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Cited by 1,860SARS-CoV-2 and COVID-19 ResearchCOVID-19 Clinical Research StudiesImmune responses and vaccinations

Adaptive immunity to SARS-CoV-2 and COVID-19

Open access
Sette, Alessandro, Crotty, Shane·2021·Cell
DOI 10.1016/j.cell.2021.01.007PMC PMC7803150
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Abstract

The adaptive immune system is important for control of most viral infections. The three fundamental components of the adaptive immune system are B cells (the source of antibodies), CD4+ T cells, and CD8+ T cells. The armamentarium of B cells, CD4+ T cells, and CD8+ T cells has differing roles in different viral infections and in vaccines, and thus it is critical to directly study adaptive immunity to SARS-CoV-2 to understand COVID-19. Knowledge is now available on relationships between antigen-specific immune responses and SARS-CoV-2 infection. Although more studies are needed, a picture has begun to emerge that reveals that CD4+ T cells, CD8+ T cells, and neutralizing antibodies all contribute to control of SARS-CoV-2 in both non-hospitalized and hospitalized cases of COVID-19. The specific functions and kinetics of these adaptive immune responses are discussed, as well as their interplay with innate immunity and implications for COVID-19 vaccines and immune memory against re-infection.

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Crossref · 10.1016/j.cell.2021.01.007

Cites

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Claims the paper makes

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  • Interpretationcitation

    Fatal COVID-19 appears to be a situation of high viral burden in the absence of a substantive adaptive immune response.

    “If the adaptive immune response starts too late, fatal COVID-19 appears to be a situation where viral burden is high (Magleby et al., 2020) in the absence of a substantive adaptive immune response (Figure 2C).”
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    • cites Magleby et al., 2020

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  • Interpretationreasoning

    A massive innate immune response in the absence of T cell control results in excessive lung immunopathology in severe COVID-19.

    “It is plausible that the innate immune system tries to fill the vacuum left by the absence of a T cell response, attempting to control the virus with an ever-expanding innate immune response. That solution ends up untenable, as a massive innate response results in excessive lung immunopathology.”
    Quote in the paperSubstantial claim
  • Premisecitation

    SARS-CoV-2-specific T cell responses are significantly associated with milder COVID-19 disease.

    “Studies of acute and convalescent COVID-19 patients have observed that SARS-CoV-2-specific T cell responses are significantly associated with milder disease (Liao et al., 2020; Rydyznski Moderbacher et al., 2020; Sekine et al., 2020; Zhou et al., 2020b), suggesting that T cell responses may be important for control and resolution of a primary SARS-CoV-2 infection.”
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    • cites Liao et al., 2020 source

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    • cites Rydyznski Moderbacher et al., 2020 source

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    • cites Sekine et al., 2020 source

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  • Premisecitation

    Individuals with defective type I IFN responses have very high risk of severe or fatal COVID-19.

    “The risk of a poor early innate immune response to SARS-CoV-2 is highlighted by the striking findings of very high risk of severe or fatal COVID-19 in individuals with defective type I IFN responses (Bastard et al., 2020; Zhang et al., 2020).”
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    • cites Bastard et al., 2020 source

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    • cites Zhang et al., 2020 source

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  • Premisecitation

    SARS-CoV-2 is unusually effective at evading or delaying early innate immune responses, including type I and type III IFNs, in vitro and in humans.

    “In a SARS-CoV-2 infection, the virus is particularly effective at avoiding or delaying triggering intracellular innate immune responses associated with type I and type III IFNs in vitro (Blanco-Melo et al., 2020) and in humans (Arunachalam et al., 2020; Bastard et al., 2020; Blanco-Melo et al., 2020; Laing et al., 2020).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Blanco-Melo et al., 2020 source

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    • cites Arunachalam et al., 2020 source

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    • cites Bastard et al., 2020 source

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    • Rests on an assumption: Any virus that can cause disease in humans must have at least one immune evasion mechanism.
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  • May combine two claims.

    Interpretationreasoning

    Early adaptive immune responses are very beneficial, while late adaptive immune responses are too late to control SARS-CoV-2.

    “consistent with a working model that early adaptive immune responses are very beneficial, and late adaptive immune responses are simply too late (Figure 2C).”
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    Premisecitation

    COVID-19 is caused by the novel human pathogen SARS-CoV-2.

    “Coronavirus disease 2019 (COVID-19), caused by the novel human pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Hu et al., 2020)”
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    • cites Hu et al., 2020

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    Premisecitation

    Humans make SARS-CoV-2-specific antibodies, CD4+ T cells, and CD8+ T cells in response to infection.

    “Humans make SARS-CoV-2-specific antibodies, CD4+ T cells, and CD8+ T cells in response to SARS-CoV-2 infection (Grifoni et al., 2020; Krammer, 2020; Stephens and McElrath, 2020) (Figure 1).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Grifoni et al., 2020 source

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    • cites Krammer, 2020 source

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    • cites Stephens and McElrath, 2020 source

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    Premisecitation

    Severe end-stage COVID-19 is associated with elevated neutrophils in blood and massive neutrophil numbers in lungs, but not with preferentially elevated T cell abundance in lung tissue.

    “particularly observation of elevated frequencies of neutrophils (the most common cell type of the innate immune system) in blood (Kuri-Cervantes et al., 2020), and massive numbers of neutrophils in lungs, associated with severe, end-stage COVID-19 disease (Li et al., 2020b; Liao et al., 2020; Radermecker et al., 2020; Schurink et al., 2020). In contrast, end-stage disease is not generally”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Kuri-Cervantes et al., 2020 source

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    • cites Li et al., 2020b

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    • cites Liao et al., 2020 source

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  • May combine two claims.

    Interpretationreasoning

    If innate immune response delay is too long, the virus replicates extensively in the upper respiratory tract and lungs and adaptive immune priming is delayed, leading to severe lung disease requiring hospitalization.

    “If the innate immune response delay is too long—because of particularly efficient evasion by the virus, defective innate immunity, or a combination of both—then the virus (1) gets a large head start in replication in the upper respiratory tract (URT) and lungs, and (2) fails to prime an adaptive immune response for a long time, resulting in conditions that lead to severe enough lung disease for”
    Quote in the paperSubstantial claim

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    Premisecitation

    Ineffective IFN innate immunity is strongly associated with failure to control primary SARS-CoV-2 infection and high risk of fatal COVID-19, accompanied by innate cell immunopathology and elevated CXCL10, IL-6, and IL-8.

    “Ineffective IFN innate immunity has been strongly associated with failure to control a primary SARS-CoV-2 infection and a high risk of fatal COVID-19, accompanied by innate cell immunopathology and a plasma cytokine signature of elevated CXCL10, interleukin (IL)-6, and IL-8 in many studies (Aid et al., 2020; Kuri-Cervantes et al., 2020; Li et al., 2020b; Lucas et al., 2020; Radermecker et al., 202”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Aid et al., 2020 source

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    • cites Kuri-Cervantes et al., 2020 source

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    • cites Li et al., 2020b

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  • May combine two claims.

    Premisecitation

    Neutralizing antibodies against SARS-CoV-2 exhibit little to no somatic hypermutation and are produced by B cells with a wide range of V genes.

    “The neutralizing antibodies are produced by B cells with a wide range of heavy chain and light chain V genes (Robbiani et al., 2020; Rogers et al., 2020). SARS-CoV-2 neutralizing antibodies also exhibit little to no somatic hypermutation (Gaebler et al., 2020; Robbiani et al., 2020; Rogers et al., 2020).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Robbiani et al., 2020 source

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    • cites Rogers et al., 2020 source

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    • cites Gaebler et al., 2020

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    Premisecitation

    Spike, M, and nucleocapsid are the most prominent targets of SARS-CoV-2-specific CD4+ T cells, with substantial responses also against ORF3a and nsp3.

    “Spike, M, and nucleocapsid are the most prominent targets of SARS-CoV-2-specific CD4+ T cells (Grifoni et al., 2020), with substantial responses also against ORF3a and nsp3 (Le Bert et al., 2020; Grifoni et al., 2020; Nelde et al., 2021; Oja et al., 2020; Peng et al., 2020).”
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    • cites Grifoni et al., 2020 source

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    • cites Le Bert et al., 2020 source

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    • cites Nelde et al., 2021 source

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    Premisecitation

    The dominant cytokine produced by SARS-CoV-2-specific CD4+ T cells from COVID-19 patients is IFNγ, with a Th1 signature including TNF and IL-2.

    “The dominant cytokine produced by SARS-CoV-2-specific CD4+ T cells from COVID-19 patients is IFNγ (Braun et al., 2020; Grifoni et al., 2020; Rydyznski Moderbacher et al., 2020; Weiskopf et al., 2020), with a clear IFNγ, tumor necrosis factor (TNF), IL-2 protein signature of canonical Th1 cells (Braun et al., 2020; Rydyznski Moderbacher et al., 2020; Peng et al., 2020; Sekine et al., 2020).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Braun et al., 2020 source

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    • cites Grifoni et al., 2020 source

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    • cites Rydyznski Moderbacher et al., 2020 source

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    Premisecitation

    The vast majority of SARS-CoV-2 infected individuals seroconvert within 5-15 days post-symptom onset, with about 90% seroconversion by day 10.

    “The vast majority of SARS-CoV-2 infected individuals seroconvert within 5–15 days PSO, with ∼90% seroconversion by day 10 PSO (Long et al., 2020; Rydyznski Moderbacher et al., 2020; Premkumar et al., 2020; Ripperger et al., 2020; Suthar et al., 2020).”
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    • cites Long et al., 2020 source

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    • cites Rydyznski Moderbacher et al., 2020 source

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    • cites Premkumar et al., 2020 source

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    Premisecitation

    The receptor binding domain of Spike is the target of more than 90% of neutralizing antibodies in COVID-19 cases, with some targeting the N-terminal domain.

    “Spike is the target of SARS-CoV-2 neutralizing antibodies, and the receptor binding domain (RBD) of Spike is the target of >90% of neutralizing antibodies in COVID-19 cases (Brouwer et al., 2020; Piccoli et al., 2020; Robbiani et al., 2020; Rogers et al., 2020; Suthar et al., 2020), with some neutralizing antibodies instead targeting the N-terminal domain (NTD) (Liu et al., 2020).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Brouwer et al., 2020 source

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    • cites Piccoli et al., 2020 source

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    • cites Robbiani et al., 2020 source

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    Interpretationcitation

    Instances of antibody-associated disease pathology with certain SARS immunizations were not FcR-dependent and appear more likely to be immune complex driven inflammation.

    “the instances of antibody-associated disease pathology with certain SARS immunizations were not FcR-dependent and appear more likely to be immune complex driven inflammation (Sariol and Perlman, 2020).”
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    • cites Sariol and Perlman, 2020

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    It is expected that blood IgG and IgA levels are reflected in the lung airways.

    “given the tight relationship between the lungs and the circulatory system, it is expected that blood IgG and IgA levels are reflected in the lung airways.”
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    Premisecitation

    High neutralizing antibody titers are associated with severe disease and potentially extrafollicular B cell responses.

    “High neutralizing antibody titers are associated with severe disease and potentially extrafollicular B cell responses (Piccoli et al., 2020; Woodruff et al., 2020), while SARS-CoV-2-specific Tfh cells have different associations depending on the study (Juno et al., 2020; Meckiff et al., 2020; Rydyznski Moderbacher et al., 2020; Oja et al., 2020).”
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    • cites Piccoli et al., 2020 source

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    • cites Woodruff et al., 2020 source

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    Premisecitation

    At least some individuals are low or negative to commercial IgG assays while retaining detectable SARS-CoV-2 CD4+ T cells, representing 1%-10% of PCR-confirmed SARS-CoV-2 infections.

    “at least some individuals are low or negative to commercial IgG assays, while retaining detectable SARS-CoV-2 CD4+ T cells. Current estimates are these individuals represent 1%–10% of PCR-confirmed SARS-CoV-2 infections (Gudbjartsson et al., 2020; Lipsitch et al., 2020; Nelde et al., 2021; Schwarzkopf et al., 2021; Sekine et al., 2020).”
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    • cites Gudbjartsson et al., 2020 source

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    • cites Lipsitch et al., 2020 source

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    • cites Nelde et al., 2021 source

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    Premisecitation

    Approximately 10% of severe COVID-19 cases are in people with type I IFN autoantibodies, and over 90% of those cases were men.

    “∼10% of severe COVID-19 cases are in people with type I IFN autoantibodies, and strikingly, over 90% of those cases were men (Bastard et al., 2020).”
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    • cites Bastard et al., 2020 source

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    Interpretationcitation

    The HCoV challenge studies provide evidence for immune memory that at least provided protection from clinical symptoms and reduced viral shedding, and this provides support for the potential efficacy of a SARS-CoV-2 vaccine.

    “Thus, the studies provide evidence for immune memory that at least provided protection from clinical symptoms and reduced viral shedding; this also provides support for the potential efficacy of a SARS-CoV-2 vaccine.”
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    • cites Callow et al., 1990 source

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    • cites Reed, 1984 source

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    Premisenone given

    Among COVID-19 cases, almost all individuals become seropositive and almost all become positive for SARS-CoV-2 CD4+ T cells.

    “Among COVID-19 cases, almost all individuals become seropositive, and almost all individuals become positive for SARS-CoV-2 CD4+ T cells.”
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    Premisecitation

    At 6 months post-infection, approximately 90% of subjects were positive for memory CD4+ T cells and approximately 70% for memory CD8+ T cells.

    “Specifically assessing T cells at 6 months post-infection in 95 subjects, one study found ∼90% positive for memory CD4+ T cells and ∼70% positive for memory CD8+ T cells (Zuo et al., 2020a).”
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    • cites Zuo et al., 2020a

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    Premisecitation

    There is an approximately 1,000-fold range in the magnitude of antibody responses to SARS-CoV-2, as well as heterogeneity in the magnitude of SARS-CoV-2-specific CD4+ and CD8+ T cell responses.

    “There is an ∼1,000-fold range in the magnitude of antibody responses to SARS-CoV-2, as well as heterogeneity in the magnitude of SARS-CoV-2-specific CD4+ T cell and CD8+ T cell responses (Grifoni et al., 2020; Rydyznski Moderbacher et al., 2020).”
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    • cites Grifoni et al., 2020 source

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    • cites Rydyznski Moderbacher et al., 2020 source

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    Interpretationcitation

    Asymptomatic SARS-CoV-2 cases tend to have lower Spike and nucleocapsid IgG titers, and it is plausible that they are enriched for individuals with undetectable antibodies by commercial serological assays but circulating SARS-CoV-2 T cells.

    “Given that asymptomatic cases of SARS-CoV-2 infection tend to have lower Spike and nucleocapsid IgG titers (Piccoli et al., 2020), it is plausible that asymptomatic cases are enriched for individuals with undetectable antibodies by commercial serological assays but possess circulating SARS-CoV-2 T cells”
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    • cites Piccoli et al., 2020 source

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    • Rests on an assumption: Many commercial serological assays have limited sensitivity for low-level Spike IgG.

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    Premisecitation

    MERS Spike IgG did not persist for 2 years in mild or subclinical cases, whereas T cell memory did persist.

    “MERS Spike IgG did not persist for 2 years in mild or subclinical cases, whereas T cell memory did persist (Sariol and Perlman, 2020).”
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    • cites Sariol and Perlman, 2020

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    Interpretationreasoning

    Older individuals are more likely to have a naive T cell pool insufficient to make a detectable SARS-CoV-2 T cell response or to make a response so slowly that the virus has too much of a head start.

    “the older the person is the more likely they possess a naive T cell pool insufficient to make a detectable SARS-CoV-2 T cell response or make a SARS-CoV-2 T cell response so slowly that the virus has too much of a head start to be overcome.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: A T cell response to any new viral infection depends on the repertoire of naive T cells.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    There are anecdotal examples of SARS-CoV-2 re-infection.

    “There are anecdotal examples of SARS-CoV-2 re-infection”
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    Premisenone given

    Current nonhuman primate models require high doses of SARS-CoV-2 and produce relatively short and mild disease kinetics.

    “although the current nonhuman primate models are quite valuable, infection requires high doses of SARS-CoV-2, and the disease kinetics are relatively short and mild.”
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    Premisecitation

    The Spike D614G variant is now globally common, binds ACE2 more tightly, and is more transmissible.

    “The Spike D614G variant that is now globally common (that binds ACE2 more tightly and is more transmissible)”
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    • cites Hou et al., 2020 source

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    • cites Korber et al., 2020 source

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    Interpretationreasoning

    SARS-CoV-2 is a relatively easy neutralization target that elicits a diverse array of antibodies in each person.

    “indicating that SARS-CoV-2 is a relatively easy neutralization target that elicits a diverse array of antibodies in each person”
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    Interpretationcitation

    Data so far indicate that T cell memory, B cell memory, and antibodies are all likely to persist for years in most individuals infected by SARS-CoV-2.

    “data so far indicate that T cell memory, B cell memory, and antibodies are all likely to persist for years in most individuals infected by SARS-CoV-2 (Dan et al., 2021; Gaebler et al., 2020; Wajnberg et al., 2020; Zuo et al., 2020a).”
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    • cites Dan et al., 2021 source

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    • cites Wajnberg et al., 2020 source

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    Interpretationreasoning

    Current information is insufficient to determine how rare re-infections are or whether they occur in individuals with detectable immune memory.

    “there is currently insufficient information to tell how rare re-infections are and whether they occur in individuals with detectable immune memory.”
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    Premisecitation

    The Spike N439 variant has enhanced ACE2 binding but is still robustly neutralized by serum from the vast majority of COVID-19 patients.

    “The Spike N439 variant has enhanced binding to ACE2 but has been shown to still be robustly neutralized by serum from the vast majority of COVID-19 patients”
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    • cites Thomson et al., 2020

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    Interpretationcitation

    Antibody titers were not a surrogate indicator of the magnitude of memory T cells, suggesting that simple antibody serodiagnostic tests will not be a robust indicator of protective immunity in people previously infected with SARS-CoV-2.

    “Antibody titers were not a surrogate indicator of the magnitude of memory T cells (Dan et al., 2021), suggesting that simple antibody serodiagnostic tests will not be a robust indicator of protective immunity in people previously infected with SARS-CoV-2.”
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    • cites Dan et al., 2021 source

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    Premisecitation

    In two nonhuman primate studies, animals previously infected with SARS-CoV-2 were protected against high-dose re-challenge one month later, and protection was associated with neutralizing antibodies.

    “Animals infected with SARS-CoV-2 were protected from a high dose re-challenge with SARS-CoV-2 1 month later, and protection was associated with neutralizing antibodies”
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    • cites Chandrashekar et al., 2020 source

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    • cites Deng et al., 2020 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Immunization occurs well in advance of infection, giving the adaptive immune system time to respond, expand, and mature.

    “immunization occurs well in advance of infection, giving the adaptive immune system time to respond, expand, and mature.”
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    Premisecitation

    AstraZeneca/Oxford ChAdOx1 interim phase 3 results showed per-protocol efficacy against COVID-19 of 62% and overall efficacy of 70%, with 131 total cases.

    “Per protocol, efficacy against COVID-19 was 62% and overall efficacy was 70% (131 total cases)”
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    • cites Voysey et al., 2021 source

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    Premisenone given

    Both RNA vaccines received Emergency Use Authorization from the FDA in December.

    “Both vaccines received Emergency Use Authorization from the FDA in December.”
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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Many vaccines are close to 100% effective, including vaccines against respiratory pathogens such as smallpox and measles.

    “many vaccines are close to 100% effective, including vaccines against respiratory pathogens such as smallpox and measles.”
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    Interpretationreasoning

    SARS-CoV-2 infection may elicit better protective immunity in the upper respiratory tract than major current COVID-19 vaccine candidates because infection occurs at that site and is more likely to elicit tissue-resident memory.

    “It is plausible that SARS-CoV-2 infection may elicit better protective immunity in the URT than any of the major current COVID-19 vaccine candidates, because infection occurs at that site and is therefore more likely to elicit tissue-resident memory.”
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    Premisecitation

    The Pfizer/BioNtech phase 3 interim analysis showed 95% efficacy at preventing disease, with 170 COVID-19 cases for FDA evaluation and 94 cases in the initial release.

    “the vaccine had 95% efficacy at preventing disease, with 170 COVID-19 cases for the U.S. Food and Drug Administration (FDA) to evaluate (94 cases in the initial release)”
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    • cites U.S. Food and Drug Administration, 2020b

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    Premisecitation

    Moderna mRNA-1273 phase 3 interim results showed 94% efficacy at protection from COVID-19, with 196 total cases for FDA review.

    “94% efficacy at protection from COVID-19 was reported, with 196 total cases to evaluate in the FDA review”
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    • cites Baden et al., 2020

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  • May combine two claims.

    Interpretationreasoning

    Overall interim results from the two RNA vaccine trials were virtually identical, with 94% and 95% efficacy and similar other outcomes.

    “Overall, the interim results from the two COVID-19 RNA vaccine trials were virtually identical, with 94% and 95% efficacy and similar other outcomes.”
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    Interpretationreasoning

    Vaccines overcome the speed problem of adaptive immunity and T cell responses because priming occurs well before virus exposure.

    “vaccines overcome/bypass the speed problem of adaptive immunity and T cell responses. Priming of the immune system by a vaccine happens well in advance of virus exposure.”
    Quote in the paperSubstantial claim

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    Premisecitation

    The Pfizer vaccine is safe, having been injected into over 20,000 people with two doses and no serious safety concerns.

    “The vaccine is also safe, having been injected into over 20,000 people, with two doses (>40,000 immunizations) and no serious safety concerns”
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    • cites U.S. Food and Drug Administration, 2020b

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    Interpretationcitation

    Several nonhuman primate COVID-19 vaccine studies are consistent with the possibility that COVID-19 vaccines prevent severe disease in humans but may not prevent upper respiratory tract infection.

    “Several non-human primate COVID-19 vaccine studies are consistent with the possibility of COVDI-19 vaccines preventing severe disease in humans but possibly not preventing URT infection”
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    • cites Corbett et al., 2020 source

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    • cites van Doremalen et al., 2020 source

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    • cites Gao et al., 2020 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Moderna mRNA-1273 is also a full-length membrane-anchored SARS-CoV-2 Spike with P-P trimer stabilization mutations.

    “The Moderna RNA vaccine mRNA-1273 is also a full-length (membrane-anchored) SARS-CoV-2 Spike with P-P trimer stabilization mutations.”
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    Premisenone given

    Lung infection is a major component of severe COVID-19 and is relatively slow, while upper respiratory tract infection is important for transmission.

    “Although lung infection is a major component of severe COVID-19 (and relatively slow), URT infection is important for transmission.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Pfizer BNT162b2 has been tested for immunogenicity in individuals over 65 years old, with limited but encouraging results; antibody responses were similar in both age groups.

    “The Pfizer BNT162b2 vaccine has been tested for immunogenicity in individuals >65 years old, and the results were limited but encouraging. Antibody responses were similar in both age groups”
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    • cites Walsh et al., 2020 source

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    Premisecitation

    In the Moderna trial, there were 30 severe COVID-19 cases, all in the placebo group, indicating the vaccine works very well at preventing severe COVID-19.

    “There were 30 severe cases of COVID-19 in the trial, all of which were in the placebo group, indicated the Moderna vaccine works very well at preventing severe COVID-19”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Baden et al., 2020

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The current pertussis vaccine prevents clinical disease but not infection, and probably not transmission.

    “the current pertussis vaccine prevents clinical disease but not infection, and probably not transmission”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Warfel et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The symptomatic-case endpoint was chosen because preventing systemic disease is the primary goal of COVID-19 vaccines and continuous infection checking of 40,000 people for months would be extraordinarily challenging.

    “This endpoint was decided on because preventing systemic disease is the primary goal of COVID-19 vaccines, and it would be extraordinarily challenging to check 40,000 people for SARS2 infections continuously for months.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Those studies used other antigens and different vaccine formulations.

    “However, those studies were with other antigens and different vaccine formulations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    The safety profile of the two RNA vaccines is excellent, with a combined more than 70,000 doses administered and no serious adverse events.

    “The safety profile of the two vaccines is also excellent, with a combined >70,000 doses administered and no serious adverse events.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Multiple candidate vaccines had similar immunogenicity profiles to the COVID-19 RNA vaccines in humans, with equivalent or better neutralizing antibody titers or CD4+ T cell responses.

    “Multiple candidate vaccines had similar immunogenicity profiles to the COVID-19 RNA vaccines in humans, with equivalent or better neutralizing antibody titers or CD4+ T cell responses”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Folegatti et al., 2020 source

      Not checked in the free run.

    • cites Jackson et al., 2020 source

      Not checked in the free run.

    • cites Keech et al., 2020 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    There is no specific reason not to expect multiple other candidate COVID-19 vaccines to do well in humans now, although phase 3 clinical trial outcomes are difficult to predict.

    “In sum, there is no specific reason not to expect multiple other candidate COVID-19 vaccines to do well in humans now; although, of course, vaccine phase 3 clinical trial outcomes are notoriously difficult to predict.”
    Quote in the paperNot a substantial claim
53 of 53

  • The paper relies on this without support.

    Adaptive immune responses are important for control and clearance of almost all viral infections that cause disease in humans, and immune memory is central to vaccine success.

    “Given that adaptive immune responses are important for the control and clearance of almost all viral infections that cause disease in humans, and adaptive immune responses and immune memory are central to the success of all vaccines, it is critical to understand adaptive responses to SARS-CoV-2.”

  • The paper relies on this without support.

    Neutralizing antibody responses are generally T cell-dependent.

    “because neutralizing antibody responses are generally T cell-dependent.”

  • The paper relies on this without support.

    Antibodies mostly stop viruses outside cells and T cells stop viruses inside cells.

    “In oversimplified terms, antibodies mostly stop viruses outside of cells and T cells stop viruses inside of cells.”

  • The paper relies on this without support.

    Higher antigen load drives higher antibody titers.

    “In general, and in various animal models, higher antigen load drives higher antibody titers.”

  • The paper relies on this without support.

    SARS-CoV-2 infects epithelial cells of the upper respiratory tract and lungs.

    “SARS-CoV-2 infects epithelial cells of the URT (nasal passages and throat) and lungs (bronchi and lung alveoli).”

  • The paper relies on this without support.

    Any virus that can cause disease in humans must have at least one immune evasion mechanism.

    “Any virus that can cause disease in humans must have at least one immune evasion mechanism—at least one immune evasion “trick.””

  • The paper relies on this without support.

    Adaptive immune responses take about 6–10 days after priming to generate sufficient cells to control a viral infection.

    “Adaptive immune responses take time to generate sufficient cells to control a viral infection, ∼6–10 days after priming (Figure 2A), due to the inherent time demands for extensive proliferation and differentiation of naive cells into effector cells.”

  • The authors state this as an assumption.

    A change in nucleocapsid IgG titers should be assigned to a single viral infection with the highest titer because of cross-reactivity.

    “if one assumes that a change in nucleocapsid IgG titers should be assigned to a single viral infection with the highest titer (due to cross-reactivity)”

  • The paper relies on this without support.

    Many commercial serological assays have limited sensitivity for low-level Spike IgG.

    “many commercial serological assays have limited sensitivity for low level Spike IgG”

  • The paper relies on this without support.

    A T cell response to any new viral infection depends on the repertoire of naive T cells.

    “A T cell response to any new viral infection depends on the repertoire of naive T cells.”

  • The paper relies on this without support.

    Sterilizing immunity against viruses can only be achieved by high-titer neutralizing antibodies.

    “Sterilizing immunity against viruses can only be accomplished by high-titer neutralizing antibodies”

  • The paper relies on this without support.

    Memory B and T cells can take several days to reactivate and generate recall responses.

    “Memory B and T cells can take several days to reactivate and generate recall responses.”

  • The paper relies on this without support.

    For most viral infections that elicit immunological memory, protective immunity from re-infection, or at least re-infection causing clinical disease, lasts for multiple years or more in most individuals.

    “For most viral infections that elicit immunological memory, protective immunity from re-infection—or at least re-infection resulting in clinical disease—lasts for multiple years or more in most individuals.”

  • The paper relies on this without support.

    Many RNA viruses, such as measles and polioviruses, exhibit antigenic stability and unchanging serotypes over many years.

    “Many RNA viruses, such as measles and polioviruses, exhibit antigenic stability and unchanging serotypes over periods of many years.”

  • The paper relies on this without support.

    Immune memory is the source of protection by almost all vaccines.

    “Immune memory is the source of protection by almost all vaccines”

  • The paper relies on this without support.

    Almost all COVID-19 vaccines target Spike only.

    “because almost all COVID-19 vaccines target Spike only.”

  • The paper relies on this without support.

    Older individuals are at much higher risk for severe COVID-19.

    “Older individuals are at much higher risk for severe COVID-19.”

  • The paper relies on this without support.

    A number of human vaccines against respiratory pathogens do not depend on local T cell memory or are very unlikely to elicit upper respiratory tract T cell memory.

    “A number of human vaccines against respiratory pathogens do not depend on local T cell memory, or are very unlikely to elicit URT T cell memory”
18 of 18

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?

  • Innate immune cells are differently programmed in mild versus severe COVID-19, with corresponding differences in adaptive immunity.

    “a scenario emerges with rather differently programmed innate immune cells in mild versus severe disease courses”

    From COVID-19 and the human innate immune system (2021) · cites this paper as Sette and Crotty, 2021

  • Individuals 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”

    From Impact of SARS-CoV-2 variants on the total CD4+ and CD8+ T cell reactivity in infected or vaccinated individuals (2021) · cites this paper as [33]

  • CD4+ 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”

    From Impact of SARS-CoV-2 variants on the total CD4+ and CD8+ T cell reactivity in infected or vaccinated individuals (2021) · cites this paper as [33]

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 7

  1. Anderson, 2020, Seasonal human coronavirus antibodies are boosted upon SARS-CoV-2 infection but not associated with protection, medRxiv
  2. Lumley, 2020, Antibodies to SARS-CoV-2 are associated with protection against reinfection, N. Engl. J. Med.
  3. Murugesan, 2020, Interferon-gamma release assay for accurate detection of SARS-CoV-2 T cell response, Clin. Infect. Dis.
  4. Oran, 2020, Prevalence of Asymptomatic SARS-CoV-2 Infection : A Narrative Review, Ann. Intern. Med., 173, 362, 10.7326/M20-3012 · DOI
  5. Walsh, 2020, Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates, N. Engl. J. Med., 383, 2439, 10.1056/NEJMoa2027906 · DOI · Paper page
  6. Wang, 2020, Enhanced SARS-CoV-2 Neutralization by Secretory IgA in vitro, bioRxiv
  7. Wyllie, 2020, SARS-CoV-2 responsive T cell numbers are associated with protection from COVID-19: A prospective cohort study in keyworkers, medRxiv

Cited by

Sorted by citations

Authors
Sette, A., & Crotty, S.
Affiliations
La Jolla Institute for Immunology (US)
Corresponding author
Crotty, Shane
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2021-02
Volume
184
Issue
4
Pages
861-880
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2021.01.007
PMC
PMC7803150
OpenAlex
W3119858919
Cited by
1,860
References
174
Citations by year
2026: 103 · 2025: 196 · 2024: 259 · 2023: 376 · 2022: 555 · 2021: 365 · 2020: 5
FWCI
45.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
Keywords
SARS-CoV-2, COVID-19 pandemic, adaptive immunity, B cells, CD4+ T cells, CD8+ T cells, neutralizing antibodies, antigen-specific immune response, innate immunity, COVID-19 vaccines, immunological memory, reinfection, virus control
MeSH terms
Race Factors, COVID-19, SARS-CoV-2, COVID-19 Vaccines, Post-Acute COVID-19 Syndrome, Age Factors, B-Lymphocytes, Clinical Trials as Topic, Humans, Immunologic Memory, Sex Factors, T-Lymphocyte Subsets, Viral Load, Adaptive Immunity

About these checks

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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