Biodegradable Polyester Nanoparticle Vaccines Deliver Self-Amplifying mRNA in Mice at Low Doses

Delivery of self-amplifying mRNA (SAM) has high potential for infectious disease vaccination due to its self-adjuvanting and dose-sparing properties. Yet a challenge is the susceptibility of SAM to degradation and the need for SAM to reach the cytosol fully intact to enable self-amplification. Lipid nanoparticles are successfully deployed at incredible speed for mRNA vaccination, but aspects such as cold storage, manufacturing, efficiency of delivery, and the therapeutic window can benefit from further improvement. To investigate alternatives to lipid nanoparticles, a class of >200 biodegradable end-capped lipophilic poly(beta-amino ester)s (PBAEs) that enable efficient delivery of SAM in vitro and in vivo as assessed by measuring expression of SAM encoding reporter proteins is developed. The ability of these polymers to deliver SAM intramuscularly in mice is evaluated, and a polymer-based formulation that yields up to 37-fold higher intramuscular (IM) expression of SAM compared to injected naked SAM is identified. Using the same nanoparticle formulation to deliver a SAM encoding rabies virus glycoprotein, the vaccine elicits superior immunogenicity compared to naked SAM delivery, leading to seroconversion in mice at low RNA injection doses. These biodegradable nanomaterials may be useful in the development of next-generation RNA vaccines for infectious diseases.Copyright © 2023 The Authors. Advanced Therapeutics published by Wiley-VCH GmbH.

Re-vaccination against SARS-COV2 in allogeneic HSCT patients: Repeated primary vaccines doses increases seroconversion rates

Patients undergoing treatment for haematological malignancies have been shown to have reduced antibody responses to vaccination against SARS-COV2. This is particularly important in patients who have undergone allogeneic haemopoietic stem cell transplantation (HSCT), in whom there is limited data about vaccine efficacy. In this retrospective single-centre analysis, we present data on serologic responses following one, two, three or four doses of either Pfizer-BioNTech (PB), AstraZeneca (AZ) or Moderna (MU) SARS-CoV- 2 vaccines from a series of 75 patients who have undergone allogeneic HSCT within 2 years from the time they were revaccinated. The seroconversion rates following post-HSCT vaccination were found to be 50.7%, 78%, 79% and 83% following the first, second, third and fourth primary post -HSCT vaccine doses, respectively. The median time from allograft to first revaccination was 145 days (range 79-700). Our findings suggest that failure to respond to the first SARS-CoV- 2 vaccine post-HSCT was associated with the presence of acute GVHD (p = 0.042) and treatment with rituximab within 12 months of vaccination (p = 0.019). A statistical trend was observed with the presence of chronic GVHD and failure to seroconvert following the second (p = 0.07) and third (p = 0.09) post-HSCT vaccine doses. Patients who had received one or more SARS-CoV- 2 vaccines prior to having an allogeneic stem cell transplant were more likely to demonstrate a positive antibody response following the first dose of revaccination against Sars-CoV- 2 (p = 0.019) and retained this seropositivity following subsequent doses. The incidence of confirmed COVID-19 diagnosis among this cohort at the time of analysis was 16%. 17% of these were hospitalised and there was one recorded death (8%) secondary to COVID-19 in a patient who was 15.7 months post allogeneic transplant. In summary, this study suggests that despite the initial low seroconversion rates observed postallogeneic transplant, increasing levels of antibody response are seen post the second primary vaccine dose. In addition, there seems to be lower risk of mortality secondary to COVID-19 in this vaccinated population, compared to what was reported in the earlier phases of the pandemic prior to use of SARS-COV2 vaccination. This adds support to the widely adopted policy of early full revaccination with repeat of primary vaccine doses and boosters post-HSCT to reduce mortality in this population. Finally, we have identified rituximab use and active GVHD as potential risk factors influencing serological responses to SARS-COV2 vaccination and further work should focus on further characterising this risk and optimum dosing schedule both pre-and post-transplant.

HUMORAL AND CELLULAR IMMUNOGENICITY INDUCED BY THIRD BOOSTER OF SARS-CoV-2 VACCINES IN PATIENTS WITH RHEUMATIC MUSCULOSKELETAL DISEASES

BackgroundAmid the coronavirus disease 2019 (COVID-19) crisis, two messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have benefited most people worldwide. While healthy people can acquire sufficient humoral immunity against COVID-19 even in the elderly by vaccination with three doses of vaccine., recent studies have shown that complex factors other than age, including the type of vaccines and immunosuppressive drugs, are associated with immunogenicity in patients with rheumatic musculoskeletal disease (RMD). Identifying factors that contribute to the vulnerability of those patients to acquire not only humoral but also cellular immunity to SARS-CoV-2 despite multiple vaccinations is crucial for establishing an appropriate booster vaccine strategy.ObjectivesTo assess humoral,and T cell immune responses after third doses of mRNA vaccines against SARS-CoV-2.MethodsThis prospective observational study included consecutive RMD patients treated with immunosuppressant who received three doses of mRNA vaccines including BNT162b2 and mRNA-1273. Blood samples were obtained 2-6 weeks after second and third dose of mRNA vaccines. We measured neutralizing antibody titres, which against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 and seroconversion rates to evaluate the humoral responses. We also assessed T-cell immunity responses using interferon releasing assay against SARS-CoV-2.ResultsA total of 586 patients with RMD treated with mmunosuppressive treatments were enrolled. The mean age was 54 years, and 70% of the patients were female. Seroconversion rates and neutralizing antibody titres after third vaccination of SARS-CoV-2 were significantly higher compared to those after second vaccination (seroconversion rate, 94.5% vs 83.6%, p<0.001;titres of neutralizing antibody, 48.2 IU/mL vs 11.0 IU/mL, p<0.001, respectively). Interferon releasing assay after third vaccinations demonstrated that T cell reaction against SARS-CoV-2 was also increased from that of second vaccination (interferon for antigen 1, 1.11.9 vs 0.61.9, p=0.004,interferon for antigen 2, 1.72.6 vs 0.82.3, p=0.004). Humoral and cellular immunogenicity did not differ between the types of third vaccination including full dose of BNT162 and half dose of mRNA1273.(neutralizing antibody titers, 47.8±76.1 IU/mL vs 49.0±60.1 IU/mL, p<0.001;interferon for antigen 1, 1.12.0 vs 1.01.5, p=0.004, respectively). Attenuated humoral response to third vaccination was associated with BNT162b2 as second vaccination age (>60 years old), glucocorticoid (equivalent to prednisolone > 7.5 mg/day), and immunosuppressant use including mycophenolate, and rituximab. On another front, use of mycophenolate and abatacept or tacrolimus but not rituximab were identified as negative factors for T-cell reactions against SARS-CoV-2. Although 53 patients (9.0%) who had been immunised with third-vaccination contracted COVID-19 during Omicron pandemic phase, no one developed severe pulmonary disease that required corticosteroid therapy.ConclusionOur results demonstrated third mRNA vaccination booster of SARS-CoV-2 contributed to restore both humeral and cellular immunity in RMD patients with immunosuppressants. We also identified that certain immunosuppressive therapy with older RMD patients having BNT162b2 as a second vaccination may need additional booster vaccination.Reference[1]Furer V, Eviatar T, Freund T, et al. Ann Rheum Dis. 2022 Nov;81(11):1594-1602. doi: 10.1136/ard-2022-222550.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

A cross-sectional study on the seroprevalence of the SARS-CoV-2 IgG antibody in patients with cancer from central Kerala

Background: Patients with cancer are vulnerable to coronavirus disease 2019 (COVID-19). Given the rising number of COVID-19 cases and relaxation of stringent COVID-19 protocols, assessment of the level of protective immunity to COVID-19 in patients with cancer has assumed importance. Objective(s): Our primary objective was to evaluate the seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in patients with cancer. Material(s) and Method(s): We conducted a cross-sectional study on 100 patients with solid tumors attending our Oncology Department at the Believers Church Medical College, Kerala, India, between December 2020 and June 2021. Seroprevalence was assessed using the VITROS Anti-SARS-CoV-2 IgG test (Ortho-Clinical Diagnostics, Rochester, NY, USA). Additionally, we assessed the factors associated with seropositivity and collected data regarding the general experience of patients with cancer during the pandemic. Result(s): The median age of the participants was 62 years (IQR, 53-69.8);52 (52%) were males. The seroprevalence of the SARS-CoV-2 IgG antibodies was 11% (95% CI, 4.8-17.1). Age < 50 years was the only factor that was significantly associated with a higher rate of COVID-19 antibodies (77% vs 8.9% in patients >= 50 years;P = 0.007), and sex, smoking, and the use of alcohol did not show any association. The majority (77/100, 77%) of the patients were worried about contracting COVID-19 infection;some even deferred cancer-directed treatment because of the fear of visiting health care settings. Conclusion(s): Low seroprevalence of SARS-CoV-2 IgG antibodies in unvaccinated patients with cancer is a matter of concern as it indicates that many of these patients are still vulnerable to infection. There is an urgent need to continue implementing strict safety measures in oncology centers and to encourage widespread COVID-19 vaccination to prevent the uncontrolled spread of COVID-19 among patients with cancer. (Funded by the institution, Believers Church Medical College, Kerala).Copyright © 2023 Neurology India, Neurological Society of India Published by Wolters Kluwer - Medknow.

REVACCINATION OF PATIENTS WITH SLE OR RA WITHOUT AN INITIAL COVID-19 VACCINE RESPONSE ELICITS SEROCONVERSION IN HALF OF THE PATIENTS

BackgroundTreatment with Rituximab (RTX) in patients with rheumatic diseases (RD) has presented a challenge during the COVID-19 pandemic, as RTX leads to markedly reduced and often undetectable antibody responses after COVID-19 vaccination (1).ObjectivesTo investigate the effect of COVID-19 mRNA revaccination (two doses) on the antibody response in patients with RD who were initial vaccine non-responders. Further, to examine if B-cell levels or T-cell responses before revaccination predicted seroconversion.MethodsFrom a RD cohort (COPANARD) vaccinated with the standard two-dose COVID-19 vaccinations, we enrolled cases without detectable antibody responses (n=17) and controls with detectable antibody response (n=29). Blood donors (n=32) were included as additional controls. Samples were collected before and six weeks after completed revaccination. Total antibodies (abs) and specific IgG, IgA, and IgM against SARS-CoV-2 spike protein, SARS-CoV-2 neutralizing abs, and SARS-CoV-2 reacting CD4+ and CD8+ T-cells were measured before and after revaccination. B-cells (CD19+CD45+) were quantified before revaccination. This study was funded by the Danish Rheumatism Association.ResultsPatient demographics are given in Table 1. Forty-seven percent of cases had detectable total SARS-CoV-2 abs and neutralizing abs after revaccination. However, antibody levels were significantly lower than in controls and blood donors (p<0.008), Figure 1A+B. Revaccination induced an antibody class switch in cases with a decrease in detectable IgM abs (Baseline 11/17, Followup 3/17) and increase in IgG. No significant difference was observed in T-cell responses before and after revaccination between the three groups, Figure 1C. The proportion of cases with detectable CD4+ T cells increased from 69% to 88% (p=0.25), and for CD8+ T cells, the proportion decreased from 88% to 82% (p=1.00). Only 29% of cases had measurable B-cells compared to 100% of controls and blood donors, Figure 1D. Fifty percent of revaccinated cases who seroconverted had measurable B-cells before revaccination, Figure 1D.Univariate logistic regression analysis was performed to analyze if active RTX treatment, the presence of B-cells, or a positive T-cell response prior to revaccination predicted seroconversion of total SARS-CoV-2-abs in the patient cohort. We did not find a significant explanatory effect of either variable in the univariate logistic models, data not shown.Table 1.DemographicsCases Revaccination, n=17Controls Boost, n=29Female sex, no(%)1482%2172%Age, median (IQR)6549 - 706762 - 72Disease duration, years1510 - 18229 - 31Rheumatoid Arthritis/SLE13/410/19None DMARD529%828%Prednisone424%13%Methotrexate741%1241%Hydroxychloroquine212%414%None biologic treatment424%931%Rituximab1271%0TNF-inhibitors16%724%JAK-inhibitors0621%IL-6-inhibitors, Abatacept, Benlysta0724%Previous rituximab treatmentAny rituximab treatment1694%13%RTX within the last 15 months, no1488%0Cumulative total dose, mg134-242Time from RTX to revaccination, months95-1249Figure 1.ConclusionIn conclusion, forty-seven percent of initial non-responders were able to seroconvert after two-dose revaccination. However, plasma concentrations of the antibodies against SARS-COV-2 and the levels of neutralizing capacity remained significantly lower than in immunocompetent blood donors. B-cell levels or T-cell responses before revaccination did not predict seroconversion. Our study suggests that patients with RDs who did not mount a detectable serological response to a COVID-19 mRNA vaccine have a T cell response similar to immunocompetent controls. Future studies should establish the antibody levels that identify RD patients without sufficient protection against SARS-CoV-2 infection.References[1]Troldborg A, et al. Time Since Rituximab Treatment Is Essential for Developing a Humoral Response to COVID-19 mRNA Vaccines in Patients With Rheumatic Diseases. J Rheumatol. 2022.AcknowledgementsThe Danish Rheumatism Association [grant number R203-A7217]. We acknowledge all patients and blood donors contributing to the stud for their invaluable participation. The authors would like to thank Sif Kaas Nielsen and Mads Engelhardt Knudsen, the Laboratory of Molecular Medicine at Rigshospitalet, for their excellent technical assistance in analyzing the samples.Disclosure of InterestsNone Declared.

EFFICACY AND SAFETY OF ANTI-SARS-CoV-2 VACCINATION IN PEOPLE WITH RMDs: RESULTS FROM A SYSTEMATIC LITERATURE REVIEW

BackgroundAs the third year of the pandemic begins, over 13 billion doses of anti-SARS-CoV-2 vaccines have been administrated worldwide and growing evidence on their efficacy and safety in people with RMDs has accrued.ObjectivesTo update our previous systematic literature review (SLR)[1] on efficacy and safety of anti-SARS-CoV-2 vaccination in people with rheumatic and musculoskeletal diseases (RMDs)MethodsA literature search according to the PICO framework was conducted on July 22, 2022 to identify references in seven databases published after June 1, 2021 (end date of previous SLR). Title and s were independently screened by 3 investigators (AA, AN and FK). Eligibility criteria were stricter in terms of requirement of the inclusion of control group or undertaking a multivariable analysis. However, for some outcomes (e.g., RMD flares), descriptive studies were also included due to the paucity of data. Data extraction and risk of bias (RoB) assessment were performed as in the previous SLR.ResultsOf 1583 references, 219 were included for full text assessment and 30 fulfilled the eligibility criteria. Recent studies confirmed that a full vaccination cycle was generally immunogenic, though the seroconversion rate and the anti-spike antibody (Ab) titre were lower in patients with RMDs compared to healthy controls. Vaccination was also able to induce neutralising antibodies (NAb) but the seroconversion rate and the neutralising activity were lower than in controls. Glucocorticoids, mycophenolate mofetil, rituximab and abatacept were negatively associated with Ab and NAb seroconversion. Two studies specifically investigating RTX-treated RMD patients identified an association between lower dose and longer period of time after the last RTX infusion before vaccination and higher likelihood of Ab seroconversion. The majority of breakthrough infections (B-INFs) were asymptomatic and, if symptomatic, mild to moderate. A higher number of vaccine doses was associated with a lower incidence and severity of B-INFs, although B-INF incidence rate was generally higher in the post-delta variant period. Higher disease activity was associated with higher likelihood of severe/critical B-INFs. Regarding safety, in general, patients with RMDs showed higher rates of mild AEs compared to the general population, however severe AEs were rare, if any. Disease flares have been observed in/reported by less than 10% of patients in the various cohorts and although often requiring treatment with glucocorticoids or change of the ongoing immunosuppressive therapy, hospitalization was generally not needed. Pre-vaccination colchicine prophylaxis seemed useful to prevent gout flares in the post-vaccination trimester.ConclusionOverall anti-SARS-CoV-2 vaccination is immunogenic and safe in patients with RMDs. However, careful and individualised assessment of the ongoing therapy and disease activity when planning the vaccination schedule is necessary to minimise the risk of reduced immunogenicity, post-vaccination disease flares and breakthrough infections.Reference[1]Kroon FPB, Najm A, Alunno A, Schoones JW, Landewé RBM, Machado PM, Navarro Compán V. Ann Rheum Dis. 2022;81(3):422-432Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Transient Decrease in Incidence Rate of Maternal Primary Cytomegalovirus Infection during the COVID-19 Pandemic in Japan.

This study evaluated the impact of the coronavirus disease 2019 (COVID-19) pandemic on the occurrence of maternal primary cytomegalovirus (CMV) infection in Japan. We performed a nested case-control study using data from maternal CMV antibody screening under the Cytomegalovirus in Mother and infant-engaged Virus serology (CMieV) program in Mie, Japan. Pregnant women with negative IgG antibodies at ≤20 weeks of gestation who were retested at ≥28 weeks were enrolled. The study period was divided into 2015-2019 as the pre-pandemic and 2020-2022 as the pandemic period, and the study site included 26 institutions conducting the CMieV program. The incidence rate of maternal IgG seroconversion was compared between the pre-pandemic (7008 women enrolled) and pandemic (2020, 1283 women enrolled; 2021, 1100 women; and 2022, 398 women) periods. Sixty-one women in the pre-pandemic period and five, four, and five women during 2020, 2021, and 2022, respectively, showed IgG seroconversion. The incidence rates in 2020 and 2021 were lower (p < 0.05) than that in the pre-pandemic period. Our data suggest a transient decrease in the incidence of maternal primary CMV infection in Japan during the COVID-19 pandemic, which could be due to prevention and hygiene measures taken at the population level.

Chapter 13 - The effect of COVID-19 on cancer immunotherapy and cancer care

: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), identified in Wuhan, China, in December 2019, rapidly spread globally to become a devastating global pandemic. The SARS-CoV-2 (coronavirus disease 2019 [COVID-19]) respiratory illness was initially reported in the United States in the state of Washington in January 2020. COVID-19 respiratory virus proved to be an extremely contagious illness with clinical features of fever, cough, dyspnea, malaise, and rapidly progressing severe interstitial pneumonia. Since the beginning of 2020, COVID-19 has been responsible for an unimagined level of deaths and socioeconomic disruption. The patient with malignancy and a suppressed immune system was, as expected, at increased risk for contracting COVID-19. Patients with cancer, when infected, had a more difficult clinical course and an increased rate of mortality. In the intervening 2+ years, much has been learned regarding the ability of the patient with cancer's immune system to not only fight the progression of their cancer but to effectively respond to newly available mRNA vaccines against COVID-19. As the pandemic continues, careful management of the vulnerable patient with cancer is essential.

Humoral Immune Response to Sars-Cov-2 Third Vaccine in Patients with Autoimmune Rheumatic Diseases without Seroconversion after the Initial 2-Dose Regimen

Objectives: To evaluate the humoral immune response to the third dose (booster) of vaccine against SARS-CoV-2 in patients with autoimmune rheumatic diseases who were seronegative after a two-dose regimen. Method(s): Observational study. Patients with autoimmune rheumatic diseases who had not achieved seroconversion after a two-dose vaccine schedule against SARS-CoV-2 were included. To assess the humoral immune response, anti-RBD IgG (S protein receptor binding domain) neutralizing antibody titers were determined by ELISA (cutoff titer 200). The determination was made between 30 to 45 days after the third dose. Result(s): From 66 patients who received SARS-CoV-2 vaccination, 18 patients (29.5%) were seronegative after a two-dose schedule. 61% had SLE, 77% had comorbidities (61% with hypertension, p = 0.03). Patients were on treatment: 10 with prednisone (8 with doses greater than 10 mg/d, p = 0.01), 10 with hydroxychloroquine, one with methotrexate, one with leflunomide, four with azathioprine, five with my cophenolatemofetil and five with rituximab (they are the total number of non-responders on biological treatment, p = 0.03). Regarding the primary vaccination regimen, 11 received BBIBP-CorV (p = 0.01), 5 AZD1222, 1 Gam-COVID-Vac and 1 mRNA1273/Gam-COVID-Vac heterologous scheme. Of these 18 non-responders, 14 received a third dose;nine patients (62%) presented anti-RBD IgG detectable. Of the five patients who did not respond to the booster vaccination, three had received BBIBP-CorV as the initial schedule and the vaccines applied as a third dose were Ad5-nCoV (1), BNT162b2 (1), AZD 1222 (2) and Gam-COVID-Vac (1). They were being treated with: rituximab (2), azathioprine (2) and mycophenolate mofetil (1). Treatment with higher doses of prednisone was the only factor associated with non-seroconversion to the third dose (8 +/- 4.5;p 0.02). Conclusion(s): The third dose of SARS-CoV-2 vaccine allowed to improve the serological response to vaccination, achieving a seroconversion of 62% in this group of patients.

Week 48 results of a phase 3 randomized controlled trial of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) vs dolutegravir 1 emtricitabine/tenofovir disoproxil fumarate (DTG 1 F/TDF) as initial treatment in HIV-1/HBV-coinfected adults (ALLIANCE)

Background/Aims: The clinical course of hepatitis B virus (HBV) infection in individuals with HIV-1 coinfection is marked by accelerated disease progression. A tenofovir-containing antiretroviral regimen is recommended in most people with HIV-1/HBV-coinfection, but there have not been randomized studies of tenofovir disoproxil fumarate (TDF) vs tenofovir alafenamide (TAF) in treatment- naive HIV-1/HBV-coinfected individuals. We report primary endpoint results from a Phase 3 study comparing bictegravir/emtricitabine/ TAF (B/F/TAF) vs dolutegravir + emtricitabine/TDF (DTG + F/TDF) at Week (W)48 in participants initiating treatment for both viruses. Method(s): Adults with HIV-1/HBV coinfection were randomized 1:1 to initiate blinded treatment with B/F/TAF or DTG + F/TDF (with placebo). Primary endpoints were the proportion of participants with HIV-1 RNA<50 copies/mL (FDA Snapshot) and plasma HBV DNA<29 IU/mL (missing = failure) at W48. Noninferiority was assessed with 95% CI (12% margin). Secondary and other endpoints included change from baseline cluster of differentiation 4 (CD4) count, proportion with hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) loss/seroconversion, and alanine transaminase (ALT) normalization (AASLD criteria). Result(s): Participants (N = 243) were randomized and treated (B/F/ TAF [n = 121], DTG + F/TDF [n = 122]) from 11 countries in Asia, Europe, North, and Latin America. Baseline characteristics were median age of 32 years, 4.5% female, 88% Asian, 30% HIV-1 RNA>100,000 c/mL, 40% CD4<200 cells/lL, median HBV DNA 8.1 log10 IU/mL, 78% HBeAg+. At W48, B/F/TAF was noninferior to DTG + F/TDF at achieving HIV-1 RNA<50 copies/mL (95% vs 91%, difference 4.1%;95% CI -2.5%-10.8%;P = 0.21), with mean CD4 gains of + 200 and + 175 cells/lL, respectively. B/F/TAF was superior to DTG + F/TDF at achieving HBV DNA<29 IU/mL (63% vs 43%, difference 16.6%;95% CI 5.9%-27.3%;P = 0.0023). Participants treated with B/F/TAF vs DTG + F/TDF had numerically higher HBsAg loss (13% vs 6%;P = 0.059), HBeAg loss (26% vs 14%;P = 0.055), HBeAg seroconversion (23% vs 11%;P = 0.031), and ALT normalization (73% vs 55%;P = 0.066). The most frequent adverse events among participants treated with B/F/TAF vs DTG + F/TDF were upper respiratory tract infection (17% vs 11%), COVID- 19 (13% vs 11%), pyrexia (9% vs 12%), ALT increase (7% vs 11%), and nasopharyngitis (11% vs 4%). ALT flares (elevations at >= 2 consecutive postbaseline visits) occurred in 11 participants (7 B/F/ TAF, 4 DTG + F/TDF), and all resolved. Conclusion(s): Among adults with HIV-1/HBV-coinfection starting antiviral therapy, both B/F/TAF and DTG + F/TDF had high HIV-1 suppression at year 1, with B/F/TAF resulting in superior HBV DNA suppression and significantly more HBeAg seroconversion. Safety findings were similar between groups.

Effects of Homologous and Heterologous Booster Vaccinations of the Inactivated Dual-Adjuvanted Vaccine Vla2001 against Covid-19 Including Variants of Concern: A Phase 3 Randomized Clinical Trial

Intro: VLA2001 is a highly-purified, inactivated whole-virus SARS-CoV-2 vaccine based on a dual-adjuvant system of Alum and CpG1018 for induction of a robust immune response. The vaccine was designed using a well-established technology platform and has received full marketing authorization in Europe. In a pivotal Phase 3 trial, VLA2001 demonstrated superior neutralizing antibody geometric mean titers (GMT) to the comparator, AstraZeneca's AZD1222, as well as non-inferior seroconversion rates two weeks after priming. The extension of the Phase 3 trial evaluated safety and immunogenicity of homologous and heterologous booster vaccinations of VLA2001. Method(s): This is a randomized observer-blind controlled, pivotal trial conducted in the UK in participants aged >=18 years who were randomly assigned 2:1 to receive two doses of VLA2001 or AZD1222, 28 days apart. A booster with VLA2001 was administered to eligible participants at 7 to 8 months after priming. The primary safety outcome was the frequency and severity of any adverse event following the booster vaccination. The primary immunogenicity outcomes were the GMT and fold increase of neutralizing antibodies against SARS-CoV-2 two weeks after the booster vaccination. The study is registered under NCT04864561. Finding(s): A booster dose of VLA2001 is well-tolerated in both AZD1222 and VLA2001 primed participants. High neutralizing antibody titers and fold- increases were generated two weeks following a booster of VLA2001. Cross- neutralizing serological responses against Delta and the Omicron BA.4/BA.5 variants of concern are elicited following a homologous or heterologous booster dose in VLA2001 or AZD1222 primed participants, respectively. Additionally, VLA2001 induced broad T-cell responses with antigen-specific IFN-gamma producing T-cells against the Spike, the Nucleocapsid and the Membrane protein. Conclusion(s): Homologous and heterologous booster doses of VLA2001 demonstrated a favorable tolerability profile irrespective of priming and induced broadly reactive neutralizing antibodies against the ancestral virus and variants of concern, including the currently circulating BA.4/BA.5.Copyright © 2023

Phase 3 Study of Safety and Immunogenicity of Gbp510 Vaccine Adjuvanted with As03 in Adults

Intro: GBP510 contains the self-assembling recombinant nanoparticle displaying SARS-CoV-2 Spike protein receptor binding domain and is adjuvanted with AS03. We report interim Phase 3 study (NCT05007951) results up to 4 weeks post-dose 2 (Data-cut: March-18-2022), where immunogenicity to the D614G ancestral strain and safety of 25mug GBP510/AS03 candidate was compared to ChAdOx1-S (Vaxzevria). Method(s): This Phase 3 randomized, active-controlled, observer-blind, parallel- group study in adults was conducted in 6 countries. Cohort1: 1,895 subjects (naive to COVID-19 vaccination and infection) randomized at 2:1 ratio (GBP510/AS03:ChAdOx1-S) to assess immunogenicity and safety;Cohort 2: 2,141 subjects at 5:1 ratio, regardless of their serostatus at screening for safety assessment. Subjects were vaccinated twice at a 4-week interval with 0.5 mL of the test vaccine (GBP510/AS03) or active control (ChAdOx1-S) in deltoid muscle. The primary objective was to demonstrate the superiority of geometric mean titer (GMT) and non-inferiority in seroconversion rate (SCR: >=4-fold rise from baseline) of neutralizing antibodies over ChAdOx1-S by live-virus neutralization assay (FRNT). Finding(s): At 2 weeks post-dose 2, GMT ratio of the two groups (Test vaccine/Active control) was 2.93 [95% CI: 2.63, 3.27], satisfying the hypothesis of superiority (95% CI lower limit> 1). The SCR difference (Test vaccine - Active control) was 10.76% [95% CI: 7.68, 14.32], satisfying the hypothesis of non- inferiority (95% CI lower limit> -5%). Good cell-mediated immune responses for Th1 cytokines were also observed with the test vaccine (FluoroSpot). The AE incidence rate for the test vaccine was higher than the active control for solicited local AEs (56.69% vs 49.20%), and comparable for solicited systemic AEs (51.21% vs 53.51%) and unsolicited AEs (13.34% vs 14.66%) after any vaccination. Conclusion(s): Higher immune responses were observed with GBP510/AS03 compared to ChAdOx1-S against D614G strain after 2 weeks post-dose 2. GBP510/AS03 showed a clinically acceptable safety profile;no safety concerns were identified during the study period.Copyright © 2023

Results of screening examination of employees of a medical hospital for antibodies to SARS-CoV-2

While providing medical care to patients with a new coronavirus infection, medical workers are at risk of developing COVID-19 significantly more often than the general population. In addition to morbidity risks, an important question is the duration of the immune response to COVID-19. The aim of our study is to assess the incidence of COVID-19 and the duration of the persistence of anti-SARS-CoV-2 antibodies among hospital medical staff. Material and methods. We conducted a retrospective non-randomized single-center study, based on the analysis of the laboratory database of the Municipal Clinical Hospital No. 52 (Moscow). The results of the 2160 employees were included into analysis. The inclusion criteria were as follows: at least one result of antibody determination to SARS-CoV-2 in period from June 2020 to January 2021;the date of the last antibody determination to SARS-CoV-2 no earlier than November 1, 2020. Additionally, a group of 100 employees were selected for further investigation of the persistence of immunoglobulin G (IgG) antibodies to SARS-CoV-2. Additionally, a group of 100 employees was selected, who had a confirmed fact of seroconversion for IgG and the presence of at least three results of IgG to SARS-CoV-2 determination with an interval of at least 4 weeks. Results. According to IgG determination results, by January 2021, 66.6% of all hospital employees have already been ill with COVID-19. The medical staff who worked with patients with COVID-19 been ill with COVID-19 in 78.2% of cases. The share of sick medical personnel who did not work with this group of patients was 55.3%. The first termination of antibodies persistence to SARS-CoV-2 from employees was marked from 3-4 months of observation. After 7-9 months, 23% of the observed group became seronegative. Odds ratio for the risk of COVID-19 for medical staff, who worked with COVID-19 patients was 2.89 (95% CI 2.34-3.56) to other medical staff and 3.6 (95% CI 2.82-4.59) to non-medical staff. Conclusion. The incidence of COVID-19 and the risk of infection among medical workers is significantly higher than among the general population, which dictates the need of further improvement of COVID-19 prevention measures among medical workers.Copyright © 2022 by the authors.

Immune Responses to Mrna Vaccines against Sars-Cov2 in Patients with Immune-Mediated Inflammatory Rheumatic Diseases

Background/Aims Patients with immune-mediated rheumatic diseases (IMRD) are commonly treated with immunosuppressors and are prone to infections. Recently introduced mRNA SARS-Cov2 vaccines have demonstrated extraordinary efficacy across all ages. Immunosuppressed patients were excluded from phase III trials with SARS-We aim to fully characterize B and T cell immune responses elicited by mRNA SARS-Cov2 vaccines in patients with rheumatic diseases under immunotherapies, and to identify which drugs reduce vaccine's immunogenicity. Methods Humoral, CD4 and CD8 immune responses were investigated in 147 SARS-Cov2-naive patients with selected rheumatic diseases under immunosuppression after a two-dose regimen of SARS-Cov2 mRNA vaccine. Responses were compared with age, gender, and diseasematched IMRD patients not receiving immunosuppressors and with healthy controls Results IMRD patients showed decreased seroconversion rates (63% vs 100%, p=0.04) and cellular immune responses (59% vs 100%, p=0.007). Patients on methotrexate achieved seroconversion in 62% of cases and cellular responses in 80% of cases. Abatacept deeply affected humoral and cellular responses. Rituximab (31% responders) and belimumab (50% responders) showed severely impaired humoral responses but cellular responses were often preserved. Antibody titers were reduced with mycophenolate and azathioprine but preserved with leflunomide. Conclusion IMRD patients exhibit impaired SARS-CoV-2 vaccine-immunogenicity, variably reduced with immunosuppressors. Among commonly used therapies, abatacept and B-cell depleting therapies show the most deleterious effects, while anticytokines preserved immunogenicity. The effects of cumulative methotrexate and glucocorticoid doses on immunogenicity should be considered. Humoral and cellular responses are weakly correlated, but CD4 and CD8 tightly correlate. Seroconversion alone might not reflect the vaccine's immunogenicity.

Clinical and immunological parallels in children patients with COVID-19

The problem of the incidence of new coronavirus infection in childhood is becoming increasingly important. At the same time, questions arise regarding the peculiarities of the pathogenesis of COVID-19 in children. The aim of the research was to study the clinical and immunological features of COVID-19 in children hospitalized with a severe course of the disease. Material and methods. We examined 53 children from 0 to 15 years old, hospitalized with suspected new coronavirus infection at Children's Clinical Hospital No. 3 in Novosibirsk from October to December 2020. Determination of specific IgM and IgG antibodies to SARS-CoV-2 antigens in serum blood was carried out using the ELISA method. SARS-CoV-2 virus RNA in nasopharyngeal and oropharyngeal swabs was determined using commercial kits for PCR diagnostics. A z-test was used to compare relative numbers. The significance level was taken equal to 5% (p=0.05). Results and discussion. All examined children hospitalized with suspected COVID-19, regardless of the duration of the disease, had specific IgG antibodies to SARS-CoV-2 antigens, which confirms earlier contact with the new coronavirus in relation to the time of the examination. In 63.6% of cases, specific IgM antibodies of the class to SARS-CoV-2 were detected in the blood serum, in 6% of cases the result was doubtful. IgM antibodies were not detected in blood serum in 30.3% of patients. The results obtained for the determination of IgG and IgM antibodies to SARS-CoV-2 antigens may reflect the atypical nature of seroconversion in COVID-19. An extremely diverse clinical symptomatology was revealed, including, in addition to catarrhal syndrome and intoxication syndrome, abdominal, meningeal, and articular syndromes. In 24.3% of children, polymorphic exanthema was detected, which may be a manifestation of the systemic nature of damage to the vascular wall. Conclusion. With serologically confirmed SARS-CoV-2 etiology of the infectious process in the examined children, an extremely diverse clinical symptomatology was revealed, which, most likely, may be associated with multiple organ damage.Copyright © Transplantologiya. The Russian Journal of Transplantation.All right reserved.

Immunogenicity of Sars-Cov-2 Vaccines by Vaccine Type in Randomised Clinical Trials

Background: Currently five SARS-CoV-2 vaccines are approved in North America (FDA) and Europe (EMA). Across the world other vaccines have been developed but not approved in high-income countries. Of the approved vaccines, 2 are mRNA vaccines, 2 are viral vectored vaccines, and 1 is a protein subunit vaccine. As immunogenicity markers are increasingly being used by regulatory agencies as surrogate markers for vaccine efficacy to inform authorization decisions, this meta-analysis compared the size of immunogenicity responses response elicited by the different COVID-19 vaccine types (mRNA, protein subunit, inactivated virus, viral vectors) and approved and unapproved COVID-19 vaccines. Method(s): Systematic review of trial registers and databases identified RCTs for SARS-CoV-2 vaccines. Risk of bias analysis was conducted using the Cochrane Risk of Bias tool. High risk of bias studies were excluded from analysis. Meta-analysis of seroconversion rates and geometric antibody titers (GMT) for neutralising (NAb) and anti-spike antibodies was conducted, each compared with a placebo using random effects model Cochrane-Mantel Haenszel Tests. Result(s): All studies assessed immunogenicity of COVID-19 vaccines on healthy non-immunocompromised adults between the age of 18 and 59. Statistically significant difference was identified between the different vaccine types for NAb GMT, anti-spike GMT, NAb seroconversion, and anti-spike seroconversion (P< 0.00001 for all). Conversely, no statistical significant difference was identified between approved and unapproved vaccines for NAb seroconversion (P=0.39), Nab GMT (P=0.36), anti-spike seroconversion (P=0.07), and antispike GMT (P=0.54). mRNA vaccines had the best immunogenicity results for NAb seroconversion, GMT, and anti-spike seroconversion. Viral vector vaccines had the lowest results for NAb seroconversion and GMT, while inactivated viruses had the lowest result for anti-spike seroconversion and mRNA vaccines for anti-spike GMT. High heterogeneity was observed across the different studies. Conclusion(s): This metanalysis of 35 randomised trials in 33,813 participants showed approved and unapproved vaccines to be comparable in postvaccination GMT values and seroconversion for both NAb and anti-spike. However, while comparing COVID-19 vaccines by vaccine types, statistically significant differences are observed. Variations in study designs, populations enrolled, and infection prevalence during trial duration could have influenced results.

A comprehensive review on the diagnosis and testing strategies for coronavirus disease

The COVID-19 outbreak has fashioned to severe threat to each and every individual in social and economic aspects in the country. This required improved wisdom to know how it is different and dominant, to diagnose and determine effective vaccines to avoid the transmission of these deadly causative agents. From this review, the probable property of these deadly transmissible viruses is related to that of SARS-CoV-2 as a fright zone of viruses. It also provides some sparks about effective and accurate diagnosis and treatment strategies. The effective management and control of panic zone of virus (PZV) and SARS-CoV-2 are more important to reduce the pandemic situation.Copyright © 2023 Inderscience Enterprises Ltd.

SARS COV-2 and other viral etiology as a possible clue for the olfactory dilemma

Background: Post-viral anosmia is responsible for more than 40% of cases of anosmia. Anosmia has been a neglected symptom in the primary healthcare setting until the emergence of the SARS-CoV-2 pandemic. The spread of SARS-CoV-2 infection highlighted new atypical symptoms of the disease, including anosmia, which has become one of the diagnostic symptoms of the disease, and epidemiological concern. We aimed to detect the incidence of SARS-CoV-2 infection within patients presented with anosmia and to test for other respiratory viruses in the negative COVID-19 patients. We also detected the recovery of anosmia and IgM/IgG against COVID-19. We prospectively included 60 outpatients with the major complaint of anosmia. Nasopharyngeal swabs were done for SARS-CoV-2 real-time PCR, and if negative, PCR to other respiratory pathogens was tested. After one month, we inquired about the recovery of smell loss together with testing for antibodies against SARS-CoV-2. Result(s): Sixty patients were enrolled in the study. Forty-six patients (76.7%) were SARS-CoV-2 PCR positive and 14 (23.3%) were negative. Rhinovirus was the commonest isolated pathogen in the negative cases (5/14). Complete recovery of anosmia occurred in 34 patients (56.7%), while partial recovery in 24 (40.0%), and no recovery in 2 patients (3.3%). The median time to complete recovery was 10 days. 28.3% (13/46) of the patients showed negative antibody response for both IgG and IgM. Conclusion(s): Sudden-onset anosmia is a symptom that is highly predictive of being COVID-19-infected. While recovery is expected within 2 weeks, some patients have no antibodies against SARS-CoV-2.Copyright © 2022, The Author(s).