Adjusted COVID-19 booster schedules balance age-dependent differences in antibody titers benefitting risk populations

We provide follow-up data on the humoral immune response after COVID-19 vaccinations of two distinct cohorts aged below 60 and over 80 years to screen for age-related differences in the longevity and magnitude of the induction of the antibody responses post booster-vaccinations. While anti-SARS-CoV-2 spike-specific IgG and neutralization capacity waned rapidly after the initial vaccination schedule, additional boosters highly benefitted the humoral immune responses especially in the elderly cohort, including the neutralization of Omikron variants. Thus, adjusted COVID-19 booster vaccination schedules are an appropriate tool to overcome limitations in the success of vaccinations.

Vaccination of SARS-CoV-2-infected individuals expands a broad range of clonally diverse affinity-matured B cell lineages (preprint)

Vaccination of SARS-CoV-2 convalescent individuals generates broad and potent antibody responses. Here, we isolated 459 spike-specific monoclonal antibodies (mAbs) from two individuals who were infected with an early ancestral strain of SARS-CoV-2 and later boosted with mRNA-1273. We characterized mAb genetic features by sequence assignments to the donors’ personal immunoglobulin genotypes and assessed antibody neutralizing activities against ancestral SARS-CoV-2, Beta, Delta, and Omicron variants. The mAbs used a broad range of immunoglobulin heavy chain (IGH) V genes in the response to all sub-determinants of the spike examined, with similar characteristics observed in both donors. IGH repertoire sequencing and B cell lineage tracing at longitudinal time points revealed extensive evolution of SARS-CoV-2 spike-binding antibodies from acute infection until vaccination five months later. These results demonstrate that highly polyclonal repertoires of affinity-matured memory B cells were efficiently recalled by vaccination, providing a basis for the potent antibody responses observed in convalescent persons following vaccination.

Assessing infection prevention and control during COVID-19 in 22 humanitarian contexts

During the Ebola outbreaks in West Africa in 2014-15 and in the Democratic Republic of Congo in 2019, poor Infection Prevention and Control (IPC) infrastructure and practices led to high numbers of health-care worker infections, and reduced people's use of health services due to fear of transmission. Based on their experience with Ebola, the International Rescue Committee developed a minimum package of IPC standards for COVID-19, aiming to enable rapid IPC improvements in health facilities serving populations affected by conflict and displacement. Here, Eldred et al discuss the components of the minimum package for IPC.

A Novel Approach of Modelling Acute Patient Care Across a Healthcare System Using Network Analysis: Effects of The SARS Cov2 Pandemic On Patient Movement (preprint)

Background: Consolidation of healthcare in the US has resulted in integrated organizations encompassing large geographic areas, with varying services and complex patient flows. Profound changes in patient volumes and behavior have occurred during the SARS Cov2 pandemic, but understanding these changes across organizations is challenging. Network analysis provides a novel approach to address this. Methods We retrospectively evaluated hospital-based encounters with an index emergency department visit in a healthcare system comprising 18 hospitals, using patient transfer as a marker of unmet clinical need. We developed quantitative models of transfers using network analysis incorporating the level of care provided (ward, progressive care, intensive care) during pre-pandemic (May 25, 2018 to March 16, 2020) and mid-pandemic (March 17, 2020 to March 8, 2021) time periods. Results 829,455 encounters were evaluated. The system functioned as a non-small-world, non-scale-free, dissociative network. Our models reflected transfer destination diversification and variations in volume between the two time points – results of intentional efforts during the pandemic. Known hub-spoke architecture correlated with quantitative analysis. Conclusion Applying network analysis in an integrated US healthcare organization demonstrates changing patterns of care and the emergence of bottlenecks in response to the SARS Cov2 pandemic, consistent with clinical experience, providing a degree of face validity. The modeling of multiple influences can identify susceptibility to stress and opportunities to strengthen the system where patient movement is common and voluminous. The technique provides a mechanism to analyze the effects of intentional and contextual changes on system behavior.

Safety and Immunogenicity Report from the Com-COV Study – a Single-Blind Randomised Non-Inferiority Trial Comparing Heterologous And Homologous Prime-Boost Schedules with An Adenoviral Vectored and mRNA COVID-19 Vaccine (preprint)

Background: Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation, however we have previously reported that heterologous schedules incorporating an adenoviral-vectored vaccine (ChAd, Vaxzevria, Astrazeneca) and an mRNA vaccine (BNT, Comirnaty, Pfizer) at a 4-week interval are more reactogenic than homologous schedules. Here we report the immunogenicity of these schedules. Methods: Com-COV (ISRCTN: 69254139, EudraCT: 2020-005085-33) is a participant-blind, non-inferiority trial evaluating vaccine reactogenicity and immunogenicity. Adults ≥ 50 years, including those with well-controlled comorbidities, were randomised across eight groups to receive ChAd/ChAd, ChAd/BNT, BNT/BNT or BNT/ChAd, administered at 28- or 84-day intervals.The primary endpoint is geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG levels (ELISA) at one-month post boost between heterologous and homologous schedules given the same prime vaccine. We tested non-inferiority of GMR using a margin of 0.63. The primary analysis was on a per-protocol population, who were seronegative at baseline. Safety analyses were performed amongst participants receiving at least one dose of study vaccines.Findings: In February 2021, 830 participants were enrolled and randomised, including 463 with a 28-day prime-boost interval whose results are reported in this paper. Participant mean age was 57.8 years, 45.8% were female, and 25.3% from ethnic minorities.The geometric mean concentration (GMC) of day 28 post-boost SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12,906 ELU/ml) was non-inferior to that in ChAd/ChAd recipients (1,392 ELU/ml) with a geometric mean ratio (GMR) of 9.2 (one-sided 97.5% CI: 7.5, ∞). In participants primed with BNT, we failed to show non-inferiority of the heterologous schedule (BNT/ChAd, GMC 7,133 ELU/ml) against the homologous schedule (BNT/BNT, GMC 14,080 ELU/ml) with a GMR of 0.51 (one-sided 97.5% CI: 0.43, ∞). Geometric mean of T cell response at 28 days post boost in the ChAd/BNT group was 185 SFC/106 PBMCs (spot forming cells/106 peripheral blood mononuclear cells) compared to 50, 80 and 99 SFC/106 PBMCs for ChAd/ChAd, BNT/BNT, and BNT/ChAd, respectively. There were four serious adverse events across all groups, none of which were considered related to immunisation.Interpretation: Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the GMCs of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. These data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines.Trial Registration: The trial is registered at www.isrctn.com as ISRCTN: 69254139.Funding: Funded by the UK Vaccine Task Force (VTF) and National Institute for Health Research (NIHR)Declaration of Interest: MDS acts on behalf of the University of Oxford as an Investigator on studies funded or sponsored by vaccine manufacturers including AstraZeneca, GlaxoSmithKline, Pfizer, Novavax, Janssen, Medimmune, and MCM vaccines. He receives no personal financial payment for this work. JSN-V-T is seconded to the Department of Health and Social Care, England. AMC and DMF are investigators on studies funded by Pfizer and Unilever. They receive no personal financial payment for this work. AF is a member of the Joint Committee on Vaccination and Immunisation and Chair of the WHO European Technical Advisory Group of Experts (ETAGE) on Immunisation. He is an investigator and/or provides consultative advice on clinical trials and studies of COVID-19 vaccines produced by AstraZeneca, Janssen, Valneva, Pfizer and Sanofi and of other vaccines from these and other manufacturers including GSK, VPI, Takeda and Bionet Asia. He receives no personal remuneration or benefits for any of this work. SNF acts on behalf of University Hospital Southampton NHS Foundation Trust as an Investigator and/or providing consultative advice on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers including Janssen, Pfizer, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Sanofi, Medimmune, Merck and Valneva vaccines and antimicrobials. He receives no personal financial payment for this work. PTH acts on behalf of St. George’s University of London as an Investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers including Janssen, Pfizer, AstraZeneca, Novavax and Valneva. He receives no personal financial payment for this work. CAG acts on behalf of University Hospitals Birmingham NHS Foundation Trust as an Investigator on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers including Janssen, Pfizer, AstraZeneca, Novavax, CureVac, Moderna, and Valneva vaccines, and receives no personal financial payment for this work. VL acts on behalf of University College London Hospitals NHS Foundation Trust as an Investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers including Pfizer, AstraZeneca and Valneva. He receives no personal financial payment for this work. TL is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and is an occasional consultant to Vaccitech unrelated to this work. Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19Ethical Approval: The trial was reviewed and approved by the South-Central Berkshire Research Ethics Committee (21/SC/0022), the University of Oxford, and the Medicines and Healthcare Products Regulatory Agency MHRA). An independent data safety monitoring board (DSMB) reviewed safety data, and local trial- site physicians provided oversight of all adverse events in real-time.

A combination of RBD and NTD neutralizing antibodies limits the generation of SARS-CoV-2 spike neutralization-escape mutants (preprint)

Most known SARS-CoV-2 neutralizing antibodies (nAbs), including those approved by the FDA for emergency use, inhibit viral infection by targeting the receptor-binding domain (RBD) of the spike (S) protein. Variants of concern (VOC) carrying mutations in the RBD or other regions of S reduce the effectiveness of many nAbs and vaccines by evading neutralization. Therefore, therapies that are less susceptible to resistance are urgently needed. Here, we characterized the memory B-cell repertoire of COVID-19 convalescent donors and analyzed their RBD and non-RBD nAbs. We found that many of the non-RBD-targeting nAbs were specific to the N-terminal domain (NTD). Using neutralization assays with authentic SARS-CoV-2 and a recombinant vesicular stomatitis virus carrying SARS-CoV-2 S protein (rVSV-SARS2), we defined a panel of potent RBD and NTD nAbs. Next, we used a combination of neutralization-escape rVSV-SARS2 mutants and a yeast display library of RBD mutants to map their epitopes. The most potent RBD nAb competed with hACE2 binding and targeted an epitope that includes residue F490. The most potent NTD nAb epitope included Y145, K150 and W152. As seen with some of the natural VOC, the neutralization potencies of COVID-19 convalescent sera were reduced by 4-16-fold against rVSV-SARS2 bearing Y145D, K150E or W152R spike mutations. Moreover, we found that combining RBD and NTD nAbs modestly enhanced their neutralization potential. Notably, the same combination of RBD and NTD nAbs limited the development of neutralization-escape mutants in vitro, suggesting such a strategy may have higher efficacy and utility for mitigating the emergence of VOC.

Cytotoxic lymphocytes are dysregulated in multisystem inflammatory syndrome in children (preprint)

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and multiple organ involvement in individuals under 21 years following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To identify genes, pathways and cell types driving MIS-C, we sequenced the blood transcriptomes of MIS-C cases, pediatric cases of coronavirus disease 2019, and healthy controls. We define a MIS-C transcriptional signature partially shared with the transcriptional response to SARS-CoV-2 infection and with the signature of Kawasaki disease, a clinically similar condition. By projecting the MIS-C signature onto a co-expression network, we identified disease gene modules and found genes downregulated in MIS-C clustered in a module enriched for the transcriptional signatures of exhausted CD8+ T-cells and CD56dimCD57+ NK cells. Bayesian network analyses revealed nine key regulators of this module, including TBX21, a central coordinator of exhausted CD8+ T-cell differentiation. Together, these findings suggest dysregulated cytotoxic lymphocyte response to SARS-Cov-2 infection in MIS-C.

SARS-CoV-2 causes severe alveolar inflammation and barrier dysfunction (preprint)

Infections with SARS-CoV-2 lead to mild to severe coronavirus disease-19 (COVID-19) with systemic symptoms. Although the viral infection originates in the respiratory system, it is unclear how the virus can overcome the alveolar barrier, which is observed in severe COVID-19 disease courses. To elucidate the viral effects on the barrier integrity and immune reactions, we used mono-cell culture systems and a complex human alveolus-on-a-chip model composed of epithelial, endothelial, and mononuclear cells. Our data show that SARS-CoV-2 efficiently infected epithelial cells with high viral loads and inflammatory response, including the interferon expression. By contrast, the adjacent endothelial layer was no infected and did neither show productive virus replication or interferon release. With prolonged infection, both cell types are damaged, and the barrier function is deteriorated, allowing the viral particles to overbear. In our study, we demonstrate that although SARS-CoV-2 is dependent on the epithelium for efficient replication, the neighboring endothelial cells are affected, e.g., by the epithelial cytokine release, which results in the damage of the alveolar barrier function and viral dissemination.