Impact of SARS-CoV-2 variants on the total CD4+ and CD8+ T cell reactivity in infected or vaccinated individuals
Open accessPublished version of a preprint
Abstract
The emergence of SARS-CoV-2 variants highlighted the need to better understand adaptive immune responses to this virus. It is important to address whether also CD4+ and CD8+ T cell responses are affected, because of the role they play in disease resolution and modulation of COVID-19 disease severity. Here we performed a comprehensive analysis of SARS-CoV-2-specific CD4+ and CD8+ T cell responses from COVID-19 convalescent subjects recognizing the ancestral strain, compared to variant lineages B.1.1.7, B.1.351, P.1, and CAL.20C as well as recipients of the Moderna (mRNA-1273) or Pfizer/BioNTech (BNT162b2) COVID-19 vaccines. Similarly, we demonstrate that the sequences of the vast majority of SARS-CoV-2 T cell epitopes are not affected by the mutations found in the variants analyzed. Overall, the results demonstrate that CD4+ and CD8+ T cell responses in convalescent COVID-19 subjects or COVID-19 mRNA vaccinees are not substantially affected by mutations found in the SARS-CoV-2 variants.
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TL;DR
SARS-CoV-2 variants B.1.1.7, B.1.351, P.1, and CAL.20C did not substantially disrupt total CD4+ or CD8+ T cell reactivity in COVID-19 convalescents or mRNA vaccine recipients. Some assay/variant combinations showed decreases in the 10%–22% range, but these were within technical variability by non-inferiority testing.
Key findings
- Total T cell reactivity against the variants was similar in magnitude and frequency to the ancestral strain, with decreases of 10%–22% in some assay/VOC combinations; 7% of previously identified CD4+ and 3% of CD8+ T cell epitopes were affected by mutations in the variants.
- In convalescents, AIM assays showed no significant differences for S variants; FluoroSPOT showed significant IFN-γ decreases of 12%, 6%, and 14% for B.1.1.7, B.1.351, and CAL.20C, respectively, but no difference for P.1, and fold-change/non-inferiority analyses indicated these were within technical fluctuation.
- In vaccinees, B.1.351 showed decreases of 14% for CD4+ and 22% for CD8+ T cells, and CAL.20C showed a 10% decrease for CD8+ T cells; B.1.1.7 and P.1 showed no significant differences, and non-inferiority testing found no biologically meaningful reduction.
- Epitope conservation analysis found 89.6%–97.1% (average 93%) of CD4+ epitopes and 97.1%–97.9% of CD8+ epitopes conserved across variants; by response magnitude, conserved epitopes accounted for averages of 91.5% (CD4+) and 98.1% (CD8+).
Methods
- Combined experimental and bioinformatics study using PBMCs from 28 COVID-19 convalescents, 29 mRNA vaccine recipients (14 Pfizer/BioNTech BNT162b2, 15 Moderna mRNA-1273), and 23 unexposed controls.
- T cell reactivity was measured by activation-induced marker (AIM) assays (OX40+CD137+ for CD4+, CD69+CD137+ for CD8+) and IFN-γ/IL-5 FluoroSPOT, using peptide megapools spanning the ancestral Wuhan sequence and B.1.1.7, B.1.351, P.1, and CAL.20C variants.
- Bioinformatics used NetMHCpan BA 4.1 to assess predicted HLA class I binding of 280 CD4+ and 523 CD8+ epitopes; non-inferiority testing compared variant responses to ancestral responses against technical repeat variability thresholds.
Limitations
- The paper states it did not assess antibody reactivity, used overlapping peptide pools that cannot exclude effects on antigen processing, was not powered to detect loss of small T cell clones or single-peptide differences, did not determine infecting virus sequences, and studied predominantly White cohorts.
- The paper also states it only tested whether ancestral-induced responses cross-recognize variants, not whether variant-induced responses cross-recognize the ancestral sequence.
- Evident from the text: no multiple-comparison correction was applied by design, sample sizes were modest, and the study was not designed or powered to compare the two mRNA vaccines or individual antigens.
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- Findingown data
IFN-γ T cell responses were detected in 17%, 50%, and 76% of unexposed, convalescent, and vaccinated donors, respectively.
“With an interferon-γ (IFN-γ) FluoroSPOT assay, IFN-γ T cell responses were detected in 17%, 50%, and 76% of unexposed, convalescent, and vaccinated donors, respectively”
Quote in the paperSubstantial claim - Findingown data
The T cell responses to the ancestral S MP were significantly higher than the DMSO controls in unexposed, convalescent, and vaccinated donors.
“The T cell responses to the ancestral S MP were significantly higher than the DMSO controls in unexposed (p < 0.0001 for CD4, p = 0.0063 for CD8, and p = 0.0036 for spot-forming cells [SFCs]/106 PBMCs by the Wilcoxon test), convalescent (p < 0.0001 for CD4, p < 0.0001 for CD8, and p = 0.0008 for SFC/106 PBMCs by the Wilcoxon test), and vaccinated donors (p < 0.0001 for CD4, p < 0.0001 for CD8, and”
Quote in the paperSubstantial claim - Findingown data
Geomean S-specific responses in convalescent donors ranged from 0.07 to 0.08 for CD4+ T cells and 0.08 to 0.10 for CD8+ T cells.
“Geomean S-specific responses ranged from 0.07 to 0.08 for CD4+ T cells and 0.08 to 0.10 for CD8+ T cells.”
Quote in the paperNot a substantial claim - Findingown data
A total of 7% and 3% of previously identified CD4+ and CD8+ T cell epitopes, respectively, are affected by mutations in the various VOCs.
“A total of 7% and 3% of previously identified CD4+ and CD8+ T cell epitopes, respectively, are affected by mutations in the various VOCs.”
Quote in the paperSubstantial claim - Findingown data
No significant difference was observed between the ancestral and VOC S peptide pools for CD4+ and CD8+ T cell reactivity in convalescent donors.
“No significant difference was observed between the ancestral and VOC S peptide pools (CD4: B.1.1.7 p = 0.17; B.1.351 p = 0.30; P.1 p = 0.21; CAL.20C p = 0.06 and CD8: B.1.1.7 p = 0.15; B.1.351 p = 0.25; P.1 p = 0.47; CAL.20C p = 0.17 by Wilcoxon test)”
Quote in the paperSubstantial claim
- Findingown data
CD4+ and CD8+ T cell reactivity in COVID-19 convalescents was significantly higher than in unexposed individuals.
“we found significantly higher reactivity in COVID-19 convalescents compared to unexposed individuals (CD4: p < 0.0001; CD8: p < 0.0001 by the Mann-Whitney test)”
Quote in the paperSubstantial claim - Findingown data
Fully conserved CD8+ T cell epitopes account for 97.8% of the recognition of the CAL.20C variant.
“fully conserved CD8+ T cell epitopes can be inferred to account for 98.3%, 98.4%, 97.9%, and 97.8% of the recognition of the B.1.1.7, B.1.351, P.1, and CAL.20C variants, respectively”
Quote in the paperSubstantial claim - Findingown data
Fully conserved S-derived CD8+ T cell epitopes account for 97.3% of the recognition of the CAL.20C variant.
“For CD8+ T cell responses, fully conserved epitopes can be inferred to account for 95.2%, 97.6%, 95.4%, and 97.3% of the recognition of B.1.1.7, B.1.351, P.1, and CAL.20C variants, respectively”
Quote in the paperSubstantial claim - Findingown data
Fully conserved CD8+ T cell epitopes account for 98.3% of the recognition of the B.1.1.7 variant.
“fully conserved CD8+ T cell epitopes can be inferred to account for 98.3%, 98.4%, 97.9%, and 97.8% of the recognition of the B.1.1.7, B.1.351, P.1, and CAL.20C variants, respectively”
Quote in the paperSubstantial claim - Findingcitation
509 (97.3%) of 523 CD8+ T cell epitopes are totally conserved within the P.1 variant.
“509 (97.3%) within the B.1.351 and P.1 variants”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [51] Tarke A. Sidney J. Kidd C.K. Dan J.M. Ramirez S.I. Yu E.D. Mateus J. da Silva Antunes R. Moore E. Rubiro P. Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases Cell Rep. Med. 2 2021 100204 33521695 PMC7837622 source
Not checked in the free run.
- Findingown data
Comparison of the variant pools to the ancestral sequence showed no significant differences for CD4+ and CD8+ T cell reactivity in the AIM assay for B.1.1.7 and P.1 in vaccinees.
“Comparison of the variant pools to the ancestral sequence showed no significant differences for CD4+ and CD8+ T cell reactivity in the AIM assay for B.1.1.7 and P.1 (CD4: B.1.1.7 p = 0.41, P.1 p = 0.29; CD8: B.1.1.7 p = 0.10, P.1 p = 0.09 by Wilcoxon test).”
Quote in the paperSubstantial claim - Findingown data
Overall, reactivity to the peptide pools spanning the variant genomes was found to be similar to that against the ancestral Wuhan strain.
“Overall, reactivity to the peptide pools spanning the variant genomes was found to be similar to that against the ancestral Wuhan strain (Figures 2 and S2).”
Quote in the paperSubstantial claim - Findingown data
508 (97.1%) of 523 CD8+ T cell epitopes are totally conserved within the B.1.1.7 variant.
“508 (97.1%) of these 523 CD8+ T cell epitopes are totally conserved within the B.1.1.7 variant”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [51] Tarke A. Sidney J. Kidd C.K. Dan J.M. Ramirez S.I. Yu E.D. Mateus J. da Silva Antunes R. Moore E. Rubiro P. Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases Cell Rep. Med. 2 2021 100204 33521695 PMC7837622 source
Not checked in the free run.
- Findingown data
The magnitude of the responses in unexposed donors was lower than in COVID-19 convalescents.
“The magnitude of the responses was lower than in COVID-19 convalescents (unexposed versus convalescent: CD4 p < 0.0001; CD8 p < 0.0001 by the Mann-Whitney test, comparison not shown in the graphs).”
Quote in the paperNot a substantial claim - Findingown data
Fully conserved S-derived CD4+ T cell epitopes account for 75.3% of the recognition of the B.1.351 variant.
“fully conserved CD4+ T cell epitopes can be inferred to account for 95.5%, 75.3%, 89.8%, and 98.3% of the recognition of B.1.1.7, B.1.351, P.1, and CAL.20C variants, respectively”
Quote in the paperSubstantial claim - Findingown data
Fully conserved S-derived CD4+ T cell epitopes account for 89.8% of the recognition of the P.1 variant.
“fully conserved CD4+ T cell epitopes can be inferred to account for 95.5%, 75.3%, 89.8%, and 98.3% of the recognition of B.1.1.7, B.1.351, P.1, and CAL.20C variants, respectively”
Quote in the paperSubstantial claim - Findingown data
The FluoroSPOT assay in vaccinees showed IFN-γ reactivity, with geomeans ranging from 58 to 74 SFCs per million PBMCs.
“The FluoroSPOT assay (Figures 3D–3F and S3C) showed IFN-γ reactivity, with geomeans ranging from 58 to the 74 SFCs per million PBMCs (Figures 3C and S3C).”
Quote in the paperNot a substantial claim - Findingown data
AIM+ T cell responses in COVID-19 convalescent donors above the threshold of positivity had a memory phenotype, preferentially enriched for central and effector memory phenotypes for CD4+ T cells and Tem phenotypes for CD8+ T cells, irrespective of the variant analyzed.
“Consistent with previous observations,39,48 AIM+ T cell responses in COVID-19 convalescent donors above the threshold of positivity (CD4 >0.016% and CD8 >0.16%, as described in Method details; Figure S4), irrespective of the variant analyzed, had a memory phenotype, preferentially enriched for central (Tcm) and effector memory (Tem) phenotypes for CD4+ T cells (CD4+Tcm CD45RA+CCR7− and CD4+Tem CD4”
Quote in the paperSubstantial claim - Findingown data
On average, fully conserved CD8+ T cell epitopes account for 98.1% of the recognition of the four variants.
“based on the ancestral sequence (Figure 4D, average of 98.1%)”
Quote in the paperSubstantial claim - Findingown data
Fully conserved CD8+ T cell epitopes account for 97.9% of the recognition of the P.1 variant.
“fully conserved CD8+ T cell epitopes can be inferred to account for 98.3%, 98.4%, 97.9%, and 97.8% of the recognition of the B.1.1.7, B.1.351, P.1, and CAL.20C variants, respectively”
Quote in the paperSubstantial claim - Findingown data
Fully conserved CD8+ T cell epitopes account for 98.4% of the recognition of the B.1.351 variant.
“fully conserved CD8+ T cell epitopes can be inferred to account for 98.3%, 98.4%, 97.9%, and 97.8% of the recognition of the B.1.1.7, B.1.351, P.1, and CAL.20C variants, respectively”
Quote in the paperSubstantial claim - Findingown data
Some T cell reactivity against the SARS-CoV-2 MPs was observed in unexposed donors.
“As expected, some T cell reactivity against the SARS-CoV-2 MPs was observed in unexposed donors”
Quote in the paperNot a substantial claim - Findingown data
On a per-donor basis, the IFN-γ response accounted for >80% of the total response, on average (range 84%-89%), irrespective of whether the ancestral strain or VOCs were considered.
“On a per-donor basis, the IFN-γ response was found to account for >80% of the total response, on average (range 84%–89%), irrespective of whether the ancestral strain or VOCs were considered (Figure 3F).”
Quote in the paperNot a substantial claim - Findingown data
No decrease in the geomean of AIM+ CD4+ or CD8+ T cell responses to the sum of all of the antigens of individual MPs tested was observed in unexposed donors.
“Similar to the COVID-19 convalescents, no decrease in the geomean of AIM+ CD4+ or CD8+ T cell responses to the sum of all of the antigens of individual MPs tested was observed in unexposed donors (Figures S2H–S2K).”
Quote in the paperNot a substantial claim - Findingown data
For the CAL.20C variant, 6 out of 11 mutations are associated with a ≥2-fold decrease in predicted HLA class I binding capacity.
“In the case of the B.1.1.7, B.1.351, P.1, and CAL.20C variants, the number of mutations associated with binding capacity decreases (conservatively defined as a 2-fold reduction) was 4 out of 15, 3 out of 14, 3 out of 14, and 6 out of 11, respectively.”
Quote in the paperNot a substantial claim - Findingown data
For the B.1.1.7 variant, 4 out of 15 mutations are associated with a ≥2-fold decrease in predicted HLA class I binding capacity.
“In the case of the B.1.1.7, B.1.351, P.1, and CAL.20C variants, the number of mutations associated with binding capacity decreases (conservatively defined as a 2-fold reduction) was 4 out of 15, 3 out of 14, 3 out of 14, and 6 out of 11, respectively.”
Quote in the paperNot a substantial claim - Findingown data
A similar overall pattern of dominant antigens was observed in this study as previously reported.
“Here, a similar overall pattern of dominant antigens was observed (Figures 2C and 2D).”
Quote in the paperNot a substantial claim - Findingown data
For vaccinees, the magnitude of responses to pools encompassing the sequences from the ancestral Wuhan genome and the VOCs ranged from a geomean of 0.15-0.17 for CD4+ T cells and a geomean of 0.10-0.15 for CD8+ T cells.
“For both CD4+ and CD8+ T cell reactivity, the magnitude of responses to pools encompassing the sequences from the ancestral Wuhan genome and the VOCs ranged from a geomean of 0.15–0.17 for CD4+ T cells and a geomean of 0.10–0.15 for CD8+ T cells (Figures 3A–3C).”
Quote in the paperSubstantial claim - Findingown data
Fully conserved S-derived CD8+ T cell epitopes account for 95.4% of the recognition of the P.1 variant.
“For CD8+ T cell responses, fully conserved epitopes can be inferred to account for 95.2%, 97.6%, 95.4%, and 97.3% of the recognition of B.1.1.7, B.1.351, P.1, and CAL.20C variants, respectively”
Quote in the paperSubstantial claim - Findingown data
The number of S-derived CD8+ T cell epitopes conserved at 100% sequence identity is on average 95.3%.
“and 95.3% for the CD8+ T cell epitopes”
Quote in the paperSubstantial claim - Findingown data
512 (97.9%) of 523 CD8+ T cell epitopes are totally conserved within the CAL.20C variant.
“512 (97.9%) within the CAL.20C variant”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [51] Tarke A. Sidney J. Kidd C.K. Dan J.M. Ramirez S.I. Yu E.D. Mateus J. da Silva Antunes R. Moore E. Rubiro P. Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases Cell Rep. Med. 2 2021 100204 33521695 PMC7837622 source
Not checked in the free run.
- Findingown data
On average, fully conserved S-derived CD4+ T cell epitopes account for 89.7% of the recognition of the four variants.
“with an average of 89.7% (Figure 4F)”
Quote in the paperSubstantial claim - Findingown data
On average, fully conserved S-derived CD8+ T cell epitopes account for 96.4% of the recognition of the four variants.
“with an average of 96.4% (Figure 4H)”
Quote in the paperSubstantial claim - Findingown data
No IL-5 reactivity was observed for any of the pools in convalescent donors.
“No IL-5 reactivity was observed for any of the pools (Figure 1E).”
Quote in the paperNot a substantial claim - Findingown data
The same pattern of similar peptide concentration sensitivity was observed for CD8+ T cell responses to S.
“The same pattern was also observed for CD8+ T cell responses to S (Figures 1G and S2E).”
Quote in the paperNot a substantial claim - Findingown data
Peptide concentration sensitivity of CD4+ T cell responses to the ancestral and four variant pools was similar.
“As shown in Figures 1F and S2D, peptide concentration sensitivity of CD4+ T cell responses to the ancestral and four variant pools was similar.”
Quote in the paperNot a substantial claim - Findingown data
89.6%, 90%, 94.3%, and 97.1% (average 93%) of the CD4+ T cell epitopes are conserved in the B.1.1.7, B1.351, P.1, and CAL.20C variants.
“As shown in Figure 4A, we found that 89.6%, 90%, 94.3%, and 97.1% (average 93%) of the CD4+ T cell epitopes are conserved in the B.1.1.7, B1.351, P.1, and CAL.20C variants.”
Quote in the paperSubstantial claim - Findingown data
The number of S-derived CD4+ T cell epitopes conserved at 100% sequence identity is on average 84.5%.
“The number of S-derived epitopes conserved at 100% sequence identity was, on average, 84.5% for the CD4+ T cell epitopes”
Quote in the paperSubstantial claim - Findingown data
Fully conserved CD4+ T cell epitopes can be inferred to account for 84.4%, 88.1%, 95.7%, and 97.8% (average 91.5%) of the recognition of the B.1.1.7, B.1.351, P.1, and CAL.20C variants, respectively, based on the ancestral sequence.
“Fully conserved CD4+ T cell epitopes can be inferred to account for 84.4%, 88.1%, 95.7%, and 97.8% (average 91.5%) of the recognition of the B.1.1.7, B.1.351, P.1, and CAL.20C variants, respectively, based on the ancestral sequence (Figure 4B).”
Quote in the paperSubstantial claim - Findingown data
Fully conserved S-derived CD8+ T cell epitopes account for 97.6% of the recognition of the B.1.351 variant.
“For CD8+ T cell responses, fully conserved epitopes can be inferred to account for 95.2%, 97.6%, 95.4%, and 97.3% of the recognition of B.1.1.7, B.1.351, P.1, and CAL.20C variants, respectively”
Quote in the paperSubstantial claim - Findingown data
Fully conserved S-derived CD4+ T cell epitopes account for 98.3% of the recognition of the CAL.20C variant.
“fully conserved CD4+ T cell epitopes can be inferred to account for 95.5%, 75.3%, 89.8%, and 98.3% of the recognition of B.1.1.7, B.1.351, P.1, and CAL.20C variants, respectively”
Quote in the paperSubstantial claim - Findingown data
Fully conserved S-derived CD4+ T cell epitopes account for 95.5% of the recognition of the B.1.1.7 variant.
“fully conserved CD4+ T cell epitopes can be inferred to account for 95.5%, 75.3%, 89.8%, and 98.3% of the recognition of B.1.1.7, B.1.351, P.1, and CAL.20C variants, respectively”
Quote in the paperSubstantial claim - Findingown data
Total CD4+ or CD8+ T cell reactivity is similar against the four variants B.1.1.7, B.1.351, P.1, and CAL.20C.
“We found similar total CD4+ or CD8+ T cell reactivity against the four variants investigated herein, B.1.1.7, B.1.351, P.1, and CAL.20C”
Quote in the paperSubstantial claim - Findingown data
Even in epitopes affected by single mutations, no negative effect on predicted HLA-binding capacity is expected in the majority of cases.
“we found that even in the epitopes affected by single mutations, no negative effect on the predicted HLA-binding capacity in the majority of cases is expected.”
Quote in the paperSubstantial claim - Findingown data
CD4+ and CD8+ T cell dose responses to the ancestral and VOC S pools were similar in vaccinated donors.
“As shown in Figures 3G, 3H, S3D, and S3E, CD4+ and CD8+ T cell dose responses to the ancestral and VOC S pools were similar.”
Quote in the paperSubstantial claim - Findingown data
Minimal IL-5 responses were observed in vaccinees, with geomean reactivity ranging from 22 to 23 SFCs/106, slightly above the limit of detection.
“Minimal IL-5 responses were observed, with geomean reactivity ranging from 22 to 23 SFCs/106, which is slightly above the limit of detection (Figure 3E).”
Quote in the paperNot a substantial claim - Findingown data
VOC mutations do not significantly disrupt the total CD4+ and CD8+ T cell responses.
“Overall, we observed that VOC mutations do not significantly disrupt the total CD4+ and CD8+ T cell responses.”
Quote in the paperSubstantial claim - Findingown data
The ancestral strain peptides elicited ex vivo IFN-γ reactivity using whole PBMCs, with a geomean of 45 SFCs/106 PBMCs (range 20-1,578).
“The results from the FluoroSPOT assay (Figures 1D and 1E) showed ex vivo IFN-γ reactivity using whole PBMCs, with a geomean of 45 SFCs/106 PBMCs (range 20–1,578) for the ancestral strain peptides.”
Quote in the paperNot a substantial claim - Findingown data
Fully conserved S-derived CD8+ T cell epitopes account for 95.2% of the recognition of the B.1.1.7 variant.
“For CD8+ T cell responses, fully conserved epitopes can be inferred to account for 95.2%, 97.6%, 95.4%, and 97.3% of the recognition of B.1.1.7, B.1.351, P.1, and CAL.20C variants, respectively”
Quote in the paperSubstantial claim - Findingown data
509 (97.3%) of 523 CD8+ T cell epitopes are totally conserved within the B.1.351 variant.
“509 (97.3%) within the B.1.351 and P.1 variants”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [51] Tarke A. Sidney J. Kidd C.K. Dan J.M. Ramirez S.I. Yu E.D. Mateus J. da Silva Antunes R. Moore E. Rubiro P. Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases Cell Rep. Med. 2 2021 100204 33521695 PMC7837622 source
Not checked in the free run.
- Findingown data
For the P.1 variant, 3 out of 14 mutations are associated with a ≥2-fold decrease in predicted HLA class I binding capacity.
“In the case of the B.1.1.7, B.1.351, P.1, and CAL.20C variants, the number of mutations associated with binding capacity decreases (conservatively defined as a 2-fold reduction) was 4 out of 15, 3 out of 14, 3 out of 14, and 6 out of 11, respectively.”
Quote in the paperNot a substantial claim - Findingown data
When the sum total of reactivity throughout the genome was considered, no decreases in reactivity compared to the ancestral were noted for the variant pools.
“When the sum total of reactivity throughout the genome was considered, no decreases in reactivity compared to the ancestral were noted for the variant pools (Figures 2A–2C, S2F, and S2G).”
Quote in the paperSubstantial claim - Findingown data
For the B.1.351 variant, 3 out of 14 mutations are associated with a ≥2-fold decrease in predicted HLA class I binding capacity.
“In the case of the B.1.1.7, B.1.351, P.1, and CAL.20C variants, the number of mutations associated with binding capacity decreases (conservatively defined as a 2-fold reduction) was 4 out of 15, 3 out of 14, 3 out of 14, and 6 out of 11, respectively.”
Quote in the paperNot a substantial claim - Findingown data
The non-inferiority test found that all CD4 and CD8 responses or IFNγ responses to any of the variant peptide pools were significantly above the lower bound threshold.
“The non-inferiority test found that all CD4 and CD8 responses or IFNγ responses to any of the variant peptide pools were significantly above the lower bound threshold.”
Quote in the paperSubstantial claim - Premisecitation
Few data are available on the potential impact of mutations associated with SARS-CoV-2 variants on T cell reactivity.
“It is therefore key to address the potential impact of mutations associated with SARS-CoV-2 variants on T cell reactivity; however, few data are available on this topic.46”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [46] Redd A.D. Nardin A. Kared H. Bloch E.M. Pekosz A. Laeyendecker O. Abel B. Fehlings M. Quinn T.C. Tobian A.A.R. CD8+ T cell responses in COVID-19 convalescent individuals target conserved epitopes from multiple prominent SARS-CoV-2 circulating variants medRxiv 2021 10.1101/2021.02.11.21251585 PMC8083629 34322559
Not checked in the free run.
- Interpretationown data
The SARS-CoV-2 variants analyzed here do not significantly disrupt the total SARS-CoV-2 T cell reactivity.
“Thus, the SARS-CoV-2 variants analyzed here do not significantly disrupt the total SARS-CoV-2 T cell reactivity; however, the decreases observed highlight the importance for active monitoring of T cell reactivity in the context of SARS-CoV-2 evolution.”
Quote in the paperSubstantial claim - Premisecitation
Mutations in B.1.351 and P.1 variants are associated with the more pronounced loss of neutralizing capacity.
“In contrast, mutations in B.1.351 and P.1 variants are associated with the more pronounced loss of neutralizing capacity.15,16,22,23,25”
Quote in the paperNot a substantial claim0 of 5 sources checked- cites [15] Skelly, D.T., Harding, A.C., Gilbert-Jaramillo, J., Knight, M.L., Longet, S., Brown, A., Adele, S., Adland, E., and Brown, H., et al.; Medawar Laboratory Team (2021). Vaccine-induced immunity provides more robust heterotypic immunity than natural infection to emerging SARS-CoV-2 variants of concern. Research Square, 10.21203/rs.3.rs-226857/v2. source
Not checked in the free run.
- cites [16] Wu K. Werner A.P. Koch M. Choi A. Narayanan E. Stewart-Jones G.B.E. Colpitts T. Bennett H. Boyoglu-Barnum S. Shi W. Serum Neutralizing Activity Elicited by mRNA-1273 Vaccine N. Engl. J. Med. 384 2021 1468 1470 33730471 PMC8008744 source
Not checked in the free run.
- cites [22] Wang Z. Schmidt F. Weisblum Y. Muecksch F. Barnes C.O. Finkin S. Schaefer-Babajew D. Cipolla M. Gaebler C. Lieberman J.A. mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants Nature 592 2021 616 622 33567448 PMC8503938 source
Not checked in the free run.
- cites [23] Wibmer C.K. Ayres F. Hermanus T. Madzivhandila M. Kgagudi P. Oosthuysen B. Lambson B.E. de Oliveira T. Vermeulen M. van der Berg K. SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma Nat. Med. 27 2021 622 625 33654292 source
Not checked in the free run.
- cites [25] Cele S. Gazy I. Jackson L. Hwa S.H. Tegally H. Lustig G. Giandhari J. Pillay S. Wilkinson E. Naidoo Y. Network for Genomic Surveillance in South Africa COMMIT-KZN Team Escape of SARS-CoV-2 501Y.V2 from neutralization by convalescent plasma Nature 593 2021 142 146 33780970 PMC9867906 source
Not checked in the free run.
- Premisecitation
The Novavax COVID-19 vaccine (NVX-CoV2373) has differential protective immunity against the parental strain, B.1.1.7, and B.1.351 in clinical trials (96%, 86%, and 60%, respectively).
“The Novavax COVID-19 vaccine (NVX-CoV2373) has differential protective immunity against the parental strain, B.1.1.7, and B.1.351 in clinical trials (96%, 86%, and 60%, respectively),30”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Novavax Inc Novavax COVID-19 Vaccine Demonstrates 89.3% Efficacy in UK Phase 3 Trial 2021 https://ir.novavax.com/2021-01-28-Novavax-COVID-19-Vaccine-Demonstrates-89-3-Efficacy-in-UK-Phase-3-Trial
Not checked in the free run.
- Interpretationown data
The total T cell responses are not significantly disrupted by the VOCs.
“the data presented here suggest that the total T cell responses are not significantly disrupted by the VOCs.”
Quote in the paperSubstantial claim - Study design and conductreasoning
The data do not rule out that certain individuals could be strongly affected by the mutations in specific VOCs.
“Nevertheless, our data do not rule out that certain individuals could be strongly affected by the mutations in specific VOCs.”
Quote in the paperNot a substantial claim - Interpretationown data
CD4+ and CD8+ T cells from individuals infected with the ancestral SARS-CoV-2 strain recognize VOCs with similar efficiency.
“These experiments suggest that CD4+ and CD8+ T cells from individuals infected with the ancestral SARS-CoV-2 strain recognize VOCs with similar efficiency.”
Quote in the paperSubstantial claim- Rests on an assumption: None of the VOCs analyzed were prevalent in the San Diego, California, area during the May–October 2020 collection period for convalescent donors.
- Study design and conductreasoning
The statistical power of the study does not allow detection of the loss of small populations of T cell clones that may be affected by variant sequences.
“The statistical power of this study does not allow for the sensitivity needed to detect the loss of small populations of T cell clones that may be affected by variant sequences when sampled in the presence of the majority of conserved peptides.”
Quote in the paperSubstantial claim - Interpretationreasoning
The apparent higher conservation of CD8+ T cell epitopes is expected based on the shorter length of HLA class I binding peptides (usually 9-10 amino acids) compared to class II counterparts (13-17 amino acids).
“The apparent higher conservation of CD8+ T cell epitopes is to be expected based on the shorter length of HLA class I binding peptides (usually 9–10 amino acids) as compared to their class II counterparts (13–17 amino acids).”
Quote in the paperNot a substantial claim - Interpretationown data
The vast majority of CD4+ and CD8+ T cell epitopes are unaffected by mutations found in all of the different variants.
“the analyses suggest that the vast majority of CD4+ and CD8+ T cell epitopes are unaffected by mutations found in all of the different variants.”
Quote in the paperSubstantial claim - Premisecitation
T cell responses against SARS-CoV-2 are highly multi-antigenic and multi-specific, with tens of different epitopes recognized by CD4+ and CD8+ T cells in a given individual.
“the T cell responses against SARS-CoV-2 are highly multi-antigenic and multi-specific, with tens of different epitopes recognized by CD4+ and CD8+ T cells in a given individual.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [51] Tarke A. Sidney J. Kidd C.K. Dan J.M. Ramirez S.I. Yu E.D. Mateus J. da Silva Antunes R. Moore E. Rubiro P. Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases Cell Rep. Med. 2 2021 100204 33521695 PMC7837622 source
Not checked in the free run.
- cites [52] Braun J. Loyal L. Frentsch M. Wendisch D. Georg P. Kurth F. Hippenstiel S. Dingeldey M. Kruse B. Fauchere F. SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19 Nature 587 2020 270 274 32726801 source
Not checked in the free run.
- cites [60] Ferretti A.P. Kula T. Wang Y. Nguyen D.M.V. Weinheimer A. Dunlap G.S. Xu Q. Nabilsi N. Perullo C.R. Cristofaro A.W. Unbiased Screens Show CD8+ T Cells of COVID-19 Patients Recognize Shared Epitopes in SARS-CoV-2 that Largely Reside outside the Spike Protein Immunity 53 2020 1095 1107.e3 33128877 PMC7574860 source
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- cites [62] Nelde A. Bilich T. Heitmann J.S. Maringer Y. Salih H.R. Roerden M. Lübke M. Bauer J. Rieth J. Wacker M. SARS-CoV-2-derived peptides define heterologous and COVID-19-induced T cell recognition Nat. Immunol. 22 2021 74 85 32999467 source
Not checked in the free run.
- Interpretationown data
The mutations in the variants are predicted to have minor effects on the total T cell response.
“The corresponding mutations are also predicted to have minor effects on the total T cell response”
Quote in the paperSubstantial claim - Premisecitation
CD8+ T cells are generally less tolerant of amino substitutions than CD4+ T cells.
“This effect is counterbalanced by CD8+ T cells being generally less tolerant of amino substitutions as compared to CD4+ T cells.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [47] Grifoni A. Weiskopf D. Ramirez S.I. Mateus J. Dan J.M. Moderbacher C.R. Rawlings S.A. Sutherland A. Premkumar L. Jadi R.S. Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals Cell 181 2020 1489 1501.e15 32473127 PMC7237901 source
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- cites [64] Weiskopf D. Angelo M.A. Sidney J. Peters B. Shresta S. Sette A. Immunodominance changes as a function of the infecting dengue virus serotype and primary versus secondary infection J. Virol. 88 2014 11383 11394 25056881 PMC4178794 source
Not checked in the free run.
- Study design and conductreasoning
The use of overlapping peptide pools means the study cannot exclude that some mutations may involve alterations in antigen processing for class I or class II.
“Our studies used overlapping peptide pools. As such, we cannot exclude that some of the mutations may involve alterations in terms of antigen processing for either class I or class II, which would be undetected by using pools of “preprocessed” peptides.”
Quote in the paperNot a substantial claim - Interpretationown data
Donors primed by the ancestral strain S protein, by either infection or vaccination, mount a memory T cell response able to cross-recognize the SARS-CoV-2 VOCs.
“This provides additional evidence that donors primed by the ancestral strain S protein, by either infection or vaccination, mount a memory T cell response able to cross-recognize the SARS-CoV-2 VOCs.”
Quote in the paperSubstantial claim - Study design and conductreasoning
The study cannot exclude impaired T cell recognition of specific mutated peptides because MHC binding changes do not necessarily confer TCR affinity changes.
“Alterations in major histocompatibility complex (MHC) binding do not necessarily confer changes in T cell receptor (TCR) affinity, as often several MHC-binding residues can be changed before changing TCR signaling, so we cannot exclude impaired T cell recognition of those specific mutated peptides.”
Quote in the paperSubstantial claim - Study design and conductown data
The standard deviation of corrected log-fold change values from repeat measurements was used as a threshold for what constitutes a significant, non-random change at the population level.
“We evaluated the standard deviation of these corrected log-fold change values of repeat measurements (at an individual level), and used this value as a threshold for what would constitute a significant, non-random change at the population level.”
Quote in the paperSubstantial claim - Study design and conductreasoning
Adding the level of detection to the corrected log2 fold-change calculation prevents variations near or below the detection threshold from producing inflated fold-change estimates.
“The addition of the LOD ensures that variations between measurements close to- or below the level of detection do not result in inflated fold-change estimates.”
Quote in the paperSubstantial claim - Study design and conductreasoning
Multi-hypothesis testing corrections were not applied in the study by design.
“Multi-hypothesis testing corrections (MHTC) have not been applied in the study by design.”
Quote in the paperSubstantial claim - Interpretationown data
By this approach at the population level, there is no biologically meaningful reduction in the T cell response to the variant peptide pools compared to the ancestral strain.
“Therefore, by this approach at the population level, there is no biological meaningful reduction in the T cell response to the variant pools compared to the ancestral strain.”
Quote in the paperSubstantial claim- Rests on an assumption: The corrected fold-change thresholds derived from assay variability (2.3 for CD4-AIM, 2.4 for CD8-AIM, 1.6 for FluoroSPOT) represent a biologically meaningful reduction in T cell responses.
- Premisenone given
A difference that is not statistically significant would remain non-significant even after multiple-hypothesis testing corrections.
“since a difference that is not significant would remain so even after corrections”
Quote in the paperNot a substantial claim - Study design and conductnone given
The study is not designed or powered to address differences across different proteins.
“The study is not designed or powered to address differences across different proteins.”
Quote in the paperSubstantial claim
- May combine two claims. 23
- Classified as probably not a substantial claim. 18
- The quote only partly states this claim. 1
May combine two claims.
Findingown dataThe total reactivity against SARS-CoV-2 variants is similar in terms of magnitude and frequency of response, with decreases in the 10%-22% range observed in some assay/VOC combinations.
“The total reactivity against SARS-CoV-2 variants is similar in terms of magnitude and frequency of response, with decreases in the 10%–22% range observed in some assay/VOC combinations.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe responses observed in the S MP in vaccinated donors were significantly higher than in unexposed donors, with 100% and 48% of donors positive for CD4 and CD8 responses, respectively.
“Likewise, the responses observed in the S MP in vaccinated donors were significantly higher than in unexposed donors (CD4: p < 0.0001; CD8: p < 0.0001 by Mann-Whitney test), with 100% and 48% of donors positive for CD4 and CD8 responses, respectively”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data93% and 39% of convalescent donors were positive for CD4+ and CD8+ T cell responses to ancestral S, respectively.
“with 93% and 39% of donors positive (responses above the threshold of positivity as described in Method details) for CD4+ and CD8+ T cell responses, respectively.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataNo significant differences were observed in non-inferiority test on fold change values, demonstrating that the decreases observed were within the range expected from technical repeat variation.
“No significant differences were observed, demonstrating that the decreases observed were within the range expected from technical repeat variation.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCompared to the ancestral strain, there were significant decreases of 12%, 6%, and 14% for the B.1.1.7, B.1.351, and CAL.20C variant pools in IFN-γ SFCs, while no difference was observed for P.1.
“Compared to the ancestral strain, there were significant decreases of 12%, 6%, and 14% for the B.1.1.7, B.1.351, and CAL.20C variant pools (B.1.1.7 p = 0.02; B.1.351 p = 0.03; P.1 p = 0.07, and CAL.20C p < 0.01 by Wilcoxon test), while no difference was observed for P.1”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataMarginal IL-5 production was detected in all of the conditions tested.
“Marginal IL-5 production was detected in all of the conditions tested.”
Quote in the paperNot a substantial claimMay combine two claims. The quote only partly states this claim.
Findingown dataNo significant differences were observed in non-inferiority analysis for vaccinees, indicating that the magnitude of decreases for some strains was within the expected technical assay variability.
“No significant differences were observed, indicating that the magnitude of decreases for some strains was within the expected technical assay variability (Figures S3A–S3C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingcitation93% of CD4+ and 97% of CD8+ T cell epitopes in SARS-CoV-2 are completely conserved in the variants.
“showing that 93% of CD4+ and 97% of CD8+ T cell epitopes in SARS-CoV-2 are completely conserved in the variants.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Tarke et al.
Not checked in the free run.
May combine two claims.
Findingown dataDecreases of 14% and 22% were observed with the B.1.351 pools for CD4+ and CD8+ T cells in vaccinees, and a 10% decrease with the CAL.20C pool for CD8+ T cells.
“Decreases of 14% and 22%, respectively, were observed with the B.1.351 pools for CD4+ and CD8+ T cells (B.1.351: p < 0.01 for both comparisons), and a 10% decrease with the CAL.20C pool for CD8+ T cells (p = 0.04) (Figures 3A–3C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAIM+ T cell responses in COVID-19 vaccinees had a memory phenotype regardless of the origin of the SARS-CoV-2 sequences analyzed, with preferential enrichment for Tcm and Tem for CD4 and Tem and Temra for CD8.
“Likewise, AIM+ T cell responses in COVID-19 vaccinees had a memory phenotype regardless of the origin of the SARS-CoV-2 sequences analyzed, with preferential enrichment for Tcm and Tem for CD4 (Figure S4C) and Tem and Temra for CD8 (Figure S4D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataVOC reactivity was observed for the S MPs in convalescent donors, with geomean IFN-γ SFCs per million PBMCs ranging from 38 to 45.
“VOC reactivity was observed for the S MPs in convalescent donors, with geomean IFN-γ SFCs per million PBMCs ranging from 38 to 45”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe corrected fold-change thresholds derived from repeat-measure variability were 2.3 for CD4-AIM assays, 2.4 for CD8-AIM assays, and 1.6 for FluoroSPOT.
“For CD4-AIM assays, that corresponded to a corrected fold-change of 2.3, for CD8-AIM of 2.4 and for FluoroSPOT of 1.6 as shown in Table S3.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe B.1.1.7 variant is associated with increased transmissibility, and similar epidemiological observations have been reported for the SA and BR variants.
“The B.1.1.7 variant is associated with increased transmissibility,9,10 and similar epidemiological observations have been reported for the SA and BR variants.4,5”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [9] Rambaut A. Loman N. Pybus O. Barclay W. Barrett J. Carabelli A. Connor T. Peacock T. Robertson D.L. Volz E. COVID-19 Genomics Consortium UK (CoG-UK Preliminary genomic characterisation of an emergent SARS-CoV-2 lineage in the UK defined by a novel set of spike mutations 2020 https://virological.org/t/preliminary-genomic-characterisation-of-an-emergent-sars-cov-2-lineage-in-the-uk-defined-by-a-novel-set-of-spike-mutations/563
Not checked in the free run.
- cites [10] Washington N.L. Gangavarapu K. Zeller M. Bolze A. Cirulli E.T. Barrett K.M.S. Larsen B.B. Anderson C. White S. Cassens T. Genomic epidemiology identifies emergence and rapid transmission of SARS-CoV-2 B.1.1.7 in the United States medRxiv 2021 10.1101/2021.2002.2006.21251159 PMC8009040 33861950
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- cites [4] Tegally H. Wilkinson E. Lessells R.J. Giandhari J. Pillay S. Msomi N. Mlisana K. Bhiman J.N. von Gottberg A. Walaza S. Sixteen novel lineages of SARS-CoV-2 in South Africa Nat. Med. 27 2021 440 446 33531709 source
Not checked in the free run.
- cites [5] Voloch C.M. da Silva Francisco R. Jr. de Almeida L.G.P. Cardoso C.C. Brustolini O.J. Gerber A.L. Guimarães A.P.C. Mariani D. da Costa R.M. Ferreira O.C. Jr. Covid19-UFRJ Workgroup, LNCC Workgroup, Adriana Cony Cavalcanti Genomic characterization of a novel SARS-CoV-2 lineage from Rio de Janeiro, Brazil J. Virol. 95 2021 e00119-21 PMC8139668 33649194 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIndividuals with agammaglobulinemia or pharmaceutical depletion of B cells generally experience an uncomplicated COVID-19 disease course.
“Furthermore, individuals with agammaglobulinemia or pharmaceutical depletion of B cells generally experience an uncomplicated COVID-19 disease course.33,37,38”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [33] Sette A. Crotty S. Adaptive immunity to SARS-CoV-2 and COVID-19 Cell 184 2021 861 880 33497610 PMC7803150 source
Not checked in the free run.
- cites [37] Soresina A. Moratto D. Chiarini M. Paolillo C. Baresi G. Foca E. Bezzi M. Baronio B. Giacomelli M. Badolato R. Two X-linked agammaglobulinemia patients develop pneumonia as COVID-19 manifestation but recover Pediatr. Allergy Immunol. 31 2020 565 569 32319118 PMC7264678 source
Not checked in the free run.
- cites [38] Baker D. Roberts C.A.K. Pryce G. Kang A.S. Marta M. Reyes S. Schmierer K. Giovannoni G. Amor S. COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases Clin. Exp. Immunol. 202 2020 149 161 32671831 PMC7405500 source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationCD4+ and CD8+ T cell responses play important roles in the resolution of SARS-CoV-2 infection and COVID-19, including modulating disease severity in humans and reducing viral loads in non-human primates.
“Several lines of evidence suggest that CD4+ and CD8+ T cell responses play important roles in the resolution of SARS-CoV-2 infection and COVID-19,33 including modulating disease severity in humans34,35 and reducing viral loads in non-human primates.36”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [33] Sette A. Crotty S. Adaptive immunity to SARS-CoV-2 and COVID-19 Cell 184 2021 861 880 33497610 PMC7803150 source
Not checked in the free run.
- cites [34] Rydyznski Moderbacher C. Ramirez S.I. Dan J.M. Grifoni A. Hastie K.M. Weiskopf D. Belanger S. Abbott R.K. Kim C. Choi J. Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity Cell 183 2020 996 1012.e19 33010815 PMC7494270 source
Not checked in the free run.
- cites [35] Tan A.T. Linster M. Tan C.W. Le Bert N. Chia W.N. Kunasegaran K. Zhuang Y. Tham C.Y.L. Chia A. Smith G.J.D. Early induction of functional SARS-CoV-2-specific T cells associates with rapid viral clearance and mild disease in COVID-19 patients Cell Rep. 34 2021 108728 33516277 PMC7826084 source
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- cites [36] Muñoz-Fontela C. Dowling W.E. Funnell S.G.P. Gsell P.S. Riveros-Balta A.X. Albrecht R.A. Andersen H. Baric R.S. Carroll M.W. Cavaleri M. Animal models for COVID-19 Nature 586 2020 509 515 32967005 PMC8136862 source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationRobust CD4+ and CD8+ T cell memory is induced after COVID-19, and multiple COVID-19 vaccines elicit CD4+ and CD8+ T cell responses.
“Robust CD4+ and CD8+ T cell memory is induced after COVID-19,22,39, 40, 41 and multiple COVID-19 vaccines elicit CD4+ and CD8+ T cell responses.26,42, 43, 44, 45”
Quote in the paperSubstantial claim0 of 9 sources checked- cites [22] Wang Z. Schmidt F. Weisblum Y. Muecksch F. Barnes C.O. Finkin S. Schaefer-Babajew D. Cipolla M. Gaebler C. Lieberman J.A. mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants Nature 592 2021 616 622 33567448 PMC8503938 source
Not checked in the free run.
- cites [39] Dan J.M. Mateus J. Kato Y. Hastie K.M. Yu E.D. Faliti C.E. Grifoni A. Ramirez S.I. Haupt S. Frazier A. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection Science 371 2021 eabf4063 33408181 PMC7919858 source
Not checked in the free run.
- cites [40] Peng Y. Mentzer A.J. Liu G. Yao X. Yin Z. Dong D. Dejnirattisai W. Rostron T. Supasa P. Liu C. Oxford Immunology Network Covid-19 Response T cell Consortium ISARIC4C Investigators Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19 Nat. Immunol. 21 2020 1336 1345 32887977 PMC7611020 source
Not checked in the free run.
- cites [41] Breton G. Mendoza P. Hägglöf T. Oliveira T.Y. Schaefer-Babajew D. Gaebler C. Turroja M. Hurley A. Caskey M. Nussenzweig M.C. Persistent cellular immunity to SARS-CoV-2 infection J. Exp. Med. 218 2021 e20202515 33533915 PMC7845919 source
Not checked in the free run.
- cites [26] Voysey M. Clemens S.A.C. Madhi S.A. Weckx L.Y. Folegatti P.M. Aley P.K. Angus B. Baillie V.L. Barnabas S.L. Bhorat Q.E. Oxford COVID Vaccine Trial Group Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK Lancet 397 2021 99 111 33306989 PMC7723445 source
Not checked in the free run.
- cites [42] Dowd S.M. Zalta A.K. Burgess H.J. Adkins E.C. Valdespino-Hayden Z. Pollack M.H. Double-blind randomized controlled study of the efficacy, safety and tolerability of eszopiclone vs placebo for the treatment of patients with post-traumatic stress disorder and insomnia World J. Psychiatry 10 2020 21 28 32257848 PMC7099286 source
Not checked in the free run.
- cites [43] Sadoff J. Le Gars M. Shukarev G. Heerwegh D. Truyers C. de Groot A.M. Stoop J. Tete S. Van Damme W. Leroux-Roels I. Interim Results of a Phase 1-2a Trial of Ad26.COV2.S Covid-19 Vaccine N. Engl. J. Med. 384 2021 1824 1835 33440088 PMC7821985 source
Not checked in the free run.
- cites [44] Baden L.R. El Sahly H.M. Essink B. Kotloff K. Frey S. Novak R. Diemert D. Spector S.A. Rouphael N. Creech C.B. COVE Study Group Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine N. Engl. J. Med. 384 2021 403 416 33378609 PMC7787219 source
Not checked in the free run.
- cites [45] Keech C. Albert G. Cho I. Robertson A. Reed P. Neal S. Plested J.S. Zhu M. Cloney-Clark S. Zhou H. Phase 1-2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine N. Engl. J. Med. 383 2020 2320 2332 32877576 PMC7494251 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe BNT162b2 Pfizer/BioNTech COVID-19 vaccine retains its efficacy against B.1.1.7 in the UK and in reports from Israel.
“Current epidemiological evidence is that the BNT162b2 Pfizer/BioNTech COVID-19 vaccine retains its efficacy against B.1.1.7 in the UK24 and in reports from Israel.28,29”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [24] Emary K.R.W. Golubchik T. Aley P.K. Ariani C.V. Angus B. Bibi S. Blane B. Bonsall D. Cicconi P. Charlton S. COVID-19 Genomics UK Consortium AMPHEUS Project Oxford COVID-19 Vaccine Trial Group Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial Lancet 397 2021 1351 1362 33798499 PMC8009612 source
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- cites [28] Amit S. Regev-Yochay G. Afek A. Kreiss Y. Leshem E. Early rate reductions of SARS-CoV-2 infection and COVID-19 in BNT162b2 vaccine recipients Lancet 397 2021 875 877 PMC7906709 33610193 source
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- cites [29] Dagan N. Barda N. Kepten E. Miron O. Perchik S. Katz M.A. Hernán M.A. Lipsitch M. Reis B. Balicer R.D. BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting N. Engl. J. Med. 384 2021 1412 1423 33626250 PMC7944975 source
Not checked in the free run.
May combine two claims.
PremisecitationThe AstraZeneca ChAdOx1 vaccine has been associated with a partial loss of neutralizing antibody activity against B.1.1.7 and a large loss of neutralizing activity against B.1.351.
“Concerning vaccination responses, the AstraZeneca ChAdOx1 vaccine has been associated with a partial loss of neutralizing antibody activity against B.1.1.715 and a large loss of neutralizing activity against B.1.351.26”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [15] Skelly, D.T., Harding, A.C., Gilbert-Jaramillo, J., Knight, M.L., Longet, S., Brown, A., Adele, S., Adland, E., and Brown, H., et al.; Medawar Laboratory Team (2021). Vaccine-induced immunity provides more robust heterotypic immunity than natural infection to emerging SARS-CoV-2 variants of concern. Research Square, 10.21203/rs.3.rs-226857/v2. source
Not checked in the free run.
- cites [26] Voysey M. Clemens S.A.C. Madhi S.A. Weckx L.Y. Folegatti P.M. Aley P.K. Angus B. Baillie V.L. Barnabas S.L. Bhorat Q.E. Oxford COVID Vaccine Trial Group Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK Lancet 397 2021 99 111 33306989 PMC7723445 source
Not checked in the free run.
May combine two claims.
PremisecitationChAdOx1 maintains efficacy against B.1.1.7 but has a major loss in efficacy against mild COVID-19 with the B.1.351 variant.
“ChAdOx1 maintains efficacy against B.1.1.724,27 but has a major loss in efficacy against mild COVID-19 with the B.1.351 variant.26”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [24] Emary K.R.W. Golubchik T. Aley P.K. Ariani C.V. Angus B. Bibi S. Blane B. Bonsall D. Cicconi P. Charlton S. COVID-19 Genomics UK Consortium AMPHEUS Project Oxford COVID-19 Vaccine Trial Group Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial Lancet 397 2021 1351 1362 33798499 PMC8009612 source
Not checked in the free run.
- cites [27] Hall V.J. Foulkes S. Saei A. Andrews N. Oguti B. Charlett A. Wellington E. Stowe J. Gillson N. Atti A. Effectiveness of BNT162b2 mRNA Vaccine Against Infection and COVID-19 Vaccine Coverage in Healthcare Workers in England, Multicentre Prospective Cohort Study (the SIREN Study) Lancet 397 2021 1725 1735 33901423 PMC8064668 source
Not checked in the free run.
- cites [26] Voysey M. Clemens S.A.C. Madhi S.A. Weckx L.Y. Folegatti P.M. Aley P.K. Angus B. Baillie V.L. Barnabas S.L. Bhorat Q.E. Oxford COVID Vaccine Trial Group Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK Lancet 397 2021 99 111 33306989 PMC7723445 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationSeveral of the RBD mutations directly affect ACE2 receptor-binding affinity, which may affect infectivity, viral load, or transmissibility.
“Several of the RBD mutations directly affect angiotensin-converting enzyme 2 (ACE2) receptor-binding affinity, which may affect infectivity, viral load, or transmissibility.11, 12, 13, 14”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [11] Greaney A.J. Loes A.N. Crawford K.H.D. Starr T.N. Malone K.D. Chu H.Y. Bloom J.D. Comprehensive mapping of mutations in the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human plasma antibodies Cell Host Microbe 29 2021 463 476.e6 33592168 PMC7869748 source
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- cites [12] Starr T.N. Greaney A.J. Addetia A. Hannon W.W. Choudhary M.C. Dingens A.S. Li J.Z. Bloom J.D. Prospective mapping of viral mutations that escape antibodies used to treat COVID-19 Science 371 2021 850 854 33495308 PMC7963219 source
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- cites [13] Zahradník J. Marciano S. Shemesh M. Zoler E. Chiaravalli J. Meyer B. Dym O. Elad N. Schreiber G. SARS-CoV-2 RBD in vitro evolution follows contagious mutation spread, yet generates an able infection inhibitor bioRxiv 2021 10.1101/2021.2001.2006.425392
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- cites [14] Wang P. Nair M.S. Liu L. Iketani S. Luo Y. Guo Y. Wang M. Yu J. Zhang B. Kwong P.D. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7 Nature 593 2021 130 135 33684923 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe Janssen Ad26.COV2.S 1-dose COVID-19 vaccine has relatively similar protection for moderate COVID-19 against both the ancestral strain and B.1.351 (72% and 64%, respectively).
“whereas the Janssen Ad26.COV2.S 1-dose COVID-19 vaccine has relatively similar protection for moderate COVID-19 against both the ancestral strain and B.1.351 (72% and 64%, respectively).31,32”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [31] US Food and Drug Administration Vaccines and Related Biological Products Advisory Committee February 26, 2021. Sponsor Briefing Document Addendum 2021 https://www.fda.gov/media/146218/download
Not checked in the free run.
- cites [32] US Food and Drug Administration Vaccines and Related Biological Products Advisory Committee February 26, 2021 FDA Briefing Document—Addendum--Sponsor 2021 https://www.fda.gov/media/146218/download
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe impact of B.1.1.7 mutations on neutralizing antibody titers is moderate.
“In general, the impact of B.1.1.7 mutations on neutralizing antibody titers is moderate.15, 16, 17, 18,20,24”
Quote in the paperNot a substantial claim0 of 6 sources checked- cites [15] Skelly, D.T., Harding, A.C., Gilbert-Jaramillo, J., Knight, M.L., Longet, S., Brown, A., Adele, S., Adland, E., and Brown, H., et al.; Medawar Laboratory Team (2021). Vaccine-induced immunity provides more robust heterotypic immunity than natural infection to emerging SARS-CoV-2 variants of concern. Research Square, 10.21203/rs.3.rs-226857/v2. source
Not checked in the free run.
- cites [16] Wu K. Werner A.P. Koch M. Choi A. Narayanan E. Stewart-Jones G.B.E. Colpitts T. Bennett H. Boyoglu-Barnum S. Shi W. Serum Neutralizing Activity Elicited by mRNA-1273 Vaccine N. Engl. J. Med. 384 2021 1468 1470 33730471 PMC8008744 source
Not checked in the free run.
- cites [17] Muik A. Wallisch A.K. Sänger B. Swanson K.A. Mühl J. Chen W. Cai H. Maurus D. Sarkar R. Türeci Ö. Neutralization of SARS-CoV-2 lineage B.1.1.7 pseudovirus by BNT162b2 vaccine-elicited human sera Science 371 2021 1152 1153 33514629 PMC7971771 source
Not checked in the free run.
- cites [18] Supasa P. Zhou D. Dejnirattisai W. Liu C. Mentzer A.J. Ginn H.M. Zhao Y. Duyvesteyn H.M.E. Nutalai R. Tuekprakhon A. Reduced neutralization of SARS-CoV-2 B.1.1.7 variant by convalescent and vaccine sera Cell 184 2021 2201 2211.e7 33743891 PMC7891044 source
Not checked in the free run.
- cites [20] Shen X. Tang H. McDanal C. Wagh K. Fischer W. Theiler J. Yoon H. Li D. Haynes B.F. Sanders K.O. SARS-CoV-2 variant B.1.1.7 is susceptible to neutralizing antibodies elicited by ancestral spike vaccines Cell Host Microbe 29 2021 529 539.e3 33705729 PMC7934674 source
Not checked in the free run.
- cites [24] Emary K.R.W. Golubchik T. Aley P.K. Ariani C.V. Angus B. Bibi S. Blane B. Bonsall D. Cicconi P. Charlton S. COVID-19 Genomics UK Consortium AMPHEUS Project Oxford COVID-19 Vaccine Trial Group Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial Lancet 397 2021 1351 1362 33798499 PMC8009612 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe study did not address whether substantial differences exist between the epitope specificity of responses elicited by different vaccines.
“While we have no reason to suspect that substantial differences may exist between the epitope specificity of responses elicited by different vaccines, our study did not address this point.”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductreasoningConvalescent donor samples were selected to be infected before October 2020, making it unlikely any donor would have been infected by VOCs.
“the tested samples from convalescent donors were selected to be infected before October 2020; thus, it is unlikely that any of the donors would have been infected by any of the VOCs”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductreasoningThe values in the graphs are not corrected for multiple comparisons, as a correction would decrease the statistical power for detecting significant differences; therefore, not performing multiple comparison corrections is the more conservative and stringent test.
“These values (here and in subsequent graphs) are not corrected for multiple comparisons, as a correction would decrease the statistical power for detecting significant differences; therefore, not performing multiple comparison corrections is the more conservative and stringent test.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductown dataThe non-inferiority test compared fold change values to a lower bound fold change threshold calculated based on technical repeats.
“We then performed a non-inferiority test on one sample Wilcoxon signed-rank test compared to the lower bound fold change threshold calculated based on technical repeats (Table S3).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S1 (asserted).
InterpretationreasoningSingle amino acid substitutions or deletions across large peptidomes do not significantly affect a polyclonal memory T cell response.
“it is plausible to hypothesize that single amino acid substitutions or deletions across large peptidomes do not significantly affect a polyclonal memory T cell response.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningThe cohorts investigated were predominantly White, reflective of the patient population available for recruitment.
“the cohorts investigated were predominantly White, reflective of the patient population available for recruitment.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningBecause of HLA polymorphism, the epitope repertoire recognized is likely to be substantially different from one individual to the next, greatly decreasing the likelihood of immune escape by an acute virus.
“Because of HLA polymorphism, the epitope repertoire recognized is likely to be substantially different from one individual to the next, greatly decreasing the likelihood of immune escape by an acute virus.”
Quote in the paperSubstantial claim- Rests on an assumption: Immune escape at the level of T cell responses in human populations has not been reported for acute respiratory infections.
Classified as probably not a substantial claim. May combine two claims.
Study design and conductnone givenThe study was designed to test for differences in total T cell response against the different variants and was not powered or designed to investigate differences between the mRNA vaccines or at the single-peptide level.
“Our study was designed to test for differences in total T cell response against the different variants and was not powered or designed to investigate differences between the mRNA vaccines or at the single-peptide level.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductnone givenThis study is not powered to rule out differences in individual antigens.
“It is worth noting that this specific comparison is for illustration purposes only, as this study is not powered to rule out differences in individual antigens.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown dataThe sequences of the infecting virus were not determined, so the study cannot exclude that some donors may have been exposed to variants.
“in our study, the sequences of the infecting virus were not determined, and therefore we cannot exclude that some of the donors may have been exposed to variants.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationThe present study did not assess decreases in antibody reactivity.
“The present study did not assess decreases in antibody reactivity”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Study design and conductnone givenOne amino acid difference could influence TCR signal strength and memory T cell reactivation.
“An additional limitation of the study in this respect is that one amino acid difference could influence TCR signal strength and memory T cell reactivation.”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductreasoningThe study only investigated whether total T cell responses induced by the ancestral reference sequence cross-recognize variant sequences, not whether variant-induced responses cross-recognize the ancestral sequence.
“we have only investigated whether the total T cell responses induced by the ancestral reference sequence are able to cross-recognize variant sequences, as this is relevant to the present situation. We have not examined whether responses induced by an infection with a variant sequence will be able to cross-recognize the ancestral reference sequence present in the approved vaccines.”
Quote in the paperSubstantial claim
The paper relies on this without support.
None of the VOCs analyzed were prevalent in the San Diego, California, area during the May–October 2020 collection period for convalescent donors.
“From these donors, peripheral blood mononuclear cell (PBMC) samples were collected between May and October 2020, a period when none of the VOCs analyzed were prevalent in the San Diego, California, area, where the donations from convalescent donors were obtained.”
The paper relies on this without support.
Multiple mutations in SARS-CoV-2 variants are located in regions bound by neutralizing antibodies.
“Multiple mutations were also noted in regions bound by neutralizing antibodies, so it is crucial to address the extent to which mutations associated with the variants may affect immunity induced by either SARS-CoV-2 infection or vaccination.”
The paper relies on this without support.
Immune escape at the level of T cell responses in human populations has not been reported for acute respiratory infections.
“immune escape at the level of T cell responses in human populations has not been reported for acute respiratory infections.”
The paper relies on this without support.
A key knowledge gap exists regarding the potential of emergent SARS-CoV-2 variants to evade overall recognition by human immune responses.
“The present study addresses a key knowledge gap pertaining to the potential of emergent SARS-CoV-2 variants to evade overall recognition by human immune responses.”
The paper relies on this without support.
The corrected fold-change thresholds derived from assay variability (2.3 for CD4-AIM, 2.4 for CD8-AIM, 1.6 for FluoroSPOT) represent a biologically meaningful reduction in T cell responses.
“For CD4-AIM assays, that corresponded to a corrected fold-change of 2.3, for CD8-AIM of 2.4 and for FluoroSPOT of 1.6 as shown in Table S3.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
mRNA vaccination generates spike-specific memory CD4+ and CD8+ T cell responses.
“mRNA vaccination has also been shown to generate spike-specific memory CD4+ and CD8+ T cell responses (19–22).”
From mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern (2021) · cites this paper as [21]
SARS-CoV-2 mRNA vaccination efficiently primed antigen-specific CD4+ T cells and CD8+ T cells.
“Consistent with recent studies, SARS-CoV-2 mRNA vaccination efficiently primed antigen-specific CD4+ T cells and CD8+ T cells (Fig. 5, C and D) (20–22).”
From mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern (2021) · cites this paper as [21]
Memory T cell responses have been shown to be less affected by VOCs than humoral immune responses.
“Memory T cell responses have also been shown to be less affected by VOCs than humoral immune responses (21, 50).”
From mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern (2021) · cites this paper as [21]
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No citation lists for this paper yet — checked again daily.
References 85 · Cited by 706
Research works printed but not linked: 3
- Washington, 2021, Genomic epidemiology identifies emergence and rapid transmission of SARS-CoV-2 B.1.1.7 in the United States, medRxiv
- Krammer, 2018, Is It Possible to Develop a “Universal” Influenza Virus Vaccine? Potential Target Antigens and Critical Aspects for a Universal Influenza Vaccine, Cold Spring Harb. Perspect. Biol., 10, a028845, 10.1101/cshperspect.a028845 · DOI
- da Silva Antunes, 2021, Differential T cell reactivity to endemic coronaviruses and SARS-CoV-2 in community and health care workers, J. Infect. Dis., jiab176
- Authors
- Tarke, A., Sidney, J., Methot, N., Yu, E. D., Zhang, Y., Dan, J. M., Goodwin, B., Rubiro, P., Sutherland, A., Wang, E., Frazier, A., Ramirez, S. I., Rawlings, S. A., Smith, D. M., da Silva Antunes, R., Peters, B., Scheuermann, R. H., Weiskopf, D., Crotty, S., Grifoni, A., & Sette, A.
- Affiliations
- La Jolla Institute for Immunology (US)
- J. Craig Venter Institute (US)
- University of California San Diego (US)
- Corresponding author
- Grifoni, Alba
- Sette, Alessandro
- ORCID
- Venue
- Cell Reports Medicine
- Publisher
- Elsevier BV
- Published
- 2021-07
- Volume
- 2
- Issue
- 7
- Pages
- 100355
- ISSN
- 2666-3791 (ISSN-L)
- PMC
- PMC8249675
- OpenAlex
- W3173512675
- Cited by
- 706
- References
- 85
- Citations by year
- 2026: 19 · 2025: 58 · 2024: 71 · 2023: 123 · 2022: 253 · 2021: 182
- FWCI
- 49.96
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports Medicine (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- eScholarship (California Digital Library) (submittedVersion)
- ImmPort
- Funders
- UCSD (AI007384, AI007036)
- NIH (AI036214, HHSN75N93019C00076, U01 CA260541-01, AI135078)
- National Institute of Allergy and Infectious Diseases (AI142742, 75N93019C00001, 75N9301900065)
- John and Mary Tu Foundation
- Università degli Studi di Genova
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- SARS-CoV-2 variants, COVID-19 pandemic, CD4+ T cells, CD8+ T cells, T cell epitopes, Alpha variant, Beta variant, P.1, BNT162b2, vaccine escape, T cell response, epitope mutations, convalescent patients
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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