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Cited by 265SARS-CoV-2 and COVID-19 ResearchImmune responses and vaccinationsCOVID-19 Clinical Research Studies

Prospects for durable immune control of SARS-CoV-2 and prevention of reinfection

Open access
Cromer, Deborah, Juno, Jennifer A., Khoury, David, Reynaldi, Arnold, Wheatley, Adam K., Kent, Stephen J., Davenport, Miles P.·2021·Nature Reviews Immunology
DOI 10.1038/s41577-021-00550-xPMC PMC8082486
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Abstract

Immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is central to long-term control of the current pandemic. Despite our rapidly advancing knowledge of immune memory to SARS-CoV-2, understanding how these responses translate into protection against reinfection at both the individual and population levels remains a major challenge. An ideal outcome following infection or after vaccination would be a highly protective and durable immunity that allows for the establishment of high levels of population immunity. However, current studies suggest a decay of neutralizing antibody responses in convalescent patients, and documented cases of SARS-CoV-2 reinfection are increasing. Understanding the dynamics of memory responses to SARS-CoV-2 and the mechanisms of immune control are crucial for the rational design and deployment of vaccines and for understanding the possible future trajectories of the pandemic. Here, we summarize our current understanding of immune responses to and immune control of SARS-CoV-2 and the implications for prevention of reinfection.

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  • Findingcitation

    Neutralizing antibody responses show biphasic decay over the first months after infection.

    “Neutralizing antibody responses show a biphasic decay over the first months after infection3.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Wheatley, A. K. et al. Evolution of immune responses to SARS-CoV-2 in mild-moderate COVID-19. Nat. Commun. 12, 1162 (2021).

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  • Premisecitation

    SARS-CoV-2 infection triggers neutralizing antibodies and CD4+ and CD8+ T cell responses that contribute to clearing the primary infection.

    “Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces potent immune responses that have an important role in clearing a primary infection, including neutralizing antibodies and CD4+ and CD8+ T cell responses (reviewed in ref.1).”
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    • cites ref.1

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  • Premisecitation

    Cellular immune responses to SARS-CoV-2 infection are generally more stable than antibody responses.

    “Cellular responses to infection seem to be generally more stable3,8,10 (Fig. 1) but their role in immune protection is not yet clear”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Wheatley, A. K. et al. Evolution of immune responses to SARS-CoV-2 in mild-moderate COVID-19. Nat. Commun. 12, 1162 (2021).

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    • cites [8] Dan, J. M. et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science 371, eabf4063 (2021).

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    • cites [10] Zuo, J. et al. Robust SARS-CoV-2-specific T cell immunity is maintained at 6 months following primary infection. Nat. Immunol. https://doi.org/10.1038/s41590-021-00902-8 (2021). source

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  • Premisecitation

    There is no evidence that vaccine-induced antibody responses are more durable than convalescent responses.

    “There is no evidence that vaccine-induced responses are more durable than convalescent responses (preprint data, not yet peer reviewed)24.”
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    • cites [24] Khoury, D. S. et al. What level of neutralising antibody protects from COVID-19? Preprint at medRxiv https://doi.org/10.1101/2021.03.09.21252641 (2021). source

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  • Interpretationcitation

    Documented reinfection and short-lived immunity to endemic human coronaviruses raise the prospect that protective immunity after SARS-CoV-2 infection may last months rather than years.

    “documented examples of SARS-CoV-2 reinfection as well as evidence of short-lived immunity to endemic human coronavirus (hCoV) infections raise the prospect that protective immunity after SARS-CoV-2 infection may last for months instead of years.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8] Dan, J. M. et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science 371, eabf4063 (2021).

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    • cites [10] Zuo, J. et al. Robust SARS-CoV-2-specific T cell immunity is maintained at 6 months following primary infection. Nat. Immunol. https://doi.org/10.1038/s41590-021-00902-8 (2021). source

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  • May combine two claims. 48
  • Classified as probably not a substantial claim. 6

  • May combine two claims.

    Findingcitation

    The rapid early decay of neutralization titre in the first 1-2 months after infection is consistent with IgA and IgM decay, while slower decay after 2 months is more consistent with IgG decay.

    “The rapid decay observed in the neutralization titre in the first 1–2 months after infection is consistent with the decay kinetics of IgA responses and IgM responses (not shown). The slower decay of neutralization titre after 2 months is more consistent with the slow decay of IgG responses3.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Wheatley, A. K. et al. Evolution of immune responses to SARS-CoV-2 in mild-moderate COVID-19. Nat. Commun. 12, 1162 (2021).

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  • May combine two claims.

    Findingown data

    T cell responses decay slightly slower than IgG over the first few months after infection, whereas memory B cell responses increase.

    “T cell responses decay at a slightly slower rate than IgG over the first few months after infection, whereas memory B cell responses increase.”
    Quote in the paperSubstantial claim

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    Interpretationcitation

    Epidemiological studies suggest that herd immunity through natural infection may not have been achieved even in high-infection communities, and that waning immunity plus antigenic variation may allow continued circulation.

    “epidemiological studies suggest that, even in communities with high infection rates, herd immunity through natural infection may not have been achieved, and these studies raise the possibility that a combination of waning immunity and viral antigenic variation may allow for continued circulation of the virus11,12.”
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    • cites [11] Buss, L. F. et al. Three-quarters attack rate of SARS-CoV-2 in the Brazilian Amazon during a largely unmitigated epidemic. Science 371, 288–292 (2021). source

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    • cites [12] Sridhar, D. & Gurdasani, D. Herd immunity by infection is not an option. Science 371, 230–231 (2021). source

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    Premisecitation

    Neutralizing antibody responses to SARS-CoV-2 peak within the first few weeks after symptom onset and then decay, with some people losing detectable neutralizing antibodies within months.

    “neutralizing antibody responses to SARS-CoV-2 peak within the first few weeks after symptom onset but seem to decay after this time, with a proportion of individuals losing detectable neutralizing antibodies within months after infection5”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Muecksch, F. et al. Longitudinal serological analysis and neutralizing antibody levels in coronavirus disease 2019 convalescent patients. J. Infect. Dis. 223, 389–398 (2021). source

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    Interpretationcitation

    Combining the protective titre with antibody decay suggests that neutralization-mediated protection may decline substantially over the first year and be affected by reduced neutralization of antigenic variants.

    “Combining data on the protective titre and dynamics of decay of neutralizing antibodies suggest that neutralization-mediated protection may decline substantially over the first year of infection and will also be significantly affected by the reduced neutralization of viral antigenic variants8,24.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8] Dan, J. M. et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science 371, eabf4063 (2021).

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    • cites [24] Khoury, D. S. et al. What level of neutralising antibody protects from COVID-19? Preprint at medRxiv https://doi.org/10.1101/2021.03.09.21252641 (2021). source

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    Premisecitation

    CD8+ T cell responses are induced after SARS-CoV-2 infection and seem to have a longer half-life than CD4+ T cell responses.

    “CD8+ T cell responses are also induced following SARS-CoV-2 infection, and they seem to have a longer half-life relative to the CD4+ T cell response3,8.”
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    • cites [3] Wheatley, A. K. et al. Evolution of immune responses to SARS-CoV-2 in mild-moderate COVID-19. Nat. Commun. 12, 1162 (2021).

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    • cites [8] Dan, J. M. et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science 371, eabf4063 (2021).

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  • May combine two claims.

    Interpretationreasoning

    Stable maintenance of an affinity-matured memory B cell reservoir could help mitigate subsequent infections, although recall kinetics and protective potential are undetermined.

    “The stable maintenance of a reservoir of affinity-matured memory B cells could provide a mechanism to help mitigate subsequent infections, although the kinetics of recall and protective potential of memory B cells in SARS-CoV-2 immunity are yet to be determined.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    Decay of immune memory over time is unlikely to produce a switch from immune to non-immune status but rather a gradual reduction in immunity and possibly a transfer between different immune responses that lead protection at different times.

    “Thus, the decay of immune memory over time is unlikely to produce a switch from an ‘immune’ to a ‘non-immune’ status but rather a gradual reduction in immunity and perhaps even a transfer between different immune responses that have a leading role in protection at different times.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Two studies observed similar half-lives for spike-specific CD4+ memory T cell responses, 120-139 days, and a high frequency, over 90%, of convalescent individuals having CD4+ T cell responses for 6 months after symptom onset.

    “Two studies observed similar half-lives for spike-specific CD4+ memory T cell responses (120–139 days) and reported a high (>90%) frequency of convalescent individuals having CD4+ T cell responses for 6 months after symptom onset3,8 (Fig. 1a).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Wheatley, A. K. et al. Evolution of immune responses to SARS-CoV-2 in mild-moderate COVID-19. Nat. Commun. 12, 1162 (2021).

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    • cites [8] Dan, J. M. et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science 371, eabf4063 (2021).

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    Premisecitation

    IgM and IgA1 spike-binding antibodies have early half-lives of 55 and 42 days, slowing to 118 days and more than 1,000 days beyond 70 days after infection.

    “IgM and IgA1 spike-binding antibodies have shorter half-lives of 55 days and 42 days, respectively, early after infection (before day 70 post-infection), which is similar to the early decay rate of the neutralizing antibody titre; the decline of IgM and IgA1 responses then slows to a half-life of 118 days and >1,000 days, respectively, beyond 70 days after infection3.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Wheatley, A. K. et al. Evolution of immune responses to SARS-CoV-2 in mild-moderate COVID-19. Nat. Commun. 12, 1162 (2021).

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    Interpretationreasoning

    Even if neutralizing IgG cannot fully block infection, it may slow SARS-CoV-2 growth, creating a larger time window for memory responses to be recalled and control infection before the viral peak.

    “Even if neutralizing IgG cannot fully block infection, it may still slow the rate of growth of SARS-CoV-2, creating a larger time window for memory responses to be recalled and expand to contribute to controlling infection before the viral peak (Box 1).”
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    Premisecitation

    Administration of SARS-CoV-2-specific monoclonal antibodies within the first week of symptoms in mild-to-moderate infection seems to accelerate viral clearance and reduce risk of clinical progression.

    “Evidence for this comes from studies involving the administration of SARS-CoV-2-specific monoclonal antibodies within the first week of symptoms in mild-to-moderate SARS-CoV-2 infection, which seems to accelerate the clearance of virus and reduce the risk of clinical progression36,37.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [36] Weinreich, D. M. et al. REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. N. Engl. J. Med. 384, 238–251 (2020). source

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    • cites [37] Chen, P. et al. SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19. N. Engl. J. Med. 384, 229–237 (2020). source

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    Premisecitation

    The estimated half-life of neutralization titre is about 55 days over the first 70 days after infection, and a longer-term analysis estimated an overall half-life of 90 days over the first 8 months.

    “Estimates of the half-life of the neutralization titre over the first 70 days after infection suggest an early half-life of ~55 days3, whereas a longer-term analysis suggested an overall half-life of 90 days over the first 8 months after infection8.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Wheatley, A. K. et al. Evolution of immune responses to SARS-CoV-2 in mild-moderate COVID-19. Nat. Commun. 12, 1162 (2021).

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    • cites [8] Dan, J. M. et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science 371, eabf4063 (2021).

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    Premisecitation

    Serological neutralizing antibody responses peak within 3-5 weeks after infection, and the peak magnitude correlates with clinical illness severity.

    “Studies suggest that serological neutralizing antibody responses peak within 3–5 weeks after infection, with the magnitude of the peak being correlated with the severity of clinical illness13.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Röltgen, K. et al. Defining the features and duration of antibody responses to SARS-CoV-2 infection associated with disease severity and outcome. Sci. Immunol. 5, eabe0240 (2020). source

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  • May combine two claims.

    Premisecitation

    Rapid early antibody decay is due to the short half-life of serum antibodies and short-lived antibody-secreting cells, leaving long-lived plasma cells with half-lives of months to years.

    “This pattern of rapid early decay is due to the short half-life of serum antibodies and to short-lived antibody-secreting cells, which decay with a half-life of weeks to leave a population of long-lived plasma cells with half-lives of months to years21.”
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    • cites [21] Hammarlund, E. et al. Plasma cell survival in the absence of B cell memory. Nat. Commun. 8, 1781 (2017). source

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  • May combine two claims.

    Interpretationcitation

    These studies provide evidence for strong protection from reinfection in seropositive individuals during the first few months after infection, at levels similar to vaccination.

    “These studies provide evidence for strong protection from reinfection in seropositive individuals during the first few months after infection (at levels similar to the protection seen after vaccination).”
    Quote in the paperSubstantial claim

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    Premisecitation

    Manaus had a strong SARS-CoV-2 wave in April and May 2020, low transmission from June to December 2020, and a resurgence of infection in early 2021.

    “Manaus experienced a strong wave of SARS-CoV-2 infection in April and May of 2020, which might have been expected to provide some level of protection or herd immunity in the exposed population. However, despite a low level of transmission from June to December 2020, a resurgence of infection was observed in early 2021 (refs11,57).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] Buss, L. F. et al. Three-quarters attack rate of SARS-CoV-2 in the Brazilian Amazon during a largely unmitigated epidemic. Science 371, 288–292 (2021). source

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    • cites [57] Sabino, E. C. et al. Resurgence of COVID-19 in Manaus, Brazil, despite high seroprevalence. Lancet 397, 452–455 (2021). source

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    Premisecitation

    In macaques, primary SARS-CoV-2 infection protects against subsequent viral challenge for at least 28-35 days, with re-exposure boosting binding and neutralizing antibodies and IFNγ secretion by T cells.

    “Initial studies in macaques showed that a primary infection with SARS-CoV-2 protects against subsequent viral challenge for at least 28–35 days, with re-exposure driving memory immune responses that included boosting of binding and neutralizing antibody levels as well as of IFNγ secretion by T cells46,47.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [46] Deng, W. et al. Primary exposure to SARS-CoV-2 protects against reinfection in rhesus macaques. Science 369, 818–823 (2020). source

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    • cites [47] Chandrashekar, A. et al. SARS-CoV-2 infection protects against rechallenge in rhesus macaques. Science 369, 812–817 (2020). source

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    Premisecitation

    Transfer of high titres of purified IgG from convalescent animals is sufficient to protect against viral challenge, or at lower titres to reduce duration of viral replication.

    “The transfer of high titres of purified IgG from convalescent animals is sufficient to protect against viral challenge or, at lower titres, to reduce the duration of viral replication.”
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    • cites [48] McMahan, K. et al. Correlates of protection against SARS-CoV-2 in rhesus macaques. Nature 590, 630–634 (2021). source

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    Interpretationcitation

    Individuals with different levels of immunity will suppress virus to a variable extent, and immunity functions to reduce average viral levels across the population.

    “individuals with different levels of immunity will suppress the virus to a variable extent (which will also change within the same individual over time as immunity wanes)24, and immunity functions to reduce average viral levels across the population.”
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    • cites [24] Khoury, D. S. et al. What level of neutralising antibody protects from COVID-19? Preprint at medRxiv https://doi.org/10.1101/2021.03.09.21252641 (2021). source

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    Premisecitation

    In a South Africa vaccine trial, there was no difference in infection rate between seropositive and seronegative placebo participants, 5.2% versus 5.3%, suggesting no protective effect of previous infection.

    “This study found no difference in infection rate between individuals who were seropositive and those who were seronegative (5.2% compared with 5.3%), suggesting that there was no protective effect of previous infection (preprint data, not yet peer reviewed)56.”
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    • cites [56] Shinde, V. et al. Preliminary efficacy of the NVX-CoV2373 Covid-19 vaccine against the B.1.351 variant. Preprint at medRxiv https://doi.org/10.1101/2021.02.25.21252477 (2021). source

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    Interpretationcitation

    Early results suggest monoclonal antibody cocktails may be useful in prophylaxis or early disease but less effective in treating critically ill patients when inflammation dominates.

    “Early results suggest that monoclonal antibody cocktails may be useful in prophylaxis or early disease but are less effective in treating patients who are critically ill when inflammation dominates the clinical picture41.”
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    • cites [41] Cohen, M. S. Monoclonal antibodies to disrupt progression of early covid-19 infection. N. Engl. J. Med. 384, 289–291 (2021). source

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    Premisecitation

    Emerging variants of concern have spike mutations, including B.1.1.7 with eight spike mutations, B.1.351, and P.1 with multiple spike mutations.

    “Several emerging viral variants of concern have been identified that have mutations in the spike protein, including the B.1.1.7 variant (originating from the UK and which has eight spike mutations92), the B.1.351 variant (originating from South Africa) and the P.1 variant (originating from Brazil and which also contains multiple mutations in the spike protein and is spreading widely)57,93.”
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    • cites [92] Davies, N. G. et al. Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England. Science https://doi.org/10.1126/science.abg3055 (2021). source

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    • cites [57] Sabino, E. C. et al. Resurgence of COVID-19 in Manaus, Brazil, despite high seroprevalence. Lancet 397, 452–455 (2021). source

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    • cites [93] Tegally, H. et al. Sixteen novel lineages of SARS-CoV-2 in South Africa. Nat. Med. 27, 440–446 (2021). source

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    Premisecitation

    In Denmark, a study of more than half a million individuals estimated protection of 80.5% for up to 7 months in previously PCR-positive patients, but only 47% in those over 65 years of age.

    “This study estimated a protection of 80.5% for up to 7 months in patients who had previously tested positive, although a protection of only 47% was observed in those over 65 years of age.”
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    • cites [55] Hansen, C. H., Michlmayr, D., Gubbels, S. M., Mølbak, K. & Ethelberg, S. Assessment of protection against reinfection with SARS-CoV-2 among 4 million PCR-tested individuals in Denmark in 2020: a population-level observational study. Lancet 397, 1204–1212 (2021). source

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    Interpretationcitation

    Animal models may not recapitulate all features of human infection but suggest the importance of looking beyond neutralizing antibodies for additional mechanisms of immune protection.

    “although animal models may not recapitulate all of the features of human infection49, they suggest the importance of looking beyond neutralizing antibodies for additional mechanisms of immune protection.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Khoury, D. S. et al. Measuring immunity to SARS-CoV-2 infection: comparing assays and animal models. Nat. Rev. Immunol. 20, 727–738 (2020). source

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    • Rests on an assumption: Findings from animal models can be extrapolated to human SARS-CoV-2 protective immunity despite incomplete recapitulation of human infection.

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    Interpretationcitation

    Frequencies of circulating memory B cells continue to increase for several months after recovery from COVID-19 when most other responses decline, suggesting recall of B cell memory may extend antibody-dependent protection despite waning serological titres.

    “The observations that frequencies of circulating memory B cells continue to increase for several months after recovery from COVID-19 (refs2,3,8,9,28), when most other responses are declining (Fig. 1a), suggest that recall of B cell memory may provide a mechanism to extend the duration of antibody-dependent protection in the face of waning serological titres.”
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    • cites [2] Gaebler, C. et al. Evolution of antibody immunity to SARS-CoV-2. Nature 591, 639–644 (2021). source

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    • cites [3] Wheatley, A. K. et al. Evolution of immune responses to SARS-CoV-2 in mild-moderate COVID-19. Nat. Commun. 12, 1162 (2021).

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    • cites [8] Dan, J. M. et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science 371, eabf4063 (2021).

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    • cites [9] Rodda, L. B. et al. Functional SARS-CoV-2-specific immune memory persists after mild COVID-19. Cell 184, 169–183.e117 (2021). source

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    • cites [28] Hartley, G. E. et al. Rapid generation of durable B cell memory to SARS-CoV-2 spike and nucleocapsid proteins in COVID-19 and convalescence. Sci. Immunol. 5, eabf8891 (2020). source

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    Premisecitation

    The effect of monoclonal antibodies was dose dependent and greater in patients lacking endogenous antibody responses.

    “This effect was dose dependent and was greater for those patients who lacked endogenous antibody responses.”
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    • cites [36] Weinreich, D. M. et al. REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. N. Engl. J. Med. 384, 238–251 (2020). source

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    • cites [37] Chen, P. et al. SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19. N. Engl. J. Med. 384, 229–237 (2020). source

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  • May combine two claims.

    Interpretationcitation

    In many people, strong immunity against SARS-CoV-2 infection might last under a year, while protection against severe disease could persist longer.

    “Current analyses of the rate of decay of immunity to SARS-CoV-2 and the comparison with immunity to hCoVs suggest that high-level immunity to SARS-CoV-2 infection may last less than a year in many cases but that the duration of protection from severe infection may be more durable24.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Khoury, D. S. et al. What level of neutralising antibody protects from COVID-19? Preprint at medRxiv https://doi.org/10.1101/2021.03.09.21252641 (2021). source

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    Premisecitation

    Most adults have probably had multiple hCoV exposures, and after an hCoV infection people can become reinfection-susceptible within 12-18 months.

    “By adulthood, most individuals are likely to have been exposed multiple times, with longitudinal studies and human challenge studies suggesting that individuals become susceptible to reinfection within 12–18 months after a previous hCoV infection74–78.”
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    • cites [74] Edridge, A. W. D. et al. Seasonal coronavirus protective immunity is short-lasting. Nat. Med. 26, 1691–1693 (2020). source

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    • cites [75] Galanti, M. & Shaman, J. Direct observation of repeated infections with endemic coronaviruses. J. Infect. Dis. 223, 409–415 (2020). source

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    • cites [76] Callow, K. A., Parry, H. F., Sergeant, M. & Tyrrell, D. A. The time course of the immune response to experimental coronavirus infection of man. Epidemiol. Infect. 105, 435–446 (1990). source

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    • cites [77] Callow, K. A. Effect of specific humoral immunity and some non-specific factors on resistance of volunteers to respiratory coronavirus infection. J. Hyg. 95, 173–189 (1985). source

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    • cites [78] Lepiller, Q. et al. High incidence but low burden of coronaviruses and preferential associations between respiratory viruses. J. Clin. Microbiol. 51, 3039–3046 (2013). source

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  • May combine two claims.

    Interpretationreasoning

    Immunity from neutralizing antibodies should prevent infection and therefore lower illness and transmission similarly.

    “immunity owing to neutralizing antibodies would be expected to block infection and thereby reduce both illness and transmission to a similar extent.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Most SARS-CoV-2 vaccines target only the spike protein, while some whole inactivated virus vaccines may target multiple viral antigens.

    “The majority of SARS-CoV-2 vaccines target only the spike protein, although some include the whole inactivated virus and may thus target multiple viral antigens (reviewed in ref.96).”
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    • cites ref.96

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    Premisecitation

    Natural SARS-CoV-2 infection has been estimated to give 89-95% protection, a level statistically indistinguishable from that of licensed vaccines in the short term.

    “a level of protection that is not significantly different to the 89–95% protection that has been estimated following natural infection53,54.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [53] Lumley, S. F. et al. Antibody status and incidence of SARS-CoV-2 infection in health care workers. N. Engl. J. Med. 384, 533–540 (2021). source

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    • cites [54] Abu-Raddad, L. J. et al. SARS-CoV-2 reinfection in a cohort of 43,000 antibody-positive individuals followed for up to 35 weeks. Preprint at medRxiv https://doi.org/10.1101/2021.01.15.21249731 (2021). source

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  • May combine two claims.

    Interpretationreasoning

    How much waning immunity versus circulating variants matters remains uncertain, though both probably play a part.

    “The relative importance of waning immunity and the circulation of SARS-CoV-2 variants is not yet clear, and it seems likely that both factors may have a role.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Natural infection induces immune responses against multiple viral proteins and localized responses at the initial infection sites in the upper and lower respiratory tracts.

    “immune responses following natural infection not only target multiple viral proteins but also induce immune responses that are localized to the tissue sites of initial infection (upper and lower respiratory tracts) (see figure, part a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In people with prior infection, a single vaccine dose triggers swift, strong recall of humoral immunity, and neutralizing activity usually surpasses that seen after two doses in infection-naive people.

    “the vaccination of previously infected individuals drives a rapid and very potent recall of humoral immunity, even after a single vaccine dose70–72, with serological neutralizing activity generally exceeding levels seen after two vaccine doses in naive participants.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [70] Krammer, F. et al. Antibody responses in seropositive persons after a single dose of SARS-CoV-2 mRNA vaccine. N. Engl. J. Med. https://doi.org/10.1056/NEJMc2101667 (2021). source

      Not checked in the free run.

    • cites [71] Prendecki, M. et al. Effect of previous SARS-CoV-2 infection on humoral and T-cell responses to single-dose BNT162b2 vaccine. Lancet 397, 1178–1181 (2021). source

      Not checked in the free run.

    • cites [72] Manisty, C. et al. Antibody response to first BNT162b2 dose in previously SARS-CoV-2-infected individuals. Lancet 397, 1057–1058 (2021). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    If protection fails when antibody neutralization is lost even though T cell recognition persists, this points to a primary role for neutralizing antibodies.

    “Alternatively, if the loss of antibody neutralization abrogates protection even when T cell recognition is maintained, this suggests a primary role for neutralizing antibodies95.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Madhi, S. A. et al. Efficacy of the ChAdOx1 nCoV-19 covid-19 vaccine against the B.1.351 variant. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2102214 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In the months following exposure, both infection and vaccination appear to give substantial protection against detectable SARS-CoV-2 infection.

    “These early indications suggest that both infection and vaccination provide significant protection from detectable SARS-CoV-2 infection in the first months after exposure.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Both infection and vaccination elicit responses that give solid protection in the short term against a homologous strain.

    “Immune responses induced by both infection and vaccination provide good short-term protection from infection with a homologous virus strain.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    If responses to non-spike proteins or lung-localized responses matter, then infection or whole inactivated virus vaccination might control spike variants better even when neutralizing titres to the variant are low.

    “if responses to non-spike proteins and/or localized responses in the lung are important, then natural infection or vaccination with the whole inactivated virus may maintain better immune control of spike variants, even when neutralization titres towards a variant are low (see figure, part c).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Clinical protection against SARS-CoV-2 may involve spike-specific, non-spike-specific, and lung-localized responses, but their relative contributions are unknown.

    “The clinical protection we observe may include contributions from spike-specific and non-spike-specific responses as well as localized responses in the lung (see figure, part b), the relative contribution of which is unknown.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Influenza virus also circulates continuously and reinfects often, usually causing more severe illness.

    “A similar phenomenon of ongoing circulation and frequent reinfection is also observed for influenza virus, although often resulting in more severe clinical outcomes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Endemic human coronaviruses circulate worldwide and cause widespread infection during childhood.

    “Endemic hCoVs circulate worldwide and cause widespread infection during childhood73.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Zhou, W., Wang, W., Wang, H., Lu, R. & Tan, W. First infection by all four non-severe acute respiratory syndrome human coronaviruses takes place during childhood. BMC Infect. Dis. 13, 433–433 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Lasting immunity and possible antigenic change in SARS-CoV-2 are still key difficulties.

    “the durability of immunity and the potential for antigenic variation of the virus remain major challenges going forwards.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Strong B cell and T cell memory after first infection suggests that later reinfections may be less severe and perhaps less transmissible.

    “the robust B cell and T cell memory responses induced by primary infection suggest that reinfection severity, and potentially transmission, may be mitigated over the longer term.”
    Quote in the paperSubstantial claim

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

    Interpretationcitation

    Other scenarios are plausible: vaccine protection may be brief, or it may prevent severe disease without stopping spread.

    “alternative scenarios are also possible in which vaccine efficacy is either short lived or provides protection from severe disease but does not block transmission74–78.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [74] Edridge, A. W. D. et al. Seasonal coronavirus protective immunity is short-lasting. Nat. Med. 26, 1691–1693 (2020). source

      Not checked in the free run.

    • cites [75] Galanti, M. & Shaman, J. Direct observation of repeated infections with endemic coronaviruses. J. Infect. Dis. 223, 409–415 (2020). source

      Not checked in the free run.

    • cites [76] Callow, K. A., Parry, H. F., Sergeant, M. & Tyrrell, D. A. The time course of the immune response to experimental coronavirus infection of man. Epidemiol. Infect. 105, 435–446 (1990). source

      Not checked in the free run.

    • cites [77] Callow, K. A. Effect of specific humoral immunity and some non-specific factors on resistance of volunteers to respiratory coronavirus infection. J. Hyg. 95, 173–189 (1985). source

      Not checked in the free run.

    • cites [78] Lepiller, Q. et al. High incidence but low burden of coronaviruses and preferential associations between respiratory viruses. J. Clin. Microbiol. 51, 3039–3046 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Except in the best-case scenarios, ongoing boosters with existing vaccines or new-generation SARS-CoV-2 vaccines might be needed.

    “In all but the most optimistic scenarios, it seems that either continued boosting with current vaccines or a next generation of SARS-CoV-2 vaccines may be required”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The HPV vaccine can produce antibody levels far above those from natural infection and gives stronger, longer-lasting immunity.

    “the human papilloma virus vaccine can induce antibody responses that are orders of magnitude larger than those seen in natural infection, and it induces much stronger and more durable immunity than occurs after natural infection86.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] Petaja, T. et al. Long-term persistence of systemic and mucosal immune response to HPV-16/18 AS04-adjuvanted vaccine in preteen/adolescent girls and young women. Int. J. Cancer 129, 2147–2157 (2011). source

      Not checked in the free run.

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

    Interpretationreasoning

    Should immune correlates beyond neutralizing antibodies be identified, they could guide vaccine improvement and forecasts of protection.

    “if alternative immune correlates of protection beyond neutralizing antibodies can be established, these may provide additional directions for vaccine optimization and prediction of future protection.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    After SARS-CoV-2 infection, neutralizing antibodies fall quickly in the first months, though the decline appears to slow later.

    “Immune responses, particularly neutralizing antibody responses, to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been observed to decay rapidly in the first few months after infection but the rate of decay seems to slow with time3.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Wheatley, A. K. et al. Evolution of immune responses to SARS-CoV-2 in mild-moderate COVID-19. Nat. Commun. 12, 1162 (2021).

      Not checked in the free run.

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

    Interpretationreasoning

    Antigenic variants could set off a continuing race between viral evolution and vaccine updates, similar to annual influenza vaccination.

    “the emergence of antigenic variants of SARS-CoV-2 (Box 2) raises the possibility of an ongoing ‘arms race’ between viral evolution and vaccine catch-up (as occurs for annual influenza virus vaccination).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Vaccination can raise neutralizing antibody levels, so immunizing people with prior infection might cut reinfection further.

    “The potential for higher levels of neutralizing antibodies to be induced by vaccination suggests that reinfection could be further reduced by vaccinating individuals who have been previously infected.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    When immunity falls below the level needed to block infection yet still guards against severe disease, and when post-reinfection viral loads suffice for spread, endemic transmission might boost memory and keep protection up.

    “Immunity may drop below the threshold required to prevent infection but still provide sufficient protection against severe illness. If viral levels after reinfection are high enough to enable transmission, the endemic spread of infection may boost memory responses to maintain immunity at protective levels82.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] Lavine, J. S., Bjornstad, O. N. & Antia, R. Immunological characteristics govern the transition of COVID-19 to endemicity. Science 371, 741–745 (2021). source

      Not checked in the free run.

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

    Interpretationreasoning

    Next-generation SARS-CoV-2 vaccines may need to broaden neutralization across antigenic variants.

    “expanding the breadth of neutralization against different antigenic variants may be an important requirement of next-generation vaccines.”
    Quote in the paperNot a substantial claim
53 of 53

  • The paper relies on this without support.

    Immune responses measured in blood are representative of protective immunity at mucosal and lung sites.

    “both the maintenance and role of tissue-resident memory B cells and T cells in the lungs are not well understood as most studies so far have focused on responses in blood. The presence of memory cells at the site of infection may be crucial for efficient target recognition and immune recall34,35.”

  • The paper relies on this without support.

    Findings from animal models can be extrapolated to human SARS-CoV-2 protective immunity despite incomplete recapitulation of human infection.

    “although animal models may not recapitulate all of the features of human infection49, they suggest the importance of looking beyond neutralizing antibodies for additional mechanisms of immune protection.”
2 of 2

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 [12]

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References 100 · Cited by 265

Authors
Cromer, D., Juno, J. A., Khoury, D., Reynaldi, A., Wheatley, A. K., Kent, S. J., & Davenport, M. P.
Affiliations
  • UNSW Sydney (AU)
  • The University of Melbourne (AU)
Corresponding author
  • Kent, Stephen J.
  • Davenport, Miles P.
ORCID
Venue
Nature Reviews Immunology
Publisher
Springer Science and Business Media LLC
Published
2021-04-29
Volume
21
Issue
6
Pages
395-404
ISSN
  • 1474-1733 (ISSN-L)
  • 1474-1741
DOI
10.1038/s41577-021-00550-x
PMC
PMC8082486
OpenAlex
W3157661219
Cited by
265
References
100
Citations by year
2026: 13 · 2025: 14 · 2024: 24 · 2023: 49 · 2022: 112 · 2021: 53
FWCI
6.96
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature reviews. Immunology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion)
  • UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion)
Funders
  • Australian Government
  • European Commission (HORIZON2020, 681137)
  • National Health and Medical Research Council (1149990, GNT2002073, 1115828, 1162760)
  • ARC Centre for Excellence in Convergent Bio-Nano Science and Technology
  • Medical Research Future Fund
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
Keywords
SARS-CoV-2, COVID-19 pandemic, reinfection, immunological memory, neutralizing antibodies, antibody waning, herd immunity, vaccine design, convalescent patients
MeSH terms
Reinfection, COVID-19, SARS-CoV-2, COVID-19 Vaccines, Antibodies, Viral, Antigenic Variation, B-Lymphocytes, Humans, Immunologic Memory, Time Factors, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Models, Immunological, Antibodies, Neutralizing, Pandemics

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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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