A selection of peer-reviewed articles
(most recently added papers are marked in red)
Coordinated by:Redaction Committee :
ANRS-EID/I3M: Erica Telford & Eric D'OrtenzioANRS-Emerging Infectious Diseases/Inserm- Thematic Institute of Immunology, Inflammation, Infectiology,
and Microbiology (I3M):
Claire Brugerolles; Xyomara Chavez-Pacheco; Mario Delgado-Ortega; Claire Madelaine; Inmaculada Ortega-Perez; Erica Telford
The MODCOV19 Team for the mathematical modelling subjects
Documented by (until Sept. 2020): Inserm- Collective Expertise Unit:
Bénédicte Varignon & Laurent Fleury
With a precious contribution from:
• Former members of the redaction committee: Guia Carrara; Eric D’Ortenzio; Evelyne Jouvin-Marche; Boris Lacarra; Oriane Puéchal; Renaud Vatrinet • Inserm- Department of Partnerships and External Relations (DPRE) • Inserm- USA office
JournalDateTitleAuthors and linkCountryField of expertiseKey facts
NEJM2022.01.19Effectiveness of mRNA-1273 and BNT162b2 Vaccines in QatarAbu-Raddad L.J., et al.
QatarVaccines - ImmunsationAim: to compare the protection afforded by the mRNA-1273 (Moderna) vaccine with that of the BNT162b2 (Pfizer–BioNTech) vaccine in Qatar.
- Two matched retrospective cohort studies to assess the incidence of documented SARS-CoV-2 infection after the first and second doses of the mRNA-1273 and BNT162b2 vaccines.
- Same population of persons who had received the mRNA-1273 or BNT162b2 vaccines between December 21, 2020, and October 20, 2021.

> 192,123 persons who had received two doses of mRNA-1273 matched with the same number of persons who had received two doses of BNT162b2.
> Among the mRNA-1273–vaccinated persons, 878 breakthrough infections were recorded after the second dose at a median follow-up of 89 days. Of these, 3 progressed to severe Covid-19 (acute-care hospitalization), but none progressed to critical disease (hospitalization in an intensive care unit) or death.
> Among BNT162b2-vaccinated persons, 1262 breakthrough infections were recorded after the second dose at a median follow-up of 86 days. Of these, 7 progressed to severe Covid-19, none to critical disease, and 1 to death.
> In both vaccinated cohorts, breakthrough infections tended to occur among persons with a longer interval since the time of vaccination. The divergence between the two vaccine cohorts in the incidence of documented infection started during the third week after the first dose.
> The incidences of SARS-CoV-2 infection and severe Covid-19 were lower among mRNA-1273–vaccinated persons than among BNT162b2-vaccinated persons after only one dose.
> At 6 months of follow-up after the second dose, the estimated cumulative incidence of breakthrough infection was 0.59% (95% CI, 0.55 to 0.64) among persons who received the mRNA-1273 vaccine and 0.84% (95% CI, 0.79 to 0.89) among those who received the BNT162b2 vaccine.
> The estimated overall adjusted hazard ratio for infection after the second dose of mRNA-1273 vaccine, as compared with the second dose of BNT162b2 vaccine, was 0.69 (95% CI, 0.63 to 0.75).
> The estimated overall adjusted hazard ratio for severe, critical, or fatal Covid-19 after the second dose was 0.37 (95% CI, 0.10 to 1.41).

Vaccination with mRNA-1273 was associated with a lower incidence of SARS-CoV-2 breakthrough infection than vaccination with BNT162b2; this finding is consistent with the differences in neutralizing antibody titers. However, both vaccines elicited strong protection against Covid-19–related hospitalization and death.
NEJM2022.01.19Immunogenicity and Reactogenicity of Vaccine Boosters after Ad26.COV2.S PrimingSablerolles R.S.G., et al.
NetherlandsVaccinesAim: to evaluate the immunogenicity and reactogenicity of a homologous or heterologous booster at day 28 in persons who have received an Ad26.COV2.S priming dose.

Primary end point: level of S-specific binding antibodies
Secondary end points: levels of neutralizing antibodies, S-specific T-cell responses, and reactogenicity.

> Homologous or heterologous booster vaccination in 434 participants resulted in higher levels of S-specific binding antibodies, neutralizing antibodies, and T-cell responses than a single Ad26.COV2.S vaccination.
> The increase in binding antibodies was significantly larger with heterologous regimens that included mRNA-based vaccines than with the homologous booster.
> The mRNA-1273 booster was most immunogenic and was associated with higher reactogenicity than the BNT162b2 and Ad26.COV2.S boosters. Local and systemic reactions were generally mild to moderate in the first 2 days after booster administration.

The Ad26.COV2.S and mRNA boosters had an acceptable safety profile and were immunogenic in health care workers who had received a priming dose of Ad26.COV2.S vaccine. The strongest responses occurred after boosting with mRNA-based vaccines. Boosting with any available vaccine was better than not boosting.
Science Transl Med.2022.01.18Early non-neutralizing, afucosylated antibody responses are associated with COVID-19 severityChakraborty S., et al.
USAClinicAim : To study the effect of afucosylated antibody signaling in the lungs.

A model system in which human immune complexes (ICs) of defined composition are intratracheally administered to mice that express human FcγRs was developed. Molecular and cellular changes that were triggered in the lung by distinct antibody signaling pathways were then assessed by characterization of bronchoalveolar lavage (BAL) fluid collected after IC administration.

> human IgG-Fc gamma receptor (FcγR) interactions could regulate inflammation in the lung.
> Afucosylated IgG immune complexes isolated from COVID-19 patients induced inflammatory cytokine production and robust infiltration of the lung by immune cells.
> By contrast, vaccine-elicited IgG did not promote an inflammatory lung response.

IgG-FcγR interactions are able to regulate inflammation in the lung and may define distinct lung activities associated with the IgG that are associated with severe COVID-19 and protection against infection with SARS-CoV-2.
Science2022.01.18Neutralization of SARS-CoV-2 Omicron by BNT162b2 mRNA vaccine–elicited human seraMuik A., et al.
Germany / USA
VariantsAim: to understand the effect of the new mutations in Omicron on recognition by neutralizing antibodies in vaccinated individuals.

Wuhan, Beta, Delta, or Omicron pseudoviruses were tested with sera of 51 participants that received two or three doses of the mRNA-based COVID-19 vaccine BNT162b2.

> Following two doses, sera had >22-fold reduced neutralizing titers against Omicron compared to Wuhan pseudovirus.
> One month after the third vaccine dose, Omicron-neutralizing titers were increased 23-fold compared to two doses, with titers similar to Wuhan-neutralizing titers after two doses.
> The requirement of a third vaccine dose to effectively neutralize Omicron was confirmed using live SARS-CoV-2 in a subset of participants.

These data suggest that three doses of the mRNA vaccine BNT162b2 may protect against Omicron-mediated COVID-19.
JAMA2022.01.14Effect of Subcutaneous Casirivimab and Imdevimab Antibody Combination vs Placebo on Development of Symptomatic COVID-19 in Early Asymptomatic SARS-CoV-2 InfectionO'Brien M.P., et al.
USATherapeuticsAim: to evaluate the effect of combination subcutaneous casirivimab and imdevimab on progression from early asymptomatic SARS-CoV-2 infection to symptomatic COVID-19.

- Phase 3 trial of close household contacts of a SARS-CoV-2–infected index case (enrolment July 2020–Jan 2021; follow-up until March 2021). Asymptomatic individuals (aged ≥12 years) were eligible if identified within 96 hours of index case positive test collection.
- Interventions: 1 dose of subcutaneous casirivimab and imdevimab, 1200 mg (600 mg of each; n = 158), or placebo (n = 156).
Primary end point: proportion of seronegative participants who developed symptomatic COVID-19 during the 28-day efficacy assessment period.


> 204 participants asymptomatic and seronegative at baseline included in the primary efficacy analysis.
> Subcutaneous casirivimab and imdevimab, 1200 mg, significantly prevented progression to symptomatic disease (29/100 [29.0%] vs 44/104 [42.3%] with placebo; odds ratio, 0.54 [95% CI, 0.30-0.97]; P = .04; absolute risk difference, −13.3% [95% CI, −26.3% to −0.3%]).
> Casirivimab and imdevimab reduced the number of symptomatic weeks per 1000 participants (895.7 weeks vs 1637.4 weeks with placebo; P = .03), an approximately 5.6-day reduction in symptom duration per symptomatic participant.
> Treatment with casirivimab and imdevimab also reduced the number of high viral load weeks per 1000 participants (489.8 weeks vs 811.9 weeks with placebo; P = .001).
> The proportion of participants receiving casirivimab and imdevimab who had 1 or more treatment-emergent adverse event was 33.5% vs 48.1% for placebo, including events related (25.8% vs 39.7%) or not related (11.0% vs 16.0%) to COVID-19.

Among asymptomatic SARS-CoV-2 RT-qPCR–positive individuals living with an infected household contact, treatment with subcutaneous casirivimab and imdevimab antibody combination vs placebo significantly reduced the incidence of symptomatic COVID-19 over 28 days.
Nature Med.2022.01.14Ancestral SARS-CoV-2-specific T cells cross-recognize the Omicron variantGao Y., et al.
> We report here that SARS-CoV-2 spike-specific CD4+ and CD8+ T cells induced by prior infection or BNT162b2 vaccination provide extensive immune coverage against B.1.1.529.
> The median relative frequencies of SARS-CoV-2 spike-specific CD4+ T cells that cross-recognized B.1.1.529 in previously infected or BNT162b2-vaccinated individuals were 84% and 91%, respectively, and the corresponding median relative frequencies for SARS-CoV-2 spike-specific CD8+ T cells were 70% and 92%, respectively
> Pairwise comparisons across groups further revealed that SARS-CoV-2 spike-reactive CD4+ and CD8+ T cells were functionally and phenotypically similar in response to the ancestral strain or B.1.1.529

Collectively, our data indicate that established SARS-CoV-2 spike-specific CD4+ and CD8+ T cell responses, especially after BNT162b2 vaccination, remain largely intact against B.1.1.529.
Nature Immunol.2022.01.13Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infectionPhetsouphanh C., et al.
AustraliaImmunologyAim: to study individuals with Long COVID (LC) compared to age- and gender-matched recovered individuals without LC, unexposed donors and individuals infected with other coronaviruses.

> Patients with LC had highly activated innate immune cells, lacked naive T and B cells and showed elevated expression of type I IFN (IFN-β) and type III IFN (IFN-λ1) that remained persistently high at 8 months after infection
> Using a log-linear classification model, we defined an optimal set of analytes that had the strongest association with LC among the 28 analytes measured
> Combinations of the inflammatory mediators IFN-β, PTX3, IFN-γ, IFN-λ2/3 and IL-6 associated with LC with 78.5–81.6% accuracy.

This work defines immunological parameters associated with LC and suggests future opportunities for prevention and treatment.
Nature Med.2022.01.13SARS-CoV-2 infection and COVID-19 vaccination rates in pregnant women in ScotlandStock S.J., et al.
UKPublic Health / EpidemiologyAim: to obtain data on population-level data on COVID-19 vaccine uptake in pregnancy and SARS-CoV-2 infection outcomes.

> Between 8 Dec 2020 and 31 Oct 2021 in Scotland, 25,917 COVID-19 vaccinations were given to 18,457 pregnant women.
> Vaccine coverage was substantially lower in pregnant women than in the general female population of 18−44 years; 32.3% of women giving birth in October 2021 had two doses of vaccine compared to 77.4% in all women.
> The extended perinatal mortality rate for women who gave birth within 28 d of a COVID-19 diagnosis was 22.6 per 1,000 births (95% CI 12.9−38.5; pandemic background rate 5.6 per 1,000 births; 452 out of 80,456; 95% CI 5.1−6.2).
> Overall, 77.4% (3,833 out of 4,950; 95% CI 76.2−78.6) of SARS-CoV-2 infections, 90.9% (748 out of 823; 95% CI 88.7−92.7) of SARS-CoV-2 associated with hospital admission and 98% (102 out of 104; 95% CI 92.5−99.7) of SARS-CoV-2 associated with critical care admission, as well as all baby deaths, occurred in pregnant women who were unvaccinated at the time of COVID-19 diagnosis.

Addressing low vaccine uptake rates in pregnant women is imperative to protect the health of women and babies in the ongoing pandemic.
Science Transl Med.2022.01.13Antibodies elicited by SARS-CoV-2 infection or mRNA vaccines have reduced neutralizing activity against Beta and Omicron pseudovirusesSievers B.L., et al.
USAVariantsAim: to evaluate the magnitude and breadth of the neutralizing antibody response over time in individuals after infection and in mRNA-vaccinated individuals, using pseudoparticles expressing the spike protein of several SARS-CoV-2 variants.

> Boosting increases the magnitude of the antibody response to wildtype (D614), Beta, Delta, and Omicron variants; however, the Omicron variant was the most resistant to neutralization.
> We further observed that vaccinated healthy adults had robust and broad antibody responses whereas responses may have been reduced in vaccinated pregnant women, underscoring the importance of learning how to maximize mRNA vaccine responses in pregnant populations.

Findings from this study show substantial heterogeneity in the magnitude and breadth of responses after infection and mRNA vaccination and may support the addition of more conserved viral antigens to existing SARS-CoV-2 vaccines.
Clin Infect Dis.2022.01.13Necessity of COVID-19 Vaccination in Persons Who Have Already Had COVID-19Shrestha N. K., et al.
USAVaccines - ImmunisationAim : to evaluate the necessity of COVID-19 vaccination in persons with prior COVID-19.

Employees of Cleveland Clinic working in Ohio were included. Anyone who tested positive for COVID-19 at least once before the study start date was considered previously infected. One was considered vaccinated 14 days after receiving the second dose of a COVID-19 mRNA vaccine. The cumulative incidence of COVID-19, symptomatic COVID-19, and hospitalizations for COVID-19, were examined over the next year.

> Among 52238 employees, 4718 (9%) were previously infected, and 36922 (71%) were vaccinated by the study’s end.
> Cumulative incidence of COVID-19 was substantially higher throughout for those previously uninfected who remained unvaccinated than for all other groups, lower for the vaccinated than unvaccinated, and lower for those previously infected than those not.
> Incidence of COVID-19 increased dramatically in all groups after the Omicron variant emerged.
> In multivariable Cox proportional hazards regression, both prior COVID-19 and vaccination were independently associated with significantly lower risk of COVID-19.
> Among previously infected subjects, a lower risk of COVID-19 overall was not demonstrated, but vaccination was associated with a significantly lower risk of symptomatic COVID-19 in both the pre-Omicron (HR 0.60, 95% CI 0.40–0.90) and Omicron (HR 0.36, 95% CI 0.23–0.57) phases.

Both previous infection and vaccination provide substantial protection against COVID-19. Vaccination of previously infected individuals does not provide additional protection against COVID-19 for several months, but after that provides significant protection at least against symptomatic COVID-19.
NEJM2022.01.12SARS-CoV-2 Omicron Variant Neutralization in Serum from Vaccinated and Convalescent PersonsRössler A., et al.
AustriaVariantsAim: to study whether serum samples obtained from persons who had been vaccinated against SARS-CoV-2 or who had recovered from SARS-CoV-2 infection (i.e., convalescent) would be able to neutralize the omicron variant.

Serum samples:
- 10 participants infected with alpha variant, 8 with beta, and 7 with delta.
- 10 participants had received two doses of the mRNA-1273 vaccine, 10 the ChAdOx1-S vaccine, and 20 the BNT162b2 vaccine; 20 participants received heterologous ChAdOx1-S/BNT162b2.
- 5 participants had been infected and subsequently received one or two doses of BNT162b2, and 5 had been vaccinated with two doses of mRNA-1273, ChAdOx1-S, or BNT162b2 and subsequently had breakthrough infection.

> Serum samples from vaccinated persons neutralized the omicron variant to a much lesser extent than any other variant analyzed (alpha, beta, or delta).
> Some cross-neutralization of the omicron variant in samples obtained from persons who had received either homologous BNT162b2 vaccination or heterologous ChAdOx1-S–BNT162b2 vaccination was observed, but not in samples from persons who had received homologous ChAdOx1-S vaccination.
> We did not find neutralizing antibodies against the omicron variant in serum samples obtained 4 to 6 months after receipt of the second dose of the mRNA-1273 vaccine (however, in this group, the interval between receipt of the second dose and sampling was longer than for the other groups).
> Serum samples that were obtained from convalescent participants largely did not neutralize the omicron variant, although cross-neutralization was observed against other variants.
> 9 of the 10 serum samples obtained from convalescent–vaccinated or vaccinated–convalescent participants were able to neutralize the omicron variant, although to a lesser degree than the delta variant.

The omicron variant shows immune escape. Although receipt of a third dose of BNT162b2 may increase the level of cross-neutralizing antibodies, the rapid development of new, variant-adapted vaccines is warranted.
Ann Intern Med.2022.01.11Antibody Response to a Fourth Messenger RNA COVID-19 Vaccine Dose in Kidney Transplant Recipients: A Case SeriesCaillard S., et al.
FranceVaccines - ImmunisationAim: to investigate whether a fourth dose of an mRNA-based anti–SARS-CoV-2 vaccine would increase antispike IgG titers in kidney transplant recipients who showed a weak serologic response after 3 doses.


> A fourth dose of mRNA vaccine (BNT162b2 [Pfizer], n = 34; mRNA-1273 [Moderna], n = 58) was given to 92 kidney transplant recipients from 3 independent French university hospitals (Strasbourg, Lyon, and Nantes) who had antispike IgG titers less than 143 BAU/mL 1 month after a third dose.

> There were no safety concerns with the fourth vaccine dose.
> After a median of 29 days, median antispike IgG levels increased from 16.4 BAU/mL (interquartile range, 5.9 to 62.3 BAU/mL) to 145 BAU/mL (interquartile range, 27.6 to 243 BAU/mL) (Figure) and 50% of patients reached the threshold of 143 BAU/mL. Patients who reached this threshold had a longer interval between their transplant and fourth vaccine dose and were less frequently treated with steroids.
> The percentage of patients who had antispike IgG titers above 143 BAU/mL after the fourth dose was 48% for the BNT162b2 vaccine and 52% for the mRNA-1273 vaccine, and patients who received the mRNA-1273 vaccine had higher IgG titers (median, 150 vs. 122 BAU/mL).

Our study indicates that a fourth dose of an mRNA-based vaccine produces a satisfactory antibody response in some kidney transplant recipients who did not respond adequately after 3 previous doses, and it supports the use of a fourth vaccine dose for these patients.
NEJM2022.01.12Effectiveness of BNT162b2 Vaccine against Critical Covid-19 in AdolescentsOlson S.M., et al.
USAVaccines - ImmunisationAim: to assess the real-world effectiveness of the BNT162b2 vaccine in adolescents between 12 and 18 years of age against the delta variant.
- Case patients (hospitalised for Covid-19) were compared to two hospital-based control groups: patients who had Covid-19–like symptoms but negative for SARS-CoV-2 (test-negative) and patients who did not have Covid-19–like symptoms (syndrome-negative).

> A total of 445 case patients and 777 controls were enrolled. Overall, 17 case patients (4%) and 282 controls (36%) had been fully vaccinated.
> Of the case patients, 180 (40%) were admitted to the ICU, and 127 (29%) required life support; only 2 patients in the ICU had been fully vaccinated.
> The overall effectiveness of the BNT162b2 vaccine against hospitalization for Covid-19 was 94% (95% CI, 90 to 96); the effectiveness was 95% (95% CI, 91 to 97) among test-negative controls and 94% (95% CI, 89 to 96) among syndrome-negative controls.
> The effectiveness was 98% against ICU admission and 98% against Covid-19 resulting in the receipt of life support.
> All 7 deaths occurred in patients who were unvaccinated.

Among hospitalized adolescent patients, two doses of the BNT162b2 vaccine were highly effective against Covid-19–related hospitalization and ICU admission or the receipt of life support.
NEJM2022.01.12Duration of Protection against Mild and Severe Disease by Covid-19 VaccinesAndrews N., et al.
UKVaccines - ImmunisationAim: to estimate ChAdOx1-S (ChAdOx1 nCoV-19) and BNT162b2 vaccine effectiveness against symptomatic Covid-19 and related hospitalization and death in England.
- Effectiveness was assessed according to participant age and status with regard to coexisting conditions and over time since receipt of the second vaccine dose to investigate waning of effectiveness separately for the B.1.1.7 (alpha) and B.1.617.2 (delta) variants.

> Vaccine effectiveness against symptomatic Covid-19 with the delta variant peaked in the early weeks after receipt of the second dose and then decreased by 20 weeks to 44.3% (95% CI, 43.2 to 45.4) with the ChAdOx1-S vaccine and to 66.3% (95% CI, 65.7 to 66.9) with the BNT162b2 vaccine.
> Waning of vaccine effectiveness was greater in persons 65 years of age or older than in those 40 to 64 years of age.
> At 20 weeks or more after vaccination, vaccine effectiveness decreased less against both hospitalization, to 80.0% (95% CI, 76.8 to 82.7) with the ChAdOx1-S vaccine and 91.7% (95% CI, 90.2 to 93.0) with the BNT162b2 vaccine, and death, to 84.8% (95% CI, 76.2 to 90.3) and 91.9% (95% CI, 88.5 to 94.3), respectively.
> Greater waning in vaccine effectiveness against hospitalization was observed in persons 65 years of age or older in a clinically extremely vulnerable group and in persons 40 to 64 years of age with underlying medical conditions than in healthy adults.

We observed limited waning in vaccine effectiveness against Covid-19–related hospitalization and death at 20 weeks or more after vaccination with two doses of the ChAdOx1-S or BNT162b2 vaccine. Waning was greater in older adults and in those in a clinical risk group.
NEJM2022.01.12Effectiveness of Covid-19 Vaccines over a 9-Month Period in North CarolinaLin D.Y., et al.
USAVaccines - ImmunisationAim: to estimate the effectiveness of the BNT162b2 (Pfizer–BioNTech), mRNA-1273 (Moderna), and Ad26.COV2.S (Johnson & Johnson–Janssen) vaccines in reducing the current risks of Covid-19, hospitalization, and death, as a function of time elapsed since vaccination (Dec 2020-Sept 2021)

> For the two-dose regimens of mRNA vaccines BNT162b2 (30 μg per dose) and mRNA-1273 (100 μg per dose), vaccine effectiveness against Covid-19 was 94.5% (95% CI, 94.1 to 94.9) and 95.9% (95% CI, 95.5 to 96.2), respectively, at 2 months after the first dose and decreased to 66.6% (95% CI, 65.2 to 67.8) and 80.3% (95% CI, 79.3 to 81.2), respectively, at 7 months.
> Among early recipients of BNT162b2 and mRNA-1273, effectiveness decreased by approximately 15 and 10 percentage points, respectively, from mid-June to mid-July, when the delta variant became dominant.
> For the one-dose regimen of Ad26.COV2.S (5×1010 viral particles), effectiveness against Covid-19 was 74.8% (95% CI, 72.5 to 76.9) at 1 month and decreased to 59.4% (95% CI, 57.2 to 61.5) at 5 months.
> All three vaccines maintained better effectiveness in preventing hospitalization and death than in preventing infection over time, although the two mRNA vaccines provided higher levels of protection than Ad26.COV2.S.

All three Covid-19 vaccines had durable effectiveness in reducing the risks of hospitalization and death. Waning protection against infection over time was due to both declining immunity and the emergence of the delta variant.
JAMA Netw Open2022.01.11Outcomes of SARS-CoV-2–Positive Youths Tested in Emergency DepartmentsFunk A.L., et al.
InternationalClinicsAim: to estimate the proportion of children with severe outcomes within 14 days of testing positive for SARS-CoV-2 in an emergency department (ED).

- Youth <18 years SARS-CoV-2 positive, 14-day follow-up, March 2020-June 2021

> Among 3222 patients enrolled, 3221 (>99.9%) had index visit outcome data available, 2007 (62.3%) were from the United States, 1694 (52.6%) were male, and 484 (15.0%) had a self-reported chronic illness; the median (IQR) age was 3 (0-10) years.
> After 14 days of follow-up, 735 children (22.8% [95% CI, 21.4%-24.3%]) were hospitalized, 107 (3.3% [95% CI, 2.7%-4.0%]) had severe outcomes, and 4 children (0.12% [95% CI, 0.03%-0.32%]) died.
> Characteristics associated with severe outcomes included being aged 5 to 18 years (age 5 to <10 years vs <1 year: odds ratio [OR], 1.60 [95% CI, 1.09-2.34]; age 10 to <18 years vs <1 year: OR, 2.39 [95% CI 1.38-4.14]), having a self-reported chronic illness (OR, 2.34 [95% CI, 1.59-3.44]), prior episode of pneumonia (OR, 3.15 [95% CI, 1.83-5.42]), symptoms starting 4 to 7 days prior to seeking ED care (vs starting 0-3 days before seeking care: OR, 2.22 [95% CI, 1.29-3.82]), and country (eg, Canada vs US: OR, 0.11 [95% CI, 0.05-0.23]; Costa Rica vs US: OR, 1.76 [95% CI, 1.05-2.96]; Spain vs US: OR, 0.51 [95% CI, 0.27-0.98]).
> Among a subgroup of 2510 participants discharged home from the ED after initial testing and who had complete follow-up, 50 (2.0%; 95% CI, 1.5%-2.6%) were eventually hospitalized and 12 (0.5%; 95% CI, 0.3%-0.8%) had severe outcomes.
> Compared with hospitalized SARS-CoV-2–negative youths, the risk of severe outcomes was higher among hospitalized SARS-CoV-2–positive youths (risk difference, 3.9%; 95% CI, 1.1%-6.9%).

Approximately 3% of SARS-CoV-2–positive youths tested in EDs experienced severe outcomes within 2 weeks of their ED visit. Among children discharged home from the ED, the risk was much lower.
Nature Commun.2022.01.11Rapid antigen testing as a reactive response to surges in nosocomial SARS-CoV-2 outbreak riskSmith D.R.M., et al.
FrancePublic health / EpidemiologyWe simulate SARS-CoV-2 transmission in a long-term care hospital with varying COVID-19 containment measures in place (social distancing, face masks, vaccination)

> Across scenarios, nosocomial incidence is reduced by up to 40-47% (range of means) with routine symptomatic RT-PCR testing, 59-63% with the addition of a timely round of Ag-RDT screening, and 69-75% with well-timed two-round screening.
> For the latter, a delay of 4-5 days between the two screening rounds is optimal for transmission prevention.
> Screening efficacy varies depending on test sensitivity, test type, subpopulations targeted, and community incidence

Efficiency, however, varies primarily depending on underlying outbreak risk, with health-economic benefits scaling by orders of magnitude depending on the COVID-19 containment measures in place.
Clin Microbiol Infect.2022.01.10Efficacy of favipiravir in adults with mild COVID-19: a randomized, double-blind, multicenter, placebo-controlled trial clinical trialBosaeed M., et al.
Saudi ArabiaTherapeuticsAim: to evaluate whether favipiravir reduces the time to viral clearance as documented by negative SARS-CoV-2 RT-PCR in mild COVID-19 cases compared to placebo.

> In this randomized, double-blinded, multicenter, and placebo-controlled trial, adults with PCR confirmed mild COVID-19 were recruited in an outpatient setting at seven medical facilities across Saudi Arabia.
> Participants were randomized in a 1:1 ratio to receive either favipiravir 1800 mg by mouth twice daily on day one followed by 800 mg twice daily (n=112) or a matching placebo (n=119), for a total of 5 to 7 days.

> 231 patients were randomized and began the study (median age, 37 [interquartile range: 32-44] years; 155 [67%] men), and 112 (48.5%) were assigned to the treatment group and 119 (51.5%) into the placebo group.
> The data and safety monitoring board (DSMB) recommended stopping enrollment because of futility at the interim analysis.
> The median time to viral clearance was 10 (IQR: 6-12) days in the favipiravir group and 8 (IQR: 6-12) days in the placebo group, with a hazard ratio of 0.87 for the favipiravir group (95% CI 0.571 to 1.326; p-value =0.51).
> The median time to clinical recovery was 7 days (IQR: 4-11) in the favipiravir group and 7 days (IQR: 5-10) in the placebo group. There was no difference between the two groups on the secondary outcome of hospital admission.
> There were no drug-related severe adverse events.

In this clinical trial, favipiravir therapy in mild COVID-19 patients did not reduce the time to viral clearance within 15 days of starting the treatment.
Nature Commun.2022.01.10Dynamics of spike-and nucleocapsid specific immunity during long-term follow-up and vaccination of SARS-CoV-2 convalescentsKoerber N., et al.
GermanyImmunologyAim: characterization of the dynamics of anti-viral immunity during long-term follow-up and after BNT162b2 mRNA-vaccination in convalescents after asymptomatic or mild SARS-CoV-2 infection.

> Virus-specific and virus-neutralizing antibody titers rapidly declined in convalescents over 9 months after infection
> Virus-specific cytokine-producing polyfunctional T cells persisted, among which IL-2-producing T cells correlated with virus-neutralizing antibody titers.
> Among convalescents, 5% of individuals failed to mount long-lasting immunity after infection and showed a delayed response to vaccination compared to 1% of naïve vaccinees, but successfully responded to prime/boost vaccination. This lack of induction of long-lasting adaptive immunity might have resulted either from infection with too few viruses or contact with the poorly infectious virus, where innate immunity in the upper respiratory tract might have sufficed to achieve early control of infection but may have failed to induce lasting adaptive immunity.
> 8% of convalescents showed a selective increase in virus-neutralizing antibody titers without accompanying increased frequencies of circulating SARS-CoV-2-specific T cells.
> The same convalescents, responded to vaccination with simultaneous increase in antibody and T cell immunity revealing the strength of mRNA-vaccination to increase virus-specific immunity in convalescents.

These results advocate for the use of vaccination in individuals with prior mild SARS-CoV-2 infection to further enhance immune protection for the prevention of re-infection.
Nature Commun.2022.01.10Robust and durable serological response following pediatric SARS-CoV-2 infectionRenk H., et al.
> we examine 548 children and 717 adults within 328 households with at least one member with a previous laboratory-confirmed SARS-CoV-2 infection
> we assess serological response at 3–4 months and 11–12 months after infection using a bead-based multiplex immunoassay for 23 human coronavirus antigens including SARS-CoV-2 and its Variants of Concern (VOC) and endemic human coronaviruses (HCoVs), and additionally by three commercial SARS-CoV-2 antibody assays.
> Neutralization against wild type SARS-CoV-2 and the Delta VOC are analysed in a pseudotyped virus assay

> Children, compared to adults, are five times more likely to be asymptomatic, and have higher specific antibody levels which persist longer (96.2% versus 82.9% still seropositive 11–12 months post infection)
> Of note, symptomatic and asymptomatic infections induce similar humoral responses in all age groups
> SARS-CoV-2 infection occurs independent of HCoV serostatus
> Neutralization responses of children and adults are similar, although neutralization is reduced for both against the Delta VOC.
Overall, the long-term humoral immune response to SARS-CoV-2 infection in children is of longer duration than in adults even after asymptomatic infection.
Nature Microbiol.2022.01.10Induction of robust cellular and humoral immunity against SARS-CoV-2 after a third dose of BNT162b2 vaccine in previously unresponsive older adultsRomero-Olmedo A.J., et al.
GermanyImmunologyAim: to compare SARS-CoV-2-specific antibody and T-cell responses between older and younger audults after receiving two doses of BNT162b2.
- Older adults (>80 years old, n = 51), younger control group (20–53 years old, n = 46)
- Analysis of spike-specific IgG, neutralization capacity against SARS-CoV-2 and SARS-CoV-2-reactive CD4 T cells (CD40L+ and IFNγ+) in peripheral blood

> Two doses of BNT162b2 increased neutralization capacity against wild-type and also Delta, although at a lower level. Young and older groups demonstrated a further increase (10-fold average) between first and second dose of spike-specific CD4 T cells.
> Overall antibody and CD4 T-cell response was lower in older vaccinees at a high level of significance. 10% of older adults were identifies as low-/non-responders.
> After receiving a third vaccination with BNT162b2, 4 out of 5 low-/non-responders showed antibody and T-cell responses similar to those of responders after two vaccinations.

Overall, immune responses against SARS-CoV-2 are lower in aged versus young vaccinees, although most of them mount adaptive SARS-CoV-2-specific immunity after two doses of BNT162b2. Those who are initially hardly responding to two doses can mount a virus-specific adaptive immune response after a third BNT162b2 dose.
BMJ2022.01.07Atorvastatin versus placebo in patients with covid-19 in intensive care: randomized controlled trialSadeghipour P., et al.
IranTherapeuticsAim: to assess the effect of statin treatment versus placebo on clinical outcomes in patients with covid-19 admitted to the intensive care unit (ICU).

> a multicenter, randomized controlled trial with a 2×2 factorial design in 11 hospitals in Iran.
> Atorvastatin 20 mg orally once daily versus placebo, to be continued for 30 days from randomization irrespective of hospital discharge status.
> The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or all cause mortality within 30 days from randomization. Prespecified safety outcomes included increase in liver enzyme levels more than three times the upper limit of normal and clinically diagnosed myopathy.

> Of 605 patients randomized between 29 July 2020 and 4 April 2021 for statin randomization in the INSPIRATION-S trial, 343 were co-randomized to intermediate dose versus standard dose prophylactic anticoagulation with heparin based regimens, whereas 262 were randomized after completion of the anticoagulation study. 587 of the 605 participants were included in the primary analysis of INSPIRATION-S, reported here: 290 were assigned to atorvastatin and 297 to placebo (median age 57 years (interquartile range 45-68 years); 256 (44%) women).
> The primary outcome occurred in 95 (33%) patients assigned to atorvastatin and 108 (36%) assigned to placebo (odds ratio 0.84, 95% confidence interval 0.58 to 1.21).
> Death occurred in 90 (31%) patients in the atorvastatin group and 103 (35%) in the placebo group (odds ratio 0.84, 95% confidence interval 0.58 to 1.22).
> Rates for venous thromboembolism were 2% (n=6) in the atorvastatin group and 3% (n=9) in the placebo group (odds ratio 0.71, 95% confidence interval 0.24 to 2.06).
> Myopathy was not clinically diagnosed in either group. Liver enzyme levels were increased in five (2%) patients assigned to atorvastatin and six (2%) assigned to placebo (odds ratio 0.85, 95% confidence interval 0.25 to 2.81).

In adults with covid-19 admitted to the ICU, atorvastatin was not associated with a significant reduction in the composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or all cause mortality compared with placebo. Treatment was, however, found to be safe. As the overall event rates were lower than expected, a clinically important treatment effect cannot be excluded.
JAMA Oncol.2022.01.07SARS-CoV-2 Antibody Response to 2 or 3 Doses of the BNT162b2 Vaccine in Patients Treated With Anticancer AgentsFenioux C., et al.
FranceVaccines - ImmunisationAim: to assess the immune humoral response to 2 or 3 doses of the BNT162b2 vaccine in patients treated with anticancer agents.
- Observational cohort study of adults treated with anticancer agents who received 2 or 3 doses of vaccine (Feb 1-May 31, 2021) - individuals with a weak humoral response 1 month after the second dose received a third injection.
- Humoral response was evaluated with a threshold of anti–SARS-CoV-2 spike protein antibody levels at 1000 arbitrary units (AU)/mL to neutralize less-sensitive COVID-19 variants.

> Among 163 patients (median age, 66 [27-89] years, 86 men [53%]) with solid tumors who received 2 or 3 doses of vaccine, 122 individuals (75%) were treated with chemotherapy, 15 with immunotherapy (9%), and 26 with targeted therapies (16%).
> The proportions of patients with an anti-S immunoglobulin G titer greater than 1000 AU/mL were 15% (22 of 145) at the time of the second vaccination and 65% (92 of 142) 28 days after the second vaccination.
> Humoral response decreased 3 months after the second dose.
> Treatment type was associated with humoral response; in particular, time between vaccine and chemotherapy did not interfere with the humoral response.
> Among 36 patients receiving a third dose of vaccine, a serologic response greater than 1000 AU/mL occurred in 27 individuals (75%).

This study supports the use of a third vaccine dose among patients with active cancer treatment for solid tumors.
JAMA Netw Open2022.01.07SARS-CoV-2 Reinfection Rate and Estimated Effectiveness of the Inactivated Whole Virion Vaccine BBV152 Against Reinfection Among Health Care Workers in New Delhi, IndiaMalhotra S., et al.
IndiaVaccines - ImmunisationAim: to assess the incidence density of reinfection among a cohort of HCWs and estimate the effectiveness of the inactivated whole virion vaccine BBV152 against reinfection in New Delhi, India - Vaccination with 0, 1, or 2 doses of BBV152.


> HCWs were categorized as:
- fully vaccinated (with 2 doses and ≥15 days after the second dose),
- partially vaccinated (with 1 dose or 2 doses with <15 days after the second dose),
- or unvaccinated.
> Incidence density of COVID-19 reinfection per 100 person-years was computedand included for analysis.

> Among 15 244 HCWs who participated in the study, 4978 (32.7%) were diagnosed with COVID-19.
> The reinfection incidence density was 7.26 (95% CI: 6.09-8.66) per 100 person-years (124 HCWs [2.5%]).
> Fully vaccinated HCWs had lower risk of reinfection (HR, 0.14 [95% CI, 0.08-0.23]), symptomatic reinfection (HR, 0.13 [95% CI, 0.07-0.24]), and asymptomatic reinfection (HR, 0.16 [95% CI, 0.05-0.53]) compared with unvaccinated HCWs.
> Among the 3 vaccine categories, reinfection was observed in 60 of 472 (12.7%) of unvaccinated (incidence density, 18.05 per 100 person-years; 95% CI, 14.02-23.25), 39 of 356 (11.0%) of partially vaccinated (incidence density 15.62 per 100 person-years; 95% CI, 11.42-21.38), and 17 of 1089 (1.6%) fully vaccinated (incidence density 2.18 per 100 person-years; 95% CI, 1.35-3.51) HCWs.
> The estimated effectiveness of BBV152 against reinfection was 86% (95% CI, 77%-92%); symptomatic reinfection, 87% (95% CI, 76%-93%); and asymptomatic reinfection, 84% (95% CI, 47%-95%) among fully vaccinated HCWs.
> Partial vaccination was not associated with reduced risk of reinfection.

These findings suggest that BBV152 was associated with protection against both symptomatic and asymptomatic reinfection in HCWs after a complete vaccination schedule, when the predominant circulating variant was B.1.617.2.
Cell2022.01.06mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variantGarcia-Beltran W.F., et al.
USAVariantsAim: to measure the neutralization potency of sera from 88 mRNA-1273, 111 BNT162b, and 40 Ad26.COV2.S vaccine recipients against wild-type, Delta, and Omicron SARS-CoV-2 pseudoviruses.
- Individuals that received their primary series recently (<3 months), distantly (6–12 months), or an additional “booster” dose were included, while accounting for prior SARS-CoV-2 infection.

> Neutralization of Omicron was undetectable in most vaccinees.
> However, individuals boosted with mRNA vaccines exhibited potent neutralization of Omicron, only 4–6-fold lower than wild type, suggesting enhanced cross-reactivity of neutralizing antibody responses.
> Omicron pseudovirus infects more efficiently than other variants tested.

This study highlights the importance of additional mRNA doses to broaden neutralizing antibody responses against highly divergent SARS-CoV-2 variants.
Science2022.01.06Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicryPark Y.J., et al.
InternationalTherapeuticsUnderstanding broadly neutralizing sarbecovirus antibody responses is key to developing countermeasures against SARS-CoV-2 variants and future zoonotic sarbecoviruses.

> Isolation and characterization of a human monoclonal antibody, designated S2K146, broadly neutralizing viruses belonging to SARS-CoV- and SARS-CoV-2-related sarbecovirus clades (using ACE2 as an entry receptor)
> S2K146 potently neutralized VSV pseudotypes harboring SARS-CoV-2 S glycoproteins from VOCs including Alpha, Beta, Gamma, Delta plus (AY.1/AY.2), Epsilon and Lambda
> S2K146 also weakly neutralized VSV pseudotyped harboring the K493Y/T498W mutations, which enable human ACE2-mediated entry
> S2K146 neutralized as well authentic SARS-CoV-2 and SARS-CoV-2 VOC
> Structural and functional studies show that most of the virus residues that directly bind S2K146 are also involved in binding to ACE2.
> S2K146 protects against SARS-CoV-2 Beta challenge in hamsters
> Viral passaging experiments reveal a high barrier for emergence of escape mutants, making it a good candidate for clinical development.

The conserved ACE2-binding residues present a site of vulnerability that might be leveraged for developing vaccines eliciting broad sarbecovirus immunity.
Immunity2022.01.05mRNA-1273 vaccine-induced antibodies maintain Fc-effector functions across SARS-CoV-2 Variants of ConcernKaplonek P., et al.
USAImmunologyAim: to study SARS-CoV-2 antibody effector functions that go beyond neutralisation.
- Profiling of the binding and functional capacity of convalescent antibodies and Moderna mRNA-1273 COVID-19 vaccine-induced antibodies across SARS-CoV-2 variants of concern (VOCs).

> While neutralizing responses to VOCs decreased in both groups, Fc-mediated responses were distinct.
> In convalescent individuals, while antibodies exhibited robust binding to VOCs, they showed compromised interactions with Fc-receptors.
> Conversely, vaccine-induced antibodies also bound robustly to VOCs but continued interacting with Fc-receptors and mediated antibody effector functions.

These data point to a resilience in the mRNA vaccine-induced humoral immune response that may continue to protect from SARS-CoV-2 VOCs independent of neutralization.
NEJM2022.01.05Effect of Covid-19 Vaccination on Transmission of Alpha and Delta VariantsEyre D.W., et al.
UKVaccines - ImmunisationBackground
Before Delta variant: vaccination reduced transmission of SARS-CoV-2 from infected vaccinated persons, potentially by reducing viral loads.
With Delta: vaccination still lowers the risk of infection, but similar viral loads in vaccinated and unvaccinated persons questions the degree to which vaccination prevents transmission.

Contact-testing to perform a retrospective observational cohort study involving adult contacts of SARS-CoV-2–infected adult index patients.

> Among 146,243 tested contacts of 108,498 index patients
- 54,667 (37%) had positive SARS-CoV-2 polymerase-chain-reaction (PCR) tests.
> In index patients who became infected with the alpha variant, two vaccinations with either BNT162b2 or ChAdOx1 nCoV-19, were independently associated with reduced PCR positivity in contacts
> Vaccine-associated reductions in transmission of the delta variant were smaller than those with the alpha variant
> Reductions in transmission of the delta variant after two BNT162b2 vaccinations were greater
> Variation in Ct values in index patients explained 7 to 23% of vaccine-associated reductions in transmission of the two variants.
> The reductions in transmission of the delta variant declined over time after the second vaccination, reaching levels that were similar to those in unvaccinated persons by 12 weeks in index patients who had received ChAdOx1 nCoV-19 and attenuating substantially in those who had received BNT162b2.
> Protection in contacts also declined in the 3-month period after the second vaccination.

Vaccination was associated with a smaller reduction in transmission of the delta variant than of the alpha variant, and the effects of vaccination decreased over time.
Cell2022.01.04SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responsesDejnirattisai W., et al.
> Neutralization titres of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic as well as Alpha, Beta, Gamma, Delta are substantially reduced or fail to neutralize.
> Titres against Omicron are boosted by third vaccine doses and are high in cases both vaccinated and infected by Delta.
> Mutations in Omicron knock out or substantially reduce neutralization by most of a large panel of potent monoclonal antibodies and antibodies under commercial development.
> Omicron S has structural changes from earlier viruses, combining mutations conferring tight binding to ACE2 to unleash evolution driven by immune escape, leading to a large number of mutations in the ACE2 binding site which rebalance receptor affinity to that of early pandemic viruses.
Science Transl Med.2022.12.30Inhaled remdesivir reduces viral burden in a nonhuman primate model of SARS-CoV-2 infectionVremillion M.S, et al.
Remdesivir (RDV) is a nucleotide analog prodrug with demonstrated clinical benefit in patients with coronavirus disease 2019 (COVID-19). To make RDV more convenient for non-hospitalized patients earlier in disease, administration routes other than IV are being evaluated.

> pharmacokinetics and efficacy of RDV administered by head dome inhalation in African green monkeys (AGM).

> Relative to an IV administration of RDV at 10 mg/kg, an approximately 20-fold lower dose administered by inhalation produced comparable concentrations of the pharmacologically active triphosphate in lower respiratory tract tissues.
> Distribution of the active triphosphate into the upper respiratory tract was also observed following inhaled RDV exposure.
> Inhalation RDV dosing resulted in lower systemic exposures to RDV and its metabolites as compared with IV RDV dosing.
> An efficacy study with repeated dosing of inhaled RDV in an AGM model of SARS-CoV-2 infection demonstrated reductions in viral replication in bronchoalveolar lavage fluid and respiratory tract tissues compared with placebo.
> Efficacy was observed with inhaled RDV administered once daily at a pulmonary deposited dose of 0.35 mg/kg beginning approximately 8 hours post-infection.
> The efficacy of inhaled RDV was similar to that of IV RDV administered once at 10 mg/kg followed by 5 mg/kg daily in the same study.
NEJM2022.12.30Plasma Neutralization of the SARS-CoV-2 Omicron VariantSchmidt F., et al.
USAVaccinesAim: to measure neutralizing antibody titers against Wuhan-hu-1, synthetic polymutant spike protein (PMS20), and omicron spike pseudotypes in 169 plasma specimens from 47 persons with previous infection, vaccination, or both.

> Plasma 1 month and 6 months after infection: the 50% neutralization titer (NT50) values were a mean (±SD) of 60±47 and 37±27 times lower for PMS20 than for Wuhan-hu-1, respectively, and 58±51 and 32±23 times lower for omicron than for Wuhan-hu-1.
> Similarly, plasma obtained from different persons in the same cohort 1 year after infection had NT50 values that were 34±24 times lower for PMS20 and 43±23 times lower for omicron than for Wuhan-hu-1.
> Plasma 1.3 months after receiveing two doses of an mRNA vaccine: the NT50 values were 187±24 times lower for PMS20 and 127±66 times lower for omicron than for Wuhan-hu-1 (Fig. S3A).
> At 5 months after vaccination, the neutralization potency was 58±23 times lower for PMS20 and 27±17 times lower for omicron.
> Vaccination of persons who had recovered from Covid-19 or administration of a third dose ≥6 months after the second dose of an mRNA vaccine led to a substantial gain in neutralizing activity against PMS20 and omicron. Specifically,
> After vaccination in persons who had previously been infected with SARS-CoV-2: the NT50 values were 238 times, 214 times, and 154 times greater for Wuhan-hu-1, PMS20, and omicron pseudotypes, respectively, than the prevaccination convalescent-phase titers in the same persons.
> Administration of a third dose 6 months after two doses of an mRNA vaccine (sampling 1 month after 3rd dose): the NT50 values after the booster dose were 26 times greater for Wuhan-hu-1, 35 times greater for PMS20, and 38 times greater for omicron.
> Neutralizing titers against omicron were substantial (1411 to 56,537) in all persons who had had Covid-19 and were then vaccinated and in those who had three doses of an mRNA vaccine, but titers were low or undetectable in many unvaccinated persons who had had Covid-19 and in recipients of only two doses of an mRNA vaccine.

Omicron variant shows an unprecedented degree of neutralizing antibody escape but boosting and promoting affinity maturation of antibodies will provide additional protection.
JAMA2022.12.30Characteristics and Outcomes of Hospitalized Patients in South Africa During the COVID-19 Omicron Wave Compared With Previous WavesMaslo C., et al.
South AfricaClinicMethods
> We identified the period when 26% positivity rates were reached in the previous waves (wave 1: June 14 to July 6, 2020; wave 2: December 1-23, 2020; wave 3: June 1-23, 2021) and compared them with the fourth wave (November 15 to December 7, 2021)
> All patients hospitalized with a positive COVID-19 result were included. Patient characteristics, need for oxygen supply and mechanical ventilation, admission to intensive care, length of stay (LOS), and mortality rates were extracted from the electronic administration system.
> Categorical variables were compared between waves using a χ2 test and continuous variables using 1-way analysis of variance (ANOVA). A 5% significance level (2-sided) was used

> The number of patients treated in the hospitals during the same early period of each wave differed (2351 in wave 4 vs maximum 6342 in wave 3); however, 68% to 69% of patients presenting to the emergency department with a positive COVID-19 result were admitted to the hospital in the first 3 waves vs 41.3% in wave 4.
> Patients hospitalized during wave 4 were younger (median age, 36 years vs maximum 59 years in wave 3; P < .001) with a higher proportion of females. Significantly fewer patients with comorbidities were admitted in wave 4, and the proportion presenting with an acute respiratory condition was lower (31.6% in wave 4 vs maximum 91.2% in wave 3, P < .001). Of 971 patients admitted in wave 4, 24.2% were vaccinated, 66.4% were unvaccinated, and vaccination status was unknown for 9.4%.
> The proportion of patients requiring oxygen therapy significantly decreased ( 17.6% in wave 4 vs 74% in wave 3, P < .001) as did the percentage receiving mechanical ventilation. Admission to intensive care was 18.5% in wave 4 vs 29.9% in wave 3 (P < .001)
> The median LOS (between 7 and 8 days in previous waves) decreased to 3 days in wave 4. The death rate was between 19.7% in wave 1 and 29.1% in wave 3 and decreased to 2.7% in wave 4.

Further research is needed to determine if the differences between waves are affected by preexisting acquired or natural immunity (44.3% of the adult South African population was vaccinated as of December 20215 and >50% of the population has had previous exposure to SARS-CoV-26) or if Omicron may be less pathogenic than previous variants.
NEJM2022.12.29Effectiveness of BNT162b2 Vaccine against Omicron Variant in South AfricaCollie S., et al.
South AfricaVaccinesAim: to estimate the vaccine effectiveness of two doses of the BNT162b2 vaccine (i.e., full vaccination) against hospitalization for Covid-19 caused by the omicron variant using data from Discovery Health, a South African managed care organization.

- Comparison of vaccine effectiveness (in fully vaccinated) against Covid-19 hospitalization associated with the omicron variant during omicron dominance period (Nov 15 to Dec 7 – omicron proxy period) against estimates of vaccine effectiveness during delta dominance period (Sept 1-Oct 30 – comparator period)
- Three sensitivity analyses on omicron proxy period: PCR tests showing S-gene target failure, only PCR results from patients in Gauteng province, PCR test results from patients who had been hospitalized.

> Analysis of 133,437 PCR test results for the comparator period, of which 38,155 (28.6%) obtained ≥14 days after the patient had received the second dose of vaccine, and 78,173 PCR test results for the proxy omicron period, of which 32,325 (41.4%) obtained ≥14 days after the second dose.
> Overall test positivity was 6.4% during the comparator period and 24.4% during the proxy omicron period, whereas the Covid-19 admission rate was 10.8% and 2.2%, respectively, as a percentage of positive PCR test results. Positive cases were younger during the proxy omicron period than during the comparator period.
> Vaccine effectiveness during the proxy omicron period was 70% (95% CI, 62 to 76). Vaccine effectiveness during the comparator period was 93% (95% CI, 90 to 94) against hospitalization for Covid-19.

During the proxy omicron period, a maintenance of effectiveness of the BNT162b2 vaccine was seen, although reduced, against hospital admission for Covid-19.
NEJM2022.12.29Third BNT162b2 Vaccination Neutralization of SARS-CoV-2 Omicron InfectionNamet I., et al.
IsraelVaccinesAim: to test in vitro neutralization of omicron-infected cells by serum samples of participants vaccinate with 2 or 3 BNT162b2 doses.

- Microneutralization assays with wild-type virus and beta, delta, and omicron variant isolates using serum samples from two groups of 20 health care workers who received either two doses of the BNT162b2 vaccine (mean, 165.6 days since receipt of the second dose), or three vaccine doses (mean, 25 days since receipt of the third dose)

> Receipt of three vaccine doses led to better neutralization of the wild-type virus and the three variants than receipt of two vaccine doses. The geometric mean titers (GMT) of the wild-type virus and the beta, delta, and omicron variants were 16.56, 1.27, 8.00, and 1.11, respectively, after receipt of the second vaccine dose and 891.4, 152.2, 430.5, and 107.6, respectively, after receipt of the third dose.
> A significantly lower neutralization efficiency of the BNT162b2 vaccine against all the tested variants of concern than against the wild-type virus was observed after two doses than after three. The third dose of the BNT162b2 vaccine efficiently neutralized infection with the omicron variant.

No neutralization efficiency against the omicron variant was observed after 2 doses, but this increased (by a factor of 100) after the third dose than after the second dose. However, even with three doses, neutralization against the omicron variant was lower (by a factor of 4) than that against the delta variant.
BMJ2022.12.29GP consultation rates for sequelae after acute covid-19 in patients managed in the community or hospital in the UK: population based studyWhittaker H.R., et al.
UKLong CovidAim: to describe the rates for consulting a general practitioner (GP) for sequelae after acute covid-19 in patients admitted to hospital with covid-19 and those managed in the community, and to determine how the rates change over time for patients in the community and after vaccination for covid-19.

Participants: 456 002 Covid-19 patients between 1 Aug 2020 and 14 Feb 2021 (44.7% men; median age 61 years), admitted to hospital within two weeks of diagnosis or managed in the community, and followed-up for a maximum of 9.2 months. Negative control group: individuals without covid-19 (n=38 511) and patients with influenza before the pandemic (n=21 803).

> Relative to the negative control and influenza cohorts, patients in the community (n=437 943) had significantly higher GP consultation rates for multiple sequelae, and the most common were loss of smell or taste, or both (adjusted hazard ratio 5.28, 95% CI 3.89 to 7.17, P<0.001); venous thromboembolism (3.35, 2.87 to 3.91, P<0.001); lung fibrosis (2.41, 1.37 to 4.25, P=0.002), and muscle pain (1.89, 1.63 to 2.20, P<0.001); and also for healthcare use after a diagnosis of covid-19 compared with 12 months before infection.
> For absolute proportions, the most common outcomes ≥4 weeks after a covid-19 diagnosis in patients in the community were joint pain (2.5%), anxiety (1.2%), and prescriptions for non-steroidal anti-inflammatory drugs (1.2%).
> Patients admitted to hospital (n=18 059) also had significantly higher GP consultation rates for multiple sequelae, most commonly for venous thromboembolism (16.21, 11.28 to 23.31, P<0.001), nausea (4.64, 2.24 to 9.21, P<0.001), prescriptions for paracetamol (3.68, 2.86 to 4.74, P<0.001), renal failure (3.42, 2.67 to 4.38, P<0.001), and healthcare use after a covid-19 diagnosis compared with 12 months before infection.
> For absolute proportions, the most common outcomes ≥4 weeks after a covid-19 diagnosis in patients admitted to hospital were venous thromboembolism (3.5%), joint pain (2.7%), and breathlessness (2.8%).
> In patients in the community, anxiety and depression, abdominal pain, diarrhoea, general pain, nausea, chest tightness, and tinnitus persisted throughout follow-up.
> GP consultation rates were reduced for all symptoms, prescriptions, and healthcare use, except for neuropathic pain, cognitive impairment, strong opiates, and paracetamol use in patients in the community after the first vaccination dose for covid-19 relative to before vaccination. GP consultation rates were also reduced for ischaemic heart disease, asthma, and gastro-oesophageal disease.

GP consultation rates for sequelae after acute covid-19 infection differed between patients who were admitted to hospital and those managed in the community. For individuals in the community, rates of some sequelae decreased over time but those for others, such as anxiety and depression, persisted.
Cell2022.12.24The Omicron variant is highly resistant against antibody-mediated neutralization – implications for control of the COVID-19 pandemicHoffmann M., et al.
> Omicron spike was resistant against most therapeutic antibodies but remained susceptible to inhibition by Sotrovimab.
> Omicron spike evaded neutralization by antibodies from convalescent or BNT162b2-vaccinated individuals with 10- to 44-fold higher efficiency than the spike of the Delta variant.
> Neutralization of the Omicron spike by antibodies induced upon heterologous ChAdOx1/BNT162b2-vaccination or vaccination with three doses of BNT162b2 was more efficient, but the Omicron spike still evaded neutralization more efficiently than the Delta spike.

These findings indicate that most therapeutic antibodies will be ineffective against the Omicron variant and that double immunization with BNT162b2 might not adequately protect against severe disease induced by this variant.
Science Transl Med.2022.12.23A Phase 2a clinical trial of Molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virusFischer W. A., et al.
> In a Phase 2a double-blind, placebo-controlled, randomized, multicenter clinical trial, we evaluated the safety, tolerability, and antiviral efficacy of the nucleoside analog molnupiravir in 202 unvaccinated participants with confirmed SARS-CoV-2 infection and with symptom duration <7 days.
> Participants were randomized 1:1 to receive 200 mg molnupiravir or placebo, and then 3:1 to receive molnupiravir (400 or 800 mg) or placebo, orally twice daily for 5 days. x
> Infectious virus was assessed by inoculation of cultured Vero cells with samples from nasopharyngeal swabs and was detected by RT-PCR.

> Time to viral RNA clearance (primary endpoint) was decreased in the 800 mg molnupiravir group (median 14 days) compared to the placebo group (median 15 days) (log rank p-value=0.013).
> 92.5% of participants receiving 800 mg molnupiravir achieved viral RNA clearance compared with 80.3% of placebo recipients by study end (4 weeks).
> Infectious virus (secondary endpoint) was detected in swabs from 1.9% of the 800 mg molnupiravir group compared with 16.7% of placebo group at day 3 of treatment (p =0.016).
> At day 5 of treatment, infectious virus was not isolated from any participants receiving 400 or 800 mg molnupiravir compared with 11.1% of placebo recipients (p =0.034 and 0.027, respectively).
> Molnupiravir was well tolerated, with a similar number of adverse events across all doses.
Lancet Infect Dis.2022.12.23Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trialACTIV-3/TICO study group
Efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19


> Multinational, double-blind, randomised, placebo-controlled, clinical trial
> Adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland (laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days).
> Randomisation: (2:1:2:1)- sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care.
> Administion as a single IV dose .
Primary outcome: time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation.
> Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19.
Safety outcome: death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation.
Efficacy and safety outcomes: assessed in the modified intention-to-treat population (all patients randomly assigned to treatment who started the study infusion).

> 546 patients enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178.
> At this point, enrolment was halted on the basis of the interim futility analysis: at day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74–1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67–1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74–1·58]; BRII-196 plus BRII-198 1·00 [0·68–1·46]).
> By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91–1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88–1·32]).
> The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90.

Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19.
Lancet2022.12.23Final efficacy analysis, interim safety analysis, and immunogenicity of a single dose of recombinant novel coronavirus vaccine (adenovirus type 5 vector) in adults 18 years and older: an international, multicentre, randomised, double-blinded, placebo-controlled phase 3 trialHalperin S.A., et al.
> Ad5-nCoV vaccine is a single-dose Ad5 vectored vaccine expressing the SARS-CoV-2 spike protein that was well-tolerated and immunogenic in phase 1 and 2 studies. This study reports results on the final efficacy and interim safety analyses of the phase 3 trial.

> Double-blind, randomised, international, placebo-controlled, endpoint-case driven, phase 3, clinical trial
> Adults aged 18 years older at study centres in Argentina, Chile, Mexico, Pakistan, and Russia (non unstable or severe underlying medical or psychiatric conditions; no history of a laboratory-confirmed SARS-CoV-2 infection, not pregnant or breastfeeding, no previous receipt of an adenovirus-vectored, coronavirus vaccine).
> Randomisation in a 1:1 ratio: single intramuscular dose of 0·5 mL placebo or a 0·5 mL dose of 5 × 1010 viral particle (vp)/mL Ad5-nCoV vaccine;

Primary efficacy objective: capacitity of Ad5-nCoV in preventing symptomatic, PCR-confirmed COVID-19 infection occurring at least 28 days after vaccination in all participants who were at least 28 days postvaccination
Primary safety objective: incidence of any serious adverse events or medically attended adverse events postvaccination in all participants who received a study injection.

> Study enrolment began on Sept 22, 2020, in Pakistan, Nov 6, 2020, in Mexico, Dec 2, 2020, in Russia and Chile, and Dec 17, 2020, in Argentina; 150 endpoint cases were reached on Jan 15, 2021, triggering the final primary efficacy analysis.
> One dose of Ad5-nCoV showed a 57·5% (95% CI 39·7–70·0, p=0·0026) efficacy against symptomatic, PCR-confirmed, COVID-19 infection at 28 days or more postvaccination (21 250 participants; 45 days median duration of follow-up [IQR 36–58]).
Primary safety analysis (36 717 participants)--> no significant difference in the incidence of serious adverse events (14 [0·1%] of 18 363 Ad5-nCoV recipients and 10 [0·1%] of 18 354 placebo recipients, p=0·54) or medically attended adverse events (442 [2·4%] of 18 363 Ad5-nCoV recipients and 411 [2·2%] of 18 354 placebo recipients, p=0·30) between the Ad5-nCoV or placebo groups, or any serious adverse events considered related to the study product (none in both Ad5-nCoV and placebo recipients).
In the extended safety cohort, 1004 (63·5%) of 1582 of Ad5-nCoV recipients and 729 (46·4%) of 1572 placebo recipients reported a solicited systemic adverse event (p<0·0001), of which headache was the most common (699 [44%] of Ad5-nCoV recipients and 481 [30·6%] of placebo recipients; p<0·0001). 971 (61·3%) of 1584 Ad5-nCoV recipients and 314 (20·0%) of 1573 placebo recipients reported an injection-site adverse event (p<0·0001), of which pain at the injection site was the most frequent; reported by 939 (59%) Ad5-nCoV recipients and 303 (19%) placebo recipients.

One dose of Ad5-nCoV is efficacious and safe in healthy adults aged 18 years and older.
Nature2022.12.22Local and systemic responses to SARS-CoV-2 infection in children and adultsYoshida M., et al.
UKImmunologyAim: to examine differences in response to SARS-CoV-2 infection in children and adults.

- Paediatric and adult COVID-19 patients and healthy controls (total n=93) analysis using single-cell multi-omic profiling of matched nasal, tracheal, bronchial and blood samples.

> In healthy paediatric airways, cells were already in an interferon-activated state, that upon SARS-CoV-2 infection was further induced especially in airway immune cells. Higher paediatric innate interferon-responses might restrict viral replication and disease progression.
> The systemic response in children was characterised by increases in naive lymphocytes and a depletion of natural killer cells, while in adults cytotoxic T cells and interferon-stimulated subpopulations were significantly increased.
> Evidence that dendritic cells initiate interferon signaling in early infection was found, and novel epithelial cell states that associate with COVID-19 and age were identified.

Matching nasal and blood data showed a strong interferon response in the airways with the induction of systemic interferon-stimulated populations, which were massively reduced in paediatric patients.
Nature Immunol.2022.12.22Children develop robust and sustained cross-reactive spike-specific immune responses to SARS-CoV-2 infectionDowell A.C., et al.
UKImmunologyAim: to compare antibody and cellular immunity in children (aged 3–11 years) and adults.

> Antibody responses against spike protein were high in children and seroconversion boosted responses against seasonal Beta-coronaviruses through cross-recognition of the S2 domain.
> Neutralization of viral variants was comparable between children and adults.
> Spike-specific T cell responses were more than twice as high in children and were also detected in many seronegative children, indicating pre-existing cross-reactive responses to seasonal coronaviruses.
> Children retained antibody and cellular responses 6 months after infection, whereas relative waning occurred in adults. Spike-specific responses were also broadly stable beyond 12 months.

Children generate robust, cross-reactive and sustained immune responses to SARS-CoV-2 with focused specificity for the spike protein.
NEJM2022.12.22Early Remdesivir to Prevent Progression to Severe Covid-19 in OutpatientsGottileb R.L., et al.
> Randomized, double-blind, placebo-controlled trial involving nonhospitalized patients with Covid-19 who had symptom onset within the previous 7 days and who had at least one risk factor for disease progression
>Age ≥60 years, obesity, or certain coexisting medical conditions.
> Randomly assigned to receive intravenous remdesivir (200 mg on day 1 and 100 mg on days 2 and 3) or placebo.
Primary efficacy end point: a composite of Covid-19–related hospitalization or death from any cause by day 28.
Primary safety end point: any adverse event.
Secondary end point: composite of a Covid-19–related medically attended visit or death from any cause by day 28.

> 562 patients underwent randomization and received at least one dose of remdesivir or placebo were included in the analyses:
- 279 patients in the remdesivir group and 283 in the placebo group.
> Covid-19–related hospitalization or death from any cause occurred in 2 patients (0.7%) in the remdesivir group and in 15 (5.3%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.03 to 0.59; P=0.008).
> A total of 4 of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a Covid-19–related medically attended visit by day 28 (hazard ratio, 0.19; 95% CI, 0.07 to 0.56).
> No patients had died by day 28. Adverse events occurred in 42.3% of the patients in the remdesivir group and in 46.3% of those in the placebo group.

Among nonhospitalized patients who were at high risk for Covid-19 progression, a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalization or death than placebo.
JAMA Pediatrics2022.12.21Maternal and Neonatal SARS-CoV-2 Immunoglobulin G Antibody Levels at Delivery After Receipt of the BNT162b2 Messenger RNA COVID-19 Vaccine During the Second Trimester of PregnancyKugelman N., et al.
IsraelVaccinesTo evaluate maternal and neonatal SARS-CoV-2 immunoglobulin G (IgG) antibody levels at birth after mRNA COVID-19 vaccination during the second trimester of pregnancy.

> This prospective cohort study, conducted at a single medical center in Haifa, Israel, from May to July 2021, included women with a singleton pregnancy over 24 weeks of gestation at least 7 days after receipt of their second COVID-19 vaccine dose who were not known to be previously infected with COVID-19.
> The primary outcomes were SARS-CoV-2 IgG antibody titers measured in the parturient at admission and in the umbilical cord blood within 30 minutes after delivery. Secondary outcomes were the correlation between antibody titers, feto-maternal characteristics, maternal adverse effects after vaccination, and time interval from vaccination to delivery.

> Antibody levels were measured for 129 women (mean [SD] age, 31.9 [4.9] years) and 114 neonates, with 100% of the tests having positive results. The mean (SD) gestational age at administration of the second vaccine dose was 24.9 (3.3) weeks
> Neonatal IgG titers were 2.6 times higher than maternal titers (median [range], 3315.7 [350.1-17 643.5] AU/mL vs 1185.2 [146.6-32 415.1] AU/mL). A positive correlation was demonstrated between maternal and neonatal antibodies (r = 0.92; 95% CI, 0.89-0.94).
> Multivariable analysis revealed that for each week that passed since receipt of the second vaccine dose, maternal and neonatal antibody levels changed by −10.9% (95% CI, −17.2% to −4.2%; P = .002) and −11.7% (95% CI, −19.0 to −3.8%; P = .005), respectively. For each 1-year increase in the mother’s age, maternal and neonatal antibody levels changed by −3.1% (95% CI, −5.3% to −0.9%; P = .007) and −2.7% (95% CI, −5.2% to −0.1%; P = .04), respectively.

In this cohort study, receipt of the BNT162b2 mRNA COVID-19 vaccine during the second trimester of pregnancy was associated with maternal and neonatal humoral responses, as reflected in maternal and neonatal SARS-CoV-2 IgG antibody levels measured after delivery. These findings support COVID-19 vaccination of pregnant individuals during the second trimester to achieve maternal protection and newborn safety during the pandemic.
JAMA2022.12.20Multisystem Inflammatory Syndrome in Children by COVID-19 Vaccination Status of Adolescents in FranceLevy M., et al.
FranceClinicAim: to estimate the risk of multisystem inflammatory syndrome in children (MIS-C) among adolescents by COVID-19 vaccination status during Sept-Oct 2021 in France.

- All pediatric patients diagnosed with MIS-C admitted to pediatric intensive care units or mandatorily reported to the French Public Health Agency.
- 3 sensitivity analyses: adolescents were considered vaccinated at least 14, 28, or 42 days after the first vaccine dose.

> 107 children with MIS-C were hospitalized in France and, among them, 33 (31%) were adolescents eligible for vaccination. Adolescents with MIS-C were a median (IQR) age of 13.7 (12.5-14.9) years, 27 (81%) were male, and 29 (88%) were admitted to a PICU.
> Among MIS-C children, 0 had been fully vaccinated, 7 had received 1 dose with a median (IQR) time between vaccine injection and MIS-C onset of 25 (17-37) days, and 26 had not been vaccinated.
> The HR for MIS-C was 0.09 (95% CI, 0.04-0.21; P < .001) after the first vaccine dose compared with unvaccinated adolescents. Sensitivity analyses showed similar results.

These results suggest that COVID-19 mRNA vaccination was associated with a lower incidence of MIS-C in adolescents, and that 2 doses are warranted for efficient protection.
NEJM2022.12.16Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized PatientsJayk Bernal A., et al.
InternationalTherapeuticsEfficacy and safety of Molnupiravir
- Phase 3 clinical trial to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults with mild-to-moderate Covid-19 and at least one risk factor for severe Covid-19 illness.
- 800 mg of molnupiravir or placebo twice daily for 5 days.
Primary efficacy end point: incidence hospitalization or death at day 29.

> 716 patients were assigned to receive molnupiravir and 717 to receive placebo. With the exception of an imbalance in sex, baseline characteristics were similar in the two groups.
> The superiority of molnupiravir was demonstrated at the interim analysis (50% of enrolled population): risk of hospitalization for any cause or death through day 29 was lower with molnupiravir (28 of 385 participants [7.3%]) than with placebo (53 of 377 [14.1%]) (difference, −6.8 percentage points; 95% CI, −11.3 to −2.4; P=0.001).
> In the analysis of all participants who had undergone randomization, the percentage of participants who were hospitalized or died through day 29 was lower in the molnupiravir group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, −3.0 percentage points; 95% CI, −5.9 to −0.1).
> Results of subgroup analyses were largely consistent with these overall results; in some subgroups, such as patients with evidence of previous SARS-CoV-2 infection, those with low baseline viral load, and those with diabetes, the point estimate for the difference favored placebo.
> One death was reported in the molnupiravir group and 9 in the placebo group through day 29. Adverse events were reported in 216 of 710 participants (30.4%) in the molnupiravir group and 231 of 701 (33.0%) in the placebo group.

Early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19.
Science Transl Med.2021.12.21Escape from recognition of SARS-CoV-2 Beta variant spike epitopes but overall preservation of T cell immunityRiou C., et al.
South AfricaImmunologyT cell responses play a role in protection from reinfection and severe disease, but the potential for spike mutations to affect T cell immunity is incompletely understood.

Aim: to assess neutralizing antibody and T cell responses in 44 South African COVID-19 patients infected either with the Beta variant (dominant from Nov 2020-May 2021) or infected prior to its emergence (first wave, Wuhan strain), to provide an overall measure of immune evasion.

> Robust spike-specific CD4 and CD8 T cell responses were detectable in Beta-infected patients, similar to first wave patients.
> Using peptides spanning the Beta-mutated regions, CD4 T cell responses targeting the wild type peptides were identified in 12/22 first wave patients, all of whom failed to recognize corresponding Beta-mutated peptides. However, responses to mutated regions formed only a small proportion (15.7%) of the overall CD4 response, and few patients (3/44) mounted CD8 responses that targeted the mutated regions.
> Among the spike epitopes tested, we identified three epitopes containing the D215, L18, or D80 residues that were specifically recognized by CD4 T cells, and their mutated versions were associated with a loss of response.

In spite of loss of recognition of immunogenic CD4 epitopes, CD4 and CD8 T cell responses to Beta are preserved overall. These observations may explain why several vaccines have retain protective activity against severe COVID-19 even with substantial loss of neutralizing antibody activity against Beta.
Ann Intern Med.2021.12.21COVID-19 Vaccination Effectiveness Against Infection or Death in a National U.S. Health Care SystemIoannou, G.N, et al.
USAVaccines - ImmunisationAim : to determine the effectiveness of messenger RNA COVID-19 vaccines in racially and ethnically diverse, elderly populations with high comorbidity burden.

Target trial emulation study comparing newly vaccinated persons with matched unvaccinated controls.
Among persons receiving care in the Veterans Affairs health care system (n = 5 766 638), those who received at least 1 dose of the Moderna or Pfizer–BioNTech COVID-19 vaccine from 11 December 2020 to 25 March 2021 were matched to unvaccinated controls in a 1:1 ratio according to demographic, clinical, and geographic characteristics.

> Vaccinated and unvaccinated groups were well matched; both were predominantly male (92.9% vs. 93.4%), had advanced age (mean, 68.7 years in both groups), had diverse racial and ethnic distribution (for example, Black: 17.3% vs. 17.0%, Hispanic: 6.5% vs. 6.1%), and had substantial comorbidity burden.
> Vaccine effectiveness 7 or more days after the second vaccine dose was 69% (95% CI, 67% to 70%) against SARS-CoV-2 infection and 86% (CI, 82% to 89%) against SARS-CoV-2–related death and was similar when follow-up was extended to 31 March versus 30 June.
> Vaccine effectiveness against infection decreased with increasing age and comorbidity burden.

In an elderly, diverse, high-comorbidity population, COVID-19 VE against infection was substantially lower than previously reported, but VE against death was high.
Lancet2021.12.20Two-dose ChAdOx1 nCoV-19 vaccine protection against COVID-19 hospital admissions and deaths over time: a retrospective, population-based cohort study in Scotland and BrazilKatikireddi S.V., et al.
Brazil / UKVaccines - ImmunisationAim: to investigate the association between time since two doses of ChAdOx1 nCoV-19 vaccine and risk of severe COVID-19 outcomes in Scotland (where delta was dominant), with comparative analyses in Brazil (where delta was uncommon).

- Cohorts of adults (aged ≥18 years) who received two doses of ChAdOx1 nCoV-19
- Comparison of rates of severe COVID-19 outcomes (ie, COVID-19 hospital admission or death) across fortnightly periods, relative to 2–3 weeks after the second dose.
- Scotland cohort: from May 19, 2021; Brazil cohort: from Jan 18, 2021. Follow-up in both cohorts was until Oct 25, 2021.

> 1 972 454 adults received two doses of ChAdOx1 nCoV-19 in Scotland and 42 558 839 in Brazil.
> In Scotland, rate ratios (RR) for severe COVID-19 increased to 2·01 (95% CI 1·54–2·62) at 10–11 weeks, 3·01 (2·26–3·99) at 14–15 weeks, and 5·43 (4·00–7·38) at 18–19 weeks after the second dose.
> The pattern of results was similar in Brazil, with RRs of 2·29 (2·01–2·61) at 10–11 weeks, 3·10 (2·63–3·64) at 14–15 weeks, and 4·71 (3·83–5·78) at 18–19 weeks after the second dose.
> In Scotland, vaccine effectiveness decreased from 83·7% (95% CI 79·7–87·0) at 2–3 weeks, to 75·9% (72·9–78·6) at 14–15 weeks, and 63·7% (59·6–67·4) at 18–19 weeks after the second dose.
> In Brazil, vaccine effectiveness decreased from 86·4% (85·4–87·3) at 2–3 weeks, to 59·7% (54·6–64·2) at 14–15 weeks, and 42·2% (32·4–50·6) at 18–19 weeks.

Waning vaccine protection of ChAdOx1 nCoV-19 against COVID-19 hospital admissions and deaths in both Scotland and Brazil was observed, this becoming evident within three months of the second vaccine dose.
Nature Med.2021.12.20Risk factors for PICU admission and death among children and young people hospitalized with COVID-19 and PIMS-TS in England during the first pandemic yearWard J.L., et al.
UKPublic health / EpidemiologyMethods
> Data for all hospitalizations in England among 0–17 year olds from 1 February 2019 to 31 January 2021
> We examined how sociodemographic factors and comorbidities might be risk factors for pediatric intensive care unit (PICU) admission among hospitalizations due to the following causes: Coronavirus Disease 2019 (COVID-19) and pediatric inflammatory multi-system syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the first pandemic year (2020–2021); hospitalizations due to all other non-traumatic causes in 2020–2021; hospitalizations due to all non-traumatic causes in 2019–2020; hospitalizations due to influenza in 2019–2020

> Risk of PICU admission and death from COVID-19 or PIMS-TS in CYP was very low. We identified 6,338 hospitalizations with COVID-19, of which 259 were admitted to a PICU and eight identifying which children and young people (CYP) died.
> We identified 712 hospitalizations with PIMS-TS, of which 312 were admitted to a PICU and fewer than five CYP died
> Hospitalizations with COVID-19 and PIMS-TS were more common among males, older CYP, those from socioeconomically deprived neighborhoods and those who were of non-White ethnicity (Black, Asian, Mixed or Other)
> The odds of PICU admission were increased in CYP younger than 1 month old and decreased among 15–17 year olds compared to 1–4 year olds with COVID-19; increased in older CYP and females with PIMS-TS; and increased for Black compared to White ethnicity in patients with COVID-19 and PIMS-TS
> Odds of PICU admission in COVID-19 were increased for CYP with comorbidities and highest for CYP with multiple medical problems.

Increases in odds of PICU admission associated with different comorbidities in COVID-19 showed a similar pattern to other causes of hospitalization examined and, thus, likely reflect background vulnerabilities. These findings identify distinct risk factors associated with PICU admission among CYP with COVID-19 or PIMS-TS that might aid treatment and prevention strategies.
Clin Infect Dis.2021.12.20Neutralizing Antibody Response to Pseudotype SARS-CoV-2 Differs between mRNA-1273 and BNT162b2 COVID-19 Vaccines and by History of SARS-CoV-2 InfectionTyner H. L., et al.
USAVaccines - ImmunisationMethods
> From a prospective cohort of 3,975 adult essential and frontline workers tested weekly from August 2020 to March 2021 for SARS-CoV-2 infection by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) assay irrespective of symptoms, 497 participants had sera drawn after infection (170), vaccination (327), and after both infection and vaccination (50 from the infection population). 497 participants had sera drawn after infection (170), vaccination (327), and after both infection and vaccination (50 from the infection

> Among 170 unvaccinated participants with SARS-CoV-2 infection, 158 (93%) developed neutralizing antibodies (nAb) with a Geometric mean titers (GMTs) of 1,003 (95% CI=766-1,315). Among 139 previously uninfected participants, 138 (99%) developed nAb after mRNA vaccine dose-2 with a GMT of 3,257 (95% CI = 2,596-4,052). GMT was higher among those receiving mRNA-1273 vaccine (GMT =4,698, 95%CI= 3,186-6,926) compared to BNT162b2 vaccine (GMT=2,309, 95%CI=1,825-2,919). Among 32 participants with prior SARS-CoV-2 infection, GMT was 21,655 (95%CI=14,766-31,756) after mRNA vaccine dose-1, without further increase after dose-2.

A single dose of mRNA vaccine after SARS-CoV-2 infection resulted in the highest observed nAb response. Two doses of mRNA vaccine in previously uninfected participants resulted in higher nAb to SARS-CoV-2 than after one dose of vaccine or SARS-CoV-2 infection alone. Neutralizing antibody response also differed by mRNA vaccine product.
JAMA2021.12.16Antibody Response and Variant Cross-Neutralization After SARS-CoV-2 Breakthrough InfectionBates T.A., et al.
USAImmunologyAim: to assess antibody levels and variant cross-neutralization after breakthrough infection.

- Fully vaccinated health care workers subsequently diagnosed with SARS-CoV-2 (Jan 31-Aug 18, 2021). Controls were fully vaccinated matched individuals without a breakthrough infection.
- Live SARS-CoV-2 neutralizing serum dilution titers were determined by 50% focus reduction neutralization tests (FRNT50) against isolates of the original SARS-CoV-2 strain (WA1) and variants of concern (Alpha, Beta, Gamma, and Delta).

> 26 participants with breakthrough infections (mean age, 38 years; 20 [77%] women; 24 [92%] were vaccinated with BNT162b2, sampled a median 28 days after PCR date and 213.5 days after final vaccination; 21 [81%] with mild symptoms) were matched to 26 controls (mean age, 39 years; 21 [81%] women; 26 [100%] were vaccinated with BNT162b2, sampled a median 28 days after final vaccination).
> Total RBD–specific Ig increased in participants with breakthrough infection with a median EC50 of 2152 (95% CI, 961-3596) compared with 668 (95% CI, 473-892) in controls (322% increase; P < .001).
> Median serum dilutions increased for both IgG and IgA in after breakthrough infection. IgM levels were not significantly different between groups.
> Among sequence-confirmed breakthrough cases, 10 were Delta and 9 were non-Delta infections.
> Among breakthrough cases, the median FRNT50 against WA1 was 4646 (95% CI, 2283-7053) vs 489 (95% CI, 272-822) for controls (950% increase; P < .001). In breakthrough cases, median FRNT50 against the Delta variant was 2482 (95% CI, 1072-4923) vs 243 (95%CI, 118-336) for controls (1021% increase; P < .001).
> Sera from Delta breakthrough cases displayed improved potency against the Delta variant at 99% (95% CI, 73-151) of WA1 neutralization for each participant, compared with 36% (95% CI, 33-52) for non-Delta cases and 41% (95% CI, 24-56) for controls.

This study showed substantial boosting of humoral immunity after breakthrough infection, despite predominantly mild disease, and most notably for IgA. Breakthrough sera demonstrated improved variant cross-neutralization.
Clin Infect Dis.2021.12.16Neutralization of SARS-CoV-2 Omicron variant by sera from BNT162b2 or Coronavac vaccine recipientsLu L., et al.
ChinaVariantsAim: to assess susceptibility of Omicron variant to BNT162b2 and CoronaVac vaccine-induced neutralizing antibodies is urgently needed for risk assessment.

- Live virus microneutralisation assay of Omicron variant strains HKU691 and HKU344-R346K isolated from patients, as well as Delta and Beta, by sera from 25 BNT162b2 and 25 Coronavac vaccine recipients.

> The Omicron variant strain HKU344-R346K has an additional spike R346K mutation, which is present in 8.5% of strains deposited in GISAID database.
> Only 20% and 24% of BNT162b2 recipients had detectable neutralizing antibody against the Omicron variant HKU691 and HKU344-R346K, respectively, while none of the Coronavac recipients had detectable neutralizing antibody titer against either Omicron isolate.
> For BNT162b2 recipients, the geometric mean neutralization antibody titers (GMT) of the Omicron variant isolates (5.43 and 6.42) were 35.7-39.9-fold lower than that of the ancestral virus (229.4), and the GMT of both Omicron variant isolates were significantly lower than those of the Beta and Delta variants.
> There was no significant difference in the GMT between HKU691 and HKU344-R346K.

Omicron variant escapes neutralizing antibodies elicited by BNT162b2 or Coronavac. The additional R346K mutation did not affect the neutralization susceptibility.
BMJ2021.12.16SARS-CoV-2 vaccination and myocarditis or myopericarditis: population based cohort studyHusby A., et al.
DenmarkVaccinesAim: to investigate the association between SARS-CoV-2 vaccination and myocarditis or myopericarditis.
- Participants: 4 931 775 individuals aged ≥12 years, followed from Oct 2020 to Oct 2021.
- Primary outcome: myocarditis or myopericarditis, defined as a combination of a hospital diagnosis of myocarditis or pericarditis, increased troponin levels, and a hospital stay lasting more than 24 hours.
- Follow-up time before vaccination was compared with follow-up time 0-28 days from the day of vaccination for both first and second doses.

> During follow-up, 269 participants developed myocarditis or myopericarditis, of whom 108 (40%) were 12-39 years old and 196 (73%) were male.
> Of 3 482 295 individuals vaccinated with BNT162b2, 48 developed myocarditis or myopericarditis within 28 days from the vaccination date compared with unvaccinated individuals (adjusted hazard ratio 1.34 (95% CI, 0.90 to 2.00); absolute rate 1.4 per 100 000 vaccinated individuals within 28 days of vaccination (95% CI, 1.0 to 1.8)).
> Adjusted hazard ratios (HR) among female participants only and male participants only were 3.73 (1.82 to 7.65) and 0.82 (0.50 to 1.34), respectively, with corresponding absolute rates of 1.3 (0.8 to 1.9) and 1.5 (1.0 to 2.2) per 100 000 vaccinated individuals within 28 days of vaccination, respectively.
> The adjusted HR among 12-39 year olds was 1.48 (0.74 to 2.98) and the absolute rate was 1.6 (1.0 to 2.6) per 100 000 vaccinated individuals within 28 days of vaccination.
> Among 498 814 individuals vaccinated with mRNA-1273, 21 developed myocarditis or myopericarditis within 28 days from vaccination date (adjusted HR 3.92 (2.30 to 6.68); absolute rate 4.2 per 100 000 vaccinated individuals within 28 days of vaccination (2.6 to 6.4)).
> Adjusted HR among women only and men only were 6.33 (2.11 to 18.96) and 3.22 (1.75 to 5.93), respectively, with corresponding absolute rates of 2.0 (0.7 to 4.8) and 6.3 (3.6 to 10.2) per 100 000 vaccinated individuals within 28 days of vaccination, respectively.
> The adjusted HR among 12-39 year olds was 5.24 (2.47 to 11.12) and the absolute rate was 5.7 (3.3 to 9.3) per 100 000 vaccinated individuals within 28 days of vaccination.

Vaccination with mRNA-1273 was associated with a significantly increased risk of myocarditis or myopericarditis in the Danish population, primarily driven by an increased risk among individuals aged 12-39 years, while BNT162b2 vaccination was only associated with a significantly increased risk among women. However, the absolute rate of myocarditis or myopericarditis after SARS-CoV-2 mRNA vaccination was low.
Science Transl Med.2021.12.16A SARS-CoV-2 ferritin nanoparticle vaccine elicits protective immune responses in nonhuman primatesJoyce G.M, et al.
USAVaccinesAim : to develope and evaluate an adjuvanted SARS-CoV-2 spike ferritin nanoparticle (SpFN) vaccine in nonhuman primates.

Thirty-two male and female specific-pathogen-free, research-naïve Chinese-origin rhesus macaques (age 3 to 7 years) were distributed—on the basis of age, weight, and sex—into 4 cohorts of 8 animals. Animals were vaccinated with a High-dose (50 μg) SpFN vaccine, given twice 28 days apart.

> The vaccine induced a Th1-biased CD4 T cell helper response and elicited neutralizing antibodies against SARS-CoV-2 wild-type and variants of concern, as well as against SARS-CoV-1.
> The potent humoral and cell-mediated immune responses translated into rapid elimination of replicating virus in the upper and lower airways and lung parenchyma of nonhuman primates following high-dose SARS-CoV-2 respiratory challenge.
> SpFN vaccine protected against a potent viral challenge, as replicating virus concentrations detected in the upper and lower airways of unvaccinated controls reached a mean of 10x6 to 10x7 copies/ml.

The immune response elicited by SpFN vaccination and resulting efficacy in nonhuman primates supports the utility of SpFN as a vaccine candidate for SARS-causing betacoronaviruses.
Lancet Respir Med.2021.12.16Namilumab or infliximab compared with standard of care in hospitalised patients with COVID-19 (CATALYST): a randomised, multicentre, multi-arm, multistage, open-label, adaptive, phase 2, proof-of-concept trialFisher B.A, et al.
UKTherapeuticsAim: to assess the efficacy of namilumab (a granulocyte-macrophage colony stimulating factor inhibitor) and infliximab (a tumour necrosis factor inhibitor) in hospitalised patients with COVID-19, to prioritise agents for phase 3 trials.

Randomised, multicentre, multi-arm, multistage, parallel-group, open-label, adaptive, phase 2, proof-of-concept trial (CATALYST). Patients aged ≥16 years, admitted to hospital with COVID-19 pneumonia and C-reactive protein (CRP) concentrations of 40 mg/L or greater were recruited at nine hospitals in the UK. 299 patients were screened and 146 were enrolled and randomly assigned to usual care (n=54), namilumab (n=57), or infliximab (n=35).
The primary endpoint was improvement in inflammation, measured by CRP concentration over time, analysed using Bayesian multilevel models.

> For the primary outcome, 45 patients in the usual care group were compared with 52 in the namilumab group, and 29 in the usual care group were compared with 28 in the infliximab group.
> The probabilities that the interventions were superior to usual care alone in reducing CRP concentration over time were 97% for namilumab and 15% for infliximab; the point estimates for treatment–time interactions were –0·09 (95% CI –0·19 to 0·00) for namilumab and 0·06 (–0·05 to 0·17) for infliximab.
> 134 adverse events occurred in 30 (55%) of 55 patients in the namilumab group compared with 145 in 29 (54%) of 54 in the usual care group.
> 102 adverse events occurred in 20 (69%) of 29 patients in the infliximab group compared with 112 in 17 (50%) of 34 in the usual care group.
> Death occurred in six (11%) patients in the namilumab group compared with ten (19%) in the usual care group, and in four (14%) in the infliximab group compared with five (15%) in the usual care group.

Namilumab, but not infliximab, showed proof-of-concept evidence for reduction in inflammation—as measured by CRP concentration—in hospitalised patients with COVID-19 pneumonia.
Science Immunol.2021.12.16High-affinity, neutralizing antibodies to SARS-CoV-2 can be made without T follicular helper cellsChen J.S., et al.
USAImmunologyLoss of T follicular helper (Tfh) cells and germinal centers (GC) has been observed in patients with severe COVID-19. As T cell-B cell interactions and immunoglobulin class switching still occur in these patients, non-canonical pathways of antibody production may be operative during SARS-CoV-2 infection.

> Both Tfh-dependent and -independent antibodies were induced against SARS-CoV-2 infection, SARS-CoV-2 vaccination, and influenza A virus infection.
> Even though Tfh-independent antibodies to SARS-CoV-2 had evidence of reduced somatic hypermutation, they were still high-affinity, durable, and reactive against diverse spike-derived epitopes and were capable of neutralizing both homologous SARS-CoV-2 and the B.1.351 (beta) variant of concern.
> By epitope mapping and BCR sequencing, it was found that Tfh cells focused the B cell response and therefore, in the absence of Tfh cells, a more diverse clonal repertoire was maintained.

These data support an alternative pathway for the induction of B cell responses during viral infection that enables effective, neutralizing antibody production to complement traditional GC-derived antibodies that might compensate for GCs damaged by viral inflammation.
BMJ2021.12.15Effectiveness of mRNA-1273 against delta, mu, and other emerging variants of SARS-CoV-2: test negative case-control studyBruxvoort K. J., et al.
USAVaccinesTo evaluate the effectiveness of the mRNA-1273 (Moderna covid-19 vaccine) vaccine against SARS-CoV-2 variants and assess its effectiveness against the delta variant by time since vaccination

> Test negative case-control study
> Participants: adult Kaiser Permanente Southern California (KPSC) members with a SARS-CoV-2 positive test sent for whole genome sequencing or a negative test from 1 March 2021 to 27 July 2021.

> The study included 8153 cases and their matched controls
> Two dose vaccine effectiveness was 86.7% (95% confidence interval 84.3% to 88.7%) against infection with the delta variant, 98.4% (96.9% to 99.1%) against alpha, 90.4% (73.9% to 96.5%) against mu, 96-98% against other identified variants, and 79.9% (76.9% to 82.5%) against unidentified variants (that is, specimens that failed sequencing).
> Vaccine effectiveness against hospital admission with the delta variant was 97.5% (92.7% to 99.2%)
> Vaccine effectiveness against infection with the delta variant declined from 94.1% (90.5% to 96.3%) 14-60 days after vaccination to 80.0% (70.2% to 86.6%) 151-180 days after vaccination
> Waning was less pronounced for non-delta variants. Vaccine effectiveness against delta infection was lower among people aged ≥65 years (75.2%, 59.6% to 84.8%) than those aged 18-64 years (87.9%, 85.5% to 89.9%). One dose vaccine effectiveness was 77.0% (60.7% to 86.5%) against infection with delta.

Two doses of mRNA-1273 were highly effective against all SARS-CoV-2 variants, especially against hospital admission with covid-19. However, vaccine effectiveness against infection with the delta variant moderately declined with increasing time since vaccination.
NEJM2021.12.15Efficacy and Safety of NVX-CoV2373 in Adults in the United States and MexicoDunkle, L.M, et al.
NVX-CoV2373 --> adjuvanted, recombinant spike protein nanoparticle vaccine. Proven clinical efficacy for the prevention of COVID19 in phase 2b–3 trials in the UK and South Africa.

> Phase 3 randomized, observer-blinded, placebo-controlled trial in the United States and Mexico (first half of 2021)
> Efficacy and safety of NVX-CoV2373 in (≥18 years of age)
> No history of COVID 19

Primary objective vaccine efficacy against RT PCR confimed cases occurring at least 7 days after the second dose.
Vaccine efficacy against moderate-to-severe disease and against different variants was also assessed.

Of the 29,949 participants who underwent randomization between December 27, 2020, and February 18, 2021, a total of
> 29,582 (median age, 47 years; 12.6% ≥65 years of age) received at least one dose:
- 19,714 received vaccine and 9868 placebo.
> Over a period of 3 months, 77 cases of Covid-19 were noted
- 14 among vaccine recipients and 63 among placebo recipients
> Vaccine efficacy, 90.4%; (95% [CI], 82.9 to 94.6; P<0.001).
> Ten moderate and 4 severe cases occurred, all in placebo recipients, yielding vaccine efficacy against moderate-to-severe disease of 100% (95% CI, 87.0 to 100).
> Most sequenced viral genomes (48 of 61, 79%) were variants of concern or interest
> Vaccine efficacy against any variant of concern or interest was 92.6% (95% CI, 83.6 to 96.7).
> Reactogenicity was mostly mild to moderate and transient but was more frequent among NVX-CoV2373 recipients than among placebo recipients and was more frequent after the second dose than after the first dose.

NVX-CoV2373 was safe and effective for the prevention of Covid-19.
JAMA Netw Open2021.12.15Estimated Effectiveness of COVID-19 Messenger RNA Vaccination Against SARS-CoV-2 Infection Among Older Male Veterans Health Administration Enrollees, January to September 2021Young-Xu Y., et al.
USAVaccines - ImmunisationAim: to reexamine the estimated effectiveness of the 2 COVID-19 mRNA vaccines (mRNA-1273 and BNT162b2) among fully vaccinated male veterans ≥65 years.

- Observation time was divided into 3 periods: pre-Delta (before May 2021), rising Delta (May-June 2021), and high Delta (July-Sept 2021).

> 14 238 male veterans ≥65 years with a positive SARS-CoV-2 test result (cases) and 56 952 controls.
> Estimated pre-Delta mRNA vaccine effectiveness against any SARS-CoV-2 infection was 94.5% (95% CI, 90.7-96.7) in the first month after complete vaccination (Figure; Table) and decreased to 87.9% (95% CI, 85.9-89.5) by month 3.
> During the high-Delta period, the estimated vaccine effectiveness was 62.0% (95% CI, 45.6-73.5) in the first month and decreased to 57.8% (95% CI, 52.5-62.5) by month 3, similar to the pattern from the pre-Delta period.
> The decrease in vaccine effectiveness accelerated after month 4, reaching a low of approximately 20% in months 5 through 7.

During the high-Delta period, estimated vaccine effectiveness against infections was significantly lower than pre-Delta (about 60%) and the decrease in vaccine effectiveness accelerated after month 4 after full vaccination. This effectiveness decreased significantly to around 20% in months 5 through 7.
Clin Infect Dis.2021.12.11Circulating ubiquitous RNA, a highly predictive and prognostic biomarker in hospitalized COVID-19 patientsBruneau T., et al.
FranceClinicsAim: to indentify biomarkers which quantify tissue injury, predict clinical outcomes and guide the clinical management of hospitalized COVID-19 patients.

> SARS-CoV-2 RNAemia was associated with clinical severity of COVID-19 patients.
> Plasmatic ribonuclease P (RNase P) RNAemia at admission was also highly correlated with disease severity (P<0.001) and invasive mechanical ventilation status (P<0.001) but not with pulmonary severity.
> These results indicate a consequent cell lysis process in severe and critical patients but not systematically due to lung cell death.
> Plasmatic RNase P RNA value was also significantly associated with overall survival.

Viral and ubiquitous blood biomarkers monitored by droplet-based digital PCR could be useful for the clinical monitoring and the management of hospitalized COVID-19 patients.
Clin Infect Dis.2021.12.10Clinical performance of a standardized SARS-CoV-2 interferon-γ release assay for simple detection of T-cell responses after infection or vaccinationFernández-González M., et al.
SpainClinicsAim: to evaluate a standardized interferon-γ (IFN-γ) release assay (IGRA) for detection of T-cell immune response after SARS-CoV-2 infection or vaccination.
- SARS-CoV-2 T-cell response was measured using a specific quantitative IGRA in whole blood and TrimericS-IgG and neutralizing antibodies with validated serological platforms.

> 239 individuals included (152 convalescent, 54 vaccinated and 33 uninfected unvaccinated).
> Overall sensitivity, specificity, positive (PPV) and negative (NPV) predictive values (95% CI) of the IGRA were 81.1% (74.9%‐86%), 90.9% (74.5%‐97.6%), 98.2% (94.5%‐99.5%), and 43.5% (31.8%‐55.9%), respectively.
> All vaccinated SARS-CoV-2-naïve subjects had positive IGRA at 3 months.
> In convalescent subjects the magnitude of IFN-γ responses and IGRA accuracy varied according to disease severity and duration of follow-up, with the best performance in patients with severe COVID-19 at 3-month and the worst in those with mild disease at 12-month.
> The greatest contribution of IGRA to serological tests was observed in patients with mild disease and long-term follow-up (incremental difference, 30.4%).

The IGRA assessed was a reliable method of quantifying T-cell response after SARS-COV-2 infection or vaccination. The assay is likely to add clinical value to serology in patients with mild infections.
JAMA Ophtalmol.2021.12.09Cumulative Mortality and Factors Associated With Outcomes of Mucormycosis After COVID-19 at a Multispecialty Tertiary Care Center in IndiaChoksi T., et al.
IndiaClinicsAim: to report the cumulative mortality rates at different times in cases with COVID-19–associated rhino-orbitocerebral mucormycosis (CAM) and identify risk factors for CAM-associated mortality.

> 73 consecutive patients with CAM, mean (SD) age of 53.5 (12.5) years, 48 (66%) men.
> CAM developed at a median of 28 (IQR, 15-45; range, 4-90) days after recovery from COVID-19.
> Of the 73 patients with CAM, 26 (36%) died; the cumulative probability of death was 26% (95% CI, 16%-41%) at day 7 and doubled to 53% (95% CI, 39%-69%) at day 21.
> Sinus debridement was performed in 18 of 51 patients (35%), and 5 of 52 (10%) underwent exenteration, whereas intravenous lyophilized amphotericin B was administered to 48 patients (66%).
> Receiving mechanical ventilation in the past was associated with a nearly 9-fold increased risk of death (hazard ratio [HR], 8.98; 95% CI, 2.13-38.65; P = .003), and patients who had visual acuity of light perception or better had a 46% lower risk of death (HR, 0.56; 95% CI, 0.32-0.98; P = .04).
> Intravenous amphotericin B administration was associated with a reduced rate of exenteration (0 vs 5 of 25 [20%]; P < .001). Those who received intravenous amphotericin B had a 69% reduced risk of death (HR, 0.31; 95% CI, 0.06-1.43; P = .13).

The mortality rate after rhino-orbitocerebral mucormycosis is high and a subgroup of patients with severe COVID-19 or presenting with severe orbital disease are more likely to die within 10 days of admission.
Science Transl Med.2021.12.07Robust immune responses are observed after one dose of BNT162b2 mRNA vaccine dose in SARS-CoV-2 experienced individualsSamanovic M.I., et al.
USAVaccinesAim: to evaluate longitudinal immune responses to two-dose BNT162b2 mRNA vaccination in 15 adults who had experienced COVID-19, compared to 21 adults who did not have prior COVID-19.

> Robust cytotoxic CD8+ T cell responses in both cohorts following the second dose was observed.
> SARS-CoV-2-naive individuals had progressive increases in humoral and antigen-specific antibody-secreting cell (ASC) responses following each dose of vaccine, whereas SARS-CoV-2-experienced individuals demonstrated strong humoral and antigen-specific ASC responses to the first dose but these responses were not further enhanced after the second dose of the vaccine at the time points studied.
> RBD-reactive B cells were 2-fold higher at baseline among SARS-CoV-2-experienced adults compared to SARS-CoV-2-naive adults. Following immunization, increased frequencies of RBD+ B cells were observed in both cohorts, with fold-changes of 2.9 and 4.8 in SARS-CoV-2-naive and SARS-CoV-2-experienced adults, respectively.

These data highlight the relevance of immunological history for understanding vaccine immune responses and may have implications for personalizing mRNA vaccination regimens used to prevent COVID-19, including for the deployment of booster shots.
NEJM2021.12.08BNT162b2 Vaccine Booster and Mortality Due to Covid-19Arbel R., et al.
IsraelVaccines - ImmunisationAim: to gather evidence regarding the effectiveness of the booster in lowering mortality due to Covid-19 over the Delta wave.

- Members of Clalit Health Services ≥50 years and had received two doses of BNT162b2 at least 5 months earlier.
- Mortality due to Covid-19 among participants who received the booster was compared with that among participants who did not receive the booster

> A total of 843,208 participants met the eligibility criteria, of whom 758,118 (90%) received the booster during the 54-day study period.
> Death due to Covid-19 occurred in 65 participants in the booster group (0.16 per 100,000 persons per day) and in 137 participants in the nonbooster group (2.98 per 100,000 persons per day).
> The adjusted hazard ratio for death due to Covid-19 in the booster group, as compared with the nonbooster group, was 0.10 (95% confidence interval, 0.07 to 0.14; P<0.001).

Participants who received a booster at least 5 months after a second dose of BNT162b2 had 90% lower mortality due to Covid-19 than participants who did not receive a booster.
NEJM2021.12.08Protection against Covid-19 by BNT162b2 Booster across Age GroupsBar-On Y.M., et al.
IsraelVaccines - ImmunisationAim: to gather evidence on protection against Covid-19 by BNT162b2 booster to persons in younger age groups.

- July 30-Oct 10, 2021, data on 4,696,865 persons ≥16 years who had received two doses of BNT162b2 at least 5 months earlier.
Primary analysis: comparison of rates of confirmed Covid-19, severe illness, and death among those who had received a booster dose at least 12 days earlier (booster group) with the rates among those who had not received a booster (nonbooster group).
Secondary analysis: comparison of rates in the booster group with the rates among those who had received a booster 3 to 7 days earlier (early postbooster group).

> The rate of confirmed infection was lower in the booster group than in the nonbooster group by a factor of approximately 10 (range across five age groups, 9.0 to 17.2) and was lower in the booster group than in the early postbooster group by a factor of 4.9 to 10.8. The adjusted rate difference ranged from 57.0 to 89.5 infections per 100,000 person-days in the primary analysis and from 34.4 to 38.3 in the secondary analysis.
> The rates of severe illness in the primary and secondary analyses were lower in the booster group by a factor of 17.9 (95% confidence interval [CI], 15.1 to 21.2) and 6.5 (95% CI, 5.1 to 8.2), respectively, among those 60 years of age or older and by a factor of 21.7 (95% CI, 10.6 to 44.2) and 3.7 (95% CI, 1.3 to 10.2) among those 40 to 59 years of age. The adjusted rate difference in the primary and secondary analyses was 5.4 and 1.9 cases of severe illness per 100,000 person-days among those 60 years of age or older and 0.6 and 0.1 among those 40 to 59 years of age.
> Among those 60 years of age or older, mortality was lower by a factor of 14.7 (95% CI, 10.0 to 21.4) in the primary analysis and 4.9 (95% CI, 3.1 to 7.9) in the secondary analysis. The adjusted rate difference in the primary and secondary analyses was 2.1 and 0.8 deaths per 100,000 person-days.

Across the age groups studied, rates of confirmed Covid-19 and severe illness were substantially lower among participants who received a booster dose of the BNT162b2 vaccine than among those who did not.
Nature2021.12.07Signature of long-lived memory CD8+ T cells in acute SARS-CoV-2 infectionAdamo S., et al.
SwitzerlandImmunologyAim: to characterize individual SARS-CoV-2-specific CD8+ T cells of COVID-19 patients from acute infection to one year into recovery and find a distinct signature identifying long-lived memory CD8+ T cells.

To assess the dynamics of antigen-specific T cells in COVID-19, 175 patients (RT-PCR)-confirmed COVID-19 were recruited and sampled during their symptomatic acute phase, and followed up six months and one year after acute infection.
Spectral flow cytometry combined with cellular indexing of transcriptomes and T cell receptor (TCR) sequencing was performed to characterise CD8+T Cells

> SARS-CoV-2-specific memory CD8+ T cells persisting one year after acute infection express CD45RA, interleukin-7 receptor α (CD127), and T cell factor-1 (TCF1), but they maintain low CCR7, thus resembling CD45RA+ effector-memory T (TEMRA) cells.
> Tracking individual clones of SARS-CoV-2-specific CD8+ T cells, the authors reveal that an interferon signature marks clones giving rise to long-lived cells, whereas prolonged proliferation and mammalian target of rapamycin (mTOR) signaling are associated with clonal disappearance from the blood.

Collectively, these findings demonstrate formation of memory CD8+ T cells to be dependent on a delicate balance between cytokine and TCR signaling during acute infection, which in turn influences outcomes of long-lived, circulating memory T cells in humans.
Nature2021.12.07Delayed induction of type I and III interferons mediates nasal epithelial cell permissiveness to SARS-CoV-2Hatton C.F., et al.
UKImmunologyAim: to explore the interaction between SARS-CoV-2 and innate immunity in the nasal epithelium, notably the interferon (IFN) responses.
- Single-cell RNA sequencing and proteomics to a primary cell model of human nasal epithelium differentiated at air-liquid interface.

> SARS-CoV-2 demonstrates widespread tropism for nasal epithelial cell types.
> The host response is dominated by type I and III IFNs and interferon-stimulated gene products.
> This response is notably delayed in onset relative to viral gene expression and compared to other respiratory viruses. Nevertheless, once established, the paracrine IFN response begins to impact on SARS-CoV-2 replication.
> When provided prior to infection, recombinant IFNβ or IFNλ1 induces an efficient antiviral state that potently restricts SARS-CoV-2 viral replication, preserving epithelial barrier integrity.

These data imply that the IFN-I/III response to SARS-CoV-2 initiates in the nasal airway and suggest nasal delivery of recombinant IFNs to be a potential chemoprophylactic strategy.
Science Transl Med.2021.12.07Robust immune responses are observed after one dose of BNT162b2 mRNA vaccine dose in SARS-CoV-2 experienced individualsSamanovic M. I., et al.
USAVaccines - ImmunisationHere, we evaluated longitudinal immune responses to two-dose BNT162b2 mRNA vaccination in 15 adults who had experienced COVID-19, compared to 21 adults who did not have prior COVID-19.

> Consistent with prior studies of mRNA vaccines, we observed robust cytotoxic CD8+ T cell responses in both cohorts following the second dose.
> Furthermore, SARS-CoV-2-naive individuals had progressive increases in humoral and antigen-specific antibody-secreting cell (ASC) responses following each dose of vaccine, whereas SARS-CoV-2-experienced individuals demonstrated strong humoral and antigen-specific ASC responses to the first dose but these responses were not further enhanced after the second dose of the vaccine at the time points studied.

Together, these data highlight the relevance of immunological history for understanding vaccine immune responses and may have implications for personalizing mRNA vaccination regimens used to prevent COVID-19, including for the deployment of booster shots.
Lancet Infect Dis.2021.12.07Immunogenicity and safety of a third dose of CoronaVac, and immune persistence of a two-dose schedule, in healthy adults: interim results from two single-centre, double-blind, randomised, placebo-controlled phase 2 clinical trialsZeng G., et al.
ChinaVaccines - ImmunisationAim:to assess the immune persistence of a two-dose schedule of CoronaVac, and the immunogenicity and safety of a third dose of CoronaVac, in healthy adults aged 18 years and older.

Two single-centre, double-blind, randomised, placebo-controlled phase 2 clinical trials, adults aged 18–59 years in Jiangsu, China. The main outcomes of the study were geometric mean titres (GMTs), geometric mean increases (GMIs), and seropositivity of neutralising antibody to SARS-CoV-2

> 540 (90%) of 600 participants aged 18–59 years were eligible to receive a third dose, of whom 269 (50%) received the primary third dose 2 months after the second dose and 271 (50%) received a booster dose 8 months after the second dose.
> In the 3 μg group, neutralising antibody titres induced by the first two doses declined after 6 months to near or below the seropositive cutoff (GMT of 8) for cohort 1b-14d-8m (n=53; GMT 3·9) and for cohort 2b-28d-8m (n=49; 6·8).
> When a booster dose was given 8 months after a second dose, GMTs assessed 14 days later increased to 137·9 for cohort 1b-14d-8m and 143·1 28 days later for cohort 2b-28d-8m.
> GMTs moderately increased following a primary third dose, from 21·8 on day 28 after the second dose to 45·8 on day 28 after the third dose in cohort 1a-14d-2m (n=54), and from 38·1 to 49·7 in cohort 2a-28d-2m (n=53).
> A third dose given 8 months after the second dose significantly increased neutralising antibody concentrations: GMTs increased from 42·9 on day 28 after the second dose to 158·5 on day 28 following the third dose (n=29).

A third dose of CoronaVac in adults administered 8 months after a second dose effectively recalled specific immune responses to SARS-CoV-2, which had declined substantially 6 months after two doses of CoronaVac, resulting in a remarkable increase in the concentration of antibodies and indicating that a two-dose schedule generates good immune memory, and a primary third dose given 2 months after the second dose induced slightly higher antibody titres than the primary two doses.
Lancet2021.12.06Immunogenicity, safety, and reactogenicity of heterologous COVID-19 primary vaccination incorporating mRNA, viral-vector, and protein-adjuvant vaccines in the UK (Com-COV2): a single-blind, randomised, phase 2, non-inferiority trialStuart A.S.V., et al.
UKVaccinesAim: to study mixed priming schedules incorporating an adenoviral-vectored vaccine (ChAdOx1 nCoV-19 [ChAd], AstraZeneca), two mRNA vaccines (BNT162b2 [BNT], Pfizer–BioNTech, and mRNA-1273 [m1273], Moderna) and a nanoparticle vaccine containing SARS-CoV-2 spike glycoprotein and Matrix-M adjuvant (NVX-CoV2373 [NVX], Novavax).

- Com-COV2 is a single-blind, randomised, non-inferiority trial on adults ≥50 years previously immunised with a single dose of ChAd or BNT, and assigned in a 1:1:1 ratio to receive a second dose (8–12 weeks after the first dose) with the homologous vaccine, m1273, or NVX.
- Primary endpoint: geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentrations measured by ELISA in heterologous versus homologous schedules at 28 days after the second dose (non-inferiority criterion of the GMR above 0·63 for the one-sided 98·75% CIà).
- Primary analysis: per-protocol population, who were seronegative at baseline.

> April 19-May 14, 2021: 1072 participants enrolled at a median of 9·4 weeks after receipt of a single dose of ChAd (n=540, 47% female) or BNT (n=532, 40% female).
> In ChAd-primed participants, geometric mean concentration (GMC) 28 days after a boost of SARS-CoV-2 anti-spike IgG in recipients of ChAd/m1273 (20 114 ELISA laboratory units [ELU]/mL [95% CI 18 160 to 22 279]) and ChAd/NVX (5597 ELU/mL [4756 to 6586]) was non-inferior to that of ChAd/ChAd recipients (1971 ELU/mL [1718 to 2262]) with a GMR of 10·2 (one-sided 98·75% CI 8·4 to ∞) for ChAd/m1273 and 2·8 (2·2 to ∞) for ChAd/NVX, compared with ChAd/ChAd.
> In BNT-primed participants, non-inferiority was shown for BNT/m1273 (GMC 22 978 ELU/mL [95% CI 20 597 to 25 636]) but not for BNT/NVX (8874 ELU/mL [7391 to 10 654]), compared with BNT/BNT (16 929 ELU/mL [15 025 to 19 075]) with a GMR of 1·3 (one-sided 98·75% CI 1·1 to ∞) for BNT/m1273 and 0·5 (0·4 to ∞) for BNT/NVX, compared with BNT/BNT; however, NVX still induced an 18-fold rise in GMC 28 days after vaccination.
> There were 15 serious adverse events, none considered related to immunisation.

Heterologous second dosing with m1273, but not NVX, increased transient systemic reactogenicity compared with homologous schedules. Multiple vaccines are appropriate to complete primary immunisation following priming with BNT or ChAd.
Clinl Infect Dis.2021.12.05Multisystem Inflammatory Syndrome in Children—United States, February 2020–July 2021Miller A. D., et al.
USAPublic health /
Multisystem inflammatory syndrome in children (MIS-C) is a severe hyperinflammatory condition in persons aged <21 years associated with antecedent SARS-CoV-2 infection. Our objective was to describe MIS-C cases reported to CDC’s national surveillance since the COVID-19 pandemic began

We included patients meeting the MIS-C case definition with onset date from February 19, 2020 through July 31, 2021, using CDC’s MIS-C case report form, which collects information on demographics, clinical presentation, and laboratory results.

> Of 4,901 reported cases, 4,470 met inclusion criteria. Median patient age increased over time (P<0.001), with a median of 9 years (interquartile range, 5–13 years) during the most recent (third) wave.
> Male predominance also increased (62% in third wave, P<0.001). A significant (P<0.001) increase in severe hematologic and gastrointestinal involvement was observed across the study period.
> Frequency of several cardiovascular complications (i.e., cardiac dysfunction, myocarditis, and shock/ vasopressor receipt) and renal failure declined (P<0.001)
> Provision of critical care including mechanical ventilation (P<0.001) and extracorporeal membrane oxygenation (ECMO; P=0.046) decreased, as did duration of hospitalization and mortality (each P<0.001).

Over the first 3 pandemic waves of MIS-C in the United States, cardiovascular complications and clinical outcomes including length of hospitalization, receipt of ECMO, and death decreased over time. These data serve as a baseline for monitoring future trends associated with SARS-CoV-2 B.1.617.2 (Delta) or other variants and increased COVID-19 vaccination among children.
Cell2021.12.03Protection from SARS-CoV-2 Delta one year after mRNA-1273 vaccination in rhesus macaques is coincident with anamnestic antibody response in the lungGagne M., et al.
USAVaccinesAim: to study the impact of durability of immune responses to mRNA-1873 on protection and immune responses in rhesus macaques and assessed immune responses over one year in blood, upper and lower airways.

> Neutralizing responses to Delta are low to undetectable 1yr after mRNA-1273 vaccination. Serum neutralizing titers to Delta were 280 and 34 reciprocal ID50 at weeks 6 (peak) and 48 (challenge), respectively. Antibody binding titers also decreased in bronchoalveolar lavage (BAL).
> Protection in lungs from Delta replication not observed until day 4 post-challenge. Four days after Delta challenge, virus was unculturable in BAL and subgenomic RNA declined by ∼3-log10 compared to control animals.
> In nasal swabs, sgRNA was reduced by 1-log10 and virus remained culturable. Protection in upper airway is limited one year after mRNA-1273 vaccination.
> Anamnestic antibodies (590-fold increased titer) but not T cell responses were detected in BAL by day 4 post-challenge, concomitant with protection in lungs.

mRNA-1273-mediated protection in the lungs is durable but delayed and potentially dependent on anamnestic antibody responses.
JAMA2021.12.03Immunogenicity of Extended mRNA SARS-CoV-2 Vaccine Dosing IntervalsGrunau B., et al.
CanadaVaccines - ImmunisationThis study investigated the immunogenicity of extended mRNA vaccine dosing intervals.


> For the first investigation, the mean age for the short (dosing interval range, 18-28 days) group was 39 years (43% women); 70% received BNT162b2 and 30%, mRNA-1273; for the medium (range, 42-49 days) group, the mean age was 41 years (47% women); 60% received BNT162b2 and 40%, mRNA-1273. Comparing immunogenicity based on time after the second vaccine dose (matched at mean, 56 days [SD, 26 days]), the viral neutralization geometric mean was 54.6 (GSD, 3.0) for the short group vs 230.8 (GSD, 2.0) for the medium group (P < .001).
> For the second investigation, the mean age was 41 years (60% women), 87% received BNT162b2 and 13%, mRNA-1273, for both the short (range, 21-36 days) and long (range, 102-118 days) groups. Comparing immunogenicity based on time after the first vaccine dose (mean days, 179 [SD, 4.0 days] for the short group and 180 days [SD, 5.7 days] for the long group), the viral neutralization geometric mean was 41.8 (GSD, 2.8) for the short group vs 302.3 (GSD, 2.4) for the long group (P < .001).

Longer mRNA vaccine dosing intervals demonstrated improved immunogenicity, which was consistent when responses were measured based on timing of the first or second dose. A delayed second-dose strategy could yield faster partial protection to a larger proportion of the population when vaccine supplies are limited.
These data suggest that extending dosing intervals may be particularly advantageous against the Delta variant.
Although antibody neutralization correlates with disease protection, studies should validate whether extending vaccine dosing intervals leads to more sustained vaccine protection.
Clin Infect Dis.2021.12.03Duration of SARS-CoV-2 Natural Immunity and Protection against the Delta Variant: A Retrospective Cohort StudyKim P., et al.
USAImmunologyAim: to determine whether prior infection protects against reinfection with the Delta variant and to estimate duration of immunity following COVID-19 infection.

Retrospective cohort study included 325,157 patients tested for COVID-19 via PCR from 09 March 2020 to 31 December 2020 (Delta variant analysis) and 152,656 patients tested from 09 March 2020 to 30 August 2020 (long-term effectiveness analysis) with subsequent testing through 09 September 2021. The primary outcome was reinfection, defined as a positive PCR test >90 days after initial positive test.

> Among 325,157 patients tested before 31 December 2020, 50,327 (15.5%) tested positive. After 01 July 2021 (Delta dominant period), 40 (0.08%) of the initially positive and 1,494 (0.5%) of the initially negative patients tested positive.
> Protection of prior infection against reinfection with Delta was 85.4% (95% CI, 80.0-89.3).
> For the long-term effectiveness analysis, among 152,656 patients tested before 30 August 2020, 11,186 (7.3%) tested positive. After at least 90 days, 81 (0.7%) of the initially positive patients and 7,167 (5.1%) of the initially negative patients tested positive.
> Overall protection of previous infection was 85.7% (95% CI, 82.2-88.5) and lasted up to 13 months. Patients over age 65 had slightly lower protection.

SARS-CoV-2 infection is highly protective against reinfection with the Delta variant. Immunity from prior infection lasts for at least 13 months.
Science2021.12.02Heterologous infection and vaccination shapes immunity against SARS-CoV-2 variantsReynolds C.J., et al.
UKImmunologyAim: to study the impact of initial SARS-CoV-2 infecting strain on downstream immunity to heterologous variants of concern (VOC) through a longitudinal healthcare worker cohort.

> After three antigen exposures (infection+two vaccine doses), S1 antibody, memory B cells and heterologous neutralization of B.1.351, P.1 and B.1.617.2 plateaued, while B.1.1.7 neutralization and spike T cell responses increased.
> Serology using Wuhan Hu-1 spike receptor binding domain poorly predicted neutralizing immunity against VOCs.
> Neutralization potency against VOCs changed with heterologous virus encounter and number of antigen exposures.
> Neutralization potency fell differentially depending on targeted VOCs over 5-months from the second vaccine dose.

Heterologous combinations of spike encountered during infection and vaccination shape subsequent cross-protection against VOC, with implications for future-proof next-generation vaccines.
Science2021.12.024′-Fluorouridine is an oral antiviral that blocks respiratory syncytial virus and SARS-CoV-2 replicationLieber C. M., et al.
USATherapeuticsWe describe 4′-fluorouridine (4′-FlU, EIDD-2749), a ribonucleoside analog that inhibits respiratory syncytial virus (RSV), related RNA viruses, and SARS-CoV-2 with high selectivity index in cells and human airway epithelia organoids.

> Polymerase inhibition within in vitro RdRP assays established for RSV and SARS-CoV-2 revealed transcriptional stalling after incorporation.
> Once-daily oral treatment was highly efficacious at 5 mg/kg in RSV-infected mice or 20 mg/kg in ferrets infected with different SARS-CoV-2 variants-of-concern, initiated 24 or 12 hours after infection, respectively.

These properties define 4′-FlU as a broad-spectrum candidate for the treatment of RSV, SARS-CoV-2, and related RNA virus infections.
Lancet2021.12.02Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trialMunro A.P.S., et al.
UKVaccinesAim: to investigate the reactogenicity and immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford–AstraZeneca, ChAd) or BNT162b2 (Pfizer–BioNtech; BNT).

- COV-BOOST is a multicentre, randomised, controlled, phase 2 trial on participants ≥30 years, at least 70 days post two doses of ChAd or at least 84 days post two doses of BNT primary immunisation course, with no history of SARS-CoV-2 infection.
- Participants were divided into three groups:
Group A received NVX-CoV2373 (Novavax; NVX), a half dose of NVX, ChAd, or quadrivalent meningococcal conjugate vaccine (MenACWY) control (1:1:1:1).
Group B received BNT, VLA2001 (Valneva; VLA), a half dose of VLA, Ad26.COV2.S (Janssen; Ad26) or MenACWY (1:1:1:1:1).
Group C received mRNA1273 (Moderna; m1273), CVnCov (CureVac; CVn), a half dose of BNT, or MenACWY (1:1:1:1).
Coprimary outcomes: safety and reactogenicity and immunogenicity of anti-spike IgG.

> June 1-30, 2021: 2878 participants received COVID-19 vaccine or control.
- ChAd/ChAd-primed participants: 53 years (IQR 44–61) in the younger age group and 76 years (73–78) in the older age group; 46·7% were female and 95·4% were White.
- BNT/BNT-primed participants: median ages were 51 years (41–59) in the younger age group and 78 years (75–82) in the older age group; 53·6% participants were female and 1321 91·9% were White.
> Three vaccines showed overall increased reactogenicity: m1273 after ChAd/ChAd or BNT/BNT; and ChAd and Ad26 after BNT/BNT.
> For ChAd/ChAd-primed individuals, spike IgG geometric mean ratios (GMRs) between study vaccines and controls ranged from 1·8 (99% CI 1·5–2·3) in the half VLA group to 32·3 (24·8–42·0) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·1 (95% CI 0·7–1·6) for ChAd to 3·6 (2·4–5·5) for m1273.
> For BNT/BNT-primed individuals, spike IgG GMRs ranged from 1·3 (99% CI 1·0–1·5) in the half VLA group to 11·5 (9·4–14·1) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·0 (95% CI 0·7–1·6) for half VLA to 4·7 (3·1–7·1) for m1273.
> The results were similar between those aged 30–69 years and those aged 70 years and older.
> Fatigue and pain were the most common solicited local and systemic adverse events, experienced more in people aged 30–69 years than those aged 70 years or older.
> Serious adverse events were uncommon, similar in active vaccine and control groups. In total, there were 24 serious adverse events: five in the control group, two in Ad26, five in VLA, one in VLA-half, one in BNT, two in BNT-half, two in ChAd, one in CVn, two in NVX, two in NVX-half, and one in m1273.

All study vaccines boosted antibody and neutralising responses after ChAd/ChAd initial course and all except one after BNT/BNT, with no safety concerns.
Nature Immunol.2021.12.01An immunodominant NP105–113-B*07:02 cytotoxic T cell response controls viral replication and is associated with less severe COVID-19 diseasePeng Y., et al.
UKImmunologyAim: to present an in-depth analysis to explore correlations across NP105–113-B*07:02-specific T cell responses, TCR repertoires and disease severity.

Analysis of NP105–113-B*07:02-specific T cell clones and single-cell sequencing were performed concurrently, with functional avidity and antiviral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with T cell receptor usage, transcriptome signature and disease severity (acute n = 77, convalescent n = 52).

> The authors found strong association of NP105–113-B*07:02-specific CD8+ T cell responses with mild disease.
> A beneficial association of NP105–113-B*07:02-specific T cells in COVID-19 disease progression, linked with expansion of T cell precursors, high functional avidity and antiviral effector function was observed.
>Broad immune memory pools were narrowed postinfection but NP105–113-B*07:02-specific T cells were maintained 6 months after infection with preserved antiviral efficacy to the SARS-CoV-2 Victoria strain, as well as Alpha, Beta, Gamma and Delta variants.

NP105–113-B*07:02-specific T cell responses associate with mild disease and high antiviral efficacy, pointing to inclusion for future vaccine design.
Nature Immunol.2021.12.01Structural basis for continued antibody evasion by the SARS-CoV-2 receptor binding domainNabel K.G., et al.
USAImmunologyAim: to investigate the structural plasticity of the SARS-CoV-2 spike protein RBD and its capacity to evade neutralizing antibodies.

Monoclonal antibodies from the blood of a COVID-19 convalescent individual using single B cell sorting with prefusion stabilized SARS-CoV spike protein ectodomain as bait and using established protocols were isolated. Venous blood samples from healthy mRNA-1273 and BNT162b2 vaccine recipients were obteined.

> The SARS-CoV-2 receptor binding domain (RBD) can tolerate large numbers of simultaneous antibody escape mutations and show that pseudotypes containing up to seven mutations, as opposed to the one to three found in previously studied variants of concern, are more resistant to neutralization by therapeutic antibodies and serum from vaccine recipients.
> The autors have found an antibody that binds the RBD core to neutralize pseudotypes for all tested variants but show that the RBD can acquire an N-linked glycan to escape neutralization.

These findings portend continued emergence of escape variants as SARS-CoV-2 adapts to humans.
Lancet Respir Med.2021.12.01Lenzilumab in hospitalised patients with COVID-19 pneumonia (LIVE-AIR): a phase 3, randomised, placebo-controlled trialTemsgen Z., et al.
USATherapeuticsGranulocyte-macrophage colony-stimulating factor (GM-CSF) is among cytokines that contribute to the inflammatory processes. Lenzilumab, a GM-CSF neutralising monoclonal antibody, was investigated in the LIVE-AIR trial to assess its efficacy and safety in treating COVID-19 beyond available treatments.

> In LIVE-AIR, a phase 3, randomised, double-blind, placebo-controlled trial, hospitalised adult patients with COVID-19 pneumonia not requiring invasive mechanical ventilation were recruited from 29 sites in the USA and Brazil and were randomly assigned (1:1) to receive three intravenous doses of lenzilumab (600 mg per dose) or placebo delivered 8 h apart.
> The primary endpoint was survival without invasive mechanical ventilation to day 28 in the modified intention-to-treat population (mITT), comprising all randomised participants who received at least one dose of study drug under the documented supervision of the principal investigator or sub-investigator.

> Patients were enrolled from May 5, 2020, until Jan 27, 2021. 528 patients were screened, of whom 520 were randomly assigned and included in the intention-to-treat population. 479 of these patients (n=236, lenzilumab; n=243, placebo) were included in the mITT analysis for the primary outcome.
> 311 (65%) participants were males, mean age was 61 (SD 14) years at baseline, and median C-reactive protein concentration was 79 (IQR 41–137) mg/L.
> Steroids were administered to 449 (94%) patients and remdesivir to 347 (72%) patients; 331 (69%) patients received both treatments.
> Survival without invasive mechanical ventilation to day 28 was achieved in 198 (84%; 95% CI 79–89) participants in the lenzilumab group and in 190 (78%; 72–83) patients in the placebo group, and the likelihood of survival was greater with lenzilumab than placebo (hazard ratio 1·54; 95% CI 1·02–2·32; p=0·040).
> 68 (27%) of 255 patients in the lenzilumab group and 84 (33%) of 257 patients in the placebo group experienced at least one adverse event that was at least grade 3 in severity based on CTCAE criteria. The most common treatment-emergent adverse events of grade 3 or higher were related to respiratory disorders (26%) and cardiac disorders (6%) and none led to death.

Lenzilumab significantly improved survival without invasive mechanical ventilation in hospitalised patients with COVID-19, with a safety profile similar to that of placebo. The added value of lenzilumab beyond other immunomodulators used to treat COVID-19 alongside steroids remains unknown.
NEJM2021.12.01Comparative Effectiveness of BNT162b2 and mRNA-1273 Vaccines in U.S. VeteransDickerman B.A., et al.
USAVaccines - ImmunisationAim: to evaluate the comparative effectiveness of the two mRNA vaccines BNT162b2 and mRNA-1273 for a range of outcomes across diverse populations is unknown.

- Electronic health records of U.S. veterans who received a first dose of the BNT162b2 or mRNA-1273 vaccine (Jan 4-May 14, 2021 – predominance of Alpha variant.
- Outcomes: documented SARS-CoV-2 infection, symptomatic Covid-19, hospitalization for Covid-19, admission to ICU for Covid-19, and death from Covid-19.
- To assess the influence of the B.1.617.2 (delta) variant, we emulated a second target trial that involved veterans vaccinated between July 1 and Sept 20, 2021.

> Each vaccine group included 219,842 persons.
> Over 24 weeks of follow-up in a period marked by alpha-variant predominance, the estimated risk of documented infection was 5.75 events per 1000 persons (95% CI, 5.39 to 6.23) in the BNT162b2 group and 4.52 events per 1000 persons (95% CI, 4.17 to 4.84) in the mRNA-1273 group.
> The excess number of events per 1000 persons for BNT162b2 as compared with mRNA-1273 was 1.23 (95% CI, 0.72 to 1.81) for documented infection, 0.44 (95% CI, 0.25 to 0.70) for symptomatic Covid-19, 0.55 (95% CI, 0.36 to 0.83) for hospitalization for Covid-19, 0.10 (95% CI, 0.00 to 0.26) for ICU admission for Covid-19, and 0.02 (95% CI, −0.06 to 0.12) for death from Covid-19.
> The corresponding excess risk (BNT162b2 vs. mRNA-1273) of documented infection over 12 weeks of follow-up in a period marked by delta-variant predominance was 6.54 events per 1000 persons (95% CI, −2.58 to 11.82).

The 24-week risk of Covid-19 outcomes was low after vaccination with mRNA-1273 or BNT162b2, although risks were lower with mRNA-1273 than with BNT162b2. This pattern was consistent across periods marked by alpha- and delta-variant predominance.
NEJM2021.12.01Viral Dynamics of SARS-CoV-2 Variants in Vaccinated and Unvaccinated PersonsKissler S.M., et al.
USAVirologyAim: to assess viral dynamics of SARS-CoV-2 variants in vaccinated and unvaccinated people.
- Analysis of a prospective, longitudinal set of 19,941 SARS-CoV-2 viral samples obtained from 173 participants, November 28, 2020, and August 11, 2021
- Participants: infection with alpha (36), infection with delta (36), infection with a variant that was not of current interest or concern (41), vaccinated individuals (37), unvaccinated individuals (136)


> No meaningful difference in the mean peak viral load was found, proliferation duration, clearance duration, or duration of acute infection of either the alpha or the delta variant as compared with variants not of interest or concern.
> No meaningful difference in the mean peak viral load or proliferation duration was found between vaccinated and unvaccinated participants.
> A lower peak Ct was slightly more frequent in infections with the delta variant than in those with the alpha variant or variants not of interest or concern: 13.0% of the posterior delta trajectories had a Ct<15, vs 6.9% for the alpha variant and 10.2% for variants not of interest or concern. It is unclear whether this finding reflects a limiting factor of the study.
> Breakthrough infections in vaccine recipients were characterized by a faster clearance time than that among unvaccinated participants (mean of 5.5 days (95% CI, 4.6 to 6.5) and 7.5 days (95% CI, 6.8 to 8.2), respectively). The shorter clearance time led to a shorter overall duration of infection among vaccine recipients.

This study provides data on acute SARS-CoV-2 viral dynamics for some variants of concern among vaccinated and unvaccinated persons.
NEJM2021.12.01Covid-19 Vaccine Effectiveness in New York StateRosenberg E.S., et al.
USAVaccines - ImmunisationAim: to assess whether declines in effectiveness are due to waning immunity, the B.1.617.2 (delta) variant of the SARS-CoV-2, or other causes is unknown.

- Data for 8,690,825 adults in New York State to assess the effectiveness of the BNT162b2, mRNA-1273, and Ad26.COV2.S vaccines against laboratory-confirmed Covid-19 and hospitalization with Covid-19 (i.e., Covid-19 diagnosed at or after admission).
- Vaccine effectiveness was assessed against Covid-19 from May 1 to September 3, 2021, and against hospitalization with Covid-19 from May 1 to August 31, 2021.

> There were 150,865 cases of Covid-19 and 14,477 hospitalizations with Covid-19.
> During the week of May 1, 2021, when the delta variant made up 1.8% of the circulating variants, the median vaccine effectiveness against Covid-19 was 91.3% (range, 84.1 to 97.0) for BNT162b2, 96.9% (range, 93.7 to 98.0) for mRNA-1273, and 86.6% (range, 77.8 to 89.7) for Ad26.COV2.S.
> Subsequently, effectiveness declined contemporaneously in all cohorts, from a median of 93.4% (range, 77.8 to 98.0) during the week of May 1 to a nadir of 73.5% (range, 13.8 to 90.0) around July 10, when the prevalence of the delta variant was 85.3%.
> By the week of August 28, when the prevalence of the delta variant was 99.6%, the effectiveness was 74.2% (range, 63.4 to 86.8).
> Effectiveness against hospitalization with Covid-19 among adults 18 to 64 years of age remained almost exclusively greater than 86%, with no apparent time trend.
> Effectiveness declined from May through August among persons 65 years of age or older who had received BNT162b2 (from 94.8 to 88.6%) or mRNA-1273 (from 97.1 to 93.7%). The effectiveness of Ad26.COV2.S was lower than that of the other vaccines, with no trend observed over time (range, 80.0 to 90.6%).

The effectiveness of the three vaccines against Covid-19 declined after the delta variant became predominant. The effectiveness against hospitalization remained high, with modest declines limited to BNT162b2 and mRNA-1273 recipients 65 years of age or older.
Nature Immunol.2021.11.30BNT162b2 vaccine induces divergent B cell responses to SARS-CoV-2 S1 and S2Brewer, R. C., et al.
Germany / USA
Vaccines - ImmunisationAim: to investigate the B cell response to the BNT162b2 vaccine by integrating B cell repertoire analysis with single-cell transcriptomics pre- and post-vaccination.

Nine healthy individuals were enrolled in the study. All individuals had undergone routine PCR with reverse transcription (RT–PCR) testing for SARS-CoV-2 infection before study. A detailed characterization of the B cell response to the BNT162b2 mRNA vaccine at a single-cell level was performed.

> The first vaccine dose elicits a recall response of IgA+ plasmablasts targeting the S subunit S2.
> Three weeks after the first dose, an influx of minimally mutated IgG+ memory B cells that targeted the receptor binding domain on the S subunit S1 and likely developed from the naive B cell pool was observed.
>This response was strongly boosted by the second dose and delivers potently neutralizing antibodies against SARS-CoV-2 and several of its variants.
This study provides a detailed characterization of the blood B cell response to the BNT162b2 mRNA vaccine and emphasize the importance of the second dose in inducing generation of RBD-specific antibodies that contribute to neutralization of SARS-CoV-2 variants.
Lancet2021.11.30Risk of COVID-19 hospital admission among children aged 5–17 years with asthma in Scotland: a national incident cohort studyShi T., et al.
UKPublic Health / EpidemiologyAnalysis to identify which children with asthma were at increased risk of serious COVID-19 outcomes.

> Between March 1, 2020, and July 27, 2021, 752 867 children were included in the EAVE II dataset, 63 463 (8·4%) of whom had clinician-diagnosed-and-recorded asthma of these, 4339 (6·8%) had RT-PCR confirmed SARS-CoV-2 infection. n those with confirmed infection, 67 (1·5%) were admitted to hospital with COVID-19.
> Among the 689 404 children without asthma, 40 231 (5·8%) had confirmed SARS-CoV-2 infections, of whom 382 (0·9%) were admitted to hospital with COVID-19
> The rate of COVID-19 hospital admission was higher in children with poorly controlled asthma than in those with well controlled asthma or without asthma
- When using previous hospital admission for asthma as the marker of uncontrolled asthma, the adjusted HR was 6·40 (95% CI 3·27–12·53) for those with poorly controlled asthma and 1·36 (1·02–1·80) for those with well controlled asthma, compared with those with no asthma
- When using oral corticosteroid prescriptions as the marker of uncontrolled asthma, the adjusted HR was 3·38 (1·84–6·21) for those with three or more prescribed courses of corticosteroids, 3·53 (1·87–6·67) for those with two prescribed courses of corticosteroids, 1·52 (0·90–2·57) for those with one prescribed course of corticosteroids, and 1·34 (0·98–1·82) for those with no prescribed course, compared with those with no asthma.

School-aged children with asthma with previous recent hospital admission or two or more courses of oral corticosteroids are at markedly increased risk of COVID-19 hospital admission and should be considered a priority for vaccinations. This would translate into 9124 children across Scotland and an estimated 109 448 children across the UK.
Nature Commun.2021.11.26Protective mucosal immunity against SARS-CoV-2 after heterologous systemic prime-mucosal boost immunizationLapuente D., et al.
GermanyVaccines - ImmunisationAim: to assess mucosal vaccinations with adenoviral serotype 5 and 19a vectors in mice with or without prior systemic priming.

The immunogenicity of mucosally applied viral vector vaccines as a single shot vaccine or as a booster after an intramuscular plasmid DNA prime immunization was evaluated.

> Intranasal vaccinations with adenovirus 5 and 19a vectored vaccines following a systemic plasmid DNA or mRNA priming result in systemic and mucosal immunity in mice.
> In contrast to two intramuscular applications of an mRNA vaccine, intranasal boosts with adenoviral vectors induce high levels of mucosal IgA and lung-resident memory T cells (TRM); mucosal neutralization of virus variants of concern is also enhanced.
> The mRNA prime provokes a comprehensive T cell response consisting of circulating and lung TRM after the boost, while the plasmid DNA prime induces mostly mucosal T cells.
> Concomitantly, the intranasal boost strategies lead to complete protection against a SARS-CoV-2 infection in mice. These data suggest that mucosal booster immunizations after mRNA priming is a promising approach to establish mucosal immunity in addition to systemic responses.
Lancet2021.11.26Prevention of SARS-CoV-2 transmission during a large, live, indoor gathering (SPRING): a non-inferiority, randomised, controlled trialDelaugerre C ., et al.
FrancePublic Health / EpidemiologyTo assess, under controlled conditions, whether infection rates among attendees at a large, indoor gathering event would be similar to those in non-attendees, given implementation of a comprehensive prevention strategy including antigen-screening within 3 days, medical mask wearing, and optimised ventilation.

> The non-inferiority, prospective, open-label, randomised, controlled SPRING trial was done on attendees at a live indoor concert held in the Accor Arena on May 29, 2021 in Paris, France.
> Participants, aged 18–45 years, recruited via a dedicated website, had no comorbidities, COVID-19 symptoms, or recent case contact, and had had a negative rapid antigen diagnostic test within 3 days before the concert
> The primary outcome measure was the number of patients who were SARS-CoV-2-positive by RT-PCR test on self-collected saliva 7 days post-gathering in the per-protocol population (non-inferiority margin <0·35%).

> Between May 11 and 25, 2021, 18 845 individuals registered on the dedicated website, and 10 953 were randomly selected for a pre-enrolment on-site visit.
> Among 6968 who kept the appointment and were screened, 6678 participants were randomly assigned (4451 were assigned to be attendees and 2227 to be non-attendees; median age 28 years; 59% women); 88% (3917) of attendees and 87% (1947) of non-attendees complied with follow-up requirements.
> The day 7 RT-PCR was positive for eight of the 3917 attendees (observed incidence, 0·20%; 95% CI 0·09–0·40) and three of the 1947 non-attendees (0·15%; 0·03–0·45; absolute difference, 95% CI −0·26% to 0·28%), findings that met the non-inferiority criterion for the primary endpoint.

Participation in a large, indoor, live gathering without physical distancing was not associated with increased SARS-CoV-2–transmission risk, provided a comprehensive preventive intervention was implemented
Lancet Respir Med.2021.11.26Fungal infections in mechanically ventilated patients with COVID-19 during the first wave: the French multicentre MYCOVID studyGangneux J-P., et al.
FrancePublic health / EpidemiologyAim: To identify the prevalence, risk factors, and mortality associated with IFIs in mechanically ventilated patients with COVID-19 under intensive care.

A national, multicentre, observational cohort study in 18 French intensive care units (ICUs) was performed. Adult patients (aged ≥18 years) were retrospectively and prospectively enrolled with RT-PCR-confirmed SARS-CoV-2 infection and requiring mechanical ventilation for acute respiratory distress syndrome, with all demographic and clinical and biological follow-up data anonymised and collected from electronic case report forms. Patients were systematically screened for respiratory fungal microorganisms once or twice a week during the period of mechanical ventilation up to ICU discharge.

> Between Feb 29 and July 9, 2020, we enrolled 565 mechanically ventilated patients with COVID-19. 509 patients with at least three screening samples were analysed (mean age 59·4 years [SD 12·5], 400 [79%] men). 128 (25%) patients had 138 episodes of pr/pb or possible IFIs. 76 (15%) patients fulfilled the criteria for pr/pb CAPA.
> According to multivariate analysis, age older than 62 years (odds ratio [OR] 2·34 [95% CI 1·39–3·92], p=0·0013), treatment with dexamethasone and anti-IL-6 (OR 2·71 [1·12–6·56], p=0·027), and long duration of mechanical ventilation (>14 days; OR 2·16 [1·14–4·09], p=0·019) were independently associated with pr/pb CAPA. 38 (7%) patients had one or more other pr/pb IFIs: 32 (6%) had candidaemia, six (1%) had invasive mucormycosis, and one (<1%) had invasive fusariosis.
> Multivariate analysis of associations with death, adjusted for candidaemia, for the 509 patients identified three significant factors: age older than 62 years (hazard ratio [HR] 1·71 [95% CI 1·26–2·32], p=0·0005), solid organ transplantation (HR 2·46 [1·53–3·95], p=0·0002), and pr/pb CAPA (HR 1·45 [95% CI 1·03–2·03], p=0·033).
> At time of ICU discharge, survival curves showed that overall ICU mortality was significantly higher in patients with pr/pb CAPA than in those without, at 61·8% (95% CI 50·0–72·8) versus 32·1% (27·7–36·7; p<0·0001).

This study shows the high prevalence of invasive pulmonary aspergillosis and candidaemia and high mortality associated with pr/pb CAPA in mechanically ventilated patients with COVID-19. These findings highlight the need for active surveillance of fungal pathogens in patients with severe COVID-19.