Clinical Surveillance and Evaluation of Suspected Ebola Cases in a Vaccine Trial During an Ebola Epidemic: The Sierra Leone Trial to Introduce a Vaccine Against Ebola

Clinical Surveillance and Evaluation of Suspected Ebola Cases in a Vaccine Trial During an Ebola... Abstract The Sierra Leone Trial to Introduce a Vaccine Against Ebola (STRIVE), an Ebola vaccine trial conducted during the 2014–2016 Ebola epidemic, coordinated with the Sierra Leone national response to identify Ebola cases among trial participants. The early symptoms of Ebola are similar to common vaccine reactions, so it was important to differentiate these to avoid unnecessary referral to an Ebola facility and an increased risk of Ebola exposure. STRIVE developed a modified version of the national case definition and case management algorithm to distinguish between symptoms associated with both Ebola and vaccination with the candidate Ebola vaccine (rVSV∆G-ZEBOV-GP) from those typically associated only with Ebola. For participants who presented ≤48 hours after vaccination, we used the more stringent modified case definition to trigger referral for Ebola evaluation. Participants whose symptoms did not meet case definitions could also be referred to an Ebola facility, based on clinical judgment. No Ebola cases were diagnosed among the 8651 STRIVE participants. Fifty participants were evaluated for Ebola, of whom 34 (68%) were tested after vaccination; 22 deceased participants, all of whom underwent postmortem Ebola testing, as required during the Ebola epidemic, and had negative test results, were excluded from analysis. Seven of 34 participants (21%) had symptom onset ≤48 hours after vaccination, of whom 3 met the modified case definition. The most common diagnosis among those evaluated for Ebola was malaria. STRIVE demonstrates the feasibility of conducting Ebola surveillance among persons vaccinated with rVSV-ZEBOV during an Ebola epidemic and introduces a modified case definition and case management algorithm to distinguish vaccine reactions from early symptoms of Ebola that may be useful for reducing unnecessary Ebola evaluations among persons vaccinated during Ebola outbreaks. Clinical Trials Registration ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220]. Ebola, surveillance, Ebola vaccine, rVSV∆G-ZEBOV-GP, Sierra Leone The Sierra Leone Trial to Introduce a Vaccine Against Ebola (STRIVE), a phase 2/3 clinical trial of the candidate Ebola vaccine rVSV∆G-ZEBOV-GP (Merck), was conducted among high-risk healthcare workers and frontline Ebola response workers during the 2014–2016 Ebola virus disease (Ebola) outbreak [1]. The primary outcomes of the study were vaccine efficacy and safety, and while the efficacy end points could not be evaluated because there were ultimately no cases of Ebola among trial participants, surveillance for Ebola was a critical component of the study. Ebola surveillance was complicated by the overlap in symptoms between early Ebola, other infectious diseases, and common reactions to the experimental Ebola vaccine. Data from phase 1 trials of rVSV∆G-ZEBOV-GP had shown that up to 70% of vaccinated participants experienced symptoms such as fatigue, headache, myalgia, and fever within 24–48 hours after vaccination [2, 3]. These symptoms are similar to the early symptoms of Ebola, as well as other infections common in Sierra Leone, such as malaria and typhoid fever [4, 5]. Further complicating surveillance, the Sierra Leone national response plan called for referral of all persons with suspected Ebola to Ebola facilities for isolation, evaluation, laboratory testing, and treatment, as appropriate [6, 7]. This policy was appropriate and necessary during the epidemic. However, such referral could potentially increase the risk of nosocomial exposure to Ebola. Also, because healthcare workers and frontline workers were a limited and critical resource for the epidemic response, it was important to avoid unnecessary prolonged absences from work. Thus, for STRIVE study participants, it was important to distinguish vaccine reactions from early Ebola symptoms as accurately as possible both to avoid unnecessary referral of participants for Ebola evaluation and to correctly diagnose other infectious conditions so that effective treatment would not be delayed. This article describes the STRIVE approach to and experience with Ebola surveillance, including the outcomes of participants evaluated for Ebola. This approach may be useful for reducing unnecessary Ebola evaluations and potential Ebola exposures among people who receive rVSV∆G-ZEBOV-GP during Ebola outbreaks. METHODS STRIVE was a partnership between the College of Medicine and Allied Health Sciences, University of Sierra Leone; the Ministry of Health and Sanitation in Sierra Leone; and the Centers for Disease Control and Prevention (CDC). Enrollment was conducted from April through August 2015 at 7 sites in 5 districts. Participants were individually randomized to either immediate vaccination or deferred (18–24 weeks later) vaccination. Vaccination was completed in December 2015. Details of the methods and results are reported elsewhere [1]. Ebola Surveillance Activities Ebola surveillance for STRIVE was designed and conducted through the STRIVE adverse events monitoring system in collaboration and coordination with the Sierra Leone national Ebola surveillance system [1, 8–10]. Modifications of case management as described below were implemented to decrease the risk that a participant experiencing a vaccine reaction would be unnecessarily referred to an Ebola facility for those symptoms. National and District Ebola Surveillance During the Ebola outbreak in Sierra Leone, persons with fever and ≥3 of the following symptoms met the suspected Ebola national case definition [7] (Figure 1): abdominal pain, diarrhea, difficulty breathing, difficulty swallowing, fatigue, headache, hiccups, muscle or joint pain, nausea or vomiting, unusual bleeding. A national Ebola telephone hotline was available for anyone who had or knew someone who had Ebola-like symptoms [11]. Persons who met the national case definition for suspected Ebola were referred immediately to an Ebola facility for further evaluation, isolation, laboratory testing, and management. Per Sierra Leone national protocol, all persons admitted to an Ebola facility had a blood specimen tested for Ebola by real-time reverse-transcription polymerase chain reaction (RT-PCR) analysis at one of about a dozen laboratories across the country that conducted Ebola testing for the national response. A positive real-time RT-PCR result confirmed Ebola; if the real-time RT-PCR was negative and the specimen was collected <3 days after onset of symptoms, a second specimen was collected and tested at ≥3 days [12]. Also, during the period during which STRIVE was conducted, national policy required testing for Ebola in postmortem swab specimens from deceased persons regardless of the cause of death, followed by immediate safe burials [13]. Figure 1. View largeDownload slide Ebola case definitions used during the Sierra Leone Trial to Introduce a Vaccine Against Ebola (STRIVE). aSymptoms in bold are those not known to be related to the study vaccine. Figure 1. View largeDownload slide Ebola case definitions used during the Sierra Leone Trial to Introduce a Vaccine Against Ebola (STRIVE). aSymptoms in bold are those not known to be related to the study vaccine. Identification of Possible Ebola Cases Among STRIVE Participants Several reporting systems were used in STRIVE to facilitate rapid, accurate, and complete assessment of potential Ebola among STRIVE participants [1, 9]. STRIVE participants had access to the national Ebola hotline described above, and the hotline operators were trained to ask whether callers were participants in a vaccine trial and to notify study staff when STRIVE participants made contact. STRIVE participants could also call a dedicated STRIVE medical hotline, available 24 hours a day, to report any symptoms of clinical illness, with immediate referral to a STRIVE nurse for telephone evaluation. Additionally, STRIVE study staff called participants monthly to check on their status, including any recent evaluation for Ebola, and conducted home visits when participants could not be reached by telephone [8]. STRIVE participants received medical care at no cost through referrals to designated physicians at existing healthcare facilities; details of the general provision of care to STRIVE participants are described elsewhere in this supplement [9]. STRIVE staff regularly worked with district Ebola surveillance officers to obtain laboratory results from the national Ebola surveillance system for any STRIVE participants evaluated for Ebola. STRIVE surveillance staff maintained close communication with district Ebola surveillance staff by regularly attending Ebola response meetings for surveillance updates, including discussion of newly laboratory-confirmed and suspected cases, as well as routinely visiting Ebola evaluation and treatment facilities to review admissions logs for the names of STRIVE participants. STRIVE also obtained the results of Ebola testing for participants who died, regardless of the reported cause of death. Ebola laboratory testing for suspected Ebola cases, including STRIVE participants, was conducted through the national system, to inform immediate clinical management. Duplicate samples were sent to a CDC STRIVE laboratory for processing and Ebola virus testing in accordance with Good Laboratory Practice standards. The CDC STRIVE laboratory was located within the larger CDC response laboratory in Bo District [12, 14]. Duplicate testing was possible through mid-October 2015, when the CDC response laboratory closed because the Ebola outbreak was ending. Algorithm for Initial Management of Illness in STRIVE Participants A standard approach was used to evaluate STRIVE participants for initial management of reported illness. According to this case management algorithm, those who were unvaccinated or who developed symptoms after the 48-hour postvaccination period were evaluated using the national Ebola case definition [7] and then referred for medical care as appropriate. However, STRIVE participants who developed symptoms during the initial 48 hours after vaccination and who had no known Ebola exposure were evaluated by trained study nurses, using a modified Ebola case definition, and then managed as designated in the algorithm (Figures 1 and 2). Figure 2. View largeDownload slide Algorithm for initial management of illness in participants from the Sierra Leone Trial to Introduce a Vaccine Against Ebola. Abbreviations: EVD, Ebola virus disease; PPE, personal protective equipment. Figure 2. View largeDownload slide Algorithm for initial management of illness in participants from the Sierra Leone Trial to Introduce a Vaccine Against Ebola. Abbreviations: EVD, Ebola virus disease; PPE, personal protective equipment. The modified case definition distinguished between symptoms associated with both Ebola and rVSV∆G-ZEBOV-GP receipt (fatigue, headache, loss of appetite, muscle/joint pain, and nausea) and those associated with Ebola but not typically with rVSV∆G-ZEBOV-GP receipt (abdominal pain, difficulty breathing, difficulty swallowing, hiccups, unusual breathing, vomiting) and required the presence of at least one of the latter symptoms to trigger immediate referral to an Ebola facility. Participants vaccinated within 48 hours of illness onset who met the modified case definition were immediately referred to an Ebola facility. Those who had symptoms common to vaccine administration but did not meet the more stringent modified case definition could be monitored at home for up to 24 hours, thereby deferring or avoiding admission to an Ebola facility. Study staff contacted these participants at 12-hour intervals (ie, 12 and 24 hours after the initial call) to see whether the participant’s symptoms had improved, worsened, or otherwise changed and to refer for care accordingly. However, study staff could also refer such participants for Ebola evaluation immediately or during follow-up if, on the basis of their clinical judgment, there was concern the illness could be Ebola. Additionally, study staff could refer any STRIVE participant for Ebola evaluation, regardless of when they were vaccinated and whether they met a case definition, if there was any suspicion the participant had Ebola. Data Collection and Analysis For participants evaluated for Ebola, STRIVE used a special case report form to collect information on symptoms, timing of symptom onset relative to vaccination, potential Ebola exposure, laboratory testing (blood or postmortem specimens) for Ebola, and outcome. The date of symptom onset was defined as the date of onset of the first symptom. All medical events reported within 28 days of the date of symptom onset were reviewed post hoc by 2 of the authors to assign a final diagnosis where possible. Data from participants who died of a cause not suspected to be Ebola and from whom a postmortem Ebola specimen was required per national protocol are mentioned but not included in the analysis. Data are presented using descriptive counts and frequencies. RESULTS STRIVE enrolled 8651 participants and vaccinated 7998; details have been previously reported [1]. No laboratory-confirmed Ebola cases were identified among STRIVE participants through the national Ebola surveillance system or through the additional STRIVE systems from the launch of the study on April 9 2015 through 28 July 2016, when follow-up was complete. A total of 72 participants had an Ebola evaluation form submitted: 22 died from a cause not thought to be Ebola and had routine postmortem specimens tested for Ebola; none had positive results. The remaining 50 participants, who were enrolled from all 7 enrollment/vaccination sites, are included in the analysis (Figure 3). Demographic characteristics of the 50 participants were similar to the study population as a whole; the median age was 29 years (range, 20–55 years), and 31 (62%) were male. Of these 50 participants, 34 (68%) had onset of symptoms after vaccination (symptoms in 7 began ≤48 hours after vaccination, described below); the other 16 participants had not yet been vaccinated when their symptoms began. Three of 50 participants evaluated for Ebola died. Forty-six (92%) provided at least 1 blood or postmortem sample for testing for Ebola virus (all had negative test results), and 31 (62%) were admitted to an Ebola facility. Reported symptoms included headache in 38 (76%), anorexia in 35 (70%), myalgia in 31 (62%), vomiting in 29 (58%), fatigue in 27 (54%), and fever in 27 (54%). Figure 3. View largeDownload slide Flow diagram of participants from the Sierra Leone Trial to Introduce a Vaccine Against Ebola (STRIVE) who were evaluated for Ebola. Figure 3. View largeDownload slide Flow diagram of participants from the Sierra Leone Trial to Introduce a Vaccine Against Ebola (STRIVE) who were evaluated for Ebola. Of the 34 participants with onset of symptoms after vaccination, 7 (21%) had symptom onset ≤48 hours after vaccination. Of these 7, 3 met the modified case definition, 1 met the national case definition but not the modified case definition, and 3 met neither case definition but were referred for evaluation on the basis of the judgment of the study staff. Five of these participants (2 of 3 who met the modified case definition and all 3 who met neither case definition) were admitted to an Ebola facility. All 5 who were admitted to an Ebola facility had been vaccinated and developed symptoms on or before 1 June 2015, whereas the 2 who were not admitted were vaccinated after this date, closer to the end of the epidemic. Symptoms associated with Ebola but not rVSV∆G-ZEBOV-GP reported by the 3 participants who met the modified case definition included nausea/vomiting in all 3. In addition, 1 had difficulty breathing and 1 had difficulty swallowing/hiccups. None of the 7 participants evaluated within 48 hours of vaccination died. Among the 50 participants evaluated for Ebola, 20 had malaria diagnoses, including 3 who also had typhoid fever diagnosed and 1 with a urinary tract infection. One participant each received a diagnosis of pneumonia, peptic ulcer disease, pelvic inflammatory disease, food poisoning, and loss of consciousness, and one had a triad of typhoid fever, pelvic inflammatory disease, and acute glomerulonephritis diagnosed. Sixteen participants presented with fever and some combination of nonspecific symptoms (eg, headache, myalgias, decreased appetite, dizziness, nausea, and diarrhea) that were suggestive of an infectious event, and 8 participants presented with nonspecific symptoms without fever. During the course of the work-up for Ebola, 2 participants with malaria were also reported to have human immunodeficiency virus (HIV) infection. One additional participant, with nonspecific symptoms, received a diagnosis of HIV infection after enrollment in the study but before the Ebola evaluation. Two of the 3 participants who died did so from the illness that initiated the Ebola evaluation (malaria in both cases), and the third experienced a sudden loss of consciousness, that was thought to be an acute central nervous system event. Because this participant was unconscious at presentation, which presented challenges for obtaining their medical history, an Ebola screening form was initiated, and after death a routine postmortem Ebola swab specimen was collected. DISCUSSION Conducting complete and accurate surveillance for Ebola among trial participants was a critical challenge for STRIVE. Our experience yielded insights that may be useful if and when rVSV∆G-ZEBOV-GP is deployed in future outbreak or epidemic situations. First, integration and communication with the broader public health response is both necessary and feasible, not only for coordination of surveillance but also to avoid interfering with other response activities. Second, across all the months of STRIVE participant follow-up, a relatively small number of participants (<1% of the study cohort) were referred for Ebola evaluation. Thus, at least within the context of this waning epidemic, the burden of Ebola surveillance and evaluation was manageable. This might not be the case, however, if this vaccine were used during the peak of a large Ebola outbreak. Third, STRIVE’s strategy of using a modification of the case definition and case management algorithm to distinguish vaccine reactions from symptoms of possible Ebola in participants vaccinated ≤48 hours before illness onset appears to be a practical approach for limiting unnecessary exposure to Ebola facilities. Few recently vaccinated trial participants were referred to Ebola facilities, which provided multiple benefits, including limiting lost work time for healthcare and frontline workers essential to the Ebola response. Critical to using the modified case definition was the ability to closely monitor the participants and refer them to an Ebola facility or study physician if their condition did not improve. No STRIVE participants had Ebola diagnosed, although 50 participants were evaluated for the disease. Many of these participants had other common infections diagnosed, most commonly malaria. Most participants fully recovered; 3 died. Three participants with HIV infection are described in our analysis; it is not known whether these were new diagnoses or the participants had been aware but did not reveal the diagnosis during screening, since HIV infection would have excluded them from enrolling in the study. Use of the modified Ebola case definition and case management algorithm for evaluating participants vaccinated ≤48 hours before symptom onset was an innovation developed for STRIVE. At the time STRIVE launched, limited experience from phase 1 studies had shown that VSV∆G-ZEBOV-GP commonly caused symptoms, such as fever, myalgia, fatigue, and headache, that are common early symptoms of Ebola [2, 3]. Subsequent studies, including STRIVE and other phase 2/3 studies, confirmed this reactogenicity profile [1, 15–17]. Vaccine-induced protection appears to develop about 7–10 days after vaccination [15], so admitting vaccinated persons to Ebola facilities within 1 or 2 days after vaccination might place them at increased risk for Ebola. While we unfortunately do not have information on the number of admissions to Ebola facilities avoided by use of the modified case definition, only a small number of participants were referred for symptoms starting ≤48 hours after vaccination, which is far fewer than would have been expected without the use of the modified case definition, given the known reactogenicity profile of the vaccine. Our data also show that clinical personnel conducting evaluations used their clinical judgment in decision-making, rather than adhering rigidly to case definitions and management algorithms. Of the 5 participants admitted to an Ebola facility for evaluation of symptoms starting ≤48 hours after vaccination, only 2 met the modified case definition; the other 3 did not fully meet the modified or standard case definition. The timing of the participant’s illness within the epidemic seems to have played an important role in these judgments, in that the 5 participants who were admitted within 2 days of vaccination were all vaccinated early in the trial, when Ebola and concern about Ebola were more prevalent in Sierra Leone than they were later in the trial. In STRIVE, all participants tested for Ebola had negative results of laboratory tests. Details of testing by the various national laboratories and the study laboratory that conducted this testing are beyond the scope of this article, but it is important for investigators and public health responders who deploy rVSV∆G-ZEBOV-GP to be aware that molecular testing strategies must be able to differentiate Ebola virus from rVSV∆G-ZEBOV-GP [18] or risk possible false-positive results in vaccinated persons. rVSVΔG-ZEBOV-GP has a vesicular stomatitis virus backbone genetically engineered to expresses the Zaire Ebola virus envelope glycoprotein (GP) [19]. There has been a previous report of a recipient of VSV∆G-ZEBOV-GP who developed a febrile illness and was tested according to guidelines in Europe with 2 PCR tests, of which one used the Ebola virus GP gene—the same gene as in the vaccine—as a PCR target and the other used the L gene as a target. The patient was considered not to have Ebola, based on results of dual testing (the test based on the GP gene had a positive result, and the test based on the L gene had a negative result), but the authors noted the risk of misinterpretation of the test results after rVSV∆G-ZEBOV-GP receipt if only the single GP gene target is used in PCR testing [18]. Before STRIVE commenced, with the approval of the national Ebola response laboratory leadership, STRIVE staff surveyed the Ebola response laboratories to determine the PCR targets used in each laboratory and whether there was the potential for any false-positive test results after vaccination. One laboratory that conducted Ebola testing concurrent with STRIVE used 2 PCR targets, one of which was the GP gene; close contact was maintained with this laboratory because of the potential for a false-positive result in a STRIVE participant who received vaccine. The use of 2 different PCR targets minimized the potential of false-positive test results in vaccine recipients. Beyond the limitations mentioned above, several other limitations apply to the results and conclusions described here. First, the Ebola outbreak had waned substantially by the time STRIVE started. Following the declaration by the World Health Organization that the outbreak had ended in November 2015, few cases were referred for Ebola testing [20]. Thus, relatively few suspected Ebola cases were evaluated. This was especially true for the long-term follow-up of participants in the deferred group, who were vaccinated from September to December 2015. Because no cases of Ebola were diagnosed in STRIVE participants, we were not able to assess the ability of the modified case definition to discriminate Ebola from vaccine reactions. Also, although no participant had Ebola diagnosed, it was often difficult for the study physicians to make a single unifying diagnosis for the illness that initiated the Ebola evaluation, in part because of lack of confirmatory diagnostic capabilities (eg, laboratory and radiologic testing). While malaria was the most common diagnosis, it was often made without laboratory confirmation. The routine use of antipyretics after vaccination must also be considered; STRIVE did not provide antipyretics, in large part because of concern that they might mask symptoms of Ebola, but the World Health Organization ring vaccination trial in Guinea successfully used antipyretics to address fever related to reactogenicity following vaccination [15]. There may also be a role for the use of antimalarial medications after vaccination. During the outbreak in Sierra Leone, mass administration of antimalarials in December 2014–January 2015 reduced the number of malaria cases (clinical and confirmed) and Ebola alerts for up to 3 weeks [21]. The availability of diagnostic capacity, including rapid testing, for other common infectious diseases, such as malaria and typhoid, has benefits both in facilitating appropriate treatment and in obviating unnecessary referral to an Ebola facility [22]. However, a high index of suspicion needs to be maintained for dual infections with Ebola virus and another infectious agent [23]. In summary, the STRIVE experience with conducting surveillance for Ebola cases highlights both some of the challenges of deploying rVSV∆G-ZEBOV-GP during an Ebola outbreak and some approaches for overcoming those challenges. Close coordination with the national response is essential, both to avoid inadvertent interference with response activities and to fully ascertain health outcomes. The potential for false-positive Ebola test results after vaccination emphasizes the need for careful selection of laboratory testing strategies in vaccinated persons. Use of a modified case definition and case management algorithm for evaluation of symptoms occurring ≤48 hours after vaccination appears to be a useful and feasible approach for limiting unnecessary referrals to Ebola facilities but needs further validation. Future evaluations or use of vaccines that can cause symptoms similar to those seen in the early stages of the epidemic diseases the vaccines are meant to prevent could also consider trying to distinguish vaccine reactions from the disease. Notes Acknowledgments.  We thank all of the healthcare and frontline workers who were STRIVE participants; and Sara Hersey, Oliver Morgan, Sarah Bennett, John Redd and other members of the CDC Ebola Response Team and CDC Country Office in Sierra Leone, for supporting this work; and we honor all individuals in Sierra Leone who died from Ebola. Disclaimer.  The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention or the Agency for Toxic Substances and Disease Registry. Financial support. This work was supported by the Centers for Disease Control and Prevention, the Biomedical Advanced Research and Development Authority and the National Institutes of Health, with additional support from the CDC Foundation. Supplement sponsorship. This work is part of a supplement sponsored by the Centers for Disease Control and Prevention. Potential conflicts of interest. P. D., C. R. P., and R. L. received grants from Biomedical Advanced Research and Development Authority during the conduct of the study. All other authors report no potential conflicts of interest. All authors have submitted the ICJME Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Presented in part: 65th Annual Meeting of the American Society of Tropical Medicine and Hygiene, Atlanta, Georgia, 13–17 November 2016. Abstract 1398. References 1. Samai M, Seward JF, Goldstein ST, et al.   The Sierra Leone Trial to Introduce a Vaccine against Ebola: An Evaluation of rVSV∆G-ZEBOV-GP vaccine tolerability and safety during the West Africa Ebola Outbreak. J Infect Dis Suppl  2018; 217: s6– 15. 2. Agnandji ST, Huttner A, Zinser ME, et al.   Phase 1 trials of rVSV Ebola vaccine in Africa and Europe. N Engl J Med  2016; 374: 1647– 60. Google Scholar CrossRef Search ADS PubMed  3. 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J Virol  2004; 78: 5458– 65. Google Scholar CrossRef Search ADS PubMed  20. Dahl BA, Kinzer MH, Raghunathan PL, et al.   CDC’s response to the 2014-2016 Ebola epidemic—Guinea, Liberia, and Sierra Leone. MMWR Suppl  2016; 65: 12– 20. Google Scholar CrossRef Search ADS PubMed  21. Aregawi M, Smith SJ, Sillah-Kanu M, et al.   Impact of the mass drug administration for malaria in response to the Ebola outbreak in Sierra Leone. Malar J  2016; 15: 480. Google Scholar CrossRef Search ADS PubMed  22. O’Shea MK, Clay KA, Craig DG, et al.   Diagnosis of febrile illnesses other than Ebola virus disease at an Ebola treatment unit in Sierra Leone. Clin Infect Dis  2015; 61: 795– 8. Google Scholar CrossRef Search ADS PubMed  23. Waxman M, Aluisio AR, Rege S, Levine AC. Characteristics and survival of patients with Ebola virus infection, malaria, or both in Sierra Leone: a retrospective cohort study. Lancet Infect Dis  2017; 17: 654– 60. Google Scholar CrossRef Search ADS PubMed  Published by Oxford University Press for the Infectious Diseases Society of America 2018. This work is written by (a) US Government employee(s) and is in the public domain in the US. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Infectious Diseases Oxford University Press

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Abstract

Abstract The Sierra Leone Trial to Introduce a Vaccine Against Ebola (STRIVE), an Ebola vaccine trial conducted during the 2014–2016 Ebola epidemic, coordinated with the Sierra Leone national response to identify Ebola cases among trial participants. The early symptoms of Ebola are similar to common vaccine reactions, so it was important to differentiate these to avoid unnecessary referral to an Ebola facility and an increased risk of Ebola exposure. STRIVE developed a modified version of the national case definition and case management algorithm to distinguish between symptoms associated with both Ebola and vaccination with the candidate Ebola vaccine (rVSV∆G-ZEBOV-GP) from those typically associated only with Ebola. For participants who presented ≤48 hours after vaccination, we used the more stringent modified case definition to trigger referral for Ebola evaluation. Participants whose symptoms did not meet case definitions could also be referred to an Ebola facility, based on clinical judgment. No Ebola cases were diagnosed among the 8651 STRIVE participants. Fifty participants were evaluated for Ebola, of whom 34 (68%) were tested after vaccination; 22 deceased participants, all of whom underwent postmortem Ebola testing, as required during the Ebola epidemic, and had negative test results, were excluded from analysis. Seven of 34 participants (21%) had symptom onset ≤48 hours after vaccination, of whom 3 met the modified case definition. The most common diagnosis among those evaluated for Ebola was malaria. STRIVE demonstrates the feasibility of conducting Ebola surveillance among persons vaccinated with rVSV-ZEBOV during an Ebola epidemic and introduces a modified case definition and case management algorithm to distinguish vaccine reactions from early symptoms of Ebola that may be useful for reducing unnecessary Ebola evaluations among persons vaccinated during Ebola outbreaks. Clinical Trials Registration ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220]. Ebola, surveillance, Ebola vaccine, rVSV∆G-ZEBOV-GP, Sierra Leone The Sierra Leone Trial to Introduce a Vaccine Against Ebola (STRIVE), a phase 2/3 clinical trial of the candidate Ebola vaccine rVSV∆G-ZEBOV-GP (Merck), was conducted among high-risk healthcare workers and frontline Ebola response workers during the 2014–2016 Ebola virus disease (Ebola) outbreak [1]. The primary outcomes of the study were vaccine efficacy and safety, and while the efficacy end points could not be evaluated because there were ultimately no cases of Ebola among trial participants, surveillance for Ebola was a critical component of the study. Ebola surveillance was complicated by the overlap in symptoms between early Ebola, other infectious diseases, and common reactions to the experimental Ebola vaccine. Data from phase 1 trials of rVSV∆G-ZEBOV-GP had shown that up to 70% of vaccinated participants experienced symptoms such as fatigue, headache, myalgia, and fever within 24–48 hours after vaccination [2, 3]. These symptoms are similar to the early symptoms of Ebola, as well as other infections common in Sierra Leone, such as malaria and typhoid fever [4, 5]. Further complicating surveillance, the Sierra Leone national response plan called for referral of all persons with suspected Ebola to Ebola facilities for isolation, evaluation, laboratory testing, and treatment, as appropriate [6, 7]. This policy was appropriate and necessary during the epidemic. However, such referral could potentially increase the risk of nosocomial exposure to Ebola. Also, because healthcare workers and frontline workers were a limited and critical resource for the epidemic response, it was important to avoid unnecessary prolonged absences from work. Thus, for STRIVE study participants, it was important to distinguish vaccine reactions from early Ebola symptoms as accurately as possible both to avoid unnecessary referral of participants for Ebola evaluation and to correctly diagnose other infectious conditions so that effective treatment would not be delayed. This article describes the STRIVE approach to and experience with Ebola surveillance, including the outcomes of participants evaluated for Ebola. This approach may be useful for reducing unnecessary Ebola evaluations and potential Ebola exposures among people who receive rVSV∆G-ZEBOV-GP during Ebola outbreaks. METHODS STRIVE was a partnership between the College of Medicine and Allied Health Sciences, University of Sierra Leone; the Ministry of Health and Sanitation in Sierra Leone; and the Centers for Disease Control and Prevention (CDC). Enrollment was conducted from April through August 2015 at 7 sites in 5 districts. Participants were individually randomized to either immediate vaccination or deferred (18–24 weeks later) vaccination. Vaccination was completed in December 2015. Details of the methods and results are reported elsewhere [1]. Ebola Surveillance Activities Ebola surveillance for STRIVE was designed and conducted through the STRIVE adverse events monitoring system in collaboration and coordination with the Sierra Leone national Ebola surveillance system [1, 8–10]. Modifications of case management as described below were implemented to decrease the risk that a participant experiencing a vaccine reaction would be unnecessarily referred to an Ebola facility for those symptoms. National and District Ebola Surveillance During the Ebola outbreak in Sierra Leone, persons with fever and ≥3 of the following symptoms met the suspected Ebola national case definition [7] (Figure 1): abdominal pain, diarrhea, difficulty breathing, difficulty swallowing, fatigue, headache, hiccups, muscle or joint pain, nausea or vomiting, unusual bleeding. A national Ebola telephone hotline was available for anyone who had or knew someone who had Ebola-like symptoms [11]. Persons who met the national case definition for suspected Ebola were referred immediately to an Ebola facility for further evaluation, isolation, laboratory testing, and management. Per Sierra Leone national protocol, all persons admitted to an Ebola facility had a blood specimen tested for Ebola by real-time reverse-transcription polymerase chain reaction (RT-PCR) analysis at one of about a dozen laboratories across the country that conducted Ebola testing for the national response. A positive real-time RT-PCR result confirmed Ebola; if the real-time RT-PCR was negative and the specimen was collected <3 days after onset of symptoms, a second specimen was collected and tested at ≥3 days [12]. Also, during the period during which STRIVE was conducted, national policy required testing for Ebola in postmortem swab specimens from deceased persons regardless of the cause of death, followed by immediate safe burials [13]. Figure 1. View largeDownload slide Ebola case definitions used during the Sierra Leone Trial to Introduce a Vaccine Against Ebola (STRIVE). aSymptoms in bold are those not known to be related to the study vaccine. Figure 1. View largeDownload slide Ebola case definitions used during the Sierra Leone Trial to Introduce a Vaccine Against Ebola (STRIVE). aSymptoms in bold are those not known to be related to the study vaccine. Identification of Possible Ebola Cases Among STRIVE Participants Several reporting systems were used in STRIVE to facilitate rapid, accurate, and complete assessment of potential Ebola among STRIVE participants [1, 9]. STRIVE participants had access to the national Ebola hotline described above, and the hotline operators were trained to ask whether callers were participants in a vaccine trial and to notify study staff when STRIVE participants made contact. STRIVE participants could also call a dedicated STRIVE medical hotline, available 24 hours a day, to report any symptoms of clinical illness, with immediate referral to a STRIVE nurse for telephone evaluation. Additionally, STRIVE study staff called participants monthly to check on their status, including any recent evaluation for Ebola, and conducted home visits when participants could not be reached by telephone [8]. STRIVE participants received medical care at no cost through referrals to designated physicians at existing healthcare facilities; details of the general provision of care to STRIVE participants are described elsewhere in this supplement [9]. STRIVE staff regularly worked with district Ebola surveillance officers to obtain laboratory results from the national Ebola surveillance system for any STRIVE participants evaluated for Ebola. STRIVE surveillance staff maintained close communication with district Ebola surveillance staff by regularly attending Ebola response meetings for surveillance updates, including discussion of newly laboratory-confirmed and suspected cases, as well as routinely visiting Ebola evaluation and treatment facilities to review admissions logs for the names of STRIVE participants. STRIVE also obtained the results of Ebola testing for participants who died, regardless of the reported cause of death. Ebola laboratory testing for suspected Ebola cases, including STRIVE participants, was conducted through the national system, to inform immediate clinical management. Duplicate samples were sent to a CDC STRIVE laboratory for processing and Ebola virus testing in accordance with Good Laboratory Practice standards. The CDC STRIVE laboratory was located within the larger CDC response laboratory in Bo District [12, 14]. Duplicate testing was possible through mid-October 2015, when the CDC response laboratory closed because the Ebola outbreak was ending. Algorithm for Initial Management of Illness in STRIVE Participants A standard approach was used to evaluate STRIVE participants for initial management of reported illness. According to this case management algorithm, those who were unvaccinated or who developed symptoms after the 48-hour postvaccination period were evaluated using the national Ebola case definition [7] and then referred for medical care as appropriate. However, STRIVE participants who developed symptoms during the initial 48 hours after vaccination and who had no known Ebola exposure were evaluated by trained study nurses, using a modified Ebola case definition, and then managed as designated in the algorithm (Figures 1 and 2). Figure 2. View largeDownload slide Algorithm for initial management of illness in participants from the Sierra Leone Trial to Introduce a Vaccine Against Ebola. Abbreviations: EVD, Ebola virus disease; PPE, personal protective equipment. Figure 2. View largeDownload slide Algorithm for initial management of illness in participants from the Sierra Leone Trial to Introduce a Vaccine Against Ebola. Abbreviations: EVD, Ebola virus disease; PPE, personal protective equipment. The modified case definition distinguished between symptoms associated with both Ebola and rVSV∆G-ZEBOV-GP receipt (fatigue, headache, loss of appetite, muscle/joint pain, and nausea) and those associated with Ebola but not typically with rVSV∆G-ZEBOV-GP receipt (abdominal pain, difficulty breathing, difficulty swallowing, hiccups, unusual breathing, vomiting) and required the presence of at least one of the latter symptoms to trigger immediate referral to an Ebola facility. Participants vaccinated within 48 hours of illness onset who met the modified case definition were immediately referred to an Ebola facility. Those who had symptoms common to vaccine administration but did not meet the more stringent modified case definition could be monitored at home for up to 24 hours, thereby deferring or avoiding admission to an Ebola facility. Study staff contacted these participants at 12-hour intervals (ie, 12 and 24 hours after the initial call) to see whether the participant’s symptoms had improved, worsened, or otherwise changed and to refer for care accordingly. However, study staff could also refer such participants for Ebola evaluation immediately or during follow-up if, on the basis of their clinical judgment, there was concern the illness could be Ebola. Additionally, study staff could refer any STRIVE participant for Ebola evaluation, regardless of when they were vaccinated and whether they met a case definition, if there was any suspicion the participant had Ebola. Data Collection and Analysis For participants evaluated for Ebola, STRIVE used a special case report form to collect information on symptoms, timing of symptom onset relative to vaccination, potential Ebola exposure, laboratory testing (blood or postmortem specimens) for Ebola, and outcome. The date of symptom onset was defined as the date of onset of the first symptom. All medical events reported within 28 days of the date of symptom onset were reviewed post hoc by 2 of the authors to assign a final diagnosis where possible. Data from participants who died of a cause not suspected to be Ebola and from whom a postmortem Ebola specimen was required per national protocol are mentioned but not included in the analysis. Data are presented using descriptive counts and frequencies. RESULTS STRIVE enrolled 8651 participants and vaccinated 7998; details have been previously reported [1]. No laboratory-confirmed Ebola cases were identified among STRIVE participants through the national Ebola surveillance system or through the additional STRIVE systems from the launch of the study on April 9 2015 through 28 July 2016, when follow-up was complete. A total of 72 participants had an Ebola evaluation form submitted: 22 died from a cause not thought to be Ebola and had routine postmortem specimens tested for Ebola; none had positive results. The remaining 50 participants, who were enrolled from all 7 enrollment/vaccination sites, are included in the analysis (Figure 3). Demographic characteristics of the 50 participants were similar to the study population as a whole; the median age was 29 years (range, 20–55 years), and 31 (62%) were male. Of these 50 participants, 34 (68%) had onset of symptoms after vaccination (symptoms in 7 began ≤48 hours after vaccination, described below); the other 16 participants had not yet been vaccinated when their symptoms began. Three of 50 participants evaluated for Ebola died. Forty-six (92%) provided at least 1 blood or postmortem sample for testing for Ebola virus (all had negative test results), and 31 (62%) were admitted to an Ebola facility. Reported symptoms included headache in 38 (76%), anorexia in 35 (70%), myalgia in 31 (62%), vomiting in 29 (58%), fatigue in 27 (54%), and fever in 27 (54%). Figure 3. View largeDownload slide Flow diagram of participants from the Sierra Leone Trial to Introduce a Vaccine Against Ebola (STRIVE) who were evaluated for Ebola. Figure 3. View largeDownload slide Flow diagram of participants from the Sierra Leone Trial to Introduce a Vaccine Against Ebola (STRIVE) who were evaluated for Ebola. Of the 34 participants with onset of symptoms after vaccination, 7 (21%) had symptom onset ≤48 hours after vaccination. Of these 7, 3 met the modified case definition, 1 met the national case definition but not the modified case definition, and 3 met neither case definition but were referred for evaluation on the basis of the judgment of the study staff. Five of these participants (2 of 3 who met the modified case definition and all 3 who met neither case definition) were admitted to an Ebola facility. All 5 who were admitted to an Ebola facility had been vaccinated and developed symptoms on or before 1 June 2015, whereas the 2 who were not admitted were vaccinated after this date, closer to the end of the epidemic. Symptoms associated with Ebola but not rVSV∆G-ZEBOV-GP reported by the 3 participants who met the modified case definition included nausea/vomiting in all 3. In addition, 1 had difficulty breathing and 1 had difficulty swallowing/hiccups. None of the 7 participants evaluated within 48 hours of vaccination died. Among the 50 participants evaluated for Ebola, 20 had malaria diagnoses, including 3 who also had typhoid fever diagnosed and 1 with a urinary tract infection. One participant each received a diagnosis of pneumonia, peptic ulcer disease, pelvic inflammatory disease, food poisoning, and loss of consciousness, and one had a triad of typhoid fever, pelvic inflammatory disease, and acute glomerulonephritis diagnosed. Sixteen participants presented with fever and some combination of nonspecific symptoms (eg, headache, myalgias, decreased appetite, dizziness, nausea, and diarrhea) that were suggestive of an infectious event, and 8 participants presented with nonspecific symptoms without fever. During the course of the work-up for Ebola, 2 participants with malaria were also reported to have human immunodeficiency virus (HIV) infection. One additional participant, with nonspecific symptoms, received a diagnosis of HIV infection after enrollment in the study but before the Ebola evaluation. Two of the 3 participants who died did so from the illness that initiated the Ebola evaluation (malaria in both cases), and the third experienced a sudden loss of consciousness, that was thought to be an acute central nervous system event. Because this participant was unconscious at presentation, which presented challenges for obtaining their medical history, an Ebola screening form was initiated, and after death a routine postmortem Ebola swab specimen was collected. DISCUSSION Conducting complete and accurate surveillance for Ebola among trial participants was a critical challenge for STRIVE. Our experience yielded insights that may be useful if and when rVSV∆G-ZEBOV-GP is deployed in future outbreak or epidemic situations. First, integration and communication with the broader public health response is both necessary and feasible, not only for coordination of surveillance but also to avoid interfering with other response activities. Second, across all the months of STRIVE participant follow-up, a relatively small number of participants (<1% of the study cohort) were referred for Ebola evaluation. Thus, at least within the context of this waning epidemic, the burden of Ebola surveillance and evaluation was manageable. This might not be the case, however, if this vaccine were used during the peak of a large Ebola outbreak. Third, STRIVE’s strategy of using a modification of the case definition and case management algorithm to distinguish vaccine reactions from symptoms of possible Ebola in participants vaccinated ≤48 hours before illness onset appears to be a practical approach for limiting unnecessary exposure to Ebola facilities. Few recently vaccinated trial participants were referred to Ebola facilities, which provided multiple benefits, including limiting lost work time for healthcare and frontline workers essential to the Ebola response. Critical to using the modified case definition was the ability to closely monitor the participants and refer them to an Ebola facility or study physician if their condition did not improve. No STRIVE participants had Ebola diagnosed, although 50 participants were evaluated for the disease. Many of these participants had other common infections diagnosed, most commonly malaria. Most participants fully recovered; 3 died. Three participants with HIV infection are described in our analysis; it is not known whether these were new diagnoses or the participants had been aware but did not reveal the diagnosis during screening, since HIV infection would have excluded them from enrolling in the study. Use of the modified Ebola case definition and case management algorithm for evaluating participants vaccinated ≤48 hours before symptom onset was an innovation developed for STRIVE. At the time STRIVE launched, limited experience from phase 1 studies had shown that VSV∆G-ZEBOV-GP commonly caused symptoms, such as fever, myalgia, fatigue, and headache, that are common early symptoms of Ebola [2, 3]. Subsequent studies, including STRIVE and other phase 2/3 studies, confirmed this reactogenicity profile [1, 15–17]. Vaccine-induced protection appears to develop about 7–10 days after vaccination [15], so admitting vaccinated persons to Ebola facilities within 1 or 2 days after vaccination might place them at increased risk for Ebola. While we unfortunately do not have information on the number of admissions to Ebola facilities avoided by use of the modified case definition, only a small number of participants were referred for symptoms starting ≤48 hours after vaccination, which is far fewer than would have been expected without the use of the modified case definition, given the known reactogenicity profile of the vaccine. Our data also show that clinical personnel conducting evaluations used their clinical judgment in decision-making, rather than adhering rigidly to case definitions and management algorithms. Of the 5 participants admitted to an Ebola facility for evaluation of symptoms starting ≤48 hours after vaccination, only 2 met the modified case definition; the other 3 did not fully meet the modified or standard case definition. The timing of the participant’s illness within the epidemic seems to have played an important role in these judgments, in that the 5 participants who were admitted within 2 days of vaccination were all vaccinated early in the trial, when Ebola and concern about Ebola were more prevalent in Sierra Leone than they were later in the trial. In STRIVE, all participants tested for Ebola had negative results of laboratory tests. Details of testing by the various national laboratories and the study laboratory that conducted this testing are beyond the scope of this article, but it is important for investigators and public health responders who deploy rVSV∆G-ZEBOV-GP to be aware that molecular testing strategies must be able to differentiate Ebola virus from rVSV∆G-ZEBOV-GP [18] or risk possible false-positive results in vaccinated persons. rVSVΔG-ZEBOV-GP has a vesicular stomatitis virus backbone genetically engineered to expresses the Zaire Ebola virus envelope glycoprotein (GP) [19]. There has been a previous report of a recipient of VSV∆G-ZEBOV-GP who developed a febrile illness and was tested according to guidelines in Europe with 2 PCR tests, of which one used the Ebola virus GP gene—the same gene as in the vaccine—as a PCR target and the other used the L gene as a target. The patient was considered not to have Ebola, based on results of dual testing (the test based on the GP gene had a positive result, and the test based on the L gene had a negative result), but the authors noted the risk of misinterpretation of the test results after rVSV∆G-ZEBOV-GP receipt if only the single GP gene target is used in PCR testing [18]. Before STRIVE commenced, with the approval of the national Ebola response laboratory leadership, STRIVE staff surveyed the Ebola response laboratories to determine the PCR targets used in each laboratory and whether there was the potential for any false-positive test results after vaccination. One laboratory that conducted Ebola testing concurrent with STRIVE used 2 PCR targets, one of which was the GP gene; close contact was maintained with this laboratory because of the potential for a false-positive result in a STRIVE participant who received vaccine. The use of 2 different PCR targets minimized the potential of false-positive test results in vaccine recipients. Beyond the limitations mentioned above, several other limitations apply to the results and conclusions described here. First, the Ebola outbreak had waned substantially by the time STRIVE started. Following the declaration by the World Health Organization that the outbreak had ended in November 2015, few cases were referred for Ebola testing [20]. Thus, relatively few suspected Ebola cases were evaluated. This was especially true for the long-term follow-up of participants in the deferred group, who were vaccinated from September to December 2015. Because no cases of Ebola were diagnosed in STRIVE participants, we were not able to assess the ability of the modified case definition to discriminate Ebola from vaccine reactions. Also, although no participant had Ebola diagnosed, it was often difficult for the study physicians to make a single unifying diagnosis for the illness that initiated the Ebola evaluation, in part because of lack of confirmatory diagnostic capabilities (eg, laboratory and radiologic testing). While malaria was the most common diagnosis, it was often made without laboratory confirmation. The routine use of antipyretics after vaccination must also be considered; STRIVE did not provide antipyretics, in large part because of concern that they might mask symptoms of Ebola, but the World Health Organization ring vaccination trial in Guinea successfully used antipyretics to address fever related to reactogenicity following vaccination [15]. There may also be a role for the use of antimalarial medications after vaccination. During the outbreak in Sierra Leone, mass administration of antimalarials in December 2014–January 2015 reduced the number of malaria cases (clinical and confirmed) and Ebola alerts for up to 3 weeks [21]. The availability of diagnostic capacity, including rapid testing, for other common infectious diseases, such as malaria and typhoid, has benefits both in facilitating appropriate treatment and in obviating unnecessary referral to an Ebola facility [22]. However, a high index of suspicion needs to be maintained for dual infections with Ebola virus and another infectious agent [23]. In summary, the STRIVE experience with conducting surveillance for Ebola cases highlights both some of the challenges of deploying rVSV∆G-ZEBOV-GP during an Ebola outbreak and some approaches for overcoming those challenges. Close coordination with the national response is essential, both to avoid inadvertent interference with response activities and to fully ascertain health outcomes. The potential for false-positive Ebola test results after vaccination emphasizes the need for careful selection of laboratory testing strategies in vaccinated persons. Use of a modified case definition and case management algorithm for evaluation of symptoms occurring ≤48 hours after vaccination appears to be a useful and feasible approach for limiting unnecessary referrals to Ebola facilities but needs further validation. Future evaluations or use of vaccines that can cause symptoms similar to those seen in the early stages of the epidemic diseases the vaccines are meant to prevent could also consider trying to distinguish vaccine reactions from the disease. Notes Acknowledgments.  We thank all of the healthcare and frontline workers who were STRIVE participants; and Sara Hersey, Oliver Morgan, Sarah Bennett, John Redd and other members of the CDC Ebola Response Team and CDC Country Office in Sierra Leone, for supporting this work; and we honor all individuals in Sierra Leone who died from Ebola. Disclaimer.  The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention or the Agency for Toxic Substances and Disease Registry. Financial support. This work was supported by the Centers for Disease Control and Prevention, the Biomedical Advanced Research and Development Authority and the National Institutes of Health, with additional support from the CDC Foundation. Supplement sponsorship. This work is part of a supplement sponsored by the Centers for Disease Control and Prevention. Potential conflicts of interest. P. D., C. R. P., and R. L. received grants from Biomedical Advanced Research and Development Authority during the conduct of the study. All other authors report no potential conflicts of interest. All authors have submitted the ICJME Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Presented in part: 65th Annual Meeting of the American Society of Tropical Medicine and Hygiene, Atlanta, Georgia, 13–17 November 2016. Abstract 1398. References 1. Samai M, Seward JF, Goldstein ST, et al.   The Sierra Leone Trial to Introduce a Vaccine against Ebola: An Evaluation of rVSV∆G-ZEBOV-GP vaccine tolerability and safety during the West Africa Ebola Outbreak. J Infect Dis Suppl  2018; 217: s6– 15. 2. Agnandji ST, Huttner A, Zinser ME, et al.   Phase 1 trials of rVSV Ebola vaccine in Africa and Europe. N Engl J Med  2016; 374: 1647– 60. Google Scholar CrossRef Search ADS PubMed  3. 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Google Scholar CrossRef Search ADS PubMed  Published by Oxford University Press for the Infectious Diseases Society of America 2018. This work is written by (a) US Government employee(s) and is in the public domain in the US.

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The Journal of Infectious DiseasesOxford University Press

Published: May 18, 2018

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