Antibody correlates of protection from SARS-CoV-2 reinfection prior to vaccination: a nested case-control within the SIREN study

the SIREN Study Group and the Crick COVID Immunity Pipeline Consortium, Ana Atti*, Ferdinando Insalata, Edward J Carr, Ashley D Otter, Javier Castillo-Olivares, Mary Wu, Ruth Harvey, Michael Howell, Andrew Chan, Jonathan Lyall, Nigel Temperton, Diego Cantoni, Kelly da Costa, Angalee Nadesalingam, Andrew Taylor-Kerr, Nipunadi Hettiarachchi, Caio Tranquillini, Jacqueline Hewson, Michelle J ColeSarah Foulkes, Katie Munro, Edward J M Monk, Iain D Milligan, Ezra Linley, Meera A Chand, Colin S Brown, Jasmin Islam, Amanda Semper, Andre Charlett, Jonathan L Heeney, Rupert Beale, Maria Zambon, Susan Hopkins, Tim Brooks, Victoria Hall

*Corresponding author for this work

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To investigate serological differences between SARS-CoV-2 reinfection cases and contemporary controls, to identify antibody correlates of protection against reinfection.

We performed a case-control study, comparing reinfection cases with singly infected individuals pre-vaccination, matched by gender, age, region and timing of first infection. Serum samples were tested for anti-SARS-CoV-2 spike (anti-S), anti-SARS-CoV-2 nucleocapsid (anti-N), live virus microneutralisation (LV-N) and pseudovirus microneutralisation (PV-N). Results were analysed using fixed effect linear regression and fitted into conditional logistic regression models.

We identified 23 cases and 92 controls. First infections occurred before November 2020; reinfections occurred before February 2021, pre-vaccination. Anti-S levels, LV-N and PV-N titres were significantly lower among cases; no difference was found for anti-N levels. Increasing anti-S levels were associated with reduced risk of reinfection (OR 0·63, CI 0·47-0·85), but no association for anti-N levels (OR 0·88, CI 0·73-1·05). Titres >40 were correlated with protection against reinfection for LV-N Wuhan (OR 0·02, CI 0·001–0·31) and LV-N Alpha (OR 0·07, CI 0·009–0·62). For PV-N, titres >100 were associated with protection against Wuhan (OR 0·14, CI 0·03–0·64) and Alpha (0·06, CI 0·008–0·40).

Before vaccination, protection against SARS-CoV-2 reinfection was directly correlated with anti-S levels, PV-N and LV-N titres, but not with anti-N levels. Detectable LV-N titres were sufficient for protection, whilst PV-N titres >100 were required for a protective effect.

Trial registration number
Original languageEnglish
Pages (from-to)545-556
Number of pages12
JournalJournal of Infection
Issue number5
Early online date13 Oct 2022
Publication statusPublished - 1 Nov 2022


  • SARS-CoV-2
  • Neutralising antibodies
  • SARS-CoV-2 serology
  • Reinfection
  • Immunity


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