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Cited by 560SARS-CoV-2 and COVID-19 ResearchImmune responses and vaccinationsvaccines and immunoinformatics approaches

Immunological mechanisms of vaccine-induced protection against COVID-19 in humans

Open access
Sadarangani, Manish, Marchant, Arnaud, Kollmann, Tobias R.·2021·Nature Reviews Immunology
DOI 10.1038/s41577-021-00578-zPMC PMC8246128
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Abstract

Most COVID-19 vaccines are designed to elicit immune responses, ideally neutralizing antibodies (NAbs), against the SARS-CoV-2 spike protein. Several vaccines, including mRNA, adenoviral-vectored, protein subunit and whole-cell inactivated virus vaccines, have now reported efficacy in phase III trials and have received emergency approval in many countries. The two mRNA vaccines approved to date show efficacy even after only one dose, when non-NAbs and moderate T helper 1 cell responses are detectable, but almost no NAbs. After a single dose, the adenovirus vaccines elicit polyfunctional antibodies that are capable of mediating virus neutralization and of driving other antibody-dependent effector functions, as well as potent T cell responses. These data suggest that protection may require low levels of NAbs and might involve other immune effector mechanisms including non-NAbs, T cells and innate immune mechanisms. Identifying the mechanisms of protection as well as correlates of protection is crucially important to inform further vaccine development and guide the use of licensed COVID-19 vaccines worldwide.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that COVID-19 vaccine protection probably involves mechanisms beyond neutralizing antibodies, especially after a single dose, and synthesizes efficacy and immunogenicity data from leading vaccine platforms. It calls for unbiased identification of immune correlates to guide vaccine development, dosing intervals, and responses to viral variants.

Key findings

  • The mRNA vaccines BNT162b2 and mRNA-1273 showed very high efficacy, including more than 90% protection from symptomatic disease after only one dose in the review’s summary, when neutralizing antibodies were below 5% of the post-second-dose peak; trial efficacy was 95% after two doses for both.
  • Adenoviral-vectored vaccines had mixed efficacy: ChAdOx1 nCoV-19 and Ad26.COV2.S were around 70% after one or two doses, while Gam-COVID-Vac reached about 90% after two doses; ChAdOx1 after one dose induced polyfunctional antibodies and T cell responses peaking at day 14.
  • An analysis of seven vaccines cited in the review found a rank correlation of neutralizing antibody titre with efficacy of rs = 0.79 and anti-spike binding antibody titre with efficacy of rs = 0.93 after a complete series, though it did not fully account for single-dose responses or T cells.
  • Protection may also involve non-neutralizing antibodies with Fc-mediated effector functions, TH1-biased CD4+ T cells, CD8+ T cells, and innate type I/III interferon mechanisms; vaccines were designed to avoid TH2-biased responses because of vaccine-associated enhanced respiratory disease concerns.

Methods

  • Narrative review/Progress article; no new primary data were generated. It synthesizes phase III efficacy and human immunogenicity data for five vaccines with detailed publicly available results: BNT162b2, mRNA-1273, ChAdOx1 nCoV-19, Gam-COVID-Vac, and Ad26.COV2.S, with additional vaccines summarized in tables.
  • Antibody responses are compared with convalescent serum benchmarks, and immunogenicity data are drawn largely from phase I/II trials because few immunological results from phase III efficacy trials were published.
  • Main analysis is qualitative synthesis, including discussion of a cited rank-correlation analysis across seven vaccines and proposed immune mechanisms.

Limitations

  • Stated in the paper: few immunological data from the phase III trials that determined efficacy; assays varied across studies and are not directly comparable; licensed vaccine trials lacked vector controls, so pathogen-agnostic innate effects cannot be assessed; no defined immune correlate exists; correlate analyses covered short-term efficacy of 2–3 months and did not fully consider single-dose or T cell responses; post-vaccination infections were relatively rare, limiting statistical power.
  • Evident from the text: as a review, conclusions rely on published, preprint, and company-reported data, with some vaccines included only through press releases or media reports; long-term durability, mucosal immunity, transmission blocking, and variant effects remain uncertain.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41577-021-00578-z

Cites

174 of 174 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 135 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    One or two doses of BNT162b2 and mRNA-1273 produce relatively low CD8+ T cell responses.

    “By contrast, relatively low levels of CD8+ T cell responses are elicited after one or two doses (Table 1; see Supplementary Table 1).”
    Quote in the paperSubstantial claim
  • Findingown data

    After a single dose, both BNT162b2 and mRNA-1273 induced anti-S and/or anti-RBD binding antibody levels equal to or greater than those in convalescent patients.

    “and both vaccines, after just a single dose, induced levels of anti-S and/or anti-receptor-binding domain (anti-RBD) binding antibodies that were equivalent to or higher than those observed in patients who are in convalescence (Fig. 1; see Supplementary Table 1).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Convalescent serum antibody levels provide a valid reference for comparing vaccine-induced antibody responses and for judging their protective potential.
  • Findingnone given

    In clinical trials, BNT162b2 and mRNA-1273 each gave more than 90% protection against symptomatic disease after a single dose, at a time when neutralizing antibody levels were below 5% of the post-second-dose peak.

    “Both BNT162b2 and mRNA-1273 have demonstrated very high efficacy in clinical trials, including >90% protection from symptomatic disease after only a single dose, when levels of NAbs are <5% of the post-second dose peak (Table 1; see Supplementary Figure 1).”
    Quote in the paperSubstantial claim
  • Premisecitation

    Human recovery from SARS-CoV-2 infection seems to require both antibody and cell-mediated immune responses.

    “Recovery following infection with SARS-CoV-2 in humans appears to involve both humoral and cell-mediated immunity22–24.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [22] Gudbjartsson, D. F. et al. Humoral immune response to SARS-CoV-2 in Iceland. N. Engl. J. Med. 383, 1724–1734 (2020). source

      Not checked in the free run.

    • cites [23] Del Valle, D. M. et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat. Med. 26, 1636–1643 (2020). source

      Not checked in the free run.

    • cites [24] Chen, G. et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J. Clin. Invest. 130, 2620–2629 (2020). source

      Not checked in the free run.

  • Premisecitation

    The two approved mRNA vaccines are efficacious after a single dose at a time when non-neutralizing antibodies and moderate Th1 responses are present but neutralizing antibodies are nearly absent.

    “The two mRNA vaccines approved to date show efficacy even after only one dose, when non-NAbs and moderate T helper 1 cell responses are detectable, but almost no NAbs.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [81] Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N. Engl. J. Med. 383, 2603–2615 (2020). source

      Not checked in the free run.

    • cites [82] Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2020). source

      Not checked in the free run.

    • cites [124] Walsh, E. E. et al. Safety and immunogenicity of two RNA-based COVID-19 vaccine candidates. N. Engl. J. Med. 383, 2439–2450 (2020). source

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  • May combine two claims. 42
  • Classified as probably not a substantial claim. 8

  • May combine two claims.

    Findingown data

    After two doses, both mRNA and adenoviral-vectored vaccines elicit neutralizing antibody levels equal to or higher than convalescent patients, with mRNA vaccines inducing relatively higher levels.

    “Both mRNA and adenoviral-vectored vaccines, after two doses, elicit levels of NAbs that are equivalent to or higher than those seen in patients who are in convalescence (Fig. 1), although the level of NAbs induced seems to be relatively higher with the mRNA vaccines.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Convalescent serum antibody levels provide a valid reference for comparing vaccine-induced antibody responses and for judging their protective potential.

  • May combine two claims.

    Premisecitation

    Neutralizing antibody levels correlate with viral load and are higher in more severe disease and in older versus younger adults.

    “The magnitude of these NAb responses appear to correlate with viral load, with higher responses reported in patients with more severe disease, and in older adults compared with younger adults26–29.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [26] Robbiani, D. F. et al. Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Nature 584, 437–442 (2020). source

      Not checked in the free run.

    • cites [27] Zhou, F. et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395, 1054–1062 (2020). source

      Not checked in the free run.

    • cites [28] Lee, W. T. et al. Neutralizing antibody responses in COVID-19 convalescent sera. J. Infect. Dis. 223, 47–55 (2020). source

      Not checked in the free run.

    • cites [29] Levin, A. T. et al. Assessing the age specificity of infection fatality rates for COVID-19: systematic review, meta-analysis, and public policy implications. Eur. J. Epidemiol. 35, 1123–1138 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Multiple vaccine platforms-mRNA, adenoviral vector, protein subunit, and whole-cell inactivated-have reported phase III efficacy and obtained emergency authorization in numerous countries.

    “Several vaccines, including mRNA, adenoviral-vectored, protein subunit and whole-cell inactivated virus vaccines, have now reported efficacy in phase III trials and have received emergency approval in many countries.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A single dose of adenovirus-vectored vaccines induces polyfunctional antibodies that neutralize virus and mediate other antibody-dependent effector functions, plus strong T cell responses.

    “After a single dose, the adenovirus vaccines elicit polyfunctional antibodies that are capable of mediating virus neutralization and of driving other antibody-dependent effector functions, as well as potent T cell responses.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [87] Voysey, M. et al. 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, 99–111 (2020). source

      Not checked in the free run.

    • cites [88] Voysey, M. et al. Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials. Lancet 397, 881–891 (2021). source

      Not checked in the free run.

    • cites [128] Folegatti, P. M. et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet 396, 467–478 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The data indicate that protection might need only low neutralizing antibody levels and could also involve non-neutralizing antibodies, T cells, and innate immune mechanisms.

    “These data suggest that protection may require low levels of NAbs and might involve other immune effector mechanisms including non-NAbs, T cells and innate immune mechanisms.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Immunological responses measured in phase I/II trials are representative enough of those in phase III efficacy trials to inform mechanisms of protection.

  • May combine two claims.

    Interpretationcitation

    Human and animal evidence suggests that strong cytotoxic CD8+ T cell and Th1-biased CD4+ effector responses, alongside or instead of high neutralizing antibody titers, could produce protective immunity against COVID-19.

    “Evidence from human and animal studies has suggested that in addition — or, possibly, instead of high titres of NAbs — a robust cytotoxic CD8+ T cell response and a TH1 cell-biased CD4+ T cell effector response would result in protective immunity against COVID-19 (ref.54).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Jeyanathan, M. et al. Immunological considerations for COVID-19 vaccine strategies. Nat. Rev. Immunol. 20, 615–632 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SARS-CoV-2-specific IgA appears in nasal washes and saliva during convalescence and might reduce transmission via neutralization and Fc-dependent functions.

    “SARS-CoV-2-specific IgA is detected in nasal washes and in saliva of patients who are in convalescence and could contribute to a reduced interpersonal spread through neutralization and Fc-dependent effector functions37.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Butler, S. E. et al. Features and functions of systemic and mucosal humoral immunity among SARS-CoV-2 convalescent individuals. Preprint at medRxiv https://doi.org/10.1101/2020.08.05.20168971 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Virus-specific CD8+ and CD4+ T cells, including memory CD8+ cells, persist in recovered COVID-19 patients, but their protective role against reinfection or severe disease is unclear.

    “Virus-specific CD8+ and CD4+ T cells, including CD8+ memory T cells, are present in patients who have recovered from COVID-19 (refs44,45), but their importance in protection against future infection and/or severe disease remain uncertain44,46–48.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44] Grifoni, A. et al. Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell 181, 1489–1501.e15 (2020). source

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    • cites [45] Sekine, T. et al. Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19. Cell 183, 158–168.e14 (2020). source

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  • May combine two claims.

    Premisecitation

    Th1 cells producing interferon-γ arise during acute infection, and a Th1-biased response has been proposed to associate with milder disease.

    “Interferon-γ (IFNγ)-producing T helper 1 cells (TH1 cells) are produced during acute infection, and it has been suggested that this TH1 cell-biased phenotype is associated with less severe disease24,49”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Chen, G. et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J. Clin. Invest. 130, 2620–2629 (2020). source

      Not checked in the free run.

    • cites [49] Weiskopf, D. et al. Phenotype and kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory distress syndrome. Sci. Immunol. 5, eabd2071 (2020). source

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  • May combine two claims.

    Premisecitation

    Before host cell contact, spike is in a metastable pre-fusion trimer that rearranges substantially during virus-cell fusion.

    “Prior to contact with the host cell, the S protein is in a metastable pre-fusion conformation and the trimer undergoes substantial rearrangement at the time of virus–cell fusion150,151.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [150] Li, F. Structure, function, and evolution of coronavirus spike proteins. Annu. Rev. Virol. 3, 237–261 (2016). source

      Not checked in the free run.

    • cites [151] Bosch, B. J., van der Zee, R., de Haan, C. A. & Rottier, P. J. The coronavirus spike protein is a class I virus fusion protein: structural and functional characterization of the fusion core complex. J. Virol. 77, 8801–8811 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In non-human primates, passive neutralizing antibody transfer was protective, while CD8+ T cell depletion reduced protection, indicating roles for both.

    “The passive transfer of NAbs was also found to be protective in non-human primate models, whereas removal of CD8+ T cells in the same models impaired protection, suggesting a role for both components53.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] McMahan, K. et al. Correlates of protection against SARS-CoV-2 in rhesus macaques. Nature 590, 630–634 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Type I and type III interferons seem centrally important for protection from COVID-19, though other innate components likely matter too.

    “Although it is likely that there are many innate immune components that are relevant to protection from COVID-19, type I and type III interferons appear centrally important69,70.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [69] Ahmed-Hassan, H. et al. Innate immune responses to highly pathogenic coronaviruses and other significant respiratory viral infections. Front. Immunol. 11, 1979 (2020). source

      Not checked in the free run.

    • cites [70] Park, A. & Iwasaki, A. Type I and type III interferons — induction, signaling, evasion, and application to combat COVID-19. Cell Host Microbe 27, 870–878 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Milder disease and recovery are linked to stronger clonal expansion of CD8+ T cells in lungs and blood, but causality is uncertain.

    “Milder disease and recovery have been associated with a more robust clonal expansion of CD8+ T cells in both the lungs and blood42,43, although whether this is the cause of milder disease or an effect of recovery is unclear.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [42] Liao, M. et al. Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat. Med. 26, 842–844 (2020). source

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    • cites [43] Wen, W. et al. Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing. Cell Discov. 6, 31 (2020). source

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  • May combine two claims.

    Premisecitation

    The timing of type I interferon induction is critical: early interferon appears protective, while later it may be less useful for viral control or may drive immunopathology.

    “The timing of induction of type I interferon (or type III interferon in mucosal tissue) is crucial as the presence of type I interferon early in infection appears to be protective, whereas its relevance for viral control at later time points may be reduced or may even contribute to immunopathology57,71,72.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [57] Lee, J. S. & Shin, E. C. The type I interferon response in COVID-19: implications for treatment. Nat. Rev. Immunol. 20, 585–586 (2020). source

      Not checked in the free run.

    • cites [71] Higgins, P. G. et al. Intranasal interferon as protection against experimental respiratory coronavirus infection in volunteers. Antimicrob. Agents Chemother. 24, 713–715 (1983). source

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    • cites [72] Zhou, Q. et al. Interferon-α2b treatment for COVID-19. Front. Immunol. 11, 1061 (2020). source

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  • May combine two claims.

    Premisecitation

    The spike protein is a class I fusion protein that binds ACE2 on host cells and triggers virus-cell membrane fusion.

    “The S protein is a class I fusion protein that facilitates binding of the virus to the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell surface, which triggers fusion between the virus and cell membrane110,148,149.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [110] Pardi, N. et al. Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. J. Control. Release. 217, 345–351 (2015). source

      Not checked in the free run.

    • cites [148] Hoffmann, M. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271–280.e8 (2020). source

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    • cites [149] Rauch, S., Jasny, E., Schmidt, K. E. & Petsch, B. New vaccine technologies to combat outbreak situations. Front. Immunol. 9, 1963 (2018). source

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  • May combine two claims.

    Premisecitation

    T cells are important in the host response to SARS-CoV-2 by killing infected cells, helping B cells and antibody production, and possibly lowering the risk of vaccine-induced enhanced disease.

    “As expected for a viral infection, T cells are also important mediators in the host response to SARS-CoV-2 infection, by killing infected cells, supporting B cell function and antibody responses, and, possibly, reducing the risk of vaccine-induced enhanced disease39,40”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [39] DiLillo, D. J., Tan, G. S., Palese, P. & Ravetch, J. V. Broadly neutralizing hemagglutinin stalk-specific antibodies require FcγR interactions for protection against influenza virus in vivo. Nat. Med. 20, 143–151 (2014). source

      Not checked in the free run.

    • cites [40] Excler, J. L., Ake, J., Robb, M. L., Kim, J. H. & Plotkin, S. A. Nonneutralizing functional antibodies: a new “old” paradigm for HIV vaccines. Clin. Vaccine Immunol. 21, 1023–1036 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SARS-CoV-2 evades innate immunity through several mechanisms, suggesting innate responses are probably essential for protection.

    “Like other pathogenic respiratory RNA viruses (including other coronaviruses, respiratory syncytial virus and enteroviruses)55, SARS-CoV-2 can evade innate immune responses via multiple mechanisms55,56, indicating that innate immunity is likely crucial for host protection54,57.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [54] Jeyanathan, M. et al. Immunological considerations for COVID-19 vaccine strategies. Nat. Rev. Immunol. 20, 615–632 (2020). source

      Not checked in the free run.

    • cites [55] Kikkert, M. Innate immune evasion by human respiratory RNA viruses. J. Innate Immun. 12, 4–20 (2020). source

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    • cites [56] Schultze, J. L. & Aschenbrenner, A. C. COVID-19 and the human innate immune system. Cell 184, 1671–1692 (2021). source

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    • cites [57] Lee, J. S. & Shin, E. C. The type I interferon response in COVID-19: implications for treatment. Nat. Rev. Immunol. 20, 585–586 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Mucosal immunity probably has a key role in preventing SARS-CoV-2 infection, though mucosal antibody responses in COVID-19 are poorly understood.

    “Although mucosal immunity is likely key to the prevention of SARS-CoV-2 infection, relatively little is known regarding mucosal antibody responses in COVID-19.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    No correlate of protection against COVID-19 or SARS-CoV-2 infection is currently defined, and the immune thresholds needed for vaccine efficacy remain undefined.

    “There is currently no defined correlate of protection against COVID-19 or SARS-CoV-2 infection, and as such the immunological thresholds required for vaccine efficacy have not yet been defined163.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [163] Vabret, N. et al. Immunology of COVID-19: current state of the science. Immunity 52, 910–941 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    Antigen-specific antibody and T cell responses have been measured for all vaccines discussed, but the assays differ and are not directly comparable.

    “Although antigen-specific antibodies (including NAbs) and T cell responses have been determined for all of the vaccines discussed here (Table 1), the specific assays have varied and, thus, are not directly comparable.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Prior infection or BNT162b2 vaccination efficiently primes memory B cell responses, so that a second exposure boosts those memory B cell responses.

    “a study comparing individuals who are SARS-CoV-2 naive and individuals who have recovered from SARS-CoV-2 identified that either prior infection or vaccination with BNT162b2 was able to efficiently prime memory B cell responses, such that the second exposure (first vaccine dose after previous infection or second vaccine dose in individuals who are SARS-CoV-2 naïve) resulted in boosting of memory B”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Goel, R. R. et al. Distinct antibody and memory B cell responses in SARS-CoV-2 naive and recovered individuals following mRNA vaccination. Sci. Immunol. 6, eabi6950 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Polyclonal antibodies against multiple non-RBD spike epitopes might block viral attachment, add neutralizing activity, or prevent post-attachment fusion.

    “A polyclonal antibody against multiple epitopes of the S protein beyond the RBD might, for example, inhibit viral attachment156–160, provide additional neutralizing activity161 and/or prevent post-attachment fusion162.”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [156] Wang, L. et al. Importance of neutralizing monoclonal antibodies targeting multiple antigenic sites on the Middle East respiratory syndrome coronavirus spike glycoprotein to avoid neutralization escape. J. Virol. 92, e02002-1 (2018). source

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    • cites [157] Wang, N. et al. Structural definition of a neutralization-sensitive epitope on the MERS-CoV S1-NTD. Cell Rep. 28, 3395–3405.e6 (2019). source

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    • cites [158] Chen, Y. et al. A novel neutralizing monoclonal antibody targeting the N-terminal domain of the MERS-CoV spike protein. Emerg. Microbes Infect. 6, e37 (2017). source

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    • cites [159] Rogers, T. F. et al. Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model. Science 369, 956–963 (2020). source

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    • cites [160] Shi, R. et al. A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2. Nature 584, 120–124 (2020). source

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    • cites [161] Wang, W. et al. Characterization of anti-MERS-CoV antibodies against various recombinant structural antigens of MERS-CoV in an imported case in China. Emerg. Microbes Infect. 5, e113 (2016). source

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    • cites [162] Widjaja, I. et al. Towards a solution to MERS: protective human monoclonal antibodies targeting different domains and functions of the MERS-coronavirus spike glycoprotein. Emerg. Microbes Infect. 8, 516–530 (2019). source

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

    Interpretationnone given

    An additional potential advantage of mRNA vaccines over repeated homologous viral-vectored vaccination is that anti-vector immunity will not attenuate booster responses.

    “Finally, an additional potential advantage of mRNA vaccines compared with repeated homologous administration of viral-vectored vaccines is that anti-vector immunity will not be a potential issue that may result in attenuation of responses to booster doses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Spike has an N-terminal S1 subunit and C-terminal S2 subunit; the S1 RBD binds ACE2 and can rearrange to hide or expose receptor-binding determinants.

    “The S protein consists of an amino-terminal S1 subunit and a carboxy-terminal S2 subunit. Within the S1 subunit lies the receptor-binding domain (RBD), which binds the ACE2 receptor, and this domain can undergo conformational rearrangement that transiently hides or exposes the determinants of receptor binding.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    The trials of currently licensed COVID-19 vaccines did not include a vector control, so the role of pathogen-agnostic immunity in humans cannot be assessed with available data.

    “Unfortunately, given the urgency of the situation, the trials of the currently licensed COVID-19 vaccines did not include a vector control (such as scrambled mRNA or simian adenovirus without the S protein), and therefore the role of pathogen-agnostic immunity in humans cannot be assessed with the currently available data;”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Protection after one dose of these mRNA vaccines may require very low neutralizing antibody levels, may arise from non-neutralizing antibodies acting through other effector mechanisms, and/or may be mediated by a relatively low frequency of antigen-specific T cells.

    “These data would suggest that protection after one dose of these vaccines either requires extremely low levels of NAbs, is the result of non-NAbs leading to other effector mechanisms and/or is mediated by a relatively low frequency of antigen-specific T cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    ADE and VAERD have not yet been demonstrated for SARS-CoV-2.

    “Current evidence indicates that SARS-CoV-2 does not productively infect macrophages, making enhancement of infection unlikely, and ADE and VAERD have so far not been demonstrated for SARS-CoV-2 (refs175,176).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [175] Halstead, S. B. & Katzelnick, L. COVID-19 vaccines: should we fear ADE? J. Infect. Dis. 222, 1946–1950 (2020). source

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    • cites [176] Arvin, A. M. et al. A perspective on potential antibody-dependent enhancement of SARS-CoV-2. Nature 584, 353–363 (2020). source

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

    Interpretationnone given

    Mechanisms of protection may differ after two doses versus one dose, with neutralizing antibodies possibly mediating the main protective mechanism after later doses.

    “It must also be considered that mechanisms of protection may differ after two doses versus one dose, where NAbs may mediate the predominant protective mechanism following subsequent doses of vaccine.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    mRNA-1273 produced TH1 cell responses after the first dose, with 0.05% of circulating CD4+ T cells releasing TNF and/or IL-2 after in vitro stimulation with S protein peptides.

    “mRNA-1273 was shown to elicit TH1 cell responses after the first dose, with 0.05% of circulating CD4+ T cells secreting tumour necrosis factor (TNF) and/or interleukin-2 (IL-2) following in vitro stimulation with S protein peptides73 (Table 1; see Supplementary Table 1);”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Anderson, E. J. et al. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N. Engl. J. Med. 383, 2427–2438 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Current evidence suggests SARS-CoV-2 does not productively infect macrophages, making infection enhancement unlikely.

    “Current evidence indicates that SARS-CoV-2 does not productively infect macrophages, making enhancement of infection unlikely, and ADE and VAERD have so far not been demonstrated for SARS-CoV-2 (refs175,176).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [175] Halstead, S. B. & Katzelnick, L. COVID-19 vaccines: should we fear ADE? J. Infect. Dis. 222, 1946–1950 (2020). source

      Not checked in the free run.

    • cites [176] Arvin, A. M. et al. A perspective on potential antibody-dependent enhancement of SARS-CoV-2. Nature 584, 353–363 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    That initial analysis did not fully consider efficacy and immune responses after one dose for two-dose vaccines, or T cell responses.

    “However, this analysis did not fully consider efficacy and immune responses after one dose for the two-dose vaccines, or T cell responses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Early post-implementation analyses suggest mRNA vaccines reduce asymptomatic infection incidence and nasopharyngeal viral load in people infected despite vaccination.

    “Some early post-implementation analyses have suggested that the mRNA vaccines also reduce the incidence of asymptomatic infection and the nasopharyngeal viral load in individuals who become infected despite the vaccination93,107, but it is yet unclear how this translates to risk of transmission.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [93] Dagan, N. et al. BNT162b2 mRNA COVID-19 vaccine in a nationwide mass vaccination setting. N. Engl. J. Med. 384, 1412–1423 (2021). source

      Not checked in the free run.

    • cites [107] Levine-Tiefenbrum, M. et al. Decreased SARS-CoV-2 viral load following vaccination. Preprint at medRxiv https://doi.org/10.1101/2021.02.06.21251283 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    Comprehensive analyses comparing initial post-vaccine responses in people who later become infected with those who do not will ultimately provide an answer about correlates.

    “Comprehensive and careful analyses of all immunologic data, comparing initial post-vaccine responses in individuals who are infected after vaccination with those who are not, will ultimately provide an answer.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Identifying correlates of protection would enable licensure of additional vaccines based on immunogenicity, requiring fewer participants than efficacy trials, and would allow rapid investigation of modified regimens and prediction of protection in specific populations.

    “Identifying correlates of protection will not only enable a pathway to licensure of additional vaccines based on immunogenicity, thus requiring smaller numbers of participants compared with efficacy trials, but would also allow one to rapidly investigate the effects of modified vaccination regimens (lower dose, single dose, dose spacing and heterologous vaccine) and predict protection in specific”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Gam-COVID-Vac uses different adenovirus vectors for each dose, which circumvents anti-vector immunity that could inhibit anti-S responses, as seen with Ad5-nCoV and non-COVID-19 adenovirus-based vaccines.

    “This may be, in part, due to the fact that Gam-COVID-Vac uses different adenovirus vectors for each dose (adenovirus 26 for dose one and adenovirus 5 for dose two), thus circumventing the potential problem of anti-vector immunity that could inhibit anti-S responses, as has been identified for Ad5-nCoV (refs12,91) (Table 1) and non-COVID-19 adenovirus-based vaccines92.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [12] Zhu, F. C. et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet 395, 1845–1854 (2020). source

      Not checked in the free run.

    • cites [91] Zhu, F. C. et al. Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 396, 479–488 (2020). source

      Not checked in the free run.

    • cites [92] Buchbinder, S. P. et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet 372, 1881–1893 (2008). source

      Not checked in the free run.

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

    Study design and conductreasoning

    Such analyses were expected in the first half of 2021, but high vaccine efficacy means few vaccinated people become infected, limiting statistical power until enough cases occur.

    “Such analyses are expected in the first half of 2021, but the high vaccine efficacy means the number of individuals who are infected after vaccination is relatively low, limiting the statistical power of these analyses until sufficient cases occur.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    An initial analysis of trials of seven vaccines suggested anti-S antibody is a reasonable correlate of protection, with rank correlations of 0.79 between neutralizing antibody titre and efficacy and 0.93 between anti-S binding antibody titre and efficacy after a complete vaccine series.

    “An initial analysis from trials of seven current vaccines has suggested that anti-S antibody is a reasonable correlate of protection — a robust correlation was reported between NAb titre and vaccine efficacy (rank correlation rs = 0.79) and between anti-S binding antibody titre and efficacy (rs = 0.93) after a complete vaccine series (one or two doses, depending on the vaccine)97.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [97] Kristen, A. E. et al. Evidence for antibody as a protective correlate for COVID-19 vaccines. Preprint at medRxiv https://doi.org/10.1101/2021.03.17.20200246 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Clinical trials reported reduced protection against symptomatic COVID-19 caused by the B.1.351 variant, but emerging data suggest high protection remains against severe disease and hospitalization.

    “Reduced protection against any symptomatic COVID-19 disease caused by the B.1.351 variant of concern (now known as the Beta variant) has been reported from clinical trials18, but emerging data suggest that there remains high protection against the important end points of severe disease and hospitalization99.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Abdool Karim, S. S. & de Oliveira, T. New SARS-CoV-2 variants — clinical, public health, and vaccine implications. N. Engl. J. Med. 384, 1866–1868 (2021). source

      Not checked in the free run.

    • cites [99] Abu-Raddad, L. J., Chemaitelly, H. & Butt, A. A., National Study Group for COVID-19 Vaccination. Effectiveness of the BNT162b2 COVID-19 vaccine against the B.1.1.7 and B.1.351 Variants. N. Engl. J. Med. https://doi.org/10.1056/NEJMc2104974 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ChAdOx1 nCov-19-induced antibodies facilitate monocyte-mediated and neutrophil-mediated phagocytosis; both functions are induced after one dose and substantially increased by the second.

    “ChAdOx1 nCov-19-induced antibodies were shown to facilitate monocyte-mediated and neutrophil-mediated phagocytosis. Both functions were already induced following only one dose, although they were substantially increased by the second96.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Barrett, J. R. et al. Phase 1/2 trial of SARS-CoV-2 vaccine ChAdOx1 nCoV-19 with a booster dose induces multifunctional antibody responses. Nat. Med. 27, 279–288 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The first dose of ChAdOx1 nCov-19 induces antibodies capable of antibody-dependent complement deposition, and this function increases after a second dose.

    “The first dose of ChAdOx1 nCov-19 also induces antibodies capable of antibody-dependent complement deposition; again, this functionality was increased following a second dose96.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Barrett, J. R. et al. Phase 1/2 trial of SARS-CoV-2 vaccine ChAdOx1 nCoV-19 with a booster dose induces multifunctional antibody responses. Nat. Med. 27, 279–288 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Establishing an immunologic correlate of protection that could support future vaccine licensure may become even more important.

    “It may therefore become even more important to establish an immunologic correlate of protection against COVID-19, which could be used as the basis for vaccine licensure in the future.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    Those correlation analyses used short-term efficacy over 2-3 months, and correlation with longer-term outcomes is still needed.

    “In addition, these analyses were based on short-term efficacy over 2–3 months and correlation with longer-term outcomes will also be necessary.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A second dose provides additional benefit for Gam-COVID-Vac, with efficacy around 90%.

    “Additional benefit of a second dose is evident for Gam-COVID-Vac, when efficacy is ~90%87–90 (Table 1; see Supplementary Figure 1).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [87] Voysey, M. et al. 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, 99–111 (2020). source

      Not checked in the free run.

    • cites [88] Voysey, M. et al. Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials. Lancet 397, 881–891 (2021). source

      Not checked in the free run.

    • cites [89] Janssen Biotech. COVID-19 Vaccine Ad26.COV2.S. Sponsor Briefing Document (Vaccines and Related Biological Products Advisory Committee, 2021).

      Not checked in the free run.

    • cites [90] Logunov, D. Y. et al. Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. Lancet 397, 671–681 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    As effective vaccines are deployed, large phase III efficacy trials will become increasingly difficult because of ethical issues with placebo controls when an effective vaccine exists and because disease incidence is falling in countries using vaccines.

    “As effective vaccines are gradually rolled out, conducting large phase III efficacy trials will become increasingly difficult — for many reasons, including the ethical issues of a placebo-controlled trial in the context of an effective vaccine being available and also the likelihood of decreasing disease incidence in countries where vaccines are being used — which are usually the same countries”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [105] WHO Ad Hoc Expert Group on the Next Steps for COVID-19 Vaccine Evaluation. et al. Placebo-controlled trials of COVID-19 vaccines — why we still need them. N. Engl. J. Med. 384, e2 (2020). source

      Not checked in the free run.

    • cites [106] Wendler, D., Ochoa, J., Millum, J., Grady, C. & Taylor, H. A. COVID-19 vaccine trial ethics once we have efficacious vaccines. Science 370, 1277–1279 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    Multiple immunologic parameters will likely need to be measured, and if multiple protective pathways exist, correlates may differ by time after vaccination and by vaccine.

    “The data from these early trials highlight the challenges associated with this — multiple immunologic parameters will likely need to be measured, and if there are multiple pathways of protection against disease, it is possible that correlates will be different at different time points after vaccination and/or with different vaccines.”
    Quote in the paperNot a substantial claim
45 of 45

  • The authors state this as an assumption.

    Antibodies that bind the receptor-binding domain can prevent viral entry into host cells, thereby allowing sterilizing immunity.

    “Eliciting an immune response that targets the RBD has been a major focus of vaccine development on the assumption that antibodies that bind this critical domain can prevent viral entry into host cells, thereby allowing for sterilizing immunity (that is, the complete prevention of infection)152–154”

  • The paper relies on this without support.

    Immunological responses measured in phase I/II trials are representative enough of those in phase III efficacy trials to inform mechanisms of protection.

    “Few immunological data have so far been published from the phase III trials in which vaccine efficacy was determined, and the assessment of human immunologic responses to vaccination are therefore largely reliant on analyses from the earlier phase I/II clinical trials.”

  • The paper relies on this without support.

    Despite variation in assays and convalescent sample sources, comparisons across studies are valid.

    “Although the source of the convalescent samples differed between studies (for example, asymptomatic versus mild versus severe disease), these data provide the basis on which comparisons between studies can be made”

  • The paper relies on this without support.

    Convalescent serum antibody levels provide a valid reference for comparing vaccine-induced antibody responses and for judging their protective potential.

    “a ratio of one (black horizontal dashed line) indicates equivalence in amount of antibody between individuals who are vaccinated and average value for the relevant human convalescent serum”
4 of 4

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?

  • SARS-CoV-2 infection in vaccinated people is expected to trigger memory antibody and cellular responses that could reduce disease progression.

    “SARS-CoV-2 infection in vaccinated persons is expected to trigger memory antibody and cellular responses owing to prior vaccination; these immune responses could mitigate disease progression, possibly preventing life-threatening organ failure and death.12,13”

    From Association Between mRNA Vaccination and COVID-19 Hospitalization and Disease Severity (2021) · cites this paper as [13]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • ChAdOx1 second-dose T-cell response is described in opposite directions

    Major

    The discussion says T-cell responses decreased after the second dose, whereas Table 1 says responses measured after the second dose were slightly higher than the peak measured after the first.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. Haas, E. J. et al. Nationwide vaccination campaign with BNT162b2 in israel demonstrates high vaccine effectiveness and marked declines in incidence of SARS-CoV-2 infections and COVID-19 cases, hospitalizations, and deaths. Preprint at SSRN https://ssrn.com/abstract=3811387 (2021).
  2. Pfizer. Pfizer and BioNTech confirm high efficacy and no serious safety concerns through up to six months following second dose in updated topline analysis of landmark COVID-19 vaccine study https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-confirm-high-efficacy-and-no-serious (2021).
  3. Bharat Biotech. Bharat Biotech and ICMR Announce Interim Results from Phase 3 trials of COVAXIN®; Demonstrates overall Interim Clinical Efficacy of 78% and 100% efficacy against Severe COVID-19 disease https://www.bharatbiotech.com/images/press/covaxin-phase3-clinical-trials-interim-results.pdf (2021).

Cited by

Sorted by citations

Authors
Sadarangani, M., Marchant, A., & Kollmann, T. R.
Affiliations
  • University of British Columbia (CA)
  • Université Libre de Bruxelles (BE)
  • The Kids Research Institute Australia (AU)
Corresponding author
Sadarangani, Manish
ORCID
Venue
Nature Reviews Immunology
Publisher
Springer Science and Business Media LLC
Published
2021-07-01
Volume
21
Issue
8
Pages
475-484
ISSN
  • 1474-1733 (ISSN-L)
  • 1474-1741
DOI
10.1038/s41577-021-00578-z
PMC
PMC8246128
OpenAlex
W3176668337
Cited by
560
References
162
Citations by year
2026: 25 · 2025: 44 · 2024: 57 · 2023: 157 · 2022: 216 · 2021: 61
FWCI
14.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature reviews. Immunology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • UWA Profiles and Research Repository (UWA) (submittedVersion, other-oa)
  • Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion, other-oa)
Funders
  • Children's Hospital Foundation
  • BC Children's Hospital
  • Canadian Child Health Clinician Scientist Program
  • Michael Smith Health Research BC
  • Fonds De La Recherche Scientifique - FNRS
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
Keywords
COVID-19 vaccines, SARS-CoV-2, neutralizing antibodies, vaccine-induced protection, mRNA vaccines, subunit vaccine, T cell response, correlates of protection, innate immunity
MeSH terms
COVID-19, SARS-CoV-2, COVID-19 Vaccines, Antibodies, Viral, Humans, Immunity, T-Lymphocytes, Treatment Outcome, Antibodies, Neutralizing, Spike Glycoprotein, Coronavirus

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.

Statistics and arithmetic are recomputed, not judged.

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