Natural immunity and protection against variants in South African children through five COVID-19 waves: A prospective study

BACKGROUND: Children have been largely spared from serious disease through the COVID-19 pandemic despite high exposure to SARS-CoV-2. Antibody responses to exposure and their role in protecting children from subsequent variant infection remains poorly understood.

METHODS: A prospective cohort study of children in a South African community through ancestral/Beta/Delta/Omicron BA.1/BA.2 and BA.4/BA.5 SARS-CoV-2 waves (March 2020-October 2022). Health seeking behaviour/illness was recorded and post-wave serum samples measured for IgG to Spike (CoV2-S-IgG) by ECLIA. To estimate protective CoV2-S-IgG threshold levels, logistic functions were fit to describe the correlation of CoV2-S-IgG measured before a wave and the probability for seroconversion/boosting thereafter.

FINDINGS: Despite little disease 125/366 (34·2%) children (median age 6·7y (IQR 5.9·9 7·4y) were seropositive following wave 1, rising to 53·6%, 76·0%, 96·2% and 99·2% after waves 2 (Beta), 3 (Delta), 4 and 5 (Omicron variants) respectively. CoV2-S-IgG induced by natural exposure protected against subsequent SARS-CoV-2 infection with the greatest protection for Beta and least for Omicron. Levels of IgG specific for ancestral spike (S) antigen that provided a 50% protective threshold for the subsequent wave were lowest for the Beta and highest for the Omicron BA.1/BA.2 wave. In multivariate analysis, maternal seropositivity (aOR=2·57 (95% CI: 1·72; 3·82) was strongly associated with child seropositivity.

INTERPRETATION: Children responded robustly to successive waves of SARS-CoV-2 mounting IgG responses to spike antigen that were protective against subsequent waves. In the absence of vaccination almost all children were seropositive after the 5 th wave but none were hospitalised suggesting natural immunity alone may be sufficient to protect children in a pandemic setting.

FUNDING: UK NIH GECO award (GEC111), Wellcome Biomedical resources grant (221372/Z/20/Z), Wellcome Trust Centre for Infectious Disease Research in Africa (CIDRI), Bill & Melinda Gates Foundation, USA (OPP1017641, OPP1017579) and NIH H3 Africa (U54HG009824, U01AI110466]. HZ is supported by the SA-MRC. MPN is supported by an Australian National Health and Medical Research Council Investigator Grant (APP1174455). BJQ is supported by a grant from the Bill and Melinda Gates Foundation (OPP1139859). Stefan Flasche is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant number 208812/Z/17/Z).