GRADE: rVSVΔG-ZEBOV-GP Ebola vaccine for persons in the U.S. population who are at potential occupational risk of exposure to Ebola virus (species Zaire ebolavirus)

Grading of Recommendations, Assessment, Development, and Evaluation

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Introduction

On December 19, 2019, the Food and Drug Administration (FDA) approved the rVSVΔG-ZEBOV-GP Ebola vaccine (Erbevo®, Merck) for the prevention of Ebola virus disease (EVD) due to Ebola virus (species Zaire ebolavirus; abbreviated EBOV) in adults aged 18 years or older. On February 26, 2020, the Advisory Committee on Immunization Practices (ACIP) recommended pre-exposure vaccination with rVSVΔG-ZEBOV-GP vaccine for adults aged 18 years or older in the United States population who are at potential risk of exposure to EBOV:

• Persons who are responding to an outbreak of EVD
• Persons who work as healthcare personnel (HCP)* at federally designated Ebola Treatment Centers in the United States
• Persons who work as laboratorians or other staff at biosafety-level 4 facilities in the United States

Previously, ACIP had no recommendations for the use of vaccines to prevent EVD. Beginning in September 2019, the ACIP Ebola Vaccine Work Group (WG) met regularly to define the research questions of interest, identify critical and important patient-centered outcomes, conduct a systematic review of the evidence, assess the certainty of the evidence, and make recommendations according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

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Methods and GRADE

A systematic review and assessment of the evidence for the rVSVΔG-ZEBOV-GP Ebola vaccine was conducted and presented to ACIP in February 2020.  No conflicts of interest were reported by CDC staff or the WG members involved in the review. As a basis for the systematic review, the policy question consisting of the population, intervention, comparison, and outcomes (PICO) of interest was defined according to the GRADE approach (Table 1). For each PICO question, desirable and undesirable patient-important outcomes were selected by the WG. Outcomes deemed “Critical” and “Important” by the WG are presented in Table 1. All critical outcomes were included in the evidence profiles unless otherwise indicated in Table 1. Evidence included in the profiles is the same across the three population categories.

On December 16, 2019, a literature search was executed in multiple biomedical and interdisciplinary bibliographic databases using a broad and rigorous search strategy that incorporated terms related to vaccination against Ebola virus using the rVSVΔG-ZEBOV-GP vaccine, without date or language restrictions. Results were compiled in an Endnote library and duplicate records were removed. The search was updated on January 31, 2020 to screen recent records that were not captured in the original search. Efforts were made to obtain unpublished or other relevant data not included in the search results from subject matter experts and the manufacturer and yielded one additional record for inclusion in analysis.

Records were included for analysis if they presented data on the rVSVΔG-ZEBOV-GP Ebola vaccine and involved immunocompetent adults 18 years of age or older, regardless of pregnancy status, included data for the intervention of interest and data relevant to the outcome measures being assessed; and reported primary data  from comparative or single-arm studies; randomized control trials, prospective or retrospective cohort, case-control, or cross-sectional studies. A total of 1,818 records were identified through database searches and one unpublished record was identified through other sources. A total of 1,742 of these records were excluded during title and abstract screening, leaving 77 full-text articles that were assessed for eligibility through full-text review. Of these, 59 full-text articles were excluded (Figure 1). In total, 18 articles that presented data from 11 studies were included in qualitative synthesis while 9 articles that presented data from 8 studies were included in quantitative synthesis or meta-analysis (Figure 1).

The GRADE approach for assessing the type or quality of evidence involves consideration of several criteria. Assessing the type or certainty level of the body of evidence for each outcome begins with the study design. Randomized control trials are initially classified as evidence type 1, high certainty, and observational studies as evidence type 3, low certainty. Following the identification of the initial evidence type, the body of evidence for each outcome is assessed and downgraded if there is uncertainty about any of the five following criteria: risk of bias; inconsistency, which considers statistical heterogeneity and I², defined as the percent variation across studies due to heterogeneity instead of chance; indirectness, which is the generalizability of the body of evidence to the original PICO components; imprecision, which considers the fragility of the relative and absolute effect measures as they relate to the 95% confidence intervals and optimal information size; and publication bias. The body of evidence from observational studies may be rated up due to dose-response gradient, large or very large magnitude of effect, or opposing residual confounding.

After assessing on these criteria, the body of evidence was assigned an overall evidence type or certainty level. Type 1, high certainty, evidence can be interpreted that there is a high level of confidence that the true effect lies close to that of the estimate of effect. Type 2, moderate certainty, evidence can be interpreted that there is a moderate level of confidence in the effect estimate. Type 3, low certainty, evidence can be interpreted that confidence in the effect estimate is limited. Type 4, very low certainty, evidence can be interpreted that there is little confidence in the effect estimate. This does not measure how well the individual studies were conducted, but rather how much confidence there is in the estimates of effect from the body of evidence across each outcome.

For the purposes of the evidence assessment and evidence profile tables, randomized control trial (RCT) refers to a trial which randomizes participants to an active intervention or a placebo or unvaccinated comparator arm; observational studies refer to one-arm studies, studies for whom participants were not randomized, or studies that did not provide disaggregated data to allow for the comparison between the randomized arms. Evidence was also considered observational if only data from the vaccinated study arms were included in analysis for a given outcome. Observational studies without comparators are not included in the analyzed bodies of evidence but would be evidence type 4, very low certainty.

Summary of Findings

Development of Ebola-related symptomatic illness

There was one published study with an unvaccinated comparator that was included for the body of evidence for this outcome, the publication of the final results associated with the Ça Suffit! Trial in Guinea¹. This was a two-part phase 3 cluster-randomized open-label ring vaccination trial¹. The initial findings from this trial were published in an interim report². Only data from the final report¹ was included in the analyses to prevent duplication. The initial study involved contacts and contacts of contacts of confirmed Ebola virus disease or EVD cases that were randomized to either immediate or delayed vaccination. Delayed vaccination was defined as vaccination that occurred 21 days after randomization. A follow-up study included immediate vaccination following cessation of the randomized trial. The primary outcome was the incidence of EVD with onset of 10 days or more following randomization. The 10 days accounts for the average incubation period of Ebola and unknown time for the vaccine to induce protective immunity.

Cluster- and participant-level data from randomized clusters are presented in the evidence table for this outcome in Table 2. Out of 3775 participants within 70 clusters that received immediate vaccination (between randomized and non-randomized), 0 participants developed EVD 10 days or longer after randomization¹. In contrast, of 4507 participants within 104 clusters that were delayed or never received the vaccine, 23 participants within 11 clusters developed EVD 10 days or longer after randomization¹.  Within randomized clusters, out of 2108 participants within 51 clusters that received immediate vaccination, 0 developed EVD greater than 10 days after randomization¹. In contrast, of 3075 participants within 47 clusters that were randomized to delayed vaccination, 16 participants within 7 clusters developed EVD greater than 10 days after randomization. These randomized data equate to a calculated vaccine efficacy of 100% (95% confidence interval 68.9 – 100)¹.

Given that this was a cluster randomized trial where the units of randomization were clusters, the randomized cluster-level evidence is presented in Table 2. Because the population in this study consists of contacts and contacts of contacts of EVD cases and used a ring vaccination strategy that may include post-exposure vaccination, the certainty level was downgraded one level for indirectness to the U.S. population and the intervention of interest, which is pre-exposure vaccination. The cluster-level evidence was also downgraded one level for imprecision because there were few events reported and the data do not meet the optimal information size and suggest fragility of the estimate, and the confidence interval crosses 1 and contains the potential for desirable as well as undesirable effects. Considering this assessment, the overall assessment of this body of evidence at the randomized cluster level to address the outcome of development of Ebola-related symptomatic illness is type 3, low certainty evidence (Table 2).

Participant-level data from the randomized clusters is also presented in Table 2 and was considered observational because the units of randomization within the study were clusters. Because of the very precise reduction in risk for those immediately vaccinated, the body of evidence was not rated down for imprecision at the participant level. The evidence was also rated down one level for indirectness for the same reason as the cluster-level data, however, the concerns with indirectness did not pose an inflationary effect; and therefore, the evidence could be rated up based on a very large magnitude of effect from the 96% reduction in risk for those immediately vaccinated. Taken together, overall certainty was upgraded two levels to type 2, moderate certainty evidence for this participant level data (Table 2).

Incidence of arthralgia

The outcome of incidence of arthralgia was assessed with the incidence of arthralgia or joint pain that was solicited within 0-42 days. The body of evidence of RCTs and observational studies analyzed for this outcome are presented in Tables 3a and 3b, respectively.  The body of evidence that included six RCTs^3-8 was downgraded one level for a concern for risk of bias because of lack of blinding in participants, healthcare personnel, and outcome assessors in two studies that may have influenced events reported for this outcome. Additionally, there is a concern for underreporting in one study that only solicited arthralgia at one week and one month for the majority of participants, that may have led to underreporting of events. Due to concerns with heterogeneity with an I² of 70%, this study was downgraded one level for inconsistency. Because the 95% confidence interval crosses 1 and includes a potential for possible harms as well as benefits, it was downgraded one level for imprecision. Overall, this body of evidence was assessed to be type 4, very low certainty evidence (Table 4). The body of evidence from the two observational studies^5,9 was downgraded one level for imprecision because there were few events reported suggesting fragility in the estimate. Overall, this body of evidence was assessed to be type 4, very low certainty evidence (Table 4).

Severity of arthralgia

The outcome of severity of arthralgia was assessed with the incidence of severe (grade 3) arthralgia solicited between 0-42 days and defined as significant joint pain or discomfort that prevents daily activity. The body of evidence of RCTs and observational studies analyzed for this outcome are presented in Tables 5a and 5b, respectively.  The body of evidence that included four RCTs^3,5,7,8 was downgraded one level for a concern for risk of bias because of lack of blinding in participants, healthcare personnel, and outcome assessors in two studies that may have influenced events reported for this outcome. Because of there being a concern for fragility in the estimate due to the few numbers of events reported, it was downgraded one level for imprecision. Overall, this body of evidence was assessed to be type 3, low certainty evidence (Table 6). The body of evidence for the two observational studies^5,9 was downgraded one level for imprecision because there were no events reported among vaccinated or non-vaccinated participants and it suggests fragility in the estimate. Overall, this body of evidence was assessed to be type 4, very low certainty evidence (Table 6).

Incidence of arthritis

The outcome of incidence of arthritis was assessed with an event of arthritis reported within 5-56 days of follow up. The body of evidence of RCTs and observational studies analyzed for this outcome are presented in Tables 7a and 7b, respectively. The body of evidence that included four randomized trials^3,4,6,7 was downgraded one level for a concern for risk of bias because studies used variable definitions and methods for diagnosing and reporting arthritis, and for lack of blinding in participants, healthcare personnel, and outcome assessors in two studies that may have influenced events reported for this outcome. Because the 95% confidence interval crosses 1 and includes a potential for possible harms as well as benefits, we downgraded one level for imprecision. Overall, this body of evidence was assessed to be type 3 low certainty evidence (Table 8). The body of evidence for the two observational studies^5,9 was downgraded two levels for imprecision because of a concern for fragility in the estimate due to the few number of events reported and that the 95% confidence interval crosses 1 and includes a potential for possible harms as well as benefits. Overall, this body of evidence was assessed to be type 4 very low certainty evidence (Table 8).

Vaccine-related adverse pregnancy outcomes for women inadvertently vaccinated while pregnant and women who become pregnant within in 2 months of vaccination

This outcome was assessed with incidence of pregnancy loss (defined as spontaneous abortion and stillbirth). There was one study included in the body of evidence for this outcome, a non-randomized sub-study of the Sierra Leone Trial to Introduce a Vaccine Against Ebola.¹⁰ The body of evidence for outcome was downgraded one level for indirectness because the study did not differentiate between spontaneous abortions (including induced abortion) and stillbirth, and the outcome may not accurately distinguish between events due to the vaccine. Additionally, because of there being a concern for fragility in the estimate due to the few numbers of events reported and that the 95% confidence interval crosses 1 and includes a potential for possible harms as well as benefits, it was downgraded two levels for imprecision. Overall, this body of evidence was assessed to be type 4 very low certainty evidence (Table 9). There were 3 additional studies^4,11,12 that reported on this outcome that did not have comparators. Among these 3 studies, there were 3 adverse pregnancy outcomes out of 20 pregnancies in 19 women; however, no conclusions can be made regarding the relationship between vaccination and adverse pregnancy outcomes based on these data.

Transmissibility of rVSVΔG-ZEBOV-GP vaccine virus to humans or animals

rVSVΔG-ZEBOV-GP vaccine virus dissemination was used as a surrogate for this outcome due to lack of available data on transmissibility and was assessed with detection of rVSVΔG-ZEBOV-GP in blood/plasma, saliva, and urine by RT-PCR. Data from 8 studies^{3,5,6,8,9,11,13,14} were included for the body of evidence for the surrogate outcome of detection of rVSVΔG-ZEBOV-GP in blood/plasma by RT-PCR. Across these 8 studies, on day 7 post-vaccination, 32 out of 691 vaccinated participants (or 4.6%) were RT-PCR positive for vaccine virus. On day 14 post-vaccination, 1 out of 501 (or 0.2%) of vaccinated participants were RT-PCR positive for vaccine virus; however, true estimates of duration of viremia is unknown because daily collection was not performed. Additionally, one study performed viral isolation on selected blood specimens, and all were negative. Data from 4 studies^3,8,9,13 were included for the body of evidence for the surrogate outcome of detection of rVSVΔG-ZEBOV-GP in saliva and urine by RT-PCR. Across these 4 studies, on day 7 post-vaccination, 6 out of 257 vaccinated participants (or 2.3%) were RT-PCR positive for vaccine virus in saliva while 2 out of 246 (0.8%) were positive in urine. On day 14 post-vaccination, 1 out of 98 (or 1%) of vaccinated participants were positive in saliva while 0/98 were positive in urine.

For the purposes of this outcome, only data from the vaccinated arms were included for analysis, so all included studies were considered observational. The body of evidence was downgraded one level for risk of bias because of concern for incomplete outcome data as not all who received the vaccine were tested on a given day. It was also downgraded 2 levels for indirectness because the outcome of interest to the work group was transmissibility of the vaccine virus to humans or animals. There are no data that report on transmissibility, so viral dissemination and shedding is assessed as an indirect surrogate. Additionally, RT-PCR positivity is not synonymous with infectivity. Overall, the body of evidence for both the surrogate outcomes of detection of rVSVΔG-ZEBOV-GP in blood/plasma and detection of rVSVΔG-ZEBOV-GP in saliva and urine by RT-PCR was assessed to be type 4 very low certainty evidence (Table 10a and 10b, respectively).

Vaccine-related serious adverse events

Vaccine-related serious adverse events following vaccination with rVSVΔG-ZEBOV-GP are an uncommon occurrence. Across the body of evidence from 12 clinical trials and two additional publications that describe use of vaccine through expanded use mechanisms that reported on vaccine-related serious adverse events^{3-5,7-9,11,13-17}, 3/17,119 (0.02%) vaccinees were judged to have a SAE related to or possibly related to vaccination. Two of the three were related to vaccination and included a febrile reaction and anaphylaxis, both of which resolved without sequelae.¹ One was judged to be possibly related to the vaccine, an influenza like illness, which also resolved without sequelae.¹ An additional publication¹⁸ presented serious adverse events captured during the Sierra Leone Trial to Introduce a Vaccine Against Ebola; however, overall safety findings from this trial were previously reported and included in this analysis⁷ so the additional publication was not included. Like the previous outcome, only data from the vaccinated arms were included for analysis, so the studies were considered observational for this outcome and we did not downgrade across any of the criteria. Overall, this body of evidence was assessed to be type 3 low certainty evidence.

GRADE Analysis for VSVΔG-ZEBOV-GP Ebola vaccine for persons in the U.S. population at potential occupational risk of exposure to Ebola virus

Figure 1: Diagram depicting the flow of information through the different phases of the systematic review evidence retrieval process, including the number of records identified, records included and excluded at each stage, and the reasons for exclusions.

Table 1: Policy question and definition of the Population, Intervention, Comparison, and Outcomes determined by the ACIP Ebola Vaccine Work Group for GRADE analysis.

Table 2. Evidence table for outcome of development of Ebola-related symptomatic illness

Table 3a. Estimates of effect for RCTs included in analysis for outcome of incidence of arthralgia (0-42 days)

Table 3b. Estimates of effect for observational studies included in analysis for outcome of incidence of arthralgia (0-42 days)

Table 4. Evidence table for outcome of incidence of arthralgia (0-42 days).

Table 5a. Estimates of effect for RCTs included in analysis for outcome of incidence of severe (grade 3) arthralgia (0-42 days).

Table 5b. Estimates of effect for observational studies included in analysis for outcome of incidence of severe (grade 3) arthralgia (0-42 days).

Table 6. Evidence table for outcome of incidence of severe (grade 3) arthralgia (0-42 days).

Table 7a. Estimates of effect for RCTs included in analysis for outcome of incidence of arthritis (5-56 days).

Table 7b. Estimates of effect for observational studies included in analysis for outcome of incidence of arthritis (5-56 days).

Table 8. Evidence table for outcome of incidence of arthritis (5-56 days).

Table 9. Evidence table for outcome of vaccine-related adverse pregnancy outcomes for women inadvertently vaccinated while pregnant and women who become pregnant within in 2 months of vaccination.

Table 10a. Evidence table for surrogate outcome of vaccine virus dissemination (assessed by detection of vaccine in blood/plasma by RT-PCR).

Table 10b. Evidence table for surrogate outcome vaccine virus dissemination (assessed by detection of vaccine in saliva and urine by RT-PCR).

Table 11. Evidence table for surrogate outcome of vaccine-related serious adverse events.

Footnote

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References

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