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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I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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.

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.

Although the immune correlate of protection by vaccines is often antibody to prevent acquisition and cellular functions to clear infection, the situation may be

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.

A marker of immune function that statistically correlates with protection after vaccination may be either a mechanistic correlate of protection or a nonmechanis

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.

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...

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.

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 ...

This cohort study investigates the risk of multisystem inflammatory syndrome after SARS-CoV-2 infection in vaccinated and unvaccinated children before and during the Omicron wave in Denmark.

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.

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.

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

Babies born to mothers who suffered COVID-19 disease during pregnancy seem to exhibit differences in neurodevelopmental outcomes at 6 weeks, according to a preliminary analysis presented in the 30th European ...

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.

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.

Regensburg/Erlangen/Jena – Die Datenlage zu Long COVID oder dem Post-COVID-Syndrom bei Kindern und Jugendlichen ist dünn – vor allem für Kinder, die jünger als... #LongCOVID #CoKiBa

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.

How many COVID infections will you have in your lifetime? There’s probably a limit.

The rise of allergy and autoimmune diseases is due to much more than rampant cleanliness. Is it time to throw out the hygiene hypothesis?

Data from more than 80,000 children with COVID suggests a quarter of them had symptoms that lingered for at least 4-12 weeks.

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.

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

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)

Objective To examine the relative effectiveness of a fourth dose of the Pfizer-BioNTech mRNA (BNT162b2) vaccine compared with three vaccine doses over the span of 10 weeks. Design Retrospective, test negative, case-control study, with a matched analysis and an unmatched multiple tests analysis. Setting Nationally centralised database of Maccabi Healthcare Services, an Israeli national health fund for 2.5 million people; from 10 January 2022 (seven days after the fourth dose was first given to eligible individuals) to 13 March 2022, an omicron dominant period in Israel. Participants 97 499 Maccabi Healthcare Services members aged 60 years and older, who were eligible to receive a fourth vaccine dose and obtained at least one polymerase chain reaction (PCR) test during the study. Main outcome measures Breakthrough SARS-CoV-2 infection, defined as a positive PCR test performed seven or more days after inoculation with the BNT162b2 vaccine; and breakthrough SARS-CoV-2 infection resulting in severe covid-19 disease, defined as hospital admission or death related to covid-19. Results 27 876 participants received the fourth BNT162b2 vaccine dose and 69 623 received three doses only. Of 106 participants who died during the follow-up period, 77 had had their third doses only and 23 had had their fourth doses during the first three weeks after inoculation. In the first three weeks, a fourth dose provided additional protection against both SARS-CoV-2 infection and severe disease relative to three doses of the vaccine. However, relative vaccine effectiveness against infection quickly decreased over time, peaking during the third week at 65.1% (95% confidence interval 63.0% to 67.1%) and falling to 22.0% (4.9% to 36.1%) by the end of the 10 week follow-up period. Unlike relative effectiveness against SARS-CoV-2 infection, the relative effectiveness of a fourth dose against severe covid-19 was maintained at a high level (72%) throughout follow-up. However, severe disease was a relatively rare event, occurring in

Was ist #BC007, warum ist es ein Hoffnungsträger für #LongCovid Betroffene und was sind #Aptamere ?Ein kurzer 🧵LongCovid kann unterschiedliche Ursachen haben, zwei davon sind 1) eine persistierende Infektion (evtl Paxlovid wirksam?) und 2) eine Autoimmunerkrankung 1/— Johann Holzmann (@JohannHolzmann) June 3, 2022

SARS-CoV-2 variants of concern (VOCs) possess mutations that confer resistance to neutralizing antibodies within the Spike protein and are associated with breakthrough infection and reinfection. By contrast, less is known about the escape from CD8+ T cell-mediated immunity by VOC. Here, we demonstrated that VOCs retain similar MHC-I downregulation capacity compared to the ancestral virus. However, VOCs exhibit a greater ability to suppress type I IFN than the ancestral virus. Although VOCs possess unique mutations within the ORF8 gene, which suppresses MHC-I expression, none of these mutations enhanced the ability of ORF8 to suppress MHC-I expression. Notably, MHC-I upregulation was strongly inhibited after the ancestral SARS-CoV-2 infection in vivo . Collectively, our data suggest that the ancestral SARS-CoV-2 already possesses an intrinsically potent MHC-I evasion capacity, and that further adaptation by the variants was not observed. Summary Moriyama et al. demonstrate that SARS-CoV-2 variants of concern retain similar MHC-I downregulation capacity compared to the ancestral virus. The results suggest that MHC-I evasion capacity is optimized in the ancestral virus and thus further adaptation was not observed. ### Competing Interest Statement The authors have declared no competing interest.

A significant number of COVID-19 patients develop 'long COVID', a condition defined by long-lasting debilitating, often neurological, symptoms. The pathophysiology of long COVID is unknown. Here we present in-vivo evidence of widespread neuroinflammation in long COVID, using a quantitative assessment, [18F]DPA-714 PET, in two long COVID patients. We reanalyzed historical data from three matched healthy control subjects, for comparison purposes. Both patients with long COVID had widespread increases in [18F]DPA-714 binding throughout the brain. Quantitative measures of binding (BPND values) were increased on average by 121% and 76%, respectively. This implicates profound neuroinflammation in the pathophysiology of long COVID. ### Competing Interest Statement EG has a consultancy agreement with IXICO for the reading of PET scans and is involved in investigator-initiated sponsored research with Heuron Co., Ltd. FB is member of the Radiology editorial board. AW is editor-in-chief of Nuclear Medicine and Biology. BB has received research support from EU-FP7, CTMM, ZonMw, NWO and Alzheimer Nederland. BvB has performed contract research for Rodin, IONIS, AVID, Eli Lilly, UCB, DIAN-TUI and Janssen. BvB was a speaker at a symposium organized by Springer Healthcare. BB has a consultancy agreement with IXICO for the reading of PET scans. BB is a trainer for GE. BB only receives financial compensation from Amsterdam UMC. No other potential conflicts of interest were reported. ### Clinical Trial NCT05371522 ### Funding Statement This study was funded by a ZonMw grant (number: 10430302110003) ### 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: This study was approved by the Medical Ethics Review Committee of the Amsterdam UMC, location VU Medical Center, and registered under 2021-000781-15 in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) and under [NCT05371522][1] in ClinicalTrials.gov. 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 produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05371522&atom=%2Fmedrxiv%2Fearly%2F2022%2F06%2F04%2F2022.06.02.22275916.atom