The omicron variant: what do we know so far?

The World Health Organization reported the emergence of omicron (B.1.1.529), the fifth SARS-CoV-2 variant of concern, on 25^th November 2021.¹ The first report of the omicron variant was from Botswana, followed by a case from Hong Kong. A steep rise in cases was observed in South Africa, especially from the Gauteng province in the ensuing days. The omicron variant is characterized by the S-gene target failure on a specific PCR assay. There has been increasing concern that omicron might create a “tidal wave” leading to increased pressure on healthcare resources that have already been pushed to the limit.

Transmissibility

The R₀ value, a measure of transmissibility, denotes the average number of individuals who will contract the disease from an infected person. The R₀ of the original strain of SARS-CoV-2 was 2·5; for the delta variant, it was just under 7. The R₀ value for omicron could be as high as 10.² This would explain the much more rapid doubling time of 1.2 days observed with omicron compared with 1.5 days for the delta and 1.7 days for the beta variants. 

Potential for immune escape

Cross-neutralization against omicron from previous non-omicron infection appears to be low.³ From the information available so far, there appears to be a high incidence of infection with omicron in individuals previously infected with other variants.  Most Covid-19 vaccines have been effective in the prevention of severe disease, hospitalization, and death in infections with previous variants. The high efficacy may be more dependent on T-cell immune responses than the generation of antibodies. It is of concern that in the UK, with 70% double vaccination rates, and 90% of individuals with antibodies, the caseload has been spiraling upwards. Protection against omicron may be just 10% after 6 months of a double dose vaccine compared with 40% for delta. The T cell response is against the whole spike protein and hence, vaccines that induce a robust T cell response may retain efficacy against omicron. 

Severity

The initial reports from England, Scotland, and South Africa suggest that the omicron variant may cause less severe disease than its predecessors, including delta.  

A retrospective database study from the US evaluated 14,054 patients during the period between 15^th–24^th December 2021 when omicron first emerged.⁴ The authors described this as the “emergent omicron cohort”. The outcomes of this cohort were compared with those of 563,884 patients during the period between 1^st September and 15^th December 2021 when the delta variant was the predominant strain. Propensity-score matching was carried out to adjust for differences in demographic characteristics, socioeconomic status, co-morbidities, and vaccination status. The authors analyzed the risk of emergency department visit, hospitalization, ICU admission, and mechanical ventilation during a 3-day period starting from the day of confirmation of SARS-CoV-2 infection. The emergent omicron cohort revealed significantly lower rates of emergency department visit [4.55% vs. 15.22% (risk ratio or RR: 0.30, 95% CI: 0.28-0.33)], hospitalization [1.75% vs. 3.95% (RR: 0.44, 95% CI: 0.38-0.52)], admission to ICU [0.26% vs. 0.78% (RR: 0.33, 95% CI:0.23-0.48)], and mechanical ventilation [0.07% vs. 0.43% (RR: 0.16, 95% CI: 0.08-0.32)]. The reduced risk of adverse outcomes was observed across all age groups, including the pediatric population. This study suggests that during the 10-day period when omicron emerged as the dominant strain, disease severity appeared to be significantly lower compared to the period when the delta strain was dominant.  The actual incidence of omicron infection during the 10-day period between 15^th–24^thDecember 2021 is unknown; it may have been between 22.5–58.6%.

A retrospective study compared the severity of illness between the four Covid-19 waves experienced in South Africa.⁵ The cohort between 15^th November 2021 and 7^th December 2021 was during the period when omicron emerged. The severity of illness during this period, considered to be predominantly due to omicron (the fourth wave) was compared with the first (original strain), second (beta variant), and third (delta variant) waves. The rate of hospital admission was significantly lower during the fourth wave compared to the first three waves (41.3% vs. 68–69%). The affected population was younger with more female patients during the fourth wave. The incidence of respiratory symptoms was lower in the fourth wave compared to the previous waves (31.6% in the fourth wave vs. a maximum of 91.2% in the third wave, P < 0.001). The requirement for oxygen therapy was lower during the fourth compared to the third wave (17.6% vs. 74%, P < .001). The requirement for mechanical ventilation was significantly lower in the fourth compared to the third wave (1.6% vs. 12.4%, P < 0.001). The hospital mortality rate during the fourth wave was also significantly lower at 2.7% compared with 19.7% in the first and 29.1% in the third wave.

The clinical severity of omicron infection was assessed using the S Gene Target Failure (SGTF) technique in another South African study.⁶ Infections were classified as the SGTF (omicron) or non-SGTF type (non-omicron). Multivariable regression models were used to compare symptom severity in SGTF vs. non-SGTF-infected patients and patients infected with the delta variant. Patients with SGTF infection were significantly less likely to require hospitalization compared to patients with non-SGTF infection [adjusted odds ratio (aOR) 0.2, 95% confidence interval (CI) 0.1-0.3)]. Among patients who required hospitalization, the incidence of severe disease was similar. Besides, SGTF-infected patients experienced less severe disease compared to delta infection (aOR 0.3, 95% CI 0.2-0.5).

Therapeutic options 

Monoclonal antibodies

The susceptibility of the omicron variant to the currently used monoclonal antibodies appears to be poor. Two new monoclonal antibodies, sotrovimab and DXP-604 are currently undergoing investigation. Sotrovimab may be effective against omicron; however, the dose required to prevent binding of SARS-CoV-2 to ACE receptors may be up to three times as high compared to other variants^7,8

Antiviral drugs 

Two new antiviral drugs, molnupiravir and paxlovid (nirmatrelvir-ritonavir combination) have been tested against SARS-CoV-2. The reports are unpublished, released by the manufacturers. In a phase 3 study, the oral antiviral drug molnupiravir reduced the risk of hospitalization or mortality by 50% compared to placebo in mild or moderate covid-19.⁹ In another phase 2/3 trial, the antiviral drug paxlovid was evaluated in 2,246 patients with Covid-19. The results suggested that paxlovid significantly reduced the risk of hospitalization and all-cause mortality by 89% compared to placebo among high-risk adult patients when administered within 3 days of onset of symptoms.¹⁰ Early reports suggest that antiviral drugs may retain efficacy against variants of concern including omicron.¹¹

Vaccine efficacy 

In a study from South Africa, the efficacy of two doses of the BNT162b2 (Pfizer) vaccine in preventing hospitalization was evaluated during the omicron period (15^th November – 7^th December).¹² This was compared to the period during which the delta variant was predominant. During the omicron period, vaccine efficacy at preventing hospitalization was significantly lower at 70% [95% confidence interval [CI], 62 to 76] compared to 93% [(95% CI, 90 to 94)] during the period when delta variant was predominant. Although the level of protection was lower, the vaccine still appeared to be effective in reducing hospitalization among infected patients during the omicron period.   

Neutralization of omicron-infected cells in serum samples from participants who had two doses of the BNT162b2 vaccine was compared with individuals who had three doses.¹³ Receipt of three vaccine doses led to better neutralization of the wild-type virus and the beta, delta, and omicron variants compared to the receipt of two doses. The efficacy of neutralization against omicron was higher with three compared to two doses. However, the neutralizing effect was lower with the omicron compared to the delta variant even with three doses. 

The neutralization antibody titers against omicron after a booster dose of the ChAdOx1-S (AstraZeneca) vaccine were higher compared to the antibody titers in subjects who had recovered from Covid-19 infection with the original, alpha, beta, and delta variants in a study conducted at the University of Oxford.¹⁴ The neutralization titers against omicron after one month of the booster dose were similar to titers against the delta variant after the two doses. This study suggests that a third dose of the  ChAdOx1-S vaccine may retain protection against omicron; further clinical studies are required to confirm this finding.

Key points

• The omicron variant appears to be more transmissible compared to previous variants, with a likely R₀ of 10 compared to 2·5 for the original strain and 7 for the delta variant
• The doubling time is commensurately shorter, as evident from the spiraling increase in cases across the world 
• Preliminary reports suggest that the severity of illness, especially the requirement for hospitalization, ICU admission, and respiratory support appear to be lower with omicron compared with previous variants
• Neutralizing monoclonal antibodies that are currently in use appear to be largely ineffective against omicron. Sotrovimab and DXP-604 are currently under investigation 
• The antiviral drugs, molnupiravir and paxlovid may retain efficacy against the omicron variant, according to initial reports from the manufacturers
• Currently available vaccines appear to be less efficacious in preventing infection with the omicron variant. A booster dose may enhance protection with the BNT162b2 (Pfizer) and the ChAdOx1-S (AstraZeneca) vaccines

References

1.         Classification of omicron (B.1.1.529): SARS-CoV-2 Variant of Concern. Accessed January 9, 2022. https://www.who.int/news/item/26-11-2021-classification-of-omicron-(b.1.1.529)-sars-cov-2-variant-of-concern

2.         Burki TK. omicron variant and booster Covid-19 vaccines. The Lancet Respiratory Medicine. 2021;0(0). doi:10.1016/S2213-2600(21)00559-2

3.         Zou J, Xia H, Xie X, et al. Neutralization against omicron SARS-CoV-2 from Previous Non-omicron Infection.; 2021:2021.12.20.473584. doi:10.1101/2021.12.20.473584

4.         Wang L, Berger NA, Kaelber DC, Davis PB, Volkow ND, Xu R. Comparison of Outcomes from Covid Infection in Pediatric and Adult Patients before and after the Emergence of omicron.; 2022:2021.12.30.21268495. doi:10.1101/2021.12.30.21268495

5.         Maslo C, Friedland R, Toubkin M, Laubscher A, Akaloo T, Kama B. Characteristics and Outcomes of Hospitalized Patients in South Africa During the Covid-19 omicron Wave Compared With Previous Waves. JAMA. Published online December 30, 2021. doi:10.1001/jama.2021.24868

6.         Wolter N, Jassat W, Walaza S, et al. Early Assessment of the Clinical Severity of the SARS-CoV-2 omicron Variant in South Africa. Infectious Diseases (except HIV/AIDS); 2021. doi:10.1101/2021.12.21.21268116

7.         Cameroni E, Saliba C, Bowen JE, et al. Broadly neutralizing antibodies overcome SARS-CoV-2 omicron antigenic shift. bioRxiv. Published online December 14, 2021:2021.12.12.472269. doi:10.1101/2021.12.12.472269

8.         Aggarwal A, Stella AO, Walker G, et al. SARS-CoV-2 omicron: Evasion of Potent Humoral Responses and Resistance to Clinical Immunotherapeutics Relative to Viral Variants of Concern.; 2021:2021.12.14.21267772. doi:10.1101/2021.12.14.21267772

9.         Merck and Ridgeback’s Investigational Oral Antiviral Molnupiravir Reduced the Risk of Hospitalization or Death by Approximately 50 Percent Compared to Placebo for Patients with Mild or Moderate Covid-19 in Positive Interim Analysis of Phase 3 Study. Merck.com. Accessed January 8, 2022. https://www.merck.com/news/merck-and-ridgebacks-investigational-oral-antiviral-molnupiravir-reduced-the-risk-of-hospitalization-or-death-by-approximately-50-percent-compared-to-placebo-for-patients-with-mild-or-moderat/

10.       Pfizer Announces Additional Phase 2/3 Study Results Confirming Robust Efficacy of Novel Covid-19 Oral Antiviral Treatment Candidate in Reducing Risk of Hospitalization or Death | Pfizer. Accessed January 8, 2022. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-announces-additional-phase-23-study-results

11.       Vangeel L, De Jonghe S, Maes P, et al. Remdesivir, Molnupiravir and Nirmatrelvir Remain Active against SARS-CoV-2 omicron and Other Variants of Concern. Microbiology; 2021. doi:10.1101/2021.12.27.474275

12.       Collie S, Champion J, Moultrie H, Bekker LG, Gray G. Effectiveness of BNT162b2 Vaccine against omicron Variant in South Africa. N Engl J Med. Published online December 29, 2021:NEJMc2119270. doi:10.1056/NEJMc2119270

13.       Nemet I, Kliker L, Lustig Y, et al. Third BNT162b2 Vaccination Neutralization of SARS-CoV-2 omicron Infection. N Engl J Med. Published online December 29, 2021:NEJMc2119358. doi:10.1056/NEJMc2119358

14.       Dejnirattisai W, Huo J, Zhou D, et al. omicron-B.1.1.529 Leads to Widespread Escape from Neutralizing Antibody Responses. Microbiology; 2021. doi:10.1101/2021.12.03.471045