Study: Natural and hybrid immunity following four COVID-19 waves in a South African cohort. Image Credit: Andrii Vodolazhskyi/Shutterstock

Natural and Hybrid Immunity Dynamics in South African Mothers

In a recent study posted to the medRxiv* preprint server, researchers evaluated natural and hybrid immunity after four coronavirus disease 2019 (COVID-19) waves in South Africa.

Study: Natural and hybrid immunity after four COVID-19 waves in a South African cohort† Image Credit: Andrii Vodolazhskyi/Shutterstock


Infection with ancestral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) provides partial protection against reinfection with the same strain and closely related variants. Protection against reinfection may result from the presence of anti-receptor binding domain (anti-RBD) antibodies and antigen-specific T cells.

Reports indicate that primary vaccination with COVID-19 vaccines provides poor protection against symptomatic infection with the Omicron variant. In the context of natural infection, the link between antibody responses and subsequent protection against reinfection is poorly understood, as most studies have focused on vaccine-induced immune responses.

Nevertheless, vaccinating recovering individuals results in stronger protection than infection or vaccination alone. This type of immunity is called hybrid immunity and increases protection against different variants, probably as a result of immune maturation.

About the study

In the current study, researchers examined natural and hybrid immune responses in a cohort of South African mothers. The study population consisted of a convenience sample of mothers from a suburban community during the four COVID-19 waves. South Africa witnessed four COVID-19 waves, first at the onset of the pandemic, and subsequent spikes were caused by SARS-CoV-2 Beta (second), Delta (third) and Omicron (fourth) variants.

The research team measured serological responses to SARS-CoV-2 in serum samples after each wave. They tested for immunoglobulin G (IgG) antibodies against the spike (S) protein of the ancestral strain, Beta, Delta or Omicron variant. Participants were excluded from seroprevalence assessment after vaccination.

Risk factors associated with seropositivity were identified using generalized estimation equations (GEE). The GEE models were adjusted for age, marital status, human immunodeficiency virus (HIV) infection, education level, employment, household size and income, asthma, and smoking.


The study population consisted of 339 mothers, mainly of low socioeconomic status. Smoking was self-reported by 124 subjects and 69 participants had an HIV infection. During the study period, 18 individuals contracted SARS-CoV-2 and three cases were hospitalized due to COVID-19; no deaths were recorded.

Two subjects received Janssen’s Ad.26COV2.S vaccine before their second sampling (during the beta wave). Before the third wave, 19 mothers were vaccinated with Ad.26COV.2S and 76 with Pfizer’s BNT162b2 vaccine. About 45.4% (154) of the participants had been vaccinated with both vaccines before the fourth wave.

Seropositivity was recorded in more than half of the study population after the first wave of COVID-19. Seropositivity among unvaccinated subjects increased to 74.3% after the beta wave, 89.8% after the third wave and 97.9% after the fourth wave. Only five participants were seronegative during the four waves.

In unadjusted analysis, maternal weight, HIV infection and age were positively associated with seropositivity, while smoking was inversely associated. After adjustment, individuals living in busy households showed a higher probability of seropositivity, while smoking was associated with seronegativity.

Seroconversion was evident in 52% of seronegative mothers after the first and second COVID-19 wave. After the third and fourth wave, 66% and 77% of the subjects, respectively, showed seroconversion. The highest anti-S IgG concentrations in the unvaccinated mothers were observed after the Omicron wave. In addition, antibody concentrations in each wave were higher in mothers who were seropositive in previous COVID-19 waves than in seronegative subjects.

The probability of boosting in participants with low pre-wave IgG titres was 53% during the second wave, 68% and 84% during the third and fourth wave, respectively. In contrast, the boost rates in those with the high antibody titers were low at 17%, 39%, and 29% during the Beta, Delta, and Omicron waves, respectively. The authors noted that significantly higher pre-wave anti-ancestral S protein IgG titers were required before the Omicron wave to confer 50% protection against infection.

Of the vaccinated subjects, 87.7% showed seropositivity before vaccination. Antibody titers to all S protein variants after partial or complete vaccination with the BNT162b2 vaccine were significantly higher in mothers with seropositivity before vaccination than in seronegative subjects. IgG titers did not increase after the second vaccine dose in those with pre-vaccination seropositivity, although a second dose increased IgG levels in seronegative mothers.


The authors found a high seroprevalence in a low-income suburban community in South Africa. Seropositivity in natural infection conferred protection against SARS-CoV-2 Beta and Delta variants, but significantly high antibody titers were required for protection against Omicron.

Vaccination of seropositive mothers resulted in higher anti-S protein IgG concentrations than seronegative subjects. The authors noted that most HIV-positive vaccinated mothers were protected against the Omicron variant. The results indicated that vaccination of seropositive humans could confer adequate immunity against known and related SARS-CoV-2 variants.

*Important announcement

medRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, should guide clinical practice/health-related behavior, or be treated as established information.

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