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1.
Critical Care ; 26:1-15, 2022.
Article in English | ProQuest Central | ID: covidwho-2038848

ABSTRACT

Acute neuropsychiatric impairments occur in over 70% of patients with acute lung injury. Mechanical ventilation is a well-known precipitant of acute lung injury and is strongly associated with the development of acute delirium and anxiety phenotypes. In prior studies, we demonstrated that IL-6 mediates neuropathological changes in the frontal cortex and hippocampus of animals with mechanical ventilation-induced brain injury;however, the effect of systemic IL-6 inhibition on structural and functional acute neuropsychiatric phenotypes is not known. We hypothesized that a murine model of mechanical ventilation-induced acute lung injury (VILI) would induce neural injury to the amygdala and hippocampus, brain regions that are implicated in diverse neuropsychiatric conditions, and corresponding delirium- and anxiety-like functional impairments. Furthermore, we hypothesized that these structural and functional changes would reverse with systemic IL-6 inhibition. VILI was induced using high tidal volume (35 cc/kg) mechanical ventilation. Cleaved caspase-3 (CC3) expression was quantified as a neural injury marker and found to be significantly increased in the VILI group compared to spontaneously breathing or anesthetized and mechanically ventilated mice with 10 cc/kg tidal volume. VILI mice treated with systemic IL-6 inhibition had significantly reduced amygdalar and hippocampal CC3 expression compared to saline-treated animals and demonstrated amelioration in acute neuropsychiatric behaviors in open field, elevated plus maze, and Y-maze tests. Overall, these data provide evidence of a pathogenic role of systemic IL-6 in mediating structural and functional acute neuropsychiatric symptoms in VILI and provide preclinical justification to assess IL-6 inhibition as a potential intervention to ameliorate acute neuropsychiatric phenotypes following VILI.

2.
Respiratory Research ; 23:1-11, 2022.
Article in English | ProQuest Central | ID: covidwho-2038754

ABSTRACT

Background Acute respiratory distress syndrome (ARDS) is a life-threatening disease caused by the induction of inflammatory cytokines and chemokines in the lungs. There is a dearth of drug applications that can be used to prevent cytokine storms in ARDS treatment. This study was designed to investigate the effects of tocilizumab and dexamethasone on oxidative stress, antioxidant parameters, and cytokine storms in acute lung injury caused by oleic acid in rats. Methods Adult male rats were divided into five groups: the CN (healthy rats, n = 6), OA (oleic acid administration, n = 6), OA + TCZ-2 (oleic acid and tocilizumab at 2 mg/kg, n = 6), OA + TCZ-4 (oleic acid and tocilizumab at 4 mg/kg, n = 6), and OA + DEX-10 (oleic acid and dexamethasone at 10 mg/kg, n = 6) groups. All animals were euthanized after treatment for histopathological, immunohistochemical, biochemical, PCR, and SEM analyses. Results Expressions of TNF-α, IL-1β, IL-6, and IL-8 cytokines in rats with acute lung injury induced by oleic acid were downregulated in the TCZ and DEX groups compared to the OA group (P < 0.05). The MDA level in lung tissues was statistically lower in the OA + TCZ-4 group compared to the OA group. It was further determined that SOD, GSH, and CAT levels were decreased in the OA group and increased in the TCZ and DEX groups (P < 0.05). Histopathological findings such as thickening of the alveoli, hyperemia, and peribronchial cell infiltration were found to be similar when lung tissues of the TCZ and DEX groups were compared to the control group. With SEM imaging of the lung tissues, it was found that the alveolar lining layer had become indistinct in the OA, OA + TCZ-2, and OA + TCZ-4 groups. Conclusions In this model of acute lung injury caused by oleic acid, tocilizumab and dexamethasone were effective in preventing cytokine storms by downregulating the expression of proinflammatory cytokines including TNF-α, IL-1β, IL-6, and IL-8. Against the downregulation of antioxidant parameters such as SOD and GSH in the lung tissues caused by oleic acid, tocilizumab and dexamethasone upregulated them and showed protective effects against cell damage.

3.
BMC Genomics ; 23:1-11, 2022.
Article in English | ProQuest Central | ID: covidwho-2038658

ABSTRACT

Phage ImmunoPrecipitation Sequencing (PhIP-Seq) is a recently developed technology to assess antibody reactivity, quantifying antibody binding towards hundreds of thousands of candidate epitopes. The output from PhIP-Seq experiments are read count matrices, similar to RNA-Seq data;however some important differences do exist. In this manuscript we investigated whether the publicly available method edgeR (Robinson et al., Bioinformatics 26(1):139–140, 2010) for normalization and analysis of RNA-Seq data is also suitable for PhIP-Seq data. We find that edgeR is remarkably effective, but improvements can be made and introduce a Bayesian framework specifically tailored for data from PhIP-Seq experiments (Bayesian Enrichment Estimation in R, BEER).

4.
Public Health Rep ; : 333549221119143, 2022.
Article in English | PubMed | ID: covidwho-2038476

ABSTRACT

OBJECTIVES: First responders, including firefighters, emergency medical technicians (EMTs), paramedics, and law enforcement officers, are working on the front lines to fight the COVID-19 pandemic and facing an increased risk of infection. This study assessed the seroprevalence of SARS-CoV-2 infection among first responders in northeastern Ohio. METHODS: A survey and immunoglobulin G antibody test against SARS-CoV-2 nucleocapsid protein were offered to University Hospitals Health System-affiliated first-responder departments during May to September 2020. The survey contained questions about demographic characteristics and history of SARS-CoV-2 infection. A total of 3080 first responders with diverse job assignments from more than 400 fire and police departments participated in the study. RESULTS: Of 3080 participants, 73 (2.4%) were seropositive and 26 (0.8%) had previously positive real-time polymerase chain reaction results. Asymptomatic infection accounted for 46.6% (34 of 73) of seropositivity. By occupation, rates of seropositivity were highest among administration/support staff (3.8%), followed by paramedics (3.0%), EMTs (2.6%), firefighters (2.2%), and law enforcement officers (0.8%). Work-associated exposure rates to COVID-19 patients were: paramedics (48.2%), firefighters (37.1%), EMTs (32.3%), law enforcement officers (7.7%), and administration/support staff (4.4%). Self-reported community exposure was positively correlated with self-reported work-associated exposure rate (correlation coefficient = 0.99). Neither self-reported community nor work-associated exposure was correlated with SARS-CoV-2 seroprevalence. We found no significant difference in seroprevalence among sex/gender or age groups;however, Black participants had a higher positivity rate than participants of other racial groups despite reporting lower exposure. CONCLUSIONS: Despite the high work-associated exposure rate to SARS-CoV-2 infection, first responders with various roles demonstrated seroprevalence no higher than their administrative/supportive colleagues, which suggests infection control measures are effective in preventing work-related infection.

5.
Immunity ; 2022 Aug 05.
Article in English | MEDLINE | ID: covidwho-2036138

ABSTRACT

Large-scale vaccination campaigns have prevented countless hospitalizations and deaths due to COVID-19. However, the emergence of SARS-CoV-2 variants that escape from immunity challenges the effectiveness of current vaccines. Given this continuing evolution, an important question is when and how to update SARS-CoV-2 vaccines to antigenically match circulating variants, similarly to seasonal influenza viruses where antigenic drift necessitates periodic vaccine updates. Here, we studied SARS-CoV-2 antigenic drift by assessing neutralizing activity against variants of concern (VOCs) in a set of sera from patients infected with viral sequence-confirmed VOCs. Infections with D614G or Alpha strains induced the broadest immunity, whereas individuals infected with other VOCs had more strain-specific responses. Omicron BA.1 and BA.2 were substantially resistant to neutralization by sera elicited by all other variants. Antigenic cartography revealed that Omicron BA.1 and BA.2 were antigenically most distinct from D614G, associated with immune escape, and possibly will require vaccine updates to ensure vaccine effectiveness.

6.
Lancet Global Health ; 10(10):e1473-e1484, 2022.
Article in English | CAB Abstracts | ID: covidwho-2036657

ABSTRACT

Background: An estimated 15% of girls aged 9-14 years worldwide have been vaccinated against human papillomavirus (HPV) with the recommended two-dose or three-dose schedules. A one-dose HPV vaccine schedule would be simpler and cheaper to deliver. We report immunogenicity and safety results of different doses of two different HPV vaccines in Tanzanian girls.

7.
Lancet Global Health ; 10(10):e1485-e1493, 2022.
Article in English | CAB Abstracts | ID: covidwho-2036656

ABSTRACT

Background: Human papillomavirus (HPV) vaccines are given as a two-dose schedule in children aged 9-14 years, or as three doses in older individuals. We compared antibody responses after one dose of HPV vaccine in the Dose Reduction Immunobridging and Safety Study (DoRIS), a randomised trial of different HPV vaccine schedules in Tanzania, to those from two observational HPV vaccine trials that found high efficacy of one dose up to 11 years against HPV16 and HPV18 (Costa Rica Vaccine Trial [CVT] and Institutional Agency for Research on Cancer [IARC] India trial).

8.
The Lancet Infectious Diseases ; 22(10):1430, 2022.
Article in English | ProQuest Central | ID: covidwho-2036649

ABSTRACT

Full-dose anticoagulation in COVID-19 patients Full-dose anticoagulation lowers the risk of blood-clotting complications compared with standard-dose prophylactic anticoagulation, according to a clinical trial in critically ill COVID-19 patients across the USA. The study did not include a control group, and the time from symptom onset to starting antiviral therapy varied among the patients. For more on baseline SARS-CoV-2 antigen levels and illness severity see Ann Intern Med 2022;published online Aug 30. https://doi.org/10.7326/m22-0924 For more on full-dose anticoagulation and COVID-19 see Circulation 2022;published online Aug 29. https://doi.org/10.1161/circulationaha.122.061533 For more on COVID-19 antiviral combinations see J Infect 2022;published online July 31. https://doi.org/10.1016/j.jinf.2022.07.023 For more on dolutegravir-based ART and pregnancy see N Engl J Med 2022;387: 799–809 For more on HBV and HDV treatment see Gut 2022;published online Aug 17. https://doi.org/10.1136/gutjnl-2022-327216 For more on tecovirimat and monkeypox see JAMA 2022;published online Aug 22. https://doi.org/10.1001/jama.2022.15336 For more on an injectable tuberculosis treatment see Nat Commun 2022;13: 4455

9.
Annals of Oncology ; 33(Suppl. 3):S225-S225, 2022.
Article in English | GIM | ID: covidwho-2035756

ABSTRACT

Background: The COVID-19 pandemic has led to more than 260 million infections and 55 million deaths as of early December 2021, worldwide. Vaccinating people against COVID-19 is considered as he best approach to overcome the pandemic since COVID 19-vaccines are effective and can reduce the risk of getting and spreading the virus. However, their efficacy and safety in patients with underlying disease such as cancers have not been approved yet. Here we report a cohort study on immunogenicity and safety of the inactivated SARS-CoV-2 vaccine (BBIBP-CorV) in patients with breast cancer, who were vaccinated as a part of a national plan for vaccination of patients with special diseases.

10.
J Med Virol ; 2022.
Article in English | PubMed | ID: covidwho-2034907

ABSTRACT

The most widely used vaccines were mRNA, viral vector, and inactivated virus with two-dose schedules. In Brazil, the CoronaVac (Sinovac) was the first vaccine approved for emergency use and the third dose was administered, preferably, with the BNT162b2 vaccine. We evaluated antibody levels after six months of the booster dose with BNT162B2 in previous recipients of CoronaVac and whether a subsequent SARS-COV-2 infection enhances the antibody response. We analyze of the humoral response, S IgM for the SARS-CoV-2, S IgG and N IgG in samples collected before the third dose and six months after the third dose. The presence of antibodies was measured by using Abbott Architect i2000SR. The IgM and IgG anti-spike were stimulated mainly in 30D/3D with a decline over time. The IgG anti-N was stimulated predominantly in 90/3D and 180/3D. The N IgG levels were 50 and 35 times higher in the positive PCR group in 90/3D and 180/3D, respectively. The S IgG titers were 1.5 times elevated in the positive PCR group, in 180/3D. The BNT162b2 boosted the S IgG levels, decreasing after the 60 days. The booster shot induced IgM and IgG antibodies against Spike protein. Infection after vaccination increased antibodies against protein N. This article is protected by copyright. All rights reserved.

11.
Vestnik Rossiyskoy voyenno meditsinskoy akademii ; 4:147-152, 2021.
Article in Russian | GIM | ID: covidwho-2034544

ABSTRACT

The article presents the results of a study of the immunogenicity and reactogenicity of the vaccine Gam-COVID-Vac (Sputnik V) when used in military personnel undergoing military service on conscription. From 300 military personnel consistently vaccinated with one and two components of Gam-COVID-Vac at the intervals of 21 days, blood serum was obtained and examined three times: before vaccination, and 30 and 60 days after the introduction of the first component of the vaccine. In the blood serums, the content of Class G antibodies to the SARS-CoV-2 was determined by the method of solid-phase enzyme immunoassay. After immunization with the Gam-COVID-Vac vaccine, the average geometric titer of Class G antibodies to SARS-CoV-2 -in the blood serum of a military personnel obtained during the second and third examinations (5.02 log2 and 5.67 log2) increased by 2.4 and 2.7 times, respectively (p < 0.05), compared to the same indicator before the vaccination (2.11 log2). Total of 30 days after the introduction of the first component of the vaccine (Nine days after the introduction of the second component of the vaccine), Class G antibodies to the new coronavirus SARS-CoV-2 were detected in the 86.7% of military personnel, and after 60 days - in 92% of vaccinated. Studies have revealed moderate reactogenicity of the vaccine. Moreover, the proportion of postvaccination reactions in the first 3-5 days after the introduction of the second component of the vaccine was less after the introduction of the first component of the vaccine. So, if after the introduction of the first component of the vaccine, an increase in body temperature > 37 degrees C was observed in 20% of military personnel, then after the introduction of the second component only in 9%, and the share of local reactions decreased from 9-4%. There have been no cases of serious adverse events after immunization of military personnel with the Gam-COVID-Vac vaccine.

12.
Chinese Journal of Virology ; 36(6):997-1003, 2020.
Article in Chinese | GIM | ID: covidwho-2034152

ABSTRACT

To investigate the characteristics of the nucleic acids of severe acute respiratory syndrome coronavirus (SARS-CoV) -2 and antibodies in different specimens obtained from coronavirus disease 2019 (COVID-19) patients;if a correlation between these parameters and the disease course was present. The throat swabs and stool samples of 39 COVID-19 patients admitted to our hospital were collected in this study. Real-time reverse transcription-quantitative polymerase chain reaction (RT-PCR) was undertaken on throat swabs and stool samples. Peripheral blood was taken and serum levels of immunoglobulin IgM and IgG measured. Results showed That, Throat swabs and stool samples tested positive for the nucleic acid of SARS-CoV-Z, but nucleic acid levels were reduced significantly 15 days after disease onset compared with that upon diagnosis. The Ct value of the nucleic acid test was increased significantly. Serum levels of IgM and IgG were significantly higher than those of healthy people. nucleic acid loads in throat swabs and stool samples as well as serum levels of IgM and IgG were highly correlated with the disease course (r = 0.7387,0.5696, -0.546 and 0.6117,respectively, P < 0.05). In this study nucleic acid loads in throat swabs and stool samples as well as serum levels of IgM and IgG are highly correlated with the course of COVID-19.

13.
Chinese Journal of Virology ; 36(6):1009-1013, 2020.
Article in Chinese | GIM | ID: covidwho-2034140

ABSTRACT

To determine if a method to detect antibodies against SARS-CoV-2 can be applied clinically. In this retrospective study, the sera samples of 39 patients with newly diagnosed coronavirus disease 2019 (COVID- 19) and 90 healthy people were analyzed by antibody-detection reagents within enzyme-linked immunosorbent assays. The sera samples of confirmed cases at different onset times and 40 suspected cases were also tested. Then. we combined the results of antibody tests. nucleic-acid tests, and patient data. The sensitivity and specificity for SARS-COV-2-specific total antibodies was 92.31% and 100%, respectively. The production time of total antibodies in serum samples increased with time. and the median detection time was 13 days. The result of antibody testing of one confirmed case preceded the result of the nucleic-acid test. Moreover, the antibodies 0f 40 suspected cases were all negative. Detection of the total antibodies against SARS-CoV-2 can be used as an auxiliary diagnostic indicator of infection by this virus, as well as a supplementary means to exclude suspected cases/populations in areas with a high prevalence of negative detection of the nucleic acids of SARS-CoV-2.

14.
Vaccine ; 2022.
Article in English | ScienceDirect | ID: covidwho-2031726

ABSTRACT

Two messenger RNA (mRNA)-based vaccines are widely used globally to prevent coronavirus disease 2019 (COVID-19). Both vaccine formulations contain PEGylated lipids in their composition, in the form of polyethylene glycol [PEG] 2000 dimyristoyl glycerol for mRNA-1273, and 2 [(polyethylene glycol)-2000]-N,N-ditetradecylacetamide for BNT162b2. It is known that some PEGylated drugs and products for human use which contain PEG are capable of eliciting immune responses that lead to to detectable PEG-specific antibodies in serum. In this study, we determined if any of the components of mRNA-1273 or BNT162b2 formulations elicited PEG-specific antibody responses in serum by enzyme linked immunosorbent assay (ELISA). We detected an increase in the reactivity to mRNA vaccine formulations in mRNA-1273 but not BNT162b2 vaccinees' sera in a prime-boost dependent manner. Furthermore, we observed the same pattern of reactivity against irrelevant lipid nanoparticles from an influenza virus mRNA formulation and found that the reactivity of such antibodies correlated well with antibody levels against high and low molecular weight PEG. Using sera from participants selected based on the vaccine-associated side effects experienced after vaccination, including delayed onset, injection site or severe allergic reactions, we found no obvious association between PEG antibodies and adverse reactions. Overall, our data shows a differential induction of anti-PEG antibodies by mRNA-1273 and BNT162b2. The clinical relevance of PEG reactive antibodies induced by administration of the mRNA-1273 vaccine, and the potential interaction of these antibodies with other PEGylated drugs remains to be explored.

15.
Lancet Reg Health West Pac ; 29:100586, 2022.
Article in English | ScienceDirect | ID: covidwho-2031544

ABSTRACT

Background: BNT162b2, an mRNA vaccine against COVID-19, is being utilised worldwide, but immunogenicity and safety data in Chinese individuals are limited. Methods: This phase 2, randomised, double-blind, placebo-controlled trial included healthy or medically stable individuals aged 18-85 years enrolled at two clinical sites in China. Participants were stratified by age (</=55 or >55 years) and randomly assigned (3:1) by an independent randomisation professional to receive two doses of intramuscular BNT162b2 30 mug or placebo, administered 21 days apart. Study participants, study personnel, investigators, statisticians, and the sponsor's study management team were blinded to treatment assignment. Primary immunogenicity endpoints were the geometric mean titers (GMTs) of neutralising antibodies to live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and seroconversion rates (SCR) 1 month after the second dose. Safety assessments included reactogenicity within 14 days of vaccination, adverse events (AEs), and clinical laboratory parameters. Randomised participants who received at least one dose were included in the efficacy and safety analyses on a complete case basis (incomplete/missing data not imputed). Results up to 6 months after the second dose are reported. Findings: Overall, 959 participants (all of Han ethnicity) who were recruited between December 5th, 2020 and January 9th, 2021 received at least one injection (BNT162b2, n=720;placebo, n=239). At 1 month after the second dose, the 50% neutralising antibody GMT was 294.4 (95% CI;281.1-308.4) in the BNT162b2 group and 5.0 (95% CI;5.0-5.0) in the placebo group. SCRs were 99.7% (95% CI;99.0%-100.0%) and 0% (95% CI;0.0%-1.5%), respectively (p<0.0001 vs placebo). Although the GMT of neutralising antibodies in the BNT162b2 group was greatly reduced at 6 months after the second dose, the SCR still remained at 58.8%. BNT162b2-elicited sera neutralised SARS-CoV-2 variants of concern. T-cell responses were detected in 58/73 (79.5%) BNT162b2 recipients. Reactogenicity was mild or moderate in severity and resolved within a few days after onset. Unsolicited AEs were uncommon at 1 month following vaccine administration, and there were no vaccine-related serious AEs at 1 month or 6 months after the second dose. Interpretation: BNT162b2 vaccination induced a robust immune response with acceptable tolerability in Han Chinese adults. However, follow-up duration was relatively short and COVID-19 rates were not assessed. Safety data collection is continuing until 12 months after the second dose. Funding: BioNTech - sponsored the trial. Shanghai Fosun Pharmaceutical Development Inc. (Fosun Pharma) - conducted the trial, funded medical writing. ClinicalTrialsgov registration number: NCT04649021. Trial status: Completed.

16.
Int J Infect Dis ; 2022.
Article in English | ScienceDirect | ID: covidwho-2031341

ABSTRACT

OBJECTIVES: Neutralizing monoclonal antibodies (moAbs) improve clinical outcomes in COVID-19 patients when administered during the initial days of infection. The action of moAbs may impair generation or maintenance of effective immune memory, similar to that demonstrated in other viral diseases. We aimed to evaluate short-term memory T-cell responses in patients effectively treated with bamlanivimab/etesevimab, casirivimab/imdevimab, or sotrovimab. METHODS: Spike-specific T-cell responses were analyzed in 23 COVID-19 patients (vaccinated or unvaccinated) before and after a median of 50 (range: 28-93) days from moAb treatment, compared with 11 vaccinated healthy-controls. T-cell responses were measured by interferon-gamma-ELISpot and flow cytometric activation-induced marker assay. RESULTS: No statistically significant difference in spike-specific T-cell responses was observed between moAb-treated patients and vaccinated healthy-controls. Bamlanivimab/etesevimab and casirivimab/imdevimab groups showed significant increases in cellular responses in paired baseline/post-recovery series, as well as vaccinated patients receiving sotrovimab. By contrast, unvaccinated patients prescribed sotrovimab presented no statistically significant increases in T-cell-responses, suggesting diverse impacts of different moAbs on the evolution of spike-specific T-cell responses in vaccinated and unvaccinated patients. CONCLUSIONS: The moAbs did not hinder short-term-memory spike-specific T-cell responses in the overall group of patients, however differences among moAbs must be further investigated both in vaccinated and unvaccinated individuals.

17.
Infect Dis Now ; 2022.
Article in English | ScienceDirect | ID: covidwho-2031322

ABSTRACT

During the SARS CoV-2 primary infection, the neutralizing antibodies focused against the spike (S) glycoproteins are responsible for blockage of virus-host cell interaction. The cellular response mediated by CD4+ and CD8+ T-cells is responsible for control of viremia. Immune memory against SARS-CoV-2 depends on virus type, replication kinetics and route of penetration. The formation and persistence of germinal centers are critical for the generation of affinity-matured plasma cells and memory B cells capable of mediating durable immunity. They can persist up to 30 weeks after vaccination and several months after infection. Heterogeneity in the longevity of the vaccination-induced GC response is significant.

18.
eClinicalMedicine ; 53:101655, 2022.
Article in English | ScienceDirect | ID: covidwho-2031252

ABSTRACT

Summary Background More than half the global population has been exposed to SARS-CoV-2. Naturally induced immunity influences the outcome of subsequent exposure to variants and vaccine responses. We measured anti-spike IgG responses to explore the basis for this enhanced immunity. Methods A prospective cohort study of mothers in a South African community through ancestral/beta/delta/omicron SARS-CoV-2 waves (March 2020-February 2022). Health seeking behaviour/illness were recorded and post-wave serum samples probed for IgG to Spike (CoV2-S-IgG) by ECLISA. To estimate protective CoV2-S-IgG threshold levels, logistic functions were fit to describe the correlation of CoV2-S-IgG measured before a wave and the probability for seroconversion/boosting thereafter for unvaccinated and vaccinated adults. Findings Despite little disease, 176/339 (51·9%) participants were seropositive following wave 1, rising to 74%, 89·8% and 97·3% after waves 2, 3 and 4 respectively. CoV2-S-IgG induced by natural exposure protected against subsequent SARS-CoV-2 infection with the greatest protection for beta and least for omicron. Vaccination induced higher CoV2-S-IgG in seropositive compared to naïve vaccinees. Amongst seropositive participants, proportions above the 50% protection against infection threshold were 69% (95% CrI: 62, 72) following 1 vaccine dose, 63% (95% CrI: 63, 75) following 2 doses and only 11% (95% CrI: 7, 14) in unvaccinated during the omicron wave. Interpretation Naturally induced CoV2-S-IgG do not achieve high enough levels to prevent omicron infection in most exposed individuals but are substantially boosted by vaccination leading to significant protection. A single vaccination in those with prior immunity is more immunogenic than 2 doses in a naïve vaccinee and may provide adequate protection. Funding

19.
eBioMedicine ; 84:104270, 2022.
Article in English | ScienceDirect | ID: covidwho-2031243

ABSTRACT

Summary Background Genetically distinct viral variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been recorded since January 2020. The introduction of global vaccine programs has contributed to lower COVID-19 hospitalisation and mortality rates, particularly in developed countries. In late 2021, Omicron BA.1 emerged, with substantially altered genetic differences and clinical effects from other variants of concern. Shortly after dominating global spread in early 2022, BA.1 was supplanted by the genetically distinct Omicron lineage BA.2. A sub-lineage of BA.2, designated BA.5, presently has an outgrowth advantage over BA.2 and other BA.2 sub-lineages. Here we study the neutralisation of Omicron BA.1, BA.2 and BA.5 and pre-Omicron variants using a range of vaccine and convalescent sera and therapeutic monoclonal antibodies using a live virus neutralisation assay. Using primary nasopharyngeal swabs, we also tested the relative fitness of BA.5 compared to pre-Omicron and Omicron viral lineages in their ability to use the ACE2-TMPRSS2 pathway. Methods Using low passage clinical isolates of Clade A.2.2, Beta, Delta, BA.1, BA.2 and BA.5, we determined humoral neutralisation in vitro in vaccinated and convalescent cohorts, using concentrated human IgG pooled from thousands of plasma donors, and licensed monoclonal antibody therapies. We then determined infectivity to particle ratios in primary nasopharyngeal samples and expanded low passage isolates in a genetically engineered ACE2/TMPRSS2 cell line in the presence and absence of the TMPRSS2 inhibitor Nafamostat. Findings Peak responses to 3 doses of BNT162b2 vaccine were associated with a 9-fold reduction in neutralisation for Omicron lineages BA.1, BA.2 and BA.5. Concentrated pooled human IgG from convalescent and vaccinated donors and BNT162b2 vaccination with BA.1 breakthrough infections were associated with greater breadth of neutralisation, although the potency was still reduced 7-fold across all Omicron lineages. Testing of clinical grade antibodies revealed a 14.3-fold reduction using Evusheld and 16.8-fold reduction using Sotrovimab for the BA.5. Whilst the infectivity of BA.1 and BA.2 was attenuated in ACE2/TMPRSS2 entry, BA.5 was observed to be equivalent to that of an early 2020 circulating clade and had greater sensitivity to the TMPRSS2 inhibitor Nafamostat. Interpretation Observations support all Omicron variants to significantly escape neutralising antibodies across a range of vaccination and/or convalescent responses. Potency of therapeutic monoclonal antibodies is also reduced and differs across Omicron lineages. The key difference of BA.5 from other Omicron sub-variants is the reversion in tropism back to using the well-known ACE2-TMPRSS2 pathway, utilised efficiently by pre-Omicron lineages. Monitoring if these changes influence transmission and/or disease severity will be key for ongoing tracking and management of Omicron waves globally. Funding This work was primarily supported by Australian Medical Foundation research grants MRF2005760 (ST, GM & WDR), MRF2001684 (ADK and ST) and Medical Research Future Fund Antiviral Development Call grant (WDR), Medical Research Future Fund COVID-19 grant (MRFF2001684, ADK & SGT) and the New South Wales Health COVID-19 Research Grants Round 2 (SGT).

20.
Biosensors and Bioelectronics ; : 114710, 2022.
Article in English | ScienceDirect | ID: covidwho-2031160

ABSTRACT

COVID-19 is still unfolding, while many people have been vaccinated. In comparison to nucleic acid testing (NAT), antibody-based immunoassays are faster and more convenient. However, its application has been hampered by its lower sensitivity and the existing fact that by traditional immunoassays, the measurable seroconversion time of pathogen-specific antibodies, such as IgM or IgG, lags far behind that of nucleic acids. Herein, by combining the single molecule array platform (Simoa), RBD, and a previously identified SARS-CoV-2 S2 protein derivatized 12-aa peptide (S2-78), we developed and optimized an ultrasensitive assay (UIM-COVID-19 assay). Sera collected from three sources were tested, i.e., convalescents, inactivated virus vaccine-immunized donors and wild-type authentic SARS-CoV-2-infected rhesus monkeys. The sensitivities of UIM-COVID-19 assays are 100–10,000 times higher than those of conventional flow cytometry, which is a relatively sensitive detection method at present. For the established UIM-COVID-19 assay using RBD as a probe, the IgG and IgM seroconversion times after vaccination were 7.5 and 8.6 days vs. 21.4 and 24 days for the flow cytometry assay, respectively. In addition, using S2-78 as a probe, the UIM-COVID-19 assay could differentiate COVID-19 patients (convalescents) from healthy people and patients with other diseases, with AUCs ranging from 0.85–0.95. In summary, the UIM-COVID-19 we developed here is a promising ultrasensitive biodetection strategy that has the potential to be applied for both immunological studies and diagnostics.

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