ABSTRACT
OBJECTIVES: An increase evasion of the SARS-CoV-2 virus toward vaccination strategies and natural immunity has been rapidly described notably because of the mutations in the spike receptor binding domain and the N-terminal domain. METHODS: Participants of the CRO-VAX HCP study who received the bivalent booster were followed up at 6 months. A pseudovirus-neutralization test was used to assess the neutralization potency of antibodies against D614G, Delta, BA.1, BA.5, XBB.1.5, BA.2.86, FL.1.5.1, and JN-1. RESULTS: The neutralizing capacity of antibodies against the Omicron variant or its subvariants was significantly reduced compared with D614G and Delta (P <0.0001). The lowest neutralizing response that was observed with JN-1 (geometric mean titers [GMTs] = 22.1) was also significantly lower than XBB.1.5 (GMT = 29.5, P <0.0001), BA.2.86 (GMT = 29.6, P <0.0001), and FL.1.5.1 (GMT = 25.2, P <0.0001). Participants who contracted a breakthrough infection because of XBB.1.5 had significantly higher neutralizing antibodies against all variants than uninfected participants, especially against the Omicron variant and its subvariants. CONCLUSIONS: Our results confirm that JN.1 is one of the most immune-evading variants to date and that the BA.2.86 subvariant did not show an increased immunity escape compared with XBB.1.5. The stronger response in breakthrough infection cases with the Omicron variant and its subvariants supports the need to use vaccine antigens that target circulating variants.
Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , BNT162 Vaccine , COVID-19 , Immunization, Secondary , SARS-CoV-2 , Humans , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/prevention & control , COVID-19/immunology , SARS-CoV-2/immunology , Male , Female , BNT162 Vaccine/immunology , BNT162 Vaccine/administration & dosage , Adult , Middle Aged , COVID-19 Vaccines/immunology , COVID-19 Vaccines/administration & dosage , Spike Glycoprotein, Coronavirus/immunology , Neutralization TestsABSTRACT
Vaccines against SARS-CoV-2 were developed during the pandemic including the BNT162b2 and the mRNA-1273. We evaluated the levels of binding antibodies against the receptor binding domain and the levels of NAbs in individuals who developed a breakthrough infection after having received three doses of mRNA-1273. A total of 51 participants were included. The breakthrough group was compared to a 1:1 matched-control group. Among the 51 individuals, 18 (35%) developed a breakthrough infection. The GMT of NAbs against the BA.1 in the BK population was 278.1 (95%CI: 168.1-324.1). This titer was significantly lower compared to the matched-control group when considering all data (GMT = 477.4; 95%CI: 316.2-541.0; p = 0.0057). Results were similar for the BA.5 (GMT = 152.0 (95%CI: 76.9-172.9) for breakthrough and 262.0 (95%CI: 171.3-301.8) for control (p = 0.0043)). Our study found that individuals receiving the mRNA-1273 booster and who developed a breakthrough infection presented lower levels of binding antibodies and NAbs before the infection as compared to a matched-control group.
Subject(s)
2019-nCoV Vaccine mRNA-1273 , Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , COVID-19 , Health Personnel , Immunization, Secondary , SARS-CoV-2 , Humans , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/blood , 2019-nCoV Vaccine mRNA-1273/immunology , 2019-nCoV Vaccine mRNA-1273/administration & dosage , COVID-19/immunology , COVID-19/virology , COVID-19/prevention & control , Antibodies, Viral/immunology , Antibodies, Viral/blood , SARS-CoV-2/immunology , SARS-CoV-2/genetics , Male , Female , Adult , COVID-19 Vaccines/immunology , COVID-19 Vaccines/administration & dosage , Middle Aged , BNT162 Vaccine/administration & dosage , BNT162 Vaccine/immunology , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/genetics , Breakthrough InfectionsABSTRACT
Studies about the duration of the humoral and cellular response following the bivalent booster administration are still scarce. We aimed at assessing the humoral and cellular response in a cohort of healthcare workers that received this booster. Blood samples were collected before the administration of the bivalent booster from Pfizer-BioNTech and after 14, 28, 90, and 180 days. Neutralizing antibodies against either the D614G strain, the delta variant, the BA.5 variant, or the XBB.1.5 subvariant were measured. The cellular response was assessed by measurement of the release of interferon gamma from T cells in response to an in vitro SARS-CoV-2 stimulation. A substantial waning of neutralizing antibodies was observed after 6 months (23.1-fold decrease), especially considering the XBB.1.5 subvariant. The estimated T1/2 of neutralizing antibodies was 16.1 days (95% CI = 10.2-38.4 days). Although most participants still present a robust cellular response after 6 months (i.e., 95%), a significant decrease was also observed compared to the peak response (0.95 vs. 0.41 UI/L, p = 0.0083). A significant waning of the humoral and cellular response was observed after 6 months. These data can also help competent national authorities in their recommendation regarding the administration of an additional booster.
Subject(s)
BNT162 Vaccine , Complementary Therapies , Humans , Immunity, Cellular , Antibodies, Neutralizing , Health PersonnelSubject(s)
Heterocyclic Compounds, 2-Ring , Neoplasms , Thiadiazoles , Humans , Receptors, Neurokinin-3 , Neoplasms/drug therapyABSTRACT
INTRODUCTION: During the signal detection process, statistical methods are used to identify drug-event combinations (DECs) which are disproportionately reported when compared with other drugs and events in the entire database. We hypothesise that the high volume of COVID-19 vaccine adverse drug reaction (ADR) reports transmitted to EudraVigilance may have affected the performance of disproportionality statistics used in routine signal detection, potentially resulting in signals either being masked, or false associations being flagged as potential signals. OBJECTIVE: Our aim was to study the impact of COVID-19 vaccine spontaneous reporting on statistical signal detection in EudraVigilance. METHODS: We recalculated the reporting odds ratio (ROR) for signals that were previously discussed at the level of the Pharmacovigilance Risk Assessment Committee, or signals that were retrieved from EudraVigilance, by omitting COVID-19 vaccine reports from the standard ROR calculation and then comparing the lower confidence interval (LCI) of the recalculated ROR to the LCI of the actual ROR in EudraVigilance. RESULTS: In total, 52 signals for 38 active substances were reviewed. For 35 signals, the LCI of the recalculated ROR value was lower than the LCI of the actual ROR (suggesting that COVID-19 vaccine ADR reporting had a positive effect on the strength of the signal) while for 15 signals the LCI of the recalculated ROR value was higher than the LCI of the actual ROR (suggesting that COVID-19 vaccine ADR reporting had an attenuating effect on the strength of the signal). For two signals, no change in the ROR was observed. In our analysis, six significant results were found. Five DECs were found to be masked: bleomycin and immune thrombocytopenia (actual ROR LCI = 0.94, recalculated ROR LCI = 1.02), vortioxetine and heavy menstrual bleeding (actual ROR LCI = 0.3, recalculated ROR LCI = 1.06), caplacizumab and heavy menstrual bleeding (actual ROR LCI = 0.98, recalculated ROR LCI = 3.47), ziprasidone and amenorrhoea (actual ROR LCI = 0.84, recalculated ROR LCI = 1.67), and azacitidine and pericarditis (actual ROR LCI = 0.81, recalculated ROR LCI = 2.01). For the DEC of adalimumab and immune reconstitution inflammatory syndrome, the LCI of the actual ROR value was 1.14 and removing COVID-19 vaccine reporting resulted in an LCI of the recalculated ROR value of 0.94 (below threshold). CONCLUSIONS: We demonstrated five cases of masking and one case of false-positive association due to the influence of COVID-19 vaccine spontaneous reporting on the ROR. This suggests that the high number of adverse drug reaction reports for COVID-19 vaccines in EudraVigilance has the potential to affect routine statistical signal detection activities. The impact of COVID-19 vaccine ADR reports on current signal detection practices requires further evaluation and solutions to tackle masking issues in EudraVigilance may need to be developed.
Subject(s)
COVID-19 , Drug-Related Side Effects and Adverse Reactions , Menorrhagia , Female , Humans , COVID-19 Vaccines/adverse effects , Adverse Drug Reaction Reporting Systems , COVID-19/prevention & control , Databases, Factual , PharmacovigilanceABSTRACT
The rapid and large-scale roll-out of new COVID-19 vaccines has led to unprecedented challenges in assessing vaccine safety. In 2021, the European Medicines Agency (EMA) processed about 1.7 million safety reports related to COVID-19 vaccines in the EudraVigilance (EV) database and identified more than 900 potential signals. Beyond the large amount of information to be processed, the evaluation of safety signals has faced several difficulties and limitations, both in the assessment of case reports and in the investigation of databases. The evaluation of a signal of corneal graft rejection (CGR) with Vaxzevria® was no exception to this. In this commentary, we present the challenges encountered in making regulatory decisions in the context of evolving evidence and knowledge. The pandemic crisis emphasised the importance of quick and proactive communication to address the many questions and, above all, to ensure the transparency of safety data.
ABSTRACT
Coronavirus Disease 2019 (COVID-19) vaccination has resulted in excellent protection against fatal disease, including in older adults. However, risk factors for post-vaccination fatal COVID-19 are largely unknown. We comprehensively studied three large nursing home outbreaks (20-35% fatal cases among residents) by combining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) aerosol monitoring, whole-genome phylogenetic analysis and immunovirological profiling of nasal mucosa by digital nCounter transcriptomics. Phylogenetic investigations indicated that each outbreak stemmed from a single introduction event, although with different variants (Delta, Gamma and Mu). SARS-CoV-2 was detected in aerosol samples up to 52 d after the initial infection. Combining demographic, immune and viral parameters, the best predictive models for mortality comprised IFNB1 or age, viral ORF7a and ACE2 receptor transcripts. Comparison with published pre-vaccine fatal COVID-19 transcriptomic and genomic signatures uncovered a unique IRF3 low/IRF7 high immune signature in post-vaccine fatal COVID-19 outbreaks. A multi-layered strategy, including environmental sampling, immunomonitoring and early antiviral therapy, should be considered to prevent post-vaccination COVID-19 mortality in nursing homes.
Subject(s)
COVID-19 , Humans , Aged , Phylogeny , COVID-19/epidemiology , SARS-CoV-2/genetics , Nursing Homes , Vaccination , Disease Outbreaks/prevention & controlABSTRACT
OBJECTIVES: To assess the long-term humoral immunity induced by booster administration, as well as the ability of binding antibody and surrogate virus neutralization tests (sVNT) to predict neutralizing antibodies (NAbs) against the SARS-CoV-2 Omicron variant. METHODS: A total of 269 sera samples were analyzed from 64 healthcare workers who had received a homologous booster dose of BNT162b2. Neutralizing antibodies assessed by sVNT and anti-RBD IgG measured with the sCOVG assay (Siemens Healthineers®) were analyzed at five timepoints; before and up to 6 months following the booster. Antibody titers were correlated with neutralizing antibodies against the Omicron BA.1 variant obtained by pseudovirus neutralization test (pVNT) as a reference method. RESULTS: While Wild-type sVNT percentage of inhibition (POI) remained above 98.6% throughout the follow-up period after booster administration, anti-RBD IgG and NAbs assessed by Omicron BA.1 pVNT showed respectively a 3.4-fold and 13.3-fold decrease after 6 months compared to the peak reached at day 14. NAbs assessed by Omicron sVNT followed a steady decline until reaching a POI of 53.4%. Anti-RBD IgG and Omicron sVNT assays were strongly correlated (r=0.90) and performed similarly to predict the presence of neutralizing antibodies with Omicron pVNT (area under the ROC: 0.82 for both assays). In addition, new adapted cut-off values of anti-RBD IgG (>1,276 BAU/mL) and Omicron sVNT (POI>46.6%) were found to be better predictors of neutralizing activity. CONCLUSIONS: This study showed a significant drop in humoral immunity 6 months after booster administration. Anti-RBD IgG and Omicron sVNT assays were highly correlated and could predict neutralizing activity with moderate performance.
Subject(s)
Antibodies, Neutralizing , COVID-19 , Humans , SARS-CoV-2 , Neutralization Tests , BNT162 Vaccine , Kinetics , Immunoglobulin G , Antibodies, ViralABSTRACT
BACKGROUND: A SARS-CoV-2+Flu A/B+RSV Combo Rapid test may be more relevant than Rapid Antigen Diagnostic (RAD) tests targeting only SARS-CoV-2 since we are facing a concurrent circulation of these viruses during the winter season. OBJECTIVES: To assess the clinical performance of a SARS-CoV-2+Flu A/B+RSV Combo test in comparison to a multiplex RT-qPCR. STUDY DESIGN: Residual nasopharyngeal swabs issued from 178 patients were included. All patients, adults and children, were symptomatic and presented at the emergency department with flu-like symptoms. Characterization of the infectious viral agent was done by RT-qPCR. The viral load was expressed as cycle threshold (Ct). Samples were then tested using the multiplex RAD test Fluorecare®à¸ SARS-CoV-2 & Influenza A/B & RSV Antigen Combo Test. Data analysis was carried out using descriptive statistics. RESULTS: The sensitivity of the test varies according to the virus, with the highest sensitivity observed for Influenza A (80.8.% [95%CI: 67.2 - 94.4]) and the lowest sensitivity observed for RSV (41.5% [95%CI: 26.2 - 56.8]). Higher sensitivities were observed for samples with high viral loads (Ct < 20) and decrease with low viral loads. The specificity for SARS-CoV-2, RSV and Influenza A and B was >95%. CONCLUSIONS: The Fluorecare® combo antigenic presents satisfying performance in real-life clinical setting for Influenza A and B in samples with high viral load. This could be useful to allow a rapid (self-)isolation as the transmissibility of these viruses increase with the viral load. According to our results, its use to rule-out SARS-CoV-2 and RSV infection is not sufficient.
Subject(s)
COVID-19 , Influenza, Human , Respiratory Syncytial Virus Infections , Adult , Child , Humans , Influenza, Human/diagnosis , SARS-CoV-2 , COVID-19/diagnosis , Respiratory Syncytial Virus Infections/diagnosis , Immunologic Tests , Sensitivity and SpecificityABSTRACT
OBJECTIVES: The BNT162b2 messenger RNA vaccine is highly effective in reducing COVID-19 infection, hospitalization and death. However, many subjects developed a breakthrough infection despite a full vaccination scheme. Since the waned efficacy of mRNA vaccines is correlated with the decrease of antibodies occurring over time, we aimed at evaluating whether lower levels of antibodies were associated with an increased risk of breakthrough infection in a cohort of breakthrough subjects that received three vaccine doses. METHODS: Total binding antibodies against the RBD of the S1 subunit (Roche Diagnostics, Machelen, Belgium) and neutralizing antibodies using the Omicron B.1.1.529 variant pseudovirus were measured. Based on individual kinetic curves, the antibody titer of each subject was interpolated just before the breakthrough infection and compared to a matched-control group that did not develop a breakthrough infection. RESULTS: Lower levels of total binding and neutralizing antibodies were observed compared to the control group (6.900 [95% CI; 5.101-9.470] vs. 11.395 BAU/mL [8.627-15.050] [p=0.0301] and 26.6 [18.0-39.3] vs. 59.5 dilution titer-1 [32.3-110] [p=0.0042], respectively). The difference between breakthrough and control subjects was mostly observed for neutralizing antibodies before three months after the homologous booster administration (46.5 [18.2-119] vs. 381 [285-509] [p=0.0156]). Considering the measurement of total binding antibodies before 3 months, there was no significant difference (p=0.4375). CONCLUSIONS: In conclusion, our results showed that subjects that developed a breakthrough infection had lower levels of neutralizing and total binding antibodies compared to controls. The difference was mostly noticeable considering neutralizing antibodies, especially for infections occurring before 3 months after the booster administration.
Subject(s)
COVID-19 , Humans , Breakthrough Infections , BNT162 Vaccine , Antibodies, Neutralizing , Delivery of Health Care , Antibodies, ViralABSTRACT
The most intuitive question for market access for medicinal products is the benefit/risk (B/R) balance. The B/R assessment can conceptually be divided into subquestions related to establishing efficacy and safety. There are additional layers to the B/R ratio for medical products, including questions related to dose selection, clinical and nonclinical pharmacology, and drug quality. Explicitly stating the actual questions and how they contribute to the overall B/R provides a structure that fosters better informed cross-domain discussions. There is currently no systematic approach in the regulatory setting to assess and establish the acceptability of alternative methods and data sources. In most cases, the medicinal product sponsors tend to prioritize traditional data types and methods, which are well accepted by regulators for inclusion in regulatory submissions. This, in addition to the absence of rigor in the use and validation of new data types and methods, and the limited training of assessors in related fields can lead to increased regulatory skepticism toward new data types and methods. A data-knowledge backbone is needed to mitigate the uncertainty in efficacy and safety characterization. This white paper discusses the value of explicitly redefining and restructuring the regulatory scientific decision making around the scientific question to be addressed. The ecosystem proposed is based on three pillars: (i) a repository connecting questions, data, and methods; (ii) the development and validation of high-quality standards for data and methods; and (iii) credibility assessment. The ecosystem is applied to four use cases for illustration. The need for training and regulatory guidance is also discussed.
Subject(s)
Decision Making , Ecosystem , Humans , Risk AssessmentABSTRACT
Prior to deployment of coronavirus disease 2019 (COVID-19) vaccines in the European Union in 2021, a high vaccine uptake leading to an unprecedented volume of safety data from spontaneous reports and real-world evidence, was anticipated. The European Medicines Agency (EMA) implemented specific activities to ensure enhanced monitoring of emerging vaccine safety information, including intensive monitoring of reports of adverse events of special interest and the use of observed-to-expected analyses. The EMA also commissioned several independent observational studies using a large network of electronic healthcare databases and primary data collection via mobile and web-based applications. This preparedness was key for two high-profile safety signals: thrombosis with thrombocytopenia syndrome (TTS), a new clinical entity associated with adenovirus-vectored vaccines, and myocarditis/pericarditis with messenger RNA vaccines. With no existing case definition nor background rates, the signal of TTS posed particular challenges. Nevertheless, it was rapidly identified, evaluated, contextualized and the risk minimized thanks to close surveillance and an efficient use of available evidence, clinical expertise and flexible regulatory tools. The two signals illustrated the complementarity between spontaneous and real-world data, the former enabling rapid risk identification and communication, the latter enabling further characterization. The COVID-19 pandemic has tremendously enhanced the development of tools and methods to harness the unprecedented volume of safety data generated for the vaccines. Areas for further improvement include the need for better and harmonized data collection across Member States (e.g., stratified vaccine exposure) to support signal evaluation in all population groups, risk contextualization, and safety communication.
Subject(s)
COVID-19 , Vaccines , Humans , COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , Pandemics/prevention & control , Vaccines/adverse effects , Data CollectionABSTRACT
Evidence about the long-term persistence of the booster-mediated immunity against Omicron is mandatory for pandemic management and deployment of vaccination strategies. A total of 155 healthcare professionals (104 COVID-19 naive and 51 with a history of SARS-CoV-2 infection) received a homologous BNT162b2 booster. Binding antibodies against the spike protein and neutralizing antibodies against Omicron were measured at several time points before and up to 6 months after the booster. Geometric mean titers of measured antibodies were correlated to vaccine efficacy (VE) against symptomatic disease. Compared to the highest response, a significant 10.2- and 11.5-fold decrease in neutralizing titers was observed after 6 months in participants with and without history of SARS-CoV-2 infection. A corresponding 2.5- and 2.9-fold decrease in binding antibodies was observed. The estimated T1/2 of neutralizing antibodies in participants with and without history of SARS-CoV-2 infection was 42 (95% confidence interval [CI]: 25-137) and 36 days (95% CI: 25-65). Estimated T1/2 were longer for binding antibodies: 168 (95% CI: 116-303) and 139 days (95% CI: 113-180), respectively. Both binding and neutralizing antibodies were strongly correlated to VE (r = 0.83 and 0.89). However, binding and neutralizing antibodies were modestly correlated, and a high proportion of subjects (36.7%) with high binding antibody titers (i.e., >8434 BAU/ml) did not have neutralizing activity. A considerable decay of the humoral response was observed 6 months after the booster, and was strongly correlated with VE. Our study also shows that commercial assays available in clinical laboratories might require adaptation to better predict neutralization in the Omicron era.