Protection against symptomatic SARS-CoV-2 BA.5 infection conferred by the Pfizer-BioNTech Original/BA.4-5 bivalent vaccine compared to the mRNA Original (ancestral) monovalent vaccines - a matched cohort study in France (preprint)

This cohort study aimed to evaluate the protection against symptomatic SARS-CoV-2 infection conferred by the Pfizer-BioNTech Original/BA.4-5 bivalent vaccine compared to mRNA Original (ancestral) monovalent vaccines. Individuals of [≥]60 years old who received a booster dose between 03/10/2022 and 06/11/2022, when both the bivalent and monovalent vaccines were used in France, were included. Individuals who received a booster dose with (1) a monovalent Original mRNA vaccine (Pfizer- BioNTech or Moderna) or (2) the bivalent Pfizer-BioNTech Original/BA.4-5 vaccine were matched. The outcome of interest was a positive SARS-CoV-2 RT-PCR or antigenic test associated to self-reported symptoms, at least seven days after receiving the booster dose. Data were analysed with a Cox Proportional-Hazards model adjusted for the presence of previous infection, age, sex, and the presence of medium risk comorbidities. A total of 136852 individuals were included and followed for a median period of 77days. The bivalent vaccine conferred an additional protection of 8% [95% CI: 0% - 16%, p=0.045] against symptomatic SARS-CoV-2 infection compared to the monovalent vaccines.

Effectiveness of second booster compared to first booster and protection conferred by previous SARS CoV-2 infection against symptomatic Omicron BA.2 and BA.4/5 in France (preprint)

In face of evidence of rapid waning of vaccine effectiveness against Omicron and its sub-lineages, a second booster with mRNA vaccines was recommended for the most vulnerable in France. We used a test negative design to estimate the effectiveness of the second booster relative to the first booster and the protection conferred by a previous SARS-CoV-2 infection, against symptomatic Omicron BA.2 or BA.4/5. We included symptomatic ≥60 years old individuals tested for SARS-CoV-2 in March 21-October 30, 2022. Compared to a 181-210 days old first booster, a second booster restored protection with an effectiveness of 39% [95%CI: 38% - 41%], 7-30 days post-vaccination This gain in protection was lower than the one observed with the first booster, at equal time points since vaccination. High levels of protection were associated to previous SARS-CoV-2 infection, especially if the infection was recent and occurred when an antigenic-related variant was dominant.

Risk of SARS-CoV-2 reinfection is time- and variant-dependant, France, January 2021 to August 2022 (preprint)

Since the emergence of Omicron, reinfections with SARS-CoV-2 have been rising. We estimated the risk of SARS-CoV-2 reinfection in the widely vaccinated French population, from January to August 2022. At nine weeks post-infection, the relative risk of reinfection, primary infection with pre-Delta variants being the reference group, was estimated at 0.43 [95%CI 0.40-0.47] if the primary infection was attributed to Delta, 0.21% [95%CI 0.19-0.24] with BA.1 and 0.17% [95% CI 0.15-0.18] with BA.2, and rapidly waned overtime. After a BA.1 primary infection the protection was similar against BA.2 or BA.4/5 reinfection.

Serious hospital events following symptomatic infection with Sars-CoV-2 Omicron and Delta variants: an exposed-unexposed cohort study in December 2021 from the COVID-19 surveillance databases in France (preprint)

Background: A rapid increase in incidence of the SARS-CoV-2 Omicron variant in France in December 2021, while the Delta variant was prevailing since July 2021. Aim: To determine whether the risk of occurrence of a serious hospital event in adults following symptomatic SARS-CoV-2 infection differs for Omicron versus Delta. Methods: A retrospective cohort study from 06/12/2021 to 07/01/2022. The outcome was a serious hospital event (admission to intensive care unit OR admission to critical care unit OR death). Omicron and Delta symptomatic cases were matched on the week of virological diagnosis and on age. Risk was adjusted for age, sex, vaccination status, presence of comorbidity and region of residence using Cox proportional-hazards model. Results: 149,064 cases were included of which 497 had a serious hospital event (447 in the Delta arm, 50 in the Omicron arm). The risk of serious event was lower among Omicron versus Delta cases (adjusted Hazard Ratio, aHR=0.13 CI95 0.09-0.18 in 18 to 79 yo, aHR=0.30 CI95 0.17-0.54 in 80+ yo). The risk increased sharply with age and was lower in vaccinated compared to unvaccinated, without interaction between variant and vaccination status (aHR=0.15 CI95 0.11-0.19 for 18-79 yo with primary vaccination versus unvaccinated), was higher in cases with comorbidities (aHR = 3.70 CI95 2.66-5.13 fort 18-79 yo with very-high-risk comorbidity versus no comorbidity) and in males. Conclusion: This study confirms the lower severity of Omicron. The vaccine protection is essential in the elderly as they have a high risk of severe hospital events following infection with Omicron, even if much this risk is lower than with Delta.

Head-to-head comparison of direct-input RT-PCR and RT-LAMP against RTqPCR on extracted RNA for rapid SARS-CoV-2 diagnostics (preprint)

Viral pandemics, such as Covid-19, pose serious threats to human societies. To control the spread of highly contagious viruses such as SARS-CoV-2, effective test-trace-isolate strategies require population-wide, systematic testing. Currently, RT-qPCR on extracted RNA is the only broadly accepted test for SARS-CoV-2 diagnostics, which bears the risk of supply chain bottlenecks, often exaggerated by dependencies on proprietary reagents. Here, we directly compare the performance of gold standard diagnostic RT-qPCR on extracted RNA to direct input RT-PCR, RT-LAMP and bead-LAMP on 384 primary patient samples collected from individuals with suspected Covid-19 infection. With a simple five minute crude sample inactivation step and one hour of total reaction time, we achieve assay sensitivities of 98% (direct RT-PCR), 93% (bead-LAMP) and 82% (RTLAMP) for clinically relevant samples (diagnostic RT-qPCR Ct <35) and a specificity of >98%. For direct RT-PCR, our data further demonstrate a perfect agreement between real-time and end-point measurements, which allow a simple binary classification similar to the powerful visual readout of colorimetric LAMP assays. Our study provides highly sensitive and specific, easy to implement, rapid and cost-effective alternatives to diagnostic RT-qPCR tests.

SARSeq, a robust and highly multiplexed NGS assay for parallel detection of SARS-CoV2 and other respiratory infections (preprint)

During a pandemic, mitigation as well as protection of system-critical or vulnerable institutions requires massive parallel, yet cost effective testing to monitor the spread of agents such as the current SARS-CoV2 virus. Here we present SARSeq, saliva analysis by RNA sequencing, as an approach to monitor presence of SARS-CoV2 and other respiratory viruses performed on tens of thousands of samples in parallel. SARSeq is based on next generation sequencing of multiple amplicons generated in parallel in a multiplexed RT-PCR reaction. It relies on a two-dimensional unique dual indexing strategy using four indices in total for unambiguous and scalable assignment of reads to individual samples. We calibrated this method using dilutions of synthetic RNA and virions to show sensitivity down to few molecules, and applied it to hundreds of patient samples validating robust performance across various sample types. Double blinded benchmarking to gold-standard quantitative RT-PCR performed in a clinical setting and a human diagnostics laboratory showed robust performance up to a Ct of 36. The false positive rate, likely due to cross contamination during sample pipetting, was estimated at 0.04-0.1%. In addition to SARS-CoV2, SARSeq detects Influenza A and B viruses as well as human rhinovirus and can be easily expanded to include detection of other pathogens. In sum, SARSeq is an ideal platform for differential diagnostic of respiratory diseases at a scale, as is required during a pandemic.