Z. Al-Aly et al.

Outcomes of the SARS-CoV-2 reinfection

Research Square, June 2022; doi.org/10.21203/rs.3.rs-1749502/v1

Abstract

First infection with SARS-CoV-2 is associated with increased risk of acute and post-acute death and sequelae in the pulmonary and extrapulmonary organ systems. However, whether reinfection adds to the risk incurred after the first infection is not clear. Here we use the national health care databases of the US Department of Veterans Affairs to build a cohort of people with first infection (n = 257,427), reinfection (2 or more infections, n = 38,926), and a non-infected control group (n = 5,396,855) to estimate risks and 6-month burdens of all-cause mortality, hospitalization, and a set of pre-specified incident outcomes. We show that compared to people with first infection, reinfection contributes additional risks of all-cause mortality, hospitalization, and adverse health outcomes in the pulmonary and several extrapulmonary organ systems (cardiovascular disorders, coagulation and hematologic disorders, diabetes, fatigue, gastrointestinal disorders, kidney disorders, mental health disorders, musculoskeletal disorders, and neurologic disorders); the risks were evident in those who were unvaccinated, had 1 shot, or 2 or more shots prior to the second infection; the risks were most pronounced in the acute phase, but persisted in the post-acute phase of reinfection, and most were still evident at 6 months after reinfection. Compared to non-infected controls, assessment of the cumulative risks of repeated infection showed that the risk and burden increased in a graded fashion according to the number of infections. The constellation of findings show that reinfection adds non-trivial risks of all-cause mortality, hospitalization, and adverse health outcomes in the acute and post-acute phase of the reinfection. Reducing overall burden of death and disease due to SARS-CoV-2 will require strategies for reinfection prevention.

R. Rubin

From positive to negative to positive again—the mystery of why covid-19 rebounds in some patients who take Paxlovid

JAMA, June 2022; doi:10.1001/jama.2022.9925

Abstract

Director of the Aaron Diamond AIDS Research Center at Columbia University managed to avoid contracting COVID-19 for more than 2 years. But SARS-CoV-2 finally got the best of the pioneering HIV researcher on an April trip to Paris for, of all things, a 2-day COVID-19 conference.

jama_rubin_2022_mn_220048_1655397810.78549.pdf

J. Quandt et al.

Omicron BA.1 breakthrough infection drives cross-variant neutralization and memory B cell formation against conserved epitopes

Science Immunology, June 2022 ; doi: 10.1126/sciimmunol.abq2427

Abstract

Omicron is the evolutionarily most distinct SARS-CoV-2 variant of concern (VOC) to date. We report that Omicron BA.1 breakthrough infection in BNT162b2-vaccinated individuals resulted in strong neutralizing activity against Omicron BA.1, BA.2 and previous SARS-CoV-2 VOCs, but not against the Omicron sublineages BA.4 and BA.5. BA.1 breakthrough infection induced a robust recall response, primarily expanding BMEM cells against epitopes shared broadly amongst variants, rather than inducing BA.1-specific B cells. The vaccination-imprinted BMEM cell pool had sufficient plasticity to be remodeled by heterologous SARS-CoV-2 spike glycoprotein exposure. While selective amplification of BMEM cells recognizing shared epitopes allows for effective neutralization of most variants that evade previously established immunity, susceptibility to escape by variants that acquire alterations at hitherto conserved sites may be heightened.

M. Charness et al.

Rapid Relapse of Symptomatic SARS-CoV-2 Infection Following Early Suppression with Nirmatrelvir/Ritonavir

Research Square, May 2022; doi.org/10.21203/rs.3.rs-1588371/v2

Abstract

We describe relapse of COVID-19 symptoms and SARS-CoV-2 viral load following nirmatrelvir/ritonavir (NM/R) in 8 non-immunocompromised patients aged 31 to 71-years-old. Most patients improved rapidly after treatment with NM/R and had negative antigen or PCR tests prior to relapse on Days 9-12 of their illness. Relapse symptoms were described most frequently as cold symptoms, though some patients experiencing a recurrence of fatigue and headache. All relapses resolved without additional antiviral treatment. Viral load during relapse was comparable to levels during initial infection. Sequencing in three patients indicated that relapse was not due to a treatment-emergent mutation or infection with a different viral strain. One patient transmitted SARS-CoV-2 to two family members during relapse. The presence of high viral load and the occurrence of one transmission event suggest that patients with relapse should isolate until antigen testing is negative.

G. Arbor et al.

SARS-CoV-2 vaccination diversifies the CD4+ spike-reactive T cell repertoire in patients with prior SARS-CoV-2 infection

eBioMedicine, May 2022; doi.org/10.1016/j. ebiom.2022.104048

Abstract

Background COVID-19 mRNA vaccines elicit strong T and B cell responses to the SARS-CoV-2 spike glycoprotein in both SARS-CoV-2 nay¨ve and experienced patients. However, it is unknown whether the post-vaccine CD4+ T cell responses seen in patients with a history of COVID-19 are due to restimulation of T cell clonotypes that were first activated during natural infection or if they are the result of new clones activated by the vaccine.

Methods To address this question, we analyzed the SARS-CoV-2 spike glycoprotein-specific CD4+ T cell receptor repertoire before and after vaccination in 10 COVID-19 convalescent patients and 4 SARS-CoV-2 nayive healthy donor vaccine recipients. We used the viral Functional Expansion of Specific T cells (ViraFEST) assay to quantitatively identify specific SARS-CoV-2 and common cold coronavirus CD4+ T cell clonotypes post COVID-19 disease resolution and post mRNA SARS-CoV-2 vaccination.

Findings We found that while some preexisting T cell receptor clonotypes persisted, the post-vaccine repertoire consisted mainly of vaccine-induced clones and was largely distinct from the repertoire induced by natural infection. Vaccination-induced clones led to an overall maintenance of the total number of SARS-CoV-2 reactive clonotypes over time through expansion of novel clonotypes only stimulated through vaccination. Additionally, we demonstrated that the vaccine preferentially induces T cells that are only specific for SARS-CoV-2 antigens, rather than T cells that cross-recognize SARS-CoV-2/common cold coronaviruses.

Interpretation These data demonstrate that SARS-CoV-2 vaccination in patients with prior SARS-CoV-2 infection induces a new antigen-specific repertoire and sheds light on the differential immune responses induced by vaccination versus natural infection.

M.P. Sormani et al.

Breakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies during the Delta and the Omicron waves in Italy

eBioMedicine, May 2022; doi.org/10.1016/j. ebiom.2022.104042

Abstract

Background In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in patients with MS (pwMS) under different DMTs and to identify correlates of reduced protection.

Methods This is a prospective Italian multicenter cohort study, long-term clinical follow-up of the CovaXiMS (Covid-19 vaccine in Multiple Sclerosis) study. 1855 pwMS scheduled for SARS-CoV-2 mRNA vaccination were enrolled and followed up to a mean time of 10 months. The cumulative incidence of breakthrough Covid-19 cases in pwMS was calculated before and after December 2021, to separate the Delta from the Omicron waves and to account for the advent of the third vaccine dose.

Findings 1705 pwMS received 2 m-RNA vaccine doses, 21/28 days apart. Of them, 1508 (88.5%) had blood assessment 4 weeks after the second vaccine dose and 1154/1266 (92%) received the third dose after a mean interval of 210 days (range 90-342 days) after the second dose. During follow-up, 131 breakthrough Covid-19 infections (33 during the Delta and 98 during the Omicron wave) were observed. The probability to be infected during the Delta wave was associated with SARS-CoV-2 antibody levels measured after 4 weeks from the second vaccine dose (HR=0.57, p < 0.001); the protective role of antibodies was preserved over the whole follow up (HR=0.57, 95%CI=0.43-0.75, p < 0.001), with a significant reduction (HR=1.40, 95%CI=1.01-1.94, p=0.04) for the Omicron cases. The third dose significantly reduced the risk of infection (HR=0.44, 95%CI=0.21-0.90,p=0.025) during the Omicron wave.

Interpretation The risk of breakthrough SARS-CoV-2 infections is mainly associated with reduced levels of the virus-specific humoral immune response.

P.Nordström et al.

Risk of SARS-CoV-2 reinfection and COVID-19 hospitalisation in individuals with natural and hybrid immunity: a retrospective, total population cohort study in Sweden

The Lancet, March 2022; doi.org/10.1016/ S1473-3099(22)00143-8

Abstract

Background: Real-world evidence supporting vaccination against COVID-19 in individuals who have recovered from a previous SARS-CoV-2 infection is sparse. We aimed to investigate the long-term protection from a previous infection (natural immunity) and whether natural immunity plus vaccination (hybrid immunity) was associated with additional protection.

Methods: In this retrospective cohort study, we formed three cohorts using Swedish nationwide registers managed by the Public Health Agency of Sweden, the National Board of Health and Welfare, and Statistics Sweden. Cohort 1 included unvaccinated individuals with natural immunity matched pairwise on birth year and sex to unvaccinated individuals without natural immunity at baseline. Cohort 2 and cohort 3 included individuals vaccinated with one dose (one-dose hybrid immunity) or two doses (two-dose hybrid immunity) of a COVID-19 vaccine, respectively, after a previous infection, matched pairwise on birth year and sex to individuals with natural immunity at baseline. Outcomes of this study were documented SARS-CoV-2 infection from March 20, 2020, until Oct 4, 2021, and inpatient hospitalisation with COVID-19 as main diagnosis from March 30, 2020, until Sept 5, 2021.

Findings: Cohort 1 was comprised of 2 039 106 individuals, cohort 2 of 962 318 individuals, and cohort 3 of 567 810 individuals. During a mean follow-up of 164 days (SD 100), 34 090 individuals with natural immunity in cohort 1 were registered as having had a SARS-CoV-2 reinfection compared with 99 168 infections in non-immune individuals; the numbers of hospitalisations were 3195 and 1976, respectively. After the first 3 months, natural immunity was associated with a 95% lower risk of SARS-CoV-2 infection (adjusted hazard ratio [aHR] 0·05 [95% CI 0·05–0·05] p<0·001) and an 87% (0·13 [0·11–0·16]; p<0·001) lower risk of COVID-19 hospitalisation for up to 20 months of follow-up. During a mean follow-up of 52 days (SD 38) in cohort 2, 639 individuals with one-dose hybrid immunity were registered with a SARS-CoV-2 reinfection, compared with 1662 individuals with natural immunity (numbers of hospitalisations were eight and 113, respectively). One-dose hybrid immunity was associated with a 58% lower risk of SARS-CoV-2 reinfection (aHR 0·42 [95% CI 0·38–0·47]; p<0·001) than natural immunity up to the first 2 months, with evidence of attenuation thereafter up to 9 months (p<0·001) of follow-up. During a mean follow-up of 66 days (SD 53) in cohort 3, 438 individuals with two-dose hybrid immunity were registered as having had a SARS-CoV-2 reinfection, compared with 808 individuals with natural immunity (numbers of hospitalisations were six and 40, respectively). Two-dose hybrid immunity was associated with a 66% lower risk of SARS-CoV-2 reinfection (aHR 0·34 [95% CI 0·31–0·39]; p<0·001) than natural immunity, with no significant attenuation up to 9 months (p=0·07). To prevent one reinfection in the natural immunity cohort during follow-up, 767 individuals needed to be vaccinated with two doses. Both one-dose (HR adjusted for age and baseline date 0·06 [95% CI 0·03–0·12]; p<0·001) and two-dose (HR adjusted for age and baseline date 0·10 [0·04–0·22]; p<0·001) hybrid immunity were associated with a lower risk of COVID-19 hospitalisation than natural immunity.

Interpretation: The risk of SARS-CoV-2 reinfection and COVID-19 hospitalisation in individuals who have survived and recovered from a previous infection remained low for up to 20 months. Vaccination seemed to further decrease the risk of both outcomes for up to 9 months, although the differences in absolute numbers, especially in hospitalisations, were small. These findings suggest that if passports are used for societal restrictions, they should acknowledge either a previous infection or vaccination as proof of immunity, as opposed to vaccination only.

Moreira E.D. et al.

Safety and Efficacy of a Third Dose of BNT162b2 Covid-19 Vaccine

The NEJM, https://www.nejm.org/doi/pdf/10.1056/NEJMoa2200674?articleTools=true

CONTENUTO E COMMENTO: Trial clinico controllato randomizzato di fase 3 (giugno-agosto 2021), finalizzato a valutare l’efficacia e la sicurezza di una terza dose booster di vaccino per Sars-CoV2 BNT162b2. In particolare, 5081 partecipanti allo studio hanno ricevuto una terza dose di vaccino e 5044 invece il placebo, almeno a 6 mesi dalle precedenti due dosi di vaccino Pfizer. Per quanto riguarda il profilo di sicurezza nel corso del follow-up (mediana di 2.5 mesi) non sono state riscontrate segnalazioni di nuove reazioni avverse, con la maggior parte delle reazioni di grado lieve e moderato, perlopiù correlate al sito di iniezione. Le reazioni avverse severe sono state riscontrate con maggiore frequenza nel gruppo dei vaccinati rispetto al placebo (0.5% vs 0.3%) Nessun caso di miocardite o pericardite è stato riportato. Per quanto riguarda l’efficacia della dose booster, nel gruppo ricevente il vaccino, solo 6 pazienti sono risultati positivi ad almeno una settimana dalla somministrazione. Viceversa, nel gruppo ricevente il placebo, sono stati 123 i casi di infezione da Sars-CoV2 segnalati. I dati finora acquisiti in fase 2-3 di questo trial mostrano una efficacia complessiva della dose booster del 90%, da 7 giorni fino a 6 mesi dalla somministrazione con una efficacia del 95.3% ad una mediana di 2.5 mesi di follow-up in pazienti senza storia di pregressa infezione. Non sono stati osservati casi di COVID-19 severo nel gruppo di pazienti vaccinati. Sicuramente i risultati preliminari dimostrano l’importanza e l’efficacia di una terza dose booster di vaccino, seppur in tal caso i dati riguardano un periodo storico in cui la variante predominate era la Delta, con limitazioni legate inoltre ai differenti tempi di ricezione della dose booster nella popolazione di studio e alla perdita di partecipanti nel gruppo placebo per permettere la ricezione della terza dose in casi speciifici.

Poopalasingam N. et al.

Determining the reliability of rapid SARS-CoV-2 antigen detection in fully vaccinated individuals

J Clin Virol.,

https://reader.elsevier.com/reader/sd/pii/S1386653222000555?token=D94DF78CF507A4B7DDFC572CCE8B43798838AE7FA0E09A9F5BAE93C528261A4A6107D7A4E328040FCD9E56ADD4069D10&originRegion=eu-west-1&originCreation=20220311154957

CONTENUTO E COMMENTO : Questo studio valuta la capacità diagnostica del test antigenico rapido in soggetti vaccinati. Sono stati arruolati individui vaccinati ai quali sono stati effettuati due tamponi nasofaringei, uno per il test molecolare e l’altro per il test antigenico ; per la comparazione fra vaccinati e non vaccinati è stato utilizzato come riferimento un dataset precedentemente pubblicato dallo stesso gruppo di studio. Sono stati rilevati 76 campioni positivi mediante test molecolare e 45 campioni positivi mediante test antigenico. La sensibilità stratificata in base al numero di cicli (≤20, ≤25 e ≤30) è stata rispettivamente del 100.0%, 94.4% e 81.1% ; nessuno dei 23 campioni risultati positivi all’esame molecolare con cicli ≥30 è stato rilevato come positivo dal test antigenico. Per bassi valori di cicli di amplificazione non è stata documentata differenza di sensibilità in vaccinati o non vaccinati ; per valori medi ed elevati di cicli è stata documentata una ridotta sensibilità del test nei non vaccinati. La specificità del test antigenico è stata del 99.7% e la performance del test non è stata influenzata dalla presenza o meno di sintomi.

 I risultati dello studio confermano l’estrema utilità del test antigenico per valori elevati valori di carica virale, mantenendo un eccellente potere diagnostico anche nei soggetti vaccinati, mentre, come già ampiamente osservato in precedenti studi, si conferma essere poco sensibile in presenza di basse cariche virali.

Miyamoto S. Et al.

Vaccination-infection interval determines cross-neutralization potency to SARS-CoV-2 Omicron after breakthrough infection by other variants

Med 2022, https://linkinghub.elsevier.com/retrieve/pii/S2666634022000897

CONTENUTO E COMMENTO: : Studio condotto su 30 campioni di individui con 2 dosi di vaccino BNT162b2 testati tramite neutralization assay su VSV pseudovirus e virus vivo. Da questo studio emerge un’importante perdita della potenza neutralizzante nel tempo contro omicron in entrambi gli assay (di 18,5 e 8 volte per gli assay a pseudovirus e virus vivo al tempo precoce (30 giorni) e 5,4 e 3 volte al tempo tardivo (10 giorni). I sieri degli individui con infezioni breakthrough sostenute da variani alpha e delta e vaccinazione BNT162b2 hanno potenza crossneutralizzante maggiore contro la variante omicron e a livelli comparabili a quelli di altre varianti, mentre i sieri dei vaccinati senza infezione breakthrough hanno una potenza neutralizzante contro omicron molto minore. Sembrerebbe inoltre che i sieri degli individui con infezione delta abbiano una attivita’ crossneutralizzante contro omicron maggiore che coloro con infezione alpha.  In piu’, un piu’ lungo intervallo tra vaccinazione e infezione breakthrough si e’ mostrato ottimale per una migliore risposta anticorpale contro la variante omicron nei sieri di individui con infezione breakthrough non omicron, sia come potenza che come ampiezza della risposta. Il grado di correlazione tra attivita’ neutralizzante e intervallo di vaccinazione-infezione e’ maggiore per le varianti beta e omicron, mentre per la variante delta il pattern e’ completamente diverso. Le infezioni breakthrough dopo vaccinazione hanno sviluppato una robusta risposta crossneutralizzante contro molte varianti di SARS-CoV2, dovuta in larga parte alle cellule B della memoria indotte dalla precedente vaccinazione.

LIMITI: piccolo campione, fattori confondenti come la severita’ di patologia non affrontati, non accurate stima degli ordini di grandezza dei titoli neutralizzanti nei partecipanti senza infezioni breakthrough, non considerati sieri raccolti immediatamente dopo l’infezione breakthrough, non studiata correlazione tra attivita’ neutralizzante e replicazione in vivo, non studiata la dose booster.

Stegger M, et al.

Occurrence and significance of Omicron BA.1 infection followed by BA.2 reinfection

MedRxiv, https://www.medrxiv.org/content/10.1101/2022.02.19.22271112v1

CONTENUTO E COMMENTO: Grosso studio danese (non ancora peer-reviewed) condotto sui dati raccolti da diversi registri nazionali tra il 22 novembre 2021 e il 11 febbraio 2022.

In questo lasso di tempo, su un totale di 1,8 milioni di casi di infezione, 187 individui hanno sviluppato reinfezione (definita come il riscontro di due tamponi positivi a distanza di minimo 20 - 60 giorni l’uno dall’altro) e, tra questi, 47 sono stati reinfettati dalla sottovariante BA.2 dopo infezione da BA.1. 

Tale studio conferma la possibilità di re-infezione precoce da BA.2 in seguito a infezione da BA.1. Inoltre, lo studio mette in risalto come la popolazione di re-infetti fosse costituita principalmente da soggetti giovani non vaccinati, e come nessuna di queste reinfezioni sia evoluta verso ricovero o malattia severa.

Hammerman A. et al.

Effectiveness of the BNT162b2 Vaccine after Recovery from Covid-19

NEJM, https://www.nejm.org/doi/full/10.1056/NEJMoa2119497

CONTENUTO E COMMENTO : : studio osservazionale retrospettivo di coorte effettuato sui dati medici elettronici di partecipanti iscritti al sistema Clalit Health Services che fossero guariti da un’infezione da SARS-CoV2 documentata da almeno 100 giorni e prima di aver ricevuto qualunque vaccinazione, nel il 23 agosto 2020 e il 31 maggio 2021.

Dei 149032 inclusi, 65676 non eranovaccinati alla fine dellostudio mentre 83356 loerano (BNT162b2) : analizzando l’outcomeprimario (tasso di reinfezione) dell’interacoorte, ci sono stati 354 reinfezionineivaccinati (2,46 casi per 100 000 persone al giorno) e 2168 nei non vaccinati (10,21 casi per 100 000 persone al giorno).

Neipazientisopra i 65 anni, ci sono state 28 reinfezionisu 9384 vaccinati (1,4 casi/100 000 persone/giorno) e 48 su 4799 nei non vaccinati (3,02). L’HR aggiustato per reinfezione nei vaccinati vs non vaccinatiera di 0.18 (95% intervallo di confidenza [CI], 0.16 a 0.20) neipazientitra i 16 e I 64 anni e 0.40 (95% CI, 0.24 a 0.64) tracolorodai 65 anni in su. Pertanto l’efficacia vaccinale stimataera 82% (95% CI, 80 a 84) neipazienti piu’ giovani e 60% (95% CI, 36 a 76) neipartecipantidai 65 anni in su.

Focalizzandosiinvecesul’outcome secondario (efficacia vaccinale tracolorocheavesseropoiricevutouna o due dosi), 67560 (81%) hannoricevutouna dose, 15251 (0.7%) due, e 545 (0.7%) tre. L’HR aggiustato per reinfezioneneipazienti con una dose rispetto a quelli con due era di 0.98 (95% CI, 0.64 a 1.50).

E’ evidente come la vaccinazione con BNT162b2 protegga contro la reinfezioneneipazienticheabbianogia’ avuto l’infezione, sebbene in misura minore neipazientisopra i 65 anni. L’analisi secondaria ha mostrato come l’aumento del numero di dosi in questocampione non siaassociato a unamiglioreefficacia.

LIMITAZIONI : studio real world con molti fattori confondenti non controllati ; esposizione a SARS-CoV2 variabilenel corso dello studio ; casidefiniti da RTqPCR per cuipossibileesclusione dei pazientipositivi ma non testati (ipotesiche i vaccinati con patologia piu’ lieve non si sianotestati, ma effettuandoun’analisisultasso di testinggenerale, questoera piu’ frequentenelgruppovaccinato); non analisi di gravita’, ospedalizzazione o morte ; analizzata la solaefficacia del vaccino BNT162b2.

Altarawneh HN; et al.

Protection against the Omicron Variant from Previous SARS-CoV-2 Infection

NEJM, https://www.nejm.org/doi/full/10.1056/NEJMc2200133

CONTENUTO E COMMENTO : Grosso studio caso-controllo condotto in Qatar su dati estratti da un database nazionale, analizzante il rischio di re-infezione (definito come tampone PCR nuovamente positivo a distanza di almeno 90 giorni da una positività precedente) da variante Omicron in seguito ad infezione da una diversa variante, escludendo dall’analisi gli individui vaccinati. Casi (PCR + con meno di 30 cicli di replicazione) e controlli (PCR -) sono stati appaiati per genere, classe di età, nazionalità, e data di positivizzazione.

Nei risultati, l’intervallo di tempo mediano tra infezione iniziale e reinfezione è stato, rispettivamente, 279, 254 e 314 giorni per le varianti Alpha, Delta e Omicron. Invece, l’efficacia di una iniziale infezione nel prevenire l’incidenza di re-infezione si è dimostrata del 90% e 96% nei confronti delle varianti Alpha e Delta, mentre solo del 56% nei confronti della variante Omicron. Infine, l’efficacia nel prevenire la malattia severa si è dimostrata essere, rispettivamente, del 70%, 100% e 88% per le varianti Alpha, Delta e Omicron.

Kojima N et al

Protective immunity after recovery from SARS-CoV-2 infection

Lancet Infect Dis., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8575467/pdf/main.pdf

CONTENUTO E COMMENTO : « Comment » sulla prestigiosa rivista « Lancet Infectious Diseases » riguardo allo sviluppo di immunità protettiva in seguito all’infezione da SARS-CoV-2. Gli autori hanno revisionato diversi studi epidemiologici e clinici pubblicati negli ultimi due anni, alcuni dei quali condotti durante il periodo della variante « delta », che mostrano una riduzione del rischio di reinfezione da SARS-CoV-2 del 80.5-100% in chi ha precedentemente sviluppato COVID-19. Vengono presentati altri studi che mostrano bassissimi tassi di reinfezione in chi ha già avuto una prima infezione da SARS-CoV-2. Non è chiaro ancora quanto duri l’immunità in seguito a una prima infezione, sebbene alcuni lavori lascino intendere che la protezione duri fino a 10 mesi. Gli autori si soffermano  sul fatto che la determinazione degli anticorpi rappresenti solo un parziale predittore della risposta immunitaria, che è costituita anche da una non trascurabile componente cellulare. L’articolo si chiude con una riflessione sull’utilità della vaccinazione nei soggetti guariti dall’infezione da SARS-CoV-2 : gli autori sono infatti dell’idea che chi guarisce da COVID-19 dovrebbe essere considerato alla stregua di un soggetto vaccinato, in quanto a partecipazione ad eventi pubblici, possibilità di lavorare o di viaggiare.

Goldberg Y et al.

Waning Immunity after the BNT162b2 Vaccine in Israel

NEJM, https://www.nejm.org/doi/full/10.1056/NEJMoa2114228

CONTENTUO : Studio esplorante le ragioni del recente aumento di casi di COVID-19 in Israele, paese che ha implementato un’efficace campagna di vaccinazione di massa a partire da dicembre 2020. Analizzando i dati di quasi 5 milioni di soggetti, nel periodo compreso tra l’11 e il 31 luglio, si è visto che il rischio di contrarre un’infezione “breakthrough” aumenta significativamente già a distanza di due mesi dalla vaccinazione, e tale riscontro è risultato valido per tutte le fasce d’età. Secondo gli autori, una possibile spiegazione di questo fenomeno può essere l’avvento della variante Delta.

COMMENTO: Israele, mediante una collaborazione attuata con Pfizer, ha ottenuto per primo una quantità di vaccini sufficiente ad effettuare una vaccinazione di massa della popolazione, già a partire da dicembre 2020. In questo modo ha dominato l’epidemia praticamente azzerando i casi, il che ha consentito il ritorno a una “vita normale”. Ma a seguito dell’avvento della variante Delta è stata riscontrata la riemergenza di infezioni e di malattia grave in un numero consistente di soggetti completamente vaccinati. Il  dato è stato riscontrato in percentuali significative anche nella fascia di età 40-59 anni, oltre che nei soggetti con più di 60 anni. Questo studio è stato lo studio più significativo che raccomanda l’adozione della terza dose non solo per i soggetti più fragili e anziani.

Milne G.

Does infection with or vaccination against SARS-CoV-2 lead to lasting immunity?

Lancet Respiratory Medicine, https://www.thelancet.com/action/showPdf?pii=S2213-2600%2821%2900407-0

CONTENUTO E COMMENTO: Questo lavoro ci riporta all’annosa questione della reinfezione da SARS-CoV-2. Approfondire tale problematica è necessaria a comprendere la continua evoluzione dell’epidemiologia di questo virus. Gli autori trovano che le evidenze di alcuni studi e di ampio studi osservazionali, coerentemente con la ricerca sul altri virus respiratori comuni, una risposta immunologica protettiva dura per circa 5-12 mesi dall’infezione primaria, con la reinfezione più probabile data una risposta umorale priamria insifficientemente robusta.

Bergwerk M et al.

Covid-19 Breakthrough Infections in Vaccinated Health Care Workers

NEJM, https://www.nejm.org/doi/full/10.1056/NEJMoa2109072

CONTENUTO: Studio prospettico di incidenza di infezioni “breakthrough” tra gli operatori sanitari del più grande ospedale isreaeliano. Su 1497 operatori sanitari vaccinati, sono state documentate 39 infezioni. In tali soggetti, la quantità di anticorpi neutralizzanti presenti nel periodo peri-infezione è risultata significativamente minore rispetto ai controlli non infetti e, anche tra chi è andato incontro a infezione “breakthrough”, la quantità di anticorpi neutralizzanti peri-infezione è risultata inversamente correlata con l’infettività. Dal punto di vista clinico, tutte le infezioni sono risultate paucisintomatiche.

COMMENTO: Questo studio retrospettivo condotto su operatori sanitari vaccinati evidenzia alcuni punti di sicuro interesse: 1) un rapporto di proporzionalità inversa fra alti titoli di anticorpi neutralizzanti e elevato carico virale con i casi di recidive (39 su 1.497 vaccinati); 2) la presenza di malattia lieve o di infezione asintomatica in questi soggetti; 3) l’assenza di infezioni secondarie.

In sostanza mentre non è tuttora chiaramente definito il ruolo dei test voirologici, lo studio prospetta l’importanza di correlare il titolo anticorpale con la protezione di fronte a recidive o reinfezioni.

Townsend JP, et al.

Lancet Microbe

The durability of immunity against reinfection by SARS-CoV-2: a comparative evolutionary study

Lancet Microbe, https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(21)00219-6/fulltext

CONTENUTO : Studio combinante i dati provenienti da (1) analisi filogenetica di 174 genomi di coronavirus umani (2) espressione quantitativa di IgG anti-coronavirus e (3) incidenza di eventi di reinfezione al fine di stimare la probabilità di reinfezione da SARS-CoV2 in un contesto epidemiologico di endemia (malattia stabilmente presente a livello di una specifica popolazione). Analizzando questi dati, lo studio stima che le reinfezioni da SARS-CoV2, in un contesto di endemia, incorreranno con una frequenza mediana di 16 mesi, quindi significativamente più spesso rispetto agli attuali coronavirus endemici umani.

COMMENTO: Lo studio affronta un problema molto attuale sotto il profilo di sanità pubblica e in particolare di policy vaccinale, anche in Italia. Il dato del declino dell’immunità conferita dal superamento della COVID e del conseguente rischio di reinfezione, conferma la necessità di vaccinare anche i soggetti che hanno avuto la COVID-19 in qualsiasi espressività clinica.

Caputo V. et al.

Age and Sex Modulate SARS-CoV-2 Viral Load Kinetics: A Longitudinal Analysis of 1735 Subjects.

J Pers Med., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8470027/pdf/jpm-11-00882.pdf

CONTENUTO : Studio con un’ampia numerosità campionaria (1735 soggetti) che mira a valutare le differenze nella durata dell’infezione e la carica virale fra i pazienti con infezione da ceppo originale e i pazienti con infezione da ceppi varianti. Rispetto ai pazienti con infezione da ceppo originale, i pazienti con infezione da variante alfa sembrano avere un’infezione più duratura e una carica virale più alta, a fronte di una simile velocità di decremento della carica virale. Inoltre i pazienti di sesso maschile sembrano avere cariche virali più elevate e un più rapido decremento della carica virale, mentre i pazienti con infezione da ceppo originale che mostrano un decremento più lento della carica virale sembrano essere più anziani.

COMMENTO: Lo studio fornisce un quadro della cinetica della carica virale nel corso della storia naturale dell’infezione da SARS-CoV-2. Gli autori identificano alcuni dei determinanti che influenzano la cinetica (come ad esempio: età e sesso) e forniscono informazioni utili per la gestione clinica individualizzata dei soggetti infetti.

I dati vanno inseriti in un contesto più ampio e moderno della medicina personalizzata/medicina di  precisione che prevede che, anche nel caso delle infezioni virali, il management del paziente tenga nel dovuto conto non solo i dati clinici e eziopatogenetici ma anche le caratteristiche genotipiche e fenotipiche (genetica, ambiente, stile di vita ecc.) del paziente.

European Centre for Disease Prevention and Control (ECDC)

Assessing SARS-CoV-2 circulation, variants of concern, non-pharmaceutical interventions and vaccine rollout in the EU/EEA, 16th update.

https://www.ecdc.europa.eu/sites/default/files/documents/covid-19-rapid-risk-assessment-16th-update-september-2021.pdf

CONTENUTO: Si tratta dell’ultimo report dell’ECDC, uscito il 30.09.2021, che riporta i dati europei sulla circolazione di SARS-CoV-2, sul rischio rappresentato dalla circolazione delle varianti, sui tassi di copertura vaccinale ecc.

Tra i dati nuovi rilevati in questo report molto aggiornato ed interessante, ci sono i dati aggiornati sulla sieroprevalenza e la reinfezione da SARS-CoV-2, nonché le prove disponibili sull'efficacia del vaccino COVID-19 e sul declino dell'immunità.

COMMENTO : interessante articolo dove si riportano i casi dovuti alla variante delta in europa dove si e arrivati ad una prevalenza del 99%

Nell articolo si discute come inequivocabilmente la vaccinazione limitando la circolazione virale ha limitato il numero di infezioni.

Twohig KA et al.

Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B.1.617.2) compared with alpha (B.1.1.7) variants of concern: a cohort study

Lancet Infectious Diseases, https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00475-8/fulltext

CONTENUTO: Grosso studio confrontante il rischio di ospedalizzazione e accesso in pronto soccorso tra pazienti infetti dalla variante Delta e pazienti infetti da variante Alpha. Tra i 43.338 soggetti coinvolti, i pazienti infetti da variante Delta hanno presentato un più alto rischio di presentarsi in pronto soccorso entro 14 giorni dalla diagnosi. Tali risultati suggeriscono che la diffusione della variante Dealta tra soggetti non vaccinati si riflette su più alti livelli di stress a carico del sistema sanitario.

COMMENTO: : Questa pubblicazione evidenzia per i pazienti affetti da SARS-CoV-2 un significativo rischio relativo (aHR) globale di ospedalizzazione e ricovero in terapia intensiva. Questo rischio relativo è più elevato per i pazienti affetti dalla variante delta rispetto alla variante alfa. Il 74% dei pazienti nello studio non era vaccinato sia nel gruppo alfa che nel gruppo delta e il differente rischio relativo fra le due varianti, più elevato nel gruppo delta, si riscontrava sia nei soggetti vaccinati che non vaccinati. Questi dati suggeriscono che alla variante delta, rispetto alla variante alfa, vada attribuita una maggiore trasmissibilità ma anche una più grave espressività clinica.

Brinkley-Rubinstein L et al

Breakthrough SARS-CoV-2 Infections in Prison after Vaccination

NEJM, July 2021 ; DOI: 10.1056/NEJMc2108479

COMMENTO : We conducted a study to analyze weekly PCR test results that were obtained in the RIDOC system from March 9 to May 6, 2021. RIDOC policy includes a 10-day isolation period for all persons who have symptoms or a positive Covid-19 test. A test-based end-of-isolation strategy was initiated on March 10. According to this protocol, if negative results were obtained on two PCR tests

that had been performed 24 hours apart, isolation could end early.

Rennert L et al

Risk of SARS-CoV-2 reinfection in a university student population

CID, May 2021; doi.org/10.1093/cid/ciab454

COMMENTO : We assess protection from previous SARS-CoV-2 infection in a population of 16,101 university students (2,021 with and 14,080 without previous infection). The risk of re-infection during the Spring 2021 semester was 2.2% among previously infected students; estimated protection from previous SARS-CoV-2 infection was 84% (95% CI: 78%-88%).

The Centers for Disease Control and Prevention MMWR Morb Mortal Wkly Rep

COVID-19 Vaccine Breakthrough Infections Reported to CDC — United States, January 1–April 30, 2021

https://www.cdc.gov/mmwr/volumes/70/wr/mm7021e3.htm?s_cid=mm7021e3_w#suggestedcitation

COMMENTO: A total of 10,262 SARS-CoV-2 vaccine breakthrough infections had been reported from 46 U.S. states and territories as of April 30, 2021. Among these cases, 6,446 (63%) occurred in females, and the median patient age was 58 years (interquartile range = 40–74 years). Based on preliminary data, 2,725 (27%) vaccine breakthrough infections were asymptomatic, 995 (10%) patients were known to be hospitalized, and 160 (2%) patients died. Among the 995 hospitalized patients, 289 (29%) were asymptomatic or hospitalized for a reason unrelated to COVID-19. The median age of patients who died was 82 years (interquartile range = 71–89 years); 28 (18%) decedents were asymptomatic or died from a cause unrelated to COVID-19. Sequence data were available from 555 (5%) reported cases, 356 (64%) of which were identified as SARS-CoV-2 variants of concern,§ including B.1.1.7 (199; 56%), B.1.429 (88; 25%), B.1.427 (28; 8%), P.1 (28; 8%), and B.1.351 (13; 4%).

Zhang L et al

Reverse-transcribed SARS-CoV-2 RNA can integrate into the genome of cultured human cells and can be expressed in patient-derived tissues

PNAS, May 2021; doi.org/10.1073/pnas.2105968118

COMMENTO : Prolonged detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and recurrence of PCR-positive tests have been widely reported in patients after recovery from COVID-19, but some of these patients do not appear to shed infectious virus. We investigated the possibility that SARS-CoV-2 RNAs can be reverse-transcribed and integrated into the DNA of humancells in culture and that transcription of the integrated sequences might account for some of the positive PCR tests seen in patients. In support of this hypothesis, we found that DNA copies of SARS-CoV-2 sequences can be integrated into the genome of infected humancells. We found target site duplications flanking the viral sequences and consensus LINE1 endonuclease recognition sequences at the integration sites, consistent with a LINE1 retrotransposon-mediated, target-primed reverse transcription and retropositionmechanism. We also found, in some patient-derived tissues, evidence suggesting that a large fraction of the viral sequencesis transcribed from integrated DNA copies of viral sequences, generating viral–host chimeric transcripts. The integration and transcription of viral sequences may thus contribute to the detection of viral RNA by PCR in patients after infection and clinical recovery. Because we have detected only subgenomic sequences derived mainly from the 3′ end of the viral genome integrated into the DNA of the host cell, infectious virus cannot be produced from the integrated subgenomic SARS-CoV-2 sequences.

Amorim MR et al

Respiratory Viral Shedding in Healthcare Workers Reinfected with SARS-CoV-2, Brazil, 2020

Emerging Infectious Diseases, April 2021; doi.org/10.3201/eid2706.210558

COMMENTO : We documented 4 cases of severe acute respiratory syndrome coronavirus 2 reinfection by non–variant of concern strains among health car eworkers in Campinas, Brazil. We isolated infectious particles from nasopharyngeal secretions during both infection episodes. Improved and continued protection measures are necessary to mitigate the risk for reinfection among healthcare workers.

Hall VJ et al

SARS-CoV-2 infection rates of antibody-positive compared with antibody-negative health-care workers in England: a large, multicentre, prospective cohort study (SIREN)

The Lancet, April 2021; doi.org/10.1016/S0140-6736(21)00675-9

COMMENTO : Background : Increased understanding of whether individuals who have recovered from COVID-19 are protected from future SARS-CoV-2 infection is an urgent requirement. We aimed to investigate whether antibodies against SARS-CoV-2 were associated with a decreased risk of symptomatic and asymptomatic reinfection.

Methods : A large, multicentre, prospective cohort study was done, with participants recruited from publicly funded hospitals in all regions of England. All health-care workers, support staff, and administrative staff working at hospitals who could remain engaged in follow-up for 12 months were eligible to join The SARS-CoV-2 Immunity and Reinfection Evaluation study. Participants were excluded if they had no PCR tests after enrolment, enrolled after Dec 31, 2020, or had insufficient PCR and antibody data for cohort assignment. Participants attended regular SARS-CoV-2 PCR and antibody testing (every 2–4 weeks) and completed questionnaires every 2 weeks on symptoms and exposures. At enrolment, participants were assigned to either the positive cohort (antibody positive, or previous positive PCR or antibody test) or negative cohort (antibody negative, no previous positive PCR or antibody test). The primary outcome was a reinfection in the positive cohort or a primary infection in the negative cohort, determined by PCR tests. Potential reinfections were clinically reviewed and classified according to case definitions (confirmed, probable, or possible) and symptom-status, depending on the hierarchy of evidence. Primary infections in the negative cohort were defined as a first positive PCR test and seroconversions were excluded when not associated with a positive PCR test. A proportional hazards frailty model using a Poisson distribution was used to estimate incidence rate ratios (IRR) to compare infection rates in the two cohorts.

Findings : From June 18, 2020, to Dec 31, 2020, 30 625 participants were enrolled into the study. 51 participants withdrew from the study, 4913 were excluded, and 25 661 participants (with linked data on antibody and PCR testing) were included in the analysis. Data were extracted from all sources on Feb 5, 2021, and include data up to and including Jan 11, 2021. 155 infections were detected in the baseline positive cohort of 8278 participants, collectively contributing 2 047 113 person-days of follow-up. This compares with 1704 new PCR positive infections in the negative cohort of 17 383 participants, contributing 2 971 436 person-days of follow-up. The incidence density was 7·6 reinfections per 100 000 person-days in the positive cohort, compared with 57·3 primary infections per 100 000 person-days in the negative cohort, between June, 2020, and January, 2021. The adjusted IRR was 0·159 for all reinfections (95% CI 0·13–0·19) compared with PCR-confirmed primary infections. The median interval between primary infection and reinfection was more than 200 days.

Interpretation : A previous history of SARS-CoV-2 infection was associated with an 84% lower risk of infection, with median protective effect observed 7 months following primary infection. This time period is the minimum probable effect because seroconversions were not included. This study shows that previous infection with SARS-CoV-2 induces effective immunity to future infections in most individuals.

Klein J et al

Case Study: Longitudinal immune profiling of a SARS-CoV-2 reinfection in a solid organ transplant recipient

medRXiv – not peer reviewed, March 2021;  doi.org/10.1101/2021.03.24.21253992

COMMENTO : Prior to the emergence of antigenically distinct SARS-CoV-2 variants, reinfections were reported infrequently - presumably due to the generation of durable and protective immune responses. However, case reports also suggested that rare, repeated infections may occur as soon as 48 days following initial disease onset. The underlying immunologic deficiencies enabling SARS-CoV-2 reinfections are currently unknown. Here we describe a renal transplant recipient who developed recurrent, symptomatic SARS-CoV-2 infection - confirmed by whole virus genome sequencing - 7 months after primary infection. To elucidate the immunological mechanisms responsible for SARS-CoV-2 reinfection, we performed longitudinal profiling of cellular and humoral responses during both primary and recurrent SARS-CoV-2 infection. We found that the patient responded to the primary infection with transient, poor-quality adaptive immune responses. The patient’s immune system was further compromised by intervening treatment for acute rejection of the renal allograft prior to reinfection. Importantly, we also identified the development of neutralizing antibodies and the formation of humoral memory responses prior to SARS-CoV-2 reinfection. However, these neutralizing antibodies failed to confer protection against reinfection, suggesting that additional factors are required for efficient prevention of SARS-CoV-2 reinfection. Further, we found no evidence supporting viral evasion of primary adaptive immune responses, suggesting that susceptibility to reinfection may be determined by host factors rather than pathogen adaptation in this patient. In summary, our study suggests that a low neutralizing antibody presence alone is not sufficient to confer resistance against reinfection. Thus, patients with solid organ transplantation, or patients who are otherwise immunosuppressed, who recover from infection with SARS-CoV-2 may not develop sufficient protective immunity and are at risk of reinfection.

Sheehan MM et al

Reinfection Rates among Patients who Previously Tested Positive for COVID-19: a Retrospective Cohort Study

Clinical Infectious Diseases, March 2021; doi.org/10.1093/cid/ciab234

COMMENTO : Protection afforded from prior disease among patients with coronavirus disease 2019 (COVID-19) infection is unknown. If infection provides substantial long-lasting immunity, it may be appropriate to reconsider vaccination distribution plans.

Methods : This retrospective cohort study of one multi-hospital health system included 150,325 patients tested for COVID-19 infection via PCR from March 12, 2020 to August 30, 2020. Testing performed up to February 24, 2021 in these patients was included for analysis. The main outcome was reinfection, defined as infection ≥ 90 days after initial testing. Secondary outcomes were symptomatic infection and protection of prior infection against reinfection.

Results : Of 150,325 patients, 8,845 (5.9%) tested positive and 141,480 (94.1%) tested negative prior to August 30. 1,278 (14.4%) of the positive patients were retested after 90 days, and 62 had possible reinfection. Of those, 31 (50%) were symptomatic. Of those with initial negative testing, 5,449 (3.9%) were subsequently positive and 3,191 of those (58.5%) were symptomatic. Protection offered from prior infection was 81.8% (95% confidence interval 76.6 to 85.8), and against symptomatic infection was 84.5% (95% confidence interval 77.9 to 89.1). This protection increased over time.

Conclusions : Prior infection in patients with COVID-19 was highly protective against reinfection and symptomatic disease. This protection increased over time, suggesting that viral shedding or ongoing immune response may persist beyond 90 days and may not represent true reinfection. As vaccine supply is limited, patients with known history of COVID-19 could delay early vaccination to allow for the most vulnerable to access the vaccine and slow transmission

Dan J et al

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Immunity and Reinfection

Clinical Infectious Diseases, January 2021 ; doi.org/10.1093/cid/ciaa1936

COMMENTO: Establishing reinfection or recrudescence of SARS-CoV-2 is not a simple feat. A few case reports have demonstrated phylogenetic confirmation of reinfection [5–7]. It is well established that viral RNA can be detected in the nasopharynx many months after initial infection, particularly in immunocompromised individuals. Demonstrating reinfection necessitates phylogenetic analyses to confirm that a virus detected during subsequent illness is a unique variant. This is made even more difficult by the relatively slow evolutionary rate of SARS-CoV-2, driven by the proofreading ability of SARS-CoV-2 viral polymerase complex.

Lee JT et al

Clinical and Laboratory Findings in Patients with Potential SARS-CoV-2 Reinfection, May–July 2020

Clinical Infectious Diseases, February 2021; DOI: 10.1093/cid/ciab148

COMMENTO: Background : Weinvestigated patients withpotential SARS-CoV-2 reinfection in the United States during May–July 2020.

Methods : Weconducted case finding for patients withpotential SARS-CoV-2 reinfectionthrough the Emerging Infections Network. Cases reportedwerescreened for laboratory and clinicalfindings of potential reinfection followed by requests for medical records and laboratoryspecimens. Availablemedical records wereabstracted to characterize patient demographics, comorbidities, clinical course, and laboratory test results. Submitted specimens under wentfurther testing, including RT-PCR, viral culture, who legenome sequencing, subgenomic RNA PCR, and testing for anti-SARS-CoV-2 total antibody.

Results : Among 73 potential reinfection patients with available records, 30 patients had recurrent COVID-19 symptoms explained by alternative diagnoses with concurrent SARS-CoV-2 positive RT-PCR, 24 patients remained asymptomatic after recovery but had recurrent or persistent RT-PCR, and 19 patients had recurrent COVID-19 symptoms with concurrent SARS-CoV-2 positive RT-PCR but no alternative diagnoses. These 19 patients had symptom recurrence a median of 57 days after initial symptom onset (interquartile range: 47 – 76). Six of these patients had paired specimens available for furthertesting, but none had laboratory findings confirming reinfections. Testing of an additionalthree patients withrecurrent symptoms and alternative diagnoses also did not confirm reinfection.

Conclusions : We did not confirm SARS-CoV-2 reinfection within 90 days of the initial infection based on the clinical and laboratory characteristics of cases in this investigation. Our findings support current CDC guidance around quarantine and testing for patients who have recovered from COVID-19.

Reuken PA et al

Severe clinical relapse in an immunocompromised host with persistent SARS-CoV-2 infection

Leukemia, February 2021; doi.org/10.1038/s41375-021-01175-8

COMMENTO : Whether people who have recovered from COVID-19 can be re-infected by SARS-CoV-2 is a matter of debate. Antibodiesagainst SARS-CoV-2 can bedetected in up to 98.6% of patients after infection, but onlyin 67% of patients with CLL. In thiscontext, anti-CD20 therapyis of specialinterest, as the memory B-cells are crucial for the development of immunityagainst SARS-CoV-2. A recentstudyfrom China has revealedthat the failure to mount a robust humoral responseagainst SARS-CoV-2 is associated with re-detection of SARS-CoV-2 in 7.3% of patients. In addition, patients with hematological malignancies are also more vulnerable to a severe course.

Lumley SF et al

Antibody Status and Incidence of SARS-CoV-2Infection in Health Care Workers

NEJM, 23 December 2020; DOI: 10.1056/NEJMoa2034545

COMMENTO : BACKGROUND : The relationshipbetween the presence of antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the risk of subsequentreinfection remains unclear.

METHODS : Weinvestigated the incidence of SARS-CoV-2 infection confirmed by polymerasechainreaction (PCR) in seropositive and seronegativehealth care workersattendingtesting of asymptomatic and symptomatic staff at Oxford UniversityHospitalsin the United Kingdom. Baseline antibodystatuswasdetermined by anti-spike(primaryanalysis) and anti-nucleocapsid IgG assays, and staff memberswerefollowed for up to 31 weeks. We estimated the relative incidence of PCR-positive testresults and new symptomatic infection according to antibodystatus, adjusting forage, participant-reportedgender, and changes in incidence over time.

RESULTS : A total of 12,541 health care workers participated and had anti-spike IgG measured; 11,364 were followed up after negative antibody results and 1265 after positive results, including 88 in whom seroconversion occurred during follow-up. A total of 223 anti-spike–seronegative health care workers had a positive PCR test (1.09 per 10,000 days at risk), 100 during screening while they were asymptomatic and 123 while symptomatic, whereas 2 anti-spike–seropositive health care workers had a positive PCR test (0.13 per 10,000 days at risk), and both workers were asymptomatic when tested (adjusted incidence rate ratio, 0.11; 95% confidence interval, 0.03 to 0.44; P=0.002). There were no symptomatic infections in workerswithanti-spike antibodies. Rate ratios weresimilarwhen the anti-nucleocapsid IgG assay was used alone or in combination with the anti-spike IgG assay to determine baseline status.

CONCLUSIONS : The presence of anti-spike or anti-nucleocapsid IgG antibodies was associated with a substantially reduced risk of SARS-CoV-2 reinfection in the ensuing 6 months.

Hall V et al

Do antibody positive healthcare workers have lower SARS-CoV-2 infection rates than antibody negative healthcare workers? Large multi-centre prospective cohort study (the SIREN study), England: June to November 2020

MedRXiv, 15 January 2021; doi.org/10.1101/2021.01.13.21249642

COMMENTO : Background There is an urgent need to betterunderstandwhetherindividualswho have recoveredfrom COVID-19 are protectedfrom future SARS-CoV-2 infection.

Methods A large multi-centre prospective cohortwasrecruitedfrompubliclyfundedhospital staff in the UK. Participants attendedregular SARS-CoV-2 PCR and antibodytesting (every 2-4 weeks) and completedfortnightly questionnaires on symptoms and exposures. At enrolment, participants wereassigned to either the positive cohort (antibody positive or prior PCR/antibody test positive) or negativecohort (antibodynegative, not previouslyknown to bePCR/antibody positive). Potentialreinfectionswereclinicallyreviewed and classifiedaccording to case definitions (confirmed, probable, possible (subdivided by symptom-status)) depending on hierarchy of evidence. Individuals in the primary infection wereexcludedfromthisanalysis if infection wasconfirmed by antibodyonly. Reinfection rates in the positive cohortwerecomparedagainst new PCR positives in the negativecohortusing a mixed effective multivariable logisticregressionanalysis.

Findings Between 18 June and 09 November 2020, 44 reinfections (2 probable, 42 possible) were detected in the baseline positive cohort of 6,614 participants, collectively contributing 1,339,078 days of follow-up. This compares with 318 new PCR positive infections and 94 antibody seroconversions in the negative cohort of 14,173 participants, contributing 1,868,646 days of follow-up. The incidence density per 100,000 persondaysbetween June and November 2020 was 3.3 reinfections in the positive cohort, comparedwith 22.4 new PCR confirmed infections in the negativecohort. The adjustedodds ratio was 0.17 for all reinfections (95% CI 0.13-0.24) compared to PCR confirmedprimary infections. The medianintervalbetweenprimary infection and reinfectionwas over 160 days.

Interpretation A priorhistory of SARS-CoV-2 infection wasassociatedwith an 83% lowerrisk of infection, withmedian protective effectobserved five monthsfollowingprimary infection. This is the minimum likelyeffect as seroconversionswere not included.

 Vasques Nonaka CK et al

Genomic evidence of a SARS-CoV-2 reinfection case with E484K spikemutation in Brazil

Preprint - not peer reviewed, 6 January 2021;  doi: 10.20944/preprints202101.0132.v1

COMMENTO : To date, uncertainty remains about how long the protective immune responses against SARSCoV-2 persists and the first reports of suspected reinfection began to be described in recovered patients months after the first episode. Viral evolution may favor reinfections, and the recently described spike mutations, particularly in the receptor binding domain (RBD) in SARS-CoV2 lineages circulating in the UK, South Africa, and most recently in Brazil, have raised concern on their potential impact in infectivity and immune escape. We report the first case of reinfection from genetically distinct SARS-CoV-2 lineage presenting the E484K spike mutation in Brazil, a variant associated with escape from neutralizing antibodies.

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