Quantifying the value of viral genomics when inferring who infected whom in the 2014-16 Ebola virus outbreak in Guinea.

Transmission trees can be established through detailed contact histories, statistical or phylogenetic inference, or a combination of methods. Each approach has its limitations, and the extent to which they succeed in revealing a 'true' transmission history remains unclear. In this study, we compared the transmission trees obtained through contact tracing investigations and various inference methods to identify the contribution and value of each approach. We studied eighty-six sequenced cases reported in Guinea between March and November 2015. Contact tracing investigations classified these cases into eight independent transmission chains. We inferred the transmission history from the genetic sequences of the cases (phylogenetic approach), their onset date (epidemiological approach), and a combination of both (combined approach). The inferred transmission trees were then compared to those from the contact tracing investigations. Inference methods using individual data sources (i.e. the phylogenetic analysis and the epidemiological approach) were insufficiently informative to accurately reconstruct the transmission trees and the direction of transmission. The combined approach was able to identify a reduced pool of infectors for each case and highlight likely connections among chains classified as independent by the contact tracing investigations. Overall, the transmissions identified by the contact tracing investigations agreed with the evolutionary history of the viral genomes, even though some cases appeared to be misclassified. Therefore, collecting genetic sequences during outbreak is key to supplement the information contained in contact tracing investigations. Although none of the methods we used could identify one unique infector per case, the combined approach highlighted the added value of mixing epidemiological and genetic information to reconstruct who infected whom.

SARS-CoV-2 in the Republic of Guinea: Fragment and Whole-Genome Sequencing, Phylogenetic Analysis

Genetic diversity of SARS-CoV-2 isolates circulating in the Republic of Guinea in May and June 2020, as well as in March 2021, has been demonstrated using fragment (S gene) and whole genome sequencing of 14 strains. Analysis of nucleotide sequences and phylogenetic constructs make it possible to divide the studied strains into 3 groups. Comparison of the obtained data with the already available epidemiological data proves the initial importation of COVID-19 from Western European countries, and also demonstrates four independent import routes in two time periods (March 2020 and no later than March 2021).

Longitudinal antibody and T cell responses in Ebola virus disease survivors and contacts: an observational cohort study.

BACKGROUND: The 2013-16 Ebola virus disease epidemic in west Africa caused international alarm due to its rapid and extensive spread resulting in a significant death toll and social unrest within the affected region. The large number of cases provided an opportunity to study the long-term kinetics of Zaire ebolavirus-specific immune response of survivors in addition to known contacts of those infected with the virus. METHODS: In this observational cohort study, we worked with leaders of Ebola virus disease survivor associations in two regions of Guinea, Guéckédou and Coyah, to recruit survivors of Ebola virus disease, contacts from households of individuals known to have had Ebola virus disease, and individuals who were not knowingly associated with infected individuals or had not had Ebola virus disease symptoms to serve as negative controls. We did Zaire ebolavirus glycoprotein-specific T cell analysis on peripheral blood mononuclear cells (PBMCs) on location in Guinea and transported plasma and PBMCs back to Europe for antibody quantification by ELISA, functional neutralising antibody analysis using live Zaire ebolavirus, and T cell phenotype studies. We report on the longitudinal cellular and humoral response among Ebola virus disease survivors and highlight potentially paucisymptomatic infection. FINDINGS: We recruited 117 survivors of Ebola virus disease, 66 contacts, and 23 negative controls. The mean neutralising antibody titre among the Ebola virus disease survivors 3-14 months after infection was 1/174 (95% CI 1/136-1/223). Individual results varied greatly from 1/10 to more than 1/1000 but were on average ten times greater than that induced after 1 month by single dose Ebola virus vaccines. Following reactivation with glycoprotein peptide, the mean T cell responses among 116 Ebola virus disease survivors as measured by ELISpot was 305 spot-forming units (95% CI 257-353). The dominant CD8+ polyfunctional T cell phenotype, as measured among 53 Ebola virus disease survivors, was interferon γ+, tumour necrosis factor+, interleukin-2-, and the mean response was 0·046% of total CD8+ T cells (95% CI 0·021-0·071). Additionally, both neutralising antibody and T cell responses were detected in six (9%) of 66 Ebola virus disease contacts. We also noted that four (3%) of 117 individuals with Ebola virus disease infections did not have circulating Ebola virus-specific antibodies 3 months after infection. INTERPRETATION: The continuous high titre of neutralising antibodies and increased T cell response might support the concept of long-term protective immunity in survivors. The existence of antibody and T cell responses in contacts of individuals with Ebola virus disease adds further evidence to the existence of sub-clinical Ebola virus infection. FUNDING: US Food & Drug Administration, Horizon 2020 EU EVIDENT, Wellcome, UK Department for International Development. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Determinants of Transmission Risk During the Late Stage of the West African Ebola Epidemic.

Understanding risk factors for Ebola transmission is key for effective prediction and design of interventions. We used data on 860 cases in 129 chains of transmission from the latter half of the 2013-2016 Ebola epidemic in Guinea. Using negative binomial regression, we determined characteristics associated with the number of secondary cases resulting from each infected individual. We found that attending an Ebola treatment unit was associated with a 38% decrease in secondary cases (incidence rate ratio (IRR) = 0.62, 95% confidence interval (CI): 0.38, 0.99) among individuals that did not survive. Unsafe burial was associated with a higher number of secondary cases (IRR = 1.82, 95% CI: 1.10, 3.02). The average number of secondary cases was higher for the first generation of a transmission chain (mean = 1.77) compared with subsequent generations (mean = 0.70). Children were least likely to transmit (IRR = 0.35, 95% CI: 0.21, 0.57) compared with adults, whereas older adults were associated with higher numbers of secondary cases. Men were less likely to transmit than women (IRR = 0.71, 95% CI: 0.55, 0.93). This detailed surveillance data set provided an invaluable insight into transmission routes and risks. Our analysis highlights the key role that age, receiving treatment, and safe burial played in the spread of EVD.

Temporo-spatial dynamics and behavioural patterns of 2012 cholera epidemic in the African mega-city of Conakry, Guinea.

BACKGROUND: Cholera is endemic in Guinea, having suffered consecutive outbreaks from 2004 to 2008 followed by a lull until the 2012 epidemic. Here we describe the temporal-spatial and behavioural characteristics of cholera cases in Conakry during a three-year period, including the large-scale 2012 epidemic. METHODS: We used the national and African Cholera Surveillance Network (Africhol) surveillance data collected from every cholera treatment centre in Conakry city from August 2011 to December 2013. The prevalence of suspect and confirmed cholera cases, the case fatality ratio (CFR), and the factors associated with suspected cholera were described according to three periods: pre-epidemic (A), epidemic 2012 (B) and post epidemic (C). Weekly attack rates and temporal-spatial clustering were calculated at municipality level for period B. Cholera was confirmed by culture at the cholera national reference laboratory. RESULTS: A total of 4559 suspect cases were reported: 66, 4437, and 66 suspect cases in periods A, B and C, respectively. Among the 204 suspect cases with culture results available, 6%, 60%, and 70% were confirmed in periods A, B, and C, respectively. With 0.3%, the CFR was significantly lower in period B than in periods A (7.6%) and C (7.1%). The overall attack rate was 0.28% in period B, ranging from 0.17% to 0.31% across municipalities. Concomitantly, a cluster of cases was identified in two districts in the northern part of Conakry. At 14%, rice water stools were less frequent in period A than in period B and C (78% and 84%). Dehydration (31% vs 94% and 89%) and coma (0.4% vs 3.1% and 2.9%) were lower during period B than in periods A and C. The treatment of drinking water was less frequent in period A, while there were more reports of recent travel in period C. CONCLUSIONS: The epidemic dynamic and the sociological description of suspect cases before, during, and after the large-scale epidemic revealed that the Vibrio cholerae was already present before the epidemic. However, it appeared that infected individuals reacted differently in terms of disease severity as well as their access to treated water and travel habits. Such an in-depth description of cholera epidemics should be systematically carried out in cholera endemic settings in order to prioritize higher risk areas, identify transmission factors, and optimize preventive interventions.

Use of Vibrio cholerae vaccine in an outbreak in Guinea.

BACKGROUND: The use of vaccines to prevent and control cholera is currently under debate. Shanchol is one of the two oral cholera vaccines prequalified by the World Health Organization; however, its effectiveness under field conditions and the protection it confers in the first months after administration remain unknown. The main objective of this study was to estimate the short-term effectiveness of two doses of Shanchol used as a part of the integrated response to a cholera outbreak in Africa. METHODS: We conducted a matched case-control study in Guinea between May 20 and October 19, 2012. Suspected cholera cases were confirmed by means of a rapid test, and controls were selected among neighbors of the same age and sex as the case patients. The odds of vaccination were compared between case patients and controls in bivariate and adjusted conditional logistic-regression models. Vaccine effectiveness was calculated as (1-odds ratio)×100. RESULTS: Between June 8 and October 19, 2012, we enrolled 40 case patients and 160 controls in the study for the primary analysis. After adjustment for potentially confounding variables, vaccination with two complete doses was associated with significant protection against cholera (effectiveness, 86.6%; 95% confidence interval, 56.7 to 95.8; P=0.001). CONCLUSIONS: In this study, Shanchol was effective when used in response to a cholera outbreak in Guinea. This study provides evidence supporting the addition of vaccination as part of the response to an outbreak. It also supports the ongoing efforts to establish a cholera vaccine stockpile for emergency use, which would enhance outbreak prevention and control strategies. (Funded by Médecins sans Frontières.).

First outbreak response using an oral cholera vaccine in Africa: vaccine coverage, acceptability and surveillance of adverse events, Guinea, 2012.

BACKGROUND: Despite World Health Organization (WHO) prequalification of two safe and effective oral cholera vaccines (OCV), concerns about the acceptability, potential diversion of resources, cost and feasibility of implementing timely campaigns has discouraged their use. In 2012, the Ministry of Health of Guinea, with the support of Médecins Sans Frontières organized the first mass vaccination campaign using a two-dose OCV (Shanchol) as an additional control measure to respond to the on-going nationwide epidemic. Overall, 316,250 vaccines were delivered. Here, we present the results of vaccination coverage, acceptability and surveillance of adverse events. METHODOLOGY/PRINCIPAL FINDINGS: We performed a cross-sectional cluster survey and implemented adverse event surveillance. The study population included individuals older than 12 months, eligible for vaccination, and residing in the areas targeted for vaccination (Forécariah and Boffa, Guinea). Data sources were household interviews with verification by vaccination card and notifications of adverse events from surveillance at vaccination posts and health centres. In total 5,248 people were included in the survey, 3,993 in Boffa and 1,255 in Forécariah. Overall, 89.4% [95%CI:86.4-91.8%] and 87.7% [95%CI:84.2-90.6%] were vaccinated during the first round and 79.8% [95%CI:75.6-83.4%] and 82.9% [95%CI:76.6-87.7%] during the second round in Boffa and Forécariah respectively. The two dose vaccine coverage (including card and oral reporting) was 75.8% [95%CI: 71.2-75.9%] in Boffa and 75.9% [95%CI: 69.8-80.9%] in Forécariah respectively. Vaccination coverage was higher in children. The main reason for non-vaccination was absence. No severe adverse events were notified. CONCLUSIONS/SIGNIFICANCE: The well-accepted mass vaccination campaign reached high coverage in a remote area with a mobile population. Although OCV should not be foreseen as the long-term solution for global cholera control, they should be integrated as an additional tool into the response.

Use of a cholera rapid diagnostic test during a mass vaccination campaign in response to an epidemic in Guinea, 2012.

BACKGROUND: During the 2012 cholera outbreak in the Republic of Guinea, the Ministry of Health, supported by Médecins Sans Frontières - Operational Center Geneva, used the oral cholera vaccine Shanchol as a part of the emergency response. The rapid diagnostic test (RDT) Crystal VC, widely used during outbreaks, detects lipopolysaccharide antigens of Vibrio cholerae O1 and O139, both included in Shanchol. In the context of reactive use of a whole-cell cholera vaccine in a region where cholera cases have been reported, it is essential to know what proportion of vaccinated individuals would be reactive to the RDT and for how long after vaccination. METHODOLOGY/PRINCIPAL FINDINGS: A total of 108 vaccinated individuals, selected systematically among all persons older than one year, were included at vaccination sites and 106 were included in the analysis. Stools samples of this cohort of vaccinated participants were collected and tested with the RDT every day until the test was negative for two consecutive visits or for a maximum of 7 days. A total of 94.3% of cholera vaccine recipients had a positive test after vaccination; all except one of these positive results were reactive only with the O139 antigen. The mean time to become negative in those with an initial positive result after vaccination was 3.8 days, standard deviation 1.1 days. CONCLUSIONS/SIGNIFICANCE: The RDT Crystal VC becomes positive in persons recently vaccinated against cholera, although almost exclusively to the O139 antigen. This reactivity largely disappeared within five days after vaccination. These results suggest that the test can be used normally as soon as 24 hours after vaccination in a context of O1 epidemics, which represent the vast majority of cases, and after a period of five days in areas where V. cholerae O139 is present. The reason why only O139 test line became positive remains to be investigated.