ABSTRACT
Introduction: There are no reports in LATAM related to longitudinal humoral and cellular response to adenovirus based COVID-19 vaccines in people with Multiple Sclerosis (pwMS) under different disease modifying therapies (DMTs) and neutralization of the Omicron and Wuhan variants of SARS-COV-2. Methods: IgG anti- SARS-COV-2 spike titer were measured in a cohort of 101 pwMS under fingolimod, dimethyl fumarate, cladribine and antiCD20, as well as 28 healthy controls (HC) were measured 6 weeks after vaccination with 2nd dose (Sputnik V or AZD1222) and 3nd dose (homologous or heterologous schedule). Neutralizing capacity was against Omicron (BA.1) and Wuhan (D614G) variants and pseudotyped particles and Cellular response were analyzed. Results: Multivariate regression analysis showed anti-cd20 (ß= -,349, 95% CI: -3655.6 - -369.01, p=0.017) and fingolimod (ß=-,399, 95% CI: -3363.8 - -250.9, p=0.023) treatments as an independent factor associated with low antibody response (r2 adjusted=0.157). After the 2nd dose we found a correlation between total and neutralizing titers against D614G (rho=0.6; p<0.001; slope 0.8, 95%CI:0.4-1.3), with no differences between DMTs. Neutralization capacity was lower for BA.1 (slope 0.3, 95%CI:0.1-0.4). After the 3rd dose, neutralization of BA.1 improved (slope: 0.9 95%CI:0.6-1.2), without differences between DMTs. A fraction of pwMS generated anti-Spike CD4+ and CD8+ T cell response. In contrast, pwMS under antiCD20 generated CD8+TNF+IL2+ response without differences with HC, even in the absence of humoral response. The 3rd dose significantly increased the neutralization against the Omicron, as observed in the immunocompetent population. Discussion: Findings regarding humoral and cellular response are consistent with previous reports.
Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , COVID-19 , Immunosuppressive Agents , Multiple Sclerosis , SARS-CoV-2 , Humans , Male , Female , Immunosuppressive Agents/therapeutic use , COVID-19 Vaccines/immunology , COVID-19 Vaccines/administration & dosage , SARS-CoV-2/immunology , Middle Aged , Multiple Sclerosis/immunology , Multiple Sclerosis/drug therapy , COVID-19/immunology , COVID-19/prevention & control , Adult , Antibodies, Viral/blood , Antibodies, Viral/immunology , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/blood , Argentina , Adenoviridae/genetics , Adenoviridae/immunology , Immunity, Humoral , Spike Glycoprotein, Coronavirus/immunologyABSTRACT
Identifying immune correlates of risk following COVID-19 vaccine boosters has become paramount as a result of the challenges in generating additional efficacy data. The trial data described here was collected in the United States, with a large part of the study conduct coinciding with the emergence of the SARS-CoV-2 Omicron BA.1 variant. The vaccine trial involved the administration of a booster dose of Ad26.COV2·S at least 6 months after primary vaccination with either a single dose of Ad26.COV2·S or a 2-dose BNT162b2 vaccine regimen. Immunogenicity was assessed through Wuhan Spike binding antibodies (bAb), neutralizing antibodies (nAb), and Omicron BA.1 cross-neutralizing antibodies (nAb BA.1) at Day 1 (pre-boost), Day 15-, and 6-months post-boost. Immune correlates analyses demonstrate that, higher titers of bAb, nAb, and nAb BA.1 at Day 15 were consistently associated with a lower risk of symptomatic COVID-19 following a booster dose of Ad26.COV2·S, irrespective of the primary vaccine regimen. Similar results were obtained using multivariable analyses. Furthermore, Day 1 nAb levels against the Wuhan reference strain exhibited a statistically significant inverse relationship with the risk of symptomatic COVID-19. These findings highlight the value of assessing immune correlates for vaccine boosters, especially in the context of emerging SARS-CoV-2 variants. Clinical trials registration:NCT04999111.
Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , COVID-19 , Immunization, Secondary , SARS-CoV-2 , Humans , COVID-19/immunology , COVID-19/prevention & control , Antibodies, Viral/blood , Antibodies, Viral/immunology , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , SARS-CoV-2/immunology , Male , Female , Middle Aged , Adult , COVID-19 Vaccines/immunology , COVID-19 Vaccines/administration & dosage , Immunogenicity, Vaccine , Young Adult , Ad26COVS1/immunology , BNT162 Vaccine/immunology , BNT162 Vaccine/administration & dosage , Aged , Spike Glycoprotein, Coronavirus/immunologyABSTRACT
BACKGROUND: The clinical benefit of coronavirus disease 2019 (COVID-19) treatments against new circulating variants remains unclear. We sought to describe characteristics and clinical outcomes of highest risk patients with COVID-19 receiving early COVID-19 treatments in Scotland. METHODS: Retrospective cohort study of non-hospitalized patients diagnosed with COVID-19 from December 1, 2021-October 25, 2022, using Scottish administrative health data. We included adult patients who met ≥ 1 of the National Health Service highest risk criteria for early COVID-19 treatment and received outpatient treatment with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or no early COVID-19 treatment. Index date was defined as the earliest of COVID-19 diagnosis or early COVID-19 treatment. Baseline characteristics and acute clinical outcomes in the 28 days following index were reported. Values of ≤ 5 were suppressed. RESULTS: In total, 2548 patients were included (492: sotrovimab, 276: nirmatrelvir/ritonavir, 71: molnupiravir, and 1709: eligible highest risk untreated). Patients aged ≥ 75 years accounted for 6.9% (n = 34/492), 21.0% (n = 58/276), 16.9% (n = 12/71) and 13.2% (n = 225/1709) of the cohorts, respectively. Advanced renal disease was reported in 6.7% (n = 33/492) of sotrovimab-treated and 4.7% (n = 81/1709) of untreated patients, and ≤ 5 nirmatrelvir/ritonavir-treated and molnupiravir-treated patients. All-cause hospitalizations were experienced by 5.3% (n = 25/476) of sotrovimab-treated patients, 6.9% (n = 12/175) of nirmatrelvir/ritonavir-treated patients, ≤ 5 (suppressed number) molnupiravir-treated patients and 13.3% (n = 216/1622) of untreated patients. There were no deaths in the treated cohorts; mortality was 4.3% (n = 70/1622) among untreated patients. CONCLUSIONS: Sotrovimab was often used by patients who were aged < 75 years. Among patients receiving early COVID-19 treatment, proportions of 28-day all-cause hospitalization and death were low.
Subject(s)
Antiviral Agents , COVID-19 Drug Treatment , COVID-19 , Disease Progression , SARS-CoV-2 , Humans , Antiviral Agents/therapeutic use , Retrospective Studies , Male , Female , Middle Aged , Aged , SARS-CoV-2/drug effects , COVID-19/mortality , Adult , Treatment Outcome , Scotland/epidemiology , Antibodies, Monoclonal, Humanized/therapeutic use , Ritonavir/therapeutic use , Aged, 80 and over , Cytidine/analogs & derivatives , HydroxylaminesABSTRACT
BACKGROUND: Mutations present in emerging SARS-CoV-2 variants permit evasion of neutralization with prototype vaccines. A novel Omicron BA.1 subvariant-specific vaccine (NVX-CoV2515) was tested alone or as a bivalent preparation with the prototype vaccine (NVX-CoV2373) to assess antibody responses to SARS-CoV-2. METHODS: Participants aged 18 to 64 years immunized with 3 doses of prototype mRNA vaccines were randomized 1:1:1 to receive a single dose of NVX-CoV2515, NVX-CoV2373, or the bivalent mixture in a phase 3 study investigating heterologous boosting with SARS-CoV-2 recombinant spike protein vaccines. Immunogenicity was measured 14 and 28 days after vaccination for the SARS-CoV-2 Omicron BA.1 sublineage and ancestral strain. Safety profiles of vaccines were assessed. RESULTS: Of participants who received trial vaccine (N = 829), those administered NVX-CoV2515 (n = 286) demonstrated a superior neutralizing antibody response to BA.1 vs NVX-CoV2373 (n = 274) at day 14 (geometric mean titer ratio, 1.6; 95% CI, 1.33-2.03). Seroresponse rates were 73.4% (91/124; 95% CI, 64.7-80.9) for NVX-CoV2515 vs 50.9% (59/116; 95% CI, 41.4-60.3) for NVX-CoV2373. All formulations were similarly well tolerated. CONCLUSIONS: NVX-CoV2515 elicited a superior neutralizing antibody response against the Omicron BA.1 subvariant as compared with NVX-CoV2373 when administered as a fourth dose. Safety data were consistent with the established safety profile of NVX-CoV2373. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov (NCT05372588).
Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , COVID-19 , Immunization, Secondary , Immunogenicity, Vaccine , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Humans , COVID-19 Vaccines/immunology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/adverse effects , Adult , SARS-CoV-2/immunology , SARS-CoV-2/genetics , Antibodies, Viral/blood , Antibodies, Viral/immunology , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/genetics , Male , Female , COVID-19/prevention & control , COVID-19/immunology , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Young Adult , Middle Aged , Adolescent , Vaccines, Synthetic/immunology , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/adverse effectsABSTRACT
OBJECTIVE: Sotrovimab, a dual-action, engineered human monoclonal antibody, has been demonstrated to significantly reduce the risk of hospitalisation and death in high-risk patients with COVID-19. Here, we describe the real-world use of, and outcomes from, sotrovimab treatment in Belgium during the Delta and Omicron waves among patients with COVID-19 at high risk of developing severe disease. METHODS: This was a multicentric, single-arm observational cohort study of non-hospitalised patients receiving outpatient sotrovimab treatment between 1 November 2021 and 2 August 2022 at nine hospitals in Belgium. The primary outcomes were all-cause and COVID-19-related hospitalisations and all-cause deaths during the 29-day acute follow-up period from first administration of sotrovimab. RESULTS: A total of 634 patients were included (63.4% aged < 65 years; 50.3% male). A high proportion (67.7%; n = 429/634) of patients were immunocompromised, with 36.9% (n = 234/634) actively treated for malignancy. During the 29-day acute period, 12.5% (n = 79/634) of sotrovimab-treated patients were hospitalised due to any cause (median duration 4 days; median time to hospitalisation 14 days) and 1.1% (n = 7/634) died due to any cause. The proportion of sotrovimab-treated patients experiencing COVID-19-related hospitalisation was highest during the Delta predominance and Delta/BA.1 codominance (both 6.3%) periods. During the BA.1 predominance, BA.1/BA.2 codominance and BA.2/BA.5 codominance periods, COVID-19-related hospitalisations were consistently low (all ≤2.7%). CONCLUSION: This study indicated low rates of COVID-19-related hospitalisations and all-cause deaths in sotrovimab-treated patients in Belgium, including during Omicron subvariant periods, despite over two-thirds of the study population being immunocompromised.
Subject(s)
Antibodies, Monoclonal, Humanized , COVID-19 Drug Treatment , COVID-19 , Hospitalization , Humans , Male , Belgium/epidemiology , Female , Middle Aged , Antibodies, Monoclonal, Humanized/therapeutic use , Aged , COVID-19/mortality , COVID-19/epidemiology , Hospitalization/statistics & numerical data , SARS-CoV-2 , Disease Progression , Adult , Cohort Studies , Treatment Outcome , Severity of Illness Index , Antibodies, NeutralizingABSTRACT
BACKGROUND: SARS-CoV-2, first identified in late 2019, has given rise to numerous variants of concern (VOCs), posing a significant threat to human health. The emergence of Omicron BA.1.1 towards the end of 2021 led to a pandemic in early 2022. At present, the lethal mouse model for the study of SARS-CoV-2 needs supplementation, and the alterations in neutrophils and monocytes caused by different strains remain to be elucidated. METHODS: Human ACE2 transgenic mice were inoculated with the SARS-CoV-2 prototype and Omicron BA.1, respectively. The pathogenicity of the two strains was evaluated by observing clinical symptoms, viral load and pathology. Complete blood count, immunohistochemistry and flow cytometry were performed to detect the alterations of neutrophils and monocytes caused by the two strains. RESULTS: Our findings revealed that Omicron BA.1 exhibited significantly lower virulence compared to the SARS-CoV-2 prototype in the mouse model. Additionally, we observed a significant increase in the proportion of neutrophils late in infection with the SARS-CoV-2 prototype and Omicron BA.1. We found that the proportion of monocytes increased at first and then decreased. The trends in the changes in the proportions of neutrophils and monocytes induced by the two strains were similar. CONCLUSION: Our study provides valuable insights into the utility of mouse models for simulating the severe disease of SARS-CoV-2 prototype infection and the milder manifestation associated with Omicron BA.1. SARS-CoV-2 prototype and Omicron BA.1 resulted in similar trends in the changes in neutrophils and monocytes.
ABSTRACT
COVID-19 caused by Omicron BA.1 has resulted in a global humanitarian crisis. In this COVID-19 pandemic era, hypertension has been receiving increased attention. Omicron BA.1 infection combined with hypertension created a serious public health problem and complicated the treatment and prognosis of COVID-19. The aim of our study was to assess the implications of hypertension for the clinical manifestations of adult patients (APs) infected with Omicron BA.1. This single-center retrospective cohort study enrolled consecutive COVID-19 APs, who were admitted to Tianjin First Central Hospital from 01 August 2022 to 30 November 2022. All included APs were divided into two groups: hypertension and non-hypertension group. The APs' baseline demographic, laboratory, clinical, and radiological characteristics were collected and analyzed. Of 512 APs admitted with PCR proven COVID-19, 161 (31.45%) APs had comorbid hypertension. Hypertension APs have older age, higher body mass index, lower Ct-values of the viral target genes at admission, and longer hospital stay than non-hypertension APs. Furthermore, hypertension aggravates the clinical classification, impairs liver, kidney, and myocardium function, and abnormalizes the coagulation system in Omicron BA.1- infected APs. Moreover, hypertension elevates inflammation levels and lung lesion involvement while weakened virus-specific IgM level in APs with Omicron BA.1 infection. Hypertension APs tend to have worse clinical conditions at baseline than those non-hypertension APs. This study indicates that hypertension is a contributor to the poor clinical manifestations of Omicron BA.1-infected APs and supports that steps to control blood pressure should be a vital consideration for reducing the burden of Omicron BA.1 infection in hypertension individuals. IMPORTANCE: This study provided inclusive insight regarding the relationship between hypertension and Omicron BA.1 infection and supported that hypertension was an adverse factor for COVID-19 APs. In conclusion, this study showed that hypertension was considered to be associated with severe conditions, and a contributor to poor clinical manifestations. Proper medical management of hypertension patients is an imperative step in mitigating the severity of Omicron BA.1 variant infection.
Subject(s)
COVID-19 , Hypertension , SARS-CoV-2 , Humans , COVID-19/complications , COVID-19/virology , Hypertension/complications , Male , Female , Middle Aged , SARS-CoV-2/genetics , Retrospective Studies , Adult , AgedABSTRACT
The Omicron variant of SARS-CoV-2, characterized by multiple subvariants including BA.1, XBB.1.5, EG.5, and JN.1, became the predominant strain in early 2022. Studies indicate that Omicron replicates less efficiently in lung tissue compared to the ancestral strain. However, the infectivity of Omicron in the gastrointestinal tract is not fully defined, despite the fact that 70% of COVID-19 patients experience digestive disease symptoms. Here, using primary human colonoids, we found that, regardless of individual variability, Omicron infects colon cells similarly or less effectively than the ancestral strain or the Delta variant. The variant induced limited type III interferon expression and showed no significant impact on epithelial integrity. Further experiments revealed inefficient cell-to-cell spread and spike protein cleavage in the Omicron spike protein, possibly contributing to its lower infectious particle levels. The findings highlight the variant-specific replication differences in human colonoids, providing insights into the enteric tropism of Omicron and its relevance to long COVID symptoms.
Subject(s)
COVID-19 , Colon , Epithelial Cells , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Humans , SARS-CoV-2/genetics , SARS-CoV-2/physiology , SARS-CoV-2/pathogenicity , Colon/virology , COVID-19/virology , Epithelial Cells/virology , Spike Glycoprotein, Coronavirus/metabolism , Spike Glycoprotein, Coronavirus/genetics , Virus Replication , Interferon LambdaABSTRACT
The role of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.1 Spike (S) on disease pathogenesis was investigated. For this, we generated recombinant viruses harboring the S D614G mutation (rWA1-D614G) and the Omicron BA.1 S gene (rWA1-Omi-S) in the backbone of the ancestral SARS-CoV-2 WA1 strain genome. The recombinant viruses were characterized in vitro and in vivo. Viral entry, cell-cell fusion, plaque size, and the replication kinetics of the rWA1-Omi-S virus were markedly impaired when compared to the rWA1-D614G virus, demonstrating a lower fusogenicity and ability to spread cell-to-cell of rWA1-Omi-S. To assess the contribution of the Omicron BA.1 S protein to SARS-CoV-2 pathogenesis, the pathogenicity of rWA1-D614G and rWA1-Omi-S viruses was compared in a feline model. While the rWA1-D614G-inoculated cats were lethargic and showed increased body temperatures on days 2 and 3 post-infection (pi), rWA1-Omi-S-inoculated cats remained subclinical and gained weight throughout the 14-day experimental period. Animals inoculated with rWA1-D614G presented higher infectious virus shedding in nasal secretions, when compared to rWA1-Omi-S-inoculated animals. In addition, tissue replication of the rWA1-Omi-S was markedly reduced compared to the rWA1-D614G, as evidenced by lower viral load in tissues on days 3 and 5 pi. Histologic examination of the nasal turbinate and lungs revealed intense inflammatory infiltration in rWA1-D614G-inoculated animals, whereas rWA1-Omi-S-inoculated cats presented only mild to modest inflammation. Together, these results demonstrate that the S protein is a major virulence determinant for SARS-CoV-2 playing a major role for the attenuated phenotype of the Omicron virus. IMPORTANCE: We have demonstrated that the Omicron BA.1.1 variant presents lower pathogenicity when compared to D614G (B.1) lineage in a feline model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. There are over 50 mutations across the Omicron genome, of which more than two-thirds are present in the Spike (S) protein. To assess the role of the Omicron BA.1 S on virus pathogenesis, recombinant viruses harboring the S D614G mutation (rWA1-D614G) and the Omicron BA.1 Spike gene (rWA1-Omi-S) in the backbone of the ancestral SARS-CoV-2 WA1 were generated. While the Omicron BA.1 S promoted early entry into cells, it led to impaired fusogenic activity and cell-cell spread. Infection studies with the recombinant viruses in a relevant naturally susceptible feline model of SARS-CoV-2 infection here revealed an attenuated phenotype of rWA1-Omi-S, demonstrating that the Omi-S is a major determinant of the attenuated disease phenotype of Omicron strains.
Subject(s)
COVID-19 , Orthopoxvirus , SARS-CoV-2 , Animals , Cats , COVID-19/virology , Phenotype , SARS-CoV-2/classification , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/metabolism , Virulence , Virulence Factors/geneticsABSTRACT
Several countries have recommended a booster dose of Pfizer BNT162b2 vaccine for subjects under the age of 60, who have already received the first dose of ChAdOx1. This is due to several ChAdOx1 vaccine-associated adverse vascular events and thrombocytopenia. Neutralization assay and quantitative IgG anti-SARS-CoV-2 Spike antibody (anti-S-IgG) were conducted to investigate the long-term responses to vaccine treatment in a cohort of Sardinian participants, who have received heterologous Prime-Boost Vaccination via ChAdOx1 vector vaccine and a booster dose via BNT162b2. The obtained results were compared with those of a cohort of healthcare workers (HCW) who received homologous BNT162b2 (BNT/BNT/BNT) vaccination. One month (T2) and five months after the second and before the third dose (T3), anti-spike antibody or neutralizing titers in the subjects vaccinated with ChAdOx1-S/BNT162b2 were significantly higher than those who experienced the ChAdOx1-S/ChAdOx1-S or BNT162b2/BNT162b2 schedule. These results suggest that a ChAdOx1-S/BNT162b2 regimen provides a more robust antibody response than either of the homologous regimens. However, the anti-spike antibodies or neutralizing titers after the third injection (mRNA vaccine) of ChAdOx1-S as a second dose and BNT162b2 were not statistically different. Homologous and heterologous vaccination provided a strong antibody response. Neutralizing activities were also described against the Omicron BA.1 variant in a sub-group (40) representative of the three vaccination regimens among our cohort.
Subject(s)
BNT162 Vaccine , COVID-19 , Humans , ChAdOx1 nCoV-19 , SARS-CoV-2/genetics , COVID-19/prevention & control , Vaccination , Antibodies, Viral , Immunoglobulin GABSTRACT
Vaccination with the primary two-dose series of SARS-CoV-2 mRNA protects against infection with the ancestral strain, and limits the presentation of severe disease after re-infection by multiple variants of concern (VOC), including Omicron, despite the lack of a strong neutralizing response to these variants. We compared antibody responses in serum samples collected from mRNA-1273 (Moderna) vaccinated subjects to identify mechanisms of immune escape and cross-protection. Using pseudovirus constructs containing domain-specific amino acid changes representative of Omicron BA.1, combined with domain competition and RBD-antibody depletion, we showed that RBD antibodies were primarily responsible for virus neutralization and variant escape. Antibodies to NTD played a less significant role in antibody neutralization but acted along with RBD to enhance neutralization. S2 of Omicron BA.1 had no impact on neutralization escape, suggesting it is a less critical domain for antibody neutralization; however, it was as capable as S1 at eliciting IgG3 responses and NK-cell mediated, antibody-dependent cell cytotoxicity (ADCC). Antibody neutralization and ADCC activities to RBD, NTD, and S1 were all prone to BA.1 escape. In contrast, ADCC activities to S2 resisted BA.1 escape. In conclusion, S2 antibodies showed potent ADCC function and resisted Omicron BA.1 escape, suggesting that S2 contributes to cross-protection against Omicron BA.1. In line with its conserved nature, S2 may hold promise as a vaccine target against future variants of SARS-CoV-2.
Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Humans , Spike Glycoprotein, Coronavirus/genetics , COVID-19/prevention & control , SARS-CoV-2 , Immunoglobulin G , Antibody-Dependent Cell Cytotoxicity , Killer Cells, Natural , RNA, MessengerABSTRACT
Virus-specific antibodies are crucial for protective immunity against SARS-CoV-2. Assessing functional antibodies through conventional or pseudotyped virus neutralisation tests (pVNT) requires high biosafety levels. Alternatively, the virus-free surrogate virus neutralisation test (sVNT) quantifies antibodies interfering with spike binding to angiotensin-converting enzyme 2. We evaluated secreted nanoluciferase-tagged spike protein fragments as diagnostic antigens in the sVNT in a vaccination cohort. Initially, spike fragments were tested in a capture enzyme immunoassay (EIA), identifying the receptor binding domain (RBD) as the optimal diagnostic antigen. The sensitivity of the in-house sVNT applying the nanoluciferase-labelled RBD equalled or surpassed that of a commercial sVNT (cPass, GenScript Diagnostics) and an in-house pVNT four weeks after the first vaccination (98% vs. 94% and 72%, respectively), reaching 100% in all assays four weeks after the second and third vaccinations. When testing serum reactivity with Omicron BA.1 spike, the sVNT and pVNT displayed superior discrimination between wild-type- and variant-specific serum reactivity compared to a capture EIA. This was most pronounced after the first and second vaccinations, with the third vaccination resulting in robust, cross-reactive BA.1 construct detection. In conclusion, utilising nanoluciferase-labelled antigens permits the quantification of SARS-CoV-2-specific inhibitory antibodies. Designed as flexible modular systems, the assays can be readily adjusted for monitoring vaccine efficacy.
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The emergence of novel SARS-CoV-2 variants has raised concerns about the ability of COVID-19 vaccination programs to establish adequate herd immunity levels in the population. This study assessed the effectiveness of adapted vaccines in preventing SARS-CoV-2 infection and the ability of the adapted vaccines to establish herd immunity against emerging Omicron variants. A systematic literature review was conducted to estimate the absolute vaccine effectiveness (aVE) in preventing SARS-CoV-2 infection using adapted vaccines targeting Omicron variants. The ability of the adapted vaccines to establish herd immunity was assessed by taking into account the following factors: aVE, Ro values of SARS-CoV-2 and the use of non-pharmacological interventions (NPIs). This study found meta-analysis-based aVEs in preventing severe disease and SARS-CoV-2 infection of 56-60% and 36-39%, respectively. Adapted vaccines could not establish herd immunity against the Omicron BA.1 and BA.4-5 variants without using non-pharmacological interventions (NPIs). The adapted vaccines could establish herd immunity only by achieving >80% vaccination coverage, using NPIs with greater effectiveness and when 20-30% of individuals were already protected against SARS-CoV-2 in the population. New adapted COVID-19 vaccines with greater effectiveness in preventing SARS-CoV-2 infection must be developed to increase herd immunity levels against emerging SARS-CoV-2 variants in the population.
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Introduction: Following the emergence of SARS-CoV-2 in 2020, care homes were disproportionately impacted by high mortality and morbidity of vulnerable elderly residents. Non-pharmaceutical interventions (NPIs) and improved infection control measures together with vaccination campaigns have since improved outcomes of infection. We studied the utility of past infection status, recent vaccination and anti-S antibody titres as possible correlates of protection against a newly emergent Omicron variant infection. Methods: Prospective longitudinal surveillance of nine sentinel London care homes from April 2020 onwards found that all experienced COVID-19 outbreaks due to Omicron (BA.1) during December 2021 and January 2022, despite extensive prior SARS-CoV-2 exposure and high COVID-19 vaccination rates, including booster vaccines (>70% residents, >40% staff). Results: Detailed investigation showed that 46% (133/288) of Omicron BA.1 infections were SARS-CoV-2 reinfections. Two and three COVID-19 vaccine doses were protective against Omicron infection within 2-9 weeks of vaccination, though protection waned from 10 weeks post-vaccination. Prior infection provided additional protection in vaccinated individuals, approximately halving the risk of SARS-CoV-2 infection. Discussion: Anti-S antibody titre showed a dose-dependent protective effect but did not fully account for the protection provided by vaccination or past infection, indicating that other mechanisms of protection are also involved.
Subject(s)
COVID-19 Vaccines , COVID-19 , Aged , Humans , Prospective Studies , Reinfection , Antibodies , COVID-19/epidemiology , COVID-19/prevention & control , SARS-CoV-2ABSTRACT
BACKGROUND: Mutations present in emerging SARS-CoV-2 variants permit evasion of neutralization with prototype vaccines. A novel Omicron BA.1 subvariant-specific vaccine (NVX-CoV2515) was tested alone, or as a bivalent preparation in combination with the prototype vaccine (NVX-CoV2373), to assess antibody responses to SARS-CoV-2. METHODS: Participants aged 18 to 64 years immunized with 3 doses of prototype mRNA vaccines were randomized 1:1:1 to receive a single dose of NVX-CoV2515, NVX-CoV2373, or bivalent mixture in a phase 3 study investigating heterologous boosting with SARS-CoV-2 recombinant spike protein vaccines. Immunogenicity was measured 14 and 28 days after vaccination for the SARS-CoV-2 Omicron BA.1 sublineage and ancestral strain. Safety profiles of vaccines were assessed. RESULTS: Of participants who received trial vaccine (N = 829), those administered NVX-CoV2515 (n = 286) demonstrated superior neutralizing antibody response to BA.1 versus NVX-CoV2373 (n = 274) at Day 14 (geometric mean titer ratio [95% CI]: 1.6 [1.33, 2.03]). Seroresponse rates [n/N; 95% CI] were 73.4% [91/124; 64.7, 80.9] for NVX-CoV2515 versus 50.9% [59/116; 41.4, 60.3] for NVX-CoV2373. All formulations were similarly well-tolerated. CONCLUSIONS: NVX-CoV2515 elicited a superior neutralizing antibody response against the Omicron BA.1 subvariant compared with NVX-CoV2373 when administered as a fourth dose. Safety data were consistent with the established safety profile of NVX-CoV2373.
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How infection by a viral variant showing antigenic drift impacts a preformed mature human memory B cell (MBC) repertoire remains an open question. Here, we studied the MBC response up to 6 months after SARS-CoV-2 Omicron BA.1 breakthrough infection in individuals previously vaccinated with three doses of the COVID-19 mRNA vaccine. Longitudinal analysis, using single-cell multi-omics and functional analysis of monoclonal antibodies from RBD-specific MBCs, revealed that a BA.1 breakthrough infection mostly recruited pre-existing cross-reactive MBCs with limited de novo response against BA.1-restricted epitopes. Reorganization of clonal hierarchy and new rounds of germinal center reactions, however, combined to maintain diversity and induce progressive maturation of the MBC repertoire against common Hu-1 and BA.1, but not BA.5-restricted, SARS-CoV-2 Spike RBD epitopes. Such remodeling was further associated with a marked improvement in overall neutralizing breadth and potency. These findings have fundamental implications for the design of future vaccination booster strategies.
Subject(s)
COVID-19 Vaccines , COVID-19 , Humans , SARS-CoV-2 , Memory B Cells , Breakthrough Infections , Epitopes , Antibodies, Viral , Antibodies, NeutralizingABSTRACT
Objective: To investigate whether Omicron BA.1 breakthrough infection after receiving the SARS-CoV-2 vaccine could create a strong immunity barrier. Methods: Blood samples were collected at two different time points from 124 Omicron BA.1 breakthrough infected patients and 124 controls matched for age, gender, and vaccination profile. Live virus-neutralizing antibodies against five SARS-CoV-2 variants, including WT, Gamma, Beta, Delta, and Omicron BA.1, and T-lymphocyte lymphocyte counts in both groups were measured and statistically analyzed. Results: The neutralizing antibody titers against five different variants of SARS-CoV-2 were significantly increased in the vaccinated population infected with the Omicron BA.1 variant at 3 months after infection, but mainly increased the antibody level against the WT strain, and the antibody against the Omicron strain was the lowest. The neutralizing antibody level decreased rapidly 6 months after infection. The T-lymphocyte cell counts of patients with mild and moderate disease recovered at 3 months and completely returned to the normal state at 6 months. Conclusion: Omicron BA.1 breakthrough infection mainly evoked humoral immune memory in the original strain after vaccination and hardly produced neutralizing antibodies specific to Omicron BA.1. Neutralizing antibodies against the different strains declined rapidly and showed features similar to those of influenza. Thus, T-lymphocytes may play an important role in recovery.
Subject(s)
Antibodies, Neutralizing , COVID-19 , Humans , Prospective Studies , SARS-CoV-2 , Breakthrough Infections , COVID-19 Vaccines , T-Lymphocytes , China/epidemiology , Antibodies, ViralABSTRACT
Antibodies triggering Fc-mediated NK cell activity may contribute to protection against disease caused by SARS-CoV-2 infection in humans. However, how these Fc-mediated humoral responses compare between individuals displaying hybrid immunity (Vac-ex) and those fully vaccinated with no history of SARS-CoV-2 infection (Vac-n) and whether they correlate with neutralizing antibody (NtAb) responses remains largely undetermined. In this retrospective study serum samples from 50 individuals (median age, 44.5 years; range, 11-85; 25 males), 25 Vac-ex and 25 Vac-n were studied. A flow-cytometry-based antibody-mediated NK-cell activation assay was used to quantitate effector NK-cells stimulated to express LAMP1 (lysosomal associated membrane protein 1), MIP1 (Macrophage inflammatory protein 1), and interferon-γ (IFNγ); NK cells isolated from two donors (D1 and D2) were used. NtAb levels targeting the Spike protein of Wuhan-Hu-1 and Omicron BA.1 SARS-CoV-2 variants were quantitated using a SARS-CoV-2 S pseudotyped neutralization assay. Regardless of the SARS-CoV-2 variant S antigen used in the NK-cell activation assay, the frequency of NK cells stimulated to express LAMP-1, MIP1ß, and IFNγ was higher in Vac-ex compared with Vac-n (p values ranging from 0.07 to 0.006) for D1; this was only seen for BA.1 when NK cells from D2 were employed. The frequency of functional NK cells activated by antibody binding to either Wuhan-Hu-1 or Omicron BA.1 S protein was not significantly different for both VAC-ex and VAC-n. In contrast, NtAb titers against BA.1 were around 10-fold lower than that against Wuhan-Hu-1. Vac-ex displayed higher NtAb titers against both (sub)variants than Vac-n. NK-cell responses correlated poorly with NtAb titers (ρ ≤ 0.30). The data demonstrate higher cross-reactivity across variants of concern for antibodies triggering Fc-mediated NK cell than for NtAb. Moreover, Vac-Ex seemed to display more robust functional antibody responses as compared with Vac-n.
Subject(s)
Blood Group Antigens , COVID-19 , Male , Humans , Adult , SARS-CoV-2/genetics , Antibodies, Neutralizing , Antibody Formation , Retrospective Studies , Spike Glycoprotein, Coronavirus/genetics , COVID-19/prevention & control , Killer Cells, Natural , Interferon-gamma , Antibodies, ViralABSTRACT
We aimed to evaluate the association between the humoral and cellular immune responses and symptomatic SARS-CoV-2 infection with Delta or Omicron BA.1 variants in fully vaccinated outpatients. Anti-receptor binding domain (RBD) IgG levels and interferon-gamma (IFN-γ) release were evaluated at PCR-diagnosis of SARS-CoV-2 in 636 samples from negative and positive patients during Delta and Omicron BA.1 periods. Median levels of anti-RBD IgG in positive patients were significantly lower than in negative patients for both variants (p < 0.05). The frequency of Omicron BA.1 infection in patients with anti-RBD IgG concentrations ≥1000 binding antibody units (BAU)/mL was 51.0% and decreased to 34.4% in patients with concentrations ≥3000 BAU/mL. For Delta infection, the frequency of infection was significantly lower when applying the same anti-RBD IgG thresholds (13.3% and 5.3% respectively, p < 0.05). In addition, individuals in the hybrid immunity group had a 4.5 times lower risk of Delta infection compared to the homologous vaccination group (aOR = 0.22, 95% CI: [0.05-0.64]. No significant decrease in the risk of Omicron BA.1 infection was observed in the hybrid group compared to the homologous group, but the risk decreased within the hybrid group as anti-RBD IgG titers increased (aOR = 0.08, 95% CI: [0.01-0.41], p = 0.008). IFN-γ release post-SARS-CoV-2 peptide stimulation was not different between samples from patients infected (either with Delta or Omicron BA.1 variant) or not (p > 0.05). Our results show that high circulating levels of anti-RBD IgG and hybrid immunity were independently associated with a lower risk of symptomatic SARS-CoV-2 infection in outpatients with differences according to the infecting variant (www.clinicaltrials.gov; ID NCT05060939).
Subject(s)
COVID-19 , Hepatitis D , Humans , Outpatients , SARS-CoV-2 , COVID-19/prevention & control , Interferon-gamma , Immunoglobulin G , Antibodies, ViralABSTRACT
As the COVID-19 pandemic continues, variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to emerge. Immunogenicity evaluation of vaccines and identification of correlates of protection for vaccine effectiveness is critical to aid the development of vaccines against emerging variants. Anti-recombinant spike (rS) protein immunoglobulin G (IgG) quantitation in the systemic circulation (serum/plasma) is shown to correlate with vaccine efficacy. Thus, an enzyme-linked immunosorbent assay (ELISA)-based binding assay to detect SARS-CoV-2 (ancestral and variant strains) anti-rS IgG in human serum samples was developed and validated. This assay successfully met acceptance criteria for inter/intra-assay precision, specificity, selectivity, linearity, lower/upper limits of quantitation, matrix effects, and assay robustness. The analyte in serum was stable for up to 8 freeze/thaw cycles and 2 years in -80 °C storage. Similar results were observed for the Beta, Delta, and Omicron BA.1/BA.5/XBB.1.5 variant-adapted assays. Anti-rS IgG assay results correlated significantly with neutralization and receptor binding inhibition assays. In addition, usage of international reference standards allows data extrapolation to WHO international units (BAU/mL), facilitating comparison of results with other IgG assays. This anti-rS IgG assay is a robust, high-throughput method to evaluate binding IgG responses to S protein in serum, enabling rapid development of effective vaccines against emerging COVID-19 variants.