Special Issue: Understanding the impact of aging on the susceptibility and response to COVID-19 infection. (Special Issue: Understanding the impact of aging on the susceptibility and response to COVID-19 infection.)

This journal issue includes 15 articles that discuss continent-wide evolutionary trends of emerging SARS-CoV-2 variants;use of convalescent plasma therapy in hospitalised adult patients with non-critical COVID-19;evidence for preserved insulin responsiveness in the aging rat brain;SARS-CoV-2 infection in HIV-infected patients;different patterns of excess all-cause mortality by age and sex in Hungary during the 2nd and 3rd waves of the COVID-19 pandemic;mutational landscape of the newly emerging Omicron (B.1.1.529) variant and comparison of mutations with VOCs and VOIs.

Rituximab and Covid-19 Vaccines, Are They Fit for Purpose?

Background/Aims Since the COVID-19 outbreak the rheumatology community have been concerned about the risk of SARS-CoV-2 infection in patients prescribed immunosuppressing medications. Data suggests that patients receiving Rrtuximab are at increased risk of developing severe outcomes from COVID-19 (1). In our unit all patients receiving rituximab were selected to receive a targeted vaccination and booster programme with all patients receiving at least 2 vaccinations and up to 3 booster vaccinations. We studied the efficacy of the COVID-19 vaccines in rituximab patients, by checking the the Roche Elecsys Anti-SARS-CoV-2-S (Spike) IgG/IgM total antibody levels post vaccination. Our aim was to assess the vaccination response in patients receiving rituximab and to offer advice on continued shielding or alternatively passive immunization with tixagevimab/cilgavimab in those patients who did not mount a response. Methods Taking 39 patients currently on rituximab therapy, we measured Anti- SARS-CoV-2-S (Spike) antibody levels post vaccination. We recorded whether the test was positive or negative, and the numerical result. We recorded rituximab dates of administration and dates of vaccines. We also recorded diagnosis, co-prescribed DMARDs, immunoglobulin levels, white cell and lymphocyte counts. We took record of whether or not the patient subsequently contracted COVID-19, required a hospital admission, ICU or died. Results Of our 39 patients, 21 had Anti-SARS-CoV-2-S (Spike) antibody levels checked. Of these patients, 7 (33%) had a negative spike protein result. Of the patients with a positive result, 8 (38%) had an antibody level between 0-250U/ML, and only 6 (28.6%) had a level >250U/ML (The manufacturer advises that a level above 0.8U/ML is a positive result). Of patients with a negative result, 1 patient had received 3 vaccines, 5 patients had received 4, and 1 patient had 5. All of the patients had received a vaccine >4 weeks prior to receiving the drug. Two patients were co-prescribed Belimumab, 3 were co-prescribed low-dose methotrexate and 2 were not on additional disease modifying agents. The diagnoses of these patients were, 2 patients with SLE, 4 with SPRA, and 1 MPO Vasculitis. There were no significant findings in lymphocyte count, white cell count or immunoglobulin levels. Conclusion These findings suggest that our current COVID-19 vaccination and booster programme may not provide adequate response in patients receiving rituximab therapy. Despite this being a small cohort, these results show that 33% of patients have not mounted a vaccine response and this is concerning. We suggest that vaccine response should be checked in all patients receiving rituximab therapy and those patients who do not mount a vaccine response should be offered passive immunity and advised of possible additional risks regarding COVID-19 exposure.

[Efficacy and safety of patients immunization with chronic obstructive pulmonary disease with monoclonal antibodies].

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by a high level of morbidity and mortality and is associated with significant social and economic damage to the health system and society. COPD and COVID-19 have many potentially negative relationships that can lead to worse outcomes of COVID-19, including impaired lung function, old age and the presence of concomitant diseases Aim. To assess efficacy and safety of the drug Tixagevimab + Cilgavimab for the pre-contact prevention of COVID-19 infection in patients with COPD. MATERIAL AND METHODS: A total of 324 male patients were included in the study, who were treated or monitored at the Regional Clinic Hospital №3 and the Regional Pulmonological Center of Chelyabinsk in April-May 2022. The main endpoints of observation, for 3 and 6 months, to assess the effectiveness were the dynamics of shortness of breath according to The Modified Medical Research Council Dyspnea Scale - mMRC, the The forced expiratory volume in 1 second, the number of exacerbations, emergency calls, hospitalizations, polymerase chain reaction for SARS-CoV-2. Local and general reactions after immunization were evaluated. The drug Evusheld (150 mg Tixsagevimab +150 mg Cilgavimab, AstraZeneca) was used for immunization. RESULTS AND CONCLUSION: The effectiveness of pre-contact prevention of COVID-19 was 88.8%. The administration of the drug does not provoke an exacerbation of the underlying disease. The main clinical and functional indicators have positive dynamics by the 6th month of follow-up. The drug is well tolerated and has no significant both early and late complications.

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.

Egg Yolk Antibody for Passive Immunization: Status, Challenges, and Prospects.

The immunoglobulin Y (IgY) derived from hyperimmune egg yolk is a promising passive immune agent to combat microbial infections in humans and livestock. Numerous studies have been performed to develop specific egg yolk IgY for pathogen control, but with limited success. To date, the efficacy of commercial IgY products, which are all delivered through an oral route, has not been approved or endorsed by any regulatory authorities. Several challenging issues of the IgY-based passive immunization, which were not fully recognized and holistically discussed in previous publications, have impeded the development of effective egg yolk IgY products for humans and animals. This review summarizes major challenges of this technology, including in vivo stability, purification, heterologous immunogenicity, and repertoire diversity of egg yolk IgY. To tackle these challenges, potential solutions, such as encapsulation technologies to stabilize IgY, are discussed. Exploration of this technology to combat the COVID-19 pandemic is also updated in this review.

Clinical progress of therapeutics and vaccines: Rising hope against COVID-19 treatment.

Cases of deaths due to COVID-19 (COrona VIrus Disease-19) infection are increasing gradually worldwide. Immense research is ongoing to control this pandemic condition. Continual research outcomes are indicating that therapeutic and prophylactic agents are the possible hope to prevent the pandemic from spreading and to combat this increasing death count. Experience gained from previous coronavirus infections (eg., SARS (Severe Acute Respiratory Syndrome), MERS (Middle Ease Respiratory Syndrome), accumulated clinical knowledge during this pandemic, and research helped to identify a few therapeutic agents for emergency treatment of COVID-19. Thereby, monoclonal antibodies, antivirals, broad-spectrum antimicrobials, immunomodulators, and supplements are being suggested for treatment depending on the stage of the disease. These recommended treatments are authorized under medical supervision in emergency conditions only. Urgent need to control the pandemic condition had resulted in various approaches of repurposing the existing drugs, However, poorly designed clinical trials and associated outcomes do not provide enough evidence to fully approve treatments against COVID-19. So far, World Health Organization (WHO) authorized three vaccines as prophylactic against SARS-CoV-2. Here, we discussed about various therapeutic agents, their clinical trials, and limitations of trials for the management of COVID-19. Further, we have also spotlighted different vaccines in research in combating COVID-19.

Passive pre-exposure immunization by tixagevimab/cilgavimab in patients with hematological malignancy and COVID-19: matched-paired analysis in the EPICOVIDEHA registry.

Only few studies have analyzed the efficacy of tixagevimab/cilgavimab to prevent severe Coronavirus disease 2019 (COVID-19) and related complications in hematologic malignancies (HM) patients. Here, we report cases of breakthrough COVID-19 after prophylactic tixagevimab/cilgavimab from the EPICOVIDEHA registry). We identified 47 patients that had received prophylaxis with tixagevimab/cilgavimab in the EPICOVIDEHA registry. Lymphoproliferative disorders (44/47, 93.6%) were the main underlying HM. SARS-CoV-2 strains were genotyped in 7 (14.9%) cases only, and all belonged to the omicron variant. Forty (85.1%) patients had received vaccinations prior to tixagevimab/cilgavimab, the majority of them with at least two doses. Eleven (23.4%) patients had a mild SARS-CoV-2 infection, 21 (44.7%) a moderate infection, while 8 (17.0%) had severe infection and 2 (4.3%) critical. Thirty-six (76.6%) patients were treated, either with monoclonal antibodies, antivirals, corticosteroids, or with combination schemes. Overall, 10 (21.3%) were admitted to a hospital. Among these, two (4.3%) were transferred to intensive care unit and one (2.1%) of them died. Our data seem to show that the use of tixagevimab/cilgavimab may lead to a COVID-19 severity reduction in HM patients; however, further studies should incorporate further HM patients to confirm the best drug administration strategies in immunocompromised patients.

Human Antibodies for Viral Infections.

Antibodies have been used to prevent or treat viral infections since the nineteenth century, but the full potential to use passive immunization for infectious diseases has yet to be realized. The advent of efficient methods for isolating broad and potently neutralizing human monoclonal antibodies is enabling us to develop antibodies with unprecedented activities. The discovery of IgG Fc region modifications that extend antibody half-life in humans to three months or more suggests that antibodies could become the principal tool with which we manage future viral epidemics. Antibodies for members of most virus families that cause severe disease in humans have been isolated, and many of them are in clinical development, an area that has accelerated during the effort to prevent or treat COVID-19 (coronavirus disease 2019). Broad and potently neutralizing antibodies are also important research reagents for identification of protective epitopes that can be engineered into active vaccines through structure-based reverse vaccinology.

Evaluation of Non-Clinical Toxicity Studies of COVID-19 Vaccines

Absence of a relevant animal disease model and lack of the use of supportive studies have limited the process of rapid development of SARS-CoV-2 vaccines. This study has evaluated how the choice of species selection and study design affected the outcomes of the non-clinical toxicity studies of the various SARS-CoV-2 vaccine concepts. The study has been focused on safety aspects i.e. on the Developmental and Reproductive Toxicity (DART) and Repeated Dose Toxicity (RDT) studies. Rat and rabbitwere themost commonly used species in preclinical toxicity testing. Some COVID-19 vaccine candidates show a DART study design suboptimal for antibody transfer during lactation. The toxicity studies showed no serious adverse effects.Minor effectswere expected, i.e. local reactogenicity, immune response and macroscopic findings at the injection site. In addition, comments received during the EMA assessment of the vaccines have been evaluated and consisted most frequently of commentary on study design, species selection and missing data regardless of the utilized vaccine concept. Use of supportive platform studies often substantiated the commentary on these main three categories. Animal model-based toxicity testing has shown limited value in establishing safety of the vaccines, and, more importantly, low translational value in supporting clinical development. From a 3R perspective sponsors are encouraged to focus on products from the supportive platform, both with respect to DART and RDT studies. Regulatory emphasis on data obtained from vaccines with the same platform technology data can be used to support marketing approval of new vaccines.

Guidance on the use of convalescent plasma to treat immunocompromised patients with COVID-19.

COVID-19 convalescent plasma (CCP) is a safe and effective treatment for COVID-19 in immune compromised (IC) patients. IC patients have a higher risk of persistent infection, severe disease and death from COVID-19. Despite the continued clinical use of CCP to treat IC patients, the optimal dose, frequency/schedule, and duration of CCP treatment has yet to be determined, and related best practices guidelines are lacking. A group of individuals with expertise spanning infectious diseases, virology and transfusion medicine was assembled to render an expert opinion statement pertaining to the use of CCP for IC patients. For optimal effect, CCP should be recently and locally collected to match circulating variant. CCP should be considered for the treatment of IC patients with acute and protracted COVID-19; dosage depends on clinical setting (acute vs protracted COVID-19). CCP containing high-titer SARS-CoV-2 antibodies, retains activity against circulating SARS-CoV-2 variants, which have otherwise rendered monoclonal antibodies ineffective.