Egalement disponible en francais sous le titre : Declaration provisoire sur l'utilisation du vaccin rVSVG-ZEBOV-GP pour la prevention de la maladie a virus Ebola This publication can be made available in alternative formats upon request.# PREAMBLE
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidencebased recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Over the coming years NACI will be refining methodological approaches to include these factors. Not all NACI statements will require in-depth analyses of all programmatic factors. As NACI works towards full implementation of the expanded mandate, select statements will include varying degrees of programmatic analyses for public health programs.
PHAC acknowledges that the advice and recommendations set out in this interim statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. As the advice is provided for an investigational product that has not yet received regulatory authorization for sale in Canada, people administering the premarket vaccine should also be aware of the contents of the pharmacy manual and investigator's brochure provided by the manufacturer. Recommendations for use and other information set out herein may differ from that set out in the pharmacy manual and investigator's brochure of the pre-market vaccine. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest. 

# TABLE OF CONTENTS
SUMMARY

# How
NACI makes the following interim recommendations for post-exposure prophylaxis against ZEBOV for the pre-market rVSVG-ZEBOV-GP vaccine stockpiled in the NESS:
- The vaccine should be offered to non-pregnant immunocompetent adults who have had an exposure to ZEBOV in Canada; and  The vaccine may be considered for pregnant women, infants, children, adolescents, and immunocompromised individuals who have had an exposure to ZEBOV in Canada.
NACI recommends that the pre-market rVSVG-ZEBOV-GP vaccine stockpiled in the NESS may be considered as pre-exposure prophylaxis against ZEBOV for non-pregnant immunocompetent adults in exceptional situations when a dedicated team of healthcare workers is anticipated to provide direct care for a confirmed case with symptomatic ZEBOV infection, if vaccine is available.

# Why
EVD is a rare, severe, acute viral illness with a case fatality rate in humans ranging from 25-90%. Although uncertainties around safety, immunogenicity, efficacy, and effectiveness remain, vaccination with the rVSVG-ZEBOV-GP vaccine currently offers the best available protection against EVD caused by ZEBOV infection given the potential for severe harm from EVD and few options for reducing case fatality. The rVSVG-ZEBOV-GP vaccine has shown few serious adverse events, despite a high degree of reactogenicity, and is immunogenic in non-pregnant immunocompetent adults. The vaccine has been shown to be efficacious in preventing EVD in the context of community outbreaks, if symptoms of EVD did not appear within 10 days of vaccination.

# I. INTRODUCTION
Ebola virus disease (EVD) is a rare, severe, acute viral illness in humans and non-human primates caused by ribonucleic acid viruses from the genus Ebolavirus, a member of the Filoviridae family (1) . Of the five well-described Ebolavirus species, four are known to cause illness in humans. The Zaire ebolavirus (ZEBOV) is considered the most virulent of these species, having the highest case fatality rate and being responsible for the majority of outbreaks to date.
EVD has an incubation period of 2-21 days, with most cases experiencing onset of symptoms around 4-10 days after exposure. Within 10 days of symptom onset, fatal cases will experience severe symptoms and succumb to the disease. Symptoms usually begin with a sudden onset of flu-like symptoms, such as fever, myalgia, severe headache, and malaise, typically followed by worsening gastrointestinal symptoms and fluid loss. Haemorrhage is a late manifestation and, in recent outbreaks, occurs in fewer than half of cases, usually from the gastrointestinal tract or other mucosa. Case fatality in humans ranges from 25-90%.
Non-fatal cases typically begin recovery 6-11 days after onset of symptoms. Full recovery occurs over a long period of time and is often associated with long-term sequelae. During recovery, Ebolavirus can persist in some body fluids such as semen, urine, and breast milk. Follow-up of a cohort of EVD survivors in Liberia has demonstrated persistence of ZEBOV in semen for up to 40 months with a range of 233 to 1178 days and a median of 551 days (2) . Viral relapse can also occur (3) .
Infectiousness starts from the time of symptom onset and the risk of transmission is highest when viral load is greatest. Person-to-person transmission can occur through direct physical contact with body fluids from an infected symptomatic person or dead body, or indirectly through physical contact with surfaces and fomites that are contaminated with these fluids. With the exception of the potential for sexual transmission during the convalescent period, Ebolavirus has not been demonstrated to spread to others by an asymptomatic person. Ebolavirus is not transmitted between humans through casual interactions or airborne transmission, but can be transmitted by aerosol-generating medical procedures.
EVD has generally been geographically limited to outbreak-prone areas of sub-Saharan Africa.
Between 1976 and 2012, sporadic cases and outbreaks of EVD were reported in several African countries. During the 2014-2016 West Africa EVD outbreak, the largest recorded outbreak of EVD to date, imported cases were identified in other countries in Africa, Europe, and North America. Limited secondary transmission in the United States and Spain from cases that have travelled from Africa has been reported (4,5) . There has been an ongoing outbreak of EVD since August 2018 in the Democratic Republic of the Congo (DRC), which is the second largest outbreak at the time of writing. No cases of EVD have been identified in Canada to date.
With the ongoing outbreak of EVD in the DRC, it is possible that Canada will receive an imported case of EVD prior to the authorization of a vaccine for EVD by Health Canada. As part of contingency planning for an imported EVD case, the Public Health Agency of Canada (PHAC) has procured Merck's investigational vaccine for EVD, the rVSVG-ZEBOV-GP vaccine (also referred to as the V920 Ebola Zaire Vaccine and Ervebo), for the National Emergency Strategic Stockpile (NESS) through Health Canada's Special Access Programme. On recommendation of the European Medicines Agency (EMA), the European Commission granted a conditional marketing authorization for this vaccine on November 11, 2019 and the World Health Organization (WHO) prequalified the vaccine (i.e., the vaccine met WHO's standards for quality, safety, and efficacy) on November 12, 2019. The rVSVG-ZEBOV-GP vaccine was approved by the United States Food and Drug Administration on December 19, 2019. NACI generally issues guidance only for immunizing agents that have been authorized by Health Canada. However, in this exceptional circumstance, PHAC has requested pre-market guidance from NACI on this investigational product because a limited quantity has been stockpiled in Canada for emergency use.
Merck's rVSVG-ZEBOV-GP vaccine is a live-attenuated, recombinant vesicular stomatitis virus (rVSV)-based vector vaccine, in which the vaccine vector's envelope glycoprotein (GP) is deleted and replaced with the ZEBOV envelope GP. The vaccine does not contain live ZEBOV. Many clinical trials have been completed using Merck's investigational vaccine, including doseranging trials to assess its safety and immunogenicity and a large cluster-randomized trial to evaluate its efficacy during the 2014-2016 West Africa outbreak.
There are several other investigational vaccines for EVD undergoing human trials (6) , but the rVSVG-ZEBOV-GP vaccine is the only one that is currently in widespread use despite its investigational status. The rVSVG-ZEBOV-GP vaccine has been available on compassionate grounds for both the 2014-2016 West Africa outbreak and the ongoing outbreak in the DRC. As of November 16, 2019, 253,545 people at risk in the DRC have received the vaccine (7) .
For the DRC outbreak, the WHO Strategic Advisory Group of Experts (SAGE) on Immunization recommended a "ring vaccination" strategy to protect those at highest risk of EVD in the outbreak (8) . Ring vaccination involves contact tracing and vaccination of the contacts of an EVD case and the contacts of those contacts. As the situation in the DRC deteriorated in early 2019, additional vaccination strategies have been recommended for outbreak control (9) . These recommendations were devised for the epidemiological and public health situation in Africa and therefore are not directly applicable for the Canadian context.
Further details on EVD, including outbreak updates, can be found on the Government of Canada website.

# Guidance objective
The objective of this advisory committee interim statement is to review the safety, immunogenicity, efficacy, and effectiveness evidence available for the rVSVG-ZEBOV-GP vaccine and to provide interim guidance on the emergency use of this pre-market vaccine stockpiled in the NESS for the prevention of severe disease in individuals exposed to ZEBOV.
Advice on the following are outside the scope of NACI's mandate and therefore are not addressed in this interim statement: a) vaccination of travellers to areas outside of Canada that are prone to EVD outbreaks - ; b) the use of passive immunizing agents such as ZMapp for treating EVD; c) symptom management and clinical treatment of EVD; d) stockpile recommendations; and e) infection prevention and control (IPC) measures for EVD.

# II. METHODS
In brief, the broad stages in the preparation of a NACI advisory committee statement are:
- Knowledge synthesis; 2. Synthesis of the body of evidence of benefits and harms, considering the quality of the evidence and magnitude of effects observed; and 3. Translation of evidence into a recommendation. Details regarding NACI's evidence-based process for developing a statement are outlined in Evidence-based Recommendations for Immunization  Methods of the National Advisory Committee on Immunization.
Rapid reviews were conducted on the safety, immunogenicity, efficacy, and effectiveness of the rVSVG-ZEBOV-GP vaccine in humans and non-human primates and the effectiveness of the ring vaccination strategy in preventing EVD transmission. The search strategy was developed in consultation with a librarian from the Health Library of Health Canada and PHAC and included two separate searches (search strategies can be found in Appendix A). One search included terms specific to the rVSVG-ZEBOV-GP vaccine and the other included terms for ring vaccination. The literature searches were performed in 12 bibliographic databases and one clinical trial database. The searches were restricted to studies published in English or French. No publication date restrictions were applied. The final database search was executed on March 29, 2019 for the rVSVG-ZEBOV-GP vaccine and March 14, 2019 for ring vaccination. Hand searches of the reference lists of included articles and relevant reviews were performed. As the rVSVG-ZEBOV-GP vaccine has not yet been licensed for use in any jurisdiction at the time of literature review, adverse event reporting for this pre-market vaccine are not expected through passive vaccine safety surveillance systems such as the Canadian Adverse Events Following Immunization Surveillance System (CAEFISS) and therefore these surveillance systems were not searched for case reports.
Articles retrieved from the searches were screened by title and abstract. The full text of articles deemed relevant based on inclusion and exclusion criteria, or that had insufficient information to exclude, were retrieved and assessed for eligibility through full-text screening. Study selection was completed independently by two reviewers. Disagreements between the two reviewers were resolved by discussion and reaching a consensus. Data from included studies were extracted into evidence tables. The quality of evidence for individual studies and for the body of evidence was assessed using the criteria outlined by Harris et al. (10) . Data extraction and quality assessment were both completed by one reviewer and verified by a second reviewer. Results from included studies were synthesized narratively in the evidence tables. Geometric mean titre (GMT) values for varying dose levels of the rVSVG-ZEBOV-GP vaccine were extracted separately.
Knowledge synthesis was performed by LZ and AK. Proposed recommendations for vaccine use were developed by NACI's EVD Vaccine Working Group and reviewed for input by NACI's Vaccine Safety Working Group, the Canadian Immunization Committee, the Council of Chief Medical Officers of Health, and the EVD-Clinical Treatment Centre Task Group. The manufacturer was invited to present preclinical and clinical data for their vaccine to the EVD Vaccine Working Group on May 7, 2019 and was further consulted to identify additional safety data for the following special populations: pregnant and breastfeeding women, infants, children, adolescents, and immunocompromised individuals. A PHAC technical advisor (LZ) presented the findings of the knowledge synthesis to NACI on June 6, 2019. The evidence and proposed recommendations were discussed by the NACI EVD Vaccine Working Group in June and July 2019 and the proposed recommendations were deliberated by NACI on July 31, 2019. Given that this is a pre-market vaccine, NACI's Vaccine Safety Working Group was also consulted in June 2019 on the proposed recommendations. Following thorough review of the evidence and assessing the risk-benefit of vaccination with the pre-market vaccine, NACI reached consensus on specific recommendations. As part of the standard pre-release process for NACI statements, the manufacturer was consulted to identify any factual errors contained in the interim statement prior to publication. The descriptions of relevant considerations, rationale, and knowledge gaps on the use of the pre-market rVSVG-ZEBOV-GP vaccine are described in the following sections.

# III. VACCINE
A flow diagram of the study selection process can be found in Appendix B. After database searching, hand searching, and eligibility screening, 37 studies-26 studies in humans (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(41)(42)(43)(44) and 11 studies in non-human primates, including an unpublished study not reported here (31)(32)(33)(34)(35)(36)(37)(38)(39)(40) were included for review. Of the 26 studies in humans, 19 studies reported on unique subjects (12-16, 19-21, 24-29, 41-44) while the remainder offered supplemental data or provided additional analyses. Of these 19 studies, there were seven phase 1 dose-ranging clinical trials (12)(13)(14)(15)(16)19) (five were randomized placebo-controlled (12)(13)(14)(15)(16)19) ), one phase 2 randomized controlled trial (20) (the phase 3 component of this study was cancelled due to declining EVD cases), three phase 3 randomized controlled trials (21,24,25) (two were cluster-randomized comparing immediate to delayed vaccination (21,24) ), three ring vaccination field studies (26,27,44) , two prospective cohort studies (29,41) , one cross-sectional survey on safety (42) , and two case reports of post-exposure prophylaxis (PEP) following needlestick or sharps injuries (28,43) . The total vaccinated sample sizes by dose and outcome for the studies conducted in humans are tabulated in Table 1. The majority of subjects received the 210 7 plaque-forming unit (PFU) dose, which is the nominal dose of the vaccine deployed for use in the 2014-2016 West Africa outbreak and in the ongoing outbreak in the DRC. Safety information that was presented to the Global Advisory Committee on Vaccine Safety on June 5-6, 2019 (45) are included to supplement the review findings.
Six modelling studies were also identified that modeled the effects of ring vaccination on control of EVD outbreaks in the African context (46)(47)(48)(49)(50)(51) . These modeling studies were reviewed by NACI, but are not further discussed in this interim statement as the findings do not directly relate to the Canadian context. 310 3 n/a 2 (n=84) 3 (n=104) 310 4 n/a 2 (n=84) 2 (n=84) 110 5 n/a 1 (n=10) 1 (n=10) 310 5 n/a 3 (n=135) 4 (n=145) 510 5 n/a 1 (n=10) 1 (n=10) 310 6 n/a 6 (n=169) 5 (n=159) 910 6 n/a 1 (n=50) 1 (n=50) 110 7 n/a 1 (n=35) 1 (n=35) 210 7 4 (n=99,049) 8 (n=1652) 13 (n=150,204) * 510 7 n/a 1 (n=16) 2 (n=17) 110 8 n/a 3 (n=319) 4 (n=341)
Abbreviations: n/a: not available; PFU: plaque-forming unit. - Total vaccinated sample sizes by dose level and outcome are approximated based on the number of study subjects planned to be given the vaccine. These numbers are based on published articles included for review and therefore may differ from other tabulated sources.  Dose values are based on the vaccine potencies reported in the included studies. These dose values may not correspond directly to the potency of the pre-market vaccine product available for use in Canada. * The vaccinated sample size for this dose level includes an estimated 130,000 individuals who were vaccinated in the DRC (45) .
Most included studies with evaluable study designs according to the Harris et al. criteria (10) received a "good" rating, with the exception of two studies receiving a "fair" rating due to interruptions in study protocol (15,21) . For all other study designs that were not evaluable with the Harris et al. criteria, no critical flaws were noted besides the intrinsic limitations of those designs.
Extracted study data are presented in the evidence table in Appendix C for human studies and Appendix D for non-human primate studies (data from an unpublished study in non-human primates are not summarized in the evidence table ). GMT point estimates and corresponding 95% confidence intervals (95% CI) from the human studies for the varying dose levels of the rVSVG-ZEBOV-GP vaccine are summarized in Appendix E. The overall patterns in the data are described for the outcomes of interest in the following sections.

# III.1 EFFICACY AND EFFECTIVENESS
Four studies assessed vaccine efficacy or effectiveness in humans in the context of ring vaccination (21,26,27,44) . Two case reports described PEP of healthcare or laboratory workers following high-risk needlestick or sharps injuries (28,43) . Six studies looking at survival following lethal ZEBOV challenge after pre-exposure prophylaxis (PrEP) (32)(33)(34)(35)(36)40) and two studies looking at survival following PEP after lethal ZEBOV challenge (31,38) were conducted in non-human primates.

# Ring vaccination
Ring vaccination, originally used for smallpox control and eradication, has been used broadly as an outbreak control measure in response to EVD activity. Ring vaccination involves tracking the epidemic and recruiting individuals at increased risk of infection based on their connection to a confirmed case of disease (52) . Ring vaccination typically includes a mix of PEP and PrEP based on confirmed and anticipated (e.g., for healthcare and frontline workers) exposure, respectively, for contacts of cases and contacts of those contacts.
In a phase 3 cluster randomized ring vaccination trial conducted in Guinea during the 2014-2016 West Africa outbreak, vaccine efficacy against EVD occurring 10 or more days after randomization was 100% (95% CI: 77.0-100.0%) comparing all vaccinated contacts and contacts of contacts randomized to receive the vaccine immediately (n=3775) with all contacts and contacts of contacts randomized to receive the vaccine 21 days after randomization and never-vaccinated (n=7995) (21) . The overall vaccine effectiveness in protecting all contacts and contacts of contacts in the randomized clusters (including unvaccinated cluster members; n=4513 immediate and 4529 delayed vaccination) against onset of EVD 10 days or more from randomization was 64.6% (95% CI: -44.2-91.3%). EVD cases occurred at similar attack rates within the first 10 days after randomization regardless of vaccination status; 11 cases among immediately vaccinated adults (0.5%) and 21 cases among all eligible adults assigned to delayed vaccination (0.7%) had onset of symptoms within 10 days of randomization. No cases of EVD occurred 10 days or more after randomization in the immediately vaccinated clusters compared with 16 cases among eligible individuals in delayed clusters. Vaccine effectiveness at 10 days or more post-vaccination against death due to EVD was 100%.
The preliminary estimate of vaccine effectiveness from the ongoing compassionate use ring vaccination program in the DRC (n=93,965 vaccinated) against onset of illness 10 days or more post-vaccination was 97.5% (95% CI: 95.8-98.5%) (44) . There were 71 cases of EVD among vaccinated individuals; 56 developed symptoms within 10 days of vaccination and only nine of these individuals died while 15 individuals developed symptoms 10 days or later following vaccination and none of these individuals died. Vaccine effectiveness at 10 days or more postvaccination against death due to EVD was also 100% in this study.
Results from these ring vaccination studies suggest that the vaccine was efficacious in preventing EVD, if symptoms of EVD did not appear within 10 days of vaccination. Based on these study findings, 10 days is the time after which vaccinees are assumed to be protected whereas less than 10 days post-vaccination is the period where vaccinees are not protected or partially protected (44) . Correlation between immune response and protection was not investigated in these studies. Ring vaccination was also found to be effective in contributing to outbreak control. However, the relative impact of vaccination on outbreak control compared to other factors (e.g., declining incidence of EVD, other public health measures) was not determined. Furthermore, as these studies were performed during ongoing community-based outbreaks and included contacts who may not have had a high-risk interaction with an index case, the study findings provide evidence of protection but do not differentiate whether it is preor post-exposure protection. Two other ring vaccination studies conducted during communitybased outbreaks of ZEBOV in Guinea (n=1510 vaccinated) (27) and Liberia (n=210 vaccinated) (26) did not identify secondary cases of EVD occurring among vaccine recipients. These two studies were not designed to assess the impact of vaccination on outbreak control.
The characteristics of the rings, or clusters, that comprise these ring vaccination studies were expectedly heterogeneous: 73-96% of contacts were contacts of contacts (i.e., secondary contacts), 4-27% of contacts were high-risk contacts (i.e., had close physical contact with an EVD case's body, body fluids, linens, or clothing), 7-20% of contacts were healthcare or frontline workers, median number of days from confirmation of EVD in the index case to vaccination of contacts ranged from 7-15 days, and cluster sizes ranged from several dozen to several hundred people (21,26,27,44) . Pregnant or breastfeeding women and children under six years of age were excluded from receiving the vaccine in these studies. Vaccine efficacy or effectiveness for children and adolescents 6-17 years of age and immunocompromised individuals were not separately reported.

# Prophylaxis after needlestick or sharps injury
There are several case reports of PEP following needlestick or sharps injuries. A laboratory worker was vaccinated with a 510 7 PFU dose 48 hours after needlestick injury with a syringe containing live ZEBOV (28) . Five healthcare workers were vaccinated with a 110 8 PFU dose 1-3 days after potential ZEBOV exposure resulting from sharps injuries sustained in West Africa (43) . These exposures did not result in evidence of infection, but it is not possible to determine whether this was due to vaccine effect or lack of transmission following the needlestick injury.

# Efficacy in non-human primates
For PrEP, complete protection was achieved with the vaccine (mostly at the 110 7 PFU dose) given 7-28 days before intramuscularly-administered lethal ZEBOV challenge (1000 PFU) (32,(34)(35)(36)40) and partial protection was achieved with the vaccine (510 7 PFU dose) given three days before lethal challenge in healthy animals (36) . Partial protection was also achieved with the vaccine (110 7 PFU dose) given 31 days before lethal challenge in immunodeficient SHIVinfected animals (33) .
For PEP, one study found that 50% of animals survived without showing signs of severe disease after vaccination (210 7 PFU dose) within 20-30 minutes of lethal challenge while both controls died (31) . Another study found no difference in survival among vaccinated (210 7 PFU dose) or control groups when vaccinated at 1 hour and/or 24 hours after lethal challenge (38) .

# III.2 IMMUNOGENICITY
Ten studies evaluated immunogenicity following vaccination with the rVSVG-ZEBOV-GP vaccine of varying dose levels in humans (12-16, 19, 20, 26, 29) and eight studies assessed immunogenicity following vaccination in non-human primates (31)(32)(33)(34)(35)(36)(37)40) . It is important to note that no immunological correlate of protection has been established for EVD, so it is difficult to interpret immunogenicity findings in the context of disease prevention.

# Immunoglobulin G antibody response
The most robustly assessed immunogenicity outcome was the ZEBOV envelope GP-specific immunoglobulin G (IgG) antibody response (12-16, 19, 20, 26, 29) . Most subjects seroconverted (i.e., had a four-fold or greater increase from baseline titre) by day 14 post-vaccination and all subjects seroconverted by day 28 regardless of dose. There was a high degree of interindividual variability in IgG antibody response regardless of dose. A dose-response relationship was observed with the speed and amplitude of response. However, there appeared to be diminishing marginal antibody response with increasing dose; GMTs were similar at higher doses due to the wide and overlapping 95% CI, suggesting a plateau of the dose-response curve at higher doses. One trial found a potential age-response relationship, where children and adolescents 6-17 years of age were observed to respond slower than adults (19) . GMTs generally peaked by day 28 and persisted to 1-2 years post-vaccination without significant decline and without significant difference across dose levels. Persistence of IgG antibody response beyond two years after vaccination is unknown. There are ongoing studies looking at antibody persistence up to three (53) or five (54,55) years following primary vaccination. A protective threshold of IgG antibody response has not been established.
A phase 1 dose-ranging trial looking at a two-dose regimen given on days 0 and 28 found that the second dose was associated with a short-term advantage with respect to the amplitude of response, but there was no significant difference in long-term titres between one-and two-dose regimens (12) . Anamnestic response following a booster dose more than 28 days after the priming dose has not been characterized. There are currently ongoing studies investigating a booster given at 56 days (55) or 18 months (53) .
Seroconversion rates at one-month post-vaccination was found to be significantly lower in a small sample of HIV-infected adults (n=13) compared to non-HIV-infected adults (n=383) in Liberia (20) . There is currently a phase 2 randomized controlled trial in progress evaluating the safety and immunogenicity of the vaccine in HIV-infected adults and adolescents at two Canadian sites and two African sites (Burkina Faso and Senegal) (56) . Immunogenicity data for pregnant and breastfeeding women, infants, children under six years of age, and persons with other immunocompromising conditions are not available.

# Neutralizing antibody response
Several phase 1 clinical trials also looked at neutralizing antibody responses (12)(13)(14)(15)(16)19) . The neutralizing antibody response appeared to be well-correlated with the IgG response; there was a dose-dependent response, with titres peaking at day 28 post-vaccination, and some evidence of persistence over 6 months-2 years. A neutralizing antibody protective threshold has not been established.

# Other immune response outcomes
A few studies were identified that investigated cell-mediated responses and changes to cytokine profiles and circulating host microRNA following vaccination. A dose-dependent CD169 expression was observed, suggesting a dose effect in monocyte activation (15) . Both CD4+ and CD8+ T cells showed increased activity post-vaccination (17) . Circulating follicular T helper cells were correlated with IgG titres (11) . One study found that vaccination led to a skewing in the cytokine profiles that promote humoral immune responses (11) . Another study found a significant induction of cytokines involved in the promotion of cell-mediated response, activation of antigenpresenting cells, and growth and survival of antigen-specific cytotoxic T lymphocytes (17) . Higher doses were found to elicit stronger interlocked cytokine networks compared with lower doses (17) . Vaccination was also found to be accompanied by dose-dependent changes in circulating host microRNA (18) . The importance and impact of these responses have not been elucidated.

# Immunogenicity in non-human primates
For PrEP, modest IgG titres were detected in most animals by day 28 post-vaccination (day of lethal ZEBOV challenge) (31-36, 38, 40) , including in immunodeficient SHIV-infected animals (33) , whereas neutralizing antibody was not detectable in most animals (31,35,36,40) . A depletion study revealed a minimal role for CD8+ T cell immunity in vaccine-mediated protection (37) .
For PEP, IgG titres were detectable between 1-2 weeks after vaccination at 20-30 minutes, 1 hour, or 24 hours after lethal ZEBOV challenge (31,38) .

# III.3 SAFETY
Sixteen studies evaluated safety following vaccination with the rVSVG-ZEBOV-GP vaccine of varying dose levels in humans (12-16, 19-21, 24-28, 41-43) . Five studies in non-human primates reported clinical symptoms following vaccination (32)(33)(34)(35)(36) and one study in non-human primates specifically looked at neurological symptoms following intrathalamic injection of the vaccine or wild-type rVSV (39) .

# Solicited adverse events
The majority of study subjects vaccinated with the rVSVG-ZEBOV-GP vaccine were immunocompetent adults who were not pregnant or breastfeeding. The vaccine is highly reactogenic; over 80% of study subjects were reported by multiple studies as having experienced at least one adverse event (15,16,24,25,42) . The most frequently reported symptoms were injection site pain, fever, headache, malaise, and myalgia. Although the degree of reactogenicity was high across dose levels, these adverse events were generally transient and mild-to-moderate in intensity. The onset of systemic symptoms typically occurred within three days after vaccination. A phase 1 dose-ranging trial looking at a two-dose regimen given on days 0 and 28 found a lower rate of adverse events after the second dose than after the first dose (12) .

# Unexpected adverse events
Unexpected adverse events reported in an early clinical trial include arthralgia, arthritis, dermatitis, and vasculitis (15) . Follow up studies, including the large phase 3 ring vaccination trial in Guinea, found arthralgia and arthritis to be less frequent, transient, and of mild-to-moderate intensity (13,14,16,20,21,42,43) , but occurring at higher rates compared to placebo (25) or no vaccination (24,41) . One study found the female sex and a medical history of arthritis as significant risk factors for the development of arthritis post-vaccination, but not treatment dose or age (30) . The median time to onset of arthritis was about 10 days and the mean duration was 6 days in blinded trials, though a few events persisted for months to years (45) . Dermatitis and vasculitis were also infrequently reported, generally mild-to-moderate in intensity, and of short duration (12,16,42,43) , and occurred at higher rates compared to placebo (25) or no vaccination (24) . Some dose-ranging studies found that there is likely a trend towards lower reactogenicity with lower doses (13)(14)(15) , but the unexpected adverse events did not appear to be related to the dose.

# Serious adverse events
Serious adverse events were infrequently reported following more than 150,000 vaccinations across all dose levels. In the studies included for review, only two serious adverse events were judged to be vaccine-related (both for the 210 7 PFU dose): one febrile reaction and one anaphylaxis (21) . Analysis of double-blinded trials found serious adverse events occurred in 3.4% of vaccine recipients, with the most common event being malaria, compared with 7.8% of placebo recipients (45) . In over 130,000 vaccinated individuals in the DRC, 228 serious adverse events were identified between August 7, 2018 and June 5, 2019; of these events, only a few, including one case of anaphylaxis, were attributed to the vaccine (45) .

# Special populations
There are limited safety data in pregnant women, children and adolescents 6-17 years of age, and immunocompromised individuals. In three studies that excluded pregnant and breastfeeding women from vaccination, a small number of enrolled subjects became pregnant within two months after vaccination and very few were pregnant when vaccinated (19,24,41,45) . One randomized trial (n=261) found a higher frequency of pregnancy loss in those who received the vaccine immediately compared with those who received delayed vaccination. The reasons for this observation are unknown. Three studies that included children and adolescents 6-17 years of age (n=537) found an adverse events profile that is similar to adults (19,21,27) , but with fewer arthralgia events than adults (21,27) . Two serious adverse events attributed to gastroenteritis and respiratory failure occurred in one of 22 HIV-infected vaccinees (20) . Safety data are currently not available for breastfeeding women, infants, children under 6 years of age, and persons with other immunocompromising conditions.
A phase 2 randomized controlled trial including children with age greater than or equal to 1 year (54) and a phase 2 randomized controlled trial in HIV-infected adults and adolescents with oneand two-dose regimens are in progress (56) . As of June 29, 2019, 34,522 children and adolescents 1-17 years of age have been vaccinated under the WHO compassionate use protocol in the ongoing outbreak in the DRC (7) . In February 2019, the ethics committee of the DRC authorized the expansion of the compassionate use protocol to include vaccination of pregnant and breastfeeding women and children under 1 year of age (8) . In May 2019, authorities in the DRC simplified safety follow-up requirements to passive reporting of serious adverse events by phone and active follow-up of only pregnant women and children under 1 year of age (9) . Specific safety results have not yet been published for these vaccinated individuals; however, no serious safety concerns have been identified so far by WHO or the manufacturer.

# Vaccine vector viremia and shedding
Low-level, transient, and dose-dependent rVSV viremia was seen for some subjects on days 1-3 after vaccination, becoming undetectable by days 7-14 (12-16, 20, 28, 43) . Viremia was seen more frequently in children and adolescents compared to adults in one study (19) .
Transmissibility of vaccine virus to people outside of the target vaccine population is not known, as no data are available on secondary transmission (45) , but is unlikely. Very few vaccinees had measurable shedding of the vaccine virus in urine and saliva (13,14,16) . Viral shedding in saliva was seen more frequently in children and adolescents compared to adults (19) . Absent or minimal vaccine virus shedding was observed in oral, nasal, and/or rectal swab samples from animal studies and the wild-type rVSV has naturally low transmissibility (57,58) .

# Leukocyte counts
Transient, asymptomatic, dose-related decreases in leukocytes were observed in some subjects and mostly within 2 days post-vaccination (12,14,15,19) .

# Safety in non-human primates
The rVSVG-ZEBOV-GP vaccine appeared to be well-tolerated in non-human primates, showing no evidence of clinical illness in the period following pre-exposure vaccination (32)(33)(34)(35)(36) . Intrathalamic injection of the vaccine showed a lack of neurovirulence compared to the wild-type rVSV (39) .

# IV. PRECAUTIONS

# Potential interference with ZMapp
No individuals have received both the rVSVG-ZEBOV-GP vaccine and the ZMapp monoclonal antibody cocktail for EVD treatment to date. Therefore, timing of administration and potential interference between these two products are currently unknown. Administration of these products close together may result in decreased effectiveness of the rVSVG-ZEBOV-GP vaccine and/or ZMapp because the monoclonal antibody has high affinity for the ZEBOV envelope GP expressed by the vaccine vector and the vaccine virus must replicate over time in order to elicit immune responses.
In the post-exposure setting, expert clinical opinion should be sought when deciding whether ZMapp, the rVSVG-ZEBOV-GP vaccine, or a combination of the two is the most appropriate response, taking into account the specifics of the exposure event.

# Vaccine virus shedding
Transmission of the vaccine virus has not been reported to date. In clinical trials, very few vaccine recipients had measurable shedding of the vaccine virus in urine and saliva (13,14,16) and low-level rVSV viremia observed in some vaccine recipients became undetectable by days 7-14 (12-16, 20, 28, 43) . It is not known if the vaccine virus is secreted in human breast milk. There is no data available regarding the effects of vaccinating breastfeeding women on their infants. Absent or minimal vaccine virus shedding was observed in oral, nasal, and/or rectal swab samples from animal studies and the wild-type rVSV has naturally low transmissibility (57,58) . Although the risk of transmitting the rVSVG-ZEBOV-GP vaccine virus to people outside of the target vaccine population appears to be extremely low, vaccine recipients should be informed that the rVSVG-ZEBOV-GP vaccine does not contain live Ebolavirus, but is comprised of a liveattenuated recombinant virus, rVSV, that has the theoretical potential to be transmitted to contacts of the vaccinated individual.
Based on expert opinion and taking into consideration the precautions for use made by the EMA (59) , individuals vaccinated with the rVSVG-ZEBOV-GP vaccine should avoid close contact (including exposure to blood and body fluids) with immunocompromised individuals, pregnant or breastfeeding women, and infants for at least six weeks following vaccination, unless those individuals also have an indication for the rVSVG-ZEBOV-GP vaccine.
Similarly, as a precaution, women should avoid breastfeeding and their infants should not have contact with maternal blood and body fluids, where feasible, for at least six weeks following vaccination, unless vaccination with the rVSVG-ZEBOV-GP vaccine is also indicated for the infant.

# V. INTERIM RECOMMENDATIONS
After careful review of available evidence (see Section III) and considering current knowledge gaps (see Section VI), NACI makes the following interim recommendations on the emergency use of the pre-market rVSVG-ZEBOV-GP vaccine stockpiled in the NESS for PEP and PrEP in a Canadian context, recognizing:
- The lack of regulatory approval of the rVSVG-ZEBOV-GP vaccine in Canada at the time of writing;  The limited quantity of this pre-market vaccine available in Canada; and  The fact that the EVD outbreak in the DRC is a Public Health Emergency of International Concern at the time of writing, and the global rVSVG-ZEBOV-GP vaccine supply is being prioritized for those most at risk in Africa where there can be the greatest impact.
As the regulatory, supply, and evidence context for the rVSVG-ZEBOV-GP vaccine evolves, NACI will revisit these interim recommendations as needed.
A dose-sparing strategy for the use of the rVSVG-ZEBOV-GP vaccine, and associated evidence, may be reviewed and considered by NACI if the need arises.

# Exposure definition
For the interim recommendations, exposures - to ZEBOV that are considered to pose risk are:  Unprotected direct physical contact (i.e., through non-intact skin or mucous membranes) with (60,61) : o non-intact skin, mucous membranes, blood, or other body fluids (e.g., stool, emesis, urine, saliva, semen, sweat, breast milk) of a ZEBOV-infected individual; o linens or clothing contaminated with ZEBOV-infected blood or body fluids; o the dead body of a ZEBOV-infected individual; and/or o any other known source of ZEBOV, including contaminated medical instruments, fomites or other contaminated environmental surfaces, laboratory specimens, or animals;  Unprotected exposure following assistance with the performance of an aerosolgenerating medical procedure (62) ;  Unprotected sexual contact with an acute or convalescent EVD case (ZEBOV has been demonstrated to persist in semen for up to 40 months (2) ) with laboratory-confirmed ZEBOV infection (60) ; and/or  Unprotected handling and/or consumption of ZEBOV-contaminated bush meat products from Africa (63) . 

# Strength of NACI recommendations
Please note:  A strong NACI recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present.  A discretionary NACI recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable.
Please see Table 2 for a more detailed explanation of strength of NACI recommendations and grade of the body of evidence. Please see Tables 3 and 4 for details on the ratings of the quality of individual studies.
V. 

# Summary of evidence and rationale
- The vaccine has shown few serious adverse events, despite a high degree of reactogenicity, and is immunogenic in non-pregnant immunocompetent adults. The vaccine has been shown to be efficacious in preventing EVD in the context of community outbreaks, if symptoms of EVD did not appear within 10 days of vaccination. However, because these efficacy studies were performed during community-based outbreaks of ZEBOV in Africa, they do not provide direct evidence of post-exposure protection.  The lack of regulatory review and authorization may decrease the acceptability of this pre-market vaccine; however, the potential for severe harm from EVD in those who have had an exposure to ZEBOV and the safety and immunogenicity profile of the vaccine established in non-pregnant immunocompetent adults may improve its acceptability among these individuals.

# Interim recommendation 1b
1b. NACI recommends that the pre-market rVSVG-ZEBOV-GP vaccine may be considered as PEP against ZEBOV for pregnant women, infants, children, adolescents, and immunocompromised individuals who have had an exposure to ZEBOV (Discretionary NACI Recommendation)  NACI concludes that there is currently insufficient evidence to recommend vaccination of pregnant women, infants, children, adolescents, and immunocompromised individuals who have had an exposure to ZEBOV with the rVSVG-ZEBOV-GP vaccine (Grade I Evidence). Therefore, this interim recommendation is based on expert opinion.

# Summary of evidence and rationale
- There are limited safety data for pregnant women, children and adolescents 6-17 years of age, and immunocompromised individuals. One randomized trial found a higher frequency of pregnancy loss in those who received immediate vaccination vs. delayed vaccination. Three studies that included children and adolescents 6-17 years of age found an adverse events profile that is similar to adults, but with fewer arthralgia events than adults. Two serious adverse events attributed to gastroenteritis and respiratory failure occurred in one of 22 HIV-infected vaccinees. Safety data are not currently available for infants and children under 6 years of age.  There is limited evidence of slower immune response in children 6-17 years of age after vaccination than adults. There is also limited evidence of less optimal immune response in HIV-infected individuals compared with non-HIV-infected individuals. No immunogenicity data are available for pregnant women, infants, and children under 6 years of age.  Vaccine has been given to these special populations as part of outbreak control measures in the DRC. As of June 29, 2019, 34,522 children and adolescents 1-17 years of age have been vaccinated. In February 2019, the authorities in the DRC authorized the expansion of the compassionate use protocol to include pregnant and breastfeeding women and children under 1 year of age. In May 2019, the authorities simplified safety follow-up requirements to passive reporting of serious adverse events by phone and active follow-up was limited to pregnant women and children under 1 year of age. Specific safety results have not yet been published for these vaccinated individuals; however, no serious safety concerns have been identified so far by WHO or the manufacturer.  A risk-benefit assessment of this pre-market vaccine, taking into consideration uncertainties in the safety and efficacy of the vaccine, the potential for severe harm from EVD, and the nature and intensity of exposure, should be conducted when deciding whether to vaccinate individuals in these special populations.
Interim recommendation 2 2. When used as PEP against ZEBOV, NACI recommends that the pre-market rVSVG-ZEBOV-GP vaccine should be given as expeditiously as possible, targeting within 72 hours of exposure for susceptible, asymptomatic exposed individuals, but may be considered up to 10 days post-exposure, as the incubation period for EVD can range from 2-21 days and vaccination within 10 days of exposure may confer protection (Strong NACI Recommendation)  NACI concludes that there is currently insufficient evidence to define a vaccination window for effective PEP in preventing severe disease after exposure to ZEBOV (Grade I Evidence). Therefore, this interim recommendation is based on expert opinion.

# Summary of evidence and rationale
- The vaccine has been shown to be efficacious in preventing EVD in the context of community outbreaks, if symptoms of EVD did not appear within 10 days of vaccination.
The median time from confirmation of EVD in an index case to vaccination of contacts in these studies ranged from 7-15 days. However, because these efficacy studies were performed during community-based outbreaks of ZEBOV in Africa, they do not provide direct evidence of timing for post-exposure protection.  In studies with non-human primates, partial post-exposure protection against EVD was achieved if vaccinated within 20-30 minutes of intramuscular challenge with a lethal concentration of ZEBOV. No protection against EVD was observed if vaccinated at 1 and/or 24 hours after lethal intramuscular ZEBOV challenge. Data derived from animal studies should be interpreted with caution when used to inform clinical decision making since time-to-death is shorter and mortality rate is higher following intramuscular infection, likely shortening the window of efficacy of post-exposure vaccination compared to mucosal infection. Several instances of PEP given within 3 days of a needlestick or sharps injury have been reported. A laboratory worker was vaccinated with a 510 7 PFU dose 48 hours after a needlestick injury with a syringe containing ZEBOV. Five healthcare workers were vaccinated with a 110 8 PFU dose 1-3 days after sharps injuries in West Africa. There was no evidence that these exposures resulted in infection but it is not possible to determine whether this was due to vaccine effect or lack of transmission following the needlestick injury.  Expert clinical opinion should be emergently sought in the management of individuals who are potentially exposed to ZEBOV from a needlestick injury, as the window for effective PEP after intramuscular exposure to ZEBOV is unknown, but likely to be small, and the vaccine may not be immediately available for administration. The risk of severe disease from intramuscular exposure to ZEBOV (e.g., needlestick injury from a ZEBOVcontaminated needle and syringe) is greater than mucosal exposure (e.g., unprotected direct physical contact through non-intact skin or mucous membranes with non-intact skin, mucous membranes, blood, or other body fluids of a ZEBOV-infected individual).  Common systemic reactions following vaccination include fever, headache, malaise, and myalgia, resembling the early symptoms of EVD. However, typical onset of vaccine reactions is expected within 3 days after vaccination compared with onset of clinical symptoms 4-10 days after exposure to ZEBOV. Therefore, clinical management of reported illness among individuals who have had an exposure to ZEBOV should take into consideration vaccination status, timing of symptom onset relative to vaccination, and presence of any symptoms typically associated with EVD but not with vaccination (e.g., sore throat, nausea and vomiting, diarrhea, haemorrhaging) to mitigate unnecessary referrals to EVD treatment units. Antipyretics have been used for the management or prevention of post-vaccination fever without identified safety concerns (21) , but the use of antipyretics may mask early EVD symptoms.

# Interim recommendation 3
- NACI recommends that the pre-market rVSVG-ZEBOV-GP vaccine may be considered as PEP against ZEBOV for individuals who have received a previous dose of the premarket rVSVG-ZEBOV-GP vaccine more than 18 months prior to a current exposure to ZEBOV (Discretionary NACI Recommendation)  NACI concludes that while there is currently fair evidence of immunogenicity up to two years post-vaccination (Grade B Evidence), there is insufficient evidence to define a serological threshold of protection against ZEBOV or to suggest a need for revaccination (Grade I Evidence). Therefore, this interim recommendation is based on expert opinion.
Summary of evidence and rationale  GMTs of IgG antibody to the ZEBOV envelope GP reported in clinical trials generally peaked by day 28 and persisted to two years post-vaccination without significant decline. Immune correlates of protection and the relative importance of IgG antibody response
have not yet been established. Long-term vaccine efficacy has not been demonstrated.
There is limited evidence that the rate of adverse events following a second dose given at 28 days post-vaccination is lower than after the first dose. Due to the potential for severe harm from EVD and the uncertainty around the durability and thresholds of vaccine protection, re-vaccination with the rVSVG-ZEBOV-GP vaccine may be considered as a precaution after an exposure to ZEBOV occurring more than 18 months after a previous dose of the rVSVG-ZEBOV-GP vaccine.  Expert clinical opinion should be sought when deciding whether to re-vaccinate an individual who has previously received another vaccine for EVD with the rVSVG-ZEBOV-GP vaccine.

# Interim recommendation 4 4. When used as PEP against ZEBOV, NACI recommends that the pre-market rVSVG-ZEBOV-GP vaccine should not be given simultaneously with other live or inactivated vaccines due to the potential for immune interference and the need to be able to monitor for potential symptoms of EVD and rVSVG-ZEBOV-GP vaccine adverse events without potential confounding from other vaccine adverse events (Strong NACI Recommendation)
- NACI concludes that there is currently insufficient evidence to recommend concurrent administration of the pre-market rVSVG-ZEBOV-GP vaccine with other vaccines (Grade I Evidence). Therefore, this interim recommendation is based on expert opinion.

# Summary of evidence and rationale
- Although live-attenuated or inactivated vaccines given by the parenteral route may generally be administered concurrently with other vaccines without concern, there is no data available on the concurrent administration of the rVSVG-ZEBOV-GP vaccine with other vaccines. Given the potential for immune interference and the need to be able to monitor for potential symptoms of EVD and rVSVG-ZEBOV-GP vaccine adverse events without potential confounding from other vaccine adverse events, the pre-market rVSVG-ZEBOV-GP vaccine should not be given as PEP against ZEBOV simultaneously with other live or inactivated vaccines in this exceptional situation. Other live-attenuated or inactivated vaccines should be administered at a minimal interval of four weeks after vaccination with the rVSVG-ZEBOV-GP vaccine. However, given the potential for severe harm from EVD, vaccination with the rVSVG-ZEBOV-GP vaccine should not be delayed even if it is within four weeks of a previous vaccine.  Considering the ethical principles of beneficence and non-maleficence, delaying any other vaccines to prioritize the pre-market rVSVG-ZEBOV-GP vaccine for individuals who have had an exposure to ZEBOV is acceptable and ethically justifiable.
V. 

# Summary of evidence and rationale
- The vaccine has shown few serious adverse events, despite a high degree of reactogenicity, and is immunogenic in non-pregnant immunocompetent adults. The vaccine has been shown to be efficacious in preventing EVD in the context of community outbreaks, if symptoms of EVD did not appear within 10 days of vaccination. However, because these efficacy studies were performed during community-based outbreaks of ZEBOV in Africa, they do not provide direct evidence of post-exposure protection.  Expert clinical opinion should be emergently sought in the management of individuals who are potentially exposed to ZEBOV from a needlestick injury. Appropriately implemented IPC measures, such as using personal protective equipment and following correct donning and doffing procedures, offer feasible and effective methods of protection against EVD infection. However, due to the nature of the work, there exists a small risk of needlestick injury among healthcare workers providing direct care to EVD cases and laboratory workers handling ZEBOV. The risk of severe disease from intramuscular exposure to ZEBOV (e.g., needlestick injury from a ZEBOV-contaminated needle and syringe) is greater than mucosal exposure (e.g., unprotected direct physical contact through non-intact skin or mucous membranes with non-intact skin, mucous membranes, blood, or other body fluids of a ZEBOV-infected individual).  The lack of regulatory review and authorization may decrease the acceptability of this pre-market vaccine. However, given the potential for severe harm from EVD in those who have had an exposure to ZEBOV and the safety and immunogenicity profile of the vaccine for non-pregnant immunocompetent adults, offering the pre-market rVSVG-ZEBOV-GP vaccine to these individuals is acceptable and ethically justifiable.

# Interim recommendation 5b
5b. NACI recommends that the pre-market rVSVG-ZEBOV-GP vaccine may be considered as PEP against ZEBOV for pregnant or immunocompromised individuals who have had an occupational exposure to ZEBOV in Canadian healthcare or laboratory settings (Discretionary NACI Recommendation)  NACI concludes that there is currently insufficient evidence to recommend vaccination of pregnant and immunocompromised individuals who have had an occupational exposure to ZEBOV in Canadian healthcare or laboratory settings with the rVSVG-ZEBOV-GP vaccine (Grade I Evidence). Therefore, this interim recommendation is based on expert opinion.

# Summary of evidence and rationale
- Safety data are limited for pregnant and immunocompromised individuals. One randomized trial found a higher frequency of pregnancy loss in those who received immediate vaccination vs. delayed vaccination. Two serious adverse events attributed to gastroenteritis and respiratory failure occurred in one of 22 HIV-infected vaccinees.  There is limited evidence of less optimal immune response in HIV-infected individuals compared with non-HIV-infected individuals. No immunogenicity data are available for pregnant women.  Vaccine has been given to these special populations, as well as infants, children, and adolescents, as part of outbreak control measures in the DRC. In February 2019, the authorities in the DRC authorized the expansion of the compassionate use protocol to include pregnant and breastfeeding women and children under 1 year of age. In May 2019, the authorities simplified safety follow-up requirements to passive reporting of serious adverse events by phone and active follow-up was limited to pregnant women and children under 1 year of age. Specific safety results have not yet been published for these vaccinated individuals; however, no serious safety concerns have been identified so far by WHO or the manufacturer.  Expert clinical opinion should be emergently sought in the management of individuals who are potentially exposed to ZEBOV from a needlestick injury. Appropriately implemented IPC measures, such as using personal protective equipment and following correct donning and doffing procedures, offer feasible and effective methods of protection against EVD infection. However, due to the nature of the work, there exists a small risk of needlestick injury among healthcare workers providing direct care to EVD cases and laboratory workers handling ZEBOV. The risk of severe disease from intramuscular exposure to ZEBOV (e.g., needlestick injury from a ZEBOV-contaminated needle and syringe) is greater than mucosal exposure (e.g., unprotected direct physical contact through non-intact skin or mucous membranes with non-intact skin, mucous membranes, blood, or other body fluids of a ZEBOV-infected individual).  A risk-benefit assessment of this pre-market vaccine, taking into consideration uncertainties in the safety and efficacy of the vaccine, the potential for severe harm from EVD, and the nature and intensity of exposure, should be conducted when deciding whether to vaccinate individuals in these special populations.
Interim recommendations 2 through 4 also apply to individuals who have had an occupational exposure to ZEBOV in Canadian healthcare or laboratory settings.

# V.3 PRE-EXPOSURE PROPHYLAXIS
Advice on PrEP for travellers is not provided in this interim statement on the emergency use of the pre-market rVSVG-ZEBOV-GP vaccine stockpiled in the NESS.

# Interim recommendation 6
- NACI recommends that the pre-market rVSVG-ZEBOV-GP vaccine may be considered as PrEP against ZEBOV for non-pregnant immunocompetent adults in exceptional situations when a dedicated team of healthcare workers is anticipated to provide direct care for a confirmed case with symptomatic ZEBOV infection, if vaccine is available (Discretionary NACI Recommendation)  NACI concludes that there is currently fair evidence of safety, immunogenicity, efficacy, and effectiveness to recommend vaccination of non-pregnant immunocompetent adults at risk of exposure to ZEBOV (Grade B Evidence) and insufficient evidence of long-term protection beyond two years post-vaccination (Grade I Evidence). Therefore, this interim recommendation is based on expert opinion.

# Summary of evidence and rationale
- The vaccine has shown few serious adverse events, despite a high degree of reactogenicity, and is immunogenic in non-pregnant immunocompetent adults. The vaccine has been shown to be efficacious in preventing EVD in the context of community outbreaks, if symptoms of EVD did not appear within 10 days of vaccination. However, because these efficacy studies were performed during community-based outbreaks of ZEBOV in Africa, they do not provide direct evidence of pre-exposure protection. GMTs of IgG antibody to the ZEBOV envelope GP reported in clinical trials generally peaked by day 28 and persisted to two years post-vaccination without significant decline. Long-term vaccine efficacy is unknown.  Although the acceptability of this narrow interim recommendation for PrEP may be low among healthcare workers who perceive themselves to be at risk of exposure to ZEBOV, wider PrEP against ZEBOV is currently not feasible or recommended at this time in Canada based on the limited availability of the pre-market vaccine in Canada and globally and the potentially large number of Canadian healthcare workers who may have some perceived risk of exposure to ZEBOV (there have been no cases of EVD in Canada to date).  Appropriately implemented IPC measures, such as using personal protective equipment and following correct donning and doffing procedures, offer feasible and effective methods of protection against EVD infection and should be followed as the situation dictates, regardless of vaccination status.  Vaccine-derived adverse events may mimic early EVD symptoms; therefore, clinical management of reported illness among vaccinated individuals who have had an exposure to ZEBOV should take into consideration vaccination status, timing of symptom onset relative to vaccination, and presence of any symptoms typically associated with EVD but not with vaccination.

# VI. KNOWLEDGE GAPS
After careful review of available evidence, NACI has identified the need for further research to address current knowledge gaps where data are absent or limited. NACI recognizes that there are studies already in progress that may address many of these gaps but the findings of these studies were not yet available at the time of review. Identified knowledge gaps include:
- Immune correlates of protection have not been established.  The window of vaccination for effective PEP is unknown.  The degree of post-exposure protection (e.g., decreasing infectiousness and clinical illness in individuals that had already acquired infection) is unknown.  Cross-protective efficacy against other Ebolavirus species or Marburg virus in humans is unknown, though the vaccine is unlikely to protect against these other viruses of the Filoviridae family due to significant differences in viral antigens.  Safety and immunogenicity data for children and adolescents 6-17 years of age and immunocompromised individuals are limited. Safety data are limited and immunogenicity data are not available for pregnant women. Safety and immunogenicity data are not available for breastfeeding women, infants, and children under 6 years of age.  Transmissibility of the vaccine virus is unknown, including whether the vaccine virus is secreted in human breast milk.  Persistence of immune response beyond two years after vaccination is unknown.  Long-term vaccine efficacy is unknown.  Anamnestic response following a booster dose more than 28 days after the priming dose has not been characterized.  Interference with ZMapp or other passive immunizing agents against EVD is unknown.  Safety of concurrent administration with other vaccines is unknown.   

# TABLES

# Quality rating Description
Good A study (including meta-analyses or systematic reviews) that meets all design-specific criteria - well.

# Fair
A study (including meta-analyses or systematic reviews) that does not meet (or it is not clear that it meets) at least one design-specific criterion - but has no known "fatal flaw".

# Poor
A study (including meta-analyses or systematic reviews) that has at least one design-specific - "fatal flaw", or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations.   

# LIST OF ABBREVIATIONS

# Search strategy for rVSVG-ZEBOV-GP vaccine in Scopus ( ( ( TITLE-ABS-KEY ( rvsv-zebov OR vsvdg-zebov OR vsv-ebov OR v920 ) ) OR ( TITLE-ABS-KEY ( recombinant AND vesicular AND stomatitis AND virus AND zaire AND ebola AND virus OR recombinant AND vesicular AND stomatitis AND virus AND zaire AND ebolavirus ) ) ) OR ( ( TITLE-ABS-KEY ( merck OR "National Microbiology Laboratory" OR "Public Health Agency of
Canada" OR phac OR newlink ) ) AND ( TITLE-ABS-KEY ( ebola- ) ) ) ) AND ( LIMIT-TO ( LANGUAGE , "English" ) OR LIMIT-TO ( LANGUAGE , "French" ) ) PFU dose groups) and persisting with minimal change to day 360. Dose response was observed with the highest titres at day 28 postvaccination in the 110 8 and 210 7 PFU dose groups (no statistically significant difference between these dose groups) and the lowest titres in the 310 3 and 310 4 PFU dose groups. Time to onset of the immune response was dose-related, with seroconversion rates lower in the low-dose groups than in the highdose groups.  IgG and neutralizing antibodies were both dose-related, strongly correlated at day 28, and persisted for 1 year. concentrations than adults without baseline GP-specific antibodies at day 56 post-vaccination at some doses.  70-100% vaccinated with doses 310 4 PFU reached 4-fold increase of GP-specific GMT by day 28, with titres peaking at day 56 and persisting higher than baseline up to 180 days post-vaccination. Highest titres were observed with the 210 7 PFU dose regardless of baseline antibody status.

# Search strategy for rVSVG-ZEBOV-GP vaccine in

# Safety
Children and adolescents  0% and 7% of children and adolescents, respectively, were seropositive for GP-specific IgG antibodies at baseline. As in adults, those with pre-existing immunity had higher responses to the vaccine at days 28 and 56 post-vaccination.  95% of children and 100% of adolescents who received a 210 7 PFU dose reached 4-fold increase of GP-specific GMT by day 28, with titres peaking at 180 days postvaccination. HIV-infected individuals  Of 22 HIV-infected individuals who received the vaccine, two serious adverse events that were attributed to gastroenteritis and respiratory failure occurred in one subject.

# All vaccinees

# Citation
Henao-Restrepo et al. 2017 (21) Henao-Restrepo et al. 2015 (22) (interim findings)  Control animals started to show clinical signs of disease and high ZEBOV plasma titres on day 6 after challenge and succumbed to ZEBOV infection on days 6, 7, and 8. None of the 3 rVSVG-ZEBOV-GP-vaccinated animals became sick from the ZEBOV challenge and all 3 animals survived. A transient low level rVSV viremia was detected on day 2 after vaccination in plasma from 4 of 6 rVSVG-ZEBOV-GP-vaccinated animals. rVSV was not detected in swab samples of any animal.  By day of ZEBOV challenge (28 days postvaccination), all rVSVG-ZEBOV-GP-vaccinated animals had developed modest IgG antibody titres against ZEBOV GP and these titres increased after ZEBOV challenge.  No evidence of IFN- or TNF- production in CD4+ or CD8+ T cells was found before or after ZEBOV challenges in any of the animals.  No animals showed any signs of clinical symptoms after vaccination.  Tissue viremia from aerosol challenge mimicked patterns found in IM challenge.

# Citation
Geisbert et al.
2008 (33) Vaccine rVSVG-ZEBOV-GP:  110 7 PFU Saline placebo

# Time of administration
Pre-exposure: 31 days before lethal ZEBOV challenge Of 9 adult rhesus macaques with clinical evidence of SHIV infection (reduced CD4+ T cell counts and SHIV viremia in 4 of 9), 6 received the rVSVG-ZEBOV-GP vaccine and 3 receive placebo. All vaccine recipients and 2 controls were challenged with an IM  4 of the 6 rVSVG-ZEBOV-GP-vaccinated SHIVinfected animals and both placebo control animals started to show clinical signs of disease on day 6 after challenge. Disease progressed in 2 of the rVSVG-ZEBOV-GP-vaccinated SHIV-infected animals and both of the placebo control animals; these 2 rVSVG-ZEBOV-GP-vaccinated animals died on days 9 and 13 and the placebo control animals died on days 9 and 10. Animals that did not survive had the lowest CD4+ counts, suggesting that CD4+ T cells may play a role in mediating protection

# Study Intervention - Population Summary of key findings
The Sudan ebolavirus macaque challenge model was not uniformly lethal. 

# Study

# Study design Intervention - Population Summary of key findings
Level & quality of evidence hospital of the treatment unit.

# Sample size
Total: 210 of 650 (32%) of enumerated contacts and contacts of contacts were vaccinated.

# Baseline characteristics
Median age of 33 years. 14% female.

# Citation
Gsell et al. 2017 (27) Design Ring vaccination study from March 17 to April 21, 2016 Location Guinea