Home | 7 Days | 04 | 05 | 06 | 07 | 08 | 09 | 10 | 11 | 12
2021: 01 | 02 | 03 | 04 | 05 | 06

By Christian Hoffmann &
Bernd S. Kamps

31 March

Vaccine

Thompson MG, Burgess JL, Naleway AL, et al. Interim Estimates of Vaccine Effectiveness of BNT162b2 and mRNA-1273 COVID-19 Vaccines in Preventing SARS-CoV-2 Infection Among Health Care Personnel, First Responders, and Other Essential and Frontline Workers — Eight U.S. Locations, December 2020–March 2021. MMWR Morb Mortal Wkly Rep. ePub: 29 March 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7013e3.htm

In this prospective cohort of 3950 health care personnel, first responders, and other essential and frontline workers who completed weekly SARS-CoV-2 testing for 13 consecutive weeks, mRNA vaccine effectiveness of full immunization (≥ 14 days after second dose) was 90% against SARS-CoV-2 infections regardless of symptom status; vaccine effectiveness of partial immunization (≥ 14 days after first dose but before second dose) was 80%.

Variants

Francisco MA, Zavascki AP, Lamb WP, et al. Detection of SARS-CoV-2 lineage P.1 in patients from a region with exponentially increasing hospitalisation rate, February 2021, Rio Grande do Sul, Southern Brazil. Euro Surveill Accepted: 25 Mar 2021, 2021. Full text: https://doi.org/10.2807/1560-7917.ES.2021.26.12.2100276

From epidemiological week 6, starting on 7 February 2021, until 6 March, the number of hospitalizations for COVID-19 in Rio Grande do Sul, the southernmost state of Brazil in the South region, increased from 1738 inpatients to 6995 (3.8-fold). This resulted in the collapse of the state healthcare system. The overwhelming increase in hospitalizations temporally coincided with the finding that lineage P.1 became predominant (although a small number of specimens was taken).

 

Immunology

Rendeiro AF, Ravichandran H, Bram Y, et al. The spatial landscape of lung pathology during COVID-19 progression. Nature March 29, 2021. https://www.nature.com/articles/s41586-021-03475-6

A comprehensive examination of the response of the human lung to infection from macroscopic to single-cell level.

 

Daamen AR, Bachali P, Owen KA, et al. Comprehensive transcriptomic analysis of COVID-19 blood, lung, and airway. Sci Rep March 29, 2021. 11, 7052 (2021). https://doi.org/10.1038/s41598-021-86002-x

More on the pathogenesis of COVID-19 driven by populations of myeloid-lineage cells with highly inflammatory but distinct transcriptional signatures in each compartment. The authors found a systemic, but compartmentalized immune/inflammatory response with specific signs of cellular activation in blood, lung and airways.

 

Diagnostics

Parikh BA, Wallace MA, McCune BT. The Effects of “Dry Swab” Incubation on SARS-CoV-2 Molecular Testing. The Journal of Applied Laboratory Medicine 29 March 2021 https://academic.oup.com/jalm/advance-article/doi/10.1093/jalm/jfab010/6149478?searchresult=1

In this study, all dry swabs tested on days 1, 2, and 7 provided results that were within 2 cycle thresholds of the average values for swabs hydrated in the same media and tested on day 0. There was no statistical difference in Ct values between swabs incubated in liquid media versus dry swabs incubated at room temperature prior to hydration in liquid media. The ability to obtain robust Ct values from dry swabs stored for a week at room temperature despite culture negativity has important implications for SARS-CoV-2 testing.

 

30 March

One year ago, we published the first edition of COVID Reference. It was a document on the fulminant accumulation of clinical knowledge about an emergent infectious disease in the previous three months. At that time, treatment strategies were tentative, the unutterable hydroxychloroquine was still en vogue, the multisystem inflammatory syndrome in children (MIS–C) as yet unheard of, and nobody knew about Long COVID or variants.

>>> more

 

29 March

Article of the Day

Kupferschmidt K, Vogel G. A rare clotting disorder may cloud the world’s hopes for AstraZeneca’s COVID-19 vaccine. Science 2021, published 27 March. Full text: https://www.sciencemag.org/news/2021/03/rare-clotting-disorder-may-cloud-worlds-hopes-astrazenecas-covid-19-vaccine

VIPIT – vaccine-induced prothrombotic immune thrombocytopenia – is a preliminary explanation for the unusual strokes and clotting disorders recorded in at least 30 recipients of the AstraZeneca vaccine. A summary.

Transmission

Moschovis PP, Yonker LM, Shah J, et al. Aerosol transmission of SARS-CoV-2 by children and adults during the COVID-19 pandemic. Pediatric Pulmonology 2021. Full text: https://onlinelibrary.wiley.com/doi/epdf/10.1002/ppul.25330

The authors outline the major methods of transmission of SARS-CoV-2 focusing on aerosol transmission and reviewing the principles of aerosol science and discussing their implications for mitigating the spread of SARS-CoV-2.

 

Clinical

Bamidis AD, Koehler P, di Cristanziano V, et al. First manifestation of adult-onset Still’s disease after COVID-19. Lancet Rheumatol 2021, published 26 March. Full text: https://doi.org/10.1016/S2665-9913(21)00072-2

First report of adult-onset Still’s disease (AOSD) showing that long COVID can mimic AOSD and delay diagnosis. The patient was treated with the IL-1 receptor antagonist anakinra (subcutaneous, 100 mg/day).

 

Klein J, Brito AF, Trubin P, et al. Case Study: Longitudinal immune profiling of a SARS-CoV-2 reinfection in a solid organ transplant recipient. medRxiv 2021, posted 26 March. Full text: https://doi.org/10.1101/2021.03.24.21253992

Patients with solid organ transplantation or those who are otherwise immunosuppressed who recover from infection with SARS-CoV-2, may not develop sufficient protective immunity and are at risk of reinfection.

 

Beyond Corona

Boyoglu-Barnum S, Ellis D, Gillespie RA, et al. Quadrivalent influenza nanoparticle vaccines induce broad protection. Nature (2021). Full text: https://doi.org/10.1038/s41586-021-03365-x

A supra-seasonal flu vaccine? Computationally designed, two-component nanoparticle immunogens induced potently neutralizing and broadly protective antibody responses against a wide variety of influenza viruses. Unlike current influenza vaccines, the nanoparticle vaccines also protected against diverse viruses NOT in the vaccine formulation (including distant avian viruses like H5N1 and H7N9). This ‘mosaic’ vaccine is now being manufactured for a Phase I clinical trial through the Vaccine Research Center at the NIH.

 

28 March

Vaccines

ANSM 20210326. Point de situation sur la surveillance des vaccins contre la COVID-19 – Période du 12/03/2021 au 18/03/2021. Agence nationale pour la sécurité du médicament et des produits de Santé 2021, published 26 March 2021. Full text: https://ansm.sante.fr/actualites/point-de-situation-sur-la-surveillance-des-vaccins-contre-la-covid-19-periode-du-12-03-2021-au-18-03-2021

On 26 March, the French National Medicine Safety Agency (Agence nationale pour la sécurité du médicament et des produits de Santé – ANSM) declared that there is a risk of atypical thrombosis associated with the AstraZeneca vaccine. The Agency reports 9 cases of big vein thromboses that are atypical by their location (mostly cerebral, but also digestive) and associated with thrombocytopenia and coagulation disorders. With some 1,430,000 injections of the AstraZeneca vaccine as of 18 March 2021, this is one case per 158,000 injections. These cases occurred within a median time of 8.5 days after vaccination in persons without particular risk factors (7 patients under 55 years of age, 2 more than 55 years). Between 12 and 18 March, two deaths were reported, including that of a medical student who died several days after being vaccinated. In the coming months of relative vaccine abundance, the AstraZeneca vaccine does not have a good star.

 

McEllistrem MC, Clancy CJ, Buehrle DJ, et al. Single dose of a mRNA SARS-CoV-2 vaccine is associated with lower nasopharyngeal viral load among nursing home residents with asymptomatic COVID-19. Clin Infect Dis 2021, published 26 March. Full text: https://doi.org/10.1093/cid/ciab263

In nursing home residents with asymptomatic COVID-19 diagnosed through twice-weekly surveillance testing, single dose BNT162b2 vaccination (Pfizer-BioNTech) was associated with -2.4 mean log₁₀ lower nasopharyngeal viral load than that detected in absence of vaccination (p = 0.004).

 

Irwin A. What it will take to vaccinate the world against COVID-19. Nature 2021, published 25 March. Full text: https://www.nature.com/articles/d41586-021-00727-3

Within just a few months, pharmaceutical firms have produced hundreds of millions of doses of COVID-19 vaccine. But the world needs billions — and as fast as possible. This situation is fuelling a campaign to temporarily waive intellectual-property rights so that manufacturers in poorer countries can make the vaccines more quickly themselves.

 

Variants

Abbasi J. How the US Failed to Prioritize SARS-CoV-2 Variant Surveillance. JAMA. 2021 Mar 24. PubMed: https://pubmed.gov/33760030. Full-text: https://doi.org/10.1001/jama.2021.3368

Until late last fall, public health departments had no federal mandate or additional funding to sequence samples, although new variants were an inevitability.

 

Clinical

Molteni E, Astley CM, Ma W, et al. Symptoms and syndromes associated with SARS-CoV-2 infection and severity in pregnant women from two community cohorts. Sci Rep 11, 6928 (2021). https://doi.org/10.1038/s41598-021-86452-3

Pregnant and non-pregnant women positive for SARS-CoV-2 infection were not different in syndromic severity, except for gastrointestinal symptoms.

 

Avouac J, Drumez E, Hachulla E, et al. COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases treated with rituximab: a cohort study. Lancet Rheumatol 2021, published 25 March. Full text: https://doi.org/10.1016/S2665-9913(21)00059-X

Rituximab therapy is associated with more severe COVID-19 (defined in this study as admission to an ICU or death). Rituximab will have to be prescribed with particular caution in patients with inflammatory rheumatic and musculoskeletal diseases.

 

Beyond Corona

Gray GE, Bekker LG, Laher F, et al. Vaccine Efficacy of ALVAC-HIV and Bivalent Subtype C gp120–MF59 in Adults. N Engl J Med 2021, publishd 25 March. Full text: https://doi.org/10.1056/NEJMoa2031499

Most of the 75.7 million persons with human immunodeficiency virus (HIV) infection worldwide are in sub-Saharan Africa, where subtype C of HIV type 1 (HIV-1) is prevalent. The ALVAC–gp120 regimen did not prevent HIV-1 infection among participants in South Africa despite previous evidence of immunogenicity.

 

27 March

Variants

McCormick KD, Jacobs JL, Mellors JW. The emerging plasticity of SARS-CoV-2. Science 2021, published 26 March. Full text: https://doi.org/10.1126/science.abg4493

Another excellent summary and extension of our Variants chapter. By John Mellors and colleagues.

 

Epidemiology

Salyer S, Maeda J, Sembuche S, et al. The first and second waves of the COVID-19 pandemic in Africa: a cross-sectional study. Lancet 2021, published 24 March. Full text: https://doi.org/10.1016/S0140-6736(21)00632-2

Although the first wave of the COVID-19 pandemic progressed more slowly in Africa than the rest of the world, by December 2020, the second wave appeared to be much more aggressive with many more cases.

 

Vaccines

Hughes MM, Wang A, Grossman MK, et al. County-Level COVID-19 Vaccination Coverage and Social Vulnerability — United States, December 14, 2020–March 1, 2021. MMWR Morb Mortal Wkly Rep 2021;70:431–436. Full text: http://dx.doi.org/10.15585/mmwr.mm7012e1

In the first 2.5 months of the US vaccination program, high social vulnerability counties had lower COVID-19 vaccination coverage than did low social vulnerability counties. Although vaccination coverage estimates by county-level social vulnerability varied widely among states, disparities in vaccination coverage were observed in the majority of states.

 

Diagnosis

Chakraborty D, Agrawal A, Maiti S. Rapid identification and tracking of SARS-CoV-2 variants of concern. Lancet 2021, published 22 March. Full text: https://doi.org/10.1016/S0140-6736(21)00470-0

Detecting SARS-CoV-2 variants with CRISPR for less than $15 in less than 90 minutes?

 

Clinical

Lefrancq N, Paireau J, Hozé N, et al. Evolution of outcomes for patients hospitalised during the first 9 months of the SARS-CoV-2 pandemic in France: A retrospective national surveillance data analysis. Lancet Regional Health, March 2021. Full-text: https://doi.org/10.1016/j.lanepe.2021.100087

Better get COVID-19 between waves when hospital capacities are not stretched to the limit. The authors find that both the probability of death and the probability of entering ICU were significantly correlated with COVID-19 ICU occupancy.

 

Fernández-Prada M, Rivero-Calle I, Calvache-González A, Martinón-Torres F. Acute onset supraclavicular lymphadenopathy coinciding with intramuscular mRNA vaccination against COVID-19 may be related to vaccine injection technique, Spain, January and February 2021. Euro Surveill. 2021;26(10). Full text: https://doi.org/10.2807/1560-7917.ES.2021.26.10.2100193

The authors describe a series of 20 clinical cases with acute onset of single supraclavicular lymphadenopathy coinciding with the ipsilateral intramuscular administration of a dose of an mRNA vaccine.

 

Beyond COVID-19

Kirtane AR, Verma M, Karandikar P, et al. Nanotechnology approaches for global infectious diseases. Nat. Nanotechnol. 2021, published 22 March. Full-text: https://doi.org/10.1038/s41565-021-00866-8

The formulation of new and existing drugs into nano-sized carriers promises to overcome several challenges associated with the treatment of malaria, tuberculosis and HIV infection, including low on-target bioavailability, sub-therapeutic drug accumulation in microbial sanctuaries and reservoirs, and low patient adherence due to drug-related toxicities and extended therapeutic regimens.

 

26 March

Variants

Volz E, Mishra S, Chand M, et al. Assessing transmissibility of SARS-CoV-2 lineage B.1.1.7 in England. Nature (2021). Full text: https://doi.org/10.1038/s41586-021-03470-x

The preprint we presented on 13 January now published in Nature: the authors describe the new SARS-CoV-2 lineage B.1.1.7 (AKA VOC 202012/01) which originated in England, late Summer to early Autumn 2020. The data indicate a transient shift in the age composition of reported cases, with a larger share of under-20-year-olds among B.1.1.7 cases than among historical cases. B.1.1.7 has a substantial transmission advantage with a 50% to 100% higher reproduction number.

 

Transmission

Forbes H, Morton CE, Bacon S, et al. Association between living with children and outcomes from covid-19: OpenSAFELY cohort study of 12 million adults in England. BMJ 2021; 372. Full text: https://doi.org/10.1136/bmj.n628

Does the risk of SARS-CoV-2 infection and outcomes of COVID-19 differ between adults living with and without children? In the second UK wave (1 September to 18 December 2020), the authors found an increased risk of SARS-CoV-2 infection and COVID-19-related hospital admission for adults living with children of all age groups in the second wave. For adults aged over 65 years, they also found an increased risk of infection associated with living with children of any age and of ICU admission and death from COVID-19 for those living with children aged 0-18 years.

 

Huang N, Pérez P, Kato T, et al. SARS-CoV-2 infection of the oral cavity and saliva. Nat Med (2021). https://doi.org/10.1038/s41591-021-01296-8

The oral cavity is an important site for SARS-CoV-2 infection. The authors discuss saliva as a potential transmission route.

 

Vaccines

Stamatatos L, Czartoski J, Wan YH, et al. mRNA vaccination boosts cross-variant neutralizing antibodies elicited by SARS-CoV-2 infection. Science 2021, published 25 March. Full text: https://science.sciencemag.org/content/early/2021/03/24/science.abg9175

The preprint we presented on 10 February now published in Science. The study highlights the importance of vaccinating both uninfected and previously infected persons to elicit cross-variant neutralizing antibodies.

 

Desmond a, Offit PA. On the Shoulders of Giants — From Jenner’s Cowpox to mRNA Covid Vaccines. N Engl J Med 2021; 384:1081-1083. Full text: https://doi.org/10.1056/NEJMp2034334

mRNA vaccines will change the course of the COVID-19 pandemic and the impact of other infectious diseases. Their development goes back to 2008 when Katalin Karikó, Drew Weissman, and colleagues modified messenger RNA (mRNA) using nucleoside analogues. These modifications stabilized the molecule and eliminated its capacity for inducing innate immunity, thereby making mRNA a vaccination tool (Karikó K 2008). A short vaccine history for the weekend.

 

Abdool Karim SS, de Oliveira T. New SARS-CoV-2 Variants — Clinical, Public Health, and Vaccine Implications. N Engl J Med 2021, published 24 March. Full text: https://doi.org/10.1056/NEJMc2100362

 

Bradley T, Grundberg E, Selvarangan R, et al. Antibody Responses after a Single Dose of SARS-CoV-2 mRNA Vaccine. N Engl J Med 2021, 2021, published 23 March. https://www.nejm.org/doi/full/10.1056/NEJMc2102051

Three weeks after a single vaccination, persons with recent SARS-CoV-2 infection or seropositive status had higher levels of antibody to four SARS-CoV-2 antigens and higher levels of antibodies with neutralizing characteristics than did those with no history of infection.

 

25 March

Variants

Edara VV, Norwood C, Floyd K, et al. Infection and vaccine-induced antibody binding and neutralization of the B.1.351 SARS-CoV-2 variant. Cell Host Microbe 2021, published 20 March. Full text: https://doi.org/10.1016/j.chom.2021.03.009

Despite reduced antibody titers against the B.1.351 variant (first detected in South Africa), sera from infected and vaccinated individuals containing polyclonal antibodies to the spike protein could still neutralize SARS-CoV-2 B.1.351. The authors conclude that protective humoral immunity may be retained against this variant.

 

Transmission

Plesner Lyngse F, Mølbak K, Træholt Frank K, et al. Association between SARS-CoV-2 Transmission Risk, Viral Load, and Age: A Nationwide Study in Danish Households. medRxiv 2021, posted 5 March. Full-text: https://doi.org/10.1101/2021.02.28.21252608

Should age have a higher impact than Ct value on the risk of SARS-CoV-2 transmission? This is the conclusion of a study by Frederik Lyngse et al. who found an almost linearly increasing transmission risk with age of the primary cases for adults (≥ 20 years) and negatively for children (< 20 years). They also found that the risk of SARS-CoV-2 transmission was negatively associated—approximately linear—with the Ct values of the tested primary cases. However, even for relatively high Ct values, the risk of transmission was not negligible, e.g. for primary cases with a Ct value of 38, the authors found a transmission risk of 8%.

 

Immunology

Thakkar A. Pradhan K, Jindal S, et al. Patterns of seroconversion for SARS-CoV-2 IgG in patients with malignant disease and association with anticancer therapy. Nat Cancer 2021, published 22 March. Full-text: https://doi.org/10.1038/s43018-021-00191-y

Two hundred and sixty-one patients with a cancer diagnosis underwent SARS-CoV-2 IgG testing and demonstrated a high rate of seroconversion (92%). Significantly lower seroconversion was seen in patients with hematological malignancies (82%), patients who received anti-CD-20 antibody therapy (59%) and stem cell transplant (60%). Notably, all 17 patients who received immunotherapy, including 16 that received anti-PD-1/PD-L1 monoclonal antibodies, developed SARS-CoV-2 IgG antibodies (100% seroconversion).

 

Stertz S, Hale BG. Interferon system deficiencies exacerbating severe pandemic virus infections. Trends Microbiol 2021, published 20 March. Full-text: https://doi.org/10.1016/j.tim.2021.03.001

An emerging concept is that genetic and non-genetic deficiencies in interferon system components lead to uncontrolled viral replication and severe illness in a subset of people. Intriguingly, new findings suggest that individuals with auto-antibodies neutralizing the antiviral function of interferon are at increased risk of severe COVID-19. The authors discuss key questions surrounding how such auto-antibodies develop and function, as well as the general implications of diagnosing interferon deficiencies for personalized therapies.

 

Vaccines

Keehner J, Pfeffer MA, Longhurst CA, et al. SARS-CoV-2 Infection after Vaccination in Health Care Workers in California. N Engl J Med 2021, 2021, published 23 March. https://www.nejm.org/doi/full/10.1056/NEJMc2101927

COVID-19 infection after complete vaccination? Possible, but rare. At the University of California, San Diego (UCSD) and the University of California, Los Angeles (UCLA) health systems, 379 persons (/36,659 who received the first dose, and /28,184 of whom received the second dose) tested positive for SARS-CoV-2 at least 1 day after vaccination, the majority (71%) of whom tested positive within the first 2 weeks after the first dose. After receiving both vaccinations, 37 health care workers tested positive; of these workers, 22 had positive test results 1 to 7 days after the second dose. Only 8 health care workers tested positive 8 to 14 days after the second vaccination, and 7 tested positive 15 or more days after the second vaccination.

 

Daniel W, Nivet M, Warner J, Podolsky KD. Early Evidence of the Effect of SARS-CoV-2 Vaccine at One Medical Center. N Engl J Med 2021, 2021, published 23 March. https://www.nejm.org/doi/full/10.1056/NEJMc2102153

Vaccine efficacy among employees of a medical center. Daniel et al. report 234 SARS-CoV-2 infections in 8969 non-vaccinated employees, 112 in 6144 partially vaccinated employees, and 4 among 8121 fully vaccinated employees, p < 0.01 for all pairwise comparisons. Next problem: vaccine hesitancy. Only 78% of employees were vaccinated by March 5.

 

Clinical

Altibi AM, Pallavi B, Liaqat H, et al. Characteristics and comparative clinical outcomes of prisoner versus non-prisoner populations hospitalized with COVID-19. Sci Rep 11, 6488 (2021). https://doi.org/10.1038/s41598-021-85916-w

Prisons in the United States have become a hotbed for spreading COVID-19 within said institutions. What about the clinical outcome after hospitalization for COVID-19? You know the answer: prisoner status was associated with more severe clinical presentation, higher rates of ICU admissions, vasopressors requirement, intubation, in-hospital mortality, and 30-day mortality.

 

24 March

Transmission

Paper of the Day

Leung NHL. Transmissibility and transmission of respiratory viruses. Nat Rev Microbiol 2021, published 22 March. Full text: https://doi.org/10.1038/s41579-021-00535-6

Excellent summary.

 

Prevention

Kiang MV, Chin ET, Huynh BQ, et al. Routine asymptomatic testing strategies for airline travel during the COVID-19 pandemic: a simulation study. Lancet Infect Dis 2021, published 22 March. Full-text: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00134-1/fulltext

Large-scale computer simulation to provide a comprehensive comparison of possible SARS-CoV-2 testing and quarantine strategies to facilitate safe airline travel. First message: the strategy of a rapid antigen test on the day of travel might give similar results to the pre-travel PCR test strategy. However, a significant proportion of infectious individuals will not be identified. Second message: an abbreviated quarantine with post-travel testing is probably needed to reduce population-level transmission due to importation of infection when travelling from a high to low incidence setting. Without vaccines, air travel will not return to pre-COVID-19 levels.

 

Virology

Jackson B, Rambaut A, Pybus OG, et al. Recombinant SARS-CoV-2 genomes involving lineage B.1.1.7 in the UK. Virological 2021, posted 17 March. Full text: https://virological.org/t/recombinant-sars-cov-2-genomes-involving-lineage-b-1-1-7-in-the-uk/658

The authors report SARS-CoV-2 genome sequences with some sections carrying mutations characteristic of B.1.1.7, while other sections carried mutations specific to another lineage. The timing, location, and genetic composition of the mosaic sequences provide evidence that they originated through recombination in co-infected individuals in the UK.

 

Immunology

McCallum M, De Marco a, Lempp FA, et al. N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2. Cell 2021, published 16 March. Full text: https://doi.org/10.1016/j.cell.2021.03.028

McCallum et al. describe 41 human monoclonal Abs (mAbs) derived from memory B cells, which recognize the SARS-CoV-2 S N-terminal domain (NTD) and show that a subset of them neutralize SARS-CoV-2 ultra-potently. The authors underline the importance of NTD-specific neutralizing mAbs for protective immunity and vaccine design.

 

Greaney AJ, Starr TN, Barnes CO, et al. Mutational escape from the polyclonal antibody response to SARS-CoV-2 infection is largely shaped by a single class of antibodies. bioRxiv 2021, posted 18 March. Full text: https://doi.org/10.1101/2021.03.17.435863

Although the human immune system can produce antibodies that target diverse RBD epitopes, in practice the polyclonal response to infection is dominated by a single class of antibodies targeting an epitope that is already undergoing rapid evolution. These “class 2” antibodies target the face of the receptor-binding ridge that is accessible in both “up” and “down” RBD conformations. A mutation (E484K) that escapes this antibody class is present in many emerging viral lineages, including B.1.351, P.1, P.2, and B.1.526​.

 

Benedict C, Cedernaes J. Could a good night’s sleep improve COVID-19 vaccine efficacy? Lancet Respir Med. 2021 Mar 12:S2213-2600(21)00126-0. PubMed: https://pubmed.gov/33721558. Full text: https://doi.org/10.1016/S2213-2600(21)00126-0

Could the timing of vaccination affect the immune response to COVID-19 vaccines? Should we all take a nap after vaccination? It wouldn’t do any harm.

 

Long COVID

Arnold DT, Milne A, Samms E, et al. Are vaccines safe in patients with Long COVID? A prospective observational study. bioRxiv 2021, posted 14 March. Full text: https://doi.org/10.1101/2021.03.11.21253225

Observational study of 44 vaccinated participants and 22 matched unvaccinated participants. Most were highly symptomatic of Long COVID at 8 months (82% in both groups had at least 1 persistent symptom), with fatigue (61%), breathlessness (50%) and insomnia (38%) predominating. When compared to matched unvaccinated participants from the same cohort, those who had received a vaccine had a small overall improvement in Long COVID symptoms, with a decrease in worsening symptoms (5.6% vaccinated vs 14.2% unvaccinated) and increase in symptom resolution (23.2% vaccinated vs 15.4% unvaccinated) (p = 0.035). Placebo effect? Hopefully not.

 

23 March

Long COVID

Paper of the Day

Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nat Med 2021, published 22 March. Full-text: https://doi.org/10.1038/s41591-021-01283-z

The authors provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae, and discuss relevant considerations for the multidisciplinary care of COVID-19 survivors.

 

Variants

Hoffmann M, Arora P, Groß R, et al. SARS-CoV-2 variants B.1.351 and P.1 escape from neutralizing antibodies. Cell 2021, accepted 16 March. Full-text: https://doi.org/10.1016/j.cell.2021.03.036

The authors show that entry of all variants into human cells is susceptible to blockade by the entry inhibitors soluble ACE2, Camostat, EK-1 and EK-1-C4. In contrast, entry of B.1.351 and P.1 was partially (casirivimab) or fully (bamlanivimab) resistant to monoclonal antibodies. Moreover, entry of these variants was less efficiently inhibited by plasma from convalescent COVID-19 patients and sera from individuals vaccinated with the Pfizer-BioNTech vaccine.

 

Transmission

Couthinho M, Darcie Marquitti FM, Souto Ferreira L, et al. Model-based estimation of transmissibility and reinfection of SARS-CoV-2 P.1 variant. medRxiv 2021, posted 9 March. Full-text: https://doi.org/10.1101/2021.03.03.21252706

From December, 2020 to February, 2021, Manaus was devastated by four times more COVID-19 cases compared to its previous peak (April, 2020). The probable culprit: the new P.1 variant. In this pre-print, the authors describe the transmissibility of P.1. to be about 2.5 times higher compared to the historical variant in Manaus. The probability of re-infection by P.1 seems to be low, though: 6.4% (95% CI: 5.7–7.1%).

 

Ferasin L, Fritz M, Ferasin H, et al. Myocarditis in naturally infected pets with the British variant of COVID-19. bioRxiv 2021, posted 18 March. Full-text: https://doi.org/10.1101/2021.03.18.435945

Given the enhanced infectivity and transmissibility of the B.1.1.7 variant, is there a risk that companion animals may play a more significant role in SARS-CoV-2 outbreak dynamics than previously appreciated? The authors report the first cases of infection of domestic cats and dogs by the British B.1.1.7 variant. They also discovered that many owners and handlers of these pets had developed COVID-19 respiratory symptoms 3-6 weeks before their pets became ill.

 

Vaccines

Khoury DS, Cromer D, Reynaldi A, et al. What level of neutralising antibody protects from COVID-19? medRxiv 2021, posted 11 March. Full-text: https://doi.org/10.1101/2021.03.09.21252641

Predictive models of immune protection are useful to identify immune correlates of protection to assist in the future deployment of vaccines. Here, the authors modelled the relationship between in vitro neutralisation levels and observed protection from SARS-CoV-2 infection using data from seven current vaccines as well as convalescent cohorts. They report that neutralisation level is highly predictive of immune protection. Attention: this is a pre-print, so don’t take the data for granted. However, in the future, with vaccines abundantly available, we will use figures such as Figure 1 to decide whether to prefer product A over product B.

 

Tauzin A, Nayrac M, Benlarbi M, et al. A single BNT162b2 mRNA dose elicits antibodies with Fc-mediated effector functions and boost pre-existing humoral and T cell responses. bioRxiv 2021, posted 18 March. Full-text: https://doi.org/10.1101/2021.03.18.435972

No neutralising activity in SARS-CoV-2 naïve individuals three weeks after a single dose of the Pfizer-BioNTech vaccine. However, the authors detected strong anti-receptor binding domain (RBD) and spike antibodies with Fc-mediated effector functions and cellular responses dominated by the CD4+ T cell component. These data provide support to spacing the doses of two-vaccine regimens to vaccinate a larger pool of the population in the context of vaccine scarcity against SARS-CoV-2.

 

22 March

Epidemiology

Rennert L, McMahan C, Kalbaugh CA, et al. Surveillance-based informative testing for detection and containment of SARS-CoV-2 outbreaks on a public university campus: an observational and modelling study. Lancet Child Adolescent Health March 19, 2021. https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00060-2/fulltext

There is a strong need for testing strategies for mitigating SARS-CoV-2 spread on college and university campuses. The authors implemented a novel surveillance-based informative testing (SBIT) strategy for SARS-CoV-2 detection. In this setting, random testing is done to detect potential cluster outbreaks (eg, residence hall outbreaks). Upon detection of an outbreak, a portion of available tests the following day are allocated to the entire cluster. SBIT was effective in detecting and containing COVID-19 outbreaks and mitigating SARS-CoV-2.

 

Immunology

Clark SA, Clark LE, Pan J, et al. SARS-CoV-2 evolution in an immunocompromised host reveals shared neutralization escape mechanisms. Cell March 16, 2021. https://www.cell.com/cell/fulltext/S0092-8674(21)00355-X

Viral evolution in a persistently infected immunocompromised individual: mutations found in late-stage evolved S variants confer resistance to a common class of SARS-CoV-2 neutralizing antibodies. Resistance extends to the polyclonal serum immunoglobulins healthy convalescent donors and to monoclonal antibodies in clinical use. This case shows how SARS-CoV-2 can evolve solutions to bind ACE2 while escaping neutralization by major classes of human neutralizing antibodies.

 

Collateral damage

Adlhoch C, Mook P, Lamb F, et al. Very little influenza in the WHO European Region during the 2020/21 season, weeks 40 2020 to 8 2021. Eurosurveillance 18 March 2021, Volume 26, Issue 11. https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2021.26.11.2100221

Almost no flu this year. This 2020/21 influenza season is exceptional since the creation of the Global Influenza Surveillance and Response System (GISRS) network in 1952. Positivity was 0.1% (33/25,606) this season compared to an average positivity of 38% (14,966/39,407) between week 40 year X and week 8 the following year. Yes, this was statistically significant.

 

Treatment

Driouich JS, Cochin M, Lingas G. et al. Favipiravir antiviral efficacy against SARS-CoV-2 in a hamster model. Nat Commun March 19, 2021, 12, 1735. https://www.nature.com/articles/s41467-021-21992-w

In hamsters, favipiravir has a strong dose effect, when treatment is initiated before or simultaneously with infection. This led to reduction of infectious titers in lungs and clinical alleviation of the disease.

 

Solaymani-Dodaran M, Ghanei M, Bagheri M, et al. Safety and efficacy of Favipiravir in moderate to severe SARS-CoV-2 pneumonia. Int Immunopharmacol. 2021 Mar 11;95:107522. PubMed: https://pubmed.gov/33735712. Full-text: https://doi.org/10.1016/j.intimp.2021.107522

In humans, this may be different. A large RCT from Iran, 380 patients randomly allocated into favipiravir and lopinavir/ritonavir, found no clinical benefit of favipiravir. Though the trial was hampered by some methodological issues (as well as its open label design), it seems obvious that patients who are hospitalized due to pneumonia and have passed the viral replication phase, are unlikely to benefit from antiviral treatment.

 

21 March

Epidemiology

Sandmann FG, Davies NG, Vassall A, et al. The potential health and economic value of SARS-CoV-2 vaccination alongside physical distancing in the UK: a transmission model-based future scenario analysis and economic evaluation. Lancet Inf Dis March 18, 2021. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00079-7/fulltext

In a modelling study from the UK, highlighting the substantial health and economic value of introducing SARS-CoV-2 vaccination. Without the initial lockdown, vaccination, and increased physical distancing, the authors estimate that 3.1 million (0.84–4.5) deaths would occur in the UK over the next 10 years.

 

Vaccine

Hassan AO, Feldmann F, Zhao H, et al. A single intranasal dose of chimpanzee adenovirus-vectored vaccine protects against SARS-CoV-2 infection in rhesus macaques. Cell Rep Med March 17, 2021. https://www.cell.com/action/showPdf?pii=S2666-3791%2821%2900046-X

The future? An intranasally-administered chimpanzee adenovirus-vectored vaccine encoding a pre-fusion stabilized spike (S) protein (ChAd-SARS-CoV-2-S) worked well in macaques. A single intranasal dose induced neutralizing antibodies and T cell responses and limited or prevented infection in the upper and lower respiratory tract after a SARS-CoV-2 challenge.

 

Immunology

Wang Z, Yang X, Zhong J, et al. Exposure to SARS-CoV-2 generates T-cell memory in the absence of a detectable viral infection. Nat Commun March 19, 2021, 12, 1724. https://www.nature.com/articles/s41467-021-22036-z

Close contacts who are SARS-CoV-2-exposed are often both PCR- and antibody-negative, indicating that SARS-CoV-2 failed to establish a successful infection in these individuals, presumably due to their exposure to limited numbers of viral particles or a short time of exposure. This interesting study has evaluated T cell responses in 90 recovered COVID-19 patients and 69 close contacts. 58% of close contacts had virus-specific memory CD4+ and 14% of close contacts had virus-specific memory CD8+ T cells. Pool sizes and quality of T memory cells from close contacts were around half of those from COVID-19 patients.

 

Severe COVID-19

INSPIRATION Investigators. Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit. JAMA March 18, 2021. doi:10.1001/jama.2021.4152. https://jamanetwork.com/journals/jama/fullarticle/2777829?resultClick=1

No need to increase the dose of prophylactic anticoagulation: a large RCT indicates no clinical benefit of intermediate dose compared with standard dose prophylactic anticoagulation in 452 patients with COVID-19 admitted to the intensive care unit (ICU).

 

Co-morbidities

Salter A, Fox RJ, Newsome SD, et al. Outcomes and Risk Factors Associated With SARS-CoV-2 Infection in a North American Registry of Patients With Multiple Sclerosis. JAMA Neurol March 19, 2021; Full-text: https://doi.org/10.1001/jamaneurol.2021.0688

Huge cross-sectional study of 1626 North American patients with MS and COVID-19. Increased disability was independently associated with worse clinical severity, as well as older age, Black race, cardiovascular co-morbidities, and recent treatment with corticosteroids.

 

20 March

Epidemiology

Pekar J, Worobey M, Moshiri N, et al. Timing the SARS-CoV-2 index case in Hubei province. Science 18 Mar 2021: eabf8003. DOI: 10.1126/science.abf8003. https://science.sciencemag.org/content/early/2021/03/17/science.abf8003

Shit happened in October/November 2019: employing a coalescent framework to combine retrospective molecular clock inference with forward epidemiological simulations, the authors determine here how long SARS-CoV-2 could have been circulating prior to its “official” recognition. Results define the period between mid-October and mid-November 2019 as the plausible interval when the first case of SARS-CoV-2 emerged in Hubei province.

 

Variants

Grint DJ, Wing K, Williamson E, et al. Case fatality risk of the SARS-CoV-2 variant of concern B.1.1.7 in England, 16 November to 5 February. Volume 26, Issue 11, 18 March 2021. https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2021.26.11.2100256

Evidence grows that B.1.1.7 is more dangerous. In this data drawn from the OpenSAFELY electronic health records secure research platform (covering 40% of England’s population registered with a general practitioner), there was a consistently higher (about two thirds) absolute risk of death by 28 days after a SARS-CoV-2-positive test in all groups stratified by age, sex and presence of co-morbidities.

 

Immunology

He Z, Ren L, Yang J, et al. Seroprevalence and humoral immune durability of anti-SARS-CoV-2 antibodies in Wuhan, China: a longitudinal, population-level, cross-sectional study. Lancet March 20, 2021 Volume 397, ISSUE 10279, P1075-1084, March 20, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00238-5/fulltext

This cross-sectional study from Wuhan suggests durable protection against SARS-CoV-2. Among 3599 randomly selected families with 9702 individuals, baseline adjusted seroprevalence was 6.9%. Although titers of IgG decreased over the 9-month study period, the proportion of individuals who had IgG antibodies did not decrease substantially. Neutralizing antibodies were found in 39·8% of the seropositive subgroup; encouragingly, this proportion was also sustained. Of note, more than 80% of those surveyed who were seropositive were asymptomatic.

 

Andolfo I, Russo R, Larorsa, et al. Common variants at 21q22.3 locus influence MX1 and TMPRSS2 gene expression and susceptibility to severe COVID-19. iScience March 17, 2021. https://www.cell.com/action/showPdf?pii=S2589-0042%2821%2900290-X

Analyzing the genome of 7970 individuals hospitalized for COVID-19, this Italian group found some host genetic factors to influence the course of COVID-19. Five SNPs within TMPRSS2/MX1 locus (chromosome 21) were associated with severe COVID-19. The minor alleles of these five SNPs correlated with a reduced risk of developing severe COVID-19 and a high level of MX1 expression in blood (note that the odds ratios were not that dramatic, ranging from 0.5 to 1.5).

 

Vaccine

Moore S, Hill EM, Tildesley MJ, et al. Vaccination and non-pharmaceutical interventions for COVID-19: a mathematical modelling study. Lancet Inf Dis March 18, 2021. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00143-2/fulltext

Vaccination alone is not enough. This modeling study from UK indicates that in the absence of non-pharmaceutical interventions (NPIs), even with the most optimistic assumption that the vaccine will prevent 85% of infections, R is estimated to be 1.58 (95% CI 1.36–1.84) once all eligible adults have been offered both doses of the vaccine. Under the default uptake scenario, removal of all NPIs once the vaccination program is complete is predicted to lead to 21,400 deaths due to COVID-19 for a vaccine that prevents 85% of infections, although this number increases to 96,700 deaths if the vaccine only prevents 60% of infections.

 

19 March

Variants

Paper of the Day

Wu K, Werner AP, Koch M. Serum Neutralizing Activity Elicited by mRNA-1273 Vaccine. NEJM March 17, 2021. https://www.nejm.org/doi/full/10.1056/NEJMc2102179

What about Moderna’s mRNA vaccine and the new variants? This study saw a decrease in titers of neutralizing antibodies against the P.1 variant, the B.1.427/B.1.429 variant, the B.1.1.7+E484K variant, and the B.1.351 variant as well as a subset of its mutations in the RBD. Protection against these lineages remains “to be determined”.

 

Clinical

Hansen CH, Michlmayr D, Gubbels SM. Assessment of protection against reinfection with SARS-CoV-2 among 4 million PCR-tested individuals in Denmark in 2020: a population-level observational study. Lancet March 17, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00575-4/fulltext

This large study from Denmark probably provides the best data to date on protection against re-infection. Among eligible PCR-positive individuals from the first surge of the epidemic, 72 (0.65%) tested positive again during the second surge compared to 16,819 (3.27%) of 514,271 who tested negative during the first surge. Protection against repeat infection was 80.5% (95% CI: 75.4–84.5). Of note, there was no evidence of waning protection over time.

 

Long COVID-19

The Writing Committee for the COMEBAC Study Group. Four-Month Clinical Status of a Cohort of Patients After Hospitalization for COVID-19. JAMA. March 17, 2021. https://jamanetwork.com/journals/jama/article-abstract/2777787

How is it going after four months? Not so well. This study included 142 of 172 ICU patients and 336 of 662 non-ICU patients from Paris. During a telephone interview, 244/478 patients (51%) declared at least one symptom that did not exist before COVID-19: fatigue in 31%, cognitive symptoms in 21%, and new-onset dyspnea in 16%. CT lung scan abnormalities were found in 108 of 171 patients (63%), mainly subtle ground-glass opacities. Fibrotic lesions were observed in 33 (19%).

 

Treatment

Cremer PC, Abbate A, Hudock K, et al. Mavrilimumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation (MASH-COVID): an investigator initiated, multicentre, double-blind, randomised, placebo-controlled trial. Lancet Rheumatology March 17, 2021. DOI: https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(21)00070-9/fulltext

Mavrilimumab is a monoclonal antibody that binds to the GM-CSF receptor and blocks intracellular signalling of GM-CSF. Based on this mechanism of action, the putative role of increased GM-CSF in adverse outcomes from COVID-19, and encouraging results from an observational study, the authors initiated a small RCT of 40 patients to evaluate whether mavrilimumab works in severe COVID-19. It didn’t.

 

Jevalikar G, Mithal A, Singh A, et al. Lack of association of baseline 25-hydroxyvitamin D levels with disease severity and mortality in Indian patients hospitalized for COVID-19. Sci Rep 11, 6258 (2021). https://www.nature.com/articles/s41598-021-85809-y

Oh, again, no effect of vitamin D. In this prospective observational study on 404 patients, serum 25-OHD levels at admission did not correlate with inflammatory markers, clinical outcomes, or mortality in hospitalized COVID-19 patients. Treatment of vitamin D deficiency with cholecalciferol did not make any difference to the outcomes.

 

18 March

Vaccine/Variants

Mahdi SA, Baillie C, Cutland CL, et al. Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant. NEJM, March 16, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2102214

No protection from mild-to-moderate COVID-19 with AstraZeneca in this large RCT on young (median age 30 years), HIV-negative patients in South Africa. Infections were seen in 23 of 717 placebo recipients (3.2%) and in 19 of 750 vaccine recipients (2.5%), for an efficacy of 21.9% (95% CI, −49.9 to 59.8). Main caveat: as there were no cases of hospitalization in the study, it remains unclear whether ChAdOx1 nCov-19 may protect against severe infection with the B.1.351 variant.

 

Krutikov M, Hayward A, Shallcrosse L. Spread of a Variant SARS-CoV-2 in Long-Term Care Facilities in England March 16, 2021. NEJM March 16, 2021. https://www.nejm.org/doi/full/10.1056/NEJMc2035906

Rapid spread in staff and residents of long-term care facilities in the UK. Within a few weeks (between November 16 and December 13), the proportion of positive samples with S gene target failure (a proxy for B.1.1.7) increased from 70 of 582 (12.0%) to 491 of 813 (60.4%). This increase was associated with a decrease in median Ct values (from 27 to 21).

 

Immunology

Abayasingam A, Balachandran H, Agapiou D, et al. Long-term persistence of RBD-positive memory B cells encoding neutralising antibodies in SARS-CoV-2 infection. Cell Rep Med March 14, 2021. https://www.cell.com/action/showPdf?pii=S2666-3791%2821%2900044-6

Good news. The loss of neutralising antibodies (NAb) in plasma may be countered by the maintenance of neutralising capacity in the memory B cell repertoire. Despite the declining NAb titers, in the great majority of participants, memory B cells against RBD were maintained and even increased in numbers at four to six months following infection in 12/13 participants.

 

Co-morbidities

Desai A, Gainor JF, Hegde A. et al. COVID-19 vaccine guidance for patients with cancer participating in oncology clinical trials. Nat Rev Clin Oncol March 15, 2021. https://doi.org/10.1038/s41571-021-00487-z

Continued quality oncological care requires that patients with cancer, including those involved in trials, be prioritized for COVID-19 vaccination, which should not affect trial eligibility. This important perspective provides operational COVID-19 vaccine guidance for patients participating in oncology clinical trials.

 

Treatment

Yuan S, Yin X, Meng X, et al. Clofazimine broadly inhibits coronaviruses including SARS-CoV-2. Nature March 16, 2021). https://www.nature.com/articles/s41586-021-03431-4

Clofazimine, an anti-leprosy drug with a favorable safety profile, appears to possess pan-coronaviral inhibitory activity by inhibiting viral spike-mediated cell fusion and viral helicase activity. In hamsters, prophylactic or therapeutic administration of clofazimine significantly reduced viral load in the lung and also mitigated inflammation.

 

17 March

Variants

Challen R, Brooks-Pollock E, Read JM, Dyson L, Tsaneva-Atanasova K, Danon L. Risk of mortality in patients infected with SARS-CoV-2 variant of concern 202012/1: matched cohort study. BMJ. 2021 Mar 9;372:n579. PubMed: https://pubmed.gov/33687922. Full-text: https://doi.org/10.1136/bmj.n579

Is B.1.1.7 more lethal? In this large study from the UK, mortality hazard ratio associated with infection with “B.1.1.7” (S gene negative) was 1.64 (95% CI: 1.32 to 2.04) in the community, compared with previously circulating variants. However, even though the authors controlled for some biases, their matched control approach bears several limitations. Let’s take it as a first hint, but not as proof.

 

Clinical

Sheehan MM, Reddy AJ, Rothberg MB, et al. Reinfection Rates among Patients who Previously Tested Positive for COVID-19: a Retrospective Cohort Study. Clinical Infectious Diseases March 15, 2021, ciab234. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab234/6170939

Previous infection appears to offer high levels of protection against symptomatic infection, as well as severe disease, for at least 8 months: in this retrospective cohort study of one multi-hospital health system in Ohio and Florida, protection against symptomatic infection was 84.5% (95% CI: 77.9 to 89.1).

 

Lambrecq V, Hanin A, Munoz-Musat E, et al. Association of Clinical, Biological, and Brain Magnetic Resonance Imaging Findings With Electroencephalographic Findings for Patients With COVID-19. JAMA Netw Open March 15, 2021. 2021; 4(3):e211489. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2777441?resultClick=1

In this retrospective study from Paris, 9/664 (1%) of hospitalized patients presented with brain injury that was defined as COVID-19-related encephalopathy. Six had movement disorders, 7 had frontal syndrome, 4 had brainstem impairment, 4 had periodic EEG discharges, and 3 had MRI white matter–enhancing lesions.

 

Vaccine

Boyarsky BJ, Werbel WA, Avery RK, et al. Immunogenicity of a Single Dose of SARS-CoV-2 Messenger RNA Vaccine in Solid Organ Transplant Recipients. JAMA March 15, 2021. https://jamanetwork.com/journals/jama/fullarticle/2777685?resultClick=1

In this multicenter study on 436 solid organ transplant recipients taking different immunosuppressive agents, only 76 (17%) had detectable antibodies (anti-S1 or anti–receptor-binding domain) at a median of 20 days after the first dose of vaccine. These results contrast with the robust early immunogenicity observed in mRNA vaccine trials.

 

Britton A, Jacobs Slifka KM, Edens C, et al. Effectiveness of the Pfizer-BioNTech COVID-19 Vaccine Among Residents of Two Skilled Nursing Facilities Experiencing COVID-19 Outbreaks — Connecticut, December 2020–February 2021. MMWR Morb Mortal Wkly Rep. ePub: 15 March 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7011e3.htm

Retrospective study in a total of 463 residents of two skilled nursing facilities, estimating effectiveness of partial vaccination in preventing SARS-CoV-2 infection to be 63% (95% CI: 33%–79%).

 

16 March

Top 5 instead of Top 10

We started working on covidreference.com a year ago. Since then, we have selected, evaluated and discussed almost 3500 Top 10 papers every day of the week (from a total of 112,586 papers listed in PubMed on March 14 – don’t blame us too much if we missed one or two). However, during the last months we’ve gotten the impression that 5 important papers per day should be enough. We will be as rigorous as ever in our selection.

 

Diagnostics

Paltiel DA, Zheng A, Sax PA. Clinical and Economic Effects of Widespread Rapid Testing to Decrease SARS-CoV-2 Transmission. Annals Int Medicine 9 March 2021, https://www.acpjournals.org/doi/10.7326/M21-0510

High-frequency home testing for SARS-CoV-2 with an inexpensive, imperfect test could contribute to pandemic control at justifiable cost. Large reductions in infections, mortality, and hospitalizations were seen under different behavioral assumptions and testing frequencies.

 

Immunology

Szabo PA, Dogra P, Gray JI, et al. Longitudinal profiling of respiratory and systemic immune responses reveals myeloid cell-driven lung inflammation in severe COVID-19. Immunity March 11, 2021. DOI: https://www.cell.com/action/showPdf?pii=S1074-7613%2821%2900117-5

More insights into the immune processes driving COVID-19 lung pathology with therapeutic implications for targeting inflammation in the respiratory tract. The authors have identified a key role for airway myeloid cells, primarily macrophages and monocytes, in driving and perpetuating immune cell recruitment and lung inflammation, consistent with their associations with older age and mortality.

 

Variants

Garcia-Beltran WF, Lam EC, Denis KS, et al. Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity. Cell March 12, 2021. https://www.cell.com/cell/fulltext/S0092-8674(21)00298-1

Among 99 individuals who received one or two doses of mRNA vaccines, most individuals receiving a single dose did not raise sufficient antibody titers to provide detectable cross neutralization to B.1.351. This supports the importance of 2-dose regimens to acheive protective titers.

 

Altman DM, Boyton RJ, Beale R. Immunity to SARS-CoV-2 variants of concern. Science 12 Mar 2021: Vol. 371, Issue 6534, pp. 1103-1104. https://science.sciencemag.org/content/371/6534/1103

Brilliant brief review about not only immunity to variants but also on methodological issues. Assessment of variants on neutralization are complicated by the variability of pseudotype assays used.

 

Li Y, Ma ML, Lei Q, et al. Linear epitope landscape of the SARS-CoV-2 Spike protein constructed from 1,051 COVID-19 patients. Cell Reports March 12, 2021. DOI:https://doi.org/10.1016/j.celrep.2021.108915

What part of the spike protein is highly immunogeneic? By analyzing the serum IgG response of 1051 COVID-19 patients with a peptide microarray, the authors built a comprehensive epitope landscape that covers the entire sequence of the SARS-CoV-2 spike protein. A set of 16 highly immunogenic epitopes outside of the RBD region were identified. The antibody responses against several epitopes are associated with severity. Little neutralization activity was observed for the antibodies against the highly immunogenic epitopes.

 

Long COVID-19

Perlis RH, Ognyanova K, Santillana M, et al. Association of Acute Symptoms of COVID-19 and Symptoms of Depression in Adults. JAMA Netw Open. 2021; 4(3):e213223. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2777421?resultClick=1

Depression may be considered as potential neuropsychiatric sequelae. Among more than 3900 individuals with prior COVID-19 surveyed between May 2020 and January 2021, 52.4% met criteria for moderate or greater symptoms of major depression. Symptoms were more prevalent in younger and in male patients.

 

15 March

Co-morbidities

Paper of the Day

Elliott A, Saul M, Zeng J, et al. Pan-cancer analysis of RNA expression of ANGIOTENSIN-I-CONVERTING ENZYME 2 reveals high variability and possible impact on COVID-19 clinical outcomes. Sci Rep 11, 5639 (2021). https://www.nature.com/articles/s41598-021-84731-7

What are the biologic underpinnings of increased COVID-19 morbidity in cancer patients? This study showed significant differences in ACE2 and protease expression in normal and malignant tissues with a subgroup expressing very high levels of ACE2 RNA (in particular in NSCLC and gastrointestinal cancer). These findings, together with the increased presence of inflammatory cells in tumors displaying high ACE2 levels might explain why cancer patients are more severely affected by COVID-19.

 

Arnold J, Winthrop K, Emery P, et al. COVID-19 vaccination and antirheumatic therapy. Rheumatology 12 March 2021, keab223, https://doi.org/10.1093/rheumatology/keab223

Some evidence indicates immunosuppressive therapy inhibits humoral response to the influenza, pneumococcal and hepatitis B vaccines. The degree to which this will translate to impaired COVID-19 vaccine responses is unclear. This article outlines the existing data on the effect of anti-rheumatic therapy on vaccine responses in patients with inflammatory arthritis and formulates a possible pragmatic management strategy for COVID-19 vaccination.

 

Epidemiology

van den Berg P, Schechter-Perkins EM, Jack RS, et al. Effectiveness of three versus six feet of physical distancing for controlling spread of COVID-19 among primary and secondary students and staff: A retrospective, state-wide cohort study. Clinical Infectious Diseases 10 March 2021, ciab230, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab230/6167856?searchresult=1

Incident cases of SARS-CoV-2 in students and staff in Massachusetts public schools among districts with different physical distancing requirements did not differ, suggesting that the less physical distancing recommendation can be adopted in school settings without negatively impacting safety.

 

Transmission

Jordan I, Fernandez de Sevilla M, Bassat Q, et al. Transmission of SARS-CoV-2 infection among children in summer schools applying stringent control measures in Barcelona, Spain. Clinical Infectious Diseases, 12 March 2021, ciab227, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab227/6168543

Among the more than 2000 repeatedly screened participants, the transmission rate of SARS-CoV-2 infection among children attending school-like facilities under strict prevention measures was lower than that reported for the general population.

 

Soriano-Arandes A, Gatell A, Serrano P, et al. Household SARS-CoV-2 transmission and children: a network prospective study. Clinical Infectious Diseases 12 March 2021, ciab228, https://doi.org/10.1093/cid/ciab228

Same direction: children are unlikely to cause household COVID-19 clusters or be major drivers of the pandemic even if attending school. Among 1040 COVID-19 patients < 16 years, more than 70% (756) were secondary to an adult infection, while only 7.7% (80) were index cases.

 

Immunology

Flynn RA, Belk JA, Qi Y, et al. Discovery and functional interrogation of SARS-CoV-2 RNA-host protein interactions. Cell March 11, 2021. https://www.cell.com/cell/fulltext/S0092-8674(21)00297-X

Using comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS), Ryan A. Flynn and colleagues identified 309 host proteins that bind the SARS-CoV-2 RNA during active infection. Their work provides a comprehensive catalog of functional SARS-CoV-2 RNA-host protein interactions, which can inform studies to understand the host-virus interface.

 

Clinical

Brehm TT, van der Meirschen M, Hennigs A, et al. Comparison of clinical characteristics and disease outcome of COVID-19 and seasonal influenza. Sci Rep 11, 5803 (2021). https://www.nature.com/articles/s41598-021-85081-0

Again, it’s no flu. Thomas Theo Brehm and colleagues from Hamburg compared 166 patients with COVID-19 diagnosed between February and June 2020, and 255 patients with seasonal influenza diagnosed during the 2017–18 season at the same hospital. Although patients with COVID-19 were younger and had fewer comorbidities, they had a longer duration of hospitalization, a more frequent need of invasive ventilation and were more frequently admitted to the intensive care unit.

 

Almadhi MA, Abdulrahman A, Alawadhi A, et al. The effect of ABO blood group and antibody class on the risk of COVID-19 infection and severity of clinical outcomes. Sci Rep 11, 5745 (2021). https://doi.org/10.1038/s41598-021-84810-9

In this large study from Bahrein, no association between antibodies and either risk of infection or susceptibility to severe infection was found, possibly indicating that an unexplored underlying factor may be causing the association, not necessarily the blood group or type of antibodies present.

 

Severe COVID-19

Lin X, Fu B, Yin S, et al. ORF8 contributes to cytokine storm during SARS-CoV-2 infection by activating IL-17 pathway. iScience March 09, 2021. https://www.cell.com/iscience/fulltext/S2589-0042(21)00261-3

SARS-CoV-2 coding protein open reading frame 8 (ORF8) acts as a contributing factor to the cytokine storm during COVID-19 infection. ORF8 activated the IL-17 signaling pathway and promoted the expression of pro-inflammatory factors. Treatment of IL17RA antibody protects mice from ORF8-induced inflammation.

 

Collateral damage (and benefits)

Li L, Neuroth LM, Valachovic E, et al. Association Between Changes in Social Distancing Policies in Ohio and Traffic Volume and Injuries, January Through July 2020. JAMA March 9, 2021;325(10):1003-100. https://jamanetwork.com/journals/jama/fullarticle/2777228

Better stay home, it’s better for everybody. Compared to 2019, the period between the stay-at-home order and retail reopening (March 23 through May 11, 2020) in Ohio saw 55% fewer motor vehicle crash involvements, 47% fewer injuries, 34% fewer severe/fatal injuries, and 44% lower traffic volume.

 

Treatment

Bertoglio F, Meier D, Langreder N, et al. SARS-CoV-2 neutralizing human recombinant antibodies selected from pre-pandemic healthy donors binding at RBD-ACE2 interface. Nat Commun March 11, 2021, 12, 1577. https://www.nature.com/articles/s41467-021-21609-2

Successful isolation and characterization of a fully human, recombinant anti-spike neutralizing monoclonal antibody from a universal, human naïve antibody gene library that was constructed before the emergence of SARS-CoV-2. This work shows how neutralizing antibodies can be efficiently selected rapidly without the need of convalescent patient material.

 

14 March

Immunology

Paper of the Day

Amanat F, Thapa M, Lei T, et al. The plasmablast response to SARS-CoV-2 mRNA vaccination is dominated by non-neutralizing antibodies that target both the NTD and the RBD. medRxiv 2021, posted 9 March. Full-text: https://doi.org/10.1101/2021.03.07.21253098

Florian Krammer, Fatima Amanat and colleagues studied the plasmablast response to SARS-CoV-2 mRNA-based vaccination. The authors demonstrate that the antibody responses to SARS-CoV-2 mRNA vaccination comprise a large proportion of non-neutralizing antibodies and are co-dominated by NTD and RBD antibodies. The NTD portion of the spike represents, therefore, an important vaccine target. Since all viral variants of concern are heavily mutated in this region, these observations warrant further attention to optimize SARS-CoV-2 vaccines. Finally, broadly cross-reactive mAbs to β-coronavirus spike proteins are induced after vaccination and suggest a potential development path for a pan-β-coronavirus vaccine.

 

Ellebedy A, Turner J, O’halloran J, et al. SARS-CoV-2 mRNA vaccines induce a robust germinal centre reaction in humans. Research Square 2021, posted 9 March. Full-text: https://doi.org/10.21203/rs.3.rs-310773/v1

Did you feel that your arm is on “fire” after getting your SARS-CoV-2 mRNA vaccine? Did you get some fine needle aspirates of your draining axillary lymph nodes? You could have investigated the dynamics of antibody secreting plasmablasts (PBs) and germinal center (GC) B cells induced by these vaccines in SARS-CoV-2 naïve and antigen-experienced humans. Ellebedy et al did just that. They demonstrated that SARS-CoV-2 mRNA-based vaccination of humans induces a robust and persistent GC B cell response that engages pre-existing as well as new B cell clones. High-affinity, broad, and durable humoral immunity on the horizon?

 

Muecksch F, Weisblum Y, Barnes CO, et al. Development of potency, breadth and resilience to viral escape mutations in SARS-CoV-2 neutralizing antibodies. bioRxiv 2021, posted 8 March. Full-text: https://doi.org/10.1101/2021.03.07.434227

Might affinity maturation generate antibodies that are resilient to viral evolution? Paul Bieniasz, Frauke Muecksch and colleagues think so. After analyzing six independent antibody lineages, they found that for certain ones, maturation enabled neutralization of circulating SARS-CoV-2 variants of concern and heterologous sarbecoviruses. The authors conclude that increasing antibody diversity through prolonged or repeated antigen exposure may improve protection against diversifying SARS-CoV-2 populations, and perhaps against other pandemic threat coronaviruses.

 

Epidemiology

CMMID 202103. European COVID-19 Forecast hub. London School of Hygiene & Tropical Medicine and ECDC 2021. Website: https://covid19forecasthub.eu

The European COVID-19 Forecast hub aims to collate and meaningfully combine short-term forecasts of COVID-19 from across Europe in order to 1) improve situational awareness and 2) quantify the current trajectory of COVID-19 everywhere whilst acknowledging uncertainty.

Graphic

 

Mallapaty S. The search for animals harbouring coronavirus — and why it matters. Nature 2021, published 2 March. Full-text: https://www.nature.com/articles/d41586-021-00531-z

Monitoring pets, livestock and wildlife to see where SARS-CoV-2 could hide, and whether it might resurge.

Graphic

 

Transmission

Hensley MK, Bain WG, Jacobs J, et al. Intractable Coronavirus Disease 2019 (COVID-19) and Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Replication in a Chimeric Antigen Receptor-Modified T-Cell Therapy Recipient: A Case Study. Clin Infect Dis 2021. Full-text: https://doi.org/10.1093/cid/ciab072

Prolonged transmission from immunosuppressed patients is possible. A chimeric antigen receptor-modified T cell therapy recipient developed severe coronavirus disease 2019, intractable RNAemia, and viral replication lasting > 2 months. Deep sequencing revealed multiple sequence variants consistent with intra-host viral evolution.

 

Virology

Braun KM, Moreno GK, Halfmann PJ, et al. Transmission of SARS-CoV-2 in domestic cats imposes a narrow bottleneck. PLOS Pathogens 2021, published 26 February. Full-text: https://doi.org/10.1371/journal.ppat.1009373

How is genetic variation generated and selected within and between individual hosts? Using domestic cats as a model, Thomas Friedrich, Katarina Braun and colleagues show that within-host SARS-CoV-2 genetic variation is predominantly influenced by genetic drift and purifying selection. In particular, they identified a notable variant at amino acid position 655 in spike (H655Y), which was previously shown to confer escape from human monoclonal antibodies. This variant arises rapidly and persists at intermediate frequencies in index cats.

 

Variants

Grint DJ, Wing K, Williamson E, et al. Case fatality risk of the SARS-CoV-2 variant of concern B.1.1.7 in England. MedRxiv 2021, posted 8 March. Full-text: https://doi.org/10.1101/2021.03.04.21252528

The authors draw data from a research platform that covers 40% of England’s population registered with a general practitioner. B.1.1.7 status was known for 184,786 people. The B.1.1.7 group was younger with a lower proportion of older cases (80+: 0.9% VOC vs. 1.6% non-B.1.1.7 cases), with fewer co-morbidities (2+ co-morbidities: 2.9% vs. 3.8%). After controlling for co-morbidities, age, week, region & other sociodemographics, the authors found an increased risk of death for B.1.1.7 compared with non-B.1.1.7 cases (HR: 1.67; 95% CI: 1.34 – 2.09; P < 0.0001).

 

Tablizo FA, Kim KM, Lapid CM, et al. Genome sequencing and analysis of an emergent SARS-CoV-2 variant characterized by multiple spike protein mutations detected from the Central Visayas Region of the Philippines. medRxiv 2021, posted 6 March. Full-text: https://doi.org/10.1101/2021.03.03.21252812

The authors describe the emergence of a new SARS-CoV-2 lineage, mainly from the Central Visayas region of the Philippines: 13 lineage-defining mutations, including the co-occurrence of the E484K, N501Y, and P681H mutations at the spike protein region, as well as three additional radical amino acid replacements towards the C-terminal end of the said protein. A three amino acid deletion at positions 141 to 143 (LGV141_143del) in the spike protein is reminiscent of a region preceding the 144Y deletion found in the B.1.1.7 variant. See also the ‘P.3’ proposition by Andrew Rambaut: https://github.com/cov-lineages/pango-designation/issues/27.

 

Vaccines

Shah A, Gribben C, Bishop J, et al. Effect of vaccination on transmission of COVID-19: an observational study in healthcare workers and their households. GitHub preprint, posted 12 March. Full-text: https://github.com/ChronicDiseaseEpi/hcw/blob/master/vaccine_manuscript.pdf

Household members of vaccinated healthcare workers have a lower risk for being infected with SARS-CoV-2 (rate per 100 person-years 9∙40 versus 5∙93; HR 0∙70, 95% CI: 0∙63 to 0∙78). This is the result of a Scottish cohort comprised of 194,362 household members (mean age 31∙1 ± 20∙9 years) and 144,525 healthcare workers (mean age 44∙4 ± 11∙4 years). As household members of healthcare workers can also be infected by other people, this 30% risk reduction is probably an underestimate of the effect vaccination will have on transmission of SARS-CoV-2.

 

Fischer R, van Doremalen N, Adney D, et al. ChAdOx1 nCoV-19 (AZD1222) protects against SARS-CoV-2 B.1.351 and B.1.1.7. bioRxiv 2021, posted 11 March. Full-text: https://doi.org/10.1101/2021.03.11.435000

Thinking of maybe not getting the vaccine because of the new variants? Think again! Here, Robert Fischer, Neeltje van Doremalen and colleagues show a lack of disease in Syrian hamsters vaccinated with the AstraZeneca vaccine when infected with B.1.1.7 or B.1.351 (first detected in the UK and South Africa, respectively). The authors observed a 9.5-fold reduction of virus-neutralizing antibody titer in vaccinated hamster sera against B.1.351 compared to B.1.1.7. Vaccinated hamsters challenged with B.1.1.7 or B.1.351 did not lose weight compared to control animals. Interesting data from a pre-print paper that need to be confirmed in clinical vaccine practice.

 

Public Health England 20210222. PHE monitoring of the early impact and effectiveness of COVID-19 vaccination in England. UK Government 2021, 22 February; accessed 5 March 2021. Full-text: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/963532/COVID-19_vaccine_effectiveness_surveillance_report_February_2021_FINAL.pdf

Public Health England reports on 11,860 confirmed cases of COVID in those aged over 80 years. The Pfizer-BioNTech vaccine effectiveness was 57% (95% CI: 48-63%) from 28 days after the first dose of vaccination. In 8119 individuals aged over 80 years with a confirmed PCR positive test and followed for at least 21 days, the case fatality ratio was lower in cases vaccinated at least 14 days before onset than in unvaccinated cases. This would indicate that within vaccinated individuals who do become symptomatic the vaccine confers additional protection against death.

 

Ghebreyesus TA. A ‘me first’ approach to vaccination won’t defeat Covid. The Guardian 2021, published 5 March. Full-text: https://www.theguardian.com/commentisfree/2021/mar/05/vaccination-covid-vaccines-rich-nations

Of the 225m vaccines administered so far, most have been in a handful of rich nations. This has to change, for all our sakes, says Tedros Adhanom Ghebreyesus, director general of WHO. The normal rules of business that protect the profits of vaccine manufacturers will have to be set aside if that is what it takes to ensure everybody is immunized against SARS-CoV-2. See also Boseley S. A ‘me first’ approach to vaccination won’t defeat Covid. The Guardian 2021, published 5 March. Full-text: https://www.theguardian.com/world/2021/mar/05/covid-vaccines-who-chief-backs-patent-waiver-to-boost-production

 

Boseley S, Brooks L. UK will diverge from EU and US on approving tweaked Covid vaccines. The Guardian 2021, published 4 March. Full-text: https://www.theguardian.com/society/2021/mar/04/vaccines-tweaked-for-covid-variants-will-be-fast-tracked-safely-says-uk-regulator

The UK will adopt a different standard from Europe and the US when it considers approval for coronavirus vaccines that have been tweaked to deal with variants, the UK regulator has said.

 

Clinical

Wohlfahrt J, Fonager J, Albertsen M, et al. Increased Risk of Hospitalisation Associated with Infection with SARS-CoV-2 Lineage B.1.1.7 in Denmark. Lancet Preprints 2021, posted 2 March. Full-text: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3792894

Infection with B.1.1.7 was associated with an increased risk of hospitalization compared with other lineages (adjusted odds ratio: 1.64).

 

13 March

Variants

Paper of the Day

Collier DA, De Marco A, Ferreira IA, et al. Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies. Nature March 11, 2021. https://www.nature.com/articles/s41586-021-03412-7

A pseudovirus bearing S protein with the full set of mutations present in the B.1.1.7 variant did result in a small reduction in neutralization by sera from vaccinees that was more marked following the first dose vs the second dose. Worryingly, Dami A. Collier and colleagues measured further reduction in neutralization titers by vaccine sera when E484K was present alongside the B.1.1.7 S mutations. They conclude that “E484K emergence on a B.1.1.7 background represents a threat to the vaccine BNT162b”.

 

Borges V, Sousa C, Menezes L, et al. Tracking SARS-CoV-2 lineage B.1.1.7 dissemination: insights from nationwide spike gene target failure (SGTF) and spike gene late detection (SGTL) data, Portugal, week 49 2020 to week 3 2021. Eurosurveillance Mar 11, 2021, Article Volume 26, Issue 10. https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2021.26.10.2100130

Dissemination of the B.1.1.7 lineage in Portugal. Both SGTF and SGTL (a proxy for monitoring trends of B.1.1.7) samples had significantly lower median Ct values of N and ORF1ab gene targets (ca 3.5 and 1.8 Ct units, respectively) compared with samples where the S gene was unbiasedly detected.

 

Epidemiology

Sartorius B, Lawson AB, Pullan RL. Modelling and predicting the spatio-temporal spread of COVID-19, associated deaths and impact of key risk factors in England. Sci Rep 11, March 8, 2021, 5378. https://doi.org/10.1038/s41598-021-83780-2

This high resolution spatial–temporal model highlights differences in epidemic dynamics across small areas in England, emphasizing the importance of monitoring at a granular sub-national scale. A geographically staggered approach combined with enhanced community surveillance will be increasingly important.

 

Boffetta P, Violante F, Durando P, et al. Determinants of SARS-CoV-2 infection in Italian healthcare workers: a multicenter study. Sci Rep March 11, 2021, 5788. https://www.nature.com/articles/s41598-021-85215-4.pdf

The prevalence of infection ranged from 3% to 22%, and was correlated with that of the respective areas within Italy. Of note, there was a lack of a clear pattern in risk according to job categories.

 

Vaccine

Krammer F, Srivastava K, Alshammary H, et al. Antibody Responses in Seropositive Persons after a Single Dose of SARS-CoV-2 mRNA Vaccine. March 10, 2021. https://www.nejm.org/doi/full/10.1056/NEJMc2101667

In 110 vaccinees, the antibody titers of those with pre-existing infection were 10 to 45 times higher than those of vaccinees without pre-existing immunity at the same time points after the first mRNA vaccine dose. The problem with all these studies: until we know whether this translates into similar protection, the one-shot strategy will not gain widespread acceptance. When we do know one day, this will largely not matter (there will be enough vaccine available) and will only be interesting for cost reasons.

 

Steinberg J, Thomas A, Iravavi A. 18Fluorodeoxyglucose PET/CT findings in a systemic inflammatory response syndrome after COVID-19 vaccine. Lancet March 08, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00464-5/fulltext

Julie Steinberg and colleagues from St. Louis describe an interesting case of a (self-resolving) systemic inflammatory response syndrome in a 65-year-old woman, starting one day after Moderna’s mRNA vaccine. PET/CT showed uptake in the fat stranding posterior to the right deltoid, moderately increased uptake within multiple right axillary lymph nodes and diffusely increased splenic uptake.

 

Fernández-Prada M, Rivero-Calle I, Calvache-González A, Martinón-Torres F. Acute onset supraclavicular lymphadenopathy coinciding with intramuscular mRNA vaccination against COVID-19 may be related to vaccine injection technique, Spain, January and February 2021. Euro Surveill. 2021;26(10):pii=2100193. https://doi.org/10.2807/1560-7917.ES.2021.26.10.2100193

María Fernández-Prada and colleagues report on 20 female HCWs with acute onset of a single supraclavicular lymphadenopathy coinciding with the ipsilateral intramuscular administration of an mRNA vaccine. Of note, 17 reported that the injection point had been unusually high. All lymphadenopathies had inflammatory symptoms (pain, swelling), were rounded and mobile, and all but one appeared in the first 24 h to 9 days after vaccine administration. All improved clinically, and 15 completely resolved between 5 and 16 days from onset.

 

Transmission

Klompas M, Baker MA, Griesbach D, et al. Transmission of SARS-CoV-2 from asymptomatic and presymptomatic individuals in healthcare settings despite medical masks and eye protection. Clinical Infectious Diseases, 11 March 2021. ciab218, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab218/6168040?searchresult=1

Three instances of SARS-CoV-2 transmission in Boston, despite medical masks and eye protection, including one transmission despite both parties being masked. Whole genome sequencing confirmed perfect homology between source and exposed persons’ viruses in all cases. These findings teach the importance of not relying upon medical masks and eye protection alone.

 

Pan X, Li X, Kong P, et al. Assessment of Use and Fit of Face Masks Among Individuals in Public During the COVID-19 Pandemic in China. JAMA Netw Open March 11, 2021, 4(3):e212574. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2777405?resultClick=1

“Wear a mask.” If it were only that simple, even in China! For this study, during July and August 2020, 6003 (!) people wearing masks were assessed at public places, such as markets, train stations, airports, hospitals, and schools in Beijing, Yunnan, Shanxi, and Jiangsu. Face mask airtightness was commonly suboptimal, mostly secondary to gaps at the upper face mask edge. Sealing the upper face mask edge with an adhesive tape was associated with significantly improving the airtightness of commonly used face masks.

 

Long COVID-19

Sudre CH, Murray B, Varsavsky T, et al. Attributes and predictors of long COVID. Nat Med March 10, 2021. https://www.nature.com/articles/s41591-021-01292-y

Is it possible to predict long COVID-19? Among 4182 people who self-reported their symptoms prospectively in the COVID Symptom Study app, a total of 558 (13.3%) reported symptoms lasting ≥ 28 days, 189 (4.5%) for ≥ 8 weeks and 95 (2.3%) for ≥ 12 weeks. Experiencing more than five symptoms during the first week of illness was associated with long COVID in all sexes and age groups (odds ratio = 3.5). Main caveat: the population was limited by being confined to app contributors (disproportionately female patients). May not be generalizable.

 

12 March

Vaccine

Paper of the Day

Stephenson KE, Le Gars M, Sadoff J, et al. Immunogenicity of the Ad26.COV2.S Vaccine for COVID-19. JAMA March 11, 2021. https://jamanetwork.com/journals/jama/fullarticle/2777598

The COVID-19 vaccine from Janssen (Johnson & Johnson) is the fourth vaccine recommended in the EU for preventing COVID-19. Ad26.COV2.S is a recombinant, replication-incompetent Ad26 vector encoding the full length and stabilized SARS-CoV-2 S protein derived from the first Wuhan strain. This phase I study (in 25 recipients from Boston) shows that a single immunization induced rapid binding and neutralization antibody responses as well as cellular immune responses, including induction of RBD-specific binding antibodies in 90% of vaccine recipients by day 8.

 

Vijayasingham L, Bischof E, Wolfe J. Sex-disaggregated data in COVID-19 vaccine trials. Lancet March 05, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00384-6/fulltext

Lavanya Vijayasingham and colleagues argue that sex factors, including sex-disaggregated analysis and reporting, are still neglected in COVID-19 trial data reporting.

 

Epidemiology

Richard Q, Alizon S, Choisy M, et al. Age-structured non-pharmaceutical interventions for optimal control of COVID-19 epidemic. PLOS Computational Biology March 4, 2021. https://doi.org/10.1371/journal.pcbi.1008776

Complex models, trying to elucidate that countries with contrasted population age-structures and social or physical contacts may need different NPIs.

 

Bokharaie VS. A study on the effects of containment policies and vaccination on the spread of SARS-CoV-2. PLOS March 4, 2021. https://doi.org/10.1371/journal.pone.0247439

Same direction. A method to predict the spread of the SARS-CoV-2 in a population with a known age-structure, and then, to quantify the effects of various containment policies, including those policies that affect each age-group differently.

 

Mulenga LB, Hines JZ, Fwoloshi S, et al. Prevalence of SARS-CoV-2 in six districts in Zambia in July, 2020: a cross-sectional cluster sample survey. Lancet Global Health March 09, 2021. https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(21)00053-X/fulltext

Almost 1 in 100 diagnosed: According to this first large cross-sectional cluster-sample survey of households in Africa (performed in July), the number of laboratory-confirmed cases reported in official statistics in Zambia underestimated SARS-CoV-2 infections by a factor of 92.

 

Virology

Lythgoe KA, Hall M, Ferretti L, et al. SARS-CoV-2 within-host diversity and transmission. Science 09 Mar 2021: eabg0821 Full-text: https://doi.org/10.1126/science.abg0821

Katrina A. Lythgoe and colleagues deep-sequenced 1313 clinical samples from the UK. Interestingly, most samples harbored few intrahost variants, and estimated transmission bottleneck sizes were very small, with maximum likelihood estimates between 1 and 8 among household transmission pairs, meaning that if mutations do arise they will be prone to loss at the point of transmission. The results suggest that transmission-enhancing and/or immune-escape variants are likely to arise infrequently, but could spread rapidly if successfully transmitted.

 

Clinical

Poletti P, Tirani M, Cereda D, et al. Association of Age With Likelihood of Developing Symptoms and Critical Disease Among Close Contacts Exposed to Patients With Confirmed SARS-CoV-2 Infection in Italy. JAMA Netw Open March 10, 2021;4(3):e211085. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2777314

Of 5484 quarantined case contacts who were monitored daily for symptoms for at least 2 weeks, 2824 (51.5%) tested positive. The proportion of infected persons who developed symptoms ranged from 18.1% (95% CI, 13.9%-22.9%) among participants younger than 20 years to 64.6% (95% CI, 56.6%-72.0%) for those aged 80 years or older.

 

Long COVID

Weng J, Li Y, Li J, et al. Gastrointestinal sequelae 90 days after discharge for COVID-19. Lancet Gastroenterology Hepatology March 9, 2021. https://www.thelancet.com/journals/langas/article/PIIS2468-1253(21)00076-5/fulltext

In this retrospective study from Hubei and Guangdong provinces, 52 (44%) of 117 patients reported gastrointestinal symptoms after discharge at a 90 day telephone interview: loss of appetite (24%), nausea (18%), acid reflux (18%), and diarrhoea (15%). Of note, severe illness during hospitalisation was not associated with post-discharge gastrointestinal sequelae.

 

Collateral damage (and benefits)

Maselli-Schoueri JH, Werneck de Carvalho LE, Affonso Fonseca FL, et al. Hospital Admissions Associated With Noncommunicable Diseases During the COVID-19 Outbreak in Brazil. JAMA Netw Open March 8, 2021; 4(3):e210799. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2777139 Reduction in hospital admissions for NCDs from January to June 2020 compared with the corresponding period in each of the 3 previous years in São Paulo, Brazil. Decrease was 68% for musculoskeletal diseases, 44% for metabolic diseases, 38% for CVDs, and 35% for neoplasms.

 

Treatment

Ozaki K, Reinhard CT. The future lifespan of Earth’s oxygenated atmosphere. Nat. Geosci. 14, 138–142 (2021). https://doi.org/10.1038/s41561-021-00693-5

We’d prefer to present other papers in this section. However, there is some good news: we’ll get some more weeks to find a potent treatment for SARS-CoV-2. Using a combined biogeochemistry and climate model to examine the likely timescale of oxygen-rich atmospheric conditions on Earth, these authors estimate that the mean future lifespan of Earth’s atmosphere, with oxygen levels more than 1% of the present atmospheric level, is 1.08 ± 0.14 billion years.

 

11 March

Variants

Paper of the Day

Tegally H, Wilkinson E, Giovanetti M. et al. Emergence of a SARS-CoV-2 variant of concern with mutations in spike glycoprotein. Nature March 9, 2021. https://www.nature.com/articles/s41586-021-03402-9_reference.pdf

The future “reference” paper on the detection of B.1.351 (or 501Y.V2), characterized by eight lineage-defining mutations in the spike protein, including three at important residues in the receptor-binding domain (K417N, E484K and N501Y). This lineage was identified in South Africa after the first epidemic wave in a severely affected metropolitan area, and spread rapidly. The genomic data, showing the rapid expansion and displacement of other lineages in multiple regions, suggest that this lineage is associated with a selection advantage, most plausibly as a result of increased transmissibility or immune escape. Nevertheless, congrats to co-author Wolfgang Preiser!

 

Epidemiology

Agrawal S, Orschler L, Lackner S. Long-term monitoring of SARS-CoV-2 RNA in wastewater of the Frankfurt metropolitan area in Southern Germany. Sci Rep 11, 5372 (2021). https://www.nature.com/articles/s41598-021-84914-2

After monitoring the time course of the SARS-CoV-2 RNA concentration in raw sewage in the Frankfurt metropolitan area for several months, Shelesh Agrawal and colleagues believe that wastewater-based epidemiology has the potential to serve as an early warning system for SARS-CoV-2 infections and as a monitoring system to identify global hotspots.

 

Brault V, Mallein B, Rupprecht JF, et al. Group testing as a strategy for COVID-19 epidemiological monitoring and community surveillance. PLOS Computational Biology, March 4, 2021. https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1008726

Group testing could provide the means for regular and massive screenings. In this paper, the authors do not address any diagnostic problems—e.g. how to use a minimal number of tests to obtain an individual diagnostic—but rather focus on population-scale application of pooling.

 

Immunology

Grzelak L, Velay A, Madec Y, et al. Sex differences in the evolution of neutralizing antibodies to SARS-CoV-2. Journal of Infectious Diseases 07 March 2021, jiab127, https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab127/6161322?searchresult=1

More robust humoral responses in women than in men? In 308 healthcare workers with mild disease, anti-S and anti-N antibodies were detected in 99% and 59% of individuals at 3-6 months, respectively. Anti-S antibodies and NAbs declined faster in males than in females, independently of age and BMI, suggesting an association of sex with evolution of the humoral response.

 

Vaccine

Saad-Roy CM, Morris SE, Metcalf JE, et al. Epidemiological and evolutionary considerations of SARS-CoV-2 vaccine dosing regimes. Science 09 Mar 2021: eabg8663. https://science.sciencemag.org/content/early/2021/03/08/science.abg8663

Delaying the second dose? Maybe easier said than done. Chadi Saad-Roy and colleagues urge caution. According to their models, a vaccine strategy with a very long inter-dose period could lead to marginal short-term benefits at the cost of a higher infection burden in the long term and substantially more potential for viral evolution and the development of new variants. However, current uncertainties surrounding the strength and duration of adaptive immunity in response to natural infection or vaccination lead to very broad range of possible outcomes of various dosing regimens.

 

Capetti AF, Stangalini CA, Borgonovo F, et al. Impressive boosting of anti-S1/S2 IgG production in COVID-19-experienced patients after the first shot of the BNT162b2 mRNA COVID-19 Vaccine. Clinical Infectious Diseases 06 March 2021, ciab214, https://doi.org/10.1093/cid/ciab214

But is one shot enough after infection? The next study, comparing COVID-19 naïve people versus asymptomatic/pauci-symptomatic (A/P) people versus symptomatic/hospitalized (S/H) COVID-19 patients. Titers (logarithmic scale!) before and after the first dose of the BNT162b2 vaccine.

 

Virology

Baggen J, Persoons L, Vanstreels E, et al. Genome-wide CRISPR screening identifies TMEM106B as a proviral host factor for SARS-CoV-2. Nat Genet March 8, 2021. https://www.nature.com/articles/s41588-021-00805-2.pdf

Jim Baggen and colleagues from Belgium have identified two new host factors required for coronavirus infection. The lysosomal protein TMEM106B serves as an essential specific host factor for SARS-CoV-2 infection in multiple human cell lines. The phosphoinositide 3-kinase (PI3K) type 3 appears to be a common host factor for SARS-CoV-2 that could be targeted by small molecules.

 

Diagnostics

Shrotri M, Harris RJ, Rodger A, Planche T, Sanderson F, Mahungu T, et al. Persistence of SARS-CoV-2 N-antibody response in healthcare workers, London, UK. Emerg Infect Dis. 2021 Apr [date cited]. https://wwwnc.cdc.gov/eid/article/27/4/20-4554_article

Nucleocapsid (N) antibodies appear more stable than Spike (S) antibodies in the short term. N antibody titers were stable and sustained for < 12 weeks in 312 seropositive participants. This was consistent across demographic and clinical variables and contrasts with reports of short-term antibody waning.

 

Van Elslande J, Gruwier L, Godderis P. Estimated half-life of SARS-CoV-2 anti-spike antibodies more than double the half-life of anti-nucleocapsid antibodies in healthcare workers. Clinical Infectious Diseases 08 March 2021, ciab219, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab219/6162856?searchresult=1

Oops, the opposite? See title. We would like to attend a Zoom meeting between Madhumita Shrotri and Jan Van Elslande. Different time periods, methods, participants? The debate goes on.

 

Noh JY, Kwak JE, Yang JS, et al. Longitudinal assessment of anti-SARS-CoV-2 immune responses for six months based on the clinical severity of COVID-19. Journal of Infectious Diseases 04 March 2021, jiab124, https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab124/6158870?searchresult=1

Ji Yun Noh and colleagues from Seoul have investigated the longitudinal profile of anti-SARS-CoV-2 antibodies in patients who recovered from COVID-19. Neutralizing antibodies were detected in 86.9% until six months after diagnosis of SARS-CoV-2 infection. Patients with pneumonia had significantly higher titers (and stronger T cell immunity) than patients without.

 

10 March

Variants

Paper of the Day

Wang P, Nair MS, Liu L, et al. Antibody Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7. Nature March 8, 2021. https://www.nature.com/articles/s41586-021-03398-2

For younger readers: once upon a time, in the stone age (c. 1996), David Ho from the Aaron Diamond Center was deemed “man of the year” (Time Magazine), after explaining the dynamics of HIV replication to the world. Today he explains why B.1.351 is so worrisome. While B.1.1.7 is refractory to neutralization by many mAbs but not more resistant to convalescent plasma (CP) or vaccinee sera (VS), B.1.351 is not only refractory to neutralization by almost all mAbs but also by CP (9.4 fold) and VS (10.3-12.4 fold). SARS-CoV-2 “is traveling in a direction that could ultimately lead to escape from our current therapeutic and prophylactic interventions directed to the viral spike”.

 

Epidemiology

Chen X, Chen Z, Azman AS, et al. Serological evidence of human infection with SARS-CoV-2: a systematic review and meta-analysis. Lancet March 08, 2021. https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(21)00026-7/fulltext

After reviewing 404 (!) studies, the authors conclude that antibody-mediated herd immunity is far from being reached in most settings. Of note, the pooled infection-to-case ratio was similar between the region of the Americas (6.9, 95% CI: 2.7–17.3) and the European region (8.4, 95% CI: 6.5–10.7), but higher in India (56.5, 95% CI: 28.5–112.0), the only country in the South-East Asia region with data.

 

Leung K, Wu JT, Leung GM. Real-time tracking and prediction of COVID-19 infection using digital proxies of population mobility and mixing. Nat Commun 12, 1501 (2021). https://www.nature.com/articles/s41467-021-21776-2

Big Brother is watching you. However, sometimes he can be helpful. Using digital transactions made on Octopus cards (which are ubiquitously used by the Hong Kong population), the authors describe a framework that integrates digital proxies of human mobility and physical mixing into conventional epidemic models. At the end of the day, real-time estimates of Rt (accurate nowcast and short-term forecast of the epidemic) was obtained in Hong Kong.

 

Vaccine

Ella R, Reddy S, Jogdand H, et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: interim results from a double-blind, randomised, multicentre, phase 2 trial, and 3-month follow-up of a double-blind, randomised phase 1 trial. Lancet March 08, 2021. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00070-0/fulltext

Inactivated vaccines have the advantage of being easily stored and shipped. BBV152 (COVAXIN) is a whole-virion inactivated SARS-CoV-2 vaccine adjuvanted with Algel-IMDG. An imidazoquinoline molecule (IMDG), a TLR7/8 agonist, is added to augment cell-mediated responses. According to the Phase I/II data from India presented here, BBV152 has shown the potential to provide durable humoral and cell-mediated immune responses (even against variants of concern). The Algel-IMDG formulation was selected for the ongoing Phase III efficacy trial, which involves 25,800 volunteers. BBV152 has received emergency use authorisation in India.

 

Rapaka RR, Hammershaimb EA, Neuzil KM. Are some COVID vaccines better than others? Interpreting and comparing estimates of efficacy in trials of COVID-19 vaccines. Clinical Infectious Diseases 06 March 2021, ciab213, https://doi.org/10.1093/cid/ciab213

Do you have colleagues who still “prefer” the BioNTech vaccine? Give him this viewpoint to read. Rekha Rapaka and colleagues from Maryland discuss the caveats of cross-trial comparisons. And why it matters how point estimates of efficacy were determined, in what epidemiologic setting, and against what endpoints.

 

Blumenthal KG, Robinson LB, Camargo Jr CA, et al. Acute Allergic Reactions to mRNA COVID-19 Vaccines. JAMA March 8, 2021; https://jamanetwork.com/journals/jama/fullarticle/2777417?resultClick=1

Of 64,900 vaccine recipients in Massachusetts, anaphylaxis was confirmed in 16 (0.025%). Of note, 15/16 were female, 10 had a prior history of allergies and 5 had a history of anaphylaxis. Mean time to anaphylaxis onset was 17 minutes (range, 1-120). All recovered.

 

Transmission

Paul LA, Daneman N, Brown KA, et al. Characteristics associated with household transmission of SARS-CoV-2 in Ontario, Canada: A cohort study. Clinical Infectious Diseases 05 March 2021, ciab186, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab186/6159706

Among 26,714 cases of COVID-19 residing in 21,226 households, longer testing delays (≥ 5 days versus 0 days, OR = 3.02) and male gender (OR = 1.28) were associated with greater odds of household secondary transmission, as well as (not surprisingly) larger average family size and a higher proportion of households with multiple persons per room.

 

Clinical

Kompaniyets L, Goodman AB, Belay B, et al. Body Mass Index and Risk for COVID-19–Related Hospitalization, Intensive Care Unit Admission, Invasive Mechanical Ventilation, and Death — United States, March–December 2020. MMWR Morb Mortal Wkly Rep. ePub: 8 March 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7010e4.htm

Among 148,494 US adults with COVID-19, a non-linear “dose response” relationship was found between body mass index and COVID-19 severity, with lowest risks at BMIs near the threshold between healthy weight and overweight in most instances, then increasing with higher BMI. Overweight and obesity were risk factors for invasive mechanical ventilation. Obesity was a risk factor for hospitalization and death, particularly among adults aged < 65 years.

Graphic

 

Lugon JC, Smit M, Salamun J, et al. Novel outpatient management of mild to moderate COVID-19 spares hospital capacity and safeguards patient outcome: The Geneva PneumoCoV-Ambu study. PLOS One, March 4, 2021. https://doi.org/10.1371/journal.pone.0247774

Calling patients every 48 hours for the first 10 days following diagnosis, with a standardized interview about self-reported symptoms or every 24 hours if patients presented a worsening clinical condition: this small study in relatively young patients shows that such an outpatient management of mild to moderate COVID-19-related pneumonia is possible. Costly and unnecessary hospitalizations were avoided and hospital capacity was spared.

Treatment

Loffredo M, Lucero H, Chen DY, et al. The in-vitro effect of famotidine on sars-cov-2 proteases and virus replication. Sci Rep March 8, 2021, 11, 5433. https://www.nature.com/articles/s41598-021-84782-w

In silico studies have proposed one of the two SARS-CoV-2 proteases, 3CL^pro or PL^pro, as potential molecular targets of famotidine activity. Somewhat disappointing: Madeline Loffredo and colleagues show here that the drug neither binds with nor inhibits the functions of these proteases.

 

9 March

Immunology

Paper of the Day

Huang L, Shi Y, Gong B, et al. Dynamic blood single-cell immune responses in patients with COVID-19. Sig Transduct Target Ther March 6, 2021, 6, 110. https://doi.org/10.1038/s41392-021-00526-2

More details on pathogenesis, mainly the host immune process, imbalances and pathways. In this incredible work, Lulin Huang and colleagues obtained single-cell mRNA sequencing data of 341,420 (!) peripheral blood mononuclear cells and 185,430 clonotypic T cells and 28,802 clonotypic B cells from 25 samples of 16 patients with COVID-19 for dynamic studies.

 

Gao L, Zhou J, Yang S, et al. The dichotomous and incomplete adaptive immunity in COVID-19 patients with different disease severity. Sig Transduct Target Ther 6, 113 (2021). https://doi.org/10.1038/s41392-021-00525-3

Specific B-cell and T-cell responses in 74 symptomatic patients with various disease severity: B cell responses were only transiently induced in early infection phase in asymptomatic or mild patients. In keeping with this, sustained GC responses that give rise to long-term memory B cells and IgG-secreting plasma cells were almost absent in these patients. This may explain that asymptomatic patients often fail to generate long-term SARS-CoV-2-specific IgG response. in contrast to humoral immunity, the virus-specific TH1 and CD8+ T cell immune responses were rapidly induced and sustained in asymptomatic or mild symptomatic patients as compared to patients with moderate or severe disease.

 

Casado JL, Häemmerle J, Vizcarra P, et al. SARS CoV-2 infections in health care workers with pre-existing T cell response: a prospective cohort study. March 02, 2021. https://doi.org/10.1016/j.cmi.2021.02.020

José L. Casado and colleagues from Madrid looked at pre-existing T-cell responses. Twenty of 38 HCWs included (53%) had a previous specific CD8+ T cell response that does not seems to reduce incident SARS-CoV-2 infections, but may contribute to asymptomatic or mild disease, rapid viral clearance and differences in seroconversion.

 

Epidemiology

Guy GP Jr., Lee FC, Sunshine G, et al. Association of State-Issued Mask Mandates and Allowing On-Premises Restaurant Dining with County-Level COVID-19 Case and Death Growth Rates — United States, March 1–December 31, 2020. MMWR Morb Mortal Wkly Rep. ePub: 5 March 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7010e3.htm

Mask mandates were associated with statistically significant decreases in county-level daily COVID-19 case and death growth rates within 20 days of implementation. Allowing on-premises restaurant dining was associated with increases in county-level case and death growth rates within 41–80 days after reopening. It will be a while until we can finally go to the restaurant again (does anyone else know how to order a dish?)

 

Virology

Liu Y, Hu G, Wang Y, et al. Functional and genetic analysis of viral receptor ACE2 orthologs reveals a broad potential host range of SARS-CoV-2. PNAS March 23, 2021 118 (12) e2025373118; https://www.pnas.org/content/118/12/e2025373118

SARS-CoV-2 has the potential to infect a broad range of mammalian hosts, including domestic animals, pets, livestock, and animals commonly found in zoos and aquaria.

 

Variants

Alexandre G, Bosetti P, Feri A, et al. Early assessment of diffusion and possible expansion of SARS-CoV-2 Lineage 20I/501Y.V1 (B.1.1.7, variant of concern 202012/01) in France, January to March 2021. Euro Surveill. 2021;26(9):pii=2100133. https://doi.org/10.2807/1560-7917.ES.2021.26.9.2100133

Spread of B.1.1.7. in France, in January. The authors estimate the population-level effective reproduction number will be respectively 39% (95%: 33–45%) and 56% (95%: 50–62%) higher on 1 March and 1 April 2021 than what would be expected if only the classical lineages were circulating.

 

Vaccine

Nawwar AA, Searle J, Singh R, Lyburn ID. Oxford-AstraZeneca COVID-19 vaccination induced lymphadenopathy on [18F]Choline PET/CT-not only an FDG finding. Eur J Nucl Med Mol Imaging. 2021 Mar 4:1-2. PubMed: https://pubmed.gov/33661328. Full-text: https://doi.org/10.1007/s00259-021-05279-2

Lymphadenopathy is seen in some people after vaccination. In this case report of a cancer patient who underwent PET/CT 3 days after vaccination, nodal uptake was reactive in the axilla. Nice pictures.

 

Clinical

Wongvibulsin S, Garibaldi BT, Antar AAR, et al. Development of Severe COVID-19 Adaptive Risk Predictor (SCARP), a Calculator to Predict Severe Disease or Death in Hospitalized Patients With COVID-19. Ann Intern Med. 2021 Mar 2. PubMed: https://pubmed.gov/33646849. Full-text: https://doi.org/10.7326/M20-6754

Using longitudinal data from more than 3000 patients hospitalized with COVID-19, the authors have developed a novel tool that can provide dynamic risk predictions for progression from moderate disease to severe illness or death in patients with COVID-19 at any time within the first 14 days of their hospitalization – on the basis of readily available clinical information. Check this out: https://rsconnect.biostat.jhsph.edu/covid_trajectory

 

Comorbidities

Ardestani A, Azizi Z. Targeting glucose metabolism for treatment of COVID-19. Sig Transduct Target Ther March 6, 2021, 6, 112. https://doi.org/10.1038/s41392-021-00532-4

Some thoughts on how dysregulated glucose metabolism in people with diabetes may explain the increased susceptibility to SARS-CoV-2 and why uncontrolled diabetes can lead to excessive adaptive immune reactions in patients with critical COVID-19 symptoms.

 

Long COVID

Subbaraman N. US health agency will invest $1 billion to investigate ‘long COVID’. Nature News 04 March 2021. https://www.nature.com/articles/d41586-021-00586-y

Nidhi Subbaraman reports that the US will spend big on research into ‘long COVID’ — the long-lasting health effects of a SARS-CoV-2 infection (see our recent review) for which experts have coined a new term: post-acute sequelae SARS-CoV-2 infection (PASC).

 

Treatment

Vimaleswaran KS, Frouhi NG, Khunti K. Vitamin D and covid-19. BMJ 04 March 2021; 372 doi: https://doi.org/10.1136/bmj.n544

Is there a role of vitamin D in prevention and management of COVID-19? The authors of this editorial believe that “existing evidence supports a compelling case for further research”.

 

French

If you read French, read Les hôpitaux et cliniques d’Ile-de-France vont déprogrammer 40 % de leurs activités. Le Monde 2021, published 8 March. Full-text : https://www.lemonde.fr/sante/article/2021/03/08/covid-19-les-hopitaux-et-cliniques-d-ile-de-france-vont-deprogrammer-40-de-leurs-activites_6072352_1651302.html

L’agence régionale de santé d’Ile-de-France a donné « l’ordre ferme » aux hôpitaux franciliens de déprogrammer 40 % de leurs activités, afin d’augmenter le nombre de lits de réanimation réservés aux personnes atteintes du Covid-19.

 

8 March

Variants

Firestone MJ, Lorentz AJ, Meyer S, et al. First Identified Cases of SARS-CoV-2 Variant P.1 in the United States — Minnesota, January 2021. MMWR Morb Mortal Wkly Rep. ePub: 3 March 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7010e1.htm

The arrival of P.1 in the US. Both guys had returned from southeastern Brazil. According to the authors, this “underscores the importance of community prevention strategies to slow transmission of SARS-CoV-2 including use of well-fitting masks, physical distancing, washing hands, quarantine, testing of persons who have had contact with a person with laboratory-confirmed COVID-19, isolating persons with symptoms of COVID-19 or with diagnosed COVID-19 and” (comment: last but not least) “adhering to CDC recommendations to delay travel”. Maybe it’s not the best idea to vacation in Brazil right now.

 

Ojelade M, Rodriguez A, Gonzalez D, et al. Travel from the United Kingdom to the United States by a Symptomatic Patient Infected with the SARS-CoV-2 B.1.1.7 Variant — Texas, January 2021. MMWR Morb Mortal Wkly Rep. ePub: 3 March 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7010e2.htm?s_cid=mm7010e2_w

Another jerk who traveled from UK to US after experiencing COVID-19–compatible symptoms, infected with the B.1.1.7 variant. “Persons should not travel if they are experiencing symptoms compatible with COVID-19 or if they have received a positive SARS-CoV-2 test result and have not met criteria to discontinue isolation, have had close contact with a person with suspected or confirmed COVID-19 and have not subsequently met criteria to end quarantine, or have a pending SARS-CoV-2 viral test result”. Fully agreed.

 

Fujino T, Nomoto H, Kutsuna S, Ujiie M, Suzuki T, Sato R, et al. Novel SARS-CoV-2 variant identified in travelers from Brazil to Japan. Emerg Infect Dis. 2021 Apr [date cited]. https://doi.org/10.3201/eid2704.210138

A family of four, traveling in early January to Tokyo, Japan, from Amazonas state in Brazil via Istanbul, Turkey (by the way, wouldn’t it have been shorter heading west?). Souvenir: A new lineage, resembling P.1, but with some interesting new mutations.

 

Maggi F, Novazzi F, Genoni A, Baj A, Spezia PG, Focosi D, et al. Imported SARS-CoV-2 variant P.1 detected in traveler returning from Brazil to Italy. Emerg Infect Dis. 2021 Apr [date cited]. https://doi.org/10.3201/eid2704.210183

A family of three, flying from São Paulo/Brazil to Madrid, Spain, and from there to Milan Malpensa Airport in Italy, in mid-January. In the luggage: P.1.

 

Diagnostics

Ott IM, Strine MS, Watkins AE, Boot M, Kalinich CC, Harden CA, et al. Stability of SARS-CoV-2 RNA in nonsupplemented saliva. Emerg Infect Dis. 2021 Apr [date cited]. https://wwwnc.cdc.gov/eid/article/27/4/20-4199_article

Use saliva and simple plastic tubes! For this important study, saliva from COVID-19 inpatients and at-risk healthcare workers was collected into sterile wide-mouth containers without preservatives (nonsupplemented) to evaluate the temporal stability of SARS-CoV-2 RNA at different holding temperatures. Of note, SARS-CoV-2 RNA from saliva was consistently detected at similar levels regardless of the holding time and temperatures tested.

 

Clinical

Nguyen NT, Chinn J, Nahmias J, et al. Outcomes and Mortality Among Adults Hospitalized With COVID-19 at US Medical Centers. JAMA Netw Open March 5, 2021;4(3):e210417. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2777028

The largest US cohort of hospitalized COVID-19 adults to date. Among 192,550 adults hospitalized with COVID-19, 55,593 (28.9%) were admitted to the ICU and 26,221 (13.6%) died during the index hospitalization. Not surprisingly, in-hospital mortality increased with increasing age; 179 of 12 644 patients (1.4%) aged 18 to 29 years died, and 8277 of 31135 patients (26.6%) 80 years or older died. Of the patients admitted to the ICU, 15 431 of 55 593 (27.8%) died. The median hospital length of stay among patients who were not admitted to the ICU was 6 days, with a median cost per admission of $10 520. The median hospital length of stay for those admitted to the ICU was 15 days, with a median cost per admission of $39 825. Of note, mortality declined over the course of the 6-month period, from 22.1 % in March to 6.5 % in August.

 

Karagiannidis C, Windisch W, McAuley DF, et al. Major differences in ICU admissions during the first and second COVID-19 wave in Germany. Lancet Resp Med March 05, 2021. https://doi.org/10.1016/S2213-2600(21)00101-6

According to Christian Karagiannidis and colleagues who have analysed the data from the federal German hospital payment institute, their data “clearly suggests a dramatic improvement in the management of patients with COVID-19”. Compared with in the first wave, 50% less of all hospitalised patients were admitted to the ICU during the second wave of the pandemic. By contrast, the prognosis of ICU patients, those requiring mechanical ventilation and those not, remained unimproved.

 

Comorbidities

Attauabi M, Seidelin J, Burisch J; Danish COVID-IBD Study Group. Association between 5-aminosalicylates in patients with IBD and risk of severe COVID-19: an artefactual result of research methodology? Gut. 2021 Mar 3:gutjnl-2021-324397. PubMed: https://pubmed.gov/33658323. Full-text: https://doi.org/10.1136/gutjnl-2021-324397

Discussion whether use mesalamine/sulfasalazine is associated with an increased risk of severe COVID-19 in people with inflammatory bowel disease (IBD). And how to adjust for any potential effect modifiers and confounders in order to determine the granular effect of IBD-related medications. No definitive answer yet.

Ungaro RC, Brenner EJ, Gearry RB, et al. Effect of IBD medications on COVID-19 outcomes: results from an international registry. Gut. 2020 Oct 20:gutjnl-2020-322539. PubMed: https://pubmed.gov/33082265. Full-text: https://doi.org/10.1136/gutjnl-2020-322539

 

Treatment

PRINCIPLE Trial Collaborative Group. Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet March 04, 2021. https://doi.org/10.1016/S0140-6736(21)00461-X

Azithromycin makes no sense. This UK-based, open-label, adaptive platform randomised trial of interventions against COVID-19 in people at increased risk of an adverse clinical course (PRINCIPLE) randomly assigned people aged 65 years and older, or 50 years and older with at least one comorbidity, who had been unwell for 14 days or less with suspected COVID-19, to usual care plus azithromycin 500 mg daily for three days, usual care plus other interventions, or usual care alone. In total, 402 (80%) of 500 participants in the azithromycin group and 631 (77%) of 823 participants in the usual care alone group reported feeling recovered within 28 days.

 

Pediatrics

LaRovere KL, Riggs BJ, Poussaint TY, et al. Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome. JAMA Neurol March 5, 2021. doi:10.1001/jamaneurol.2021.0504. https://jamanetwork.com/journals/jamaneurology/fullarticle/2777392?resultClick=1

In this study of 1.695 patients 21 years or younger hospitalized at 61 US hospitals for acute COVID-19 or multisystem inflammatory syndrome, 365 (22%) had neurologic involvement. Among those with neurologic involvement, 322 (88%) had transient symptoms and survived, and 43 (12%) developed life-threatening conditions clinically adjudicated to be associated with COVID-19, including severe encephalopathy (n = 15; 5 with splenial lesions), stroke (n = 12), CNS infection/demyelination (n = 8), Guillain-Barré syndrome/variants (n = 4), and acute fulminant cerebral edema (n = 4).

 

Spanish

If you read Spanish, read Zafra M, Linde P, López JV. Así puede pasar el aire (y el coronavirus) de unas viviendas a otras a través del baño. El País 2021, published 7 March. Full-text: https://elpais.com/sociedad/2021-03-06/asi-puede-pasar-el-aire-y-el-coronavirus-de-unas-viviendas-a-otras-a-traves-del-bano.html

Los conductos de ventilación de los baños en edificios antiguos conectan los pisos y, en circunstancias muy concretas, se sospecha que pueden ser una vía de contagio de la covid.

 

French

If you read French, read Covid-19 : l’appel des ordres de santé à tous les soignants, « faites-vous vacciner », c’est un « devoir déontologique ». Le Monde 2021, published 7 March. Full-text : https://www.lemonde.fr/planete/article/2021/03/07/faites-vous-vacciner-l-appel-des-ordres-de-sante-a-tous-les-soignants_6072226_3244.html

Ils sont fous, les Gaulois? Seul un tiers des soignants sont actuellement vaccinés en France. « Ce n’est pas tolérable », estime Alain Fischer, le coordinateur de la campagne de vaccination. Les soignants sont « les plus exposés au virus, tout en étant au contact des populations les plus fragiles », estiment les organisations signataires. Ils doivent se faire vacciner « parce que cela relève de leur devoir déontologique, protéger leurs patients en toutes circonstances, et parce qu’il est impératif qu’ils puissent eux-mêmes se protéger contre le virus, ainsi que leurs proches, et freiner la propagation de l’épidémie », poursuivent-elles. Soyons plus clair encore (the CR Editors): Si vous êtes incapables de vous faire vacciner, changez de métier.

 

7 March

Variants

Paper of the Day

De Souza WM, Amorm MR, Sesti-Costa R, et al. Levels of SARS-CoV-2 Lineage P.1 Neutralization by Antibodies Elicited after Natural Infection and Vaccination. Lancet Preprints 2021, posted 1 March. Full-text: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3793486

William de Souza and colleagues isolated two P.1-containing specimens from nasopharyngeal and bronchoalveolar lavage samples of patients in Manaus, Brazil. They found that the immune plasma of COVID-19 convalescent blood donors had 6-fold less neutralizing capacity against the P.1 than against the B lineage. Moreover, five months after booster immunization with the Chinese CoronaVac vaccine, plasma from vaccinated individuals failed to efficiently neutralize P.1 lineage isolates.

 

Faria NR, Mellan TA, Whittaker C, et al. Genomics and epidemiology of a novel SARS-CoV-2 lineage in Manaus, Brazil. MedRxiv 2021, posted 3 March. Full-text: https://doi.org/10.1101/2021.02.26.21252554

Using a combination of genomic and epidemiological data, Nuno Faria and colleagues characterize the emergence and characteristics of P.1 that acquired 17 mutations, including the trio in the spike protein (K417T, E484K and N501Y) associated with increased binding to the human ACE2 receptor. The authors show that P.1 emerged around early November 2020. They estimate that P.1 could be 1.4–2.2 times more transmissible and able to evade 25-61% of protective immunity elicited by previous infection with non-P.1 lineages.

 

Wang P, Wang M, Yu J, et al. Increased Resistance of SARS-CoV-2 Variant P.1 to Antibody Neutralization. bioRxiv 2021, posted 2 March. Full-text: https://doi.org/10.1101/2021.03.01.433466

David D. Ho, Pengfei Wang and colleagues report that P.1 is not only refractory to multiple neutralizing monoclonal antibodies, but also more resistant to neutralization by convalescent plasma (6.5-fold) and vaccinee sera (2.2-2.8-fold).

 

Cele S, Gazy I, Jackson L, et al. Escape of SARS-CoV-2 501Y.V2 from neutralization by convalescent plasma. MedRxiv 2021, posted 27 February. Full-text: https://doi.org/10.1101/2021.01.26.21250224
We already knew that people previously infected with the non-B.1.351 variant don’t neutralize B.1.351 very effectively. Now Alex Sigal, Tulio de Oliveira, Sandile Cele and colleagues show that people infected with B.1.351 can neutralize both B.1.351 and (to a slightly lesser extent) ‘regular’ non-B.1.351 viruses (Cele 2021). If these data are confirmed, a variant B.1.351-targeted booster vaccine could be a solution for countries where B.1.351 is the dominant strain.

 

Starr TN, Greaney AJ, Dingens AS, Bloom JD. Complete map of SARS-CoV-2 RBD mutations that escape the monoclonal antibody LY-CoV555 and its cocktail with LY-CoV016. bioRxiv 2021, posted 21 February. Full-text: https://doi.org/10.1101/2021.02.17.431683

Jesse Bloom, Tyler Starr and colleagues completely map all mutations to the SARS-CoV-2 spike receptor binding domain (RBD) that escape binding by LY-CoV555 (bamlanivimab, a monoclonal antibody manufactured by Lilly), and its cocktail combination with LY-CoV016. Individual mutations that escape binding are present in B.1.351 and P.1 (E484K escapes LY-CoV555, K417N/T escape LY-CoV016). Additionally, the L452R mutation in the B.1.429 lineage escapes LY-CoV555.

 

Transmission

Dinklage F, Ehmann A, Erdmann E, et al. Why Is the Risk of Coronavirus Transmission so High Indoors? Die Zeit 2020, published 26 November. Full-text: https://www.zeit.de/wissen/gesundheit/2020-11/coronavirus-aerosols-infection-risk-hotspot-interiors

Whenever people gather in closed spaces, the infection risk climbs. This interactive tool shows how the coronavirus spreads. Find out how safe your environment is. See also the German version.

 

Immunology

Tarke A, Sidney J, Methot N, et al. Negligible impact of SARS-CoV-2 variants on CD4+ and CD8+ T cell reactivity in COVID-19 exposed donors and vaccinees. bioRxiv 2021, posted 1 March. Full-text: https://doi.org/10.1101/2021.02.27.433180

Good news from the T cell front. Alessandro Sette, Alba Grifoni, Shane Crotty, Alison Tarke and colleagues did a comprehensive analysis of SARS-CoV-2-specific CD4+ and CD8+ T cell responses from COVID-19 convalescent subjects recognizing the ancestral strain, compared to variant lineages B.1.1.7, B.1.351, P.1, and CAL.20C as well as recipients of the Moderna (mRNA-1273) or the Pfizer/BioNTech (BNT162b2) COVID-19 vaccines. The comfortable result: CD4+ and CD8+ T cell responses in convalescent COVID-19 subjects or COVID-19 mRNA vaccinees are not substantially affected by mutations found in the SARS-CoV-2 variants.

 

Vaccines

Vasileiou E, Simpson CR, Robertson C, et al. Effectiveness of First Dose of COVID-19 Vaccines Against Hospital Admissions in Scotland: National Prospective Cohort Study of 5.4 Million People. Lancet Preprints 2021, posted 19 February. Full-text: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3789264

A single dose of the Pfizer-BioNTech or AstraZeneca vaccine results in substantial reductions in the risk of COVID-19 related hospitalization. In a study from Scotland, the first vaccine dose protected well over 80% of vaccinees against COVID-19 related hospitalization at 28-34 days post-vaccination (Pfizer-BioNTech: 85%; AstraZeneca: 94%). Comparable results (81%) were seen in people aged ≥ 80 years (Vasileiou 2021).

 

Hall VJ, Foulkes S, Saei A, et al. Effectiveness of BNT162b2 mRNA Vaccine Against Infection and COVID-19 Vaccine Coverage in Healthcare Workers in England, Multicentre Prospective Cohort Study (the SIREN Study) Victoria Jane Hall. Lancet Preprints 2021, published 22 February. Full-text: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3790399

These data from the SIREN (Sarscov2 Immunity and REinfection EvaluatioN) study suggest that the Pfizer-BioNTech vaccine effectively prevents both symptomatic and asymptomatic infection in working age adults. (The SIREN study is a prospective cohort study among staff working in publicly funded hospitals.) The vaccine was 72% effective (95% CI 58-86) 21 days after first dose and 86% effective (95% CI 76-97) seven days after two doses in the antibody negative cohort (Hall 2021).

 

French

If you read French, read Covid-19 : « A court terme, l’effet positif des vaccins risque de ne pas suffire pour compenser l’impact délétère des variants ». Le Monde 2021, published 6 March. Full-text : https://www.lemonde.fr/planete/article/2021/03/06/covid-19-a-court-terme-l-effet-positif-des-vaccins-risque-de-ne-pas-suffire-pour-compenser-l-impact-deletere-des-variants_6072159_3244.html

Simon Cauchemez, modélisateur à l’Institut Pasteur, doute que les mesures actuelles permettent une amélioration à la mi-avril, comme espéré par le gouvernement.

 

Mandard S. Covid-19 : les pics de pollution aux particules fines soupçonnés de jouer un rôle dans le rebond épidémique. Le Monde 2021, published 6 March. Full-text : https://www.lemonde.fr/planete/article/2021/03/06/covid-19-les-pics-de-pollution-aux-particules-fines-soupconnes-de-jouer-un-role-dans-le-rebond-epidemique_6072189_3244.html

Pour l’épidémiologiste Antoine Flahault, les épisodes de pollution liés aux sables du Sahara pourraient expliquer la reprise des contaminations et des hospitalisations.

 

Editorial. Covid-19 : changer le regard sur le vaccin. Le Monde 2021, published 5 March. Full-text : https://www.lemonde.fr/idees/article/2021/03/05/covid-19-changer-le-regard-sur-le-vaccin_6072064_3232.html

Cinq semaines après avoir exclu le reconfinement général du pays que de nombreux médecins appelaient de leurs vœux, Emmanuel Macron peut se targuer de deux résultats. A ce jour, l’épidémie n’a pas connu de hausse exponentielle, comme certains modèles le laissaient craindre. Et aucun de ses opposants politiques ne lui fait grief d’avoir fait ce choix risqué. Compte tenu de la fragilité économique et psychologique du pays, il existe désormais un quasi-consensus pour rejeter cette solution radicale. La partie, cependant, est encore loin d’être gagnée.

 

6 March

Variants

Paper of the Day

Shen X, Tang H, McDanal C, et al. SARS-CoV-2 variant B.1.1.7 is susceptible to neutralizing antibodies elicited by ancestral Spike vaccines. Cell Host Microbe March 03, 2021. https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(21)00102-5

Good news. Using a lentivirus-based pseudovirus assay, Xiaoying Shen and colleagues from Duke, Durham, US, show that B.1.1.7 is probably not a neutralization escape variant of concern for COVID-19 vaccines. Moreover, B.1.1.7 is unlikely to increase the risk of SARS-CoV-2 re-infection.

 

Wibmer CK, Ayres F, Hermanus T, et al. SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma. Nature Medicine 02 March 2021. https://www.nature.com/articles/s41591-021-01285-x

B.1.351 is a bigger problem. This study (for months available as a pre-print only, now as a beautiful paper in Nature Medicine) shows that this lineage completely escapes three classes of therapeutically relevant antibodies. The B.1.351 pseudovirus also exhibited substantial to complete escape from neutralization, but not binding, by convalescent plasma. The overwhelming majority of monoclonal antibodies already on the path to licensure target residues K417 or E484 and are therefore likely to be futile against this variant.

 

Virology

Schroeder S, Pott F, Niemeyer D, et al. Interferon antagonism by SARS-CoV-2: a functional study using reverse genetics. Lancet Microbe March 04, 2021. https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(21)00027-6/fulltext

Do differences in receptor usage determine all the differences in disease presentation between SARS-CoV and SARS-CoV-2? This work by Christian Drosten and colleagues shows that SARS-CoV-2 suppresses cytokine induction and interferon signaling with lower efficiency than SARS-CoV, despite the shared genome architecture and expression of homologous viral proteins. Gene encoding protein 6 as a genetic marker of virulence varied between SARS-CoV and SARS-CoV-2, thus providing a target for genome-based surveillance of circulating strains of SARS-CoV-2. The authors recommend to monitor sequence evolution of SARS-CoV ORF6.

 

Immunology

Bost P, De Sanctis F, Canè S et al. Deciphering the state of immune silence in fatal COVID-19 patients. Nat Commun March 4, 2021 12, 1428. https://www.nature.com/articles/s41467-021-21702-6#citeas

This study shows innate and adaptive immune dysfunction, including loss of immune suppression by blood myeloid cells and the replacement of lung memory CD8+ T cells by naive T cells, suggesting a state of “immune silence” that correlates with a severe clinical manifestation and fatal outcome.

 

Diagnostics

Azzolini C, Donati S, Premi E, et al. SARS-CoV-2 on Ocular Surfaces in a Cohort of Patients With COVID-19 From the Lombardy Region, Italy. JAMA Ophthalmology March 4, 2021. https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2777178

SARS-CoV-2 was present on the ocular surface in 52 of 91 COVID-19 patients, showing a wide variability in the viral load. Some had positive conjunctival swabs while having a negative nasopharyngeal swab. However, the authors did not determine the infectivity of the viral material detected. Clinical relevance remains unclear.

 

Moshe M, Daunt A, Flower B, et al. SARS-CoV-2 lateral flow assays for possible use in national covid-19 seroprevalence surveys (React 2): diagnostic accuracy study. BMJ. 2021 Mar 2;372:n423. PubMed: https://pubmed.gov/33653694 . Full-text: https://doi.org/10.1136/bmj.n423

In contrast to routine serology assays, the use of lateral flow immunoassays (LFIAs) does not require the support of central laboratories and offers a rapid and affordable method of testing. This study shows that LFIA sensitivity is variable on serum and finger prick testing, and often differs from that stated by the manufacturer. Specificity of all LFIAs was high. However, none showed sufficient sensitivity and specificity to be considered for routine clinical use. One further LFIA (Surescreen) was identified as suitable for use in seroprevalence studies because it showed comparable performance to the LFIA currently used in the React 2 seroprevalence studies (Fortress). However, the performance of Surescreen was not significantly better than Fortress.

 

Clinical

Martinez MW, Tucker AM, Bloom J, et al. Prevalence of Inflammatory Heart Disease Among Professional Athletes With Prior COVID-19 Infection Who Received Systematic Return-to-Play Cardiac Screening. JAMA Cardiol March 4 2021; https://jamanetwork.com/journals/jamacardiology/fullarticle/2777308

“The virus challenged me and I defeated it.” That’s what Zlatan Ibrahimovic, famous Swedish soccer player who caught COVID-19 last September, posted on Instagram (you don’t know him? Then please take 94 seconds: https://www.youtube.com/watch?v=GcCVfNA7otY).

“But you are not Zlatan. Do not challenge the virus. Use your head, respect the rules. Social distancing and masks, always. We will win.”

Zlatan was right! But should we have been worried about him? Probably not. In this multicenter, retrospective cross-sectional study of RTP cardiac testing performed on 789 professional athletes with COVID-19 (58% symptomatic, 42% asymptomatic or pauci-symptomatic), imaging evidence of inflammatory heart disease (performed around 3 weeks after positive testing) that resulted in restriction from play was identified in 5 athletes (0.6%) only. No adverse cardiac events occurred in the athletes who underwent cardiac screening and resumed professional sport participation. Thus, with regard to mild COVID-19, there were many Zlatans. On the field, however, there is only one.

 

Comorbidities

Bloom CI, Drake TM, Docherty AB, et al. Risk of adverse outcomes in patients with underlying respiratory conditions admitted to hospital with COVID-19: a national, multicentre prospective cohort study using the ISARIC WHO Clinical Characterisation Protocol UK. Lancet Resp Med March 04, 2021. https://doi.org/10.1016/S2213-2600(21)00013-8

Analyzing 75,463 patients from the UK, Chloe Bloom and colleagues show that patients with chronic pulmonary disease had a high level of mortality, with a prevalence of 40% for in-hospital death. Of patients with asthma, only those with severe asthma had increased mortality compared to those without an underlying respiratory condition. Patients with asthma (aged ≥ 50 years) had a lower mortality risk if they had used inhaled corticosteroids within 2 weeks of admission.

 

Treatment

López-Medina E, López P, Hurtado IC, et al. Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial. JAMA March 4, 2021; doi: 10.1001/jama.2021.3071. https://jamanetwork.com/journals/jama/fullarticle/2777389

The next hydroxychloroquine? Because of some evidence of activity in vitro, ivermectin has attracted huge interest. Several countries have included ivermectin in their treatment guidelines, leading to a surge in the demand for the drug by the general population and even alleged distribution of veterinary formulations. In this RCT that included 476 patients from Cali, Colombia, the duration of symptoms was not significantly different for patients who received either a 5-day course of ivermectin or placebo (median time to resolution of symptoms, 10 vs 12 days; hazard ratio for resolution of symptoms, 1.07). This is consistent with PK models showing that ivermectin levels do not reach the IC50 even for a dose level 10-times higher than the approved dose.

Graphic

 

Lescure FX, Honda H, Fowler RA, et al. Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Resp Med March 04, 2021. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00099-0/fulltext

This large placebo-controlled multinational Phase III trial evaluated two doses of sarilumab, an interleukin-6 receptor inhibitor, in 416 patients with severe or critical COVID-19. At day 29, no significant differences were seen between the arms. The authors bravely suggest several potential reasons for why sarilumab was not effective (IL-6 insufficient to quell the inflammatory phase of the disease, patient selection not based on inflammation markers, dosage too low, use of confounding concomitant steroids, etc). However, this strategy seems not be a game changer in this pandemic.

 

French

If you read French, read HerzbergN, Aeberhardt C. Covid-19 : comment la lutte contre les variants pourrait modifier les stratégies vaccinales. Le Monde 2021, published 25 February. Full-text : https://www.lemonde.fr/planete/article/2021/02/25/covid-19-la-lutte-contre-les-variants-s-organise_6071122_3244.html

L’apparition de nouvelles mutations du virus contraint les laboratoires à adapter leurs vaccins, les agences sanitaires à inventer de nouvelles procédures réglementaires, et les Etats à réexaminer leur stratégie vaccinale.

 

5 March

Variants

Paper of the Day

Davies NG, Abbott S, Barnard RS, et al. Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England. Science 03 Mar 2021: eabg3055. Full-text: https://science.sciencemag.org/content/early/2021/03/03/science.abg3055

Difficult months ahead: the B.1.1.7 variant emerged in southeast England in November 2020 and is rapidly spreading toward dominance. In this brilliant article, Nicholas Davies and colleagues from London estimate that this variant has a 43–90% (range of 95% credible intervals 38–130%) higher reproduction number than pre-existing variants. A fitted two-strain dynamic transmission model shows that B.1.1.7. will lead to large resurgences of COVID-19 cases. Without stringent control measures, including limited closure of educational institutions and a greatly accelerated vaccine roll-out, COVID-19 hospitalizations and deaths across England in 2021 will exceed those in 2020.

 

Virology

Murray CJ, Piot P. The Potential Future of the COVID-19 Pandemic. JAMA March 3, 2021. Full-text: https://jamanetwork.com/journals/jama/fullarticle/2777343

Will SARS-CoV-2 become a recurrent seasonal Infection? Peter Piot and Christopher Murray don’t know, how could they? According to their nice viewpoint, there is too much uncertainty about the probability and frequency of emergence of new variants, the reduction in vaccine efficacy for each variant, the critical question of cross-variant immunity, and the consistency of safe human behavior. However, the prospect of persistent and seasonal COVID-19 is real.

 

Immunology

Le Bert N, Clapham HE, Tan AT. Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection. J Exp Med March 1, 2021. 218 (5): e20202617. https://doi.org/10.1084/jem.20202617

Nina Le Bert and colleagues from Singapore studies T cells longitudinally in a cohort of asymptomatic (n = 85) and symptomatic (n = 75) COVID-19 patients after seroconversion. Important findings: asymptomatic SARS-CoV-2-infected individuals are not characterized by weak antiviral immunity; on the contrary, they mount a highly functional virus-specific cellular immune response.

 

Vaccine

Kimberly G. Blumenthal KG, Freeman EE, Saff RR. Delayed Large Local Reactions to mRNA-1273 Vaccine against SARS-CoV-2. NEJM, March 3, 2021. DOI: 10.1056/NEJMc2102131. https://www.nejm.org/doi/full/10.1056/NEJMc2102131

Case series of 12 delayed large but varying local reactions to the mRNA-1273 vaccine, with a median onset on day 8 after the first dose. After the second shot, 6 had no recurrence, 3 had similar and 3 had recurrent reactions that were of a lower grade than those after the initial dose.

 

Kadire SR, Wachter RM, Lurie N. Delayed Second Dose versus Standard Regimen for Covid-19 Vaccination. N Engl J Med March 4, 2021; 384:e28. DOI: 10.1056/NEJMclde2101987. https://www.nejm.org/doi/full/10.1056/NEJMclde2101987

Nice case vignette on the question of whether we delay the second dose. Robert M. Wachter says yes, Nicole Lurie says no. No clear winner.

 

Transmission

Shumsky RA, Debo L, Lebeaux RM, et al. Retail store customer flow and COVID-19 transmission. PNAS February 26, 2021. https://doi.org/10.1073/pnas.2019225118

Nice modelling study on how customer flows in retail stores affect the rate of COVID-19 transmission. The model calculates the disease transmission rate in a retail environment and determines how the rate depends on the customer flow policy (one-way versus two-way), the travel speed distribution, and store size. Restricting customer flow to one-way movement is highly effective if direct exposure is the dominant mode of transmission. However, it is not effective if more indirect (“wake”) exposure dominates.

 

Schumm MA, Hadaya JE, Mody N, et al. Filtering Facepiece Respirator (N95 Respirator) Reprocessing: A Systematic Review. JAMA. March 3, 2021; doi: 10.1001/jama.2021.2531. https://jamanetwork.com/journals/jama/fullarticle/2777342?resultClick=1

Max A. Schumm and colleagues have reviewed 42 studies (through January 31, 2021) that examined 65 types of masks. Ultraviolet germicidal irradiation, vaporized hydrogen peroxide, moist heat, and microwave-generated steam processing effectively sterilized N95 respirators and retained filtration performance. Ultraviolet irradiation and vaporized hydrogen peroxide damaged respirators the least.

 

Collateral damage

Knudsen AK, Stene-Larsen K, Gustavson K, et al. Prevalence of mental disorders, suicidal ideation and suicides in the general population before and during the COVID-19 pandemic in Norway: A population-based repeated cross-sectional analysis. Lancet Regional Health February 27, 2021. Volume 4, 100071, May 01, 2021DOI: https://doi.org/10.1016/j.lanepe.2021.100071

Credible data from Norway: except for a decrease in mental disorders in the first pandemic period, the findings suggest stable levels of mental disorders, suicidal ideation and suicide deaths during the first six months of the COVID-19 pandemic compared to pre-pandemic levels.

 

Treatment

Touafchia A, Bagheri H, Carrié D, et al. Serious bradycardia and remdesivir for coronavirus 2019 (COVID-19): a new safety concerns. Clin Microbiol Infection February 26, 2021. DOI: https://doi.org/10.1016/j.cmi.2021.02.013

Oops: this post-marketing study in a real-world setting suggests that the use of remdesivir is significantly associated with an increased risk of reporting bradycardia and serious bradycardia when compared with the use of hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids.

 

Lamontagne F, Agoritsas T, Siemieniuk R, et al. A living WHO guideline on drugs to prevent covid-19. BMJ. 2021 Mar 1;372:n526. PubMed: https://pubmed.gov/33649077. Full-text: https://doi.org/10.1136/bmj.n526

This is the first version of a living (up-to-date, evolving and EBM) guideline, focusing on the evidence for hydroxychloroquine. 53 authors from 45 centers say on 12 pages, “Do not use it!”

 

4 March

Vaccine

Paper of the Day

Oliver SE, Gargano JW, Scobie H, et al. The Advisory Committee on Immunization Practices’ Interim Recommendation for Use of Janssen COVID-19 Vaccine — United States, February 2021. MMWR Morb Mortal Wkly Rep. ePub: 2 March 2021. DOI: https://www.cdc.gov/mmwr/volumes/70/wr/mm7009e4.htm

The Janssen COVID-19 vaccine is a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector vaccine, encoding the stabilized prefusion spike glycoprotein of SARS-CoV-2. On February 27, 2021, the FDA issued an Emergency Use Authorization (EUA). This is an interim recommendation for use in persons aged ≥ 18 years for the prevention of COVID-19, discussing the available data and the question who to vaccinate and when. Answer: everybody, ASAP. Of note, the Janssen vaccine seems to work in the B.1.351 lineage from South Africa as well in the P.2 lineage from Brazil.

 

Epidemiology

Van Loon W, Hommes F, Theuring S, et al. Renewed absence of SARS-CoV-2 infections in the day care context in Berlin, January 2021. Clinical Infectious Diseases March 2. Full-text: https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab199/6155930

The second round of a longitudinal study in 12 randomly selected kindergartens across Berlin including 156 children, 80 staff, and 488 household members of children and staff. According to the authors, repeated absence of SARS-CoV-2 infection four months apart, at weekly community incidences of 38 (first round in September) and 110/100,000, support the initial interpretation that kindergartens are not silent transmission reservoirs.

 

Virology

Phuong HVM, Tung TS, Trang UTH, et al. Novel mutation of SARS-CoV-2, Vietnam, July 2020. Emerg Infect Dis. 2021 May [date cited]. https://doi.org/10.3201/eid2705.210013

Now that the whole world is sequencing the virus, we are likely to see many such studies. A cluster in Danang, Vietnam, began July 25, 2020, and resulted in 551 confirmed cases and 35 deaths. The authors analyzed 26 sequences from this cluster and identified a novel shared mutation in non-structural protein 9, suggesting a single introduction into Vietnam. The single-nucleotide polymorphism, C835T, was not reported in any other sequences collected globally. However, it has no known associations with virulence or transmissibility.

 

Variants

Plante JA, Mitchell BM, Plante KS, et al. The Variant Gambit: COVID’s Next Move. Cell Host Microbe March 01, 2021. https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(21)00099-8

Nice review that outlines factors driving SARS-CoV-2 variant evolution, explores the potential impact of specific mutations and examines the risk of further mutations. Jessica A. Plante and colleagues from the World Reference Center for Emerging Viruses and Arboviruses consider also the experimental studies needed to understand the threat these variants pose.

 

Transmission, Prevention

Lubrano R, Bliose S, Testa A, et al. Assessment of Respiratory Function in Infants and Young Children Wearing Face Masks During the COVID-19 Pandemic. JAMA Netw Open March 2, 2021. 4(3):e210414. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2776928

Are surgical masks associated with episodes of oxygen desaturation or respiratory distress among children? This study from Italy says no. Among 47 children (22 aged 24 months or younger!) the use of facial masks was not associated with significant changes in Sao2 or Petco2.

 

Wilmes P, Zimmer J, Schulz J, et al. SARS-CoV-2 transmission risk from asymptomatic carriers: Results from a mass screening programme in Luxembourg. Lancet Regional Health February 27, 2021. DOI: https://doi.org/10.1016/j.lanepe.2021.100056

To accompany the lifting of COVID-19 lockdown measures, Luxembourg implemented a mass screening (MS) program. Based on a participation of 49% amongst the resident population and 22% amongst cross-border workers, the MS program allowed identification of 1099 cases corresponding to 26% of positive cases related to an early summer epidemic wave. Among the index cases, 567 (67%) reported symptoms at the time of being informed of their positive test result (these may have been pre-symptomatic at the time of the test), whereas 283 (33%) were asymptomatic. Asymptomatic individuals had significant secondary attack rates, both in households and among close contacts, but these were lower compared to those for symptomatic cases.

 

Clinical

Van den Hurk K, Merz EM, Prinsze FJ, et al. Low awareness of past SARS-CoV-2 infection in healthy plasma donors. Cell Reports Med February 25, 2021. https://doi.org/10.1016/j.xcrm.2021.100222

See title. They know nothing. Katja van den Hurk and colleagues asked individuals donating plasma across the Netherlands between May 11th and 18th 2020. Among 3676 with antibody and questionnaire data, 239 (6.5%) were positive for SARS-CoV-2 antibodies. Of those, 48% did not suspect COVID-19 despite the majority reporting symptoms. 11% of seropositive individuals reported no symptims and 27% very mild symptoms at any time during the first peak of the epidemic. Anosmia/ageusia and fever were most strongly associated with seropositivity. Almost 13% of the individuals who tested negative for SARS-CoV-2 did suspect a SARS-CoV-2 infection, a large majority (84%) because of symptoms indicative of COVID-19.

 

Baldassarri M, Picchiotti N, Fava F, et al. Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males. EBioMedicine. 2021 Feb 26;65:103246. PubMed: https://pubmed.gov/33647767. Full-text: https://doi.org/10.1016/j.ebiom.2021.103246

A genetic polymorphism predisposing some men to develop a more severe disease irrespective of age: in a cohort of 1178 men and women with COVID-19, Margherita Baldassarri from Siena, Italy, and colleagues used a supervised Machine Learning approach on a synthetic representation of genetic variability due to poly-amino acid repeats. Comparing the genotype of patients with extreme manifestations (severe vs. asymptomatic), they found an association between the poly-glutamine repeat number of the androgen receptor (AR) gene, serum testosterone concentrations, and COVID-19 outcome in male patients. Failure of the endocrine feedback to overcome AR signaling defects by increasing testosterone levels during the infection leads to the fact that polyQ ≥ 23 becomes dominant to testosterone levels for the clinical outcome.

 

Strålin K, Wahlström E, Walther S, et al. Mortality trends among hospitalised COVID-19 patients in Sweden: A nationwide observational cohort study. Lancet Regional Health February 26, 2021 DOI: https://doi.org/10.1016/j.lanepe.2021.100054

There was a gradual decline in mortality during the spring of 2020 in Swedish hospitalised COVID-19 patients. The results remained after adjustment for age, sex, co-morbidities, level of care dependency, country of birth, healthcare region, and SAPS3 (ICU treated patients). Read about the many explanations for this phenomenon. However, the bottom line is that in studies using mortality as an endpoint, the timing of inclusion may play a crucial role regarding outcome. The results of before-and-after studies on specific interventions should be interpreted with caution.

 

Collateral damage (today: benefit)

Shepherd JP, Moore SC, Long A, et al. Association Between COVID-19 Lockdown Measures and Emergency Department Visits for Violence-Related Injuries in Cardiff, Wales. JAMA March 2, 2021. 2021; 325(9):885-887. https://jamanetwork.com/journals/jama/article-abstract/2776868

Less violence during lockdown. In Cardiff, Wales, the average weekly number of violent injury admissions dropped from 28.4 to 16.5 during lockdown. There was also a 92% reduction in weapon use. This may reflect closure of city center pubs and clubs where most violence takes place. Cheers.

 

3 March

Vaccine

Paper of the Day

Saadat S, Tehrani ZR, Logue J, et al. Binding and Neutralization Antibody Titers After a Single Vaccine Dose in Health Care Workers Previously Infected With SARS-CoV-2. JAMA. March 1, 2021. doi:10.1001/jama.2021.3341. https://jamanetwork.com/journals/jama/fullarticle/2777171?resultClick=1

Health care workers with previous COVID-19, based on laboratory-confirmed serology testing, had higher antibody titer responses to a single dose of mRNA vaccine (Pfizer-BioNTech or Moderna, depending on personal preference and availability) than those who were not previously infected. Although the groups were small and only 59 volunteers were enrolled (17 in the Ab-negative, 16 in the asymptomatic, and 26 in the symptomatic group), this data indicates that one shot is enough in people with prior infection. Of note, titers did not differ between asymptomatic and symptomatic disease.

 

Virology

Tse H, Lung CD, Wong SC, et al. Emergence of a Severe Acute Respiratory Syndrome Coronavirus 2 virus variant with novel genomic architecture in Hong Kong. Clinical Infectious Diseases 02 March 2021, ciab198, https://doi.org/10.1093/cid/ciab198

SARS-CoV-2 lineages have emerged continuously, mostly through the genomic accumulation of substitutions. Herman Tse and colleagues highlight the considerable evolutionary potential of SARS-CoV-2. They report three infections caused by a variant with a novel genomic architecture resulting from deletion of an 882-nucleotide region spanning ORF6 to ORF8 together with duplication and transposition of a 57-nucleotide segment from the 5’-untranslated region (UTR). The tolerance of a major and unusual genomic arrangement led to the formation of ORF6x, which involved recruitment of typically non-coding sequences into the open reading frame. These events greatly increased the genetic diversity of SARS-CoV-2, thereby accelerating the evolution of new potentially advantageous genotypes and compensating for the relatively low mutation rates in coronaviruses. On a more immediate note, caution is warranted when using diagnostic assays targeting only accessory genes or proteins such as Orf8, given the risk of false-negative results.

 

Clinical

Rodebaugh TL, Frumkin MR, Reiersen AM, et al. Acute symptoms of mild to moderate COVID-19 are highly heterogeneous across individuals and over time. Open Forum Infectious Diseases March 1, ofab090, https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab090/6154666

Thomas L. Rodebaugh from St. Louis, US, and colleagues asked 162 participants with acute COVID-19 to respond to surveys up to 31 times for up to 17 days. Several statistical methods were used to characterize the temporal dynamics of these symptoms. Results: the course of symptoms during the initial weeks of COVID-19 is highly heterogeneous and is neither predictable nor easily characterized using typical survey methods. However, the pattern of symptoms over time suggested a fluctuating course for many patients. Participants who showed clinical deterioration were more likely to present with higher reports of severity of cough and diarrhea.

 

Cavanaugh AM, Thoroughman D, Miranda H, Spicer K. Suspected Recurrent SARS-CoV-2 Infections Among Residents of a Skilled Nursing Facility During a Second COVID-19 Outbreak — Kentucky, July–November 2020. MMWR Morb Mortal Wkly Rep 2021;70:273–277. https://www.cdc.gov/mmwr/volumes/70/wr/mm7008a3.htm?s_cid=mm7008a3_w#suggestedcitation

Five residents of a skilled nursing facility received positive PCR results in two separate COVID-19 outbreaks separated by 3 months. Residents received at least four negative test results between the two outbreaks, suggesting the possibility of reinfection. Severity of disease in the five residents during the second outbreak was worse than that during the first outbreak and included one death.

 

Long COVID

Gacci M, Coppi M, Baldi E, et al. Semen impairment and occurrence of SARS-CoV-2 virus in semen after recovery from COVID-19. Human Reproduction March 1, 2021. Full-text: https://academic.oup.com/humrep/advance-article/doi/10.1093/humrep/deab026/6125160

Mauro Gacci from Florence, Italy, and colleagues performed a large prospective cross-sectional study on 43 sexually active men who were known to have recovered from SARS-CoV-2 (3-6 weeks after negative swab). One patient had a positive PCR in semen (21 days after the second negative swab). Of note, 11/43 were oligo-crypto-azoospermic and all azoospermic patients reported a previous unimpaired fertility status suggesting that semen impairment was due to COVID-19. However, a main limitation of the study is the lack of samples obtained prior to COVID-19.

 

Severe COVID-19

Yang P, Zhao Y, Li J. et al. Downregulated miR-451a as a feature of the plasma cfRNA landscape reveals regulatory networks of IL-6/IL-6R-associated cytokine storms in COVID-19 patients. Cell Mol Immunol (2021). https://doi.org/10.1038/s41423-021-00652-5

Cell-free circulating RNAs (cfRNAs) in plasma carry information from pathologic sites, and they have been reported to play important roles in disease development. Compared with healthy donors, significantly higher mRNA expression of IL-6R was observed; miR-451a, a known negative regulator of IL-6R translation, was down-regulated, which may promote IL-6R expression at the protein level.

 

Co-morbidities

Jee J, Stonestrom AJ, Devlin S, et al. Oncologic immunomodulatory agents in patients with cancer and COVID-19. Sci Rep March 1, 2021, 11, 4814 (2021). https://doi.org/10.1038/s41598-021-84137-5. https://www.nature.com/articles/s41598-021-84137-5

A large single-center, retrospective analysis of 820 cancer patients with COVID-19 treated with various immunomodulatory agents within 90 days prior to SARS-CoV-2 diagnosis, mainly anti-CD20 therapies (rituximab, ofatumumab, or obinutuzumab) and immunotherapy (PD-1, PDL-1, or CTLA-4 blockade). Of note, whereas cytotoxic chemotherapy itself was not a risk for worse outcomes, pre-COVID-19 neutropenia was associated with worse COVID-19. In assessing whether certain oncologic medications are associated with worse COVID-19 outcomes, considering cancer type, degree of effect (i.e. neutropenia or other bone marrow suppression) and other patient-specific factors is crucial.

 

Treatment

Janiaud P, Axfors C, Ioannidis JP, et al. Recruitment and Results Reporting of COVID-19 Randomized Clinical Trials Registered in the First 100 Days of the Pandemic. JAMA Netw Open March 1, 2021;4(3):e210330. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2776802

All RCTs (n = 516) registered in ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform between January 1 and April 9, 2020, were included. Overall, 30% of COVID-19 RCTs initiated in the first 100 days of the pandemic did not begin recruitment, and only 10% had results reported by mid-October, suggesting the possibility of substantial research waste.

 

Li S, Liu S, Jiang Z, et al. Study on the promotion of lymphocytes in patients with COVID-19 by broad-spectrum chemokine receptor inhibitor vMIP-II and its Mechanism of signal transmission in vitro. Sig Transduct Target Ther March2, 2012. 6, 104. https://doi.org/10.1038/s41392-021-00516-4

Viral macrophage inflammatory protein (vMIP) is a homologue of a chemokine derived from the recombinant natural human herpes virus 8 gene. It has been proved that vMIP can effectively inhibit the process of HIV infecting target cells through chemokine receptors. In this pilot study, 10 patients and 35 uninfected volunteers from Wuhan were treated with vMIP (given as injection). vMIP-II significantly improved the lymphocyte decrease of COVID-19. It was shown that vMIP-II inhibits multiple chemokine receptors and their related phosphorylation signaling pathways. In other words, this study shows that vMIP-II can reconstruct the cellular immune function lost in acute SARS-CoV-2 infection. The elucidation of the molecular mechanism of vMIP-II increasing CD8+ TCM provides a new strategy for the treatment of COVID-19.

 

Pediatric

Takefuji Y. Besançon L, Steadson D, Flahault A. Ludvigsson JF. Open Schools, Covid-19, and Child and Teacher Morbidity in Sweden. NEJM March 1, 2021, DOI: 10.1056/NEJMc2101280. https://www.nejm.org/doi/full/10.1056/NEJMc2101280?query=featured_home

Ludvigsson JF. The first eight months of Sweden’s COVID-19 strategy and the key actions and actors that were involved. Acta Paediatr 2020;109:2459-2471. https://doi.org/10.1111/apa.15582

Controversial discussion about the Swedish approach. Sweden allowed COVID-19 to spread in the hope that the population would develop “herd immunity.” The younger the patients, the fewer deaths due to COVID-19 were reported by Ludvigsson et al. (Feb. 18 issue). The authors of the correspondence letters don’t believe that this was a good idea.

 

2 March

Immunology

Paper of the Day

Shen B, Tasdogan A, Ubellacker JM, et al. A mechanosensitive peri-arteriolar niche for osteogenesis and lymphopoiesis. Nature, February 24, 2021. https://doi.org/10.1038/s41586-021-03298-5

Exercise will boost your immune system! What we all “knew” already, can now be explained. A specialized type of bone cell progenitor has been identified in the bone marrow and shown to support the generation of lymphocytes in response to movement. Bo Shen and colleagues have identified a role for movement in stimulating communication between one type of stromal cell and immune progenitors in mice, ultimately helping the animals to fight infection. The discovery that mechanosensitive osteogenic progenitors have a role in fighting infections is exciting.

 

Balz K, Kaushik A, Chen M, et al. Homologies between SARS-CoV-2 and allergen proteins may direct T cell-mediated heterologous immune responses. Sci Rep February 25, 2021, 11, 4792. https://doi.org/10.1038/s41598-021-84320-8

Different systematic bioinformatic approaches were used to identify potentially cross-reactive allergen- and SARS-CoV-2-T cell epitopes. Numerous candidate epitope pairs were identified, highlighting an important role of MHC class I inhalant allergens. According to Kathrin Balz and colleagues, findings generate further hypotheses in how the adaptive immune system responds differentially with respect to the atopy status of the host. Their study warrants an immediate investigation of these predicted T cell epitopes to link their possible role in driving the immune response against SARS-CoV-2 and eventually shape the COVID-19 outcome.

 

Epidemiology

Lim T, Delorey M, Bestul N, et al. Changes in SARS CoV-2 Seroprevalence Over Time in Ten Sites in the United States, March – August, 2020. Clin Infect Dis. 2021 Feb 26:ciab185. PubMed: https://pubmed.gov/33639620. Full-text: https://doi.org/10.1093/cid/ciab185

In a well-designed large-scale seroprevalence study, Travis Lim and colleagues tested 78,990 specimens from ten US sites that experienced different epidemic curves, over multiple time points between March and August 2020. During this period, less than 10% of the population had detectable antibodies to SARS-CoV-2 at all sites except New York (23.2%) and Florida (13.3%).

 

Virology

Zhou D, Chan JF, Zhou B, et al. Robust SARS-CoV-2 Infection in Nasal Turbinates after Treatment with Systemic Neutralizing Antibodies. Cell Host Microbe February 24, 2021. Full-text: https://www.sciencedirect.com/science/article/pii/S1931312821000986?via%3Dihub

Viral infection in nasal turbinate may outcompete antibody treatment. Using a Syrian hamster model, the authors show that ZDY20, ZB8 and 2-15 (three of the most promising classes of RBD-specific human neutralizing Abs) prophylactic intraperitoneal or intranasal injection of individual HuNAb or DNA vaccination significantly reduced infection in the lungs but not in the nasal turbinates of hamsters intranasally challenged with SARS-CoV-2. Although post-challenge HuNAb therapy suppresses viral loads and lung damage, robust infection is observed in nasal turbinates treated within 1-3 days. This has significant implications for sub-protection, reinfection and vaccine.

 

Vaccines

Rinott E, Youngster I, Lewis YE. Reduction in COVID-19 Patients Requiring Mechanical Ventilation Following Implementation of a National COVID-19 Vaccination Program — Israel, December 2020–February 2021. MMWR Morb Mortal Wkly Rep, 26 February 2021. DOI: http://dx.doi.org/10.15585/mmwr.mm7009e3external icon.

Again, encouraging data from Israel. The percentage of COVID-19 patients aged ≥ 70 years requiring mechanical ventilation fluctuated during October–December 2020 but has considerably and consistently decreased after implementation of the vaccination campaign prioritizing older adults. The decline in the ratio of persons aged ≥ 70 years to those < 50 years requiring mechanical ventilation began around the time of start of administration of the second dose of vaccine (January 10, 2021).

 

Clinical

Cuevas AM, Clark JM, Potter JJ. Increased TLR/MyD88 signaling in patients with obesity: is there a link to COVID-19 disease severity? Int J Obes (Lond). 2021 Feb 26. PubMed: https://pubmed.gov/33637950. Full-text: https://doi.org/10.1038/s41366-021-00768-8

Why is obesity a risk factor for severe COVID-19? The authors review current knowledge and hypothesize that people with obesity, especially excess abdominal/visceral fat and associated metabolic complications, have over-expression of MyD88 in the adipose tissue and perhaps in other cells and tissues (like immune cells) that triggers an exaggerated inflammatory response of the immune system.

 

Severe COVID-19

Deinhardt-Emmer S, Böttcher S, Häring C, et al. SARS-CoV-2 causes severe epithelial inflammation and barrier dysfunction. J Virol 2021 Feb 26:JVI.00110-21. PubMed: https://pubmed.gov/33637603. Full-text: https://doi.org/10.1128/JVI.00110-21

To elucidate the viral effects on the barrier integrity and immune reactions, Stefanie Deinhardt-Emmer and colleagues from Jena, Germany used mono-cell culture systems and a complex human chip model composed of epithelial, endothelial, and mononuclear cells. SARS-CoV-2 efficiently infected epithelial cells with high viral loads and inflammatory response, including interferon expression. By contrast, the adjacent endothelial layer was not infected nor did it show productive viral replication or release of interferon. With prolonged infection, both cell types were damaged, and the barrier function was deteriorated, allowing the viral particles to have to carry too much.

 

Althaus K, Marini I, Zlamal J, et al. Antibody-induced procoagulant platelets in severe COVID-19 infection. Blood February 25, 2021, 137 (8): 1061–1071. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791311/

Severe COVID-19 is associated with antibody-mediated up-regulation of platelet apoptosis. In addition, Karina Althaus and colleagues from Tübingen, Germany found a correlation between platelet apoptosis markers and SOFA score, plasma levels of D-dimer, and the incidence of thromboembolic complications in severe COVID-19 patients. These data indicate that platelet apoptosis may contribute to sustained inflammation and increased thromboembolic risk in COVID-19 patients and could potentially present a potential therapeutic target.

 

Treatment

Piepenbrink MS, Park JG, Oladunni FS, et al. Therapeutic activity of an inhaled potent SARS-CoV-2 neutralizing human monoclonal antibody in hamsters. Cell Reports February 24, 2021. DOI: https://doi.org/10.1016/j.xcrm.2021.100218

Antibodies delivered via inhalation for the prevention and treatment of SARS-CoV-2: Michael S. Pipenbrink from Birmingham, US shows that this works. Fully human monoclonal antibodies (hmAbs) potently neutralize SARS-CoV-2. The most potent hmAb, 1212C2 was derived from an IgM memory B cell, exhibited in vivo prophylactic and therapeutic activity against SARS-CoV-2 in hamsters when delivered intraperitoneally, achieving a meaningful reduction in upper and lower respiratory viral burden and lung pathology. Furthermore, liquid nebulized inhaled treatment of SARS-CoV-2 infected hamsters with as low as 0.6 mg/kg of inhaled dose, corresponding to approximately 0.03 mg/kg of lung-deposited dose, mediated a reduction in respiratory viral burden that is below the detection limit, and mitigated lung pathology. The therapeutic efficacy achieved at an exceedingly low-dose of inhaled 1212C2 supports the rationale for local lung delivery and achieving dose-sparing benefits as compared to the conventional parenteral route of administration.

 

Bugin K, Woodcock J. Trends in COVID-19 therapeutic clinical trials. Nature Reviews Drug Discovery, 25 February 2021. https://www.nature.com/articles/d41573-021-00037-3

Janet Woodcock and Kevin Bugin have comprehensively assessed the ongoing COVID-19 therapeutic clinical development efforts worldwide. Surveying the clinical trial landscape, their most important finding is that the vast majority of trials of therapeutics for COVID-19 are not designed to yield actionable information; low randomization rates and underpowered outcome data render matters of safety and efficacy generally uninterpretable.

 

Milic J, Novella A, Meschiari M, et al. Darunavir/cobicistat is associated with negative outcomes in HIV-negative patients with severe COVID-19 pneumonia. AIDS Res Hum Retroviruses. 2021 Feb 23. PubMed: https://pubmed.gov/33619997. Full-text: https://doi.org/10.1089/AID.2020.0305

The HIV protease inhibitor darunavir doesn’t work in COVID. Didn’t we know this already? In this retrospective study in HIV-negative patients with COVID-19 pneumonia admitted to a tertiary care hospital in Modena, Italy, patients on darunavir/c (c=cobicistat is a pharmacoenhancer) had higher rates of mortality (25% vs 10%, p < 0.0001) and of mechanical ventilation and death (37% vs. 25%, p = 0.03). Multiple serious interactions associated with darunavir/c were observed in the 19 patients who died. According to the authors, darunavir/c “should not be recommended as a treatment option for COVID-19 pneumonia outside clinical trials”. The question is: why did the authors study this now?

 

1 March

Virology

Paper of the Day

Zhou B, Thi Nhu Thao T, Hoffmann D, et al. SARS-CoV-2 spike D614G change enhances replication and transmission. Nature 26 February 2021. https://www.nature.com/articles/s41586-021-03361-1

Extensive study on the first update of SARS-CoV-2, namely the mutation at codon 614 (already partially dominant last spring in many countries). It is shown that the S-614G variant has enhanced binding to human host cell surface receptor ACE2, increased replication in primary human bronchial and nasal airway epithelial cultures as well as markedly increased replication and transmissibility in hamsters and ferrets. It will be interesting to see data on such in vivo competitive advantages with the new variants.

 

Epidemiology

Mensah AA, Sinnathamby M, Zaidi A, et al. SARS-CoV-2 infections in children following the full re-opening of schools and the impact of national lockdown: prospective, national observational cohort surveillance, July-December 2020, England. J Infection February 24, 2021. https://doi.org/10.1016/j.jinf.2021.02.022

In England, childhood cases closely followed adult infection rates and national lockdown whilst keeping schools open was associated with large declines in SARS-CoV-2 infection rates, first in adults and then in school-aged children. There was a strong correlation in weekly infection rates between adults and all three educational cohorts during periods of both low and high community infection rates. Two messages from this paper: Schools are not the drivers but low community infection rates are required to allow schools to remain open safely.

 

Hyde Z. Difference in SARS-CoV-2 attack rate between children and adults may reflect bias. Clinical Infectious Diseases 26 February 2021, ciab183, https://doi.org/10.1093/cid/ciab183

In her brief review, Zoë Hyde from Perth, Australia argues that lower secondary attack rates in children compared to adults may reflect lower testing in children and reduced exposure, rather than a genuine difference in biological susceptibility. Additionally, children may shed infectious virus for a shorter period than adults and their antibody response may be less broad, with implications for both polymerase chain reaction and serological testing. After reviewing the data available so far, she thinks it likely that children are more susceptible to SARS-CoV-2 infection than first thought, and they probably play an important role in community transmission.

 

Immunology

Pawlowski C, Puranik A, Bandi H. et al. Exploratory analysis of immunization records highlights decreased SARS-CoV-2 rates in individuals with recent non-COVID-19 vaccinations. Sci Rep 11, 4741 (2021). https://doi.org/10.1038/s41598-021-83641-y

Do existing vaccines afford protection against SARS-CoV-2 infection through trained immunity? By analyzing immunization records from 137,037 individuals, Colin Pawlowski and colleagues from Cambridge found that several vaccines such as polio, MMR, flu or hepatitis A/hepatitis B vaccines administered in the past 1-5 years were associated with decreased SARS-CoV-2 infection rates, even after adjusting for geographic SARS-CoV-2 incidence and testing rates, demographics, co-morbidities, and number of other vaccinations. But can we believe this? Can we control for the “healthy user effect” (that persons who have recently had other vaccines may engage in general health-seeking behaviors which decrease their risk of SARS-CoV-2 infection)? The authors say yes. In a “negative control” experiment on patients who have recently taken cancer screens (who may also have lower rates due to the “healthy user effect”), their propensity score matching method was able to correct for confounding.

 

Transmission

Metlay JP, Haas JS, Soltoff AE, Armstrong KA. Household Transmission of SARS-CoV-2. JAMA Netw Open. 2021 Feb 1;4(2):e210304. PubMed: https://pubmed.gov/33635324. Full-text: https://doi.org/10.1001/jamanetworkopen.2021.0304

In this large hospital and ambulatory care network based in Boston, US, 7262 index cases were linked to 17,917 additional at-risk individuals assigned to the same addresses. Overall household infection risk was 10.1%. Independent factors significantly associated with higher transmission risk included age greater than 18 years and multiple comorbid conditions (adjusted OR for individuals with hypertension, 1.93). In sensitivity analyses limiting the maximum size of the household to as small as 2 persons, the calculated transmission risk increased to only 13.8%.

 

Kraay ANM, Hayashi MAL, Berendes DM, Sobolik JS, Leon JS, Lopman BA. Risk for fomite-mediated transmission of SARS-CoV-2 in child daycares, schools, nursing homes, and offices. Emerg Infect Dis. February 24, 2021. https://wwwnc.cdc.gov/eid/article/27/4/20-3631_article

SARS-CoV-2 can persist on surfaces, suggesting possible surface-mediated transmission of this pathogen. Using a transmission model to explore the potential for fomite transmission without other pathways, Alicia N.M. Kraay from Atlanta and colleagues found that fomites might be a substantial source of transmission risk, particularly in schools and child daycares. Combining surface cleaning and decontamination with mask wearing can help mitigate this risk.

 

Clinical

van Westen-Lagerweij NA, Meijer E, Meeuwsen EG, et al. Are smokers protected against SARS-CoV-2 infection (COVID-19)? The origins of the myth. npj Primary Care Respiratory Medicine February 26, 2021, volume 31, Article number: 10. https://www.nature.com/articles/s41533-021-00223-1

Do you believe that alcohol disinfects the stomach? Ok, then you don’t need to read any further. For the rest of us, this commentary dispels a few myths (or, if you will, bullsh*t studies) about smoking and COVID-19.

 

Struyf T, Deeks JJ, Dinnes J, et al. Signs and symptoms to determine if a patient presenting in primary care or hospital outpatient settings has COVID-19. Cochrane Database Syst Rev. 2021 Feb 23;2:CD013665. PubMed: https://pubmed.gov/33620086. Full-text: https://doi.org/10.1002/14651858.CD013665.pub2

Are there signs and symptoms predicting COVID-19? This Cochrane review says no.

 

Treatment

Janiaud P, Axfors C, Schmitt AM, et al. Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis. JAMA. 2021 Feb 26. PubMed: https://pubmed.gov/33635310. Full-text: https://doi.org/10.1001/jama.2021.2747

This review of all RCTs published until January 29 showed that compared with placebo or standard of care, convalescent plasma was not significantly associated with a decrease in all-cause mortality or with any benefit for other clinical outcomes.

 

Gupta A, Madhavan MV, Poterucha TJ, et al. Association between antecedent statin use and decreased mortality in hospitalized patients with COVID-19. Nat Commun 12, 1325 (2021). https://doi.org/10.1038/s41467-021-21553-1

Better take your statins! Among 1296 patients (648 statin users, 648 non-statin users) identified with 1:1 propensity-score matching, statin use was significantly associated with lower odds of in-hospital mortality within 30 days in the propensity-matched cohort (OR 0.47, 95% CI: 0.36–0.62, p < 0.001). The potential benefits from statins extend beyond cholesterol-lowering properties, as there is a robust literature supporting the anti-inflammatory properties of statins, suggesting that these drugs can stabilize and restore endothelial function. Randomized clinical trials are ongoing (and needed).

 

Herrett E, Williamson E, Brack K, et al. Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials. BMJ. 2021 Feb 24;372:n135. PubMed: https://pubmed.gov/33627334. Full-text: https://www.bmj.com/content/372/bmj.n135

And for those patients who supposedly can’t tolerate a statin, it’s probably not the case. In this nice study among 151 participants who had recently stopped or were considering stopping treatment with statins because of muscle symptoms, no difference in muscle symptom scores was found between the statin and placebo periods. Withdrawals because of intolerable muscle symptoms were 18 participants (9%) during a statin period and 13 (7%) during a placebo period. Two thirds of those completing the trial reported restarting long-term treatment with statins.