The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in Wuhan, China in December 2019, leading to a worldwide outbreak of coronavirus disease 2019 (COVID-19).

Since then, the world has been in a tailspin trying to escape the cycle of viral transmission, containment issues, economic recession, relaxation of public health restrictions followed by a surge in new infections.

Such waves are driven by new variants, the latest being the Omicron variant. These new variants sometimes possess greater transmissibility and pathogenicity or may escape host immune defenses. Alternatively, they may evade neutralization by antibodies elicited by earlier variants.

Study: SARS-CoV-2 Omicron: reduction of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern. Image Credit: Halfpoint/Shutterstock

A new study published on the medRxiv* preprint server demonstrates SARS-CoV-2 Omicron antibody escape.

Background

Different variants of SARS-CoV-2 have been identified since January 2020, coinciding with the patchy rollout of vaccines to the virus around the world. While countries with a sizable vaccination coverage initially experienced dramatic declines in hospitalizations and deaths due to COVID-19, the failure to ensure equitable and uniform vaccine supply and administration worldwide led, as was predicted, to the selection of antibody-resistant and immune-evading mutations, clustered to form new variants of concern (VOCs) of the virus.

The Omicron (B.1.1.529) variant was reported in November 2021, with the largest number of mutations in any single variant since the beginning of the pandemic. This includes key changes in the spike glycoprotein, which mediates viral recognition of the target host cell and viral entry into the cell.

First, it shows many mutations of the receptor-binding domain (RBD) of the spike protein, including at residues 484 and 477, that allow it to evade antibody recognition. Secondly, mutations at S477N, Q498R and N501Y are at the boundaries of the virus-receptor interface, stabilizing the interactions between the virus and the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell.

Thirdly, the changes at the furin cleavage site on the spike protein, at P681H, H655Yand N679K positions, help to enhance cleavage and thus the rate of membrane fusion and viral entry mediated by the host transmembrane serine protease TMPRSS2. Both the Alpha and Delta VOCs also had mutations at position 681.

The Omicron variant has the highest transmissibility of all known variants, and is displacing the Delta VOC, which has dominated the world since the first quarter of this year.

The current study examined the neutralization of virus variants using three sets of antibodies: serum from individuals vaccinated or infected with earlier variants of the virus; concentrated human antibodies from plasma donors; and approved monoclonal antibodies.

The study

The researchers had earlier developed a rapid and sensitive platform (the 20-hour live virus neutralization platform) to characterize the changes in viral biology resulting from the clustered mutations. Thus, they were able to show, within a week of the earliest positive Omicron sample in Australia, that the new variant was relatively more resistant to neutralization than the Beta, Gamma and Delta VOCs, using serum from plasma donors who had received two doses of either the ChAdOx1 nCoV-19 or BNT162b2 vaccines.

They first collected serum samples from participants in the ADAPT community-based cohort of about 200 patients who have been followed up since the onset of the pandemic in Australia. The fifty convalescent serum samples with the highest antibody responses were examined, from clades A and B in March 2020 and Clade 20F in August, ending with the Delta clade from June 2021. The second set of samples included those with the highest antibody titers after vaccination post-recovery from COVID-19.

The researchers tested neutralizing capacities with each set of samples, across the four VOCs mentioned above.

The second screening was with concentrated pooled human IgG (immunoglobulin G) antibodies from mostly American donors collected at the peak of the US vaccine rollout. This ensures that antibodies elicited by natural infection and vaccination are present in the plasma, and thus extends the potential breadth of neutralization. As a result, the true extent of immune evasion at population level would be more apparent.

The third set of tests was with therapeutic monoclonal antibodies including sotrovimab, casirivimab, imdevimab, bamlanivimab, cilgavimab and tixagevimab.

Omicron shows antibody evasion

Neutralizing antibody titers to the Omicron variant in serum from plasma donors were lower by 17 to 22-fold. Pooled concentrated human antibodies from recovered or vaccinated individuals showed a broader range of neutralization but with 16-fold reduced potency. Among the therapeutic antibodies, only sotrovimab was able to neutralize the new variant.

The scientists chose only those ADAPT serum samples that had high neutralizing titers. Samples from early clade infections showed five-fold reduction in neutralization for the Beta, 1.6-fold for the Delta and two-fold for the Delta VOC, compared to the ancestral variant, while Omicron neutralization was undetectable.

The convalescent sera samples from the Delta wave showed a neutralizing capacity that was severely reduced for the Omicron variant. Compared to a half-maximal inhibitory dose (ID50) of 770 for the wild-type virus, neutralizing titers were reduced 1.6-fold for Delta, but 3-fold for Gamma and 4-fold for the Beta variant. However, it was more than 20-fold reduced for Omicron.

The results using sera from recovered early clade infected individuals who had then got two shots of either of the two vaccines showed that, as expected, vaccinated individuals had much higher wild-type virus neutralizing titers than convalescent donors. However, neutralizing titers fell by 18 to 27-fold against the Omicron variant, compared to a four-fold reduction against the Beta variant.

With five samples of pooled concentrated human polyclonal antibodies, from more than 10,000 pooled plasma donors, the neutralizing titer was reduced by 17-fold against the Omicron variant, compared with a three-fold decrease for the Beta variant. This was from samples collected at the peak of the vaccine rollout.

Similar reductions were observed with samples collected later on, between September and October 2020, at 20-fold and 5.5-fold, respectively.

How effective are existing vaccines against Omicron?

The investigators classified data into three groups by the phase of the pandemic, namely, convalescent samples from the first, second and third (Delta) waves; convalescent-vaccinated samples; and pooled concentrated antibody samples.  

Excluding all groups without detectable neutralizing titers against Omicron, as well as those infected during the Delta wave because of the sizable differences in the Delta spike antigen, they found that first-wave donors had 20-fold lower neutralizing titers against Omicron, just as with the earlier pooled IgG samples or ADAPT cohort samples.

On average, the BNT162b2 vaccination series elicits neutralization levels to the wild-type virus that are two-fold less than those seen following natural infection. When the 20-fold reduction seen above is considered, BNT162b2 vaccine efficacy in naïve individuals is 37% against symptomatic Omicron infection, and 74% against severe infection, over the first few months post-vaccination, and in cases with a prior history of natural infection, neutralization titers are still higher. Despite the steep decline in neutralizing capacity, therefore, the BNT162b2 booster will still provide significant protection from Omicron-associated illness.

Monoclonal antibody sotrovimab and Omicron

The currently used therapeutic monoclonal antibodies (mAbs) were tested for neutralization of Omicron in cell culture. The researchers found that sotrovimab neutralized the virus at 3-fold lower potency compared to the ancestral lineage. Tixagevimab showed a 74-fold drop, while the others did not show detectable neutralization.

This may be because sotrovimab targets a highly conserved portion of the RBD, with the two mutations falling within its epitope on the Omicron RBD causing only a moderate decline in potency compared to the wildtype virus.

Implications

The study sheds light on the neutralizing activity of natural, vaccine-induced and therapeutic antibodies against the emerging variants of SARS-CoV-2. The loss of neutralizing activity by all monoclonal antibodies but sotrovimab is a serious concern, indicating the need for more effective therapeutic antibodies. Moreover, Omicron evades antibodies elicited by the ancestral variants efficiently, with several-fold reduction in the neutralizing titers, similar to but much greater than observed with the Beta and Gamma VOCs.

Also, Omicron is rapidly becoming dominant, replacing the Delta variant. This may indicate the need to develop boosters using the Omicron spike, rather than the ancestral or early variant spikes, for long-term boosting of immunity. This is especially key when involving the induction of an adequate immune response in the elderly or immunocompromised, who tend to respond weakly to the vaccine. Fortunately, sotrovimab shows neutralizing activity against this variant as well, providing a treatment modality to prevent severe disease or death.  

*Important notice

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

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.