The Omicron variant (lineage B.1.1.529), to which the SARS-CoV-2 coronavirus mutated in late November 2021, is the dominant variant on the planet. Omicron, which has displaced all other variants, continues to evolve and is now divided into five distinct sublineages, BA.1, BA.2, BA.3, BA.4, and BA.5. As of late August 2022, the prevalence of BA.4 and BA.5 continues to grow rapidly in all parts of the world, displacing all other sublineages and subvariants, including the still circulating BA.2.12.1 and BA.2.75. [1] [2] [3] [4]

With the emergence of Omicron, as well as previous and no longer relevant variants like Alpha, Beta, Gamma, and Delta, it became clear that all existing vaccines, which had previously been more or less successful against COVID-19 infection, had dramatically lost their protective power. As a result, booster vaccination campaigns had to be organized, offering the population, in effect, the third and fourth doses of vaccination, shortening the time intervals between them at the same time. But this didn’t help much either: a set of Omicron mutations [5] allowed SARS-CoV-2 to easily bypass the immune shield raised by both vaccines and a previously suffered COVID-19. Incidentally, this is why the BA.5 subvariant has been dubbed the Omicron ninja.

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This is why, when there is little hope for vaccines alone, it is important to know which drugs from the available pharmacological armamentarium remain therapeutically effective in the face of Omicron invasion. Understanding which drugs are successful against established and gaining Omicron subvariants will allow informed medical decisions to be made during the treatment of COVID-19 infection.

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Remdesivir, molnupiravir and nirmatrelvir are three antiviral drugs that have been rigorously evaluated clinically and have proven to be effective in the treatment of COVID-19 infection. These three drugs alone, which act directly on the SARS-CoV-2 coronavirus by inhibiting its replication, have been implemented into international clinical practice.

Any other antivirals, often distributed locally (at the country level), no matter what their developers claim, either do not work at all, or have inherently insufficient efficacy, or their clinical trials are characterized by inconclusive and/or biased results. Attempts to treat with dubious remedies are extremely dangerous because of the false hope for favorable outcomes and successful recovery. Remember: Human health comes before pharmaceutical business.

Veklury (remdesivir), Lagevrio (molnupiravir), and Paxlovid (nirmatrelvir + ritonavir), behind Gilead Sciences, Merck & Co., and Pfizer, are effective against any of the available Omicron subvariants. No significant relationship was found in the change in their half maximal inhibitory concentration (IC50) with respect to any Omicron subvariants. This can be explained by the fact that the indicated antivirals selected those conservative SARS-CoV-2 targets that are not particularly prone to mutation.

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Monoclonal Antibodies

There are many monoclonal antibodies on the market that are successfully used for the treatment of COVID-19 infection. Their mechanism of action is to bind to the S protein of the coronavirus SARS-CoV-2, leading to a blockade of its interaction with angiotensin-converting enzyme 2 (ACE2), a receptor that the virus uses to attach to the cell membrane and then penetrate it. Because Omicron brought many mutations to the S protein, many monoclonal antibodies lost their ability to recognize it and therefore became less effective.

Testing the neutralizing activity of monoclonal antibodies found that the most effective, that is, remaining effective against both BA.4 and BA.5, as well as earlier Omicron subvariants, is bebtelovimab (LY-CoV1404, LY3853113), developed by Canada’s AbCellera Biologics and promoted by Eli Lilly. The different Omicron subvariants had no effect at all on the neutralizing activity of bebtelovimab.

Notably, the FDA authorized bebtelovimab in mid-February 2022 based on a very modest set of data from the BLAZE-4 (NCT04634409) phase 2 clinical trial. However, given the fact that a sufficient body of information on similar anti-SARS-CoV-2 monoclonal antibodies has already been accumulated, the data collected is enough.

The neutralizing activity of all other monoclonal antibodies in the presence of Omicron has decreased hundreds of times, and therefore their use is hardly justified, making the treatment essentially useless.

Thus, sotrovimab (GSK-4182136, VIR-7831), known under the trademark Xevudy and developed by GlaxoSmithKline and Vir Biotechnology, has completely lost its ability to fight Omicron.

The neutralizing activity of a combination of casirivimab (REGN10933) and imdevimab (REGN10987), under the trademark REGEN-COV and Ronapreve by Regeneron Pharmaceuticals, against Omicron subvariants BA.4 and BA.5 decreased by a factor of 135 and 322, respectively, when compared with activity against the original nonmutant SARS-CoV-2.

Other monoclonal antibody therapies were also characterized by weak neutralizing activity against Omicron, including BA.4 and BA.5:

  • A combination of bamlanivimab (LY-CoV555, LY3819253) and etesevimab (LY-CoV016, LY3832479, JS016), developed by Eli Lilly, AbCellera, Institute of Microbiology of Chinese Academy of Sciences (IMCAS), and China’s Shanghai Junshi Biosciences
  • Regdanvimab (CT-P59) marketed by Korea’s Celltrion as Regkirona
  • A cocktail of amubarvimab (BRII-196) and romlusevimab (BRII-198), invented by China’s Brii Biosciences.

The neutralizing activity of a combination of tixagevimab (AZD8895, COV2-2130) and cilgavimab (AZD1061, COV2-2196) promoted by AstraZeneca as Evusheld (AZD7442) weakened relatively little, 6 and 31 times against Omicron subvariants BA.4 and BA.5. It would be OK, but Evusheld is not intended to treat COVID-19, it is used exclusively for pre-exposure prophylaxis in case there are contraindications for vaccination. However, in Russia and Japan, Evusheld is approved for COVID-19 treatment.

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Treatment of Omicron in Outpatients

In the vast majority of cases, COVID-19 infection has a mild-to-moderate severity that does not require any specialized treatment, and is therefore limited to symptomatic supportive therapy.

The exception is patients who are at high risk of developing a severe disease, the worsening course of which may require hospitalization or end in death. Among the key high-risk factors are lack of vaccination for COVID-19, older age, weakened immune system, presence of chronic diseases. Antiviral drugs or monoclonal antibodies should be administered as soon as possible after onset to prevent adverse outcomes in this category of patients.

Considering the clinical guidelines of the WHO [1] [2], the United States [3] and the United Kingdom [4], the expert consensus of evidence-based medicine databases [5] [6] [7], and the in vitro activity of antiviral drugs and monoclonal antibodies against the Omicron variant [8] [9] [10] [11] [12] [13], a simple algorithm for the treatment of high-risk outpatients (nonhospitalized) with mild-to-moderate COVID-19 patients who do not require supplemental oxygen is drawn.

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The optimal first choice is oral Paxlovid, which has demonstrated the highest efficacy in the treatment of COVID-19 infection during a 5-day course of therapy. Administration of Paxlovid is carried out no later than 5 days after the manifestation of disease symptoms. It is necessary to take into account the drug interactions of ritonavir in Paxlovid.

If Paxlovid is not suitable and no more than 7 days have passed after the start of COVID-19, intravenous infusions of Veklury for 3 days are justified.

If Paxlovid or Veklury are not available or cannot be administered, monoclonal antibodies or Lagevrio should be the clinical choice. Monoclonal antibodies are used as a single intravenous infusion if no more than 5 days (sotrovimab), 7 days (bebtelovimab, regdanvimab), or 10 days (casirivimab + imdevimab, bamlanivimab + etesevimab, amubarvimab + romlusevimab) have passed since the manifestation of COVID-19 symptoms. Lagevrio is prescribed as an oral 5-day course if no more than 5 days have passed.

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As for convalescent plasma (from blood donors who have successfully recovered from COVID-19 infection), its use is highly controversial. A high titer of neutralizing antibodies must be present in order for convalescent plasma to be guaranteed to work. However, plasma is formed from pools when, for example, plasma with a high concentration of antibodies is diluted with plasma with a low concentration. And it is not certain that every donor is screened for the appropriate level of antibodies. As a result, it is quite possible that there will not be enough antibodies in any dose of convalescent plasma.

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Risk of Severe COVID-19

There is a category of vulnerable patients whose COVID-19 infection is characterized by an increased risk of severe outcomes, such as hospitalization, admission to the intensive care unit (ICU), need for intubation or mechanical ventilation, and death.

High-risk patients worldwide are estimated to number approximately half of the total population.

High-risk COVID-19 patients should include people who meet at least one criterion:

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  • Age 50 and older
  • Unvaccinated, under-vaccinated, or overdue booster doses of vaccine
  • Racial or ethnic minority
  • A history of a certain disease (condition):
  • Obesity (body mass index [BMI] ≥30 kg/m2)
  • Type 1 diabetes mellitus, type 2 diabetes mellitus
  • Kidney diseases: chronic kidney disease (CKD)
  • Lung diseases: cystic fibrosis, interstitial lung disease, pulmonary embolism, pulmonary hypertension, bronchiectasis, chronic obstructive pulmonary disease (COPD)
  • Cardiovascular diseases: heart failure, coronary heart disease, cardiomyopathies
  • Cerebrovascular diseases
  • Cancer
  • Liver diseases: cirrhosis, non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, autoimmune hepatitis
  • Mental health disorders: mood disorders (including depression), schizophrenia spectrum disorders
  • Disabilities: attention deficit hyperactivity disorder (ADHD), cerebral palsy, congenital malformations, limitations with self-care or activities of daily living, intellectual and developmental disabilities, learning disabilities, spinal cord injuries
  • Other diseases: asthma, HIV, tuberculosis, primary immunodeficiencies, dementia
  • Other conditions: pregnancy (including recent pregnancy), physical inactivity, smoking (current or past), solid organ or hematopoietic cell transplantation, use of corticosteroids or other immunosuppressive medications.

People who are overweight (BMI between 25 and 29 kg/m2), have hypertension, hepatitis B, hepatitis C, sickle cell disease, thalassemia, alpha-1 antitrypsin deficiency, bronchopulmonary dysplasia, or substance use disorder are also at increased risk for severe COVID-19.

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