Exploring immunity and severe disease caused by the SARS-CoV-2 Omicron variant

By Dr. Liji Thomas, MDReviewed by Aimee MolineuxDec 23 2021

The Omicron variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in South Africa’s Gauteng Province by genomic sequencing of viral particles isolated from patients with coronavirus disease 2019 (COVID-19). The epidemiological parameters of the spread of this variant have not yet been identified.

A new preprint on the medRxiv* server describes the findings of a seroprevalence survey intended to establish the infection rates and the incidence of severe COVID-19 through December 15, 2021, in Gauteng, a crowded province that compresses a quarter of the country’s people into less than 2% of its area.  

Background

The reporting of the Omicron variant of concern (VOC) of SARS-CoV-2 on November 25, 2021 in Gauteng Province was accompanied by a description of its multiple mutations, and its predicted greater ability to spread as well as evade natural and vaccine-induced immunity.

Mutations associated with increased infectivity include R203K and G204R in the nucleocapsid (N) protein; those linked to transmissibility are the spike mutations H655Y, N679K, and P681H; Δ105-107 mutation in the non-structural proteins; and antibody-evading mutations in the spike receptor-binding domain (RBD) and N-terminal domain (NTD). At least 32 spike mutations, 6 N protein mutations, and 3 membrane protein mutations are known so far, compared with 7 spike and 1 N protein mutation in the Beta variant that is also known to evade host immunity.

With a rapid rate of spread, the Omicron now accounts for over 95% of new cases and is dominant in Gauteng Province. An earlier serosurvey by the same researchers, extending well into the Beta-driven second wave of COVID-19 in the country, showed that one in five of the population had anti-RBD immunoglobulin G (IgG) antibodies. Subsequently, a third Delta wave followed, largely replacing the Beta variant.

The current studywas based on a follow-up serosurvey in this province that was completed on December 9, 2021, providing data mostly from before the fourth Omicron-driven wave. The researchers examined the overall case trends, hospitalizations and deaths, and excess mortality in this province through December 15, 2021.

The population density in Gauteng is very high, at 737 per square kilometer, though it is as low as 200 in the West Rand district, but as high as 3,400 in Johannesburg, home to over a third of its population. The researchers re-sampled the same households as the earlier survey between November 4, 2020 to January 22, 2021, with an additional 10% to compensate for missing households due to various causes.

What did the study show?

The study obtained almost 85% of their samples before the Omicron variant was reported. Of the vaccine-eligible population of over12 million people, over a third (36%) had taken one dose at least of the Pfizer or AstraZeneca vaccine, and one in five had taken both doses. The percentage went up to 45% in those above 50 years of age.

Among the unvaccinated, either anti-spike or anti-N protein IgG antibodies were detected in over two-thirds, but if only the latter was measured, only 40% were seropositive. This shows that anti-N IgG is not a useful measure in assessing the presence of a previous infection.

Using both measures together, therefore, they found that 73% of the population had antibodies to the virus, ranging from 67% to 76% in various districts. The highest seroprevalence was in Johannesburg, going as high as 86% in certain sub-districts. The lowest district seroprevalence was in Tshwane, though here too some areas showed much higher rates than others.

More than three-quarters of females were seropositive, with 1.43-fold higher odds of seropositivity than males. The highest odds were in those above 50 years, with 80% being seropositive, while just above half of the children below 12 years had antibodies to the virus. Children in the age group 12-18 years were at more than twice therisk of seropositivity than younger children.

Those vaccinated with a COVID-19 vaccine were at more than six times the risk of being seropositive, with 93% showing the presence of antibodies, compared to 68% of unvaccinated, at all ages. Those with a history of testing positive for SARS-CoV-2 infection were at twice the odds of being seropositive compared to the untested, at 88% vs 71%.

Daily smoking was associated with seropositivity in 66% vs 78% of non-smokers. The lowest risk was in those living in informal settlements, at 66%, compared to independent houses (74%) and high-rise buildings (78%).

Daily cases rose fastest in this Omicron-driven wave, with more than 160,000 cases recorded over 31 days vs 38,500 days with the Delta wave. The peak was lower than with the third wave, however, and hospitalization rates are much lower, with 3,400 vs 10,000 hospitalizations in 31 days from the onset of the fourth and third waves, respectively. The weekly excess mortality amounted to 569 vs 2,650 over the same period, with daily deaths being ~200 vs ~670, respectively.

In fact, the third wave reported 25 excess deaths per 1,00,000 at its peak, compared to one for the fourth wave at its peak.  

Implications

The fourth wave of COVID-19 in Gauteng Province occurs despite 73% seropositivity and 36% double vaccination rates. Most of the seropositivity is due to prior infection, with more than two-thirds of unvaccinated individuals being seropositive.

In this context, we have observed a dramatic uncoupling of hospitalization and death rates from infection rate compared with previous waves.”

The Omicron variant has shown greater transmissibility than the Delta, itself with an estimated reproduction number R0 of 5-6. The high rates of Omicron infections are observed against a background of high seropositivity rates, showing that this variant evades antibodies elicited by earlier variants, and the lower hospitalization rates at the peak, at less than a third of the Delta wave peak.

While 44 people per 100,000 were being hospitalized during the Delta wave at the highest point, the corresponding figure for the Omicron wave is 13. As shown above, daily and weekly excess deaths during the fourth wave are at levels seen during the lowest points of earlier waves, indicating that the virulence of this latest variant remains to be established.

It is more than probable that the asynchrony between infections and severe disease with the Omicron variant is due to cell-mediated rather than antibody-mediated immunity. The former is likely related to both vaccination and natural infection, with over 60% of the above-50 population having received one dose of the vaccine. This group suffered over 80% of the deaths in this province prior to the onset of the fourth wave.

Earlier studies showed a diverse cell-mediated immune response targeting numerous antigens on the virus, including the spike, N and membrane proteins. Therefore, this type of immunity may be more persistent over time than antibodies, to mutations affecting the RBD or other spike regions, as with Omicron.

Natural infection generates memory T cells as well, including long-lived cytotoxic (CD8+) T-cells, which may persist for up to 255 days. Both infection- and vaccine-elicited cellular adaptive immunity may thus have led to the mildness of the current outbreak, despite the ability of Omicron to escape neutralization by antibodies to spike-based vaccines or to earlier variants with different antibody-escape mutations.

Most vaccinated individuals with a history of natural infection have hybrid immunity, and do have detectable neutralizing capacity against Omicron, but less so than the wildtype virus. The relatively low proportion of fully vaccinated individuals is an explanation for the high number of breakthrough infections and reinfections with Omicron.

These occur in people with lower neutralizing capacity due to natural immunity vs vaccine-elicited immunity, especially since South Africa provides one dose of the Johnson & Johnson vaccine Ad26.COV2.S, or two doses of the Pfizer BNT162b2 vaccine, without booster doses. With countries where vaccination coverage is high, the contributions of vaccine-induced vs natural vs hybrid immunity must be determined.

The same is the case with the Beta variant, where 11 of 87 T cell epitopes in the spike protein, induced by the AstraZeneca vaccine, were impacted by the Beta spike mutations, though high neutralizing antibody escape was noted. Despite little efficacy against mild-to-moderate disease, the vaccine showed 80% protection against severe or fatal outcomes, according to a Canadian study.

Continuing monitoring will show whether severe cases rise with the continuance of the wave, or the uncoupling effect persists. If the latter,

it may herald a turning point in the Covid-19 pandemic, if the primary goal is protection against severe disease and death rather than trying to prevent infections.”