ABSTRACT
Background: In mid-November 2021, the SARS-CoV-2 Omicron BA.1 variant was detected in Southern Africa, prompting international travel restrictions of unclear effectiveness that exacted a substantial economic toll. Methods: Amidst the BA.1 wave, we tested 13,294 COVID-19 patients in 24 African countries between mid-2021 to early 2022 for BA.1 and Delta variants using real-time reverse transcription-PCR tests. The diagnostic precision of the assays was evaluated by high-throughput sequencing in four countries. The observed BA.1 spread was compared to mobility-based mathematical simulations. Findings: By November-December 2021, BA.1 had replaced the Delta variant in all African sub-regions following a South-North gradient, with a median Rt of 2.4 up to 30 days before BA.1 became predominant. PCR-based South-North spread was in agreement with phylogeographic reconstructions relying on 939 SARS-CoV-2 genomes from GISAID. PCR-based reconstructions of country-level BA.1 predominance correlated significantly in time with the emergence of BA.1 genomic sequences on GISAID (p=0.0035, cor=0.70). First BA.1 detections in affluent settings beyond Africa were predicted adequately in time by mobility-based mathematical simulations (p<0.0001). BA.1-infected inbound travelers departing from five continents were identified in five Western countries and one Northern African country by late November/early December 2021, highlighting fast global BA.1 spread aided by international travel. Interpretation: Unilateral travel bans were poorly effective because by the time they came into effect, BA.1 was already widespread in Africa and beyond. PCR-based variant typing combined with mobility-based mathematical modelling can inform rapidly and cost-efficiently on Rt, spread to inform non-pharmaceutical interventions.
Subject(s)
COVID-19ABSTRACT
Since the start of the SARS-CoV-2 pandemic, the search for antiviral therapies has been at the forefront of medical research. To date, the 3CLpro inhibitor nirmatrelvir (Paxlovid(R)) has shown the best results in clinical trials and the greatest robustness against variants. A second SARS-CoV-2 protease inhibitor, ensitrelvir (Xocova(R)), has been developed. Ensitrelvir, currently in Phase 3, was approved in Japan under the emergency regulatory approval procedure in November 2022, and is available since March 31, 2023. One of the limitations for the use of antiviral monotherapies is the emergence of resistance mutations. Here, we experimentally generated mutants resistant to nirmatrelvir and ensitrelvir in vitro following repeating passages of SARS-CoV-2 in the presence of both antivirals. For both molecules, we demonstrated a loss of sensitivity for resistance mutants in vitro. Using a Syrian golden hamster infection model, we showed that the ensitrelvir M49L mutation confers a high level of in vivo resistance. Finally, we identified a recent increase in the prevalence of M49L-carrying sequences, which appears to be associated with multiple repeated emergence events in Japan and may be related to the use of Xocova(R) in the country since November 2022. These results highlight the strategic importance of genetic monitoring of circulating SARS-CoV-2 strains to ensure that treatments administered retain their full effectiveness. HighlightsO_LISARS-CoV-2 resistant strains to clinical stage protease inhibitors have been generated after 16 passages in vitro C_LIO_LIThe ensitrelvir resistance mutation M49L induces a strong resistance to ensitrelvir in vitro in three different isolates C_LIO_LIM49L mutation alone renders ensitrelvir treatment ineffective in vivo C_LIO_LIThe prevalence of naturally occurring M49L-mutants has increased over recent months C_LI
ABSTRACT
Unlike genomic data, serological data have not been previously leveraged to evaluate the SARS-CoV-2 variants circulation. In Bolivia, sustained genomic surveillance capacities were lacking especially at the beginning of the pandemic. In 2021 and 2022 we estimated the prevalence of anti-SARS-CoV-2 antibodies in Bolivian blood donors and explored the feasibility of using virus serum neutralization data for variants thought to have circulated to map their circulation across all departments over a year-long follow-up period. Anti-S1 and anti-NCP SARS-CoV-2 IgGs were studied, along with virus neutralization tests for ancestral-D614G, Gamma, Delta, and Omicron BA.1 lineages of SARS-CoV-2. Between 2021 and 2022, the overall prevalence of anti-S1 and anti-NCP antibodies increased reaching values over 90%, demonstrating that a large proportion of the Bolivian population was no longer naive to the virus. Viral neutralization data, analyzed through multiple approaches, revealed the spread of the Gamma variant up to 2021, particularly impacting northern departments. In 2022, Gamma continued to circulate in southernmost departments of the country and the emergence of Omicron BA.1 was detected. These trends align with publicly available genomic data from neighboring countries. Our serological analyses successfully identified both new antigenic groups, such as Omicron BA.1, and individual variants related to previously circulating groups, such as Delta. The study contributes insights into overall population immunity to SARS-CoV-2 and variant-specific immunity levels across different regions of Bolivia. It also emphasizes the potency of seroprevalence studies in informing public health decisions and underscore their value in capturing the initial phases of emerging epidemics when variant diversity is limited, facilitating timely genomic surveillance setup.
ABSTRACT
COVID-19 serological tests with a "positive", "intermediate" or "negative" result according to predefined thresholds cannot be directly interpreted as a probability of having been infected with SARS-CoV-2. Based on 81,797 continuous anti-spike tests collected in France after the first wave, a Bayesian mixture model was developed to provide a tailored infection probability for each participant. Depending on the serological value and the context (age and administrative region), a negative or a positive test could correspond to a probability of infection as high as 61.9% or as low as 68.0%, respectively. In infected individuals, the model estimated a proportion of "non-responders" of 14.5% (95% CI, 11.2-18.1%), corresponding to a sub-group of persons who exhibited a weaker serological response to SARS-CoV-2. This model allows for an individual interpretation of serological results as a probability of infection, depending on the context and without any notion of threshold.
Subject(s)
COVID-19 , Bunion, Tailor'sABSTRACT
The SARS-CoV2 Omicron variants have acquired new Spike mutations leading to escape from the most of the currently available monoclonal antibody treatments reducing the options for patients suffering from severe Covid-19. Recently, both in vitro and in vivo data have suggested that Sotrovimab could retain partial activity against recent omicron sub-lineage such as BA.5 variants, including BQ.1.1. Here we report full efficacy of Sotrovimab against BQ.1.1 viral replication as measure by RT-qPCR in a non-human primate challenge model.
Subject(s)
COVID-19ABSTRACT
The successive emergence of SARS-CoV-2 Omicron variants has completely changed the modalities of use of therapeutic monoclonal antibodies. Recent in vitro studies indicated that only Sotrovimab has maintained partial activity against BQ.1.1, a sub-variant of BA.5 that is spreading in the USA and Europe. In the present study, we used the hamster model to determine whether Sotrovimab retains antiviral activity against BQ.1.1 in vivo. Our results show that at exposures consistent with those observed in humans, Sotrovimab remains active against BQ.1.1 variant, although at a lower level than that observed against the first globally dominant BA.1 and BA.2 Omicron sublineages.
ABSTRACT
The landscape of SARS-CoV-2 variants dramatically diversified with the simultaneous appearance of multiple sub-variants originating from BA.2, BA.4 and BA.5 Omicron sub-lineages. They harbor a specific set of mutations in the spike that can make them more evasive to therapeutic monoclonal antibodies. In this study, we compared the neutralizing potential of monoclonal antibodies against the Omicron BA.2.75.2, BQ.1, BQ.1.1 and XBB variants, with a pre-Omicron Delta variant as a reference. Sotrovimab retains some activity against BA.2.75.2, BQ.1 and XBB as it did against BA.2/BA.5, but is less active against BQ.1.1. Within the Evusheld/AZD7442 cocktail, Cilgavimab lost all activity against all subvariants studied, resulting in loss of Evusheld activity. Finally, Bebtelovimab, while still active against BA.2.75, also lost all neutralizing activity against BQ.1, BQ.1.1 and XBB variants.
ABSTRACT
Background Households are specific transmission settings, as they involve close and repeated contacts between individuals of different generations. Household surveys provide a unique opportunity to better understand SARS-CoV-2 transmission and the role of individual characteristics. Here, we assessed the risk of SARS-CoV-2 acquisition from household and community exposure according to age, family ties, and socioeconomic and living conditions using data from the nationwide population-based EpiCov cohort/ORCHESTRA collaboration in November-December 2020. Methods A history of SARS-CoV-2 infection was defined by a positive Euroimmun Anti-SARS-CoV-2 ELISA IgG result in November-December 2020. We applied stochastic chain binomial models fitted to the final distribution of infections in households to data from 17,983 individuals [≥]5 years enrolled from 8,165 households. Models estimated the competing risks of being infected from community and household exposure. Results Young adults aged 18-24 years had the highest risk of extra-household infection (8.9%, [95% credible interval, Crl]: 7.5 - 10.4), whereas the oldest (>75) and the youngest (6 - 10) had the lowest risk, 2.6% (1.8 - 3.5) and 3.4% (1.9 - 5.2), respectively. Extra-household infection was also independently associated with socioeconomic conditions. Within households, the probability of person-to-person transmission increased with age: 10.6% (5.0 - 17.9) among 6-10-year-olds to 43.1% (32.6 - 53.2) among 65-74-year-olds. It was higher between partners 29.9% (25.6 - 34.3) and from mother to child 29.1% (21.4 - 37.3) than between individuals related by other family ties. Conclusion In 2020 in France, the main factors identified for extra-household infection were age and socioeconomic conditions. Intra-household infection mainly depended on age and family ties.
Subject(s)
COVID-19ABSTRACT
Background: Efficacy of COVID-19 convalescent plasma (CCP) in COVID-19 pneumonia is uncertain. Early transfusion of high antibody titre CCP may be beneficial, especially in case of underlying immunosuppression. Methods: The CORIPLASM study was a multicentric, open-label, Bayesian randomised clinical trial evaluating the efficacy of CCP in patients with moderate COVID-19 pneumonia, including patients with underlying immunosuppression. Patients hospitalised with COVID-19 for less than 9 days were assigned to receive 2 plasma units/day over 2 days (CCP) or usual care (UC) alone. Primary outcomes were the proportion of patients with a WHO-Clinical Progression Score (CPS) >= 6 on the 10-point scale on day 4 and survival without ventilation or additional immunomodulatory treatment by day 14. Main analysis was conducted on the whole population and a planned subgroup analysis was performed according to immunosuppression status. Findings: A total of 120 patients were recruited between April 16, 2020, and April 21, 2021, and assigned to CCP (n=60) or UC (n=60) with a 28 day-follow-up. The median time from symptoms onset to randomisation (days) was 7.0 [interquartile range (IQR) 5.0-9.0] and 7.0 [IQR 4.0-8.5] in CCP and UC, respectively. Thirteen (22%) patients with CCP had a WHO-CPS >= 6 at day 4 versus 8 (13%) with UC, adjusted odds ratio (aOR) 1.88 [95% confidence interval (CI), 0.71 to 5.24]. By d14, 19 (31.6%) patients with CCP and 20 (33.3%) patients with UC had ventilation, additional immunomodulatory treatment or had died. Cumulative incidence of death was 3 (5%) with CCP and 8 (13%) with UC at d14 (aHR 0.40 [95%CI 0.10 -1.53]), and 7 (12%) with CCP and 12 (20%) with UC at day 28 (aHR 0.51 [95% CI 0.20-1.32]). Subgroup analysis indicated that CCP might be associated with a lower mortality in patients with underlying immunosuppression (HR 0.37 [95% CI 0.14-0.97]). Serious adverse events were noted in 30 (50%) and 26 (43%) patients with CCP or UC, respectively. Interpretation: CCP treatment did not improve early outcomes in patients with mild-to-moderate form COVID-19 pneumonia but was associated with reduced mortality in the subgroup of immunosuppressed patients. Trial registration: clinicaltrials.gov Identifier: NCT04345991
Subject(s)
Pneumonia , Immunologic Deficiency Syndromes , Death , COVID-19ABSTRACT
SUMMARY We conducted a cross-sectional study for SARS-CoV-2 anti-S1 IgG prevalence in French blood donors (n=32605), from May-2020 to January-2021. A mathematical model combined seroprevalence with daily number of hospital admissions to estimate the probability of hospitalization upon infection and determine the number of infections while correcting for antibody decay. There was an overall seroprevalence increase over the study period and we estimate that ∼15% of the French population had been infected by SARS-CoV-2 by January-2021. The infection/hospitalization ratio increased with age, from 0.56% (18-30yo) to 6.75% (61-70yo). Half of the IgG-S1 positive individuals had no detectable antibodies 4 to 5 months after infection. The seroprevalence in group O donors (7.43%) was lower (p=0.003) than in A, B and AB donors (8.90%). We conclude, based on seroprevalence data and mathematical modelling, that the overall immunity in the French population before the vaccination campaign started was too low to achieve herd immunity.
ABSTRACT
Background. Variant-adaptated vaccines against coronavirus disease 2019 (COVID-19) as boosters are needed to increase a broader protection against SARS CoV-2 variants. New adjuvanted recombinant protein vaccines as heterologous boosters could maximize the response. Methods. In this randomized, single-blinded, multicenter trial, adults who had received two doses of Pfizer-BioNTech mRNA vaccine (BNT162b2) 3 to7 months before were randomly assigned to receive a boost of BNT162b2, Sanofi/GSK SARS-CoV-2 adjuvanted recombinant protein MV D614 (monovalent parental formulation) or SARS-CoV-2 adjuvanted recombinant protein MV B.1.351 vaccine (monovalent Beta formulation). The primary endpoint was the percentage of subjects with a [≥] 10-fold increase in neutralizing antibody titers for the Wuhan (D614) and B.1.351 (Beta) SARS-CoV-2 viral strains between day 0 and day 15. Findings. The percentages of participants whose neutralizing antibody titers against the Wuhan (D614) SARS-CoV-2 strain increased by a factor [≥]10 between day 0 and day 15 was 55.3% (95% CI 43.4-66.7) in MV D614 group (n=76), 76.1% (64.5-85.4) in MV B.1.351 (Beta) group (n=71) and 63.2% (51.3-73.9) in BNT162b2 group (n=76). These percentages were 44.7% (33.3-56.6), 84.5% (74.0-92.0) and 51.3% (39.6-63.0) for the B.1.351 (Beta) viral strain, respectively. Higher neutralizing antibodies rates against Delta and Omicron BA.1 variants were also elicited after Sanofi/GSK MV Beta vaccine compared to the other vaccines. Comparable reactogenicity profile was observed with the three vaccines. Interpretation. Heterologous boosting with the Sanofi/GSK Beta formulation vaccine resulted in a higher neutralizing antibody response against Beta variant but also the original strain and Delta and Omicron BA.1 variants, compared with mRNA BNT162b2 vaccine or the Sanofi/GSK MVD614 formulation. New vaccines containing Beta spike protein may represent an interesting strategy for broader protection against SARS CoV-2 variants.
Subject(s)
COVID-19ABSTRACT
The binding of the SARS-CoV-2 spike to angiotensin-converting enzyme 2 (ACE2) promotes virus entry into the cell. Targeting this interaction represents a promising strategy to generate antivirals. By screening a phage-display library of biosynthetic protein sequences build on a rigid alpha-helicoidal HEAT-like scaffold (named alphaReps), we selected candidates recognizing the spike receptor binding domain (RBD). Two of them (F9 and C2) bind the RBD with affinities in the nM range, displaying neutralisation activity in vitro and recognizing distinct sites, F9 overlapping the ACE2 binding motif. The F9-C2 fusion protein and a trivalent alphaRep form (C2-foldon) display 0.1 nM affinities and EC50 of 8-18 nM for neutralization of SARS-CoV-2. In hamsters, F9-C2 instillation in the nasal cavity before or during infections effectively reduced the replication of a SARS-CoV-2 strain harbouring the D614G mutation in the nasal epithelium. Furthermore, F9-C2 and/or C2-foldon effectively neutralized SARS-CoV-2 variants (including delta and omicron variants) with EC50 values ranging from 13 to 32 nM. With their high stability and their high potency against SARS-CoV-2 variants, alphaReps provide a promising tool for SARS-CoV-2 therapeutics to target the nasal cavity and mitigate virus dissemination in the proximal environment.
ABSTRACT
Recombination is a crucial process in the evolution of many organisms. Although the evolutionary reasons behind its occurrence in RNA viruses are debated, this phenomenon has been associated with major epidemiological events such as virus host range expansion, antigenic shift or variation in virulence 1,2, and this process occurs frequently in positive strand RNA viruses such as coronaviruses. The SARS-CoV-2 pandemic has been associated with the repeated emergence of variants of concern presenting increased transmissibility, severity or immune escape 3. The recent extensive circulation of Delta worldwide and its subsequent replacement by viruses of the Omicron lineage 4 (BA.1 then BA.2), have created conditions for genetic exchanges between viruses with both genetic diversity and phenotypic specificities 5-7. Here we report the identification and in vitro and in vivo characterization of a Delta-Omicron recombinant in Europe. This recombinant exhibits immune escape properties similar to Omicron, while its behavior in mice expressing the human ACE2 receptor is more similar to Delta. This recombinant provides a unique and natural opportunity to better understand the genotype to phenotype links in SARS-CoV-2.
ABSTRACT
The replacement of the Omicron BA.1 variant of SARS-CoV-2 by the BA.2 and the rapid growth of the BA.5 sub lineage, which have both different sets of mutations in the spike glycoprotein, alters the spectrum of activity of therapeutic antibodies currently licensed in the European Union. Using clinical strains of the Omicron BA.2 and BA.5 variants, we compared the neutralising power of monoclonal antibodies against the Omicron BA.1, BA.2 and BA.5 variants, using an ancestral strain (lineage B.1, D614G) and a Delta variant strain as reference. Sotrovimab/Vir-7831 is less active against BA.2 than against BA.1 (fold change reduction ~1,4) and even less active against BA.5 (fold change reduction ~2.7). Within the Evusheld /AZD7442 cocktail, Cilgavimab/AZD1061 is more active against BA.2 and BA.5 than against BA.1 (fold change increase ~32), whilst the very low activity of Tixagevimab/AZD8895 against BA.1 is not enhanced against BA.2 nor BA.5. In total, compared to BA.1, the activity of the Evusheld/AZD7442 is significantly improved against BA.2 and that against BA.5 is intermediate but closer to that against BA.2.
ABSTRACT
The efficacy of pre-exposure prophylaxis by the Tixagevimab/Cilgavimab cocktail (AZD7442) was evaluated in hamsters against a clinical BA.1 strain of SARS-CoV-2 variant Omicron. AZD7442 retains inhibitory activity against Omicron despite a substantial loss of efficacy. We estimate that Omicron virus requires about 20-times more antibodies in plasma than the ancestral B.1 strain (G614) virus to achieve a similar drug efficacy in reducing lung infectious titers.
ABSTRACT
ObjectivesTaste or smell disorders have been reported as strongly associated with COVID-19 diagnosis. We aimed to identify subject characteristics, symptom associations, and humoral response intensity associated with taste or smell disorders. Patients and methodsWe used data from SAPRIS, a study based on a consortium of five prospective cohorts gathering 279,478 participants in the French general population. In the analysis, we selected participants who were presumably infected by SARS-CoV-2 during the first epidemic wave. ResultsThe analysis included 3,439 patients with a positive ELISA-Spike. Sex (OR = 1.28 [95% CI 1.05-1.58] for women), smoking (OR = 1.54 [95% CI 1.13-2.07]), consumption of more than 2 drinks of alcohol a day (OR = 1.37 [95% CI 1.06-1.76]) were associated with a higher probability of taste or smell disorders. The relationship between age and taste or smell disorders was non-linear. Serological titers were associated with taste or smell disorders: OR = 1.31 [95% CI 1.26-1.36], OR = 1.37 [95% CI 1.33-1.42] and OR = 1.34 [95% CI 1.29-1.39] for ELISA-Spike, ELISA-Nucleocapsid and seroneutralization, respectively. Among participants with taste or smell disorders, 90% reported a wide variety of other symptoms whereas 10% reported no other symptom or only rhinorrhea. ConclusionAmong patients with a positive ELISA-Spike test, women, smokers and people drinking more than 2 drinks a day were more likely to develop taste or smell disorders. This symptom was strongly associated with a humoral response. The overwhelming majority of patients with taste or smell disorders experienced a wide variety of symptoms.
Subject(s)
COVID-19 , Olfaction Disorders , Cerebrospinal Fluid Rhinorrhea , Taste DisordersABSTRACT
The emergence and rapid spread of the Omicron variant of SARS-CoV-2, which has more than 30 substitutions in the spike glycoprotein, compromises the efficacy of currently available vaccines and therapeutic antibodies. Using a clinical strain of the Omicron variant, we analyzed the neutralizing power of eight currently used monoclonal antibodies compared to the ancestral B.1 BavPat1 D614G strain. We observed that six of these antibodies have lost their ability to neutralize the Omicron variant. Of the antibodies still having neutralizing activity, Sotrovimab/Vir-7831 shows the smallest reduction in activity, with a factor change of 3.1. Cilgavimab/AZD1061 alone shows a reduction in efficacy of 15.8, resulting in a significant loss of activity for the Evusheld cocktail (42.6 fold reduction) in which the other antibody, Tixagevimab, does not retain significant activity against Omicron. Our results suggest that the clinical efficacy of the initially proposed doses should be rapidly evaluated and the possible need to modify doses or propose combination therapies should be considered.
ABSTRACT
To address the emergence of SARS-CoV-2, multiple clinical trials in humans were rapidly started, including those involving an oral treatment by nitazoxanide, despite no or limited pre-clinical evidence of antiviral efficacy. In this work, we present a complete pre-clinical evaluation of the antiviral activity of nitazoxanide against SARS-CoV-2. First, we confirmed the in vitro efficacy of nitazoxanide and tizoxanide (its active metabolite) against SARS-CoV-2. Then, we demonstrated nitazoxanide activity in a reconstructed bronchial human airway epithelium model. In a SARS-CoV-2 virus challenge model in hamsters, oral and intranasal treatment with nitazoxanide failed to impair viral replication in commonly affected organs. We hypothesized that this could be due to insufficient diffusion of the drug into organs of interest. Indeed, our pharmacokinetic study confirmed that concentrations of tizoxanide in organs of interest were always below the in vitro EC50. These preclinical results suggest, if directly applicable to humans, that the standard formulation and dosage of nitazoxanide is not effective in providing antiviral therapy for Covid-19.