{"_asset":{"@search.score":6.537203,"Name":"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)","AlternateTitleCommaDelimited":"","Id":"8981","AssetLocationUri":null,"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 neutralisation, and reactogenicity following vaccination.

METHODS

In this prospective cohort study, 2115 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 neutralisation.

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 titres and virus neutralisation 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 whose state does not blunt rVSV-ZEBOV immune response. Pre-vaccination serological screening is not required.

","PublicationOrPresentationDate":"2024-11-07T00:00:00Z","LastModifiedDate":"2024-11-19T22:26:29.017Z","IsDeleted":false,"DigitalObjectIdentifier":"10.1186/s12916-024-03726-z","ContentTypeName":"Research","ParentContentTypeName":"Journal Article","JournalName":"BMC Medicine","ContentType":"Journal Article > Research","AvailabilityTypeId":1,"AvailabilityType":"Full Text","JournalIssue":"1","JournalVolume":"22","JournalPages":"523","JournalAbbreviation":"BMC Med","Conference":null,"ConferenceStartDate":null,"ConferenceEndDate":null,"content":"\nWatson et al. BMC Medicine (2024) 22:523 \nhttps://doi.org/10.1186/s12916-024-03726-z\n\nRESEARCH Open Access\n\n© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which \npermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the \noriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or \nother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line \nto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory \nregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this \nlicence, visit http://creativecommons.org/licenses/by/4.0/.\n\nBMC Medicine\n\nrVSV-ZEBOV vaccination in people \nwith pre-existing immunity to Ebolavirus: \nan open-label safety and immunogenicity study \nin Guinean communities affected by Ebola virus \ndisease (l’essai proches)\nConall H. Watson1, Pierre‑Stéphane Gsell2, Yper Hall1, Anton Camacho7, Ximena Riveros2, Godwin Enwere2, \nAndrea Vicari2, Séverine Danmadji Nadlaou2, Alhassane Toure2, Ismaila M. Sani2, Abdourahamane Diallo2, \nCece Kolie2, Sophie Duraffour5, Kékoura Ifono5, Andre Maomou2, Kassie Dore2, Honora A. Djidonou2, \nAminata Bagayoko2, Philos P. Damey2, Mabetty Nancy Camara2, Fatoumata Battouly Diallo2, \nFofana Thierno Oumar2, Kalidou Toure2, Mohamed Lamine Diaby2, Lansana Sylla2, Doussou Conde2, \nIbrahima Lansana Kaba2, Tom Tipton3, Rosalind M. Eggo4, Michael Marks4, Chrissy H. Roberts4, \nThomas Strecker6, Stephan Günther5, Sakoba Keita8, W. John Edmunds4†, Miles W. Carroll3† and \nAna Maria Henao‑Restrepo2*† \n\nAbstract \n\nBackground Zaire Ebolavirus disease (EVD) outbreaks can be controlled using rVSV‑ZEBOV vaccination and other \npublic health measures. People in high‑risk areas may have pre‑existing antibodies from asymptomatic Ebolavirus \nexposure that might affect response to rVSV‑ZEBOV. Therefore, we assessed the impact pre‑existing immunity had \non post‑vaccination IgG titre, virus neutralisation, and reactogenicity following vaccination.\n\nMethods In this prospective cohort study, 2115 consenting close contacts (“proches”) of EVD survivors were \nrecruited. Proches were vaccinated with rVSV‑ZEBOV and followed up for 28 days for safety and immunogenicity. Anti‑\nGP IgG titre at baseline and day 28 was assessed by ELISA. Samples from a representative subset were evaluated using \nlive virus neutralisation.\n\nResults Ten percent were seropositive at baseline. At day 28, IgG in baseline seronegative (GMT 0.106 IU/ml, 95% CI: \n0.100 to 0.113) and seropositive (GMT 0.237 IU/ml, 0.210 to 0.267) participants significantly increased from baseline \n(both p < 0.0001). There was strong correlation between antibody titres and virus neutralisation in day 28 samples \n(Spearman’s rho 0.75). Vaccinees with baseline IgG antibodies against Zaire Ebolavirus had similar safety profiles \nto those without detectable antibodies (63.6% vs 66.1% adults experienced any adverse event; 49.1% vs 60.9% \n\n†W. John Edmunds, Miles W. Carroll, and Ana Maria Henao‑Restrepo \ncontributed equally to this work.\n\n*Correspondence:\nAna Maria Henao‑Restrepo\nhenaorestrepoa@who.int\nFull list of author information is available at the end of the article\n\nhttp://creativecommons.org/licenses/by/4.0/\nhttp://crossmark.crossref.org/dialog/?doi=10.1186/s12916-024-03726-z&domain=pdf\n\n\nPage 2 of 10Watson et al. BMC Medicine (2024) 22:523 \n\nin children), with almost all adverse events graded as mild. No serious adverse events were attributed to vaccination. \nNo EVD survivors tested positive for Ebolavirus by RT‑PCR.\n\nConclusions These data add further evidence of rVSV‑ZEBOV safety and immunogenicity, including in people \nwith pre‑existing antibodies from suspected natural ZEBOV infection whose state does not blunt rVSV‑ZEBOV \nimmune response. Pre‑vaccination serological screening is not required.\n\nKeywords Ebola virus disease, Ebola, Vaccine, RVSV‑ZEBOV, Safety, Immunogenicity, Cohort study\n\nBackground\nEbolavirus (EBOV) has caused high mortality and mor-\nbidity in outbreaks of Ebola virus disease (EVD) across \nequatorial Africa [1, 2]. Sustained person-to-person \ntransmission may arise following single zoonotic trans-\nmission events and lead to large outbreaks [3–5].\n\nEVD control methods include contact tracing, case \nisolation, health education, and safe burial, with appro-\npriate community engagement [6]. Since 2016, out-\nbreak response also includes the use of a safe and highly \nefficacious attenuated replication-competent vesicular \nstomatitis virus-derived vaccine expressing the surface \nglycoprotein (GP) of Zaire ebolavirus ZEBOV (rVSV-\nZEBOV) [7, 8].\n\nPrevious studies report that rVSV-ZEBOV is safe, \nwell tolerated [7–13], and has been approved by US \nand European regulators as well as national regulatory \nauthorities in ten African countries. Serology studies \nfrom central Africa reported that in villages experienc-\ning an outbreak and in areas at risk of zoonotic trans-\nmission mean population seroprevalence will range \nfrom 2 to 29%, as measured by the detection of immu-\nnoglobulin G (IgG) to EBOV-GP in clinical samples \n[14–18]. Studies in post-outbreak communities in West \nAfrica have similarly found undiagnosed seropositive \ncontacts, referred to as asymptomatic cases, though a \nlevel of caution needs to be applied to studies in which \nantibody analysis is not supported by additional assess-\nments such as virus neutralisation.\n\nThe impact of pre-existing antibodies to EVD on \nrVSV-ZEBOV safety and immunogenicity is unknown. \nAny sign of blunted immunogenicity or safety concerns \nin previously infected individuals would warrant fur-\nther investigation. Therefore, we undertook an open-\nlabel rVSV-ZEBOV vaccination cohort study, enrolling \ncontacts of EVD cases who survived and for which ring \nvaccination was not previously implemented during the \n2013–2016 outbreak [19–21].\n\nThis study’s primary objective was to measure the \nIgG response to EBOV GP at 28 days post-vaccination \nby baseline IgG status; secondary objectives were com-\nparing the rates of serious adverse events (SAEs) and \nadverse events (AEs) by baseline serostatus; and to \n\nexplore any association between participants’ baseline \nserostatus and linked-survivor-related factors.\n\nMethods\nSetting\nThe study was conducted in Basse-Guinée region, \nGuinea. The first volunteer was recruited on 25 May 2016 \nand follow-up of the final participant completed on 21 \nSep 2016.\n\nDesign\nParticipants were contacts of EVD survivors whose onset \nof symptoms occurred within 15 months prior to the \nstart of the study. The study was a prospective cohort \nstudy examining IgG antibodies by ELISA serology at \nbaseline and at day 28 following rVSV-ZEBOV vaccina-\ntion. It also documented post-vaccination adverse events \nat days 3, 14, and 28, comparing those with raised base-\nline antibodies against those without. Survivors were \ntested using RT-PCR and were not prospectively vacci-\nnated. Baseline and day 28 EBOV GP IgG titres were also \nassessed for association with survivor-related factors, \nsuch as time since survivor EVD onset.\n\nStudy population\nIn May 2016, we identified contacts of adult or adoles-\ncent, PCR confirmed, EVD survivors who had not been \npreviously included in the rVSV-ZEBOV ring vaccina-\ntion Ebola ca suffit trial [7]. These contacts were assumed \nto be at a low but not zero risk of EVD due to potential \npersistence of viable EBOV in the body fluids of EVD \nsurvivors [14, 20, 22, 23]. Survivors were identified from \nnational surveillance records. Survivor support organisa-\ntions were also used as an information source to verify \ndata against these records. Survivors’ communities of \nresidence were cross-referenced against the records of \nthe Ebola Ça Suffit ring trial [7], to exclude survivors \nwhose contacts were already included in the trial.\n\nA revised definition of contacts of EVD survivors \nbecause of their socio-epidemiological status (“les \nproches”) was developed. It included household contacts \n(shared sleeping building or shared cooking pot), sexual \ncontacts, and second tier of people who would be at risk \nof transmission should a close contact develop EVD as a \n\n\n\nPage 3 of 10Watson et al. BMC Medicine (2024) 22:523 \n\nresult of a post-recovery transmission event, e.g. neigh-\nbours of survivors and household contacts of a sexual \ncontact of a survivor.\n\nProches were identified by trained field epidemiologists. \nThey were eligible for inclusion if they were 6 years of age \nor older and did not meet any exclusion criteria, namely: \nhistory of EVD (self-report), history of vaccination \nwith any EBOV vaccine, verbally declared pregnancy, \nor planning to conceive within 2 months of vaccina-\ntion (pregnancy tests were offered but not required), \nbreast-feeding, history of having received investigational \nresearch agents in the previous 28 days, clinically impor-\ntant immunodeficiency condition (e.g. HIV/AIDS), his-\ntory of anaphylaxis to a vaccine or vaccine component, \nor a severe illness that makes the person bed-bound or \nrequiring hospitalisation at the time of the vaccination.\n\nProcedures\nConsenting vaccinees received a single dose of at least \n2 × 107 plaque forming units of the rVSV-ZEBOV vac-\ncine (donated by Merck Sharp & Dohme, Kenilworth, \nNJ, USA) intramuscular to a deltoid. From each vaccinee, \nimmediately prior to vaccination and on day 28 (± 3 days) \npost-vaccination, up to 10 ml of venous blood for serol-\nogy was collected in a sterile serum separator tube by a \ntrained person using standard techniques. Participants \nwere observed for 30 min post-vaccination for immedi-\nate adverse reactions. Follow-up for adverse events was \ndone on days 3, 14, and 28 post-vaccination by safety \nmonitoring teams, with a window of ± 1, 2, and 3 days \nrespectively.\n\nConsenting EVD survivors provided a 10 ml venous \nblood for reverse-transcriptase polymerase chain reac-\ntion (RT-PCR) in the study laboratory in Conakry, \nGuinea. Female survivors were invited to provide a vagi-\nnal swab, and menstrual blood or breastmilk sample \nif applicable; male survivors were invited to provide a \nsemen sample. All were tested using an RT-PCR.\n\nSamples were transferred to Europe for analysis under \na signed Material Transfer Agreement issued by the Min-\nistre Sante Hygiene Publique, Guinée.\n\nData collection\nData was collected on encrypted Android tablets using \nOpenDataKit (ODK) Collect on forms designed in XLS-\nform. Uploaded data was stored in ODK Aggregate on an \nencrypted server. QR barcodes were used to link partici-\npants’ records and laboratory samples and for staff digital \nsignatures. GPS data was collected on participant loca-\ntions to aid follow-up.\n\nBaseline demographic data and contact information \nwere collected from all participants. Survivors were \nasked about possible EVD sequelae. Details of specified \n\nadverse events were solicited at each post-vaccination \nfollow-up visit, with unsolicited events also documented \non days 3 and 14. Participants were provided with a con-\ntact number on their participant enrolment card if they \nwanted to contact the study team between visits to notify \nor get advice on any possible adverse events.\n\nTo reduce the risk of important response biases, data \ncollectors were trained in information solicitation meth-\nods by experienced HIV/AIDS teams. Interviews were \nconducted away from communal settings to increase pri-\nvacy. Participants missing from safety monitoring visits \nwere actively traced by the field team to reduce loss to \nfollow-up.\n\nLaboratory methods\nEBOV GP ELISA\nAnti-EBOV GP IgG was determined by ELISA using \npreviously published methods [24, 25] with a tri-\nmerised Zaire strain GP antigen, aa 1–649 of Gen \nBank AHX24649.1 (GIN/2014/Makona-Kissidougou-C15). \nResults were standardised by inclusion of a reference \ncurve for which the reference material was a plasma \npool from three EVD survivors, calibrated against \nWHO Reference Reagent (NIBSC 15/220) [26] (Anti-\nGP titre = 0.761 ± 0.006 IU/ml (mean ± SEM, n = 13)). \nNegative control plasma pool was obtained from three \nGuinean volunteers with no prior infection with EVD or \ncontact with an EVD case-patient. Matched serum pairs \nwere tested in triplicate. Samples without a matching \npair were not tested. OD was interpolated from the refer-\nence serum curve. In the absence of well-defined thresh-\nolds for immunity or past infection, we set a serological \nthreshold based on the negative control. The threshold \nfor seropositivity was determined as 0.0429 IU/ml, three \nstandard deviations above the negative control geometric \nmean (n = 91).\n\nEBOV Zaire neutralisation assay\nFifty paired samples were selected based on having a low, \nmedium, or high baseline anti-GP IgG titres for analysis \nusing a live EBOV neutralisation assay at the Institute of \nVirology BSL4 laboratory, Philipps University of Mar-\nburg, Germany [27]. Based on previous studies, the sero-\npositivity threshold for neutralisation assays was defined \nas ≥ 1:8 geometric mean titre (GMT).\n\nStatistical analysis\nTo recruit 50 baseline-seropositive participants, a sam-\nple size of 1000 ≤ n ≤ 2000 was estimated to be required \nif pre-existing seropositivity was consistent with serosur-\nveillance in other Ebola-experienced areas.\n\nDescriptive analyses and multivariable regression were \nperformed in R (3.5) [28]. For multivariable regression \n\n\n\nPage 4 of 10Watson et al. BMC Medicine (2024) 22:523 \n\nwhere relevant variables were missing, records were \nomitted from that analysis. Serological data was com-\npared by paired t-test or Mann–Whitney test. Cor-\nrelation between ELISA and neutralisation assays was \ncompared by Spearman rank correlation coefficient. We \nset statistical significance level at 5%.\n\nResults\nWe identified 136 EVD survivors whose contacts \n(proches) were unvaccinated. For these survivors, the \ndate of discharge from Ebola treatment unit ranged \n\nfrom 16 Feb to 7 Oct 2015 (median 22 March 2015). Of \nthese, 80.1% (109/136) were located. Only 48 were con-\ntacted and all gave their consent for an interview and for \nsample collection. The remaining were not approached \nby the study team because a national effort with similar \nobjectives was initiated, and duplication was deemed not \ndesirable. In total, 2750 proches of 109 EVD survivors \nwere identified. Amongst them 77.3% (2126/2750) were \neligible for our study, and 2115 were enrolled and vacci-\nnated following consent (Fig. 1). The median number of \nscreened and vaccinated proches per EVD survivor was \n\nFig. 1 Study flowchart\n\n\n\nPage 5 of 10Watson et al. BMC Medicine (2024) 22:523 \n\n12 (range 1 to 100, IQR 7 to 21). Of the 0.5% (11/2126) \nnot then vaccinated, eight were either not present at the \ntime of vaccination or did not have a reason for non-\nvaccination status, two withdrew consent, and one had \na medical condition. Venous samples from both day 0 \nand day 28 were provided by 66.3% (1403/2115) of the \nvaccinees.\n\nHumoral immunogenicity following rVSV‑ZEBOV \nvaccination\nWe tested the 1403 matched (day 0 and 28) proches’ sam-\nples by ELISA and found that 228 (16.3%) were defined as \nseropositive at baseline (day 0).\n\nLogistic regression analysis of potential factors associ-\nated with baseline seropositivity did not find an associa-\ntion with sex, age group, or time since survivor discharge \nfrom the Ebola treatment unit (ETU) (Additional file: \nTable S1).\n\nOf the 1175 baseline seronegative participants, 955 \n(81.3%, 95% CI 78.9 to 83.4%) were seropositive by \nELISA on day 28 (Fig. 2A and B). Three (1.3%) of 228 \ninitially seropositive vaccinees were found seronega-\ntive at day 28. This could be due to waning immunity \nin weakly positive samples or assay variability. There \nwere statistically significant increases in IgG GMT at \nday 28 for both those seropositive and seronegative \nat baseline (Table 1). The day 28 GMT was higher for \n\nFig. 2 A Pre‑ and 28‑day post‑vaccination anti‑EBOV IgG ELISA titres, stratified by baseline seropositivity status. Box indicates median \nand interquartile range (IQR), whiskers 1.5*IQR. B Day 28 post‑vaccination anti‑EBOV IgG ELISA titres against pre‑vaccination titres. Blue points \nindicate samples selected on ELISA for neutralisation assay and tested successfully. C Pre‑ and 28‑day post‑vaccination Ebolavirus neutralisation \ntitres, stratified by baseline anti‑EBOV IgG ELISA titres in the subset. Box indicates median and interquartile range, whiskers 1.5*IQR. D Neutralisation \ntitres before and 28 days after vaccination in a subset of samples tested by IgG ELISA\n\n\n\nPage 6 of 10Watson et al. BMC Medicine (2024) 22:523 \n\nbaseline seropositive participants compared to the day \n28 GMT of baseline seronegative participants (p value \nfor difference < 0.0001).\n\nExamining IgG titres of those who were seronegative at \nbaseline, we found that children showed 91.1% serocon-\nversion rate (308 of 338, 95% CI 87.6 to 93.7%) compared \nwith adults who showed a 77.3% seroconversion rate by \nday 28 (647 of 837, 95% CI 74.3 to 80.0%). Children also \nhad higher day 28 IgG GMT of 0.167 (95% CI 0.149 to \n0.187) compared to adults GMT of 0.089 (95% CI 0.083 \nto 0.095, p < 0.0001). Amongst those classed as seroposi-\ntive at baseline, we found that children attained higher \nday 28 titres (GMT 0.338, 95% CI 0.266 to 0.429) than \nadults (GMT 0.211, 95% CI 0.185 to 0.242, p = 0.003).\n\nWe next sought to validate these ELISA results using \nlive virus neutralisation assays on a subset of 50 matched \nday 0 and 28 samples, 100 samples in total. These sam-\nples were identified as high, medium, or low responder. \nWe found that day 0 neutralisation GMT was 8.5 (95% \nCI 5.9 to 12.2), rising to 25.1 (95% CI 16.1 to 39.2) at day \n28, with proportion considered positive rising from 13/49 \n(26.5%) to 39/49 (79.6%). Moderate correlation with IgG \nwas seen in baseline neutralisation assay titres (Spear-\nman’s rho = 0.50; p = 0.002 on 47 degrees of freedom \n(df )). Correlation was stronger between day 28 assays \n(rho = 0.75; p < 0.0001 on 47 df ) (Fig. 2D).\n\nVaccine safety\nWe also investigated adverse events and stratified this by \nserostatus at baseline and age group (Table 2). Although \nthe immunogenicity analysis was restricted to vaccinees \nproviding paired serological samples, safety data is also \npresented for those who did not provide a day 28 serum \nsample. Prevalence was similar in both serogroups and \nthose untested. Of the 62% (1317/2215) reporting any \nadverse event, 99% (1038/1317) reported only mild \nevents. The most common adverse event in adults and \nchildren was headache (35.1% (742/2115)), followed \nby fatigue (23.7% (501/2115)) and muscle pain (14.6% \n(308/2115)) (Table 2). Most were short duration: median \n2 days (interquartile range 1–3). Participants most com-\nmonly reported adverse events at the day 3 follow-up \nvisit. The most common unsolicited adverse events in \nadults were shivers/chills (3.6% (56/1550)), dizziness \n(2.3% (36/1550)), and abdominal pain (1.2% (18/1550)); \namongst children the more frequent adverse events \ninclude abdominal pain (4.2% (24/565)) and shivers/chills \n(2.1% (12/565)) (Table 2).\n\nEight participants reported moderate adverse events \n(most commonly fatigue or muscle pain) and one \nreported severe fatigue (Table 3). No moderate or severe \nadverse events were reported in those known to be sero-\npositive at day 0.\n\nTable 1 Participant demographics and IgG titres by baseline serostatus\n\n*,†,‡ The p value for difference between these paired groups was < 0.0001\n\nProches vaccinees (n = 2115, of whom 1403 had paired serum for analysis) EVD survivors (n = 48)\n\nSerostatus Seronegative at baseline (day 0) Seropositive at baseline (day 0) Not tested (no \npaired sample)\n\nNot applicable\n\nNumber (% of those tested) 1175 (83.7%) 228 (16.3%) 712 48\n\nFemale sex (%) 440 (37.4%) 81 (35.5%) 239 (33.6%) 26 (54.2%)\n\nMedian age (IQR) 28 (15 to 46) 30 (18 to 46) 26 (18 to 40) 32 (22 to 40)\n\nAge range 6 to 99 6 to 85 6 to 90 15 to 66\n\nChildren age 6–17 years (% \nof those tested)\n\n338 (86.0%) 55 (14.0%) 172 4\n\nAdults 18 years + (% of those \ntested)\n\n837 (82.9%) 173 (17.1%) 540 44\n\nIgG geometric mean titre (GMT) (95% confidence interval (CI), p value for difference from baseline)\n\n Day 0 pre‑vaccination 0.0142 (0.0138 to 0.0146) 0.0927 (0.0838 to 0.103) N/A N/A\n\n 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\n\nSeroconversion at day 28 (%; 95% CI)\n\n Children 308/338 (91.1%, 87.6 to 93.7%)† N/A N/A N/A\n\n Adults 647/837 (77.3%, 74.3 to 80.0%)† N/A N/A N/A\n\nGMT (95% CI)\n\n Children’s baseline 0.0130 (0.0122 to 0.0138) 0.096 (0.077 to 0.120) N/A N/A\n\n Children’s day 28 0.167 (0.149 to 0.187)‡ 0.338 (0.266 to 0.429) N/A N/A\n\n Adults’ baseline 0.0147 (0.0142 to 0.0152) 0.092 (0.082 to 0.103) N/A N/A\n\n Adults’ day 28 0.089 (0.083 to 0.095)‡ 0.211 (0.185 to 0.242) N/A N/A\n\n\n\nPage 7 of 10Watson et al. BMC Medicine (2024) 22:523 \n\nAssociation between any adverse event and baseline \nserostatus was assessed by logistic regression, adjust-\ning for age group (adult/child) and sex and interaction \nbetween these factors (Additional file: Table S2). No \nassociation was observable for baseline serological sta-\ntus; adult females appeared more likely to report adverse \nevents than other groups.\n\nIn an exploratory Poisson regression of adverse event \ncount (across solicited and unsolicited AEs, Additional \nfile: Table S3), there was weak evidence of associa-\ntion between baseline seropositivity and lower count of \nadverse events after adjusting for age and sex. No inter-\nactions were identified in sensitivity analysis. Results did \nnot change under robust Poisson regression.\n\nEVD survivors\nAll 48 consented survivors completed a questionnaire, of \nwhom 14 (29.2%) reported at least one health problem \n\nsince discharge. Eye problems were most common (10, \n20.8%). Sequelae were reported across multiple organ \nsystems including neurological signs, joint problems, and \nabdominal symptoms. From the 128 body fluid samples \ntested (see Fig. 1), none tested positive for Ebolavirus by \nRT-PCR.\n\nDiscussion\nThis cohort study in Guinea provides additional evidence \nthat one dose of rVSV ZEBOV GP vaccine is safe and \nimmunogenic amongst seropositive or seronegative indi-\nviduals as assessed by IgG antibody titres to Zaire ebola-\nvirus at the time of vaccination. This supports previous \nwork which has shown this vaccine to be safe and effec-\ntive and highlights the importance of rVSV-ZEBOV in \ncontrolling future Zaire ebolavirus outbreaks [7, 29].\n\nThe finding that 16.3% of procheshad detectable IgG \nto EBOV-GP is consistent with previous community/\n\nTable 2 Number of adults and children who experienced specified and unsolicited adverse events during 28 days from vaccination, \nby pre‑vaccination serostatus\n\nAdults Children\n\nSerostatus Seronegative at \nbaseline\nn = 837\n\nSeropositive at \nbaseline\nn = 173\n\nNot tested (no \npaired sample)\nn = 540\n\nSeronegative at \nbaseline\nn = 338\n\nSeropositive at \nbaseline\nn = 55\n\nNot tested (no \npaired sample)\nn = 172Specified adverse events\n\nAny adverse event 553 (66.1%) 110 (63.6%) 321 (59.4%) 206 (60.9%) 27 (49.1%) 100 (58.1%)\n\nDiarrhoea 15 (1.8%) 1 (0.6%) 13 (2.4%) 6 (1.8%) 1 (1.8%) 1 (0.6%)\n\nFatigue 220 (26.3%) 44 (25.4%) 150 (27.8%) 52 (15.4%) 6 (10.9%) 29 (16.9%)\n\nHeadache 306 (36.6%) 60 (34.7%) 160 (29.6%) 136 (40.2%) 17 (30.9%) 63 (36.6%)\n\nInjection pain 27 (3.2%) 4 (2.3%) 21 (3.9%) 23 (6.8%) – 15 (8.7%)\n\nJoint pain 134 (16%) 35 (20.2%) 86 (15.9%) 21 (6.2%) 2 (3.6%) 10 (5.8%)\n\nMuscle pain 155 (18.5%) 24 (13.9%) 69 (12.8%) 32 (9.5%) 5 (9.1%) 23 (13.4%)\n\nVomiting 12 (1.4%) – 6 (1.1%) 13 (3.8%) – 3 (1.7%)\n\nOther (unsolicited) adverse \nevents comprising:\n\n111 (13.3%) 20 (11.6%) 62 (11.5%) 47 (13.9%) 5 (9.1%) 19 (11%)\n\n Abdominal distension 1 (0.1%) – – – – –\n\n Abdominal pain 11 (1.3%) – 7 (1.3%) 17 (5%) 1 (1.8%) 6 (3.5%)\n\n Blurred vision 2 (0.2%) – 2 (0.4%) – – –\n\n Buccal inflammation – – 1 (0.2%) – – –\n\n Constipation 1 (0.1%) – – – – –\n\n Cough 4 (0.5%) – 1 (0.2%) 2 (0.6%) – 2 (1.2%)\n\n Dizziness 20 (2.4%) 5 (2.9%) 11 (2%) 4 (1.2%) – 1 (0.6%)\n\n Epigastric pain 6 (0.7%) 1 (0.6%) 2 (0.4%) 1 (0.3%) – –\n\n Fever 4 (0.5%) – – 1 (0.3%) – 1 (0.6%)\n\n Hyperhidrosis 2 (0.2%) – – – – –\n\n Insomnia 1 (0.1%) – – – – –\n\n Loss of appetite 7 (0.8%) – 6 (1.1%) – – –\n\n Lower back pain 14 (1.7%) 7 (4%) 11 (2%) 1 (0.3%) – –\n\n Nausea 2 (0.2%) – – – – –\n\n Polyuria 1 (0.1%) – – – – –\n\n Pruritus 6 (0.7%) 3 (1.7%) 3 (0.6%) – – –\n\n Shivering/chills 36 (4.3%) 4 (2.3%) 16 (3%) 8 (2.4%) 2 (3.6%) 2 (1.2%)\n\n\n\nPage 8 of 10Watson et al. BMC Medicine (2024) 22:523 \n\ncontact studies in central Africa [14–18], and warrants \nfurther investigation into the prevalence of asympto-\nmatic cases and the mechanisms behind asymptomatic or \nabortive EBOV infections [30]. Researchers found ~ 15% \nof study participants in Guinea, Sierra Leone, and Libe-\nria in 2018 had prior EBOV-GP immunity before vacci-\nnation compared to only 5% in neighbouring Mali [31]. \nProposals for this seemingly higher level of seropreva-\nlence include the geographical and ecological differ-\nences between these two regions and prior exposure to \nrelated and potentially non-pathogenic filoviruses, such \nexposures may account for some of the elevated baseline \nresponses seen in this study [32, 33]. We did not observe \nan association between baseline seropositivity and age or \ngender, unlike a DRC study [34].\n\nFrom our results, we estimated a seroconversion rate of \n81.3% (95% CI 78.9 to 83.4%) in those who were seron-\negative at baseline, and an overall seropositivity of 84.1% \n(95% CI 82.1 to 86.0%) across all prochestested on day 28. \nThis is within the range of other immunogenicity studies \nwith the rVSV-ZEBOV vaccine that will have also used \ndifferent assay methodology and definitions of positive \noutcomes [11]. Importantly, these results provide short-\nterm data that individuals with pre-existing immunity to \nEBOV GP could experience an increase of antibody titres \nfollowing the administration of rVSV-ZEBOV.\n\nThe strong correlation observed between neutralisa-\ntion assays and IgG ELISAs following vaccination further \nsuggests the ELISA used may be an acceptable marker of \nimmunogenicity.\n\nThe frequency of adverse events between the sero-\ngroups was similar. No increase in adverse events \nreporting was identified when serogroups were further \nstratified into children and adults.\n\nIt was not possible to assess the effects of vaccination \nin prevention of infection in contacts of survivors as no \nEVD survivor tested positive for Ebolavirus by RT-PCR. \nSurvivor studies have shown that RNA detection decays \nover time in semen at variable rates in different survivors, \nand, as a consequence, transmission risks decrease over \ntime due to lower inoculum, nonviable virus, or other \nfactors. Since 2016, ≥ 95% of the EVD cases and ≥ 95% \nof their contacts and contacts of contacts have been \nenumerated in rings and vaccinated with rVSV ZEBOV \nGP. Therefore, a small fraction of contacts not yet vac-\ncinated are sparsely spread over large areas, making it \ndifficult to further assess this question in the field. It is \nalso unknown if vaccine induced antibodies can reach \nthe immune-privileged sites where it is assumed the virus \ncan remain. In 2021, one case of Ebola transmission from \na person infected in the 2013–2016 epidemic occurred, \noutside of our vaccination area [23].\n\nTable 3 Moderate and severe adverse events\n\na Denotes reported as severe. All other were moderate\nb Where precise duration is not known, ranges are given from follow-up intervals\n\nParticipant Baseline serostatus Adverse event Day of onset post‑\nvaccination\n\nDuration (days)b\n\n7 year old girl Negative Fatigue 28 2\n\nMuscle pain 28 2\n\n18 year old man Negative Headache 1 1\n\nJoint pain 1 1\n\nMuscle pain 1 1\n\n18 year old woman Negative Nausea 1 1\n\n19 year old man Unknown Dizziness 1 ≥ 3, ≤ 14\n\nLoss of appetite 1 ≥ 3, ≤ 14\n\nBuccal inflammation 1 13\n\nItching 1 13\n\n21 year old man Unknown Fatigue 0 3\n\n35 year old man Negative Joint pain 1 ≥ 3, ≤ 14\n\nMuscle pain 1 4\n\n42 year old man Unknown Fatigue 1 2\n\nMuscle pain 1 2\n\nLower back pain 1 2\n\n49 year old man Unknown Fatiguea 24 ≥ 4\n\nHeadache 24 ≥ 4\n\n63 year old man Unknown Fatigue 1 2\n\n\n\nPage 9 of 10Watson et al. BMC Medicine (2024) 22:523 \n\nConclusions\nEbola remains a pressing public health concern in many \nsub-Saharan countries. This proches vaccination study \nsuggests rVSV ZEBOV GP can be safely administered to \nindividuals with prior asymptomatic Ebola infection (or \ncross-reactivity that may have caused antibody produc-\ntion) without requiring baseline serological results. Fur-\nthermore, existence of prior EBOV GP IgG responses \nfrom suspected natural infection does not prevent the \nability of an additional dose of rVSV ZEBOV GP to \nincrease antibody titres.\n\nAbbreviations\nAEs Adverse events\ndf Degree of freedom\nETU Ebola treatment unit\nEVD Ebola virus disease\nEBOV Ebolavirus\nGMT Geometric mean titre\nGP Glycoprotein\nIgG Immunoglobulin G\nODK OpenDataKit\nRT‑PCR Reverse‑transcriptase polymerase chain reaction\nSAEs Serious adverse events\nWHO World Health Organization\nEVD Zaire Ebolavirus disease\nrVSV‑ZEBOV Zaire ebolavirus ZEBOV\n\nSupplementary Information\nThe online version contains supplementary material available at https:// doi. \norg/ 10. 1186/ s12916‑ 024‑ 03726‑z.\n\nAdditional file 1: Table S1. Adjusted logistic regression analysis of risk \nfactors for baseline seropositivity. Table S2. Association between baseline \nseropositivity, demographic risk factors, and the occurrence of adverse \nevents. Table S3. Association between baseline seropositivity, demo‑\ngraphic risk factors, and the number of adverse events in a participant.\n\nAcknowledgements\nWe gratefully acknowledge the contribution of the participants, host com‑\nmunities, field and laboratory teams, Sarah Katharina Fehling, Michael Schmidt \nand Gotthard Ludwig for scientific and technical support in biosafety level 4 \nprocedures, Megan O’Driscoll for data management, and the Government of \nGuinea. We would like to thank colleagues for helpful discussions in develop‑\nment of the study: Federica Ambrosini, Nathalie Broutet, Gabriella De Carli, \nAntonio Di Caro, Judith Glynn, Giuseppe Ippolito, Simone Lanini, Francesco \nVairo and Jimmy Whitworth.\n\nAuthors’ contributions\nCW, PG, AMHR, WJE, MC wrote the manuscript. XW, RE, AC, WJE did the analy‑\nsis. KI, YH, TT, SG, TS, MC did the immunology analysis. PG, XR, AV, AT, IM, AD, \nAB, CK, FK, AM, KD, HD, AB, PD, MC, FD, FT, KT, MD, LS, DC, IK did the field work.\n\nFunding\nThe study was funded by the UN Foundation, Washington, and the WHO, \nGeneva. The WHO was the sponsor. Laboratory processing was funded by the \nEuropean Commission (EuropeAid Cooperation Office) through contract No. \nIFS/2011/272–372 for the EMLab project, Establishment of Mobile Laboratories \nfor Pathogens up to Risk Group 4 in Combination with CBRN Capacity Building \nin sub‑Saharan Africa. Analysis and writing by CHW, AC, and WJE was funded \nby the Department of Health and Social Care using UK Aid funding, managed \nby the NIHR (Vaccine Efficacy Evaluation of Priority Emerging Diseases con‑\nsortium). The views expressed are those of the author(s) and not necessarily \nthose of the NIHR or the Department of Health and Social Care. The laboratory \n\nanalysis performed at UKHSA Porton Down was supported by a grant from \nthe Food and Drug Administration (Contract No. HHSF223201510104C).\n\nData availability\nThe data that support the findings of this study are not openly available due \nto reasons of sensitivity and are available from the corresponding author upon \nreasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\nThe study was approved by the World Health Organization (WHO) Research \nEthics Review Committee (ERC.0002723), the London School of Hygiene & \nTropical Medicine, UK, interventional research ethics committee (10523/\nRR/4674), and by the Comité National d’Ethique pour la Recherche en Santé \nof Guinea. Communities were approached and the study explained by the \nstudy’s community engagement team, and permission obtained to enter the \ncommunity. Individual written informed consent was obtained for all partici‑\npants using a signed, printed information sheet. For child participants, consent \nwas obtained from parents or guardians. Children aged 12 to 17 years also \ngave written consent. If the potential participant was illiterate, the documents \nwere read in a local language and a fingerprint collected, countersigned by a \nliterate independent witness. The teams taking informed consent were differ‑\nent from those involved in community engagement and the epidemiological \ndetermination of proches to include in the rings.\n\nCompeting interests\nThe authors declare no competing interests.\n\nAuthor details\n1 UK Health Security Agency, London, UK. 2 World Health Organization, Geneva, \nSwitzerland. 3 University of Oxford, Oxford, UK. 4 London School of Hygiene \nand Tropical Medicine, London, UK. 5 Bernhard‑Nocht‑Institut Für Tropenmedi‑\nzin, Hamburg, Germany. 6 Philips University, Marburg, Germany. 7 Epicentre, \nParis, France. 8 Ministry of Health, Conakry, Guinea. \n\nReceived: 11 June 2024 Accepted: 24 October 2024\n\nReferences\n 1. Legrand J, Grais RF, Boelle PY, Valleron AJ, Flahault A. Understanding the \n\ndynamics of Ebola epidemics. Epidemiol Infect. 2007;135:610–21.\n 2. Heymann D. Ebola: learn from the past. Nature. 2014;514:299–300.\n 3. Baize S, Pannetier D, Oestereich L, et al. 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Preliminary results on the efficacy of rVSV‑\nZEBOV‑GP Ebola vaccine using the ring vaccination strategy in the \ncontrol of an Ebola outbreak in the Democratic Republic of the Congo: \nan example of integration of research into epidemic response. 2019. \nhttps:// www. who. int/ csr/ resou rces/ publi catio ns/ ebola/ ebola‑ ring‑ vacci \nnation‑ resul ts‑ 12‑ april‑ 2019. pdf.\n\n 30. Carroll M. Serological evidence of zoonotic filovirus exposure among \nbushmeat hunters in Guinea. 2022. https:// doi. org/ 10. 21203/ rs.3. rs‑ 13475 \n02/ v1.\n\n 31. PREVAC Study Team. Randomized trial of vaccines for Zaire Ebola virus \ndisease. N Engl J Med. 2022;387:2411–24.\n\n 32. Pigott DM, Golding N, Mylne A, et al. Mapping the zoonotic niche of \nEbola virus disease in Africa. Elife. 2014;3:e04395.\n\n 33. Goldstein T, Anthony SJ, Gbakima A, et al. The discovery of Bombali virus \nadds further support for bats as hosts of ebolaviruses. Nat Microbiol. \n2018;3:1084–9.\n\n 34. Mulangu S, Alfonso VH, Hoff NA, et al. Serologic evidence of ebolavirus \ninfection in a population with no history of outbreaks in the Democratic \nRepublic of the Congo. J Infect Dis. 2018;217:529–37.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in pub‑\nlished maps and institutional affiliations.\n\nhttp://stm.sciencemag.org/content/9/385/eaaj1701.abstract\nhttp://stm.sciencemag.org/content/9/385/eaaj1701.abstract\nhttps://doi.org/10.1086/514318\nhttps://apps.who.int/iris/bitstream/handle/10665/197777/WHO_BS_2015.2280_eng.pdf\nhttps://apps.who.int/iris/bitstream/handle/10665/197777/WHO_BS_2015.2280_eng.pdf\nhttp://www.R-project.org/\nhttp://www.R-project.org/\nhttps://www.who.int/csr/resources/publications/ebola/ebola-ring-vaccination-results-12-april-2019.pdf\nhttps://www.who.int/csr/resources/publications/ebola/ebola-ring-vaccination-results-12-april-2019.pdf\nhttps://doi.org/10.21203/rs.3.rs-1347502/v1\nhttps://doi.org/10.21203/rs.3.rs-1347502/v1\n\n\trVSV-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)\n\tAbstract \n\tBackground \n\tMethods \n\tResults \n\tConclusions \n\n\tBackground\n\tMethods\n\tSetting\n\tDesign\n\tStudy population\n\tProcedures\n\tData collection\n\tLaboratory methods\n\tEBOV GP ELISA\n\n\tEBOV Zaire neutralisation assay\n\tStatistical analysis\n\n\tResults\n\tHumoral immunogenicity following rVSV-ZEBOV vaccination\n\tVaccine safety\n\tEVD survivors\n\n\tDiscussion\n\tConclusions\n\tAcknowledgements\n\tReferences\n\n\n","UrlSlug":"rvsv-zebov-vaccination-people-pre-existing-immunity-ebolavirus-open-label-safety-immunogenicity-study-guinean-communities-affected-ebola-virus","collections":[],"countries":[{"Name":"Guinea","Id":78}],"asset_languages":[{"AlternateTitle":null,"language":[{"Id":1,"Name":"English"}],"contentTranslation":[],"contentLocation":[]}],"creators":[{"Name":"Keita S","Id":18068,"ac":[{"Order":33}]},{"Name":"Strecker T","Id":19357,"ac":[{"Order":31}]},{"Name":"Camacho A","Id":19422,"ac":[{"Order":3}]},{"Name":"Edmunds WJ","Id":22925,"ac":[{"Order":34}]},{"Name":"Carroll MW","Id":23428,"ac":[{"Order":35}]},{"Name":"Duraffour S","Id":23454,"ac":[{"Order":12}]},{"Name":"Hall Y","Id":23510,"ac":[{"Order":2}]},{"Name":"Günther S","Id":24054,"ac":[{"Order":32}]},{"Name":"Enwere G","Id":26485,"ac":[{"Order":5}]},{"Name":"Riveros X","Id":26490,"ac":[{"Order":4}]},{"Name":"Henao-Restrepo AM","Id":26495,"ac":[{"Order":36}]},{"Name":"Watson CH","Id":26496,"ac":[{"Order":0}]},{"Name":"Gsell PS","Id":26499,"ac":[{"Order":1}]},{"Name":"Maomou A","Id":26815,"ac":[{"Order":14}]},{"Name":"Eggo RM","Id":28029,"ac":[{"Order":28}]},{"Name":"Marks M","Id":30361,"ac":[{"Order":29}]},{"Name":"Roberts CH","Id":30374,"ac":[{"Order":30}]},{"Name":"Ifono K","Id":31345,"ac":[{"Order":13}]},{"Name":"Vicari A","Id":35397,"ac":[{"Order":6}]},{"Name":"Nadlaou SD","Id":35398,"ac":[{"Order":7}]},{"Name":"Toure A","Id":35399,"ac":[{"Order":8}]},{"Name":"Sani IM","Id":35400,"ac":[{"Order":9}]},{"Name":"Diallo A","Id":35401,"ac":[{"Order":10}]},{"Name":"Kolie C","Id":35402,"ac":[{"Order":11}]},{"Name":"Dore K","Id":35403,"ac":[{"Order":15}]},{"Name":"Djidonou HA","Id":35404,"ac":[{"Order":16}]},{"Name":"Bagayoko A","Id":35405,"ac":[{"Order":17}]},{"Name":"Damey PP","Id":35406,"ac":[{"Order":18}]},{"Name":"Camara MN","Id":35407,"ac":[{"Order":19}]},{"Name":"Diallo FB","Id":35408,"ac":[{"Order":20}]},{"Name":"Oumar FT","Id":35409,"ac":[{"Order":21}]},{"Name":"Toure K","Id":35410,"ac":[{"Order":22}]},{"Name":"Diaby ML","Id":35411,"ac":[{"Order":23}]},{"Name":"Sylla L","Id":35412,"ac":[{"Order":24}]},{"Name":"Conde D","Id":35413,"ac":[{"Order":25}]},{"Name":"Kaba IL","Id":35414,"ac":[{"Order":26}]},{"Name":"Tipton T","Id":35415,"ac":[{"Order":27}]}],"keywords":[{"Name":"vaccination","Id":6},{"Name":"Ebola","Id":12}]}}

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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)