Correlates of protection against COVID-19 infection and intensity of symptomatic disease in vaccinated individuals exposed to SARS-CoV-2 in households in Israel (ICoFS): a prospective cohort study

Abstract

Background: Identifying COVID-19 correlates of protection and immunity thresholds is important for policy makers and vaccine development. We aimed to identify correlates of protection of BNT162b2 (Pfizer-BioNTech) vaccination against COVID-19.

Methods: In this prospective cohort study, households within a radius of 40 km of the Sheba Medical Center in Israel in which a new SARS-CoV-2 infection (defined as the index case) was detected within the previous 24 h were approached between July 25 and Nov 15, 2021. We included adults (aged >18 years) who had received one or two vaccine doses, had an initial negative SARS-CoV-2 PCR and no previous infection reported, and had a valid IgG and neutralising antibody result. The exposure of interest was baseline immune status, including IgG antibody concentration, neutralising antibody titre, and T-cell activation. The outcomes of interest were PCR-positive SARS-CoV-2 infection between day 2 and day 21 of follow-up and intensity of disease symptoms (self-reported via a telephone questionnaire) among participants who had a confirmed infection. Multivariable logistic and ordered logit ordinal regressions were used for the adjusted analysis. To identify immunological thresholds for clinical protection, we estimated the conditional probability of infection and moderate or severe disease for individuals with pre-exposure IgG and neutralising antibody concentrations above each value observed in the study data.

Findings: From 16 675 detected index cases in the study region, 5718 household members agreed to participate, 1461 of whom were eligible to be included in our study. 333 (22·8%) of 1461 household members who were not infected with SARS-CoV-2 at baseline were infected within 21 days of follow-up. The baseline (pre-exposure) IgG and neutralising antibodies were higher in participants who remained uninfected than in those who became infected (geometric mean IgG antibody concentration 168·2 binding antibody units [BAU] per mL [95% CI 158·3-178·7] vs 130·5 BAU/mL [118·3-143·8] and geometric mean neutralising antibody titre 197·5 [181·9-214·4] vs 136 ·7 [120·3-155·4]). Increasing IgG and neutralising antibody concentrations were also significantly associated with a reduced probability of increasing disease severity. Odds of infection were significantly reduced each time baseline IgG antibody concentration increased by a factor of ten (odds ratio [OR] 0·43 [95% CI 0·26-0·70]) and each time baseline neutralising antibody titre increased by a factor of two (0·82 [0·74-0·92]). In our cohort, the probability of infection if IgG antibody concentrations were higher than 500 BAU/mL was 11% and the probability of moderate disease severity was 1%; the probability of infection if neutralising antibody titres were above or equal to 1024 was 8% and the probability of moderate disease severity was 2%. T-cell activation rates were not significantly associated with reduced probability of infection (OR 1·04, 95% CI 0·83-1·30).

Interpretation: Both IgG and neutralising antibodies are correlates of protection against SARS-CoV-2 infection. Our data suggest that IgG concentrations higher than 500 BAU/mL and neutralising antibody titres of 1024 or more are thresholds for immunological protection from SARS-CoV-2 delta variant infection. Potentially, updated protective thresholds against emerging variants of concern could be calculated, which could support decision makers on administration of new vaccination strategies and on the optimal period between vaccine doses.

Funding: Israeli Ministry of Health.

Figure 1

Study design flow chart *226 households were approached by telephone and agreed to participate but were not recruited due to technical difficulties. †The total of 4257 household members excluded in the current study include: individuals who were positive for SARS-CoV-2 infection at baseline (n=926), individuals who were 18 years or younger (n=1787), individuals who had received a third vaccine dose (n=306), individuals who were unvaccinated (n=66), and individuals who were not available for serology (n=1372).

Figure 2

Baseline immune markers by infection outcome (A) IgG antibody concentrations in individuals without and with SARS-CoV-2 infection. (B) IgG antibody concentrations by severity of disease. (C) Neutralising antibody titres in individuals without and with SARS-CoV-2 infection. (D) Neutralising antibody titres by severity of disease. (E) T-cell activation in individuals without and with SARS-CoV-2 infection. (F) T-cell activation by severity of disease. Geometric means are represented by black dots, and the 95% CI is represented by the bars.

Figure 3

Probability of a household contracting SARS-CoV-2 infection with or without moderate symptoms The probability of getting infected (A) or having moderate symptoms (B) based on pre-infection IgG concentrations. The probability of getting infected (C) or having moderate symptoms (D) based on pre-infection neutralising antibody titres. The solid line denotes the calculated probability (odds ratio) given the increasing concentrations and the shaded areas denote the 95% CI. BAU=binding antibody units.