Predicting vaccine effectiveness against severe COVID-19 over time and against variants: a meta-analysis

Vaccine protection from symptomatic SARS-CoV-2 infection has been shown to be strongly correlated with neutralising antibody titres; however, this has not yet been demonstrated for severe COVID-19. To explore whether this relationship also holds for severe COVID-19, we performed a systematic search for studies reporting on protection against different SARS-CoV-2 clinical endpoints and extracted data from 15 studies. Since matched neutralising antibody titres were not available, we used the vaccine regimen, time since vaccination and variant of concern to predict corresponding neutralising antibody titres. We then compared the observed vaccine effectiveness reported in these studies to the protection predicted by a previously published model of the relationship between neutralising antibody titre and vaccine effectiveness against severe COVID-19. We find that predicted neutralising antibody titres are strongly correlated with observed vaccine effectiveness against symptomatic (Spearman ρ = 0.95, p < 0.001) and severe (Spearman ρ = 0.72, p < 0.001 for both) COVID-19 and that the loss of neutralising antibodies over time and to new variants are strongly predictive of observed vaccine protection against severe COVID-19

SARS-CoV-2 and Multiple Sclerosis: Not all immune depleting DMTs are equal or bad.

This is the peer reviewed version of the following article: Amor, S., Baker, D., Khoury, S.J., Schmierer, K. and Giovanonni, G. (2020), SARS‐CoV ‐2 and Multiple Sclerosis: Not All Immune Depleting DMTs are Equal or Bad. Ann Neurol, 87: 794-797. doi:10.1002/ana.25770, which has been published in final form at https://doi.org/10.1002/ana.25770. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsA major concern during the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic1 is the use of immunosuppressive therapies for the treatment of multiple sclerosis (MS) due to an increased risk of contracting SARS-CoV-2 and more severe disease. The Society of Italian Neurologists (SIN) and the Association of British Neurologists (ABN) MS and Neuroimmunology Advisory Group published guidance for the use of current disease modifying treatments (DMTs) in MS (Table 1)2 . However, taking into account, less conservative viewpoints3 , the emerging knowledge of the biology of SARS-CoV-2, and in particular the role of the immune mechanisms contributing to the disease, we propose modification of these guidelines since it is not clear that immunosuppression is indeed detrimental in people with MS infected with SARS-CoV-2. We are thus proposing a more nuanced approach and that the categories of DMTs should be modified based on scientific principles and the biology of severe COVID-19 (Table 2). This article is protected by copyright. All rights reserved

Monoclonal antibody levels and protection from COVID-19

Multiple monoclonal antibodies have been shown to be effective for both prophylaxis and therapy for SARS-CoV-2 infection. Here we aggregate data from randomized controlled trials assessing the use of monoclonal antibodies (mAb) in preventing symptomatic SARS-CoV-2 infection. We use data on the in vivo concentration of mAb and the associated protection from COVID-19 over time to model the dose-response relationship of mAb for prophylaxis. We estimate that 50% protection from COVID-19 is achieved with a mAb concentration of 96-fold of the in vitro IC50 (95% CI: 32—285). This relationship provides a tool for predicting the prophylactic efficacy of new mAb and against SARS-CoV-2 variants. Finally, we compare the relationship between neutralization titer and protection from COVID-19 after either mAb treatment or vaccination. We find no significant difference between the 50% protective titer for mAb and vaccination, although sample sizes limited the power to detect a difference

Supergravity for Effective Theories

Higher-derivative operators are central elements of any effective field theory. In supersymmetric theories, these operators include terms with derivatives in the K\"ahler potential. We develop a toolkit for coupling such supersymmetric effective field theories to supergravity. We explain how to write the action for minimal supergravity coupled to chiral superfields with arbitrary numbers of derivatives and curvature couplings. We discuss two examples in detail, showing how the component actions agree with the expectations from the linearized description in terms of a Ferrara-Zumino multiplet. In a companion paper, we apply the formalism to the effective theory of inflation.Comment: 26 page

Determinants of passive antibody efficacy in SARS-CoV-2 infection: a systematic review and meta-analysis

Background: Randomised controlled trials of passive antibodies as treatment and prophylaxis for COVID-19 have reported variable efficacy. However, the determinants of efficacy have not been identified. We aimed to assess how the dose and timing of administration affect treatment outcome. Methods: In this systematic review and meta-analysis, we extracted data from published studies of passive antibody treatment from Jan 1, 2019, to Jan 31, 2023, that were identified by searching multiple databases, including MEDLINE, PubMed, and ClinicalTrials.gov. We included only randomised controlled trials of passive antibody administration for the prevention or treatment of COVID-19. To compare administered antibody dose between different treatments, we used data on in-vitro neutralisation titres to normalise dose by antibody potency. We used mixed-effects regression and model fitting to analyse the relationship between timing, dose and efficacy. Findings: We found 58 randomised controlled trials that investigated passive antibody therapies for the treatment or prevention of COVID-19. Earlier clinical stage at treatment initiation was highly predictive of the efficacy of both monoclonal antibodies (p<0·0001) and convalescent plasma therapy (p=0·030) in preventing progression to subsequent stages, with either prophylaxis or treatment in outpatients showing the greatest effects. For the treatment of outpatients with COVID-19, we found a significant association between the dose administered and efficacy in preventing hospitalisation (relative risk 0·77; p<0·0001). Using this relationship, we predicted that no approved monoclonal antibody was expected to provide more than 30% efficacy against some omicron (B.1.1.529) subvariants, such as BQ.1.1. Interpretation: Early administration before hospitalisation and sufficient doses of passive antibody therapy are crucial to achieving high efficacy in preventing clinical progression. The relationship between dose and efficacy provides a framework for the rational assessment of future passive antibody prophylaxis and treatment strategies for COVID-19. Funding: The Australian Government Department of Health, Medical Research Future Fund, National Health and Medical Research Council, the University of New South Wales, Monash University, Haematology Society of Australia and New Zealand, Leukaemia Foundation, and the Victorian Government

Ectoplasm with an Edge

The construction of supersymmetric invariant actions on a spacetime manifold with a boundary is carried out using the "ectoplasm" formalism for the construction of closed forms in superspace. Non-trivial actions are obtained from the pull-backs to the bosonic bodies of closed but non-exact forms in superspace; finding supersymmetric invariants thus becomes a cohomology problem. For a spacetime with a boundary, the appropriate mathematical language changes to relative cohomology, which we use to give a general formulation of off-shell supersymmetric invariants in the presence of boundaries. We also relate this construction to the superembedding formalism for the construction of brane actions, and we give examples with bulk spacetimes of dimension 3, 4 and 5. The closed superform in the 5D example needs to be constructed as a Chern-Simons type of invariant, obtained from a closed 6-form displaying Weil triviality.Comment: 25 page

The magnitude and timing of recalled immunity after breakthrough infection is shaped by SARS-CoV-2 variants

Vaccination against SARS-CoV-2 protects from infection and improves clinical outcomes in breakthrough infections, likely reflecting residual vaccine-elicited immunity and recall of immunological memory. Here, we define the early kinetics of spike-specific humoral and cellular immunity after vaccination of seropositive individuals and after Delta or Omicron breakthrough infection in vaccinated individuals. Early longitudinal sampling revealed the timing and magnitude of recall, with the phenotypic activation of B cells preceding an increase in neutralizing antibody titers. While vaccination of seropositive individuals resulted in robust recall of humoral and T cell immunity, recall of vaccine-elicited responses was delayed and variable in magnitude during breakthrough infections and depended on the infecting variant of concern. While the delayed kinetics of immune recall provides a potential mechanism for the lack of early control of viral replication, the recall of antibodies coincided with viral clearance and likely underpins the protective effects of vaccination against severe COVID-19