Bacillus Calmette-Guerin vaccine to reduce COVID-19 infections and hospitalisations in healthcare workers: a living systematic review and prospective ALL-IN meta-analysis of individual participant data from randomised controlled trials (preprint)

BACKGROUND: The objective is to determine the impact of the Bacillus Calmette-Guerin (BCG) vaccine compared to placebo or no vaccine on COVID-19 infections and hospitalisations in healthcare workers. We are using a living and prospective approach to Individual-Participant-Data (IPD) meta-analysis of ongoing studies based on the Anytime Live and Leading Interim (ALL-IN) meta-analysis statistical methodology. METHODS: Planned and ongoing randomised controlled trials were identified from trial registries and by snowballing (final elicitation: Oct 3 2022). The methodology was specified prospectively -- with no trial results available -- for trial inclusion as well as statistical analysis. Inclusion decisions were made collaboratively based on a risk-of-bias assessment by an external protocol review committee (Cochrane risk-of-bias tool adjusted for use on protocols), expected homogeneity in treatment effect, and agreement with the predetermined event definitions. The co-primary endpoints were incidence of COVID-19 infection and COVID-19-related hospital admission. Accumulating IPD from included trials was analysed sequentially using the exact e-value logrank test (at level alpha = 0.5% for infections and level alpha = 4.5% for hospitalisations) and anytime-valid 95%-confidence intervals (CIs) for the hazard ratio (HR) for a predetermined fixed-effects approach to meta-analysis (no measures of statistical heterogeneity). Infections were included if demonstrated by PCR tests, antigen tests or suggestive lung CTs. Participants were censored at date of first COVID-19-specific vaccination and two-stage analyses were performed in calendar time, with a stratification factor per trial. RESULTS: Six trials were included in the primary analysis with 4 433 participants in total. The e-values showed no evidence of a favourable effect of minimal clinically relevance (HR < 0.8) in comparison to the null (HR = 1) for COVID-19 infections, nor for COVID-19 hospitalisations (HR < 0.7 vs HR = 1). COVID-19 infection was observed in 251 participants receiving BCG and 244 participants not receiving BCG, HR 1.02 (anytime-valid 95%-CI 0.78-1.35). COVID-19 hospitalisations were observed in 13 participants receiving BCG and 7 not receiving BCG, resulting in an uninformative estimate (HR 1.88; anytime-valid 95%-CI 0.26-13.40). DISCUSSION: It is highly unlikely that BCG has a clinically relevant effect on COVID-19 infections in healthcare workers. With only limited observations, no conclusion could be drawn for COVID-19 related hospitalisation. Due to the nature of ALL-IN meta-analysis, emerging data from new trials can be included without violating type-I error rates or interval coverage. We intend to keep this meta-analysis alive and up-to-date, as more trials report. For COVID-19 related hospitalisations, we do not expect enough future observations for a meaningful analysis. For BCG-mediated protection against COVID-19 infections, on the other hand, more observations could lead to a more precise estimate that concludes the meta-analysis for futility, meaning that the current interval excludes the HR of 0.8 predetermined as effect size of minimal clinical relevance. OTHER: No external funding. Preregistered at PROSPERO: CRD42021213069.

Safety and immunogenicity of a variant-adapted SARS-CoV-2 recombinant protein vaccine with AS03 adjuvant as a booster in adults primed with authorized vaccines (preprint)

Background Booster vaccines providing protection against emergent SARS-CoV-2 variants are needed. In an international phase 3 study, we evaluated booster vaccines containing prototype (D614) and/or Beta (B.1.351) variant recombinant spike proteins and AS03 adjuvant (CoV2 preS dTM-AS03). Methods Adults, primed 4-10 months earlier with mRNA (BNT162b2, mRNA-1273]), adenovirus-vectored (Ad26.CoV2.S, ChAdOx1nCoV-19) or adjuvanted protein (CoV2 preS dTM-AS03 [D614]) vaccines and stratified by age (18-55 and [≥]56 years), were boosted with monovalent (MV) D614 (5[≥]g, n=1285), MV (B.1351) (5g, n=707) or bivalent (BiV) (2.5[≥]g D614 plus 2.5[≥]g B.1.351, n=625) CoV2 preS dTM-AS03. SARS-CoV-2-naive adults (controls, n=479) received a primary series (two injections, 21 days apart) of CoV2 preS dTM-AS03 containing 10g D614. Antibodies to D614G, B.1.351 and Omicron BA.2 and BA.1 variants were evaluated using validated pseudovirus (lentivirus) neutralization (PsVN) assay. D614G or B.1.351 PsVN titers 14 days (D15) post-booster were compared with pre-booster (D1) titers in BNT162b2-primed participants (18-55 years old) and controls (D36), for each booster formulation (co-primary objectives). Safety was evaluated throughout the trial. Results of a planned interim analysis are presented. Results Among BNT162b2-primed adults (18-55 years old), PsVN titers against D614G or B.1.351 were significantly higher post-booster than anti-D614G titers post-primary vaccination in controls, for all booster formulations, with an anti-D614G GMT ratio (98.3% CI) of 2.16 (1.69; 2.75) for MV(D614), an anti-B.1.351 ratio of 1.96 (1.54; 2.50) for MV (B.1.351) and anti-D614G and anti-B.1.351 ratios of 2.34 (1.84; 2.96) and 1.39 (1.09; 1.77), respectively, for BiV. All booster formulations elicited cross-neutralizing antibodies against Omicron BA.2 across vaccine priming subgroups and against Omicron BA.1 (evaluated in BNT162b2-primed participants). Similar patterns in antibody responses were observed for participants aged [≥]56 years. No safety concerns were identified. Conclusion CoV2 preS dTM-AS03 boosters demonstrated acceptable safety and elicited robust neutralizing antibodies against multiple variants, regardless of priming vaccine. ClinicalTrials.gov: NCT04762680

Intentions to get vaccinated against Monkeypox in Healthcare workers in France and Belgium correlates with attitudes toward COVID-19 vaccination (preprint)

Abstract text Background Front-line healthcare workers (HCWs) could be at-risk for Monkeypox infections. Vaccine hesitancy also affects HCWs and has an impact on their own attitudes toward vaccination. In the context of the exhaustion due to COVID-19 pandemic, we aimed to evaluate intentions to get vaccinated against Monkeypox in HCWs in France and Belgium. Methods We performed a cross-sectional study (snowball sampling) using a self-administered online questionnaire to evaluate intentions to get vaccinated against Monkeypox in HCWs if a recommendation for HCWs vaccination was made. We compared demographics characteristics, vaccine readiness, eagerness for COVID-19 vaccine, and confidence in HCW with Chi-square tests, student-t and performed a binary regression. Results Amon the 397 respondents, if a specific recommendation was made for HCWs vaccination against Monkeypox was made, 55.4 % will probably get the vaccine, while 79 % would accept the vaccine if recommended to the general population. COVID-19 vaccine eagerness and having concerns about Monkeypox epidemics were associated with favorable attitude toward Monkeypox vaccination in HCWs with respective adjusted odds ratio and 95 % Confidence Interval 2.5 (1.03-6.1), 2.6 (1.3-5.3). Forty-four HCWs (11 %) self-identified as at-risk for Monkeypox infections. Conclusion Acceptance of Monkeypox vaccination in HCWs is probably moderate, HCWs are probably complacent and did not perceive the risk of Monkeypox infections in the context of professional exposure.

Immunogenicity and Safety of Beta Adjuvanted Recombinant Booster Vaccine (preprint)

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.

An open-label randomized, controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a and hydroxychloroquine in hospitalized patients with COVID-19 – Final results from the DisCoVeRy trial (preprint)

Objectives We evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in COVID-19 inpatients requiring oxygen and/or ventilatory support. While preliminary results were previously published, we present here the final results, following completion of the data monitoring. Methods We conducted a phase 3 multi-centre open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), add-on trial to Solidarity ( NCT04315948 , EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens, pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, which were stopped prematurely. Results The intention-to-treat population included 593 participants (lopinavir/ritonavir, n=147; lopinavir/ritonavir-IFN-β-1a, n=147; hydroxychloroquine, n=150; control, n=149), among whom 421 (71.0%) were male, the median age was 64 years (IQR, 54-71) and 214 (36.1%) had a severe disease. The day 15 clinical status was not improved with investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.82, (95% confidence interval [CI] 0.54-1.25, P=0.36); lopinavir/ritonavir-IFN-β-1a versus control, aOR 0.69 (95%CI 0.45-1.05, P=0.08); hydroxychloroquine versus control, aOR 0.94 (95%CI 0.62-1.41, P=0.76). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of Serious Adverse Events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms. Conclusion In adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-ß-1a and hydroxychloroquine did not improve the clinical status at day 15, nor SARS-CoV-2 clearance in respiratory tract specimens.

Public opinion on a mandatory COVID-19 vaccination policy in France: a cross sectional survey (preprint)

Objectives Reaching the last pockets of unvaccinated people is challenging, and has led to consider COVID-19 mandatory vaccination. Our aim was to assess attitudes toward COVID-19 mandatory vaccination in France before the announcement and factors associated with opposition to this type of policy. Methods Between the 10th and the 23rd of May 2021, we conducted a cross-sectional online survey among a representative sample of the French population aged 18 and over and a specific sample of the French Senior Population over 65. Results Among 3,056 respondents, 1,314 (43.0 %) were in favor of mandatory COVID-19 vaccination, 1,281 (41.9 %) were opposed to such a policy, and 461 (15.1 %) were undecided. Among opponents to COVID-19 mandatory vaccination for the general population, 385 (30.05 %) were in favor of a mandatory COVID-19 vaccination for healthcare workers (HCWs). In multivariate analysis, age groups 18-24 years, and 25-34 years were significantly more opposed than the reference group (>75 years old) with respective adjusted odds ratio (aOR) and 95 % confidence interval (95 % CI) 4.67 (1.73-12.61) and 3.74 (1.57-8.93). No intention of getting COVID-19 vaccine was strongly associated with opposition to mandatory vaccination with aOR 10.67 (95 % CI 6.41-17.76). In comparison with partisans of the center, partisans of the far left and green parties were more likely to be opposed to COVID-19 mandatory vaccine with respective aOR (95 % CI) 1;89 (1.06-3.38) and 2.08 (1.14-3.81). Conclusion Attitudes toward mandatory COVID-19 vaccination are split in the French general population, and the debate might become politicized.

Antiviral drugs in hospitalized patients with COVID-19 - the DisCoVeRy trial (preprint)

Background: Lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-beta-1a and hydroxychloroquine efficacy for COVID-19 have been evaluated, but detailed evaluation is lacking. Objective: To determine the efficacy of lopinavir/ritonavir, lopinavir/ritonavir-IFN-beta-1a, hydroxychloroquine or remdesivir for improving the clinical, virological outcomes in COVID-19 inpatients. Design: Open-label, randomized, adaptive, controlled trial. Setting: Multi-center trial with patients from France. Participants: 583 COVID-19 inpatients requiring oxygen and/or ventilatory support Intervention: Standard of care (SoC, control), SoC plus lopinavir/ritonavir (400 mg lopinavir and 100 mg ritonavir every 12h for 14 days), SoC plus lopinavir/ritonavir plus IFN-beta-1a (44 micrograms of subcutaneous IFN-beta-1a on days 1, 3, and 6), SoC plus hydroxychloroquine (400 mg twice on day 1 then 400 mg once daily for 9 days) or SoC plus remdesivir (200 mg intravenously on day 1 then 100 mg once-daily for hospitalization duration or 10 days). Measurements: The primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens and safety analyses. Results: Adjusted Odds Ratio (aOR) for the WHO 7-point ordinal scale were not in favor of investigational treatments: lopinavir/ritonavir versus control, aOR 0.83, 95%CI, 0.55 to 1.26, P=0.39; lopinavir/ritonavir-IFN-beta-1a versus control, aOR 0.69, 95%CI, 0.45 to 1.04, P=0.08; hydroxychloroquine versus control, aOR 0.93, 95%CI, 0.62 to 1.41, P=0.75. No significant effect on SARS-CoV-2 RNA clearance in respiratory tract was evidenced. Lopinavir/ritonavir-containing treatments were significantly associated with more SAE. Limitations: Not a placebo-controlled, no anti-inflammatory agents tested. Conclusion: No improvement of the clinical status at day 15 nor SARS-CoV-2 RNA clearance in respiratory tract specimens by studied drugs. This comforts the recent Solidarity findings. Registration: NCT04315948. Funding: PHRC 2020, Dim OneHealth, REACTing

Assessment of spread of SARS-CoV-2 by RT-PCR and concomitant serology in children in a region heavily affected by COVID-19 pandemic (preprint)

Background. Several studies indicated that children seem to be less frequently infected with SARS-CoV-2 and potentially less contagious. To examine the spread of SARS-CoV-2 we combined both RT-PCR testing and serology in children in the most affected region in France, during the COVID-19 epidemic. Methods. From April 14, 2020 to May 12, 2020, we conducted a cross-sectional prospective, multicenter study. Healthy controls and pauci-symptomatic children from birth to age 15 years were enrolled by 27 ambulatory pediatricians. A nasopharyngeal swab was taken for detection of SARS-CoV-2 by RT-PCR and a microsample of blood for micro-method serology. Results. Among the 605 children, 322 (53.2%) were asymptomatic and 283 (46.8%) symptomatic. RT-PCR testing and serology were positive for 11 (1.8%) and 65 (10.7%) of all children, respectively. Only 3 children were RT-PCR-positive without any antibody response have been detected. The frequency of positivity on RT-PCR for SARS-CoV-2 was significantly higher in children with positive serology than those with a negative one (12.3% vs 0.6%, p<0.001). Contact with a person with proven COVID-19 increased the odds of positivity on RT-PCR (OR 7.8, 95% confidence interval [1.5; 40.7]) and serology (15.1 [6.6; 34.6]). Conclusion. In area heavily affected by COVID-19, after the peak of the first epidemic wave and during the lockdown, the rate of children with positive SARS-CoV-2 RT-PCR was very low (1.8%), but the rate of positive on serology was higher (10.7%). Most of PCR positive children had at the same time, positive serology suggesting a low risk of transmission.