Combinatorial analysis reveals highly coordinated early-stage immune reactions that predict later antiviral immunity in mild COVID-19 patients

Capelle, Christophe; Ciré, Séverine; Domingues, Olivia; Ernens, Isabelle; Hedin, Fanny; Fischer, Aurélie; Snoeck, Chantal J.; Ammerlaan, Wim; Konstantinou, Maria; Grzyb, Kamil; Skupin, Alexander; Carty, Cara L.; Hilger, Christiane; Gilson, Georges; Celebic, Aljosa; Wilmes, Paul; Sol, Antonio del; Kaplan, Ian M.; Betsou, Fay; Abdelrahman, Tamir; Cosma, Antonio; Vaillant, Michel; Fagherazzi, Guy; Ollert, Markus; He, Feng

doi:10.1016/j.xcrm.2022.100600

Cited by 13 publications

(12 citation statements)

References 68 publications

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“…An acute infection can also induce chronic disturbance in immune subsets or an activation of an autoimmune response, which is in line with the relapses observed in long COVID [ 34 ]. In particular autoimmunity can be induced by SARS-CoV-2 virus and is dependent on the initial viral load [ 32 ] and the severity of the disease [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

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Long COVID Symptomatology After 12 Months and Its Impact on Quality of Life According to Initial Coronavirus Disease 2019 Disease Severity

Fischer

Zhang

Elbéji

et al. 2022

Open Forum Infectious Diseases

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Introduction Long COVID is characterized by a variety of symptoms and an important burden for affected people. Our objective was to describe Long COVID symptomatology according to initial COVID-19 severity. Methods Predi-COVID cohort study participants, recruited at the time of acute COVID-19 infection, completed a detailed 12-month symptoms and quality of life questionnaire. Frequencies and co-occurrences of symptoms were assessed. Results Among the 289 participants who fully completed the 12-month questionnaire, 59.5% reported at least one symptom with a median of 6 symptoms. Participants with an initial moderate or severe acute illness declared more frequently one or more symptoms (82.6% vs 38.6%, p < 0.001) and had on average 6.8 more symptoms (CI 95% [4.18; 9.38]) than initially asymptomatic participants who developed symptoms after the acute infection. Overall, 12.5% of the participants could not envisage coping with their symptoms in the long term. Frequently reported symptoms, like neurological and cardiovascular symptoms, but also less frequent such as gastrointestinal symptoms, tended to cluster. Conclusion Frequencies and burden of symptoms present 12 months after acute COVID-19 infection increased with the severity of the acute illness. Long COVID likely consists of multiple sub-categories rather than one single entity. This work will contribute to the better understanding of Long COVID and to the definition of precision health strategies.

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Section: Discussionmentioning

confidence: 99%

“…Disease severity during the acute phase of the disease was defined in 3 categories according to an adapted version of the National Institutes of Health severity classification [ 23 ]: asymptomatic, mild illness and moderate/severe illness, as previously described [ 24 ]. Hospitalized patients were included in the moderate/severe category.…”

Section: Methodsmentioning

confidence: 99%

Long COVID Symptomatology After 12 Months and Its Impact on Quality of Life According to Initial Coronavirus Disease 2019 Disease Severity

Fischer

Zhang

Elbéji

et al. 2022

Open Forum Infectious Diseases

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“…The Omicron Spike protein also adopts a distinct, more compact conformation and glycosylation patterns that shield it from NAbs [ 23 ]. The fact that prior infection and vaccination do not fully protect against infection with Omicron or symptomatic disease but do partly protect against severe disease [ 109 ] suggests that T-cells and memory B-cells [ 27 , 85 , 107 ], as well as other innate immune signatures [ 110 ] are involved.…”

Section: Discussionmentioning

confidence: 99%

Pre-Omicron Vaccine Breakthrough Infection Induces Superior Cross-Neutralization against SARS-CoV-2 Omicron BA.1 Compared to Infection Alone

Silva

Kohnen

Gilson

et al. 2022

IJMS

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SARS-CoV-2 variants raise concern because of their high transmissibility and their ability to evade neutralizing antibodies elicited by prior infection or by vaccination. Here, we compared the neutralizing abilities of sera from 70 unvaccinated COVID-19 patients infected before the emergence of variants of concern (VOCs) and of 16 vaccine breakthrough infection (BTI) cases infected with Gamma or Delta against the ancestral B.1 strain, the Gamma, Delta and Omicron BA.1 VOCs using live virus. We further determined antibody levels against the Nucleocapsid (N) and full Spike proteins, the receptor-binding domain (RBD) and the N-terminal domain (NTD) of the Spike protein. Convalescent sera featured considerable variability in the neutralization of B.1 and in the cross-neutralization of different strains. Their neutralizing capacity moderately correlated with antibody levels against the Spike protein and the RBD. All but one convalescent serum failed to neutralize Omicron BA.1. Overall, convalescent sera from patients with moderate disease had higher antibody levels and displayed a higher neutralizing ability against all strains than patients with mild or severe forms of the disease. The sera from BTI cases fell into one of two categories: half the sera had a high neutralizing activity against the ancestral B.1 strain as well as against the infecting strain, while the other half had no or a very low neutralizing activity against all strains. Although antibody levels against the spike protein and the RBD were lower in BTI sera than in unvaccinated convalescent sera, most neutralizing sera also retained partial neutralizing activity against Omicron BA.1, suggestive of a better cross-neutralization and higher affinity of vaccine-elicited antibodies over virus-induced antibodies. Accordingly, the IC50: antibody level ratios were comparable for BTI and convalescent sera, but remained lower in the neutralizing convalescent sera from patients with moderate disease than in BTI sera. The neutralizing activity of BTI sera was strongly correlated with antibodies against the Spike protein and the RBD. Together, these findings highlight qualitative differences in antibody responses elicited by infection in vaccinated and unvaccinated individuals. They further indicate that breakthrough infection with a pre-Omicron variant boosts immunity and induces cross-neutralizing antibodies against different strains, including Omicron BA.1.

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“…There are limited reports of cellular innate immune responses and their correlation with adaptive immunity. A few recent longitudinal studies have documented the early innate and adaptive immune responses during mild COVID-19 [ 13 , 14 ]; however, no reports identify a correlation of an early innate immune response with the generation of T cell responses in active COVID-19. To address this, we used TLR 3, 7, and 8 agonists to stimulate the PBMCs isolated within three days of PCR diagnosis of mild COVID-19 patients and measured the range and magnitude of innate cytokine release, which were further correlated with the degree of virus-specific T cell responses generated during active COVID-19 in mild cases where the virus was successfully cleared.…”

Section: Introductionmentioning

confidence: 99%

Proinflammatory Innate Cytokines and Distinct Metabolomic Signatures Shape the T Cell Response in Active COVID-19

et al. 2022

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The underlying factors contributing to the evolution of SARS-CoV-2-specific T cell responses during COVID-19 infection remain unidentified. To address this, we characterized innate and adaptive immune responses with metabolomic profiling longitudinally at three different time points (0–3, 7–9, and 14–16 days post-COVID-19 positivity) from young, mildly symptomatic, active COVID-19 patients infected during the first wave in mid-2020. We observed that anti-RBD IgG and viral neutralization are significantly reduced against the delta variant, compared to the ancestral strain. In contrast, compared to the ancestral strain, T cell responses remain preserved against the delta and omicron variants. We determined innate immune responses during the early stage of active infection, in response to TLR 3/7/8-mediated activation in PBMCs and serum metabolomic profiling. Correlation analysis indicated PBMCs-derived proinflammatory cytokines, IL-18, IL-1β, and IL-23, and the abundance of plasma metabolites involved in arginine biosynthesis were predictive of a robust SARS-CoV-2-specific Th1 response at a later stage (two weeks after PCR positivity). These observations may contribute to designing effective vaccines and adjuvants that promote innate immune responses and metabolites to induce a long-lasting anti-SARS-CoV-2-specific T cell response.

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Combinatorial analysis reveals highly coordinated early-stage immune reactions that predict later antiviral immunity in mild COVID-19 patients

Cited by 13 publications

References 68 publications

Long COVID Symptomatology After 12 Months and Its Impact on Quality of Life According to Initial Coronavirus Disease 2019 Disease Severity

Long COVID Symptomatology After 12 Months and Its Impact on Quality of Life According to Initial Coronavirus Disease 2019 Disease Severity

Pre-Omicron Vaccine Breakthrough Infection Induces Superior Cross-Neutralization against SARS-CoV-2 Omicron BA.1 Compared to Infection Alone

Proinflammatory Innate Cytokines and Distinct Metabolomic Signatures Shape the T Cell Response in Active COVID-19

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