Natural and hybrid immunity following four COVID-19 waves in a South African cohort

Abstract

BackgroundMore than half the global population has been exposed to SARS-CoV-2. Naturally induced immunity influences the outcome of subsequent exposure to variants and vaccine responses. We measured anti-spike IgG responses to explore the basis for this enhanced immunity.MethodsA prospective cohort study in a South African community through the ancestral/beta/delta/omicron SARS-CoV-2 waves. Health seeking behaviour/illness were recorded and post-wave serum samples probed for IgG to Spike (CoV2-S-IgG). 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 for unvaccinated and vaccinated adults.FindingsDespite little disease, 176/339 (51·9%) participants were seropositive following wave 1, rising to 74%, 89·8% and 97·3% after waves 2, 3 and 4 respectively. CoV2-S-IgG induced by natural exposure protected against subsequent SARS-CoV-2 infection with the greatest protection for beta and the least for omicron. Vaccination induced higher CoV2-S-IgG in seropositive compared to naïve vaccinees. Amongst seropositive participants, proportions above the 50% protection against infection threshold were 69% (95% CrI: 62, 72) following 1 vaccine dose, 63% (95% CrI: 63, 75) following 2 doses and only 11% (95% CrI: 7, 14) in unvaccinated during the omicron wave.InterpretationNaturally induced CoV2-S-IgG do not achieve high enough levels to prevent omicron infection in most exposed individuals but are substantially boosted by vaccination leading to significant protection. A single vaccination in those with prior immunity is more immunogenic than 2 doses in a naïve vaccinee and thus may provide adequate protection.FundingUK NIH GECO award (GEC111), 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).Research in contextEvidence before this studyNatural infection with ancestral SARS-CoV-2 virus provides partial protection against re-infection with the same and closely related SARS-CoV-2 variants, but higher rates of re-infection have been described with Omicron. In addition, vaccination against SARS-CoV2 provides relatively lower protection against symptomatic Omicron infection than for other variants. Hybrid immunity, a combination of immunity induced by natural infection and vaccination is of critical interest due to the high incidence of natural infection in many populations and increased availability of vaccination. Vaccination following infection may provide more robust immunity than either infection or vaccination alone, but there are limited data on the impact of hybrid immunity for protection against different variants or on the optimal vaccination strategy following natural infection.Added value of this studyWe leveraged a unique South African birth cohort in a poor peri-urban area, to longitudinally investigate infection, illness and serological responses to natural exposure to SARS-CoV-2 over 4 waves of the pandemic in healthy mothers. We also investigated the impact of prior natural exposure on BNT162b2 mRNA vaccine responses. We used this information to derive estimates of levels of spike-specific IgG associated with protection for subsequent infection following natural or hybrid immunity. Despite little disease, most participants were seropositive with rates rising from 52% to 74%, 90% and 97% after waves 1, 2, 3 and 4 respectively. Antibodies to spike protein induced by natural exposure protected against subsequent infection with the greatest protection for beta and the least for omicron. Antibody levels following vaccination were significantly higher in those who were seropositive prior to vaccine, compared to those seronegative. Amongst seropositive participants, proportions above the 50% protection against infection threshold were 69% following 1 vaccine dose, 63% following 2 doses and only 11% in unvaccinated during the omicron wave. In those seropositive prior to vaccination no significant increase in antibody levels occurred after the 2nd dose of vaccine, unlike the increase in seronegative participants. A single dose of vaccine in seropositive individuals induced higher antibody concentrations than two doses in seronegative recipients.Implications of all the available evidenceNaturally induced spike antibodies do not achieve high enough levels to prevent omicron infection in most exposed individuals but are substantially boosted by vaccination leading to significant protection. A single vaccination in those with prior natural immunity is more immunogenic than 2 doses in seronegative people and may provide adequate protection against omicron and other variants. Vaccination programs in populations with high seroprevalence using a single vaccination as a primary strategy should be considered.

Comparative epidemic expansion of SARS-CoV-2 variants Delta and Omicron in Amazonas, a Brazilian setting with high levels of hybrid immunity

“…Despite several studies pointing to superior immune responses among individuals with hybrid immunity to prevent Omicron infections (Wratil et al, 2022;Cele et al, 2021;Planas et al, 2021;Rössler et al, 2022;Walls et al, 2022;Gruell et al, 2022;Nielsen et al, 2022;Zar et al, 2022;Altarawneh et al, 2022a), the high percentage of people naturally infected and vaccinated (~65%) (Fig. 2A) in Amazonas in December 2021 was not able to prevent the exponential spread of the immune-evasive Omicron variant.…”

“…The immune population landscape may also shape the impact of new SARS-CoV-2 variants. Previous studies demonstrate that “hybrid immunity”, produced by a combination of infection and SARS-CoV-2 vaccination, improves the potency, breadth, and durability of serum neutralizing activity against SARS-CoV-2 variants, including Delta and Omicron, relative to either infection or vaccination alone (Andreano et al, 2021; Bates et al, 2022; Gazit et al, 2022; Goldberg et al, 2022; Hall et al, 2022; Hammerman et al, 2022; Cerqueira-Silva et al, 2022a; Wang et al, 2021; Wratil et al, 2022; Cele et al, 2021; Planas et al, 2021; Rössler et al, 2022; Walls et al, 2022; Gruell et al, 2022; Nielsen et al, 2022; Zar et al, 2022; Altarawneh et al, 2022a). Thus, populations with high hybrid immunity walls are expected to have a better protection against the impact of new SARS-CoV-2 variants carrying immune escape mutations (Crotty, 2021; Suryawanshi & Ott, 2022).…”

Feasibility of Provision and Vaccine Hesitancy at a Central Hospital COVID-19 Vaccination Site in South Africa after Four Waves of the Pandemic

“…South Africa has recorded just over 4 million COVID-19 cases and more than 102,000 deaths attributable to the illness as of February 2024 [1]. South Africa has now entered the recovery stage of the COVID-19 pandemic, and the majority of South Africans have either natural immunity from prior COVID-19 infection or vaccine-induced immunity [2,3]. New COVID-19 infection, or re-infection, is more likely to cause severe disease in highly vulnerable groups.…”