rVSV-ZEBOV vaccination in people with pre-existing immunity to Ebolavirus: an open-label safety and immunogenicity study in Guinean communities affected by Ebola virus disease (l’essai Proches)

rVSV-ZEBOV vaccination in people with pre-existing immunity to Ebolavirus: an open-label safety and immunogenicity study in Guinean communities affected by Ebola virus disease (l’essai Proches) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article rVSV-ZEBOV vaccination in people with pre-existing immunity to Ebolavirus: an open-label safety and immunogenicity study in Guinean communities affected by Ebola virus disease (l’essai Proches) Conall H Watson, Pierre-Stéphane Gsell, Yper Hall, Anton Camacho, and 32 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4562505/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Nov, 2024 Read the published version in BMC Medicine → Version 1 posted 11 You are reading this latest preprint version Abstract Background Zaire Ebolavirus disease (EVD) outbreaks can be controlled using rVSV-ZEBOV vaccination and other public health measures. People in high-risk areas may have pre-existing antibodies from asymptomatic Ebolavirus exposure that might affect response to rVSV-ZEBOV. Therefore, we assessed the impact pre-existing immunity had on post-vaccination IgG titre, virus neutralization and reactogenicity following vaccination. Methods In this prospective cohort study, 2,115 consenting close contacts (“proches”) of EVD survivors were recruited. Proches were vaccinated with rVSV-ZEBOV and followed up for 28 days for safety and immunogenicity. Anti-GP IgG titre at baseline and day 28 was assessed by ELISA. Samples from a representative subset were evaluated using live virus neutralization. Results Ten percent were seropositive at baseline. At day, 28 IgG in baseline seronegative (GMT 0.106 IU/mL, 95% CI: 0.100 to 0.113) and seropositive (GMT 0.237 IU/ml, 0.210 to 0.267) participants significantly increased from baseline (both p<0.0001). There was strong correlation between antibody concentration and virus neutralization in day 28 samples (Spearman's rho 0.75). Vaccinees with baseline IgG antibodies against Zaire Ebolavirus had similar safety profiles to those without detectable antibodies (63.6% vs 66.1% adults experienced any adverse event; 49.1% vs 60.9% in children), with almost all adverse events graded as mild. No serious adverse events were attributed to vaccination. No EVD survivors tested positive for Ebolavirus by RT-PCR. Conclusions These data add further evidence of rVSV-ZEBOV safety and immunogenicity, including in people with pre-existing antibodies from suspected natural ZEBOV infection, whichdo not blunt rVSV-ZEBOV immune response. Pre-vaccination serological screening is not required. Ebola virus disease Ebola vaccine rVSV-ZEBOV safety immunogenicity cohort study Figures Figure 1 Figure 2 Introduction Ebolavirus (EBOV) has caused high mortality and morbidity outbreaks of Ebola virus disease (EVD) across equatorial Africa. 1,2 Sustained person-to-person transmission may arise following single zoonotic transmission events and lead to large outbreaks. 3–5 EVD control methods include contact tracing, case isolation, health education and safe burial, with appropriate community engagement. 6 Since 2016, outbreak response also includes the use of a safe and highly efficacious attenuated replication-competent vesicular stomatitis virus-derived vaccine expressing the surface glycoprotein (GP) of EBOV (rVSV-ZEBOV). 7 ,8 Previous studies report that rVSV-ZEBOV is safe and well tolerated, 7–13 , It has been approved by US and European regulators as well as national regulatory authorities in ten African countries. Serology studies from central Africa reported that in villages experiencing an outbreak and in areas at risk of zoonotic transmission mean population seroprevalence will range from 2-29%, as measured by the detection of immunoglobulin G (IgG) to EBOV-GP in clinical samples. 14–18 Studies in post-outbreak communities in West Africa have similarly found undiagnosed seropositive contacts, referred to as asymptomatic cases, though a level of caution needs to be applied to studies in which antibody analysis is not supported by additional assessments i.e. virus neutralization. The impact of pre-existing antibodies to EVD on rVSV-ZEBOV safety and immunogenicity is unknown. Any sign of blunted immunogenicity or safety concerns in previously infected individuals would warrant further investigation. Therefore, we undertook an open-label rVSV-ZEBOV vaccination cohort study , enrolling contacts of EVD cases who survived and for which ring vaccination was not previously implemented during the 2013-16 outbreak. . 19 , 20,21 This study’s primary objective was to measure the IgG response to EBOV GP at 28 days post-vaccination by baseline IgG status; secondary objectives were comparing the rates of serious adverse events (SAEs) and adverse events (AEs) by baseline serostatus; and to explore any association between participants’ baseline serostatus and linked-survivor-related factors. Methods Ethics The study was approved by the World Health Organization (WHO) Research Ethics Review Committee (ERC.0002723), the London School of Hygiene & Tropical Medicine, UK, interventional research ethics committee (10523/RR/4674), and by the Comité National d'Ethique pour la Recherche en Santé. Setting The study was conducted in Basse-Guinée region, Guinea. The first volunteer was recruited on 25 May 2016 and follow up of the final participant completed on 21 Sep 2016. Design Participants were contacts of EVD survivors whose onset of symptoms occurred within 15 months prior to the start of the study. The study was a prospective cohort study examining IgG antibodies by ELISA serology at baseline and at day 28 following rVSV-ZEBOV vaccination. It also documented post-vaccination adverse events at days 3, 14 and 28, comparing those with raised baseline antibodies against those without. Survivors were tested using RT-PCR and were not prospectively vaccinated. Baseline and day 28 EBOV GP IgG concentrations were also assessed for association with survivor-related factors, such as time since survivor EVD onset. Study population In May 2016, we identified contacts of adult or adolescent, PCR confirmed, EVD survivors who had not been previously included in the rVSV-ZEBOV ring vaccination Ebola ca suffit trial. 7 These contacts were assumed to be at a low but not zero risk of EVD due to potential persistence of viable EBOV in the body fluids of EVD survivors. 14,20,22,23 Survivors were identified from national surveillance records. Survivor support organisations were also used as an information source to verify data against these records. Survivors’ communities of residence were cross-referenced against the records of the Ebola Ça Suffit ring trial, 7 to exclude survivors whose contacts were already included in the trial. A revised definition of contacts of EVD survivors because of their socio-epidemiological status (“ les proches” ) was developed. It included household contacts (shared sleeping building or shared cooking pot), sexual contacts and second tier of people who would be at risk of transmission should a close contact develop EVD as a result of a post-recovery transmission event e.g. neighbours of survivors and household contacts of a sexual contact of a survivor. Proches were identified by trained field epidemiologists. They were eligible for inclusion if they were 6 years of age or older and did not meet any exclusion criteria, namely: history of EVD (self-report), history of vaccination with any EBOV vaccine, verbally declared pregnancy, or planning to conceive within two months of vaccination (pregnancy tests were offered but not required), breast-feeding, history of having received investigational research agents in the previous 28 days, clinically important immunodeficiency condition (e.g. HIV/AIDS), history of anaphylaxis to a vaccine or vaccine component, or a severe illness that makes the person bed-bound or requiring hospitalization at the time of the vaccination. Informed Consent Communities were approached and the study explained by the study’s community engagement team, and permission obtained to enter the community. Individual written informed consent was obtained for all participants using a signed, printed information sheet. For child participants, consent was obtained from parents or guardians. Children aged 12 to 17 years also gave written consent. If the potential participant was illiterate, the documents were read in a local language and a fingerprint collected, countersigned by a literate independent witness. The teams taking informed consent were different from those involved in community engagement and the epidemiological determination of proches to include in the rings. Procedures Consenting vaccinees received a single dose of at least 2 x 10 7 plaque forming units of the rVSV-ZEBOV vaccine (donated by Merck Sharp & Dohme, Kenilworth, NJ, USA) intramuscular to a deltoid. From each vaccinee, immediately prior to vaccination and on day 28 (+/-3 days) post-vaccination, up to 10ml of venous blood for serology was collected in a sterile serum separator tube by a trained person using standard techniques. Participants were observed for 30 minutes post-vaccination for immediate adverse reactions. Follow-up for adverse events was done on days 3, 14 and 28 post-vaccination by safety monitoring teams, with a window of +/- 1, 2 and 3 days respectively. Consenting EVD survivors provided a 10ml venous blood for reverse-transcriptase polymerase chain reaction (RT-PCR) in the study laboratory in Conakry, Guinea. Female survivors were invited to provide a vaginal swab, and menstrual blood or breastmilk sample if applicable; male survivors were invited to provide a semen sample. All were tested using an RT-PCR Samples were transferred to Europe for analysis under a signed Material Transfer Agreement issued by the Ministre Sante Hygiene Publique, Guinée. Data collection Data was collected on encrypted Android tablets using OpenDataKit (ODK) Collect on forms designed in XLSform. Uploaded data was stored in ODK Aggregate on an encrypted server. QR barcodes were used to link participants records and laboratory samples and for staff digital signatures. GPS data was collected on participant locations to aid follow-up. Baseline demographic data and contact information was collected from all participants. Survivors were asked about possible EVD sequalae. Details of specified adverse events were solicited at each post-vaccination follow-up visit, with unsolicited events also documented on days 3 and 14. Participants were provided with a contact number on their participant enrolment card if they wanted to contact the study team between visits to notify or get advice on any possible adverse events. To reduce the risk of important response biases, data collectors were trained in information solicitation methods by experienced HIV/AIDS teams. Interviews were conducted away from communal settings to increase privacy. Participants missing from safety monitoring visits were actively traced by the field team to reduce loss to follow-up. Laboratory methods EBOV GP ELISA Anti-EBOV GP IgG was determined by ELISA using previously published methods 24,25 with a trimerised Zaire strain GP antigen, aa 1-649 of GenBank AHX24649.1 (GIN/2014/Makona-Kissidougou-C15). Results were standardised by inclusion of a reference curve for which the reference material was a plasma pool from three EVD survivors, calibrated against WHO Reference Reagent (NIBSC 15/220) 26 (Anti-GP concentration = 0.761 +/- 0.006 IU/ml (mean +/- SEM, n=13)). Negative control plasma pool was obtained from three Guinean volunteers with no prior infection with EVD or contact with an EVD case-patient. Matched serum pairs were tested in triplicate. Samples without a matching pair were not tested. OD was interpolated from the reference serum curve. In the absence of well-defined thresholds for immunity or past infection, we set a serological threshold based on the negative control. The threshold for seropositivity was determined as 0.0429 IU/ml, three standard deviations above the negative control geometric mean (n=91). EBOV Zaire Neutralization Assay Fifty paired samples were selected based on having a low, medium or high baseline anti-GP IgG concentration for analysis using a live EBOV neutralization assay at the Institute of Virology BSL4 laboratory, Philipps University of Marburg, Germany. 27 Based on previous studies the seropositivity threshold for neutralization assays was defined as ≥1:8 geometric mean titre (GMT). Statistical analysis To recruit 50 baseline-seropositive participants, a sample size of 1000 ≤ n ≤ 2000 was estimated to be required if pre-existing seropositivity was consistent with serosurveillance in other Ebola-experienced areas. Descriptive analyses and multivariable regression were performed in R (3.5). 28 For multivariable regression where relevant variables were missing, records were omitted from that analysis. Serological data was compared by paired t-test or Mann-Whitney test. Correlation between ELISA and neutralization assays was compared by Spearman rank correlation coefficient. We set statistical significance level at 5%. Results We identified 136 EVD survivors whose contacts ( proches ) were unvaccinated. For these survivors the date of discharge from Ebola Treatment Unit ranged from 16 Feb to 7 Oct 2015 (median 22 March 2015). Of these, 80.1% (109/136) were located. Only 48 were contacted and all gave their consent for an interview and for sample collection. The remaining were not approached by the study team because a national effort with similar objectives was initiated, and duplication was deemed not desirable. In total 2750 proches of 109 EVD survivors were identified. Among them 77.3% (2126/2750) were eligible for our study, and 2115 were enrolled and vaccinated following consent (figure 1). The median number of screened and vaccinated proches per EVD survivor was 12 (range 1 to 100, IQR 7 to 21). Of the 0.5% (11/2126) not then vaccinated eight were either not present at the time of vaccination or did not have a reason for non-vaccination recorded, two withdrew consent, and one had a medical condition. Venous samples from both day 0 and day 28 were provided by 66.3% (1403/2115) vaccinees. Humoral immunogenicity following rVSV-ZEBOV vaccination We tested the 1403 matched (day 0 and 28) proches’ samples by ELISA and found that 228 (16.3%) were defined as seropositive at baseline (day 0). Logistic regression analysis of potential factors associated with baseline seropositivity did not find an association with sex, age group, or time since survivor discharge from the Ebola treatment unit (ETU) (supplementary material table S1). Of the 1175 baseline seronegative participants, 955 (81.3%, 95%CI 78.9 to 83.4%) were seropositive by ELISA on day 28 (figure 2 panels A and B). Three (1.3%) of 228 initially seropositive vaccinees were found seronegative at day 28. This could be due to waning immunity in weakly positive samples or assay variability. There were statistically significant increases in IgG GMT at day 28 for both those seropositive and seronegative at baseline (table 1). The day 28 GMT was higher for baseline seropositive participants compared to the day 28 GMT of baseline seronegative participants (p-value for difference <0.0001). Examining IgG titres of those who were seronegative at baseline we found that children showed 91.1% seroconversion rate (308 of 338, 95%CI 87.6% to 93.7%) compared with adults who showed a 77.3% seroconversion rate by day 28(647 of 837, 95%CI 74.3 to 80.0%). Children also had higher day 28 IgG GMT of 0.167 (95%CI 0.149 to 0.187) compared to adults GMT of 0.089 (95%CI 0.083 to 0.095, p<0.0001). Amongst those classed as seropositive at baseline we found that children attained higher day 28 titres (GMT 0.338 (95%CI 0.266 to 0.429) than adults (GMT 0.211, 95%CI 0.185 to 0.242, p=0.003). We next sought to validate these ELISA results using live virus neutralization assays on a subset of 50 matched day 0 and 28 samples, 100 samples in total. These samples were identified as high, medium or low responder. We found that day 0 neutralization GMT was 8.5 (95%CI 5.9 to 12.2), rising to 25.1 (95%CI 16.1 to 39.2) at day 28, with proportion considered positive rising from 13/49 (26.5%) to 39/49 (79.6%). Moderate correlation with IgG was seen in baseline neutralization assay titres (Spearman’s rho = 0.50; p=0.002 on 47 degrees of freedom (df)). Correlation was stronger between day 28 assays (rho = 0.75; p<0.0001 on 47 df) (figure 2, panel D). Vaccine Safety We also investigated adverse events, and stratified this by serostatus at baseline and age group (Table 2). Although the immunogenicity analysis was restricted to vaccinees providing paired serological samples, safety data is also presented for those who did not provide a day 28 serum sample. Prevalence was similar in both serogroups and those untested. Of the 62% (1317/2215) reporting any adverse event, 99% (1038/1317) reported only mild events. The most common adverse event in adults and children was headache (35.1% (742/2115)), followed by fatigue (23.7% (501/2115)) and muscle pain (14.6% (308/2115)) (Table 2). Most were short duration: median two days (interquartile range 1-3). Participants most commonly reported adverse events at the day 3 follow-up visit. The most common unsolicited adverse events in adults were shivers/chills (3.6% (56/1550)), dizziness (2.3% (36/1550)), and abdominal pain (1.2% (18/1550)); amongst children the more frequent adverse events include: abdominal pain (4.2%(24/565)), and shivers/chills (2.1%(12/565)) (Table 2). Eight participants reported moderate adverse events (most commonly fatigue or muscle pain) and one reported severe fatigue (table 3). No moderate or severe adverse events were reported in those known to be seropositive at day 0. Association between any adverse event and baseline sero-status was assessed by logistic regression, adjusting for age group (adult/child) and sex and interaction between these factors (supplementary table S2). No association was observable for baseline serological status; adult females appeared more likely to report adverse events than other groups. In an exploratory Poisson regression of adverse event count (across solicited and unsolicited AEs, supplementary material table S3), there was weak evidence of association between baseline seropositivity and lower count of adverse events after adjusting for age and sex. No interactions were identified in sensitivity analysis. Results did not change under robust Poisson regression. EVD survivors All 48 consented survivors completed a questionnaire, of whom 14 (29.2%) reported at least one health problem since discharge (supplementary table S4). Eye problems were most common (10, 20.8%). Sequelae were reported across multiple organ systems including neurological signs, joint problems and abdominal symptoms. From the 128 body fluid samples tested (see figure 1), none tested positive for Ebolavirus by RT-PCR. Discussion This cohort study in Guinea provides additional evidence that one dose ofrVSV ZEBOV GP vaccine is safe and immunogenic among seropositive or seronegative individuals as assessed by IgG antibody titres to Ebolavirus at the time of vaccination. This supports previous work which has shown this vaccine to be safe and effective and highlights the importance of rVSV-ZEBOV in controlling future outbreaks. 7,29 The finding that 16.3% of proches had detectable IgG to EBOV-GP is consistent with previous community/contact studies in central Africa, 14–18 and warrants further investigation into the prevalence of asymptomatic cases and the mechanisms behind asymptomatic or abortive EBOV infections. 30 Researchers found ~15% of study participants in Guinea, Sierra Leone, Liberia in 2018 had prior EBOV-GP immunity before vaccination compared to only 5% in neighbouring Mali. 31 Proposals for this seemingly higher level of seroprevalence include the geographical and ecological differences between these two regions and prior exposure to related and potentially non-pathogenic filoviruses, such exposures may account for some of the elevated baseline responses seen in this study. 32,33 We did not observe an association between baseline seropositivity and age or gender, unlike a DRC study. 34 From our results we estimated a sero-conversion rate of 81.3% (95% CI 78.9 to 83.4%) in those who were seronegative at baseline, and an overall seropositivity of 84.1% (95% CI 82.1 to 86.0%) across all proches tested on day 28. This is within the range of other immunogenicity studies with the rVSV-ZEBOV vaccine that will have also used different assay methodology and definitions of positive outcomes. 11 Importantly, these results provide short term data that individuals with pre-existing immunity to EBOV GP could experience an increase of antibody titres following the administration of of rVSV-ZEBOV. The strong correlation observed between neutralization assays and IgG ELISAs following vaccination further suggests the ELISA used may be an acceptable marker of immunogenicity. The frequency of adverse events between the sero-groups was similar. No increase in adverse events reporting were identified when serogroups were further stratified into children and adults. It was not possible to assess the effects of vaccination in prevention of infection in contacts of survivors as no EVD survivor tested positive for Ebolavirus by RT-PCR. Survivor studies have shown that RNA detection decays over time in semen at variable rates in different survivors, and, as a consequence, transmission risks decrease over time due to lower inoculum, nonviable virus, or other factors. Since 2016, > 95% of the EVD cases and > 95% of their contacts and contacts of contacts have been enumerated in rings and vaccinated with rVSV ZEBOV GP. Therefore a small fraction of contacts not yet vaccinated are sparsely spread over large areas, making it difficult to further assess this question in the field. It is also unknown if vaccine induced antibodies can reach the immune-privileged sites where it is assumed the virus can remain. In 2021, one case of Ebola transmission from a person infected in the 2013-2016 epidemic occurred, outside of our vaccination area. 23 Ebola remains a pressing public health concern in many sub-Saharan countries. This proches vaccination study suggests rVSV ZEBOV GP can be safely administered to individuals with prior asymptomatic Ebola infection (or cross-reactivity that may have caused antibody production) without requiring baseline serological results. Furthermore, existence of prior EBOV GP IgG responses from suspected natural infection does not prevent the ability of an additional dose of rVSV ZEBOV GP to increase antibody titres. Declarations Acknowledgement We gratefully acknowledge the contribution of the participants, host communities, field and laboratory teams, Michael Schmidt and Gotthard Ludwig for technical support in biosafety level 4 procedures, Megan O’Driscoll for data management, and the Government of Guinea. We would like to thank colleagues for helpful discussions in development of the study: Federica Ambrosini, Nathalie Broutet, Gabriella De Carli, Antonio Di Caro, Judith Glynn, Giuseppe Ippolito, Simone Lanini, Francesco Vairo and Jimmy Whitworth. Funding The study was funded by the UN Foundation, Washington, and the WHO, Geneva. The WHO was the sponsor. Laboratory processing was funded by the European Commission (EuropeAid Cooperation Office) through contract No. IFS/2011/272-372 for the EMLab project, Establishment of Mobile Laboratories for Pathogens up to Risk Group 4 in Combination with CBRN Capacity Building in sub-Saharan Africa. Analysis and writing by CHW, AC, and WJE was funded by the Department of Health and Social Care using UK Aid funding, managed by the NIHR (Vaccine Efficacy Evaluation of Priority Emerging Diseases consortium). The views expressed are those of these author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The laboratory analysis performed at UKHSA Porton down was supported by a grant from the Food and Drug Administration (Contract No. HHSF223201510104C). References Legrand J, Grais RF, Boelle PY, Valleron AJ, Flahault A. 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Goldstein T, Anthony SJ, Gbakima A, et al. The discovery of Bombali virus adds further support for bats as hosts of ebolaviruses. Nat Microbiol 2018; 3 : 1084–9. Mulangu S, Alfonso VH, Hoff NA, et al. Serologic Evidence of Ebolavirus Infection in a Population With No History of Outbreaks in the Democratic Republic of the Congo. J Infect Dis 2018; 217 : 529–37. Tables . Participant demographics and IgG titres by baseline serostatus Proches Vaccinees (n=2115, of whom 1403 had paired serum for analysis) EVD Survivors (n=48) Serostatus Seronegative at baseline (day 0) Seropositive at baseline (day 0) Not tested (no paired sample) Not applicable Number (% of those tested) 1175 (83.7%) 228 (16.3%) 712 48 Female sex (%) 440 (37.4%) 81 (35.5%) 239 (33.6%) 26 (54.2%) Median age (IQR) 28 (15 to 46) 30 (18 to 46) 26 (18 to 40) 32 (22 to 40) Age range 6 to 99 6 to 85 6 to 90 15 to 66 Children age 6-17 years (% of those tested) 338 (86.0%) 55 (14.0%) 172 4 Adults 18 years+ (% of those tested) 837 (82.9%) 173 (17.1%) 540 44 IgG geometric mean titre (GMT) (95% confidence interval (CI)), p-value for difference from baseline) Day 0 pre-vaccination 0.0142 (0.0138 to 0.0146) 0.0927 (0.0838 to 0.103) N/A N/A Day 28 post vaccination 0.106 (0.100 to 0.113, p<0.0001)* 0.237 (0.210 to 0.267, p<0.0001) * N/A N/A Seroconversion at day 28 (%; 95% CI) Children 308/338 (91.1%, 87.6% to 93.7%)† N/A N/A N/A Adults 647/837 (77.3%, 74.3 to 80.0%)† N/A N/A N/A GMT (95% CI) Children’s baseline 0.0130 (0.0122 to 0.0138) 0.096 (0.077 to 0.120) N/A N/A Children’s day 28 0.167 (0.149 to 0.187) ‡ 0.338 (0.266 to 0.429) N/A N/A Adults’ baseline 0.0147 (0.0142 to 0.0152) 0.092 (0.082 to 0.103) N/A N/A Adults’ day 28 0.089 (0.083 to 0.095) ‡ 0.211 (0.185 to 0.242) N/A N/A *,†,‡ The p-value for difference between these paired groups was <0.0001. Table 2. Number of adults and children who experienced specified and unsolicited adverse events during 28 days from vaccination, by pre-vaccination serostatus Adults Children Serostatus Seronegative at baseline n=837 Seropositive at baseline n=173 Not tested (no paired sample) n=540 Seronegative at baseline n= 338 Seropositive at baseline n= 55 Not tested (no paired sample) n= 172 Specified adverse events Any adverse event 553 (66.1%) 110 (63.6%) 321 (59.4%) 206 (60.9%) 27 (49.1%) 100 (58.1%) Diarrhoea 15 (1.8%) 1 (0.6%) 13 (2.4%) 6 (1.8%) 1 (1.8%) 1 (0.6%) Fatigue 220 (26.3%) 44 (25.4%) 150 (27.8%) 52 (15.4%) 6 (10.9%) 29 (16.9%) Headache 306 (36.6%) 60 (34.7%) 160 (29.6%) 136 (40.2%) 17 (30.9%) 63 (36.6%) Injection pain 27 (3.2%) 4 (2.3%) 21 (3.9%) 23 (6.8%) - 15 (8.7%) Joint pain 134 (16%) 35 (20.2%) 86 (15.9%) 21 (6.2%) 2 (3.6%) 10 (5.8%) Muscle pain 155 (18.5%) 24 (13.9%) 69 (12.8%) 32 (9.5%) 5 (9.1%) 23 (13.4%) Vomiting 12 (1.4%) - 6 (1.1%) 13 (3.8%) - 3 (1.7%) Other (unsolicited) adverse events Comprising: 111 (13.3%) 20 (11.6%) 62 (11.5%) 47 (13.9%) 5 (9.1%) 19 (11%) Abdominal distension 1 (0.1%) - - - - - Abdominal pain 11 (1.3%) - 7 (1.3%) 17 (5%) 1 (1.8%) 6 (3.5%) Blurred vision 2 (0.2%) - 2 (0.4%) - - - Buccal inflammation - - 1 (0.2%) - - - Constipation 1 (0.1%) - - - - - Cough 4 (0.5%) - 1 (0.2%) 2 (0.6%) - 2 (1.2%) Dizziness 20 (2.4%) 5 (2.9%) 11 (2%) 4 (1.2%) - 1 (0.6%) Epigastric pain 6 (0.7%) 1 (0.6%) 2 (0.4%) 1 (0.3%) - - Fever 4 (0.5%) - - 1 (0.3%) - 1 (0.6%) Hyperhydrosis 2 (0.2%) - - - - - Insomnia 1 (0.1%) - - - - - Loss of appetite 7 (0.8%) - 6 (1.1%) - - - Lower back pain 14 (1.7%) 7 (4%) 11 (2%) 1 (0.3%) - - Nausea 2 (0.2%) - - - - - Polyuria 1 (0.1%) - - - - - Pruritus 6 (0.7%) 3 (1.7%) 3 (0.6%) - - - Shivering/chills 36 (4.3%) 4 (2.3%) 16 (3%) 8 (2.4%) 2 (3.6%) 2 (1.2%) Table 3. Moderate and severe adverse events Participant Baseline serostatus Adverse event Day of onset post-vaccination Duration (days) † 7 year old girl Negative Fatigue Muscle pain 28 28 2 2 18 year old man Negative Headache Joint pain Muscle pain 1 1 1 1 1 1 18 year old woman Negative Nausea 1 1 19 year old man Unknown Dizziness Loss of appetite Buccal inflammation Itching 1 1 1 1 ≥3, ≤14 ≥3, ≤14 13 13 21 year old man Unknown Fatigue 0 3 35 year old man Negative Joint pain Muscle pain 1 1 ≥3, ≤14 4 42 year old man Unknown Fatigue Muscle pain Lower back pain 1 1 1 2 2 2 49 year old man Unknown Fatigue* Headache 24 24 ≥4 ≥4 63 year old man Unknown Fatigue 1 2 *denotes reported as severe. All other were moderate. † Where precise duration is not known, ranges are given from follow-up intervals. Additional Declarations No competing interests reported. Supplementary Files ProchesSupplementarymaterialv0.02.docx Cite Share Download PDF Status: Published Journal Publication published 07 Nov, 2024 Read the published version in BMC Medicine → Version 1 posted Editorial decision: Revision requested 31 Jul, 2024 Reviews received at journal 31 Jul, 2024 Reviews received at journal 22 Jul, 2024 Reviews received at journal 17 Jul, 2024 Reviewers agreed at journal 03 Jul, 2024 Reviewers agreed at journal 01 Jul, 2024 Reviewers agreed at journal 28 Jun, 2024 Reviewers invited by journal 27 Jun, 2024 Editor assigned by journal 11 Jun, 2024 Submission checks completed at journal 11 Jun, 2024 First submitted to journal 11 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4562505","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":316749110,"identity":"7379d2c5-36a4-47f9-83ed-433040fadbec","order_by":0,"name":"Conall H Watson","email":"","orcid":"","institution":"UK Health Security Agency","correspondingAuthor":false,"prefix":"","firstName":"Conall","middleName":"H","lastName":"Watson","suffix":""},{"id":316749111,"identity":"fe7424cc-1689-471d-b2e3-e11f9141b580","order_by":1,"name":"Pierre-Stéphane 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flowchart\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4562505/v1/1743f5a716338ea38f0c8e80.png"},{"id":59870386,"identity":"26882ffb-c14c-4fa1-a987-67d783bf35f9","added_by":"auto","created_at":"2024-07-08 16:58:51","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":219039,"visible":true,"origin":"","legend":"\u003cp\u003epanel\u003c/p\u003e\n\u003cp\u003eA Pre-and 28 day post-vaccination anti-EBOV IgG ELISA titres, stratified by baseline seropositivity status. Box indicates median and interquartile range (IQR), whiskers 1.5*IQR.\u003c/p\u003e\n\u003cp\u003eB Day 28 post-vaccination Anti-EBOV IgG ELISA titres against pre-vaccination titres. Blue points indicate samples selected on ELISA for neutralization assay and tested successfully.\u003c/p\u003e\n\u003cp\u003eC Pre-and 28 day post-vaccination Ebolavirus neutralization titres, stratified by baseline anti-EBOV IgG ELISA titres in the subset. Box indicates median and interquartile range, whiskers 1.5*IQR.\u003c/p\u003e\n\u003cp\u003eD Neutralization titres before and 28 days after vaccination in a subset of samples tested by IgG ELISA\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4562505/v1/24d5ad339c790ec4c8f3b1d7.png"},{"id":68749782,"identity":"b71eb0bf-2555-4af3-ae2a-c17529e69f1a","added_by":"auto","created_at":"2024-11-11 16:04:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1200828,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4562505/v1/35a62756-00b0-423e-89f9-c96355eed060.pdf"},{"id":59870385,"identity":"37d75840-383e-4ee6-bb16-0e6fbe5f61e3","added_by":"auto","created_at":"2024-07-08 16:58:51","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":31250,"visible":true,"origin":"","legend":"","description":"","filename":"ProchesSupplementarymaterialv0.02.docx","url":"https://assets-eu.researchsquare.com/files/rs-4562505/v1/b935ceb29bc84e7455e9c291.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"rVSV-ZEBOV vaccination in people with pre-existing immunity to Ebolavirus: an open-label safety and immunogenicity study in Guinean communities affected by Ebola virus disease (l’essai Proches)","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEbolavirus (EBOV) has caused high mortality and morbidity outbreaks of Ebola virus disease (EVD) across equatorial Africa.\u003csup\u003e1,2\u003c/sup\u003e Sustained person-to-person transmission may arise following single zoonotic transmission events and lead to large outbreaks.\u003csup\u003e3\u0026ndash;5\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eEVD control methods include contact tracing, case isolation, health education and safe burial, with appropriate community engagement.\u003csup\u003e6\u003c/sup\u003e Since 2016, outbreak response also includes the use of a safe and highly efficacious attenuated replication-competent vesicular stomatitis virus-derived vaccine expressing the surface glycoprotein (GP) of EBOV (rVSV-ZEBOV).\u003csup\u003e7\u003c/sup\u003e\u003csup\u003e,8\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Previous studies report that rVSV-ZEBOV\u0026nbsp;is safe and well tolerated,\u003csup\u003e7\u0026ndash;13\u003c/sup\u003e, It has been approved by US and European regulators as well as national regulatory authorities in ten African countries. Serology studies from central Africa reported that in villages experiencing an outbreak and in areas at risk of zoonotic transmission mean population seroprevalence will range from 2-29%, as measured by the detection of immunoglobulin G (IgG) to EBOV-GP in clinical samples.\u003csup\u003e14\u0026ndash;18\u003c/sup\u003e Studies in post-outbreak communities in West Africa have similarly found undiagnosed seropositive contacts, referred to as asymptomatic cases, though a level of caution needs to be applied to studies in which antibody analysis is not supported by additional assessments i.e. virus neutralization.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe impact of pre-existing antibodies to EVD on rVSV-ZEBOV\u0026nbsp;safety and immunogenicity is unknown. Any sign of blunted immunogenicity or safety concerns in previously infected individuals would warrant further investigation. Therefore, we undertook an open-label rVSV-ZEBOV\u0026nbsp;vaccination cohort study , enrolling contacts of EVD cases who survived and for which ring vaccination was not previously implemented during the 2013-16 outbreak.\u003cs\u003e.\u003c/s\u003e\u003csup\u003e19\u003c/sup\u003e\u003csup\u003e,\u0026nbsp;\u003c/sup\u003e\u003csup\u003e20,21\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study\u0026rsquo;s primary objective was to measure the IgG response to EBOV GP at 28 days post-vaccination by baseline IgG status; secondary objectives were comparing the rates of serious adverse events (SAEs) and adverse events (AEs) by baseline serostatus; and to explore any association between participants\u0026rsquo; baseline serostatus and linked-survivor-related factors.\u003c/p\u003e"},{"header":"Methods","content":"\u003ch2\u003eEthics\u003c/h2\u003e\n\u003cp\u003eThe study was approved by the World Health Organization (WHO) Research Ethics Review Committee (ERC.0002723), the London School of Hygiene \u0026amp; Tropical Medicine, UK, interventional research ethics committee (10523/RR/4674), and by the Comit\u0026eacute; National d\u0026apos;Ethique pour la Recherche en Sant\u0026eacute;.\u003c/p\u003e\n\u003ch2\u003eSetting\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eThe study was conducted in Basse-Guin\u0026eacute;e region, Guinea. The first volunteer was recruited on 25 May 2016 and follow up of the final participant completed on 21 Sep 2016.\u003c/p\u003e\n\u003ch2\u003eDesign\u003c/h2\u003e\n\u003cp\u003eParticipants were contacts of EVD survivors whose onset of symptoms occurred within 15 months prior to the start of the study. The study was a prospective cohort study examining IgG antibodies by ELISA serology at baseline and at day 28 following rVSV-ZEBOV vaccination. It also documented post-vaccination adverse events at days 3, 14 and 28, comparing those with raised baseline antibodies against those without. Survivors were tested using RT-PCR and were not prospectively vaccinated. Baseline and day 28 EBOV GP IgG concentrations were also assessed for association with survivor-related factors, such as time since survivor EVD onset.\u003c/p\u003e\n\u003ch2\u003eStudy population\u003c/h2\u003e\n\u003cp\u003eIn May 2016, we identified contacts of adult or adolescent, PCR confirmed, EVD survivors who had not been previously included in the rVSV-ZEBOV ring vaccination \u003cem\u003eEbola ca suffit trial.\u003c/em\u003e\u003csup\u003e7\u003c/sup\u003e\u0026nbsp; These contacts were assumed to be at a low but not zero risk of EVD due to potential persistence of viable EBOV in the body fluids of EVD survivors.\u003csup\u003e14,20,22,23\u003c/sup\u003e Survivors were identified from national surveillance records. Survivor support organisations were also used as an information source to verify data against these records. Survivors\u0026rsquo; communities of residence were cross-referenced against the records of the Ebola \u0026Ccedil;a Suffit ring trial,\u003csup\u003e7\u003c/sup\u003e to exclude survivors whose contacts were already included in the trial.\u003c/p\u003e\n\u003cp\u003eA revised definition of contacts of EVD survivors because of their socio-epidemiological status (\u0026ldquo;\u003cem\u003eles proches\u0026rdquo;\u003c/em\u003e) was developed. It included household contacts (shared sleeping building or shared cooking pot), sexual contacts and second tier of people who would be at risk of transmission should a close contact develop EVD as a result of a post-recovery transmission event e.g. neighbours of survivors and household contacts of a sexual contact of a survivor.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eProches\u003c/em\u003e were identified by trained field epidemiologists. They were eligible for inclusion if they were 6 years of age or older and did not meet any exclusion criteria, namely: history of EVD (self-report), history of vaccination with any EBOV vaccine, verbally declared pregnancy, or planning to conceive within two months of vaccination (pregnancy tests were offered but not required), \u0026nbsp;breast-feeding, \u0026nbsp;history of having received investigational research agents in the previous 28 days, clinically important immunodeficiency condition (e.g. HIV/AIDS), history of anaphylaxis to a vaccine or vaccine component, or a severe illness that makes the person bed-bound or requiring hospitalization at the time of the vaccination.\u003c/p\u003e\n\u003ch2\u003eInformed Consent\u003c/h2\u003e\n\u003cp\u003eCommunities were approached and the study explained by the study\u0026rsquo;s community engagement team, and permission obtained to enter the community. Individual written informed consent was obtained for all participants using a signed, printed information sheet. For child participants, consent was obtained from parents or guardians. Children aged 12 to 17 years also gave written consent. If the potential participant was illiterate, the documents were read in a local language and a fingerprint collected, countersigned by a literate independent witness. The teams taking informed consent were different from those involved in community engagement and the epidemiological determination of proches to include in the rings.\u003c/p\u003e\n\u003ch2\u003eProcedures\u003c/h2\u003e\n\u003cp\u003eConsenting vaccinees received a single dose of at least 2 x 10\u003csup\u003e7\u003c/sup\u003e plaque forming units of the rVSV-ZEBOV vaccine (donated by Merck Sharp \u0026amp; Dohme, Kenilworth, NJ, USA) intramuscular to a deltoid. From each vaccinee, immediately prior to vaccination and on day 28 (+/-3 days) post-vaccination, up to 10ml of venous blood for serology was collected in a sterile serum separator tube by a trained person using standard techniques. Participants were observed for 30 minutes post-vaccination for immediate adverse reactions. Follow-up for adverse events was done on days 3, 14 and 28 post-vaccination by safety monitoring teams, with a window of +/- 1, 2 and 3 days respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsenting EVD survivors provided a 10ml venous blood for reverse-transcriptase polymerase chain reaction (RT-PCR) in the study laboratory in Conakry, Guinea. Female survivors were invited to provide a vaginal swab, and menstrual blood or breastmilk sample if applicable; male survivors were invited to provide a semen sample. All were tested using an RT-PCR\u003c/p\u003e\n\u003cp\u003eSamples were transferred to Europe for analysis under a signed Material Transfer Agreement issued by the Ministre Sante Hygiene Publique, Guin\u0026eacute;e.\u003c/p\u003e\n\u003ch2\u003eData collection\u003c/h2\u003e\n\u003cp\u003eData was collected on encrypted Android tablets using OpenDataKit (ODK) Collect on forms designed in XLSform. Uploaded data was stored in ODK Aggregate on an encrypted server. QR barcodes were used to link participants records and laboratory samples and for staff digital signatures. GPS data was collected on participant locations to aid follow-up.\u003c/p\u003e\n\u003cp\u003eBaseline demographic data and contact information was collected from all participants. Survivors were asked about possible EVD sequalae. Details of specified adverse events were solicited at each post-vaccination follow-up visit, with unsolicited events also documented on days 3 and 14. Participants were provided with a contact number on their participant enrolment card if they wanted to contact the study team between visits to notify or get advice on any possible adverse events.\u003c/p\u003e\n\u003cp\u003eTo reduce the risk of important response biases, data collectors were trained in information solicitation methods by experienced HIV/AIDS teams. Interviews were conducted away from communal settings to increase privacy. Participants missing from safety monitoring visits were actively traced by the field team to reduce loss to follow-up.\u003c/p\u003e\n\u003ch2\u003eLaboratory methods\u003c/h2\u003e\n\u003ch3\u003e\u003cstrong\u003eEBOV GP ELISA\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eAnti-EBOV GP IgG was determined by ELISA using previously published methods\u0026nbsp;\u003csup\u003e24,25\u003c/sup\u003e with a trimerised Zaire strain GP antigen, aa 1-649 of GenBank AHX24649.1 (GIN/2014/Makona-Kissidougou-C15). Results were standardised by inclusion of a reference curve for which the reference material was a plasma pool from three EVD survivors, calibrated against WHO Reference Reagent (NIBSC 15/220)\u003csup\u003e26\u003c/sup\u003e (Anti-GP concentration = 0.761 +/- 0.006 IU/ml (mean +/- SEM, n=13)). Negative control plasma pool was obtained from three Guinean volunteers with no prior infection with EVD or contact with an EVD case-patient. Matched serum pairs were tested in triplicate. Samples without a matching pair were not tested. OD was interpolated from the reference serum curve. In the absence of well-defined thresholds for immunity or past infection, we set a serological threshold based on the negative control. The threshold for seropositivity was determined as 0.0429 IU/ml, three standard deviations above the negative control geometric mean (n=91).\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eEBOV Zaire Neutralization Assay\u003c/h3\u003e\n\u003cp\u003eFifty paired samples were selected based on having a low, medium or high baseline anti-GP IgG concentration for analysis using a live EBOV neutralization assay at the Institute of Virology BSL4 laboratory, Philipps University of Marburg, Germany.\u003csup\u003e27\u003c/sup\u003e Based on previous studies the seropositivity threshold for neutralization assays was defined as\u0026nbsp;\u0026ge;1:8 geometric mean titre (GMT).\u003c/p\u003e\n\u003ch2\u003eStatistical analysis\u003c/h2\u003e\n\u003cp\u003eTo recruit 50 baseline-seropositive participants, a sample size of 1000\u0026nbsp;\u0026le;\u0026nbsp;n\u0026nbsp;\u0026le;\u0026nbsp;2000 was estimated to be required if pre-existing seropositivity was consistent with serosurveillance in other Ebola-experienced areas.\u003c/p\u003e\n\u003cp\u003eDescriptive analyses and multivariable regression were performed in R (3.5).\u003csup\u003e28\u003c/sup\u003e For multivariable regression where relevant variables were missing, records were omitted from that analysis. Serological data was compared by paired t-test or Mann-Whitney test. Correlation between ELISA and neutralization assays was compared by Spearman rank correlation coefficient. We set statistical significance level at 5%.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eWe identified 136 EVD survivors whose contacts (\u003cem\u003eproches\u003c/em\u003e) were unvaccinated. For these survivors the date of discharge from Ebola Treatment Unit ranged from 16 Feb to 7 Oct 2015 (median 22 March 2015). \u0026nbsp;Of these, 80.1% (109/136) were located. Only 48 were contacted and all gave their consent for an interview and for sample collection. The remaining were not approached by the study team because a national effort with similar objectives was initiated, and duplication was deemed not desirable. In total 2750 \u003cem\u003eproches\u003c/em\u003e of 109 EVD survivors were identified. Among them 77.3% (2126/2750) were eligible for our study, and 2115 were enrolled and vaccinated following consent (figure 1). The median number of screened and vaccinated proches per EVD survivor was 12 (range 1 to 100, IQR 7 to 21). Of the 0.5% (11/2126) not then vaccinated eight were either not present at the time of vaccination or did not have a reason for non-vaccination recorded, two withdrew consent, and one had a medical condition. \u0026nbsp;Venous samples from both day 0 and day 28 were provided by 66.3% (1403/2115) vaccinees.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHumoral immunogenicity following rVSV-ZEBOV vaccination\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe tested the 1403 matched (day 0 and 28) \u003cem\u003eproches\u0026rsquo;\u003c/em\u003e samples by ELISA and found that \u0026nbsp;228 (16.3%) were defined as seropositive at baseline (day 0).\u003c/p\u003e\n\u003cp\u003eLogistic regression analysis of potential factors associated with baseline seropositivity did not find an association with sex, age group, or time since survivor discharge from the Ebola treatment unit (ETU) (supplementary material table S1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOf the 1175 baseline seronegative participants, 955 (81.3%, 95%CI 78.9 to 83.4%) were seropositive by ELISA on day 28 (figure 2 panels A and B). Three (1.3%) of 228 initially seropositive vaccinees were found seronegative at day 28. This could be due to waning immunity in weakly positive samples or assay variability. There were statistically significant increases in IgG GMT at day 28 for both those seropositive and seronegative at baseline (table 1). The day 28 GMT was higher for baseline seropositive participants compared to the day 28 GMT of baseline seronegative participants (p-value for difference \u0026lt;0.0001).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eExamining IgG titres of those who were seronegative at baseline we found that \u0026nbsp;children showed 91.1% seroconversion rate (308 of 338, \u0026nbsp;95%CI 87.6% to 93.7%) compared with adults who showed a 77.3% seroconversion rate by day 28(647 of 837, 95%CI 74.3 to 80.0%). Children also had higher day 28 IgG GMT of 0.167 (95%CI 0.149 to 0.187) compared to adults GMT of 0.089 (95%CI 0.083 to 0.095, p\u0026lt;0.0001). Amongst those classed as seropositive at baseline we found that children attained higher day 28 titres (GMT 0.338 (95%CI 0.266 to 0.429) than adults (GMT 0.211, 95%CI 0.185 to 0.242, p=0.003).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe next sought to validate these ELISA results using live virus neutralization assays on a subset of 50 matched day 0 and 28 samples, 100 samples in total. These samples were identified as high, medium or low responder. We found that day 0 neutralization GMT was 8.5 (95%CI 5.9 to 12.2), rising to 25.1 (95%CI 16.1 to 39.2) at day 28, with proportion considered positive rising from 13/49 (26.5%) to 39/49 (79.6%). Moderate correlation with IgG was seen in baseline neutralization assay titres (Spearman\u0026rsquo;s rho = 0.50; p=0.002 on 47 degrees of freedom (df)). Correlation was stronger between day 28 assays (rho = 0.75; p\u0026lt;0.0001 on 47 df) (figure 2, panel D).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVaccine Safety\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe also investigated adverse events, and stratified this by serostatus at baseline and age group \u0026nbsp;(Table 2). Although the immunogenicity analysis was restricted to vaccinees providing paired serological samples, safety data is also presented for those who did not provide a day 28 serum sample. \u0026nbsp;Prevalence was similar in both serogroups and those untested. Of the 62% (1317/2215) reporting any adverse event, 99% (1038/1317) reported only mild events. The most common adverse event in adults and children was headache (35.1% (742/2115)), followed by fatigue (23.7% (501/2115)) and muscle pain (14.6% (308/2115)) (Table 2). Most were short duration: median two days (interquartile range 1-3). Participants most commonly reported adverse events at the day 3 follow-up visit. The most common unsolicited adverse events in adults were shivers/chills (3.6% (56/1550)), dizziness (2.3% (36/1550)), and abdominal pain (1.2% (18/1550)); amongst children the more frequent adverse events include: abdominal pain (4.2%(24/565)), and shivers/chills (2.1%(12/565)) (Table 2).\u003c/p\u003e\n\u003cp\u003eEight participants reported moderate adverse events (most commonly fatigue or muscle pain) and one reported severe fatigue (table 3). No moderate or severe adverse events were reported in those known to be seropositive at day 0.\u003c/p\u003e\n\u003cp\u003eAssociation between any adverse event and baseline sero-status was assessed by logistic regression, adjusting for age group (adult/child) and sex and interaction between these factors (supplementary table S2). No association was observable for baseline serological status; adult females appeared more likely to report adverse events than other groups.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn an exploratory Poisson regression of adverse event count (across solicited and unsolicited AEs, supplementary material table S3), there was weak evidence of association between baseline seropositivity and lower count of adverse events after adjusting for age and sex. No interactions were identified in sensitivity analysis. Results did not change under robust Poisson regression.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eEVD survivors\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eAll 48 consented survivors completed a questionnaire, of whom 14 (29.2%) reported at least one health problem since discharge (supplementary table S4). Eye problems were most common (10, 20.8%). Sequelae were reported across multiple organ systems including neurological signs, joint problems and abdominal symptoms. From the 128 body fluid samples tested (see figure 1), none tested positive for Ebolavirus by RT-PCR.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis cohort study in Guinea provides additional evidence that\u0026nbsp;one dose ofrVSV ZEBOV GP vaccine is safe and immunogenic among seropositive or seronegative individuals as assessed by IgG antibody titres to Ebolavirus at the time of vaccination. This supports previous work which has shown this vaccine to be safe and effective and highlights the importance of rVSV-ZEBOV in controlling future outbreaks.\u003csup\u003e7,29\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe finding that 16.3% of proches had detectable IgG \u0026nbsp;to EBOV-GP is consistent with previous community/contact studies in central Africa,\u003csup\u003e14\u0026ndash;18\u003c/sup\u003e and warrants further investigation into the prevalence of asymptomatic cases and the mechanisms behind asymptomatic or abortive EBOV infections.\u003csup\u003e30\u003c/sup\u003e Researchers found\u0026nbsp;~15% of study participants in Guinea, Sierra Leone, Liberia \u0026nbsp;in 2018 had prior EBOV-GP immunity before vaccination \u0026nbsp;compared to only 5% in neighbouring Mali.\u003csup\u003e31\u003c/sup\u003e Proposals for this seemingly higher level of seroprevalence include the geographical and ecological differences between these two regions and prior exposure to related and potentially non-pathogenic filoviruses, such exposures may account for some of the elevated baseline responses seen in this study.\u003csup\u003e32,33\u003c/sup\u003e We did not observe an association between baseline seropositivity and age or gender, unlike a DRC study.\u003csup\u003e34\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eFrom our results we estimated a sero-conversion rate of 81.3% (95% CI 78.9 to 83.4%) in those who were seronegative at baseline, and an overall seropositivity of 84.1% (95% CI 82.1 to 86.0%) across all \u003cem\u003eproches\u003c/em\u003e tested on day 28. This is within the range of other immunogenicity studies with the rVSV-ZEBOV vaccine that will have also used different assay methodology and definitions of positive outcomes.\u003csup\u003e11\u003c/sup\u003e Importantly, these results provide short term data that individuals with pre-existing immunity to EBOV GP could experience an increase of antibody titres following the administration of of rVSV-ZEBOV.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe\u0026nbsp;strong correlation observed between neutralization assays and IgG ELISAs following vaccination further suggests the ELISA used may be an acceptable marker of immunogenicity.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe frequency of adverse events between the sero-groups was similar. No increase in adverse events reporting were identified when serogroups were further stratified into children and adults. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIt was not possible to assess the effects of vaccination in prevention of infection in contacts of \u0026nbsp;survivors as no EVD survivor tested positive for Ebolavirus by RT-PCR. Survivor studies have shown that RNA detection decays over time in semen at variable rates in different survivors, and, as a consequence, transmission risks decrease over time due to lower inoculum, nonviable virus, or other factors. Since 2016, \u003cu\u003e\u0026gt;\u003c/u\u003e95% of the EVD cases and \u003cu\u003e\u0026gt;\u003c/u\u003e95% of their contacts and contacts of contacts have been enumerated in rings and vaccinated with rVSV ZEBOV GP. Therefore a small fraction of contacts not yet vaccinated are sparsely spread over large areas, making it difficult to further assess this question in the field. It is also unknown if vaccine induced antibodies can reach the immune-privileged sites where it is assumed the virus can remain. In 2021, one case of Ebola transmission from a person infected in the 2013-2016 epidemic occurred, outside of our vaccination area.\u003csup\u003e23\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eEbola remains a pressing public health concern in many sub-Saharan countries. This proches vaccination study suggests rVSV ZEBOV GP can be safely administered to individuals with prior asymptomatic Ebola infection (or cross-reactivity that may have caused antibody production) without requiring baseline serological results. Furthermore, existence of prior EBOV GP IgG responses from suspected natural infection does not prevent the ability of an additional dose of rVSV ZEBOV GP to increase antibody titres.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe gratefully acknowledge the contribution of the participants, host communities, field and laboratory teams, Michael Schmidt and Gotthard Ludwig for technical support in biosafety level 4 procedures, Megan O\u0026rsquo;Driscoll for data management, and the Government of Guinea.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe would like to thank colleagues for helpful discussions in development of the study: Federica Ambrosini, Nathalie Broutet, Gabriella De Carli, Antonio Di Caro, Judith Glynn, Giuseppe Ippolito, Simone Lanini, Francesco Vairo and Jimmy Whitworth.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was funded by the UN Foundation, Washington, and the WHO, Geneva. The WHO was the sponsor. Laboratory processing was funded by the European Commission (EuropeAid Cooperation Office) through contract No. IFS/2011/272-372 for the EMLab project, Establishment of Mobile Laboratories for Pathogens up to Risk Group 4 in Combination with CBRN Capacity Building in sub-Saharan Africa. Analysis and writing by CHW, AC, and WJE was funded by the Department of Health and Social Care using UK Aid funding, managed by the NIHR (Vaccine Efficacy Evaluation of Priority Emerging Diseases consortium). The views expressed are those of these author(s) and not necessarily those of the NIHR or the Department of Health and Social\u0026nbsp;Care.\u0026nbsp;The laboratory analysis performed at UKHSA Porton down was supported by a grant from the Food and Drug Administration (Contract No. HHSF223201510104C).\u0026nbsp;\u003cbr\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLegrand J, Grais RF, Boelle PY, Valleron AJ, Flahault A. Understanding the dynamics of Ebola epidemics. \u003cem\u003eEpidemiol Infect\u003c/em\u003e 2007; \u003cstrong\u003e135\u003c/strong\u003e: 610\u0026ndash;21.\u003c/li\u003e\n\u003cli\u003eHeymann D. Ebola: learn from the past. \u003cem\u003eNature\u003c/em\u003e 2014; \u003cstrong\u003e514\u003c/strong\u003e: 299\u0026ndash;300.\u003c/li\u003e\n\u003cli\u003eBaize S, Pannetier D, Oestereich L, \u003cem\u003eet al.\u003c/em\u003e Emergence of Zaire Ebola Virus Disease in Guinea. \u003cem\u003eN Engl J Med\u003c/em\u003e 2014; \u003cstrong\u003e371\u003c/strong\u003e: 1418\u0026ndash;25.\u003c/li\u003e\n\u003cli\u003eCarroll MW, Matthews DA, Hiscox JA, \u003cem\u003eet al.\u003c/em\u003e Temporal and spatial analysis of the 2014\u0026ndash;2015 Ebola virus outbreak in West Africa. \u003cem\u003eNature\u003c/em\u003e 2015. 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Geneva, 2014 https://www.who.int/csr/disease/ebola/manual_EVD/en/.\u003c/li\u003e\n\u003cli\u003eHenao-Restrepo AM, Camacho A, Longini IM, \u003cem\u003eet al.\u003c/em\u003e Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola \u0026Ccedil;a Suffit!). \u003cem\u003eLancet\u003c/em\u003e 2017; \u003cstrong\u003e389\u003c/strong\u003e: 505\u0026ndash;18.\u003c/li\u003e\n\u003cli\u003eGsell P-S, Camacho A, Kucharski AJ, \u003cem\u003eet al.\u003c/em\u003e Ring vaccination with rVSV-ZEBOV under expanded access in response to an outbreak of Ebola virus disease in Guinea, 2016: an operational and vaccine safety report. \u003cem\u003eLancet Infect Dis\u003c/em\u003e 2017; \u003cstrong\u003e3099\u003c/strong\u003e. 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A systematic review and meta-analysis of seroprevalence surveys of ebolavirus infection. \u003cem\u003eSci Data\u003c/em\u003e 2016; : 1\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003e Keita M, Keita S, Diallo B, \u003cem\u003eet al.\u003c/em\u003e Public Health Program for Decreasing Risk for Ebola Virus Disease Resurgence from Survivors of the 2013\u0026ndash;2016 Outbreak, Guinea. \u003cem\u003eEmerg Infect Dis J\u003c/em\u003e 2020; \u003cstrong\u003e26\u003c/strong\u003e: 206.\u003c/li\u003e\n\u003cli\u003e Christie A, Davies-Wayne GJ, Cordier-Lasalle T, \u003cem\u003eet al.\u003c/em\u003e Possible sexual transmission of Ebola virus - Liberia, 2015. \u003cem\u003eMMWR Morb Mortal Wkly Rep\u003c/em\u003e 2015; \u003cstrong\u003e64\u003c/strong\u003e: 479\u0026ndash;81.\u003c/li\u003e\n\u003cli\u003e Diallo B, Sissoko D, Loman NJ, \u003cem\u003eet al.\u003c/em\u003e Resurgence of Ebola Virus Disease in Guinea Linked to a Survivor With Virus Persistence in Seminal Fluid for More Than 500 Days. \u003cem\u003eClin Infect Dis\u003c/em\u003e 2016; \u003cstrong\u003e63\u003c/strong\u003e: 1353\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003e Eggo RM, Watson CH, Kucharski AJ, Camacho A, Funk S, Edmunds WJ. Duration of Ebola virus RNA persistence in semen of survivors: population-level estimates and projections. \u003cem\u003eEurosurveillance\u003c/em\u003e 2015; \u003cstrong\u003e20\u003c/strong\u003e: pii=30083.\u003c/li\u003e\n\u003cli\u003e Keita AK, Koundouno FR, Faye M, \u003cem\u003eet al.\u003c/em\u003e Resurgence of Ebola virus in 2021 in Guinea suggests a new paradigm for outbreaks. \u003cem\u003eNature\u003c/em\u003e 2021; \u003cstrong\u003e597\u003c/strong\u003e: 539\u0026ndash;43.\u003c/li\u003e\n\u003cli\u003e Ewer K, Rampling T, Venkatraman N, \u003cem\u003eet al.\u003c/em\u003e A Monovalent Chimpanzee Adenovirus Ebola Vaccine Boosted with MVA. \u003cem\u003eN Engl J Med\u003c/em\u003e 2016; \u003cstrong\u003e374\u003c/strong\u003e: 1635\u0026ndash;46.\u003c/li\u003e\n\u003cli\u003e Thom R, Tipton T, Strecker T, \u003cem\u003eet al.\u003c/em\u003e Longitudinal antibody and T cell responses in Ebola virus disease survivors and contacts: an observational cohort study. \u003cem\u003eLancet Infect Dis\u003c/em\u003e 2021; \u003cstrong\u003e21\u003c/strong\u003e: 507\u0026ndash;16.\u003c/li\u003e\n\u003cli\u003e Wilkinson DE, Page M, Almond N, \u003cem\u003eet al.\u003c/em\u003e Final Report: WHO collaborative study to assess the suitability of an interim standard for antibodies to Ebola virus. Geneva, 2015 https://apps.who.int/iris/bitstream/handle/10665/197777/WHO_BS_2015.2280_eng.pdf.\u003c/li\u003e\n\u003cli\u003e Dowall SD, Callan J, Zeltina A, \u003cem\u003eet al.\u003c/em\u003e Development of a Cost-effective Ovine Polyclonal Antibody-Based Product, EBOTAb, to Treat Ebola Virus Infection. \u003cem\u003eJ Infect Dis\u003c/em\u003e 2015; \u003cstrong\u003e213\u003c/strong\u003e: 1124\u0026ndash;33.\u003c/li\u003e\n\u003cli\u003e R Core Team. R: A language and environment for statistical computing. 2017. R-project.org.\u003c/li\u003e\n\u003cli\u003e World Health Organization. Preliminary results on the efficacy of rVSV-ZEBOV-GP Ebola vaccine using the ring vaccination strategy in the control of an Ebola outbreak in the Democratic Republic of the Congo: an example of integration of research into epidemic response. 2019 https://www.who.int/csr/resources/publications/ebola/ebola-ring-vaccination-results-12-april-2019.pdf.\u003c/li\u003e\n\u003cli\u003e Carroll M. Serological evidence of zoonotic filovirus exposure among bushmeat hunters in Guinea. 2022. DOI:10.21203/rs.3.rs-1347502/v1.\u003c/li\u003e\n\u003cli\u003e PREVAC Study Team. Randomized Trial of Vaccines for Zaire Ebola Virus Disease. \u003cem\u003eN Engl J Med\u003c/em\u003e 2022; \u003cstrong\u003e387\u003c/strong\u003e: 2411\u0026ndash;24.\u003c/li\u003e\n\u003cli\u003e Pigott DM, Golding N, Mylne A, \u003cem\u003eet al.\u003c/em\u003e Mapping the zoonotic niche of Ebola virus disease in Africa. \u003cem\u003eElife\u003c/em\u003e 2014; \u003cstrong\u003e3\u003c/strong\u003e: e04395.\u003c/li\u003e\n\u003cli\u003e Goldstein T, Anthony SJ, Gbakima A, \u003cem\u003eet al.\u003c/em\u003e The discovery of Bombali virus adds further support for bats as hosts of ebolaviruses. \u003cem\u003eNat Microbiol\u003c/em\u003e 2018; \u003cstrong\u003e3\u003c/strong\u003e: 1084\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003e Mulangu S, Alfonso VH, Hoff NA, \u003cem\u003eet al.\u003c/em\u003e Serologic Evidence of Ebolavirus Infection in a Population With No History of Outbreaks in the Democratic Republic of the Congo. \u003cem\u003eJ Infect Dis\u003c/em\u003e 2018; \u003cstrong\u003e217\u003c/strong\u003e: 529\u0026ndash;37.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e. Participant demographics and IgG titres by baseline serostatus\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.591836734693878%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"54.08163265306123%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eProches\u0026nbsp;\u003c/em\u003eVaccinees\u003c/p\u003e\n \u003cp\u003e(n=2115, of whom 1403 had paired serum for analysis)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.3265306122449%\" valign=\"top\"\u003e\n \u003cp\u003eEVD Survivors\u003c/p\u003e\n \u003cp\u003e(n=48)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.896907216494846%\" valign=\"top\"\u003e\n \u003cp\u003eSerostatus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.68041237113402%\" valign=\"top\"\u003e\n \u003cp\u003eSeronegative at baseline (day 0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003eSeropositive at baseline (day 0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003eNot tested (no paired sample)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003eNot applicable\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.896907216494846%\" valign=\"top\"\u003e\n \u003cp\u003eNumber (% of those tested)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.68041237113402%\" valign=\"top\"\u003e\n \u003cp\u003e1175 (83.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003e228 (16.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003e712\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003e48\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.896907216494846%\" valign=\"top\"\u003e\n \u003cp\u003eFemale sex (%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.68041237113402%\" valign=\"top\"\u003e\n \u003cp\u003e440 (37.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003e81 (35.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003e239 (33.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003e26 (54.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.896907216494846%\" valign=\"top\"\u003e\n \u003cp\u003eMedian age (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.68041237113402%\" valign=\"top\"\u003e\n \u003cp\u003e28 (15 to 46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003e30 (18 to 46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003e26 (18 to 40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003e32 (22 to 40)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.896907216494846%\" valign=\"top\"\u003e\n \u003cp\u003eAge range\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.68041237113402%\" valign=\"top\"\u003e\n \u003cp\u003e6 to 99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003e6 to 85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003e6 to 90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003e15 to 66\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.896907216494846%\" valign=\"top\"\u003e\n \u003cp\u003eChildren age 6-17 years\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(% of those tested)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.68041237113402%\" valign=\"top\"\u003e\n \u003cp\u003e338 (86.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003e55 (14.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003e172\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003e4\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.896907216494846%\" valign=\"top\"\u003e\n \u003cp\u003eAdults 18 years+\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(% of those tested)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.68041237113402%\" valign=\"top\"\u003e\n \u003cp\u003e837 (82.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003e173 (17.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003e540\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003e44\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eIgG geometric mean titre (GMT)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(95% confidence interval (CI)), p-value for difference from baseline)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.896907216494846%\" valign=\"top\"\u003e\n \u003cp\u003eDay 0 pre-vaccination\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003e0.0142 (0.0138 to 0.0146)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\"\u003e\n \u003cp\u003e0.0927 (0.0838 to 0.103)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.896907216494846%\" valign=\"top\"\u003e\n \u003cp\u003eDay 28 post vaccination\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003e0.106 (0.100 to 0.113, p\u0026lt;0.0001)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\"\u003e\n \u003cp\u003e0.237 (0.210 to 0.267, p\u0026lt;0.0001)\u003csup\u003e\u0026nbsp;\u003c/sup\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSeroconversion at day 28\u0026nbsp;\u003c/strong\u003e(%; 95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.896907216494846%\" valign=\"top\"\u003e\n \u003cp\u003eChildren\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003e308/338 (91.1%, 87.6% to 93.7%)\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.896907216494846%\" valign=\"top\"\u003e\n \u003cp\u003eAdults\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003e647/837 (77.3%, 74.3 to 80.0%)\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGMT\u003c/strong\u003e (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.896907216494846%\" valign=\"top\"\u003e\n \u003cp\u003eChildren\u0026rsquo;s baseline\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003e0.0130 (0.0122 to 0.0138)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\"\u003e\n \u003cp\u003e0.096 (0.077 to 0.120)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.896907216494846%\" valign=\"top\"\u003e\n \u003cp\u003eChildren\u0026rsquo;s day 28\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003e0.167 (0.149 to 0.187) \u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\"\u003e\n \u003cp\u003e0.338 (0.266 to 0.429)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.896907216494846%\" valign=\"top\"\u003e\n \u003cp\u003eAdults\u0026rsquo; baseline\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003e0.0147 (0.0142 to 0.0152)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\"\u003e\n \u003cp\u003e0.092 (0.082 to 0.103)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.896907216494846%\" valign=\"top\"\u003e\n \u003cp\u003eAdults\u0026rsquo; day 28\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.68041237113402%\"\u003e\n \u003cp\u003e0.089 (0.083 to 0.095) \u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\"\u003e\n \u003cp\u003e0.211 (0.185 to 0.242)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" valign=\"top\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*,\u0026dagger;,\u0026Dagger; The p-value for difference between these paired groups was \u0026lt;0.0001.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 2. Number of adults and children who experienced specified and unsolicited adverse events during 28 days from vaccination, by pre-vaccination serostatus\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.408163265306122%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.89795918367347%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdults\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.69387755102041%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eChildren\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.833333333333332%\" valign=\"top\"\u003e\n \u003cp\u003eSerostatus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eSeronegative at baseline\u003c/p\u003e\n \u003cp\u003en=837\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eSeropositive at baseline\u003c/p\u003e\n \u003cp\u003en=173\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eNot tested (no paired sample) n=540\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eSeronegative at baseline\u003c/p\u003e\n \u003cp\u003en= 338\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eSeropositive at baseline\u003c/p\u003e\n \u003cp\u003en= 55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eNot tested (no paired sample)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003en= 172\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" valign=\"top\"\u003e\n \u003cp\u003eSpecified adverse events\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.833333333333332%\" valign=\"top\"\u003e\n \u003cp\u003eAny adverse event\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e553 (66.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\n \u003cp\u003e110 (63.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e321 (59.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e206 (60.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" valign=\"top\"\u003e\n \u003cp\u003e27 (49.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e100 (58.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003eDiarrhoea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e15 (1.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e1 (0.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.02564102564103%\" valign=\"top\"\u003e\n \u003cp\u003e13 (2.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e6 (1.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e1 (1.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.205128205128204%\" valign=\"top\"\u003e\n \u003cp\u003e1 (0.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e220 (26.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e44 (25.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.02564102564103%\" valign=\"top\"\u003e\n \u003cp\u003e150 (27.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e52 (15.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e6 (10.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.205128205128204%\" valign=\"top\"\u003e\n \u003cp\u003e29 (16.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003eHeadache\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e306 (36.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e60 (34.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.02564102564103%\" valign=\"top\"\u003e\n \u003cp\u003e160 (29.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e136 (40.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e17 (30.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.205128205128204%\" valign=\"top\"\u003e\n \u003cp\u003e63 (36.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003eInjection pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e27 (3.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e4 (2.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.02564102564103%\" valign=\"top\"\u003e\n \u003cp\u003e21 (3.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e23 (6.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.205128205128204%\" valign=\"top\"\u003e\n \u003cp\u003e15 (8.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003eJoint pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e134 (16%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e35 (20.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.02564102564103%\" valign=\"top\"\u003e\n \u003cp\u003e86 (15.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e21 (6.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e2 (3.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.205128205128204%\" valign=\"top\"\u003e\n \u003cp\u003e10 (5.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003eMuscle pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e155 (18.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e24 (13.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.02564102564103%\" valign=\"top\"\u003e\n \u003cp\u003e69 (12.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e32 (9.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e5 (9.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.205128205128204%\" valign=\"top\"\u003e\n \u003cp\u003e23 (13.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e12 (1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.02564102564103%\" valign=\"top\"\u003e\n \u003cp\u003e6 (1.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e13 (3.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.205128205128204%\" valign=\"top\"\u003e\n \u003cp\u003e3 (1.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003eOther (unsolicited) adverse events\u003c/p\u003e\n \u003cp\u003eComprising:\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e111 (13.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e20 (11.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.02564102564103%\" valign=\"top\"\u003e\n \u003cp\u003e62 (11.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e47 (13.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e5 (9.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.205128205128204%\" valign=\"top\"\u003e\n \u003cp\u003e19 (11%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.833333333333332%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbdominal distension\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.625%\" valign=\"top\"\u003e\n \u003cp\u003e1 (0.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbdominal pain\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e11 (1.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.02564102564103%\" valign=\"top\"\u003e\n \u003cp\u003e7 (1.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e17 (5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e1 (1.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.205128205128204%\" valign=\"top\"\u003e\n \u003cp\u003e6 (3.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eBlurred vision\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e2 (0.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.02564102564103%\" valign=\"top\"\u003e\n \u003cp\u003e2 (0.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.205128205128204%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eBuccal inflammation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.02564102564103%\" valign=\"top\"\u003e\n \u003cp\u003e1 (0.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.205128205128204%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eConstipation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e1 (0.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.02564102564103%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.205128205128204%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCough\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e4 (0.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.02564102564103%\" valign=\"top\"\u003e\n \u003cp\u003e1 (0.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e2 (0.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.205128205128204%\" valign=\"top\"\u003e\n \u003cp\u003e2 (1.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDizziness\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e20 (2.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e5 (2.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.02564102564103%\" valign=\"top\"\u003e\n \u003cp\u003e11 (2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e4 (1.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.205128205128204%\" valign=\"top\"\u003e\n \u003cp\u003e1 (0.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEpigastric pain\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e6 (0.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e1 (0.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.02564102564103%\" valign=\"top\"\u003e\n \u003cp\u003e2 (0.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e1 (0.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.205128205128204%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFever\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e4 (0.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.02564102564103%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e1 (0.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.205128205128204%\" valign=\"top\"\u003e\n \u003cp\u003e1 (0.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHyperhydrosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e2 (0.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.02564102564103%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.205128205128204%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eInsomnia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e1 (0.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.02564102564103%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.205128205128204%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLoss of appetite\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e7 (0.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.02564102564103%\" valign=\"top\"\u003e\n \u003cp\u003e6 (1.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.205128205128204%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLower back pain\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e14 (1.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e7 (4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.02564102564103%\" valign=\"top\"\u003e\n \u003cp\u003e11 (2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e1 (0.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.205128205128204%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNausea\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e2 (0.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.02564102564103%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.205128205128204%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePolyuria\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e1 (0.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.02564102564103%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.205128205128204%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePruritus\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e6 (0.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e3 (1.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.02564102564103%\" valign=\"top\"\u003e\n \u003cp\u003e3 (0.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.205128205128204%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eShivering/chills\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e36 (4.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e4 (2.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.02564102564103%\" valign=\"top\"\u003e\n \u003cp\u003e16 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e8 (2.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\" valign=\"top\"\u003e\n \u003cp\u003e2 (3.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.205128205128204%\" valign=\"top\"\u003e\n \u003cp\u003e2 (1.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eTable 3. Moderate and severe adverse events\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.124792013311147%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eParticipant\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.97504159733777%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline serostatus\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.966722129783694%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdverse event\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.630615640599%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDay of onset post-vaccination\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.302828618968388%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDuration (days)\u003c/strong\u003e\u003cstrong\u003e\u0026dagger;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.124792013311147%\" valign=\"top\"\u003e\n \u003cp\u003e7 year old girl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.97504159733777%\" valign=\"top\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.966722129783694%\" valign=\"top\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003cp\u003eMuscle pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.630615640599%\" valign=\"top\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.302828618968388%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.124792013311147%\" valign=\"top\"\u003e\n \u003cp\u003e18 year old man\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.97504159733777%\" valign=\"top\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.966722129783694%\" valign=\"top\"\u003e\n \u003cp\u003eHeadache\u003c/p\u003e\n \u003cp\u003eJoint pain\u003c/p\u003e\n \u003cp\u003eMuscle pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.630615640599%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.302828618968388%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.124792013311147%\" valign=\"top\"\u003e\n \u003cp\u003e18 year old woman\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.97504159733777%\" valign=\"top\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.966722129783694%\" valign=\"top\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.630615640599%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.302828618968388%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.124792013311147%\" valign=\"top\"\u003e\n \u003cp\u003e19 year old man\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.97504159733777%\" valign=\"top\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.966722129783694%\" valign=\"top\"\u003e\n \u003cp\u003eDizziness\u003c/p\u003e\n \u003cp\u003eLoss of appetite\u003c/p\u003e\n \u003cp\u003eBuccal inflammation\u003c/p\u003e\n \u003cp\u003eItching\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.630615640599%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.302828618968388%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026ge;3,\u0026nbsp;\u0026le;14\u003c/p\u003e\n \u003cp\u003e\u0026ge;3,\u0026nbsp;\u0026le;14\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.124792013311147%\" valign=\"top\"\u003e\n \u003cp\u003e21 year old man\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.97504159733777%\" valign=\"top\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.966722129783694%\" valign=\"top\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.630615640599%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.302828618968388%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.124792013311147%\" valign=\"top\"\u003e\n \u003cp\u003e35 year old man\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.97504159733777%\" valign=\"top\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.966722129783694%\" valign=\"top\"\u003e\n \u003cp\u003eJoint pain\u003c/p\u003e\n \u003cp\u003eMuscle pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.630615640599%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.302828618968388%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026ge;3,\u0026nbsp;\u0026le;14\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.124792013311147%\" valign=\"top\"\u003e\n \u003cp\u003e42 year old man\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.97504159733777%\" valign=\"top\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.966722129783694%\" valign=\"top\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003cp\u003eMuscle pain\u003c/p\u003e\n \u003cp\u003eLower back pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.630615640599%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.302828618968388%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.124792013311147%\" valign=\"top\"\u003e\n \u003cp\u003e49 year old man\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.97504159733777%\" valign=\"top\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.966722129783694%\" valign=\"top\"\u003e\n \u003cp\u003eFatigue*\u003c/p\u003e\n \u003cp\u003eHeadache\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.630615640599%\" valign=\"top\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.302828618968388%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026ge;4\u003c/p\u003e\n \u003cp\u003e\u0026ge;4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.124792013311147%\" valign=\"top\"\u003e\n \u003cp\u003e63 year old man\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.97504159733777%\" valign=\"top\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.966722129783694%\" valign=\"top\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.630615640599%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.302828618968388%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*denotes reported as severe. All other were moderate.\u003c/p\u003e\n\u003cp\u003e\u0026dagger; Where precise duration is not known, ranges are given from follow-up intervals.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmed","sideBox":"Learn more about [BMC Medicine](http://bmcmedicine.biomedcentral.com/)","snPcode":"12916","submissionUrl":"https://submission.nature.com/new-submission/12916/3","title":"BMC Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Ebola virus disease, Ebola, vaccine, rVSV-ZEBOV, safety, immunogenicity, cohort study","lastPublishedDoi":"10.21203/rs.3.rs-4562505/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4562505/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZaire Ebolavirus disease (EVD) outbreaks can be controlled using rVSV-ZEBOV vaccination and other public health measures. \u0026nbsp;People in high-risk areas may have pre-existing antibodies from asymptomatic Ebolavirus exposure that might affect response to rVSV-ZEBOV. Therefore, we assessed the impact pre-existing immunity had on post-vaccination IgG titre, virus neutralization and reactogenicity following vaccination.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this prospective cohort study, 2,115 consenting close contacts (“proches”) of EVD survivors were recruited. Proches were vaccinated with rVSV-ZEBOV and followed up for 28 days for safety and immunogenicity. Anti-GP IgG titre at baseline and day 28 was assessed by ELISA. Samples from a representative subset were evaluated using live virus neutralization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTen percent were seropositive at baseline. At day, 28 IgG in baseline seronegative (GMT 0.106 IU/mL, 95% CI: 0.100 to 0.113) and seropositive (GMT 0.237 IU/ml, 0.210 to 0.267) participants significantly increased from baseline (both p\u0026lt;0.0001). \u0026nbsp;There was strong correlation between antibody concentration and virus neutralization in day 28 samples (Spearman's rho 0.75). Vaccinees with baseline IgG antibodies against Zaire Ebolavirus had similar safety profiles to those without detectable antibodies (63.6% vs 66.1% adults experienced any adverse event; 49.1% vs 60.9% in children), with almost all adverse events graded as mild. No serious adverse events were attributed to vaccination. No EVD survivors tested positive for Ebolavirus by RT-PCR.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThese data add further evidence of rVSV-ZEBOV safety and immunogenicity, including in people with pre-existing antibodies from suspected natural ZEBOV infection, whichdo not blunt rVSV-ZEBOV immune response. Pre-vaccination serological screening is not required.\u003c/p\u003e","manuscriptTitle":"rVSV-ZEBOV vaccination in people with pre-existing immunity to Ebolavirus: an open-label safety and immunogenicity study in Guinean communities affected by Ebola virus disease (l’essai Proches)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-08 16:58:47","doi":"10.21203/rs.3.rs-4562505/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-07-31T11:55:59+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-31T09:14:23+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-22T11:01:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-17T13:51:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"313933337057855338431404914974246908056","date":"2024-07-03T11:13:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"26003590674201172931105379306230927223","date":"2024-07-01T07:38:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"302569853149339710406465705615397584582","date":"2024-06-28T08:45:23+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-27T16:13:49+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-11T09:12:26+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-11T08:51:14+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Medicine","date":"2024-06-11T08:31:20+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmed","sideBox":"Learn more about [BMC Medicine](http://bmcmedicine.biomedcentral.com/)","snPcode":"12916","submissionUrl":"https://submission.nature.com/new-submission/12916/3","title":"BMC Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"51bcb822-812e-4129-a63d-ce2286a9bd01","owner":[],"postedDate":"July 8th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-11-11T15:58:56+00:00","versionOfRecord":{"articleIdentity":"rs-4562505","link":"https://doi.org/10.1186/s12916-024-03726-z","journal":{"identity":"bmc-medicine","isVorOnly":false,"title":"BMC Medicine"},"publishedOn":"2024-11-07 15:56:57","publishedOnDateReadable":"November 7th, 2024"},"versionCreatedAt":"2024-07-08 16:58:47","video":"","vorDoi":"10.1186/s12916-024-03726-z","vorDoiUrl":"https://doi.org/10.1186/s12916-024-03726-z","workflowStages":[]},"version":"v1","identity":"rs-4562505","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4562505","identity":"rs-4562505","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}