publicly available data was approved under the UNSW Sydney Human Research Ethics Committee (approval HC200242). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data and code will be made available on GitHub upon publication.
·medrxiv.org·
Correlates of protection, thresholds of protection, and immunobridging in SARS-CoV-2 infection
The Department of Immunization, Vaccines and Biologicals thanks the donors whose unspecified financial support has made the production of this document possible.
The Department of Immunization, Vaccines and Biologicals thanks the donors whose unspecified financial support has made the production of this document possible.
1WHO/IVB/13.01 The ability to assess the protective efficacy of a vaccine by measuring the proportion of vaccinees who generate a particular immune response, without having to measure clinical outcomes, has significant advantages. The availability and quality of such substitute endpoints1 are important for vaccine development, licensure and effectiveness monitoring. A better understanding of the interrelationships between vaccination, the immune response, protection, and clinical outcomes is thus of interest not only to regulatory authorities but also to microbiologists, immunologists, epidemiologists and statisticians. This is a complex and controversial topic, and many aspects need clarification. Although regulatory bodies have drawn up definitions for “correlates” and “surrogates” of protection for the purpose of licensure, these terms are not used consistently among regulators, nor in the broader literature. Different study designs, each with their strengths and weaknesses, have been used to evaluate immunological substitute endpoints of vaccine-induced protection. Various statistical tools have been developed to evaluate these endpoints, but few epidemiologists are familiar with the details of these methods. Immunological substitute endpoints can be relative or absolute quantities, and further information is needed on how they are affected by factors such as the challenge dose, the mechanism of action of the vaccine, the environment, or host characteristics. This document presents an overview of definitions and methods relating to studies of substitute endpoints. It aims to facilitate communication and to encourage the development of a broad research agenda on the issue. Although the greatest interest in this topic currently relates to vaccines, immunological correlates of protection have far-reaching implications for passive protection (maternal immunity and immunoglobulin prophylaxis), risk screening (e.g. tuberculin or rubella antibody testing in pregnant women) as well as for a basic understanding of pathogenesis and immunity.
·apps.who.int·
The Department of Immunization, Vaccines and Biologicals thanks the donors whose unspecified financial support has made the production of this document possible.
Correlates of Protection Induced by Vaccination
Correlates of Protection Induced by Vaccination
This paper attempts to summarize current knowledge about immune responses to vaccines that correlate with protection. Although the immune system is redundant, almost all current vaccines work through antibodies in serum or on mucosa that block infection or bacteremia/viremia and thus provide a correlate of protection. The functional characteristics of antibodies, as well as quantity, are important. Antibody may be highly correlated with protection or synergistic with other functions. Immune memory is a critical correlate: effector memory for short-incubation diseases and central memory for long-incubation diseases. Cellular immunity acts to kill or suppress intracellular pathogens and may also synergize with antibody. For some vaccines, we have no true correlates, but only useful surrogates, for an unknown protective response.
·journals.asm.org·
Correlates of Protection Induced by Vaccination
Antibody-mediated neutralization of SARS-CoV-2 - PIIS1074761322002254.pdf
Antibody-mediated neutralization of SARS-CoV-2 - PIIS1074761322002254.pdf
Neutralizing antibodies can block infection, clear pathogens, and are essential to provide long-term immu- nity. Since the onset of the pandemic, SARS-CoV-2 neutralizing antibodies have been comprehensively investigated and critical information on their development, function, and potential use to prevent and treat COVID-19 have been revealed. With the emergence of SARS-CoV-2 immune escape variants, humoral immu- nity is being challenged, and a detailed understanding of neutralizing antibodies is essential to guide vaccine design strategies as well as antibody-mediated therapies. In this review, we summarize some of the key find- ings on SARS-CoV-2 neutralizing antibodies, with a focus on their clinical application.
·cell.com·
Antibody-mediated neutralization of SARS-CoV-2 - PIIS1074761322002254.pdf
Similar patterns of [18F]-FDG brain PET hypometabolism in paediatric and adult patients with long COVID: a paediatric case series
Similar patterns of [18F]-FDG brain PET hypometabolism in paediatric and adult patients with long COVID: a paediatric case series
European Journal of Nuclear Medicine and Molecular Imaging - Several weeks after COVID-19 infection, some children report the persistence or recurrence of functional complaints. This clinical...
·link.springer.com·
Similar patterns of [18F]-FDG brain PET hypometabolism in paediatric and adult patients with long COVID: a paediatric case series
SARS-CoV-2 and probable lung cancer risk
SARS-CoV-2 and probable lung cancer risk
The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global crisis with a growing number of mortalities and morbidities worldwide. Despite performing numerous researches, there are still considerable unrevealed details regarding the long-term complications and post-infection immunity of the coronavirus disease 2019 (COVID-19). Based on pathophysiological features, SARS-CoV-2 may act similarly as an oncovirus in the lung. This letter summarized three possible oncogenic mechanisms of SARS-CoV-2 that may be associated with lung cancer development.
·bi.tbzmed.ac.ir·
SARS-CoV-2 and probable lung cancer risk
SARS-CoV-2 and probable lung cancer risk
SARS-CoV-2 and probable lung cancer risk
The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global crisis with a growing number of mortalities and morbidities worldwide. Despite performing numerous researches, there are still considerable unrevealed details ...
·ncbi.nlm.nih.gov·
SARS-CoV-2 and probable lung cancer risk
Impaired humoral immunity is associated with prolonged COVID-19 despite robust CD8 T cell responses
Impaired humoral immunity is associated with prolonged COVID-19 despite robust CD8 T cell responses
How immune dysregulation affects recovery from COVID-19 infection in patients with cancer remains unclear. We analyzed cellular and humoral immune responses in 103 patients with prior COVID-19 infection, more than 20% of whom had delayed viral clearance. Delayed clearance was associated with loss of antibodies to nucleocapsid and spike proteins with a compensatory increase in functional T cell responses. High-dimensional analysis of peripheral blood samples demonstrated increased CD8+ effector T cell differentiation and a broad but poorly converged COVID-specific T cell receptor (TCR) repertoire in patients with prolonged disease. Conversely, patients with a CD4+ dominant immunophenotype had a lower incidence of prolonged disease and exhibited a deep and highly select COVID-associated TCR repertoire, consistent with effective viral clearance and development of T cell memory. These results highlight the importance of B cells and CD4+ T cells in promoting durable SARS-CoV-2 clearance and the significance of coordinated cellular and humoral immunity for long-term disease control.
·cell.com·
Impaired humoral immunity is associated with prolonged COVID-19 despite robust CD8 T cell responses
Variant-specific symptoms of COVID-19 among 1,542,510 people in England - 2022.05.21.22275368v1.full.pdf
Variant-specific symptoms of COVID-19 among 1,542,510 people in England - 2022.05.21.22275368v1.full.pdf
Infection with SARS-CoV-2 virus is associated with a wide range of symptoms. The REal- time Assessment of Community Transmission -1 (REACT-1) study has been monitoring the spread and clinical manifestation of SARS-CoV-2 among random samples of the population in England from 1 May 2020 to 31 March 2022. We show changing symptom profiles associated with the different variants over that period, with lower reporting of loss of sense of smell and taste for Omicron compared to previous variants, and higher reporting of cold-like and influenza-like symptoms, controlling for vaccination status. Contrary to the perception that recent variants have become successively milder, Omicron BA.2 was associated with reporting more symptoms, with greater disruption to daily activities, than BA.1. With restrictions lifted and routine testing limited in many countries, monitoring the changing symptom profiles associated with SARS-CoV-2 infection and induced changes in daily activities will become increasingly important.
·medrxiv.org·
Variant-specific symptoms of COVID-19 among 1,542,510 people in England - 2022.05.21.22275368v1.full.pdf
Eric Topol on Twitter
Eric Topol on Twitter
The graph at the left is weeks behind. On the right, from Minnesota's twin cities, is where we are headed. BA.4/BA.5 has more immune evasiveness than BA.1.12.1, more transmissibility, and more pathogenic in the lab and experimental model https://t.co/x2K0UT1Tqg pic.twitter.com/JhD6Fhbhe8— Eric Topol (@EricTopol) June 6, 2022
·twitter.com·
Eric Topol on Twitter
Neutralising antibody titres as predictors of protection against SARS-CoV-2 variants and the impact of boosting: a meta-analysis - PIIS2666524721002676.pdf
Neutralising antibody titres as predictors of protection against SARS-CoV-2 variants and the impact of boosting: a meta-analysis - PIIS2666524721002676.pdf
The neutralising activity against the ancestral SARS-CoV-2 was highly predictive of neutralisation of variants of concern. Decreases in neutralisation titre to the alpha (1·6-fold), beta (8·8-fold), gamma (3·5-fold), and delta (3·9-fold) variants (compared to the ancestral virus) were not significantly different between different vaccines. Neutralisation remained strongly correlated with protection from symptomatic infection with SARS-CoV-2 variants of concern (rS=0·81, p=0·0005) and the existing model remained predictive of vaccine efficacy against variants of concern once decreases in neutralisation to the variants of concern were incorporated. Modelling of predicted vaccine efficacy against variants over time suggested that protection against symptomatic infection might decrease below 50% within the first year after vaccination for some vaccines. Boosting of previously infected individuals with existing vaccines (which target ancestral virus) is predicted to provide a higher degree of protection from infection with variants of concern than primary vaccination schedules alone.
·thelancet.com·
Neutralising antibody titres as predictors of protection against SARS-CoV-2 variants and the impact of boosting: a meta-analysis - PIIS2666524721002676.pdf
Full vaccination against COVID-19 suppresses SARS-CoV-2 delta variant and spike gene mutation frequencies and generates purifying selection pressure
Full vaccination against COVID-19 suppresses SARS-CoV-2 delta variant and spike gene mutation frequencies and generates purifying selection pressure
COVID-19 vaccination resistance has become a major challenge to prevent global SARS-CoV-2 transmission. Here we report that the vaccination coverage rate is inversely correlated to the mutation frequency of the full genome ( R 2=0.878) and spike gene ( R 2=0.829) of SARS-CoV-2 delta variants in 16 countries, suggesting that full vaccination against COVID-19, with other mitigation strategies, is critical to suppress emergent mutations. Neutrality analysis of DH and Zeng’s E tests suggested that directional selection was the major driving force of delta variant evolution. To eliminate the homogenous effects (population expansion, selective sweep etc.), the synonymous ( D syn) and nonsynonymous ( D nonsyn) polymorphisms of the delta variant spike gene were estimated with Tajima’s D statistic. Both D ratio ( D nonsyn/ D syn) and Δ D ( D syn- D nonsyn) have positive correlation with the full vaccination rate ( R 2= 0.723 and 0.505, respectively) in 19 countries, indicating that purifying selection pressure of SARS-CoV-2 spike gene increased as the vaccination coverage rate increased. Taken together, our data suggests that vaccination plays an important role in the purifying selection force of spike protein of SARS-CoV-2 delta variants. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial Not applicable ### Funding Statement No funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: No patients were involved and no IRB was required in this study. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes 1.The World Health organization. Tracking SARS-CoV-2 variants. 2. Global Initiative on Sharing All Influenza Data. 3. Coronavirus (COVID-19) Vaccinations. Our World in Data.
·medrxiv.org·
Full vaccination against COVID-19 suppresses SARS-CoV-2 delta variant and spike gene mutation frequencies and generates purifying selection pressure
Omicron BA.1 breakthrough infection drives cross-variant neutralization and memory B cell formation against conserved epitopes
Omicron BA.1 breakthrough infection drives cross-variant neutralization and memory B cell formation against conserved epitopes
Omicron is the evolutionarily most distinct SARS-CoV-2 variant of concern (VOC) to date. We report that Omicron BA.1 breakthrough infection in BNT162b2-vaccinated individuals resulted in strong neutralizing activity against Omicron BA.1, BA.2 and previous SARS-CoV-2 VOCs, but not against the Omicron sublineages BA.4 and BA.5. BA.1 breakthrough infection induced a robust recall response, primarily expanding BMEM cells against epitopes shared broadly amongst variants, rather than inducing BA.1-specific B cells. The vaccination-imprinted BMEM cell pool had sufficient plasticity to be remodeled by heterologous SARS-CoV-2 spike glycoprotein exposure. While selective amplification of BMEM cells recognizing shared epitopes allows for effective neutralization of most variants that evade previously established immunity, susceptibility to escape by variants that acquire alterations at hitherto conserved sites may be heightened.
·science.org·
Omicron BA.1 breakthrough infection drives cross-variant neutralization and memory B cell formation against conserved epitopes
Myopathy as a cause of fatigue in long-term post-COVID-19 symptoms: Evidence of skeletal muscle histopathology
Myopathy as a cause of fatigue in long-term post-COVID-19 symptoms: Evidence of skeletal muscle histopathology
Muscle weakness was present in 50%, myopathic electromyography in 75% while in all patients, there were histological changes. Muscle fiber atrophy was found in 38%, and 56% showed indications of fiber regeneration. Mitochondrial changes, comprising loss of COX activity, subsarcollemmal accumulation and/or abnormal cristae, were present in 62%. Inflammation was found in 62%, seen as T-lymphocytes and/or muscle fiber HLA-ABC expression. In 75%, capillaries were affected involving basal lamina and cells. In two patients, uncommon amounts of basal lamina were found, not only surrounding muscle fibers but also around nerves and capillaries.
·onlinelibrary.wiley.com·
Myopathy as a cause of fatigue in long-term post-COVID-19 symptoms: Evidence of skeletal muscle histopathology
Edward Nirenberg 🇺🇦 on Twitter
Edward Nirenberg 🇺🇦 on Twitter
There are so many parts of this preprint that I wish I could make basically everyone understand but if there's just one part I must pick- this. 🧵Correlates of protection, thresholds of protection, and immunobridging in SARS-CoV-2 infection https://t.co/Q0yot7muHN pic.twitter.com/TsuZdlHlcr— Edward Nirenberg 🇺🇦 (@ENirenberg) June 7, 2022
·twitter.com·
Edward Nirenberg 🇺🇦 on Twitter
Risk factors for SARS-CoV-2 infection and transmission in households with asthmatic and allergic children. A prospective surveillance study - PIIS0091674922007527.pdf
Risk factors for SARS-CoV-2 infection and transmission in households with asthmatic and allergic children. A prospective surveillance study - PIIS0091674922007527.pdf
147 households (261 participants) tested positive for SARS-CoV-2. Household SARS-129 CoV-2 infection probability was 25.8%; participant infection probability was similar for children (14.0%,CI:8.0-19.6%), teenagers (12.1%,CI:8.2-15.9%), and adults (14.0%,CI:9.5-18.4%). Infections were symptomatic in 24.5% of children, 41.2% of teenagers, and 62.5% of adults. Self-reported doctor-diagnosed asthma was not a risk factor for infection (aHR=1.04,CI:0.73-1.46), nor was upper respiratory allergy or eczema. Self-reported doctor-diagnosed food allergy was associated with lower infection risk (aHR=0.50,CI:0.32-0.81); higher BMI was associated with increased infection risk (aHR per 10-point increase:1.09,CI:1.03-1.15). Household secondary attack rate was 57.7%. Asthma was not associated with household transmission, but transmission was lower in households with food allergy (aOR=0.43,CI:0.19-0.96,p=0.04)
·jacionline.org·
Risk factors for SARS-CoV-2 infection and transmission in households with asthmatic and allergic children. A prospective surveillance study - PIIS0091674922007527.pdf