++ Pathogenesis ++

24 November

Jabagi MJ, Botton J, Bertrand M, et al. Myocardial Infarction, Stroke, and Pulmonary Embolism After BNT162b2 mRNA COVID-19 Vaccine in People Aged 75 Years or Older. JAMA November 22, 2021. https://jamanetwork.com/journals/jama/fullarticle/2786667?resultClick=1

In a nationwide study involving persons aged 75 years or older in France, no increase in the incidence of acute myocardial infarction, stroke, and pulmonary embolism was detected 14 days following each BNT162b2 mRNA vaccine dose.


23 November

Canaday DH, Oyebanji OA, Keresztesy D, et al. Significant reduction in vaccine-induced antibody levels and neutralization activity among healthcare workers and nursing home residents 6 months following COVID-19 BNT162b2 mRNA vaccination. Clinical Infectious Diseases 2021;, ciab963, https://doi.org/10.1093/cid/ciab963

A marked antibody decline at 6 months post-BNT162b2 mRNA vaccination in 130 nursing home (NH) residents and 95 healthcare workers: anti-spike, receptor-binding domain and neutralization levels dropped > 81% irrespective of prior SARS-CoV-2 infection. Notably, 69% of infection-naive NH residents had neutralizing antibodies at or below the limit of detection of the assay.


18 November

Nanisji E, Borriello D, O’Meara TR, et al. An aluminum hydroxide:CpG adjuvant enhances protection elicited by a SARS-CoV-2 receptor-binding domain vaccine in aged mice. Science Translational Medicine November 16, 2021. https://www.science.org/doi/10.1126/scitranslmed.abj5305

The RBD is an attractive candidate for a SARS-CoV-2 subunit vaccine and is relatively easy to produce at scale; however, it is poorly immunogenic on its own. complementary approach to increase the immunogenicity of vaccine antigens is the use of adjuvants. Here, the authors evaluated several combinations and found that formulating the TLR9 agonists CpG oligodeoxynucleotides with aluminum hydroxide and RBD dramatically enhanced immune responses toward RBD in young mice in a prime-boost immunization schedule.

15 November

Klok FA, Menaka M, Huisman MV, et al. Vaccine-induced immune thrombotic thrombocytopenia. Lancet Hamatology, November 11, 2021. https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(21)00306-9/fulltext

In this Viewpoint, the authors discuss the epidemiology, pathophysiology, and optimal diagnostic and therapeutic management of VITT. The most urgent questions that remain about VITT include the exact pathophysiological mechanism and the long-term management of those who survive VITT. It is uncertain what vaccine components trigger VITT, for example the adenovirus itself or the added ingredients (adjuvant, aluminum, preservatives, etc).


Pavord S, Scully M, Lester W, et al. Just how common is TTS after a second dose of the ChAdOx1 nCov-19 vaccine? The Lancet, November 13, 2021. Volume 398, ISSUE 10313, P1801. https://doi.org/10.1016/S0140-6736(21)02285-6

The authors feel it is necessary to distinguish TTS, which can have a number of causes, from vaccine-induced immune thrombocytopenia and thrombosis (VITT), which has a very specific immune pathophysiology. They believe that VITT is extremely rare after the second dose of ChAdOx1 nCov-19.


14 November

Angyal A, Longet S, Moore SC, et al. T-cell and antibody responses to first BNT162b2 vaccine dose in previously infected and SARS-CoV-2-naive UK health-care workers: a multicentre prospective cohort study. Lancet Microbe November 09, 2021. https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(21)00275-5/fulltext

A single dose of the BNT162b2 vaccine is likely to provide greater protection against SARS-CoV-2 infection in individuals with previous SARS-CoV-2 infection, than in SARS-CoV-2-naive individuals, including against variants of concern.


Johnson S, Martinez CI, Tedjakusuma SN, et al. Oral vaccination protects against SARS-CoV-2 in a Syrian hamster challenge model. The Journal of Infectious Diseases November 10, jiab561, https://doi.org/10.1093/infdis/jiab561

An oral, adenovirus-based vaccine candidate, protecting Syrian hamsters.


13 November

Lazarus R, Baos S, Cappel-Porter H, et al. Safety and immunogenicity of concomitant administration of COVID-19 vaccines (ChAdOx1 or BNT162b2) with seasonal influenza vaccines in adults in the UK (ComFluCOV): a multicentre, randomised, controlled, phase 4 trial. Lancet November 11, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02329-1/fulltext

Paper of the day. In this trial on 679 participants, concomitant vaccination with ChAdOx1 or BNT162b2 plus an age-appropriate influenza vaccine raised no safety concerns and preserved antibody responses to both vaccines.


Montoya JG, Adams AE, Bonetti V, et al. Differences in IgG Antibody Responses following BNT162b2 and mRNA-1273 SARS-CoV-2 Vaccines. Microbiol Spectr 2021 November 10;e0116221. https://journals.asm.org/doi/10.1128/Spectrum.01162-21

In this cohort of 652 clinicians at a non-profit organization, spike protein antibodies were higher with mRNA-1273 than with BNT162b2. This is biologically plausible, not because this was a non-profit organization (like Covidreference.com), but because mRNA-1273 delivers a larger amount of mRNA (100 μg mRNA) than BNT162b2 (30 μg mRNA), which is translated into spike protein.


12 November

Ella R, Reddy S, Blackwelder W, et al. Efficacy, safety, and lot-to-lot immunogenicity of an inactivated SARS-CoV-2 vaccine (BBV152): interim results of a randomised, double-blind, controlled, phase 3 trial. Lancet November 11, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02000-6/fulltext

BBV152 is a whole virion inactivated SARS-CoV-2 vaccine formulated with a toll-like receptor 7/8 agonist molecule adsorbed to alum. In this large RCT in Indian adults, 24 (0.3%) cases occurred among 8471 vaccine recipients and 106 (1.2%) among 8502 placebo recipients, giving an overall estimated vaccine efficacy of 77.8% (95% CI 65.2–86.4). Efficacy against severe COVID-19 was 93.4% (57.1–99.8). The authors found no major differences in immune responses across the broad age groups of younger (<60 years) and older (≥60 years) participants. A preliminary analysis showed an efficacy of 65.2% (95% CI 33.1–83.0) against the Delta variant.


11 November

Walter EB, Talaat KR, Sabharwal C, et al. Evaluation of the BNT162b2 Covid-19 Vaccine in Children 5 to 11 Years of Age. NEJM November 9, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2116298?query=featured_home

Paper of the day. Vaccination regimen consisting of two 10-μg doses of BNT162b2 administered 21 days apart was found to be safe, immunogenic, and efficacious in children 5 to 11 years of age. Among 2268 children, COVID-19 with onset 7 days or more after the second dose was reported in 3 recipients of the BNT162b2 vaccine and in 16 placebo recipients (vaccine efficacy, 90.7%; 95% CI, 67.7 to 98.3).


16 October

D’Agnillo F, Walters KA, Xiao Y, et al. Lung epithelial and endothelial damage, loss of tissue repair, inhibition of fibrinolysis, and cellular senescence in fatal COVID-19. Sci Transl Med. 2021 Oct 14:eabj7790. PubMed: https://pubmed.gov/34648357. Full text: https://doi.org/10.1126/scitranslmed.abj7790

The authors analyzed lung autopsy samples from 18 patients with fatal COVID-19, with symptom onset-to-death times ranging from 3 to 47 days. The results (among others): progressive diffuse alveolar damage with excessive thrombosis and late onset remodeling; loss of surfactant protein expression and defective tissue repair processes; and impaired clot fibrinolysis with increased concentrations of plasma and lung plasminogen activator inhibitor-1 (PAI-1).


7 October

Cheon IS, Li C, Son YM, et al. Immune signatures underlying post-acute COVID-19 lung sequelae. Sci Immunol. 2021 Sep 30:eabk1741. PubMed: https://pubmed.gov/34591653. Full text: https://doi.org/10.1126/sciimmunol.abk1741

Survivors of severe COVID-19 are at high risk of developing chronic pulmonary sequelae that may be accompanied by abnormal chest imaging and impaired lung function testing. The authors suggest that dysregulated respiratory CD8+ T cell responses might be associated with impaired lung function following acute COVID-19.


6 October

Ferren M, Favède V, Decimo D, et al. Hamster organotypic modeling of SARS-CoV-2 lung and brainstem infection. Nat Commun 12, 5809 (2021). Full text: https://www.nature.com/articles/s41467-021-26096-z

The authors present organotypic cultures from hamster brainstem and lung tissues that could help to study the early steps of viral infection and screening antivirals.


15 August

Ziegler CGK, Miao VN, Owings AH, et al. Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19. Cell. 2021 Jul 23:S0092-8674(21)00882-5. PubMed: https://pubmed.gov/34352228. Full text: https://doi.org/10.1016/j.cell.2021.07.023

After single-cell transcriptome sequencing of nasopharyngeal swabs from 58 people, the authors suggests that failed nasal epithelial anti-viral immunity might underlie and precede severe COVID-19.


5 August

Xydakis MS, Albers MW, Holbrook EH, et al. Post-viral effects of COVID-19 in the olfactory system and their implications. Lancet Neurol. 2021 Jul 30:S1474-4422(21)00182-4. PubMed: https://pubmed.gov/34339626. Full text: https://doi.org/10.1016/S1474-4422(21)00182-4

Why do we lose our smell with COVID-19? And what might be the consequences? The authors postulate that, “in people who have recovered from COVID-19, a chronic, recrudescent, or permanent olfactory deficit could be prognostic for an increased likelihood of neurological sequelae or neurodegenerative disorders in the long term.” See also the comment by Doty RL. The mechanisms of smell loss after SARS-CoV-2 infection. Lancet Neurol. 2021 Jul 30:S1474-4422(21)00202-7. PubMed: https://pubmed.gov/34339627. Full text: https://doi.org/10.1016/S1474-4422(21)00202-7


4 August

Chen KG, Park K, Spence JR. Studying SARS-CoV-2 infectivity and therapeutic responses with complex organoids. Nat Cell Biol (2021). https://doi.org/10.1038/s41556-021-00721-x

A review of the roles of complex organoids in the study of SARS-CoV-2 infection, modeling of COVID-19 disease pathology and of drug, antibody and vaccine development. The authors anticipate valuable lessons for the study of other viral diseases as well.


1 August

Cohen CA, Li APY, Hachim A, et al. SARS-CoV-2 specific T cell responses are lower in children and increase with age and time after infection. Nat Commun 12, 4678 (2021). Full text: https://doi.org/10.1038/s41467-021-24938-4

Could a reduced prior β coronavirus immunity and reduced T cell activation in children drive a milder COVID-19 pathogenesis? The authors found that infected children have lower CD4+ and CD8+ T cell responses to SARS-CoV-2 structural and ORF1ab proteins compared to infected adults.


27 July

Chen S, Yang L, Nilsson-Payant B, et al. SARS-CoV-2 Infected Cardiomyocytes Recruit Monocytes by Secreting CCL2. Res Sq. 2020 Nov 17:rs.3.rs-94634. PubMed: https://pubmed.gov/33236003. Full-text: https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(21)00378-7

The study provides evidence that SARS-CoV-2 infects cardiomyocytes in vivo and suggests a mechanism of immune-cell infiltration and histopathology in heart tissues of COVID-19 patients.


29 January

Johnson BA, Xie X, Bailey AL, et al. Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis. Nature (2021). Full-text: https://doi.org/10.1038/s41586-021-03237-4

The authors generated a mutant SARS-CoV-2 deleting the furin cleavage site (ΔPRRA). SARS-CoV-2 ΔPRRA replicates had faster kinetics, improved fitness in Vero E6 cells, and reduced spike protein processing as compared to parental SARS-CoV-2. However, the ΔPRRA mutant had reduced replication in a human respiratory cell line and was attenuated in both hamster and K18-hACE2 transgenic mouse models of SARS-CoV-2 pathogenesis. The findings illustrate the critical role of the furin cleavage site in SARS-CoV-2 infection and pathogenesis. In its absence, the mutant ΔPRRA virus is attenuated in its ability to replicate in certain cell types and cause disease in vivo.


24 January

Hann von Weyhern C, Kaufmann I, Neff F. Neuropathology associated with SARS-CoV-2 infection – Authors’ reply. Lancet January 23, 2021. DOI:https://doi.org/10.1016/S0140-6736(21)00097-0

Lively Discussion about various hypotheses regarding COVID-19 neuropathology (the authors report a pronounced CNS involvement with pan-encephalitis, meningitis, and brainstem neuronal cell damage in a small case series).


22 January

Khamsi R. Rogue antibodies could be driving severe COVID-19. Nature NEWS FEATURE 19 January 2021. Full-text: https://doi.org/10.1038/d41586-021-00149-1

Roxanne Khamsi summarizes the growing evidence that self-attacking ‘autoantibodies’ could be the key to understanding some of the worst cases of SARS-CoV-2 infection.


19 January

Cheng XP, Cheng MP, Gu W, et al. Cell-Free DNA Tissues-of-Origin by Methylation Profiling Reveals Significant Cell, Tissue and Organ-Specific injury related to COVID-19 Severity. Cell Med 2021, published 16 January. Full-text: https://www.cell.com/med/fulltext/S2666-6340(21)00031-3

A blood test to broadly quantify cell, tissue, and organ-specific injury due to COVID-19? That’s what Iwijn De Vlaminck and colleagues propose after performing cell-free DNA (cfDNA) profiling on 104 plasma samples from 33 COVID-19 patients. The authors suggest that cfDNA profiling – an easy-to-obtain molecular blood test – might provide quantifiable prognostic parameters and a more granular assessment of clinical severity at the time of presentation.


12 January

Grant RA, Morales-Nebreda L, Markov NS, et al. Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia. Nature 2021, published 11 January. Full-text: https://doi.org/10.1038/s41586-020-03148-w

SARS-CoV-2 might cause a slowly unfolding, spatially limited alveolitis in which alveolar macrophages harboring SARS-CoV-2 and T cells form a positive feedback loop that drives persistent alveolar inflammation. This is the result of a study that collected bronchoalveolar lavage fluid samples from 88 patients with SARS-CoV-2-induced respiratory failure and 211 patients with known or suspected pneumonia from other pathogens and subjected them to flow cytometry and bulk transcriptomic profiling.


10 January

Wei C, Wan L, Yan Q, et al. HDL-scavenger receptor B type 1 facilitates SARS-CoV-2 entry. Nat Metab. 2020 Dec;2(12):1391-1400. PubMed: https://pubmed.gov/33244168. Full-text: https://doi.org/10.1038/s42255-020-00324-0

Could high-density lipoprotein (HDL) scavenger receptor B type 1 (SR-B1) facilitate ACE2-dependent entry of SARS-CoV-2? That is the statement by Hui Zhong, Congwen Wei, finding that the S1 subunit of SARS-2-S binds to cholesterol and possibly to HDL components and facilitates SARS-CoV-2 cellular attachment, entry and infection. SARS-CoV-2 entry is inhibited by silencing SR-B1 expression and by SR-B1 antagonists. Blockade of the cholesterol-binding site on SARS-2-S1 with a monoclonal antibody inhibited HDL-enhanced SARS-CoV-2 infection.

See also the comment by Di Guardo G. SARS-CoV-2-Cholesterol Interaction: A Lot of Food for Thought. Pathogens 2021, 10(1), 32- Full-text: https://doi.org/10.3390/pathogens10010032


8 January

Meinhardt J, Radke J, Dittmayer C, et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat Neurosci (2020). Full-text: https://doi.org/10.1038/s41593-020-00758-5

Given the neurological symptoms observed in a large majority of individuals with COVID-19, does SARS-CoV-2 penetrate into the CNS? Here Frank Heppner, Jenny Meinhardt and colleagues demonstrate the presence of SARS-CoV-2 RNA and protein in anatomically distinct regions of the nasopharynx and brain. Watch SARS-CoV-2 crossing the neural–mucosal interface in olfactory mucosa (exploiting the close vicinity of olfactory mucosal, endothelial and nervous tissue), following neuroanatomical structures and penetrating defined neuroanatomical areas including the primary respiratory and cardiovascular control center in the medulla oblongata.

See also the comment by Yates D. A CNS gateway for SARS-CoV-2. Nat Rev Neurosci (2021). Full-text: https://doi.org/10.1038/s41583-020-00427-3


6 January

Henkel M, Weikert T, Marston K, et al. Lethal COVID-19: Radiological-Pathological Correlation of the Lungs. Radiol Cardiothorac Imaging 2020. Full-text: https://doi.org/10.1148/ryct.2020200406

A report of 14 patients who died from RT-PCR confirmed COVID-19. All patients underwent ante-mortem CT and autopsy. A significant proportion of ground glass opacities (GGO) correlates with the pathologic processes of diffuse alveolar damage, capillary dilatation and congestion and micro-thrombosis. Maurice Henkel, Thomas Weikert and colleagues conclude that these results underline the importance of vascular alterations as a key pathophysiological driver in lethal COVID-19.


24 December

Schmidt N, Lareau CA, Keshishian H, et al. The SARS-CoV-2 RNA–protein interactome in infected human cells. Nat Microbiol (2020). Full-text: https://doi.org/10.1038/s41564-020-00846-z

Mathias Munschauer, Nora Schmidt and colleagues provide detailed molecular insights into the identity of host factors and cellular machinery that directly and specifically bind SARS-CoV-2 RNAs during infection of human cells. They integrated CRISPR perturbation data and performed genetic and pharmacological validation experiments that together suggest functional roles for 18 RNA interactome proteins in SARS-CoV-2 infections.


15 December

Hernández Cordero AI, Li X, Yang CX, et al. Gene expression network analysis provides potential targets against SARS-CoV-2. Sci Rep 10, 21863 (2020). Full-text: https://doi.org/10.1038/s41598-020-78818-w

Cell entry of SARS-CoV-2 is facilitated by host cell angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). Here, the authors show that dozens of genes are co-expressed with ACE2 and TMPRSS2, many of which have plausible links to COVID-19 pathophysiology and might potentially be targetable with existing drugs.


14 December

Hennessy EJ, FitzGerald GA. Battle for supremacy: nucleic acid interactions between viruses and cells. J Clin Invest. 2020 Dec 8:144227. PubMed: https://pubmed.gov/33290272. Full-text: https://doi.org/10.1172/JCI144227

The variability in the clinical response to infection with SARS-CoV-2 reflects differences in host genetics and/or immune response. In this review, Elizabeth Hennessy and Garret FitzGerald examine the influence of viruses on the host epigenome and consider how variation in the epigenome may contribute to heterogeneity in the response to SARS-CoV-2.


6 December

Simoneau CR, Ott M. Modeling Multi-organ Infection by SARS-CoV-2 Using Stem Cell Technology. Cell Stem Cell 2020, published 3 December. Full-text: https://doi.org/10.1016/j.stem.2020.11.012

OVID-19 is a multi-organ disease causing characteristic complications. In this mini-review, Camille Simoneau and Melanie Ott from the Gladstone Institute of Virology, San Francisco, show that stem cell models of various organ systems—most prominently, lung, gut, heart, and brain—are at the forefront of studies aimed at understanding the role of direct infection in COVID-19 multi-organ dysfunction. A perfect reading for the weekend!