Top 10: June 2021

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By Christian Hoffmann &
Bernd S. Kamps

30 June


Pokhrel S, Kraemer BR, Burkholz S. et al. Natural variants in SARS-CoV-2 Spike protein pinpoint structural and functional hotspots with implications for prophylaxis and therapeutic strategies. Sci Rep June 23, 2021, 11, 13120.

This analysis of the frequency of variants throughout the S protein of SARS-CoV-2 identified regions of high and low divergence, which may aid in developing effective prophylactic and therapeutic treatments.



Jalkanen P, Kolehmainen P, Häkkinen HK, et al. COVID-19 mRNA vaccine induced antibody responses against three SARS-CoV-2 variants. Nat Commun June 28, 2021, 12, 3991.

After the second dose, the sera of BNT162b2-vaccinated health care workers (n = 180) from Finland effectively neutralized the SARS-CoV-2 variant with the D614G substitution and the B.1.1.7 variant, whereas the neutralization of the B.1.351 variant was five-fold reduced. However, 92% of the seronegative vaccinees had a neutralization titre of >20 for the B.1.351 variant indicating some protection.


Collateral damage (and benefit)

Wilmers CC, Nisi AC, Ranc N, et al. COVID-19 suppression of human mobility releases mountain lions from a landscape of fear. Current Biology June 23, 2021DOI:

One day, when humans will all be gone from earth, nature will quickly come out of its holes. Mountain lions first (according to this study where GPS collars were placed on six animals). Results: The drastic change in human behavior due to the Covid-19 pandemic had cascading effects on mountain lion habitat selection. Under normal circumstances, mountain lions strongly avoid urban areas. When human mobility declined by more than 50% during the Covid-19 associated lockdown, mountain lions relaxed their fear of the urban edge during the lockdown.


Wan WY, Thoon KC, Loo LH, et al. Trends in Respiratory Virus Infections During the COVID-19 Pandemic in Singapore, 2020. JAMA Netw Open June 28, 2021. 4(6):e2115973.

A decrease in influenza was already seen following relatively modest control measures, including mask-wearing recommendations among only ill or symptomatic individuals. Influenza remained nearly absent for the remainder of 2020. International travel restrictions likely contributed to this. For enterovirus/rhinovirus and adenovirus, reductions were only seen after lockdown, and these viruses rebounded earlier than others. Continued mandatory mask wearing did not appear to prevent this.



McCleskey PE, Zimmerman B, Lieberman A, et al. Epidemiologic Analysis of Chilblains Cohorts Before and During the COVID-19 Pandemic. JAMA Dermatol June 23, 2021.

This study suggests that the weak correlation between incidence of chilblains and incidence of COVID-19 infection may represent changes in pandemic behavior that led to increased diagnosis of chilblains. Very few cases of chilblains were positive for COVID-19.


29 June


Leong LEX, Soubrier J, Turra M, Denehy E, Walters L, Kassahn K, et al. Whole-genome sequencing of SARS-CoV-2 from quarantine hotel outbreak. Emerg Infect Dis June 22, 2021.

A quarantine hotel–associated community outbreak was detected in South Australia. The first identified positive case in the outbreak was a family member of a housekeeping attendant at one of the quarantine hotels. Immediate screening of close contacts rapidly identified 14 additional cases, including 2 security guards working in the same hotel. The suspected source case was a traveler having returned from the United Kingdom.



Gobeil MC, Janowska K, McDowell S, et al. Effect of natural mutations of SARS-CoV-2 on spike structure, conformation, and antigenicity. Science 24 Jun 2021: eabi6226.

This study reveals allosteric effects of mutations and mechanistic differences that drive either inter-species transmission or escape from antibody neutralization. In other words, this study explains the rapid spread of variants. There is an increased binding to ACE2, mediated both by affinity enhancing substitutions in the RBD and increased propensity for the receptor-accessible RBD up states. All variants showed increased ACE2 receptor binding and increased propensity for RBD up states. A local destabilizing effect of the RBD E484K mutation was implicated in resistance of the B.1.1.28/P.1 (Brazil) and B.1.351 (South Africa) variants to neutralizing antibodies.



Borobia AM, Carcas AJ, Pérez-Olmeda M, et al. Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial. The Lancet June 25, 2021.

A 14-day robust humoral and cellular immune response after a second dose of BNT162b2 in individuals primed with ChAdOx1-S 8–12 weeks earlier. The immune response with the heterologous vaccination schedule was within the range of those previously reported using homologous schedules. However, the main limitation of this study was the absence of a control group completing the homologous ChAdOx1-S scheme.



Roberts SC, Peaper DR, Sussman LS, et al. Utility of Mass SARS-CoV-2 Testing of Asymptomatic Patients Before Ambulatory and Inpatient Preplanned Procedures Requiring Moderate Sedation or General Anesthesia. JAMA Netw Open June 25, 2021;4(6):e2114526.

Mass pre-procedure SARS-CoV-2 nucleic acid amplification testing during a period of high community transmission. Among a total of 75,528 pre-procedure tests, 318 (0.4%) tested positive.



Hall S. COVID vaccines and breastfeeding: what the data say. Nature NEWS June 23, 2021.

Shannon Hall summarizes current knowledge. The vaccines do not pass via breastmilk, but antibodies do — providing hope that breastfed babies might have some level of protection. While reading this article, some of you will learn a new phrase: “milk mysteries”.


28 June


Ginther DK, Zambrana C. Association of Mask Mandates and COVID-19 Case Rates, Hospitalizations, and Deaths in Kansas. JAMA Netw Open June 23, 2021; 4(6):e2114514.

At the start of the mask mandate, COVID-19 case rates in mask counties were 3 times higher than in no-mask counties (15 versus 5 cases per 100,000). These trends reversed, and by October 26, 2020, cases were 2.1 times higher in no-mask counties (44 versus 21 cases per 100,000). Similar results were found for hospitalizations and deaths.



Puray-Chavez M, LaPak KM, Schrank TP. Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell. Cell Rep June 23, 2021.

Screening several human lung and head & neck cancer cell lines expressing varying levels of ACE2 and TMPRSS2, the authors identified a human lung adenocarcinoma cell line as being naturally permissive to SARS-CoV-2 infection despite no evidence of detectable ACE2 and TMPRSS2 expression. The E484D spike substitution appears to be specifically required for viral entry into H522 cells.


Cao C, Cai Z, Xiao X, et al. The architecture of the SARS-CoV-2 RNA genome inside virion. Nat Commun June 24, 2021, 12, 3917.

The authors developed a high-throughput approach for theoretically probing the in situ genome structure of any RNA virus. This RNA in situ conformation sequencing technology, named RIC-seq, allows unbiased mapping of RNA-RNA spatial interactions in living cells. In this study, the authors successfully applied the technology to probe the SARS-CoV-2 RNA genome structure in intact virions.



Choe PG, Kang CK, Kim KH, et al. Persistence of Neutralizing Antibody Response up to One Year after Asymptomatic or Symptomatic SARS-CoV-2 infection. The Journal of Infectious Diseases June 24, 2021, jiab339,

Of 16 patients (7 asymptomatic), all showed neutralizing antibody response up to 1 year after infection.



Woolf SH, Masters RK, Aron LY. Effect of the covid-19 pandemic in 2020 on life expectancy across populations in the USA and other high income countries: simulations of provisional mortality data. BMJ June 24, 2021; 373 doi:

Between 2018 and 2020, life expectancy in the US decreased by 1.87 years (to 76.87 years), 8.5 times the average decrease in peer countries (0.22 years). Losses were more pronounced among the Hispanic and non-Hispanic Black populations. Life expectancy in Black men reached its lowest level since 1998.



Tummino TA, Rezelj VV, Fischer B, et al. Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2. Science 22 Jun 2021: eabi4708.

Paper of the day. Why did so many drugs that were repurposed for antiviral activity against SARS-CoV-2 fail in vivo, despite promising effects in vitro? This milestone study may explain why. Many drugs are cationic amphiphiles, and despite their diverse structures and multiple targets, many likely have their antiviral effects via a single shared mechanism: phospholipidosis. Both because of the side effects with which it is associated, and the limited efficacy to which it leads, drugs active due to phospholipidosis are unlikely to translate in vivo. Many resources will be saved by counter-screening for phospholipidosis in simple cellular assays.


Case JB, Chen RE, Cao L, et al. Ultrapotent miniproteins targeting the SARS-CoV-2 receptor-binding domain protect against infection and disease. Cell Host Microbe June 18, 2021.

Compared to other SARS-CoV-2 antibody-based treatments, mini-proteins have several benefits: (a) due to their smaller size, they can bind each protomer of a single trimeric spike, resulting in greater potency for a given dose; (b) they can be manufactured cost-effectively; (c) if warranted, they can be refined and mixed to overcome escape and resistance by new variants. The authors have developed picomolar range mini-proteins targeting the SARS-CoV-2 spike receptor binding domain. Here, they investigated the capacity of modified versions of one lead mini-protein, LCB1, to protect against SARS-CoV-2-mediated lung disease in mice. Promising. The immunogenicity and pharmacokinetic and pharmacodynamic properties of the mini-binders in larger vertebrate animals will inform possible clinical evaluation in humans.


27 June

Variants + Long COVID Special

Today we focus on two issues: variants of concern and long COVID. First, read about some new variants of concern (VOC) and how SARS-CoV-2 has evolved to enhance viral fitness and immune evasion (and that the worst is yet to come!). Second, we summarize some long COVID studies in non-hospitalized cohorts, long-term data and studies addressing different issues such as anosmia or tauopathy.



Cai Y, Zhangf J, Xiao T, et al. Structural basis for enhanced infectivity and immune evasion of SARS-CoV-2 variants. Science 24 Jun 2021: eabi9745.

How has SARS-CoV-2 evolved to enhance viral fitness and immune evasion? This study describes cryo-EM structures of the full-length spike (S) trimers of the B.1.1.7 and B.1.351 variants, as well as their biochemical and antigenic properties. Of note, findings also suggest that the most problematic combination of mutations is not (yet) present in the existing variants examined here.


Otto SP, Day T, Arino J, et al. The origins and potential future of SARS-CoV-2 variants of concern in the evolving COVID-19 pandemic. Current Biology June 23, 2021.

Nice overview about the evolutionary processes involved in the emergence and selection of new variants of concern (VOC), about what we can expect in terms of the future emergence of VOCs, and what we can do to minimize their impact.


Jennewein MF, MacCamy AJ, Atkins NR, et al. Isolation and Characterization of Cross-Neutralizing Coronavirus Antibodies from COVID-19+ Subjects. Cell Rep June 21, 2021.

Among 198 antibodies isolated from four COVID-19+ subjects, four cross-neutralizing antibodies neutralized the B.1.351 mutant strain.


Bugembe DL, Phan MV, Ssewanyana I, et al. Emergence and spread of a SARS-CoV-2 lineage A variant (A.23.1) with altered spike protein in Uganda. Nat Microbiol June 23, 2021.

A new variant of concern? The authors describe the emergence and spread of a SARS-CoV-2 variant of the A lineage (A.23.1) with multiple protein changes throughout the viral genome. A.23.1 shares many features found in the lineage B VOCs, including alteration of key spike protein regions, especially the ACE 2 binding region, the furin cleavage site and the 613/614 change.


McEwen AE, Cohen S, Bryson-Cahn C, et al. Variants of concern are overrepresented among post-vaccination breakthrough infections of SARS-CoV-2 in Washington State. Clinical Infectious Diseases June 24, 2021, ciab581,

Across 20 vaccine breakthrough cases detected, all 20 were due to variants of concern (VOC) and had a low median Ct of 20.2 (IQR=17.1-23.3). Variants B.1.427, B.1.429, and B.1.1.7 were 3.38-fold, 1.51-fold, and 1.29-fold more common in breakthrough cases compared to controls.



Amin-Chowdhury Z, Ladhani SN. Causation or confounding: why controls are critical for characterizing long COVID. Nat Med June 17, 2021.

Read this first, in order to understand the limitations, biases and caveats in the following studies.


Blomberg B, Mohn KG, Brokstad KA, et al. Long COVID in a prospective cohort of home-isolated patients. Nat Med June 22, 2021.

In this study from Norway, 32/61 of home-isolated young adults aged 16–30 years had symptoms at 6 months, including loss of taste and/or smell (28%), fatigue (21%), dyspnea (13%), impaired concentration (13%) and memory problems (11%).

Pratt J, Lester E, Parker R. Could SARS-CoV-2 cause tauopathy? Lancet Neurology, July, 2021.
James Pratt, Evan Lester and Roy Parker believe that follow-up studies of neurological dysfunction in survivors of COVID-19 should be done, particularly in people who showed acute or subacute neurological symptoms. Such studies should continue for at least a decade and focus on young individuals in order to reduce the proportion of participants who develop tauopathies due to age.


Menezes AMB, Victora CG, Hartwig FP, et al. High prevalence of symptoms among Brazilian subjects with antibodies against SARS-CoV-2. Sci Rep June 24, 2021, 11, 13279.

Out of 849 (2.7%) participants positive for SARS-CoV-2 antibodies, only 12.1% reported no symptoms, compared to 42.2% among those negative. The main limitation: the information was collected after the individual had learned about the test result.


Bliddal S, Banasik K, Pedersen OB, et al. Acute and persistent symptoms in non-hospitalized PCR-confirmed COVID-19 patients. Sci Rep June 23, 2021, 11, 13153.

Among non-hospitalized PCR-confirmed COVID-19 patients, one third were asymptomatic while one third of symptomatic participants had persistent symptoms illustrating the heterogeneity of disease presentation. The most common persistent symptoms were fatigue and memory and concentration difficulties, reported by 36% of 198 symptomatic participants with follow-up > 4 weeks. Risk factors for persistent symptoms included female sex (women 44% vs. men 24%) and BMI.


Renaud M, Thibault C, LeNormand F, et al. Clinical Outcomes for Patients With Anosmia 1 Year After COVID-19 Diagnosis. JAMA Netw Open June 24, 2021;4(6):e2115352.

At 8 months, objective olfactory assessment confirmed full recovery in 49 of 51 patients (96%). Two patients remained hyposmic at 1 year. Findings suggest that an additional 10% gain in recovery can be expected at 12 months, compared to studies with 6 months of follow-up.


26 June

Vaccines Special

Today we have another vaccine special. Some new data on cutaneous reactions, on facial nerve palsy and myocarditis. How to overcome poor antibody response in transplant recipients, and about efficacy and effectiveness of vaccines in SARS-CoV-2 variants of concern.

Efficacy and effectiveness

Mateo-Urdiales A, Alegiani SS, Fabiani M, et al. Risk of SARS-CoV-2 infection and subsequent hospital admission and death at different time intervals since first dose of COVID-19 vaccine administration, Italy, 27 December 2020 to mid-April 2021. Eurosurveillance June 24, 2021.

Compared with the reference period, the authors observed a reduction in the overall incidence of infection (2.9 vs 1.3 per 10,000 person-days), hospitalization (0.44 vs 0.12) and death (0.18 vs 0.04), both overall and stratifying by age group, sex, geographical location and calendar period.



Yu J, Tostanoski LH, Mercado NB, et al. Protective efficacy of Ad26.COV2.S against SARS-CoV-2 B.1.351 in macaques. Nature June 23, 2021.

This study may provide an explanation of why the Johnson & Johnson vaccine worked well in South Africa. In rhesus macaques, Ad26.COV2.S induced cross-reactive antibody and T cell responses against SARS-CoV-2 variants of concern, including the B.1.351 variant.


Vaccines and Comorbidities

Mazzola A, Todesco E, Drouin S, et al. Poor Antibody Response after Two Doses of SARS-CoV-2 vaccine in Transplant Recipients. Clinical Infectious Diseases June 24, 2021, ciab580,

A low anti-spike antibody response of 28.6% was observed 28 days after BNT162b2 vaccine second dose among 133 solid organ transplant recipients.


Kamar N, Abravanel F, Marion O, et al. Three Doses of an mRNA Covid-19 Vaccine in Solid-Organ Transplant Recipients. N Engl J Med Jun 23, 2021.
Is a third jab the solution? Among the 59 solid organ transplant recipients who had been seronegative before the third dose of the BioNTech vaccine, 26 (44%) were seropositive 4 weeks after the third dose.


Adverse events

Shemer A, Pras E, Einan-Lifshitz A, et al. Association of COVID-19 Vaccination and Facial Nerve Palsy – A Case-Control Study. JAMA Otolaryngol Head Neck Surg June 24, 2021.

In this case-control study of 37 patients with acute-onset facial nerve palsy and a matched control group, no increased risk of facial nerve palsy was observed after vaccination with the Pfizer-BioNTech BNT162b2 COVID-19 vaccine.


Tamaki A, Cabrera CI, Li S, et al. Incidence of Bell Palsy in Patients With COVID-19. JAMA Otolaryngol Head Neck Surg June 24, 2021.
Bell palsy is a unilateral peripheral facial nerve palsy of sudden onset. Media reports of BP associated with vaccination have raised concerns. After matching patients with COVID-19 to vaccinated individuals (n = 63,551), there was an increased relative risk of 6.8 (P < .001) of a diagnosis of BP in those with COVID-19 compared to those who were vaccinated. The rate of recurrent BP in patients with previous BP at the time of COVID-19 diagnosis was 8.6%.


Robinson LB, Fu CX, Hashimoto D, et al. Incidence of Cutaneous Reactions After Messenger RNA COVID-19 Vaccines. JAMA Dermatol June 24, 2021.

In this prospective cohort of almost 50,000 health care employees, 1.9% self-reported cutaneous reactions after receiving the first dose of an mRNA COVID-19 vaccine. With more than 600 employees with first-dose cutaneous reactions included, 83% did not have recurrent cutaneous reactions. An additional 2.3% reported cutaneous reactions only after the second dose of the vaccine.


Rosner CM, Genovese L, Tehrani BN, et al. Myocarditis Temporally Associated with COVID-19 Vaccination. Circulation 16 Jun 2021.

Seven patients hospitalized for acute myocarditis-like illness following COVID-19 vaccination. All were white males < 40 years of age. All patients presented 3-7 days post vaccination with acute onset chest pain and biochemical evidence of myocardial injury, by cardiac troponin I. The clinical course was favorable.


Larson KF, Ammirati E, Adler ED, et al. Myocarditis after BNT162b2 and mRNA-1273 Vaccination. Circulation 16 Jun 2021.

Eight patients hospitalized with chest pain who were diagnosed with myocarditis by laboratory and cardiac magnetic resonance imaging within 2-4 days of receiving either the BNT162b2 or mRNA-1273 vaccine. All were otherwise healthy males between the ages of 21 and 56. Troponin values were elevated in all individuals.


25 June


Krause PR, Fleming TR, Longini IM, et al. SARS-CoV-2 Variants and Vaccines. NEJM June 23, 2021.

Special report on variants. So far, there is no good evidence that currently identified variants of concern evade the most important vaccine effect — that of prevention of severe disease.


Bager P, Wohlfahrt J, Fonager J, et al. Risk of hospitalisation associated with infection with SARS-CoV-2 lineage B.1.1.7 in Denmark: an observational cohort study. Lancet June 22, 2021.

In this large study on 50,958 individuals, B.1.1.7 was associated with an adjusted RR of 1.42 (95% CI 1.25–1.60; p<0.0001). The adjusted RR was increased in all strata of age and calendar period—the two covariates with the largest contribution to confounding of the crude RR.



Shroti M, Krutikov M, Palmer T, et al. Vaccine effectiveness of the first dose of ChAdOx1 nCoV-19 and BNT162b2 against SARS-CoV-2 infection in residents of long-term care facilities in England (VIVALDI): a prospective cohort study. Lancet Inf Dis June 23, 2021.

Among 10,412 care home residents aged 65 years and older, adjusted hazard ratios for PCR-positive infection relative to unvaccinated residents declined from 28 days after the first vaccine dose to 0.44 (95% CI 0.24–0.81) at 28–34 days and 0.38 (0.19–0.77) at 35–48 days. Similar effect sizes were seen for ChAdOx1 and BNT162b2 vaccines at 35–48 days.


Hyams C, Marlow R, Maseko Z. Effectiveness of BNT162b2 and ChAdOx1 nCoV-19 COVID-19 vaccination at preventing hospitalisations in people aged at least 80 years: a test-negative, case-control study. Lancet Inf Dis June 23, 2021.

Same direction: one dose of either BNT162b2 or ChAdOx1 nCoV-19 resulted in substantial risk reductions of COVID-19-related hospitalization in people aged 80 years or above. The adjusted vaccine effectiveness was 80.4% (95% CI: 36.4–94.5).


Prendecki M, Willicombe M. Single-dose SARS-CoV-2 vaccination efficacy in the elderly. Lancet Inf Dis 2021, June 23.

In their comment on the two studies above, Maria Prendecki and Michelle Willicombe argue that these two studies give cause for optimism – that despite older individuals developing decreased humoral responses to vaccines, including SARS-CoV-2, vaccine efficacy is high, and second doses will probably increase efficacy further. The results also highlight some of the difficulties in trying to make comparisons between vaccines in real-world studies.



Amin-Chowdhury Z, Ladhani SN. Causation or confounding: why controls are critical for characterizing long COVID. Nat Med June 17, 2021.

Zahin Amin-Chowdhury and Shamez N. Ladhani discuss the eminent limitations, biases and caveats of long COVID studies that have been published to date. More robust, well-conducted longitudinal studies are urgently needed for proper characterization of this syndrome.



24 June


Kwon S, Joshi AD, Lo CH. et al. Association of social distancing and face mask use with risk of COVID-19. Nat Commun Jun 21, 2021, 12, 3737.

Individuals living in communities with the greatest social distancing had a 31% lower risk of predicted COVID-19 compared with those living in communities with poor social distancing. Self-reported ‘always’ use of face mask was associated with a 62% reduced risk of predicted COVID-19 even among individuals living in a community with poor social distancing.



Bøhler AD, Strøm ME, Sandvig KU et al. Acute macular neuroretinopathy following COVID-19 vaccination. Eye June 21, 2021.

A patient who developed an acute paracentral scotoma after having received the AstraZeneca vaccine: the signs and symptoms were consistent with acute macular neuroretinopathy (AMN).


Matheney M, Maleque N, Channell N, et al. Severe Exacerbations of Systemic Capillary Leak Syndrome After COVID-19 Vaccination: A Case Series. Ann Int Med June 15, 2021.

Three patients who had severe flares of SCLS immediately after receiving standard doses of the COVID-19 vaccines (AstraZeneca, BioNTech and Moderna). The authors recommend that patients with a diagnosis or suspected diagnosis of SCLS should receive IVIG prophylaxis before vaccination.



Steenblock C, Richter S, Berger I. et al. Viral infiltration of pancreatic islets in patients with COVID-19. Nat Commun June 21, 2021, 12, 3534.

Using human islets and autopsy tissue from patients that died of COVID-19, this study provides clear proof that beta cells are permissive to infection with SARS-CoV-2. The mechanism of virus entry is not completely clear at this point as ACE2 is only expressed in beta cells in a subset of patients. Therefore, other receptors/factors may be involved in facilitating uptake of SARS-CoV-2 into beta-cells. SARS-CoV-2 may induce a local inflammation and may be associated with necroptotic cell death in islets, but the current study cannot answer in detail the mechanism that may lead to islet impairment and metabolic dysregulation.


Collateral damage (and benefits)

Lepak AJ, Taylor LN, Stone CA, et al. Association of Changes in Seasonal Respiratory Virus Activity and Ambulatory Antibiotic Prescriptions With the COVID-19 Pandemic. JAMA Intern Med June 21, 2021.

This study from Wisconsin, US demonstrated a marked decrease in respiratory virus detection, with a concomitant 79% decline in ambulatory antibiotic prescribing rates for respiratory tract infections, during the COVID-19 pandemic.


Duffy E, Thomas M, Hills T, Ritchie S. The impacts of New Zealand’s COVID-19 epidemic response on community antibiotic use and hospitalisation for pneumonia, peritonsillar abscess and rheumatic fever. Lancet Regional Health July 01, 2021.

Same findings from New Zealand. Antibiotic dispensing rates fell by 36%, suggesting that countries with high rates of antibiotic use could significantly reduce their use without an increase in morbidity.


23 June


Whaley CM, Cantor J, Pera M, et al. Assessing the Association Between Social Gatherings and COVID-19 Risk Using Birthdays. JAMA Intern Med June 21, 2021.

Yes, there is an association between household birthdays, which likely correspond to informal social gatherings, and COVID-19. Among the 2.9 million households in the study, in the top 10% of counties in COVID-19 prevalence, households with a birthday in the 2 weeks prior had 8.6 more diagnoses per 10,000 individuals compared with households without a birthday in the 2 weeks prior. The relative increase was 31% of county-level prevalence and was even larger in magnitude in households that had a recent child’s (vs adult’s) birthday.



Werbel WA, Boyarsky BJ, Ou MT, et al. Safety and Immunogenicity of a Third Dose of SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients: A Case Series. Ann Int Med 15 June, 2021.

A booster may work. In 30 patients, antibody titers increased after the third dose in one third of patients who had negative antibody titers and in all patients who had low-positive antibody titers. Vaccine reactions seem to be acceptable.



Yang AC, Kern F, Losada PM, et al. Dysregulation of brain and choroid plexus cell types in severe COVID-19. Nature Jun 21, 2021.

By combining sequencing of 65,309 nuclei in both the frontal cortex and choroid plexus along with confirmatory IHC and RT-qPCR, this study reveals several major neuropathological mechanisms in severe COVID-19.


Kentish-Barnes N, Cohen-Solal Z, Morin L, et al. Lived Experiences of Family Members of Patients With Severe COVID-19 Who Died in Intensive Care Units in France. JAMA Netw Open June 21, 2021; 4(6):e2113355.

This study reports how bereaved family members’ experiences of care, death, and mourning were disrupted during the first wave of the COVID-19 pandemic, both during hospitalization in the ICU and after the patient’s death. The main finding is “what family-centered research has taught us in the last 20 years: the presence of family members in ICUs should remain a priority”.



Saatci D, Ranger TA, Garriga C, et al. Association Between Race and COVID-19 Outcomes Among 2.6 Million Children in England. JAMA Pediatr June 21, 2021;

Compared with White children, Asian children were more likely to have COVID-19 hospital admissions (adjusted odds ratio 1.62; 95% CI: 1.12-2.36), while Black children and children of mixed or other races had comparable hospital admissions to Whites. However, ascertainment bias and residual confounding in this cohort study should be considered before drawing further conclusions.


22 June


Li D, Edwards RJ, Manne K, et al. In vitro and in vivo functions of SARS-CoV-2 infection-enhancing and neutralizing antibodies. Cell June 18, 2021.

A safety concern for the clinical use of antibodies (Abs) is antibody-dependent enhancement (ADE) of infection. This study identified potent in vitro infection-enhancing Abs from individuals infected with SARS-CoV or SARS-CoV-2, as well as the precise epitopes of infection-enhancing Abs. However, in vitro infection-enhancing Abs controlled virus in vivo and were rarely associated with enhanced lung pathology.



Karan A, Klompas M, Tucker R, et al. Patients with Undiagnosed Covid-19 to Roommates in a Large Academic Medical Center. Clinical Infectious Diseases June 18, 2021, ciab564,

Almost 40% of patients that shared a hospital room with someone with occult SARS-CoV-2 infection became infected. Among 31 exposed roommates, 12 tested positive within 14 days. The risk was highest for patients sharing rooms with individuals with very low Ct counts (< 22).


Vaccines and co-morbidities

Addeo A, Shah PK, Bordry N, et al.  Immunogenicity of SARS-CoV-2 messenger RNA Vaccines in Patients with Cancer. Cancer Cell June 18, 2021.

None of the patients with a history of anti-CD20 antibody in the 6 months prior to vaccination developed an antibody response. None of the four patients with a history of anti-CD20 antibody in the 6 months prior to vaccination developed an antibody response.


Frater J, Ewer KJ, Ogbe A, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 in HIV infection: a single-arm substudy of a phase 2/3 clinical trial. Lancet HIV, June 18, 2021.

In this study of 53 people with HIV, ChAdOx1 nCoV-19 was safe and immunogenic. There was no correlation between the magnitude of the anti-spike IgG response at day 56 and CD4 cell count or age.


Collateral damage (and benefits)

Braunstein SL, Slutsker JS, Lazar R, et al. Epidemiology of reported HIV and other sexually transmitted infections during the COVID-19 pandemic, New York City. J Inf Dis Jun 16, 2021, jiab319,

During NYC lockdown, the volume of positive HIV/STI tests, and diagnoses of HIV, chlamydia, gonorrhea, and syphilis declined substantially, reaching a nadir in April before rebounding.


21 June


García CR, Iftimi A, Briz-Redón A, et al. Trends in Incidence and Transmission Patterns of COVID-19 in Valencia, Spain. JAMA Netw Open June 18, 2021; 4(6):e2113818.

The major observation of this epidemiological cohort study of 2646 patients with COVID-19 was that the neighborhood where the COVID-19 testing facility was located also had the highest number of total connections (both inbound and outbound). Thus, hospitals with a testing facility might become a major contributor to local spread.



Aydillo T, Rombauts A, Stadlbauer D, et al. Immunological imprinting of the antibody response in COVID-19 patients. Nat Commun June 18, 2021, 12, 3781.

The induction of antibodies against conserved epitopes of seasonal coronaviruses may hinder the induction of specific antibodies toward divergent SARS-CoV-2 antigens. Immunity to other betacoronavirus spikes, like HKU1 and OC43, limited the induction of de novo responses to all SARS-CoV-2 antigens tested.



De Paula Eduardo F, Corrêa L, Heller D, et al. Salivary SARS-CoV-2 load reduction with mouthwash use: a randomized pilot clinical trial. Heliyon June 17, 2021.

Mouthwash with cetylpyridinium chloride + zinc and chlorhexidine gluconate resulted in significant reductions of the SARS-CoV-2 viral load in saliva up to 60 mins after rinsing, while hydrogen peroxide mouthwash resulted in a significant reduction up to 30 mins after rinsing.



Aman J, Duijvelaar E, Botros L, et al. Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial. Lancet Resp Med June 17, 2021.

Early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak. In this large RCT, imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in 385 patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (8% versus 14% with placebo) were attenuated after adjustment for baseline imbalances.



McArdle AJ, Vito O, Patel H. Treatment of Multisystem Inflammatory Syndrome in Children. NEJM June 16, 2021.

Large observational cohort of 614 children from 32 countries, with no evidence that recovery from MIS-C differed after primary treatment with IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone, although significant differences may emerge as more data accrue. See below.


Son BF, Murray N, Friedman K, et al. Multisystem Inflammatory Syndrome in Children — Initial Therapy and Outcomes. NEJM June 16, 2021.

This may be the case here. Surveillance data on 518 inpatients younger than 21 years of age who had MIS-C and were admitted to 1 of 58 US hospitals. In the propensity-score–matched analysis, initial treatment with IVIG plus glucocorticoids (103 patients) was associated with a lower risk of cardiovascular dysfunction on or after day 2 than IVIG alone (103 patients) (17% vs. 31%).


20 June


Iannetta M, Buccisano F, Fraboni D, et al. Baseline T-lymphocyte subset absolute counts can predict both outcome and severity in SARS-CoV-2 infected patients: a single center study. Sci Rep June 17, 2021, 11, 12762.

In this study on 160 patients, T lymphocyte subsets assessed at hospital admission were reduced in patients with increased risk of disease progression and unfavorable outcomes.



Campbell F, Archer B, Laurenson-Schafer H, et al. Increased transmissibility and global spread of SARS-CoV-2 variants of concern as at June 2021. Eurosurveillance June 2021; 26(24):pii=2100509.

This analysis of the effective reproduction number and global spread of SARS-CoV-2 variants with data available by 3 June 2021 suggest that B.1.617.2 is expected to rapidly out-compete other variants and become the dominant circulating lineage over the coming months.


Jacobson KB, Pinsky BA, Rath ME, et al. Post-vaccination SARS-CoV-2 infections and incidence of presumptive B.1.427/B.1.429 variant among healthcare personnel at a northern California academic medical center. Clin Inf Dis June 17, 2021, ciab554,

Presumptive B.1.427/B.1.429 was not more prevalent in post-vaccine cases than in unvaccinated SARS-CoV-2 healthcare personnel.



Stankov MV, Cossmann A, Bonifacius A, et al. Humoral and cellular immune responses against SARS-CoV-2 variants and human coronaviruses after single BNT162b2 vaccination. Clin Inf Dis June 16, 2021, ciab555,

This study shows suboptimal neutralizing antibody activity after a single BNT162b2 vaccination. T cells, which responded equally to spike-derived peptides from SARS-CoV-2 WT, B.1.1.7 and B.1.351 were detectable with a broad inter-individual range. The authors propose that non-neutralizing antibody function and/or cellular immunity constitute an important outcome after vaccination and may be part of the early defense against SARS-CoV-2 infection.



Bi Q, Lessler J, Eckerle I, et al. Insights into household transmission of SARS-CoV-2 from a population-based serological survey. Nat Commun June 15, 2021, 12, 3643.

This was a cross-sectional, household-based population serosurvey of 4534 people ≥ 5 years from 2267 households enrolled April-June 2020 in Geneva, Switzerland. The risk of infection from exposure to a single infected household member aged ≥ 5 years (17.3%, 13.7-21.7) was more than three-times that of extra-household exposures over the first pandemic wave (5.1%, 4.5-5.8). Young children had a lower risk of infection from household members.


Collateral damage

Hunter RF, Garcia L, de Sa TH et al. Effect of COVID-19 response policies on walking behavior in US cities. Nat Commun 12 June 15, 2021, 3652.

Analyzing mobility data from mobile devices and area-level data to study the walking patterns of 1.62 million anonymous users in 10 metropolitan areas in the US, this study reveals dramatic declines in walking, particularly utilitarian walking, while recreational walking has recovered and even surpassed pre-pandemic levels.


19 June


Wilk AJ, Lee MJ, Wei B, et al. Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19. J Exp Med June 15, 2021, 218 (8): e20210582.

These transcriptomic, epigenomic, and proteomic analyses revealed widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, including prominent hyperactivation signatures in neutrophils and NK cells.


Cheemarla NR, Watkins TA, Mihaylova VT, et al. Dynamic innate immune response determines susceptibility to SARS-CoV-2 infection and early replication kinetics. J Exp Med June 15, 2021.

The role of host innate immune defenses in restricting early infection using transcriptomics and biomarker-based tracking in serial patient nasopharyngeal samples and experiments with airway epithelial organoids. SARS-CoV-2 initially replicated exponentially, with a doubling time of ∼6 h, and induced interferon-stimulated genes (ISGs) in the upper respiratory tract, which rose with viral replication and peaked just as viral load began to decline. Most interesting finding: rhinovirus infection before SARS-CoV-2 exposure accelerated ISG responses and prevented SARS-CoV-2 replication.



Motozono C, Toyoda M, Zahradnik J, et al. SARS-CoV-2 spike L452R variant evades cellular immunity and increases infectivity. Cell Host Microbe June 14, 2021.

This study demonstrates that at least two naturally occurring mutations in the SARS-CoV-2 RBM, L452R and Y453F, escape HLA restricted cellular immunity and further promote affinity toward the viral receptor ACE2. The L452R mutation also increases the stability of the S protein and viral infectivity.


Liu C, Ginn HM, Dehnirattisai W, et al. Reduced neutralization of SARS-CoV-2 B.1.617 by vaccine and convalescent serum. Cell June 16, 2021.

The ability of monoclonal antibodies, convalescent and vaccine sera to neutralize B.1.617.1 and B.1.617.2 is reduced when compared with ancestral Wuhan strains but there is no evidence of widespread antibody escape as seen with B.1.351. However, B.1.351 and P.1 sera showed markedly more reduction in neutralization of B.1.617.2 suggesting that individuals previously infected by these variants may be more susceptible to re-infection by B.1.617.2.



Gonzalez DC, Nassau DE, Khodamoradi K et al. Sperm Parameters Before and After COVID-19 mRNA Vaccination. JAMA June 17, 2021.

No significant decreases (repeat: no significant decreases).



Guimarães PO, Quirk D, Furtado RH, et al. Tofacitinib in Patients Hospitalized with Covid-19 Pneumonia. NEJM June 16, 2021.

Tofacitinib is an orally administered selective inhibitor of Janus kinase (Jak), that blocks intracellular transduction pathways after a cytokine is bound to its receptor (as a consequence, no cellular response is triggered, and cytokine production is indirectly suppressed). Among patients hospitalized with COVID-19 pneumonia, tofacitinib led to a lower risk of death or respiratory failure through day 28 than did placebo. The cumulative incidence of death or respiratory failure was 18.1% versus 29.0% in the placebo group (risk ratio, 0.63; 95% CI: 0.41 to 0.97; p = 0.04).


18 June

Today another vaccine special on effectiveness against the delta variant and in HCW, on delayed local reactions, as well as on safety and immunogenicity in pregnant women.



Samarakoon U, Alvarez-Arango S, Blumenthal KG. Delayed Large Local Reactions to mRNA Covid-19 Vaccines in Blacks, Indigenous Persons, and People of Color. NEJM June 9, 2021.

Photos of eight large local reactions are shown. The mean time from vaccination until the onset of the reaction was 8 ± 2 days (range, 4 to 14).



Gupta K, O’Brian WJ, Bellino P, et al. Incidence of SARS-CoV-2 Infection in Health Care Workers After a Single Dose of mRNA-1273 Vaccine. JAMA Netw Open June 16, 2021;4(6):e2116416.

This study demonstrated an association between receipt of the mRNA-1273 vaccine and a reduction in SARS-CoV-2 infection in HCWs beginning 8 days after dose 1. Vaccine clinical effectiveness was 50.3% for the entire 42-day period of follow-up, 77.5% for days 8 through 42, and 95.0% for days 15 through 42.


Stowe J, Andrews N, Gower C, et al. Effectiveness of COVID-19 vaccines against hospital admission with the Delta (B.1617.2) variants. June 14, 2021.

Not peer-reviewed, but incredibly good news and very important for everybody who is talking every day with hundreds of patients about the effectiveness of the AstraZeneca vaccine. Yes, they can take their second shot! There is no need to switch. Among 14,019 symptomatic cases infected with the delta variant (first seen in India), the Pfizer/BioNTech vaccine was 96% effective against hospitalization after 2 doses. Of note, the AstraZeneca vaccine was 92% effective (71% after 1 dose) against hospitalization after 2 doses. These rates were comparable to alpha variants.



Demonbreun AR, Sancilio A, Velez ME, et al. COVID-19 mRNA vaccination generates greater IgG levels in women compared to men. J Inf Dis June 12, 2021, jiab314,

In community participants with no prior history of COVID-19, women had higher levels of mean anti-RBD IgG after vaccination compared to men. After two doses, IgG levels remained significantly higher for women (30.4 µg/ml) compared to men (20.6 µg/ml), while percent inhibition was similar (98.4% vs 97.7%).



Collier AY, McMahan K, Yu J, et al. Immunogenicity of COVID-19 mRNA Vaccines in Pregnant and Lactating Women. JAMA June 1´5 2021; 325(23):2370-2380.

In this study of 103 pregnant and lactating women, mRNA vaccines were immunogenic in and induced immune responses against SARS-CoV-2 variants.


Razzaghi H, Meghani M, Pingali C, et al. COVID-19 Vaccination Coverage Among Pregnant Women During Pregnancy — Eight Integrated Health Care Organizations, United States, December 14, 2020–May 8, 2021. MMWR Morb Mortal Wkly Rep. ePub: 15 June 2021.

As of May 8, 2021, 16.3% of pregnant women identified in the CDC Datalink had received ≥ 1 dose of a COVID-19 vaccine during pregnancy in the US. Vaccination was lowest among Hispanic (11.9%) and non-Hispanic Black women (6.0%) and women aged 18–24 years (5.5%) and highest among non-Hispanic Asian women (24.7%) and women aged 35–49 years (22.7%).


17 June


Lévy Y, Wiedemann A, Hejblum BP, et al. CD177, a specific marker of neutrophil activation, is associated with COVID-19 severity and death. iScience June 09, 2021.

This study highlights neutrophil activation as a hallmark of severe disease and CD177 assessment as a reliable prognostic marker for routine care.


Pušnik J, Richter E, Schulte B, et al. Memory B cells targeting SARS-CoV-2 spike protein and their dependence on CD4+ T cell help. Cell Rep June 11, 2021.

This study identified CD4+ T cell subsets associated with the generation of B cell memory during SARS-CoV-2 infection. Compared to severely ill, individuals who recovered from mild COVID-19 develop fewer but functionally superior spike-specific memory B cells. Generation and affinity maturation of these cells is best associated with IL-21+CD4+ T cells in recovered individuals and CD40L+CD4+ T cells in severely ill individuals.



Nyberg TR, Twohig KA, Harris RJ, et al. Risk of hospital admission for patients with SARS-CoV-2 variant B.1.1.7: cohort analysis. BMJ 2021 June 15, 2021; 373.

This retrospective analysis identified through community testing in England indicated that the risk of hospital admission within 14 days after a positive test was 1.52 (1.47 to 1.57) times higher for patients infected with the B.1.1.7 variant compared with those infected with wild-type variants, after adjustment for age, sex, deprivation, ethnicity, region, and week of diagnosis.



Xin H, Wong JY, Murphy C, et al. The incubation period distribution of coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis. Clin Inf Dis June 12, ciab501,

Mean, median and 95th percentile for incubation period are 6.3 days (range: 1.8 to 11.9 days), 5.4 days (range: 2.0 to 17.9 days) and 13.1 days (range: 3.2 to 17.8 days), respectively.



Li X, Ostropolets A, Makadia R, et al. Characterising the background incidence rates of adverse events of special interest for covid-19 vaccines in eight countries: multinational network cohort study. BMJ June 14, 2021; 373 doi:

Large variations in the observed rates of 15 pre-specified AESIs (stroke, thrombosis, myocarditis, narcolepsy, myelitis, etc) by age and sex, showing the need for stratification or standardization before using background rates for safety surveillance. Considerable population level heterogeneity in AESI rates was found between databases.


16 June


Wang Z, Muecksch F, Schaefer-Babajew D, et al. Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection. Nature June 14, 2021.

In this cohort of 63 COVID-19 convalescent individuals assessed at 1, 6 and 12 months after infection (41% also received mRNA vaccines), neutralizing activity and the number of RBD-specific memory B cells remain relatively stable for 6 to 12 months. Vaccination increases all components of the humoral response, and as expected, results in high serum neutralizing activities against variants of concern.



Kustin T, Harel N, Finkel U, et al. Evidence for increased breakthrough rates of SARS-CoV-2 variants of concern in BNT162b2-mRNA-vaccinated individuals. Nat Med June 14, 2021.

Analyzing 813 viral genome sequences, the authors showed that vaccinees who tested positive at least 7 days after the second dose were disproportionally infected with B.1.351, compared with controls. Those who tested positive between 2 weeks after the first dose and 6 days after the second dose were disproportionally infected by B.1.1.7.


Pollett SD, Richard SA, Fries AC, et al. The SARS-CoV-2 mRNA vaccine breakthrough infection phenotype includes significant symptoms, live virus shedding, and viral genetic diversity.  Clin Inf Dis June 12, 2021, ciab543.

A total of 24 “VBI” (vaccine breakthrough infections) in predominantly young healthy persons. While none required hospitalization, a proportion experienced severe symptoms and shed live virus as high as 4.130 PFU/mL. Though of relatively low magnitude, the presence of infectious virus which may indicate a transmission risk of VBI. Infecting genotypes included both variants and wild type.



Herishanu Y, Avivi I, Aharon A, et al. Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia. Blood June 10, 2021. 137 (23): 3165–3173.

Antibody response to mRNA vaccines in 167 patients with CLL was markedly impaired and affected by disease activity and treatment. In patients treated with either Bruton’s tyrosine kinase inhibitors or venetoclax ± anti-CD20 antibody, responses are relatively low.



Bauer A, Schreinlechner M Sappler N, et al. Discontinuation versus continuation of renin-angiotensin-system inhibitors in COVID-19 (ACEI-COVID): a prospective, parallel group, randomised, controlled, open-label trial. Lancet Resp Med June 11, 2021.

In this open label RCT (ACEI-COVID) performed at 35 centers in Austria and Germany, 204 patients (median age 75 years) were randomly assigned to discontinue or continue RAS inhibitors. Of note, discontinuation had no significant effect on the maximum severity of COVID-19 but led to a faster and better recovery. At 30 days, 11 (11%) in the discontinuation group and 23 (23%) in the continuation group had signs of organ dysfunction (SOFA score ≥ 1) or were dead (p = 0·017).


Kerneis M, Montalescot G. RAS inhibition and COVID-19: more questions than answers? Lancet Resp Med June 11, 2021.

Comment on ACEI-COVID. See title. Mathieu Kerneis and Gilles Montalescot argue that the study should be interpreted with great caution, considering that it derives from secondary analyses of a study that did not meet its primary endpoint.


15 June


Dinakarpandian D, Sullivan KJ, Thadaney-Israni S, et al. International Medical Graduate Physician Deaths From COVID-19 in the United States. JAMA Netw Open June 11, 2021;4(6):e2113418.

In this case series, the proportion of international medical graduates among 132 physicians (many of whom worked in primary care) who died from COVID-19 was higher than their national proportion among practicing US physicians.



Ontiveros CC, Sweeney CL, Smith C. et al. Assessing the impact of multiple ultraviolet disinfection cycles on N95 filtering facepiece respirator integrity. Sci Rep June 10 2021, 11, 12279.

UV disinfection does not compromise N95 filtering facepiece respirator integrity.



Buchan SA, Tibebu S, Daneman N, et al. Increased household secondary attacks rates with Variant of Concern SARS-CoV-2 index cases. Clin Inf Dis June 9, 2021, ciab496.

Huge study on 5617 index cases and 3397 secondary cases. In a propensity score matched analysis, the secondary attack rate for variant of concern (VOC) index cases was 1.31 times higher than non-VOC index cases. This increase was particularly accentuated for asymptomatic or pre-symptomatic index cases.



Landes SD, Turk MA, Damiani MR, et al. Risk Factors Associated With COVID-19 Outcomes Among People With Intellectual and Developmental Disabilities Receiving Residential Services. JAMA Netw Open June 8, 2021; 4(6):e2112862.

In this cohort study of 543 adults with intellectual and developmental disabilities receiving residential services in New York City, age, larger residential settings, Down syndrome, and chronic kidney disease were associated with COVID-19 diagnosis. Heart disease was associated with COVID-19 mortality.


Zhang AW, Morjaria S, Kaltsas A, et al. The Effect of Neutropenia and Filgrastim (G-CSF) in Cancer Patients With COVID-19 Infection. Clin Inf Dis June 10, 2021, ciab534,

G-CSF administration may lead to worsening clinical and respiratory status. In this observational cohort of 379 actively treated cancer patients with COVID-19, outpatient receipt of G-CSF led to an increased number of hospitalizations (HR: 3.54, 95% CI: 1.25-10.0).



Vaughn VM, Yost M, Abshire C, et al. Trends in Venous Thromboembolism Anticoagulation in Patients Hospitalized With COVID-19. JAMA Netw Open June 11, 2021;4(6):e2111788.

In this cohort study of 1351 patients hospitalized with COVID-19 in which 1127 patients received anti-coagulation, prophylactic anti-coagulation remained associated with lower mortality at 60 days.


14 June

Today we present the best clinical paper of the last week, including some new data on Long COVID. There are also two important papers on collateral damage (and benefits).



Aschman T, Schneider J, Greuel S, et al. Association Between SARS-CoV-2 Infection and Immune-Mediated Myopathy in Patients Who Have Died. JAMA Neurol June 11, 2021.

In this case-control autopsy study, SARS-CoV-2 was associated with an immune-mediated myopathy. Of 43 individuals who died with a diagnosis of COVID-19, 26 (60%) showed signs of muscle inflammation, ranging from mild to severe inflammatory myopathy. Detection of viral load was low or negative in most skeletal and cardiac muscle samples, indicating that myopathy was post-infectious, immune-mediated.


Després JP. Severe COVID-19 outcomes — the role of physical activity. Nature Reviews Endocrinology 10 June 2021.

It’s not only obesity: according to this nice review, current sedentary behaviors and lack of physical activity are also contributing to morbidity and mortality associated with COVID-19.



Perlis RH, Santillana M, Ognyanova K, et al. Factors Associated With Self-reported Symptoms of Depression Among Adults With and Without a Previous COVID-19 Diagnosis. JAMA Netw Open June 11, 2021;4:e2116612.

Some differences in phenomenology and risk factors of depression between individuals with and without prior COVID-19 illness.


Komaroff AL, Lipkin WI. Insights from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome May Help Unravel the Pathogenesis of Post-Acute COVID-19 Syndrome. Trends in Molecular Medicine June 07, 2021.

Post-COVID-19 syndrome is similar to post-infectious fatigue syndromes triggered by other infectious agents, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is associated with underlying abnormalities of the central and autonomic nervous system, immune dysregulation, disordered energy metabolism and redox imbalance. This summary of current knowledge concludes that it is still unclear if the same abnormalities will be identified in post-COVID-19 syndrome.


Collateral damage (and benefits)

Yard E, Radhakrishnan L, Ballesteros MF, et al. Emergency Department Visits for Suspected Suicide Attempts Among Persons Aged 12–25 Years Before and During the COVID-19 Pandemic — United States, January 2019–May 2021. MMWR 11 June 2021.

During February 21–March 20, 2021, suspected suicide attempt ED visits were 50.6% higher among girls aged 12–17 years than during the same period in 2019; among boys aged 12–17 years, suspected suicide attempt ED visits increased 3.7%.


Nivette AE, Zahnow R, Aguilar R et al. A global analysis of the impact of COVID-19 stay-at-home restrictions on crime. Nat Hum Behav June 2, 2021.

Crime largely decreased around the globe during COVID-19 stay-at-home orders, but with substantial variation across cities and types of crime. Property-based crimes decreased substantially, but homicide was relatively unchanged. Meta-regression results showed that more stringent restrictions over movement in public space were predictive of larger declines in crime.


Other facts to consider

No, he did not have COVID-19 and was not vaccinated.


13 June

Today we present the best papers of the last week on vaccines: some data on the effect of vaccines on unvaccinated individuals, on the effectiveness of vaccines on different variants and some papers on vaccine safety.



Milman O, Yelin I, Aharony N et al. Community-level evidence for SARS-CoV-2 vaccine protection of unvaccinated individuals. Nat Med June 10, 2021.

Vaccination provides cross-protection to unvaccinated individuals in the community: this groundbreaking study from Israel shows that on average, for each 20 percentage points of individuals who are vaccinated in a given population, the positive test fraction for the unvaccinated population decreased approximately twofold.



Pritchard E, Matthews PC, Stoesser N, et al. Impact of vaccination on new SARS-CoV-2 infections in the United Kingdom. Nat Med June 9, 2021.

The most interesting finding of this large study: there was no (no!) evidence of any difference in effectiveness between the BNT162b2 and ChAdOx1 vaccines.



Liu J, Liu Y, Xia H, et al. BNT162b2-elicited neutralization of B.1.617 and other SARS-CoV-2 variants. Nature June 10, 2021.

Good news. A total of 20 human sera, drawn 2 or 4 weeks after two doses of BNT162b2, neutralized engineered SARS-CoV-2 with different spike proteins of the delta variants (from India). B.1.617.1 was the least neutralized, probably due to the presence of both L452R and E484Q substitutions at the receptor binding site. Nevertheless, all variants were neutralized by all tested sera at titers ≥ 40.


Alter G, Yu J, Liu J, et al. Immunogenicity of Ad26.COV2.S vaccine against SARS-CoV-2 variants in humans. Nature June 9, 2021.

Median pseudovirus neutralizing antibody titers induced by Ad26.COV2.S (Johnson & Johnson) were 5.0-fold lower against the B.1.351 variant and 3.3-fold lower against the P.1 variant as compared with the original Wuhan strain, which is comparable to other vaccines. Functional non-neutralizing antibody responses and CD8+ and CD4+ T cell responses were largely preserved.



Adin ME, Isufi E, Kulon M, et al. Association of COVID-19 mRNA Vaccine With Ipsilateral Axillary Lymph Node Reactivity on Imaging. JAMA Oncol June 10, 2021;

In this study of 68 patients who had PET/CT for oncologic indications, ipsilateral axillary nodal reactivity was commonly seen after the intramuscular administration of the COVID-19 mRNA vaccines, more so after the second dose than after the first, and more commonly with the Moderna than the Pfizer vaccine.


Bourguignon A, Arnold DM, Warkentin TE, et al. Adjunct Immune Globulin for Vaccine-Induced Thrombotic Thrombocytopenia. NEJM June 9, 2020.

Three older patients with vaccine-induced immune thrombotic thrombocytopenia (VITT), occurring after the AstraZenec vaccine. Of note, all had one or more arterial thrombotic events. After the initiation of high-dose intravenous immune globulin treatment, reduced antibody-induced platelet activation in serum was seen in all three patients.


Simpson CR, Shi T, Vasileiou E et al. First-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in Scotland. Nat Med June 9, 2021.

Between 8 December 2020 and 14 April 2021, 1.71 million people from Scotland were vaccinated with the ChAdOx1 vaccine, and 0.82 million people were vaccinated with the BNT162b2 vaccine. First dose of ChAdOx1 was found to be associated with small increased risks of ITP, with suggestive evidence of an increased risk of arterial thromboembolic and hemorrhagic events. There was no overall increased risk in these adverse events in individuals receiving BNT162b2.


12 June

Today we focus on SARS-CoV-2 infections and COVID-19 in children and adolescents.



Hoch M, Vogel S, Kolberg L, et al. Weekly SARS-CoV-2 sentinel surveillance in primary schools, kindergartens, and nurseries, Germany, June‒November 2020. Emerg Infect Dis. 2021 Aug [date cited]. June 3, 2021.

Asymptomatic children attending these institutions do not appear to be driving the pandemic when appropriate infection control measures are used. Of 3169 oropharyngeal swab specimens collected in primary schools, kindergartens, and nurseries, only 2 were positive by PCR. However, the study was conducted before the emergence of SARS-CoV-2 variants.



Payne AB, Gilari Z, Godfred-Cato S, et al. Incidence of Multisystem Inflammatory Syndrome in Children Among US Persons Infected With SARS-CoV-2. JAMA Netw Open June 10, 2021;4(6):e2116420.

MIS-C incidence was 5.1 persons per 1,000,000 person-months and 316 persons per 1,000,000 SARS-CoV-2 infections in persons younger than 21 years.



Goenka A, Halliday A, Gregorova M, et al. Young infants exhibit robust functional antibody responses and restrained IFN-γ production to SARS-CoV-2. Cell Rep Med June 09, 2021.

This small study on four infants under 3 months old shows that immune responses in infants are distinct from those of their parents. Robust functional antibody responses alongside restrained IFN-γ production may help protect infants from severe COVID-19.



Roversi M, Raucci U, Pontrelli G, et al. Diagnosis of COVID-19 in children guided by lack of fever and exposure to SARS-CoV-2. Pediatr Res June 11, 2021.

Data of 2699 children who were tested for SARS-CoV-2 for a suspected infection suggest that a child without fever or contact with infected subjects is SARS-CoV-2 negative. If this were to be confirmed, many resources would be spared.



Discepolo V, Catzola A, Pierri L, et al. Bilateral Chilblain-like Lesions of the Toes Characterized by Microvascular Remodeling in Adolescents During the COVID-19 Pandemic. JAMA Netw Open June 10, 2021;4(6):e2111369.

This case series of 17 adolescents found that chilblain-like lesions of the toes emerged during the COVID-19 pandemic in otherwise healthy adolescents without signs of SARS-CoV-2 infection or other inflammatory, autoimmune, or thrombophilic phenomena.


Oliveira EA, Colosimo EA, Simões e Silva AC, et al. Clinical characteristics and risk factors for death among hospitalised children and adolescents with COVID-19 in Brazil: an analysis of a nationwide database. Lancet Child Adolesc June 10, 2021.

In this large study from Brazil, death from COVID-19 was associated with age, Indigenous ethnicity, poor geopolitical region, and pre-existing medical conditions.


11 June


Camell CD, Yousefzadeh MJ, Zhu Y, et al. Senolytics reduce coronavirus-related mortality in old mice. Science Jun 8, 2021: eabe4832.

Is this the explanation for the vulnerability of the elderly? Senescent cells (SnC) became hyper-inflammatory in response to SARS-CoV-2 S protein. Old mice acutely infected with a SARS-CoV-2-related mouse β-coronavirus experienced increased senescence and inflammation.


Nagler A, Kalaora S, Barbolin C, et al. Identification of presented SARS-CoV-2 HLA class I and HLA class II peptides using HLA-peptidomics. Cell Rep June 08, 2021.

The human leukocyte antigen (HLA)-bound viral antigens serve as an immunological signature that can be selectively recognized by T cells. This work identified 63 HLA-presented peptides derived from eight SARS-CoV-2 proteins. Shared SARS-CoV-2 peptides were identified in different cell types.



Razani N, Malekinejad M, Rutherford GW. Clarification regarding Outdoor Transmission of SARS-CoV-2 and Other Respiratory Viruses, a Systematic Review. J Inf Dis June 4, 2021, jiab298,

Update of a previous paper, supporting the initial conclusion that the risk of SARS-CoV-2 transmission is much lower outdoors than indoors. The proportion of infections happening outdoors is likely much lower than 10%, and most studies suggest that it is likely less than 1%.



Rodriguez-Smith JJ, Verweyen E, Clay GM, et al. Inflammatory biomarkers in COVID-19-associated multisystem inflammatory syndrome in children, Kawasaki disease, and macrophage activation syndrome: a cohort study. Lancet Rheumatology June 08, 2021.

Multisystem inflammatory syndrome in children (MIS-C) is a potentially life-threatening hyperinflammatory syndrome of undefined pathogenesis that occurs after primary SARS-CoV-2 infection. Specific inflammatory biomarker patterns such as the IFN-γ-induced CXCL9 can distinguish MIS-C from other hyperinflammatory syndromes, including Kawasaki disease and macrophage activation syndrome (MAS).


Kompaniyets L, Agathus NT, Nelson JM, et al. Underlying Medical Conditions Associated With Severe COVID-19 Illness Among Children. JAMA Netw Open June 7, 2021;4(6):e2111182.

This cross-sectional study on 43,465 patients with COVID-19 aged 18 years or younger found a higher risk of severe illness among children with medical complexity and certain underlying conditions, such as type 1 diabetes (strongest risk factor with an adjusted risk ratio of 2.38), cardiac and circulatory congenital anomalies, and obesity.


10 June


Meng B, Kemp SA, Papa G, et al. Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the variant of concern lineage B.1.1.7. Cell Rep June 8, 2021.

While ΔH69/V70 (a frequent deletion seen in many variants of concern) itself is not an antibody evasion mechanism, it increases infectivity associated with enhanced incorporation of cleaved spike into virions. H69/V70 does increase spike infectivity and compensates for an infectivity defect resulting from RBD mutations N439K and Y453F.



Amanat F, Thapa M, Lei T, et al. SARS-CoV-2 mRNA vaccination induces functionally diverse antibodies to NTD, RBD and S2. Cell June 08, 2021.

In this detailed profiling study of mRNA vaccine-induced polyclonal antibodies, polyclonal antibody responses in vaccinees were robust and comparable to or exceeded those seen after natural infection. However, the majority of vaccine-induced antibodies did not have neutralizing activity and were less heterogeneous. The vaccine induced cross-reactive antibodies to seasonal β-coronaviruses.



Wang R, Zhang W, Ge J, et al. Analysis of SARS-CoV-2 variant mutations reveals neutralization escape mechanisms and the ability to use ACE2 receptors from additional species. Immunity Jun 8, 2021.

The South African variant beta (B.1.351) was the most resistant to current monoclonal antibodies and convalescent plasma, followed by the Brazilian variant gamma (P.1) and the UK variant alpha (B.1.1.7). This resistance hierarchy corresponded with deletions in the N-terminal domain and K417N/T, E484K and N501Y mutations in the receptor binding domain (RBD) of SARS-CoV-2.



Thakkar A, Gonzalez-Lugo JD, Goradia N, et al. Seroconversion rates following COVID-19 vaccination amongst patients with cancer. Cancer Cell June 05, 2021.

A high seroconversion rate (94%) in 200 vaccinated patients with cancer. Seroconversion was lower in recipients following highly immunosuppressive therapies such as anti-CD20 therapies (70%) and stem cell transplantation (73%) but not immune checkpoint inhibitor therapy (97%). IgG titers were lower following vaccination with the adenoviral than with the mRNA-based vaccines.



Christie A, Henley SJ, Mattocks L, et al. Decreases in COVID-19 Cases, Emergency Department Visits, Hospital Admissions, and Deaths Among Older Adults Following the Introduction of COVID-19 Vaccine — United States, September 6, 2020–May 1, 2021. MMWR Morb Mortal Wkly Rep. ePub: 8 June 2021.

The ratio for COVID-19 deaths began to decline in mid-December while rate ratios for COVID-19 incidence, ED visits, and hospital admissions began to decline in late December to mid-January. Comparing the 2-week pre-vaccination period with 2 weeks in late April, declines were significantly greater among older adults, who had higher vaccination coverage, than among younger adults, who had lower coverage.


9 June


Hill KJ, Dewar K, Templeton K, et al. A multiregional evaluation of Ct values in SARS-CoV-2 VOC-20DEC-01 variant. J Inf Dis June 7, 2021, jiab303,

A smaller difference in median Ct value between B.1.1.7 and wild type than previously reported. The authors “encourage the scientific community to also consider alternative reasons for the increased infectivity seen” with this variant.


Rees CA, Rostad CA, Mantus G, et al. Altered amino acid profile in patients with SARS-CoV-2 infection. PNAS June 22, 2021 118 (25) e2101708118;

Low plasma arginine bioavailability has been implicated in endothelial dysfunction and immune dysregulation. Among 80 patients (28 controls, 32 adults with COVID-19, and 20 pediatric patients with COVID-19/MIS-C), mean plasma arginine and arginine bioavailability ratios were lower among adult and pediatric patients with COVID-19/MIS-C compared to controls.



Chodick G, Tene K, Patalon T, et al. Assessment of Effectiveness of 1 Dose of BNT162b2 Vaccine for SARS-CoV-2 Infection 13 to 24 Days After Immunization. JAMA Netw Open June 7, 2021; 4(6):e2115985.

In this study of 503,875 individuals from Israel who received 1 dose of the BNT162b2 vaccine, the first dose was associated with an approximately 54% reduction in the risk of symptomatic SARS-CoV-2 infections at 13 to 24 days after immunization compared to 1 to 12 days after vaccination.



Raut A, Huy NT. Rising incidence of mucormycosis in patients with COVID-19: another challenge for India amidst the second wave? Lancet Resp Med June 03, 2021.

Often referred to as the so-called black fungus, the incidence of mucormycosis has risen more rapidly during the second wave compared to the first wave of COVID-19 in India, with at least 14,872 cases as of May 28, 2021. Brief summary of the situation.


Patel A, Agarwal R, Rudramurthy SM, et al.; MucoCovi Network. Multicenter epidemiologic study of coronavirus disease–associated mucormycosis, India. Emerg Infect Dis. 2021 Sep [date cited].

A retrospective observational study involving 16 healthcare centers across India. Among 287 mucormycosis patients, 187 (65.2%) were associated with COVID-19 (CAM); CAM prevalence was 0.27% among hospitalized COVID-19 patients. Hypoxemia due to COVID-19 and inappropriate use of glucocorticoid drugs were independently associated with development of late CAM. The mortality rate for CAM patients was high (44%) but was comparable to rates for non-CAM (49%) patients.


8 June


Xiao X, Newman C, Buesching CD, et al. Animal sales from Wuhan wet markets immediately prior to the COVID-19 pandemic. Sci Rep June 7, 2021, 11, 11898.

Here the authors document 47,381 individuals from 38 species, including 31 protected species sold between May 2017 and November 2019 in Wuhan’s markets. They also note the poor conditions under which the animals were kept prior to sale. No pangolins (or bats) were traded, supporting that pangolins were not likely the spillover host at the source of the pandemic.



Sender R, Bar-On YM, Gleizer S, et al. The total number and mass of SARS-CoV-2 virions. PNAS June 3, 2021.

All SARS-CoV-2 virions currently in all human hosts have a mass of between 100 g and 10 kg. Although each infected person carries an estimated 1 billion to 100 billion virions during peak infection, their total mass is no more than 0.1 mg.



De Giorgi V, West KA, Henning AN, et al. Naturally acquired SARS-CoV-2 immunity persists for up to 11 months following infection. J Inf Dis, June 5, 2021, jiab295,

Of the 116 donors presenting for repeat timepoints, 91.4% of donors had detectable IgG levels up to 11 months post-symptom recovery, while 63% had detectable neutralizing titers. Of note, 25% of donors had neutralizing levels that dropped to an undetectable titer over time.



Vanker A, McGeer A, O’Byrne G, et al. Adverse Outcomes Associated with SARS-CoV-2 variant B.1.351 Infection in Vaccinated Residents of a Long Term Care Home, Ontario, Canada. Clin Inf Dis, June 6, 2021, ciab523,

Another outbreak of B.1.351 (south Africa) in a long term care home (LTCH) in Canada. Of the 9 residents (vaccinated with B162.B2 from BionTech/Pfizer) and infected with B.1.351, 4 developed hypoxemia. Of these, 3 (including both hospitalized patients) died.



Havers FP, Whitaker M, Self JL, et al. Hospitalization of Adolescents Aged 12–17 Years with Laboratory-Confirmed COVID-19 — COVID-NET, 14 States, March 1, 2020–April 24, 2021. MMWR Morb Mortal Wkly Rep. ePub: 4 June 2021

Among 204 adolescents who were likely hospitalized primarily for COVID-19 during January 1–March 31, 2021, 31.4% were admitted to an intensive care unit (ICU), and 4.9% required invasive mechanical ventilation; there were no associated deaths.


7 June


Lesho E, Corey B, Lebreton F, et al. Emergence of the E484K Mutation in SARS-CoV-2 Lineage B.1.1.345 in Upstate New York. Clin Infect Dis June 4, 2021, ciab507,

Case series (n=15) of infections with a SARS-CoV-2 B.1.1.345 variant (from New York) carrying the E484K mutation. E484K probably has a role in antibody evasion.



Goyal A, Reeves DB, Thakkar N, et al. Slight reduction in SARS-CoV-2 exposure viral load due to masking results in a significant reduction in transmission with widespread implementation. Sci Rep 11, 11838 (2021).

This modeling study shows that the use of masks by both a potential transmitter and exposed person substantially reduces the probability of successful transmission, even if masks only lower exposure viral load by ~ 50%. The model also predicts that moderately efficacious masks will lower exposure viral load tenfold among people who get infected despite masking, potentially limiting infection severity.



Ljungman, P., de la Camara, R., Mikulska, M. et al. COVID-19 and stem cell transplantation; results from an EBMT and GETH multicenter prospective survey. Leukemia June 2, (2021).

Among 382 COVID-19 patients having undergone allogeneic (n = 236) or autologous (n = 146) hematopoietic cell transplantation (HCT), overall survival at 6 weeks was 77.9% and 72.1% in allogeneic and autologous recipients, respectively. In total, 83.5% developed lower respiratory tract disease and 22.5% were admitted to an ICU.


Collateral damages

Sout MJ, van de Ven CJ, Parekh VI, et al. Use of Electronic Medical Records to Estimate Changes in Pregnancy and Birth Rates During the COVID-19 Pandemic. JAMA Netw Open June 3, 2021;4(6):e2111621.

In this cohort study from Michigan, a 14% reduction in pregnancy episode initiation was observed, probably due to a decrease in conceptions that followed the March 15 mandated COVID-19 pandemic societal shutdown. Prospective modeling of pregnancies currently suggests that a birth volume surge can be anticipated in summer 2021.



Lopes RD, de Barros e Silva PD, Furtado RH, et al. Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial. Lancet June 04, 2021. DOI:

In this large RCT on 615 patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Moreover, the primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation.


6 June


Lash RR, Moonan PK, Byers BL, et al. COVID-19 Case Investigation and Contact Tracing in the US, 2020. JAMA Netw Open June 3, 2021. 2021;4(6):e2115850.

In this cross-sectional study of US local COVID-19 surveillance data, contact tracing had suboptimal impact on SARS-CoV-2 transmission, largely because two out of every three cases were either not reached for interview or had named no contacts when interviewed.



Chen J, Dai L, Barrett L et al. SARS-CoV-2 proteins and anti-COVID-19 drugs induce lytic reactivation of an oncogenic virus. Commun Biol June 3, 2021, 4, 682.

New finding: SARS-CoV-2 encoded proteins and some anti-COVID-19 drugs currently used (e.g., azithromycin and nafamostat mesylate) induce lytic reactivation of human herpes virus 8, one of the major human oncogenic viruses. This may facilitate HHV-8 dissemination and initiate viral oncogenesis in immunosuppressed HHV-8+ patients exposed to and treated for COVID-19.


Wu C, Qavi AJ, Hachim A, et al. Characterization of SARS-CoV-2 N protein reveals multiple functional consequences of the C-terminal domain. iScience June 01, 2021.

Insights into the nucleocapsid (N) encoded by SARS-CoV-2 that plays key roles in the replication cycle and is a critical serological marker. This work provides a biochemical description of SARS-CoV-2 N and highlights the value of using N domains as highly specific and sensitive diagnostic markers.



Kosmicki JA, Horowitz JE, Banerjee N, et al. Pan-ancestry exome-wide association analyses of COVID-19 outcomes in 586,157 individuals. The American Journal of Human Genetics June 03, 2021

No significant associations with rare protein-coding variants and COVID-19 outcomes.


Tardif JC, Bouabdallaoui N, L’Allier PL, et al. Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial. Lancet Resp Med May 27, 2021.

In this large RCT enrolling high-risk patients from six countries (Brazil, Canada, Greece, South Africa, Spain, and US) who were not under immediate consideration for hospital admission, colchicine led to a lower rate of the composite of death or hospital admission than placebo. Among 4159 patients with PCR-confirmed COVID-19, the primary endpoint occurred in 96 (4.6%) of 2075 patients in the colchicine group and 126 (6.0%) of 2084 patients in the placebo group (odds ratio 0.75, 0.57–0.99; p = 0.042). Diarrhea was reported by 14% of patients in the colchicine group and 7% in the placebo group. But do the authors trust their own data? They conclude that “replication in other studies… is recommended”.


5 June


Hay JA, Kennedy-Shaffer L, Kanjilal S, et al. Estimating epidemiologic dynamics from cross-sectional viral load distributions. Science 03 Jun 2021: eabh0635.

Distribution of observed Ct values has varied over the course of the current pandemic. This study suggests that this can be explained as an epidemiologic phenomenon, without invoking any change in individual level viral kinetics or testing practices. Properties of the population level Ct distribution strongly correlate with estimates for the effective reproductive number or growth rate in real world settings. In other words: Ct values from single or successive cross-sectional samples of RT-qPCR data can be used to estimate the epidemic trajectory without requiring additional information from test positivity rates or serial case counts.



Maio N, Lafont BA, Sil D, et al. Fe-S cofactors in the SARS-CoV-2 RNA-dependent RNA polymerase are potential antiviral targets. Science 03 Jun 2021: eabi5224.

The catalytic subunit of the RNA-dependent RNA polymerase (RdRp) has some metal binding sites that are essential for replication and for interaction with the viral helicase. Oxidation caused their disassembly, potently inhibited the RdRp, and blocked SARS-CoV-2 replication in cell culture.



Weingarten-Gabbay S, Klaeger S, Sarkizova S, et al. Profiling SARS-CoV-2 HLA-I peptidome reveals T cell epitopes from out-of-frame ORFs. Cell June 1, 2021.

An open reading frame (ORF) is the part of the reading frame that has the ability to be translated. This work uncovers previously uncharacterized SARS-CoV-2 HLA-I peptides from out-of-frame ORFs in the SARS-CoV-2 genome. About 25% of detected HLA-I peptides originated from such out-of-frame ORFs in S and N, and some elicited strong T cell responses, highlighting the contribution of these viral epitopes to the immune response in a mouse model and convalescent COVID-19 patients.



Hag-Ali M, Al Shamsi AS, Boeijen L et al. The detection dogs test is more sensitive than real-time PCR in screening for SARS-CoV-2. Commun Biol June 3, 2021, 4, 686.

Can we use dogs at airports to identify COVID-19 patients? On training explosive detection dogs on sniffing COVID-19 odor in patients’ sweat, these dogs are able to successfully screen out 3249 individuals who tested negative for the SARS-CoV-2, from a cohort of 3290 individuals. The positive predictive value of dog detection was 52% (probability that identified individuals do truly have the disease). The negative predictive value was 99.8%. Almost better than PCR testing.



Cohen MS, Nirula A, Mulligan MJ, et al. Effect of Bamlanivimab vs Placebo on Incidence of COVID-19 Among Residents and Staff of Skilled Nursing and Assisted Living Facilities: A Randomized Clinical Trial. JAMA June 3, 2021.

Bamlanivimab (BAM), a neutralizing monoclonal antibody, is effective in reducing the incidence of mild or worse COVID-19 in residents and participants at high risk of severe COVID-19. This large Phase III RCT included 966 participants who were residents or staff at US skilled nursing facilities with at least one confirmed SARS-CoV-2 index case. The incidence of COVID-19 infection among those treated with a single infusion of BAM was 8.5% vs 15.2% with placebo, with an odds ratio of 0.43 (95% CI: 0.28-0.68). Moreover, participants who received BAM and acquired SARS-CoV-2 had lower baseline viral loads and shorter time to viral clearance. However, one limitation is that the study was conducted prior to the occurrence of variants that may have reduced susceptibility.


4 June


Takuva S, Takalani A, Garrett N, et al. Thromboembolic Events in the South African Ad26.COV2.S Vaccine Study. NEJM 3, 2021.

Interim safety data from the first 288,368 participants who were vaccinated with Ad26.COV2.S (Johnson & Johnson) in the Sisonke study — an open-label, Phase IIIb implementation study. The rate of adverse events with vaccination is low, and thromboembolic events occur mainly in persons with risk factors for thromboembolism.



Talbot HK, Martin ET; Gaglaniu M, et al. Coronavirus disease 2019 (COVID-19) Versus Influenza in Hospitalized Adult Patients in the United States: Differences in Demographic and Severity Indicators. Clin Inf Dis May 27, 2021, ciab123.

Anybody talking about “flu”? Comparing 914 hospitalized COVID-19 patients with 1937 influenza hospitalized patients of similar age groups, this study found greater severity and complications with COVID-19: more ICU admissions (AOR = 15.3), ventilator use (AOR = 15.6), 7 additional days of hospital stay in those discharged alive, and death during hospitalization (AOR = 19.8).


Russell CD, Fairfield CJ, Drake TM, et al. Co-infections, secondary infections, and antimicrobial use in patients hospitalised with COVID-19 during the first pandemic wave from the ISARIC WHO CCP-UK study: a multicentre, prospective cohort study. Lancet Microbe June 2, 2021.

In 48,902 patients admitted to UK hospitals with COVID-19, microbiologically confirmed bacterial infections were rare, and more likely to be secondary infections (mainly Gram-negative organisms and S aureus). However, the frequency and nature of antimicrobial use was concerning: 85% received one or more antimicrobials at some point during their admission.


Collateral damage

Solomon MD, Nguyen-Huynh M, Leong TK. Changes in Patterns of Hospital Visits for Acute Myocardial Infarction or Ischemic Stroke During COVID-19 Surges. JAMA June 2, 2021.

In contrast to the initial COVID-19 surge during March / April 2020, no significant declines in AMI hospitalization or stroke alerts were observed during the largest and most recent surge from October 2020 to January 2021 in Kaiser Permanente, Northern California.


Ku Z, Xie X, Hinton PR. Nasal delivery of an IgM offers broad protection from SARS-CoV-2 variants. Nature June 3, 2021.

A breakthrough in treatment? The authors have engineered an immunoglobulin M (IgM) neutralizing antibody (IgM-14) to overcome resistance. IgM-14 is > 230-fold more potent than its parental IgG-14 in neutralizing SARS-CoV-2 and potently neutralizes almost all resistant viruses, including those that are resistant to the IgGs that have been authorized for emergency use. In mice.


3 June


Patel MD, Rosenstrom E, Ivy JS, et al. Association of Simulated COVID-19 Vaccination and Nonpharmaceutical Interventions With Infections, Hospitalizations, and Mortality. JAMA Netw Open June 1, 2021;4(6):e2110782.

Interesting finding: compared with more efficacious vaccines with lower population coverage, as NPIs are removed, higher vaccination coverage with less efficacious vaccines can contribute to a larger reduction in risk of SARS-CoV-2 infection.



Callaway E. Coronavirus variants get Greek names — but will scientists use them? Nature NEWS June 1, 2021.

From Alpha to Omega, the new labelling system aims to avoid confusion and stigmatization. Ewen Callaway explains why the new system could be useful.



Martínez-Baz I, Miqueleiz A, Casado I, et al. Effectiveness of COVID-19 vaccines in preventing SARS-CoV-2 infection and hospitalisation, Navarre, Spain, January to April 2021. Euro Surveill May 27, 2021 2021;26(21):pii=2100438.

Does it make sense to vaccinate close contacts? Probably. Results of this study suggest a moderate effectiveness (35%) of BionTech/Pfizer and Astra Zeneca vaccines in preventing SARS-CoV-2 infection. Estimates increased against symptomatic and hospitalised COVID-19. Vaccine effectiveness was moderate in people with one dose (35%) and was higher after the second dose (66%), especially against hospitalisations (72% and 95%, respectively).


Vogel G, Couzin-Frankel J. Israel reports link between rare cases of heart inflammation and COVID-19 vaccination in young men. Nature NEWS June 1, 2021.

Brief summary of current knowledge: in Israel, between one in 3000 and one in 6000 men ages 16 to 24 who received the BioNTech vaccine developed myocarditis. Most cases were mild and resolved within a few weeks. It is speculated that very high antibody levels generated in young people may also, in rare cases, lead to a sort of immune overreaction that inflames the heart.


Severe COVID

Rasch S, Schmidle P, Sancak S, et al. Increased extravascular lung water index (EVLWI) reflects rapid non-cardiogenic oedema and mortality in COVID-19 associated ARDS. Sci Rep June 1, 2021, 11, 11524.

Extravascular lung water index (EVLWI) is a marker of pulmonary edema which is associated with mortality in ARDS. EVLWI values are higher in patients with COVID-19 ARDS than in comparable patients with non-COVID-19 ARDS. Changes in EVLWI correlate with severity of COVID-19 associated ARDS.



Ziemba R, Campbell KN, Yang T, et al. Excess Death Estimates in Patients with End-Stage Renal Disease — United States, February–August 2020. MMWR Morb Mortal Wkly Rep. ePub: 1 June 2021.

Based on the national trend in ESRD deaths during the first 7 months of the COVID-19 pandemic (February 1–August 31, 2020) in the US, an estimated 8.7–12.9 excess deaths per 1000 patients or 6953–10,316 excess deaths in a population of 798,611 US ESRD patients occurred.


2 June


Kamel W, Noerenberg M, Cerikan B, et al. Global analysis of protein-RNA interactions in SARS-CoV-2 infected cells reveals key regulators of infection. Molecular Cell May 24, 2021.

A systematic and comprehensive analysis of protein-RNA interactions in SARS-CoV-2 infected cells. SARS-CoV-2 infection induces a pervasive remodelling of the “RBPome” (RNA-binding proteins) which involves the upregulation and downregulation of more than 300 RBPs. Dozens of cellular proteins interact with SARS-CoV-2 RNAs and appear to be promising therapeutic approaches.



Yan L, Yang Y, Lu M, et al. Coupling of N7-methyltransferase and 3′-5′ exoribonuclease with SARS-CoV-2 polymerase reveals mechanisms for capping and proofreading. Cell May 24, 2021.

Corona viruses have the largest RNA genomes amongst RNA viruses and employ a proofreading mechanism to ensure replication fidelity. This study provides a structural basis for understanding co-transcriptional modification of SARS-CoV-2 mRNA. Results also shed light on how replication fidelity in SARS-CoV-2 is maintained.



Arnold DT, Milne A, Samms E, et al. Symptoms After COVID-19 Vaccination in Patients With Persistent Symptoms After Acute Infection: A Case Series. Ann Int Med, 25 May 2021.

In total, 36 patients who reported at least 1 persistent symptom 8 months after acute infection were vaccinated with Astra Zeneca or the BionTech vaccine. There was some improvement and no decrease in quality of life or worsening of symptoms.



Gable P, Huang JY, Gilbert SE, et al. Comparison of Less Invasive SARS-CoV-2 Diagnostic Specimens in Nursing Home Residents — Arkansas, June–August 2020. Clin Inf Dis 25 May 2021, ciab310,

Anterior nasal swabs (AN), oropharyngeal swabs (OP), and saliva specimens (SA) were effective methods for repeated testing in this population. More AN than OP were positive by viral culture. SA and OP remained RT-PCR–positive longer than AN, which could lead to unnecessary interventions if RT-PCR detection occurs after viral shedding has probably ceased.



Marion O, Del Bello A, Abravanel F, et al. Safety and Immunogenicity of Anti–SARS-CoV-2 Messenger RNA Vaccines in Recipients of Solid Organ Transplants. Ann Int Med May 25, 2021.

This large study shows a weak immunogenicity of mRNA vaccines in transplant recipients. In 367 patients the prevalence of anti–SARS-CoV-2 antibodies was 33.8% one month after the second dose. Recipients of liver transplant showed a better humoral response than recipients of other organs. According to the authors, an increased antigen dose or a third vaccine dose can be proposed to improve the vaccination response in this specific population. Of note, the French Health Authorities have recently recommended offering a third dose to immunosuppressed patients.


1 June


Liu Y, Wang Z, Rader B, et al. Associations between changes in population mobility in response to the COVID-19 pandemic and socioeconomic factors at the city level in China and country level worldwide: a retrospective, observational study. Lancet Digital Health, June 1, 2021. Volume 3, ISSUE 6, e349-e359.

Using empirical data from 358 cities in China and 121 countries globally, the authors analyzed population mobility data before and after emergency responses were introduced. Several factors were associated with reduced intra-city movement intensity, including a high proportion of people in age groups between 20 and 39 years, socioeconomic factors (ie, education level), and COVID-19-related factors (ie, lockdown status and number of COVID-19 cases). A higher sociodemographic index showed a greater reduction in mobility.



Hsu JC, Laurent-Rolle M, Pawlak JB, et al. Translational shutdown and evasion of the innate immune response by SARS-CoV-2 NSP14 protein. PNAS June 15, 2021 118 (24) e2101161118.

Another mechanism by which SARS-CoV-2 evades host antiviral responses: SARS-CoV-2 is able to shut down antiviral host protein synthesis. This is achieved by the SARS-CoV-2 nonstructural protein NSP14, a virus-encoded translation inhibitory factor.



Liu Y, Soh WT, Kishikawa JI, et al. An infectivity-enhancing site on the SARS-CoV-2 spike protein targeted by antibodies. Cell May 24, 2021.

Not only neutralizing antibodies but also enhancing antibodies are produced during SARS-CoV-2 infection. Screening a series of anti-spike monoclonal antibodies from COVID-19 patients, the authors found that some of antibodies against the N-terminal-domain (NTD) induce the open conformation of receptor binding domain (RBD) and thus enhance the binding capacity of the spike protein to ACE2 and infectivity of SARS-CoV-2. All the infectivity-enhancing antibodies bound to NTD in a similar manner and were detected at high levels in patients with severe COVID-19.


Massarweh A, Eliakim-Raz N, Stemmer A, et al. Evaluation of Seropositivity Following BNT162b2 Messenger RNA Vaccination for SARS-CoV-2 in Patients Undergoing Treatment for Cancer.  JAMA Oncol May 28, 2021.

In this cohort study of 102 patients with cancer from Israel who were receiving active treatment and 78 healthy controls, 92 patients with cancer (90%) and 100% of the controls were seropositive after the BNT162b2 vaccine (BioNTech/Pfizer). The median IgG titer in the patients with cancer was significantly lower than that in the controls. In a multivariate analysis, the only variable that was significantly associated with lower IgG titers was treatment with chemotherapy plus immunotherapy.



Yazaki S, Yoshida T, Kolima Y, et al. Difference in SARS-CoV-2 Antibody Status Between Patients With Cancer and Health Care Workers During the COVID-19 Pandemic in Japan. JAMA Oncol 28, 2021.

In this cross-sectional study including 500 patients with cancer and 1190 HCWs, the seroprevalence was similar, but the levels of IgG antibodies against nucleocapsid and spike protein were significantly lower in patients than in HCWs. Interestingly, N-IgG and S-IgG levels were significantly higher in patients who received immune checkpoint inhibitors than in those who did not.