Real-world clinical effectiveness of Tixagevimab/Cilgavimab and Regdanvimab monoclonal antibodies for COVID-19 treatment in Omicron variant-dominant period.

Several virus-neutralizing monoclonal antibodies (mAbs) have become new tools in the treatment of the coronavirus disease (COVID-19), but their effectiveness against the rapidly mutating virus is questionable. The present study investigated the effectiveness of Tixagevimab/Cilgavimab and Regdanvimab for mild and moderate COVID-19 treatment in real-world clinical practice during the Omicron variant-dominant period. Patients with known risk factors for disease progression and increasing disease severity were enrolled in the study within the first 7 days of symptom onset. Seventy-seven patients were divided into four groups: first 15 patients received 300 mg Tixagevimab/Cilgavimab intravenously (IV) and 23 patients got the same drug 300 mg intramuscularly (IM), the next 15 patients was on the same combination in dose of 600 mg IV, and 24 patients were on Regdanvimab at a dose of 40 mg/kg IV. By Day 4, 100% of Tixagevimab/Cilgavimab IV patients showed negative polymerase chain reaction results for SARS-CoV-2 Ribonucleic acid (RNA) regardless of the mAbs dose while in the Regdanvimab group 29% of the patients were positive for SARS-CoV-2 virus RNA. The testing for virus neutralizing antibodies (nAbs) to various Omicron sublineages (BA.1, BA.2, and BA.5) showed that an increase in nAb levels was detected in blood serum immediately after the drug administration only in Tixagevimab/Cilgavimab 300 mg and 600 mg IV groups. In the group of intravenous Regdanvimab, a significant increase in the level of nAbs to the Wuhan variant was detected immediately after the drug administration, while no increase in nAbs to different Omicron sublineages was observed. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT05982704.

In Vitro Efficacy of Antivirals and Monoclonal Antibodies against SARS-CoV-2 Omicron Lineages XBB.1.9.1, XBB.1.9.3, XBB.1.5, XBB.1.16, XBB.2.4, BQ.1.1.45, CH.1.1, and CL.1.

The spread of COVID-19 continues, expressed by periodic wave-like increases in morbidity and mortality. The reason for the periodic increases in morbidity is the emergence and spread of novel genetic variants of SARS-CoV-2. A decrease in the efficacy of monoclonal antibodies (mAbs) has been reported, especially against Omicron subvariants. There have been reports of a decrease in the efficacy of specific antiviral drugs as a result of mutations in the genes of non-structural proteins. This indicates the urgent need for practical healthcare to constantly monitor pathogen variability and its effect on the efficacy of preventive and therapeutic drugs. As part of this study, we report the results of the continuous monitoring of COVID-19 in Moscow using genetic and virological methods. As a result of this monitoring, we determined the dominant genetic variants and identified the variants that are most widespread, not only in Moscow, but also in other countries. A collection of viruses from more than 500 SARS-CoV-2 isolates has been obtained and characterized. The genetic lines XBB.1.9.1, XBB.1.9.3, XBB.1.5, XBB.1.16, XBB.2.4, BQ.1.1.45, CH.1.1, and CL.1, representing the greatest concern, were identified among the dominant variants. We studied the in vitro efficacy of mAbs Tixagevimab + Cilgavimab (Evusheld), Sotrovimab, Regdanvimab, Casirivimab + Imdevimab (Ronapreve), and Bebtelovimab, as well as the specific antiviral drugs Remdesivir, Molnupiravir, and Nirmatrelvir, against these genetic lines. At the current stage of the COVID-19 pandemic, the use of mAbs developed against early SARS-CoV-2 variants has little prospect. Specific antiviral drugs retain their activity, but further monitoring is needed to assess the risk of their efficacy being reduced and adjust recommendations for their use.

Safety and immunogenicity of rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine against SARS-CoV-2 in healthy adolescents: an open-label, non-randomized, multicenter, phase 1/2, dose-escalation study.

To protect young individuals against SARS-CoV-2 infection, we conducted an open-label, prospective, non-randomised dose-escalation Phase 1/2 clinical trial to evaluate the immunogenicity and safety of the prime-boost "Sputnik V" vaccine administered at 1/10 and 1/5 doses to adolescents aged 12-17 years. The study began with the vaccination of the older cohort (15-to-17-year-old participants) with the lower (1/10) dose of vaccine and then expanded to the whole group (12-to-17-year-old participants). Next, 1/5 dose was used according to the same scheme. Both doses were well tolerated by all age groups. No serious or severe adverse events were detected. Most of the solicited adverse reactions were mild. No significant differences in total frequencies of adverse events were registered between low and high doses in age-pooled groups (69.6% versus 66.7%). In contrast, the 1/5 dose induced significantly higher humoral and T cell-mediated immune responses than the 1/10 dose. The 1/5 vaccine dose elicited higher antigen-binding (both S and RBD-specific) as well as virus-neutralising antibody titres at the maximum of response (day 42), also resulting in a statistically significant difference at a distanced timepoint (day 180) compared to the 1/10 vaccine dose. Higher dose resulted in increased cross-neutralization of Delta and Omicron variants. Clinical Trial Registration: ClinicalTrials.gov, NCT04954092, LP-007632.

rAAV expressing recombinant antibody for emergency prevention and long-term prophylaxis of COVID-19.

Introduction: Numerous agents for prophylaxis of SARS-CoV-2-induced diseases are currently registered for the clinical use. Formation of the immunity happens within several weeks following vaccine administration which is their key disadvantage. In contrast, drugs based on monoclonal antibodies, enable rapid passive immunization and therefore can be used for emergency pre- and post-exposure prophylaxis of COVID-19. However rapid elimination of antibody-based drugs from the circulation limits their usage for prolonged pre-exposure prophylaxis. Methods: In current work we developed a recombinant adeno-associated viral vector (rAAV), expressing a SARS-CoV-2 spike receptor-binding domain (RBD)-specific antibody P2C5 fused with a human IgG1 Fc fragment (P2C5-Fc) using methods of molecular biotechnology and bioprocessing. Results and discussions: A P2C5-Fc antibody expressed by a proposed rAAV (rAAV-P2C5-Fc) was shown to circulate within more than 300 days in blood of transduced mice and protect animals from lethal SARS-CoV-2 virus (B.1.1.1 and Omicron BA.5 variants) lethal dose of 105 TCID50. In addition, rAAV-P2C5-Fc demonstrated 100% protective activity as emergency prevention and long-term prophylaxis, respectively. It was also demonstrated that high titers of neutralizing antibodies to the SARS-CoV-2 virus were detected in the blood serum of animals that received rAAV-P2C5-Fc for more than 10 months from the moment of administration.Our data therefore indicate applicability of an rAAV for passive immunization and induction of a rapid long-term protection against various SARS-CoV-2 variants.

Estimation of anti-orthopoxvirus immunity in Moscow residents and potential risks of spreading Monkeypox virus.

WHO has declared the outbreak of monkeypox as a public health emergency of international concern. In less than three months, monkeypox was detected in more than 30 000 people and spread to more than 80 countries around the world. It is believed that the immunity formed to smallpox vaccine can protect from monkeypox infection with high efficiency. The widespread use of Vaccinia virus has not been carried out since the 1980s, which raises the question of the level of residual immunity among the population and the identification of groups requiring priority vaccination. We conducted a cross-sectional serological study of remaining immunity among Moscow residents. To do this, a collection of blood serum samples of age group over 30 years old was formed, an in-house ELISA test system was developed, and a virus neutralization protocol was set up. Serum samples were examined for the presence of IgG antibodies against Vaccinia virus (n=2908), as well as for the ability to neutralize plaque formation with a Vaccinia virus MNIIVP-10 strain (n=299). The results indicate the presence of neutralizing antibody titer of 1/20 or more in 33.3 to 53.2% of people older than 45 years. Among people 30-45 years old who probably have not been vaccinated, the proportion with virus neutralizing antibodies ranged from 3.2 to 6.7%. Despite the higher level of antibodies in age group older than 66 years, the proportion of positive samples in this group was slightly lower than in people aged 46-65 years. The results indicate the priority of vaccination in groups younger than 45, and possibly older than 66 years to ensure the protection of the population in case of spread of monkeypox among Moscow residents. The herd immunity level needed to stop the circulation of the virus should be at least 50.25 - 65.28%.

Immunogenicity and protectivity of intranasally delivered vector-based heterologous prime-boost COVID-19 vaccine Sputnik V in mice and non-human primates.

Although unprecedented efforts aiming to stop the COVID-19 pandemic have been made over the past two years, SARSCoV-2 virus still continues to cause intolerable health and economical losses. Vaccines are considered the most effective way to prevent infectious diseases, which has been reaffirmed for COVID-19. However, in the context of the continuing virus spread because of insufficient vaccination coverage and emergence of new variants of concern, there is a high demand for vaccination strategy amendment. The ability to elicit protective immunity at the entry gates of infection provided by mucosal vaccination is key to block virus infection and transmission. Therefore, these mucosal vaccines are believed to be a "silver bullet" that could bring the pandemic to an end. Here, we demonstrate that the intranasally delivered Gam-COVID-Vac (Sputnik V) vaccine induced a robust (no less than 180 days) systemic and local immune response in mice. High immunogenic properties of the vaccine were verified in non-human primates (common marmosets) by marked IgG and neutralizing antibody (NtAb) production in blood serum, antigen-specific Tcell proliferation and cytokine release of peripheral blood mononuclear cells accompanied by formation of IgA antibodies in the nasal mucosa. We also demonstrate that Sputnik V vaccine can provide sterilizing immunity in K18-hACE2 transgenic mice exposed to experimental lethal SARS-CoV-2 infection protecting them against severe lung immunopathology and mortality. We believe that intranasal Sputnik V vaccine is a promising novel needle-free mucosal vaccine candidate for primary immunization as well as for revaccination and is worth further clinical investigation.

Single-Domain Antibodies Efficiently Neutralize SARS-CoV-2 Variants of Concern.

Virus-neutralizing antibodies are one of the few treatment options for COVID-19. The evolution of SARS-CoV-2 virus has led to the emergence of virus variants with reduced sensitivity to some antibody-based therapies. The development of potent antibodies with a broad spectrum of neutralizing activity is urgently needed. Here we isolated a panel of single-domain antibodies that specifically bind to the receptor-binding domain of SARS-CoV-2 S glycoprotein. Three of the selected antibodies exhibiting most robust neutralization potency were used to generate dimeric molecules. We observed that these modifications resulted in up to a 200-fold increase in neutralizing activity. The most potent heterodimeric molecule efficiently neutralized each of SARS-CoV-2 variant of concern, including Alpha, Beta, Gamma, Delta and Omicron variants. This heterodimeric molecule could be a promising drug candidate for a treatment for COVID-19 caused by virus variants of concern.

Neutralizing Activity of Sera from Sputnik V-Vaccinated People against Variants of Concern (VOC: B.1.1.7, B.1.351, P.1, B.1.617.2, B.1.617.3) and Moscow Endemic SARS-CoV-2 Variants.

Since the beginning of the 2021 year, all the main six vaccines against COVID-19 have been used in mass vaccination companies around the world. Virus neutralization and epidemiological efficacy drop obtained for several vaccines against the B.1.1.7, B.1.351 P.1, and B.1.617 genotypes are of concern. There is a growing number of reports on mutations in receptor-binding domain (RBD) increasing the transmissibility of the virus and escaping the neutralizing effect of antibodies. The Sputnik V vaccine is currently approved for use in more than 66 countries but its activity against variants of concern (VOC) is not extensively studied yet. Virus-neutralizing activity (VNA) of sera obtained from people vaccinated with Sputnik V in relation to internationally relevant genetic lineages B.1.1.7, B.1.351, P.1, B.1.617.2, B.1.617.3 and Moscow endemic variants B.1.1.141 (T385I) and B.1.1.317 (S477N, A522S) with mutations in the RBD domain has been assessed. The data obtained indicate no significant differences in VNA against B.1.1.7, B.1.617.3 and local genetic lineages B.1.1.141 (T385I), B.1.1.317 (S477N, A522S) with RBD mutations. For the B.1.351, P.1, and B.1.617.2 statistically significant 3.1-, 2.8-, and 2.5-fold, respectively, VNA reduction was observed. Notably, this decrease is lower than that reported in publications for other vaccines. However, a direct comparative study is necessary for a conclusion. Thus, sera from "Sputnik V"-vaccinated retain neutralizing activity against VOC B.1.1.7, B.1.351, P.1, B.1.617.2, B.1.617.3 as well as local genetic lineages B.1.1.141 and B.1.1.317 circulating in Moscow.