Estimating SARS-CoV-2 infection probabilities with serological data and a Bayesian mixture model.

The individual results of SARS-CoV-2 serological tests measured after the first pandemic wave of 2020 cannot be directly interpreted as a probability of having been infected. Plus, these results are usually returned as a binary or ternary variable, relying on predefined cut-offs. We propose a Bayesian mixture model to estimate individual infection probabilities, based on 81,797 continuous anti-spike IgG tests from Euroimmun collected in France after the first wave. This approach used serological results as a continuous variable, and was therefore not based on diagnostic cut-offs. Cumulative incidence, which is necessary to compute infection probabilities, was estimated according to age and administrative region. In France, we found that a "negative" or a "positive" test, as classified by the manufacturer, could correspond to a probability of infection as high as 61.8% or as low as 67.7%, respectively. "Indeterminate" tests encompassed probabilities of infection ranging from 10.8 to 96.6%. Our model estimated tailored individual probabilities of SARS-CoV-2 infection based on age, region, and serological result. It can be applied in other contexts, if estimates of cumulative incidence are available.

Serum and Salivary IgG and IgA Response After COVID-19 Messenger RNA Vaccination.

Importance: There is still considerable controversy in the literature regarding the capacity of intramuscular messenger RNA (mRNA) vaccination to induce a mucosal immune response. Objective: To compare serum and salivary IgG and IgA levels among mRNA-vaccinated individuals with or without previous SARS-CoV-2 infection. Design, Setting, and Participants: In this cohort study, SARS-CoV-2-naive participants and those with previous infection were consecutively included in the CoviCompare P and CoviCompare M mRNA vaccination trials and followed up to day 180 after vaccination with either the BNT162b2 (Pfizer-BioNTech) vaccine or the mRNA-1273 (Moderna) vaccine at the beginning of the COVID-19 vaccination campaign (from February 19 to June 8, 2021) in France. Data were analyzed from October 25, 2022, to July 13, 2023. Main Outcomes and Measures: An ultrasensitive digital enzyme-linked immunosorbent assay was used for the comparison of SARS-CoV-2 spike-specific serum and salivary IgG and IgA levels. Spike-specific secretory IgA level was also quantified at selected times. Results: A total of 427 individuals were included in 3 groups: participants with SARS-CoV-2 prior to vaccination who received 1 single dose of BNT162b2 (Pfizer-BioNTech) (n = 120) and SARS-CoV-2-naive individuals who received 2 doses of mRNA-1273 (Moderna) (n = 172) or 2 doses of BNT162b2 (Pfizer-BioNTech) (n = 135). The median age was 68 (IQR, 39-75) years, and 228 (53.4%) were men. SARS-CoV-2 spike-specific IgG saliva levels increased after 1 or 2 vaccine injections in individuals with previous infection and SARS-CoV-2-naive individuals. After vaccination, SARS-CoV-2-specific saliva IgA levels, normalized with respect to total IgA levels, were significantly higher in participants with previous infection, as compared with the most responsive mRNA-1273 (Moderna) recipients (median normalized levels, 155 × 10-5 vs 37 × 10-5 at day 29; 107 × 10-5 vs 54 × 10-5 at day 57; and 104 × 10-5 vs 70 × 10-5 at day 180 [P < .001]). In contrast, compared with day 1, spike-specific IgA levels in the BNT162b2-vaccinated SARS-CoV-2-naive group increased only at day 57 (36 × 10-5 vs 49 × 10-5 [P = .01]). Bona fide multimeric secretory IgA levels were significantly higher in individuals with previous infection compared with SARS-CoV-2-naive individuals after 2 antigenic stimulations (median optical density, 0.36 [IQR, 0.16-0.63] vs 0.16 [IQR, 0.10-0.22]; P < .001). Conclusions and Relevance: The findings of this cohort study suggest that mRNA vaccination was associated with mucosal immunity in individuals without prior SARS-CoV-2 infection, but at much lower levels than in previously infected individuals. Further studies are needed to determine the association between specific saliva IgA levels and prevention of infection or transmission.

First detection of Jingmen tick virus in Corsica, France and development of a real time detection system for multiple tick-associated jingmenviruses.

Jingmen tick virus (JMTV) is a recently discovered segmented RNA virus, closely related to flaviviruses. It was identified for the first time in 2014, in China and subsequently in Brazil. Following this discovery, JMTV-related sequences have been identified in arthropods, vertebrates (including humans), plants, fungus and environmental samples from Asia, America, Africa, Europe and Oceania. Several studies suggest an association between these segmented flavi-like viruses, termed jingmenviruses, and febrile illness in humans. The development of rapid diagnostic assays for these viruses is therefore crucial to be prepared for a potential epidemic, for the early detection of these viruses via vector surveillance or hospital diagnosis. In this study, we designed a RT-qPCR assay to detect tick-associated jingmenviruses, validated it and tested its range and limit of detection with six tick-associated jingmenviruses using in vitro transcripts. Then we screened ticks collected in Corsica (France) from different livestock species, in order to determine the distribution of these viruses on the island. In total, 6,269 ticks from eight species were collected from 763 cattle, 538 horses, 106 sheep and 218 wild boars and grouped in 1,715 pools. We report the first detection of JMTV in Corsica, in Rhipicephalus bursa, Hyalomma marginatum and R. sanguineus ticks collected from cattle and sheep. The highest prevalence was found in the Rhipicephalus genus. The complete genome of a Corsican JMTV was obtained from a pool of Rhipicephalus bursa ticks and shares between 94.7% and 95.1% nucleotide identity with a JMTV sequence corresponding to a human patient in Kosovo and groups phylogenetically with European JMTV strains. These results show that a Mediterranean island such as Corsica could act as a sentinel zone for future epidemics.

Increased threat of urban arboviral diseases from Aedes aegypti mosquitoes in Colombia.

Objectives: Our study targets the potential of the local urban mosquito Aedes aegypti to experimentally transmit chikungunya virus (CHIKV), dengue virus (DENV), yellow fever virus (YFV), and Zika virus (ZIKV). Methods: We collected eggs and adults of Ae. aegypti in Medellín, Colombia (from February to March 2020) for mosquito experimental infections with DENV, CHIKV, YFV and ZIKV and viral detection using the BioMark Dynamic arrays system. Results: We show that Ae. aegypti from Medellín was more prone to become infected, to disseminate and transmit CHIKV and ZIKV than DENV and YFV. Conclusions: Thus, in Colombia, chikungunya is the most serious threat to public health based on our vector competence data.

Crimean-Congo Hemorrhagic Fever Virus in Ticks Collected from Cattle, Corsica, France, 2023.

We report the detection of Crimean-Congo hemorrhagic fever virus (CCHFV) in Corsica, France. We identified CCHFV African genotype I in ticks collected from cattle at 2 different sites in southeastern and central-western Corsica, indicating an established CCHFV circulation. Healthcare professionals and at-risk groups should be alerted to CCHFV circulation in Corsica.

Exploring cell-free assays for COVID-19 serosurvey.

Serosurveys to monitor immunity toward COVID-19 in the population are primarily performed using an ELISA to screen samples for SARS-CoV-2 antibodies, followed by confirmation by a virus neutralization test, which is considered the Gold Standard. However, virus neutralization test may not be feasible for some laboratories because of the requirement for specific facilities and trained personnel. In an attempt to address this limitation, we evaluated three cell-free methods as potential alternatives for assessing SARS-CoV-2 seroprevalence in human population from plasma. We report the establishment of two inhibition ELISAs designed to detect anti-Spike RBD IgG antibodies and a microsphere quantitative suspension array technology assay, based on the Luminex xMAP platform, to measure the presence of antibodies against various SARS-CoV-2 antigens, including anti-RBD. These methods were also compared to a commercial chemiluminescent immunoassay designed for anti-RBD antibodies detection and to the combined ELISA + virus neutralization test strategy. These cell-free assays performed equally to estimate the percentage of positive and negative samples and could be used to determine the prevalence of SARS-CoV-2 antibodies in human population, at least in cohort with high-expected prevalence, without the use of seroneutralization assay.

SARS-CoV-2 infection prevalence and associated factors among primary healthcare workers in France after the third COVID-19 wave.

Data on the SARS-CoV-2 infection among primary health care workers (PHCWs) are scarce but essential to reflect on policy regarding prevention and control measures. We assessed the prevalence of PHCWs who have been infected by SARS-CoV-2 in comparison with modeling from the general population in metropolitan France, and associated factors. A cross-sectional study was conducted among general practitioners (GPs), pediatricians, dental and pharmacy workers in primary care between May and August 2021. Participants volunteered to provide a dried-blood spot for SARS-CoV-2 antibody assessment and completed a questionnaire. The primary outcome was defined as the detection of infection-induced antibodies (anti-nucleocapsid IgG, and for non-vaccinees: anti-Spike IgG and neutralizing antibodies) or previous self-reported infection (positive RT-qPCR or antigenic test, or positive ELISA test before vaccination). Estimates were adjusted using weights for representativeness and compared with prediction from the general population. Poisson regressions were used to quantify associated factors. The analysis included 1612 PHCWs. Weighted prevalences were: 31.7% (95% CI 27.5-36.0) for GPs, 28.7% (95% CI 24.4-33.0) for pediatricians, 25.2% (95% CI 20.6-31.0) for dentists, and 25.5% (95% CI 18.2-34.0) for pharmacists. Estimates were compatible with model predictions for the general population. PHCWs more likely to be infected were: GPs compared to pharmacist assistants (adjusted prevalence ratio [aPR] = 2.26; CI 95% 1.01-5.07), those living in Île-de-France (aPR = 1.53; CI 95% 1.14-2.05), South-East (aPR = 1.57; CI 95% 1.19-2.08), North-East (aPR = 1.81; CI 95% 1.38-2.37), and those having an unprotected contact with a COVID-19 case within the household (aPR = 1.48; CI 95% 1.22-1.80). Occupational factors were not associated with infection. In conclusion, the risk of SARS-CoV-2 exposure for PHCWs was more likely to have occurred in the community rather than at their workplace.

Incidence of COVID-19 mRNA vaccine symptomatic breakthrough infections during Omicron circulation in adults with or without infection prior to vaccination.

OBJECTIVES: COVID-19 vaccine breakthrough infections were frequently reported during circulation of the Omicron variant. The ANRS|MIE CoviCompareP study investigated these infections in adults vaccinated and boosted with BNT162b2 [Pfizer-BioNTech] and with/without SARS-CoV-2 infection before vaccination. METHODS: In the first half of 2021, healthy adults (aged 18-45, 65-74 and 75 or older) received either one dose of BNT162b2 (n = 120) if they had a documented history of SARS-CoV-2 infection at least five months previously, or two doses (n = 147) if they had no history confirmed by negative serological tests. A first booster dose was administered at least 6 months after the primary vaccination, and a second booster dose, if any, was reported in the database. Neutralizing antibodies (NAbs) against the European (D614G) strain and the Omicron BA.1 variant were assessed up to 28 days after the first booster dose. A case-control analysis was performed for the 252 participants who were followed up in 2022, during the Omicron waves. RESULTS: From January to October 2022, 78/252 (31%) had a documented symptomatic breakthrough infection after full vaccination: 21/117 (18%) in those who had been infected before vaccination vs. 57/135 (42%) in those who had not. In a multivariate logistic regression model, factors associated with a lower risk of breakthrough infection were older age, a higher number of booster doses, and higher levels of Omicron BA.1 NAb titers in adults with infection before vaccination, but not in those without prior infection. CONCLUSION: Our results highlight the need to consider immune markers of protection in association with infection and vaccination history.

Molecular epidemiology identifies the expansion of the DENV2 epidemic lineage from the French Caribbean Islands to French Guiana and mainland France, 2023 to 2024.

In 2023, dengue virus serotype 2 (DENV2) affected most French overseas territories. In the French Caribbean Islands, viral circulation continues with > 30,000 suspected infections by March 2024. Genome sequence analysis reveals that the epidemic lineage in the French Caribbean islands has also become established in French Guiana but not Réunion. It has moreover seeded autochthonous circulation events in mainland France. To guide prevention of further inter-territorial spread and DENV introduction in non-endemic settings, continued molecular surveillance and mosquito control are essential.

Evaluating vector competence for Yellow fever in the Caribbean.

The mosquito-borne disease, Yellow fever (YF), has been largely controlled via mass delivery of an effective vaccine and mosquito control interventions. However, there are warning signs that YF is re-emerging in both Sub-Saharan Africa and South America. Imported from Africa in slave ships, YF was responsible for devastating outbreaks in the Caribbean. In Martinique, the last YF outbreak was reported in 1908 and the mosquito Aedes aegypti was incriminated as the main vector. We evaluated the vector competence of fifteen Ae. aegypti populations for five YFV genotypes (Bolivia, Ghana, Nigeria, Sudan, and Uganda). Here we show that mosquito populations from the Caribbean and the Americas were able to transmit the five YFV genotypes, with YFV strains for Uganda and Bolivia having higher transmission success. We also observed that Ae. aegypti populations from Martinique were more susceptible to YFV infection than other populations from neighboring Caribbean islands, as well as North and South America. Our vector competence data suggest that the threat of re-emergence of YF in Martinique and the subsequent spread to Caribbean nations and beyond is plausible.

Neutralizing and enhancing monoclonal antibodies in SARS-CoV-2 convalescent patients: lessons from early variant infection and impact on shaping emerging variants.

Serological studies of COVID-19 convalescent patients have identified polyclonal lineage-specific and cross-reactive antibodies (Abs), with varying effector functions against virus variants. Individual specificities of anti-SARS-CoV-2 Abs and their impact on infectivity by other variants have been little investigated to date. Here, we dissected at a monoclonal level neutralizing and enhancing Abs elicited by early variants and how they affect infectivity of emerging variants. B cells from 13 convalescent patients originally infected by D614G or Alpha variants were immortalized to isolate 445 naturally-produced anti-SARS-CoV-2 Abs. Monoclonal antibodies (mAbs) were tested for their abilities to impact the cytopathic effect of D614G, Delta, and Omicron (BA.1) variants. Ninety-eight exhibited robust neutralization against at least one of the three variant types, while 309 showed minimal or no impact on infectivity. Thirty-eight mAbs enhanced infectivity of SARS-CoV-2. Infection with D614G/Alpha variants generated variant-specific (65 neutralizing Abs, 35 enhancing Abs) and cross-reactive (18 neutralizing Abs, 3 enhancing Abs) mAbs. Interestingly, among the neutralizing mAbs with cross-reactivity restricted to two of the three variants tested, none demonstrated specific neutralization of the Delta and Omicron variants. In contrast, cross-reactive mAbs enhancing infectivity (n = 3) were found exclusively specific to Delta and Omicron variants. Notably, two mAbs that amplified in vitro the cytopathic effect of the Delta variant also exhibited neutralization against Omicron. These findings shed light on functional diversity of cross-reactive Abs generated during SARS-CoV-2 infection and illustrate how the balance between neutralizing and enhancing Abs facilitate variant emergence.

Emergence of Oropouche fever in Latin America: a narrative review.

Since its discovery in 1955, the incidence and geographical spread of reported Oropouche virus (OROV) infections have increased. Oropouche fever has been suggested to be one of the most important vector-borne diseases in Latin America. However, both literature on OROV and genomic sequence availability are scarce, with few contributing laboratories worldwide. Three reassortant OROV glycoprotein gene variants termed Iquitos, Madre de Dios, and Perdões virus have been described from humans and non-human primates. OROV predominantly causes acute febrile illness, but severe neurological disease such as meningoencephalitis can occur. Due to unspecific symptoms, laboratory diagnostics are crucial. Several laboratory tests have been developed but robust commercial tests are hardly available. Although OROV is mainly transmitted by biting midges, it has also been detected in several mosquito species and a wide range of vertebrate hosts, which likely facilitates its widespread emergence. However, potential non-human vertebrate reservoirs have not been systematically studied. Robust animal models to investigate pathogenesis and immune responses are not available. Epidemiology, pathogenesis, transmission cycle, cross-protection from infections with OROV reassortants, and the natural history of infection remain unclear. This Review identifies Oropouche fever as a neglected disease and offers recommendations to address existing knowledge gaps, enable risk assessments, and ensure effective public health responses.

Generation and evaluation of protease inhibitor-resistant SARS-CoV-2 strains.

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®) has shown the best results in clinical trials and the greatest robustness against variants. A second SARS-CoV-2 protease inhibitor, ensitrelvir (Xocova®), 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, in the multi-passage strain, 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® 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.

Comparing the Performance of Three Models Incorporating Weather Data to Forecast Dengue Epidemics in Reunion Island, 2018-2019.

We developed mathematical models to analyze a large dengue virus (DENV) epidemic in Reunion Island in 2018-2019. Our models captured major drivers of uncertainty including the complex relationship between climate and DENV transmission, temperature trends, and underreporting. Early assessment correctly concluded that persistence of DENV transmission during the austral winter 2018 was likely and that the second epidemic wave would be larger than the first one. From November 2018, the detection probability was estimated at 10%-20% and, for this range of values, our projections were found to be remarkably accurate. Overall, we estimated that 8% and 18% of the population were infected during the first and second wave, respectively. Out of the 3 models considered, the best-fitting one was calibrated to laboratory entomological data, and accounted for temperature but not precipitation. This study showcases the contribution of modeling to strengthen risk assessments and planning of national and local authorities.

Risk Factors for Community and Intrahousehold Transmission of SARS-CoV-2: Modeling in a Nationwide French Population-Based Cohort Study, the EpiCoV Study.

We assessed the risk of acquiring severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from household and community exposure according to age, family ties, and socioeconomic and living conditions using serological data from a nationwide French population-based cohort study, the Epidémiologie et Conditions de Vie (EpiCoV) Study. A history of SARS-CoV-2 infection was defined by a positive anti-SARS-CoV-2 enzyme-linked immunosorbent assay immunoglobulin G result in November-December 2020. We applied stochastic chain binomial models fitted to the final distribution of household infections to data from 17,983 individuals aged ≥6 years from 8,165 households. Models estimated the competing risks of being infected from community and household exposure. The age group 18-24 years had the highest risk of extrahousehold infection (8.9%, 95% credible interval (CrI): 7.5, 10.4), whereas the oldest (≥75 years) and youngest (6-10 years) age groups had the lowest risk, at 2.6% (95% CrI: 1.8, 3.5) and 3.4% (95% CrI: 1.9, 5.2), respectively. Extrahousehold infection was also associated with socioeconomic conditions. Within households, the probability of person-to-person transmission increased with age, from 10.6% (95% CrI: 5.0, 17.9) among children aged 6-10 years to 43.1% (95% CrI: 32.6, 53.2) among adults aged 65-74 years. Transmission was higher between partners (29.9%, 95% CrI: 25.6, 34.3) and from mother to child (29.1%, 95% CrI: 21.4, 37.3) than between individuals related by other family ties. In 2020 in France, the main factors identified for extrahousehold SARS-CoV-2 infection were age and socioeconomic conditions. Intrahousehold infection mainly depended on age and family ties.

Sequence Data From a Travel-Associated Case of Microcephaly Highlight a Persisting Risk due to Zika Virus Circulation in Thailand.

Zika virus has been circulating in Thailand since 2002 through continuous but likely low-level circulation. Here, we describe an infection in a pregnant woman who traveled to Thailand and South America during her pregnancy. By combining phylogenetic analysis with the patient's travel history and her pregnancy timeline, we confirmed that she likely got infected in Thailand at the end of 2021. This imported case of microcephaly highlights that Zika virus circulation in the country still constitutes a health risk, even in a year of lower incidence. MAIN POINTS: Here we trace the origin of travel-acquired microcephaly to Thailand, providing additional evidence that pre-American lineages of Zika virus can harm the fetus and highlighting that Zika virus constitutes a health threat even in a year of lower incidence.

Yellow fever vaccine-associated neurologic and viscerotropic disease: a 10-year case series of the French National Reference Center for Arboviruses with clinical and immunological insights.

BACKGROUND: Immunization against the Yellow fever virus (YFV) with the 17D live-attenuated vaccine is the most effective way to prevent the disease. However, unexpected severe adverse events can occur. They consist in a neurological impairment - neurological disease (YEL-AND), a YF-like illness - viscerotropic disease (YEL-AVD) or anaphylaxis. In this article, we describe the epidemiology, clinical and biological features of YEL-AND and YEL-AVD cases reported to the French National Reference Center for Arboviruses (NRCA) in the past 10 years. METHODS: We conducted a national, retrospective study using the database of the NRCA from June 2012 to June 2022. All patients whose biological samples were sent to the NRCA for detection of YFV by serology and/or RT-qPCR for a suspected vaccine-associated adverse event were included. We collected data by reading medical records and conducted complementary neuro-immunological analysis, followed by a search for autoimmunity against type-1-interferon when samples were available at the NRCA. RESULTS: There were 10 cases of YEL-AND and 2 cases of YEL-AVD reported to the NRCA in the past 10 years, which represented an overall incidence of 0.6 for 100 000 doses. A total of 6/12 cases were previously healthy patients (50%, mean age 31 years), and 4/12 cases had cardiovascular co-morbidities (42%, mean age 56 years). The majority of YEL-AND had a favourable outcome at 6 months of follow up. One YEL-AVD patient passed. In secondary analyses, we evidenced a significant blood cerebrospinal fluid (CSF) barrier dysfunction, without intrathecal synthesis of immunoglobulin and without argument for a neuron damage. We further detected a significant rate of anti-type-1alpha interferon antibodies in 3/10 tested patients (2 YEL-AND and 1 YEL-AVD). CONCLUSION: YEL-AND and YEL-AVD are rare events that can underlie defect in the innate immunity of apparently healthy or mild co-morbid subjects. Outcome was generally favourable in the YEL-AND cases of our series, but still life-threatening or even fatal in the YEL-AVD cases.

Association of SARS-CoV-2 infection with physical activity domains and types.

Lockdown imposed in the early phase of the SARS-CoV-2 outbreak represented a specific setting where activity was restricted but still possible. The aim was to investigate the cross-sectional associations between physical activity (PA) and SARS-CoV-2 infection in a French population-based cohort. Participants completed a PA questionnaire. PA was classified into: (i) total PA; (ii) aerobic PA by intensity; (iii) strengthening PA; (iv) PA by domain and type; and (vii) by location. Sedentary time was also recorded. Seroprevalence of anti-SARS-CoV-2 antibodies was assessed. Multivariable logistic regression models controlling for sociodemographic, lifestyle, anthropometric data, health status, and adherence to recommended protective anti-SARS-CoV-2 behaviours were computed. From 22,165 participants included, 21,074 (95.1%) and 1091 (4.9%) had a negative and positive ELISA-S test result, respectively. Total PA, vigorous PA, leisure-time PA, household PA, outdoor PA and indoor PA were all associated with lower probability of SARS-CoV-2 infection. Observations made in such a setting shed light on PA possibilities in a context of restricted mobility, where the health benefits of PA should not be overlooked. Along with already well-established benefits of PA for non-communicable disease prevention, these findings provide additional evidence for policies promoting all types of PA as a lever for population health.