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Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Use of JYNNEOS (orthopoxvirus) vaccine primary series for research, clinical laboratory, response team, and healthcare personnel (Policy Questions 1 and 2)										Related Pages
										Table 1.1: Policy Question and PICO
Table 1: Policy Question and PICO
Policy question:
**Should JYNNEOS® be recommended for persons who are at risk* for occupational exposure to orthopoxviruses?**Population
Persons who are at risk* for occupational exposure to orthopoxvirusesIntervention
Vaccination with JYNNEOS®Comparison
Vaccination with ACAM2000Outcomes
Prevention of disease
Severity of disease
Serious adverse events
Myo-/ peri- carditis*Research laboratory personnel, diagnostic laboratory personnel, and orthopoxvirus and healthcare worker response teams designated by appropriate public health and antiterror authorities; clinical laboratory personnel who perform routine chemistry, hematology, and urinalysis procedures are not recommended for vaccination with ACAM2000 or JYNNEOS because the quantity of orthopoxviruses likely to be in clinical specimens of blood and body fluids is low.
Table 1.2: Policy Question 2 and PICO
Table 1: Policy Question and PICO
Policy question:
**Policy question: Should JYNNEOS® be recommended, based on shared clinical decision making, for healthcare personnel at risk* for occupational exposure to orthopoxviruses?**Population
Persons who are at risk* for occupational exposure to orthopoxvirusesIntervention
Vaccination with JYNNEOS®Comparison
Vaccination with ACAM2000Outcomes
Prevention of disease
Severity of disease
Serious adverse events
Myo-/ peri- carditis*For example, clinical trial physicians or nurses who currently treat or anticipate treating patients with replication-competent orthopoxvirus infections or persons who administer ACAM2000 smallpox vaccine
Table 2: Outcomes and Rankings
Table 2: Outcomes and Rankings
Outcome
Importance*
Included in evidence profilePrevention of disease
Critical
YesSeverity of disease
Important
YesSerious adverse events**
Critical
YesMyo-/ peri- carditis
Critical
YesMinor adverse events
Not important
No
*Three options: 1. Critical; 2.  Important but not critical; 3. Not important for decision making
**Serious adverse events were defined according to the standard FDA definition. In addition, data was collected about any smallpox vaccine-specific adverse event: postvaccinial encephalitits, eczema vaccinatum, progressive vaccinia, and generalized vaccinia.
Appendix 1: Studies Included in the Review of Evidence
Appendix 1: Studies Included in the Review of Evidence
Last name first author, Publication year
Study design
Country (or more detail, if needed)
Age (measure central tendency – mean/SD; median/IQR; range)
Total population
N Intervention
N comparison
Outcomes
Funding sourceRCT dataNCT01913353
Pittman
Pittman 2019
Phase 3, open-label,
randomized clinical trial
U.S. military, stationed in Korea
Mean 23.5
SD 4.67
433
220
213
Immunogenicity,
Surrogate efficacy (ACAM2000 challenge),
Adverse events
Bavarian Nordic, US Army Medical Research Institute of Infectious DiseasesNCT00082446
Frey1
Frey 2007
Sano 2009
Phase I, randomized, partially blinded,
placebo controlled clinical trial
USA
Mean 24.8
SD 3.8
90
30
15
Immunogenicity, Cell-mediated immunity, Surrogate efficacy (Dryvax challenge),
Adverse events
NIAIDVRC 201
Parrino1
Parrino 2007
Phase I/Ib randomized, placebo controlled, double-blinded trial
USA
Total Mean
SD NR
adults
76
19
21
Immunogenicity, safety, Dryvax challenge, cell mediated/humoral immune responses
NIAIDObservational data for the interventionNCT00437021
Frey 2
Frey et al. 2013
Troy et al. 2015
Phase II, Double-blind, Randomized, Dose-finding Study
USA
Mean 24.7
SD 4.2
208
67
NA
Safety and immunogenicity
NIAIDNCT01668537
Greenburg4
2014
Phase II, Randomized, Double-blind, Multicenter
USA
Mean 27.7
SD 6.28
651
327
NA
Safety and immunogenicity
Bavarian NordicNCT00879762
Frey3
Troy et al. 2015
Frey et al. 2014
Phase II, randomized, double blinded
USA
Mean 26.5
SD NR
91
45
NA
Safety and immunogenicity
NIAIDNCT00316602
Greenburg2
Greenberg 2015
Phase II, non-randomized, open-label
USA and Mexico
Mean 27.7
SD 6.11
632
632
NA
Safety and immunogenicity in people with atopic dermatitis
NIAID and Bavarian NordicNCT00914732
Frey4
Troy et al. 2015
Frey et al. 2015
Phase II, randomized, triple blinded
USA
Mean 27.2
SD 4.6
523
167
NA
Safety and immunogenicity
NIAID and Bavarian NordicNCT00316524
von Sonnenburg1
Zitzman-Roth et al. 2015
Partially Randomized, Partially Double-blind, Placebo-controlled Phase II Non-inferiority Study
Germany
Mean 29.8
SD 9.07
745
183
NA
Safety and immunogenicity
NIAID and Bavarian NordicNCT00189904
Greenburg1
Greenberg et al. 2013
Phase I/II, non-randomized, open-label
USA
Mean 37.9
SD NR
151
60
NA
Safety and immunogenicity in HIV positive patients
NIAIDNCT01144637
Overton2
Overton et al. 2018
Randomized, Double-Blind, Placebo-Controlled Phase III Trial
USA
Mean 27.7
SD 6.3
4005
3003
NA
immunogenicity, safety, and tolerability
Bavarian Nordic and BARDANCT00189917
von Sonnenburg2
Darsow et al. 2016
Von Sonnenburg et al. 2014
Open-label, Controlled Phase I Pilot Study
Germany
Mean NR
SD NR
60
60
NA
Safety and immunogenicity
NIAID and Bavarian NordicNCT00133575
Seaman/Wilck
Seaman et al. 2010
Wilck et al. 2010
Phase I/II, randomized, double blinded, placebo-controlled
USA
Mean 25.2, SD=3.7
72
10
NA
Safety and immunogenicity and surrogate efficacy (Dryvax challenge)
NIAIDNCT01827371
Frey5
Anderson et al. 2020
Jackson et al. 2017
Phase II, Randomized, Open-Label
USA
Mean 27.4
SD 5.3
435
115
NA
Safety and immunogenicity
NIAIDNCT02038881
Overton3
Overton et al. 2020
Phase II, Randomized, Open-label
USA
Mean 35
SD 6.7
87
58
NA
Safety and immunogenicity in HIV+ patients
Bavarian NordicNCT00316589
Overton1
Overton et al. 2015
Phase II, Multicenter, Open-label, Controlled
USA
Mean 37.5
SD 8.0
579
439
NA
Safety and immunogenicity
HHS and NIAIDNCT00189959
Pokorny
Von Kremplehuber et al. 2010
Phase II, Double-blind, randomized, Dose-finding Study
Switzerland
Mean 23.3
SD 3.0
165
55
NA
Safety and immunogenicity
NIAID and Bavarian NordicVollmar
Vollamr et al. 2005
Phase 1, randomized, double-blinded and open-label
Germany
Mean 32.8
68
16
NA
Safety and immunogenicity
Bavarian Nordic
Table 3a: Summary of Studies Reporting Outcome A – Prevention of Disease
Table 3a: Summary of Studies Reporting Outcome A – Prevention of Disease
Authors last name, pub year
Age or other characteristic of importance
N intervention
N comparison
Comparator vaccine
Absolute difference/effect estimate
Study limitations (Risk of Bias)RCT dataNCT01913353
Pittman
Pittman 2019
Mean age 23.5 y
Healthy adults
220
213
ACAM2000
PRNT GMT: Mean difference 1.93 (95% CI 1.57 to 2.39)
PRNT Seroconversion rate: Risk ratio 1.03 (95% CI 1.00 to 1.05)
Serious concerns due to open-label design and inclusion of only military soldiers (young and very healthy persons)NCT00082446
Frey 1
Frey 2007
Sano 2009
Mean age 24.8 y
Healthy adults
30
13
Dryvax
PRNT GMT: Mean difference 7.54 (95% CI 2.75 to 20.91)
PRNT Seroconversion rate: Risk ratio 1.20 (95% CI 0.93 to 1.53)
Not serious
Table 3b: Summary of Studies Reporting Outcome B – Severity of Disease
Table 3b: Summary of Studies Reporting Outcome B – Severity of Disease
Authors last name, pub year
Age or other characteristic of importance
N intervention
N comparison
Comparator vaccine
Absolute difference/effect estimate
Study limitations (Risk of Bias)RCT dataVRC 201
Parrino1
Parrino 2007
Mean age NR
Healthy adults
15
8
Dryvax
RR 1.00 (95% CI 0.83-1.20)
0 fewer developed an attenuated take reaction (from 170 fewer to 200 more)
15/15 participants developed an attenuated1 take reaction in the intervention group
8/8 participants developed an attenuated1 take reaction in the comparison group
Concerns for risk of bias due to attrition. The two groups that contributed data to the intervention and comparison for this outcome lost between 11 and 21% of participants at the time this outcome was assessed.
1“Attenuated take” was defined as a lesion in category 1 or 2. Categories: 0 (no take, i.e., no skin reaction or skin sensitivity consisting of erythema only within 24-48 hours that resolves by the 5th day without vesicle or pustule formation), 1 (modified take without vesicle, i.e., an attenuated primary vaccine site reaction with the following characteristics:  papule with or without surrounding erythema by 3rd day and without vesicle or pustule formation prior to resolution), 2 (modified take with vesicle, i.e., an attenuated primary vaccine site reaction with the following characteristics:  papule by 3rd day that becomes vesicular by 5-7th day, and dries shortly thereafter; a relatively small vesicle and areola; and the scar, if present, is usually insignificant), and 3(full take, i.e., primary take is where the inoculation site becomes reddened 3-4 days after vaccination.  A vesicle surrounded by a red areola then forms which becomes umbilicated and then pustular by the 7t to 11th day after vaccination.  The red areola enlarges by this time.  The pustule begins to dry, the redness subsides, and the lesion becomes crusted between the 2nd and 3rd week.  By the end of the 3rd week, the scab falls of leaving a permanent scar that at first is pink in color but eventually becomes flesh-colored).
Table 3c: Summary of Studies Reporting Outcome C – Serious Adverse Events (SAE)
Table 3c: Summary of Studies Reporting Outcome C – Serious Adverse Events (SAE)
Authors last name, pub year
Age or other characteristic of importance
N intervention
N comparison
Comparator vaccine
Absolute difference/effect estimate
Study limitations (Risk of Bias)RCTNCT01913353
Pittman
Pittman 2019
Mean age 23.5 y
Healthy vaccinia naïve adults
220
213
ACAM2000
Not estimable,
0/220 participants had vaccine related SAEs in the intervention group.
0/213 participants had vaccine related SAEs in the comparison group
Serious concerns because of open-label designNCT00082446
Frey 1
Frey 2007
Sano 2009
Mean age 24.8 y
Healthy vaccinia naïve adults
30
15
Dryvax
Not estimable,
0/30 participants had vaccine related SAEs in the intervention group.
0/13 participants had vaccine related SAEs in the comparison group
Not seriousVRC 201
Parrino1
Parrino 2007
Mean age NR
Healthy vaccinia naïve adults
18
21
Dryvax
Risk ratio: 0.33 (95% CI 0.01 to 7.70)
0/19 participants had vaccine related SAEs in the intervention group.
**1/191 participants had vaccine related SAEs in the comparison group**
Concerns for risk of bias due to attrition. The two groups that contributed data to the intervention and comparison for this outcome lost between 11 and 21% of participants at the time this outcome was assessed.ObsNCT00437021
Frey 2
Frey et al. 2013
Troy et al. 2015
Age: Mean 24.7
SD 4.2
Healthy vaccinia naïve adults
67
NA
NA
NA20 participants had vaccine related SAEs in the intervention groupNCT01668537
Greenburg4
2014
Age: Mean 27.7
SD 6.28
Healthy vaccinia naïve adults
327
NA
NA
NA20 participants had vaccine related SAEs in the intervention groupNCT00879762
Frey3
Troy et al. 2015
Frey et al. 2014
Age: Mean 26.5
SD NR
Healthy vaccinia naïve adults
45
NA
NA
NA20 participants had vaccine related SAEs in the intervention groupNCT00316602
Greenburg2
Greenberg 2015
Age: Mean 27.7
SD 6.11
Healthy vaccinia naïve adults and**Vaccinia naïve adults with atopic dermatitis**
623
NA
NA
NA2**1 participant had a SAE3 that was “probably related” to the vaccine in the intervention group (a healthy vaccinia naïve adult)**NCT00914732
Frey4
Troy et al. 2015
Frey et al. 2015
Age: Mean 27.2
SD 4.6
Healthy vaccinia naïve adults
167
NA
NA
NA20 participants had vaccine related SAEs in the intervention groupNCT00316524
von Sonnenburg1
Zitzman-Roth et al. 2015
Age: Mean 29.8
SD 9.07
Healthy vaccinia naïve adults
183
NA
NA
NA2**1 participant had a vaccine “related” SAE4 in the intervention group**NCT00189904
Greenburg1
Greenberg et al. 2013
Age: Mean 37.9
SD NR
HIV negative vaccinia naïve adults and **HIV positive vaccinia naive adults**
60
NA
NA
NA20 participants had vaccine related SAEs in the intervention groupNCT01144637
Overton2
Overton et al. 2018
Age: Mean 27.7
SD 6.3
Healthy vaccinia naïve adults
3003
NA
NA
NA20 participants had vaccine related SAEs in the intervention groupNCT00189917
von Sonnenburg2
Darsow et al. 2016
Von Sonnenburg et al. 2014
Age: Mean NR
SD NR
Healthy vaccinia naïve adults and **adults with either history of atopic dermatitis, active atopic dermatitis, or allergic rhinitis**
60
NA
NA
NA20 participants had vaccine related SAEs in the intervention groupNCT00133575
Seaman/Wilck
Seaman et al. 2010
Wilck et al. 2010
Age: Mean 25.2, SD=3.7
Healthy vaccinia naïve adults
10
NA
NA
NA20 participants had vaccine related SAEs in the intervention groupNCT01827371
Frey5
Anderson et al. 2020
Jackson et al. 2017
Age: Mean 27.4
SD 5.3
Healthy vaccinia naïve adults
115
NA
NA
NA2**1 participant had a vaccine “related” SAE5 in the intervention group**NCT02038881
Overton3
Overton et al. 2020
Age: Mean 35
SD 6.7**HIV positive vaccinia naïve adults**
58
NA
NA
NA20 participants had vaccine related SAEs in the intervention groupNCT00316589
Overton1
Overton et al. 2015
Age: Mean 37.5
SD 8.0
Healthy vaccinia naïve adults and **HIV positive vaccina naïve adults**
439
NA
NA
NA2**1 participant had a SAE6 that was “possibly but unlikely” related to vaccination in the intervention group (an HIV positive vaccina naïve adult)**NCT00189959
Pokorny
Von Kremplehuber et al. 2010
Age: Mean 23.3
SD 3.0
Healthy vaccinia naïve adults
54
NA
NA
NA20 participants had vaccine related SAEs in the intervention groupVollmar
Vollmar et al. 2005
Age: Mean 32.8
Healthy vaccinia naïve adult males
16
NA
NA
NA20 participants had vaccine related SAEs in the intervention group
One participant developed **elevated liver enzymes** 84 days after receiving Dryvax vaccine on day 0. The SAE was assessed to be “possibly related” to vaccination.
Intervention data was drawn from pooled single arm observational studies included in the systematic review. 4/5221 (0.08%) participants from 14 observational studies developed vaccine related serious adverse events. No smallpox vaccine-specific serious adverse event was recorded. Comparison data was drawn from historical data. In a phase III clinical trial for ACAM2000, 3/873 (0.34%) developed vaccine related serious adverse events after ACAM2000 administration. No smallpox vaccine-specific serious adverse event was recorded.
**Extra ocular muscle paresis** event in one person 8 days after second MVA-BN vaccination; deemed “probably related” by investigators.
**Sarcoidosis** event in one person during the 6 months follow up period; deemed “related” because causal relationship with vaccine could not be ruled out.
**Acute myocardial infarction**event in one person 117 days after the first MVA-BN dose. Deemed “related” to vaccination because no other reasonable etiology was found. Number at risk is 116 because one subject was initially randomized to study arm C but was vaccinated out of the window and was analyzed in study arm A.
**Pneumonia and pleurisy** event in one person 1 day after second MVA-BN dose. Deemed “possibly but unlikely” to be associated with vaccination.
Table 3d: Summary of Studies Reporting Outcome D – Myo/pericarditis
Table 3d: Summary of Studies Reporting Outcome D – Myo/pericarditis
Authors last name, pub year
Age or other characteristic of importance
N intervention
N comparison
Comparator vaccine
Absolute difference/effect estimate
Study limitations (Risk of Bias)RCTNCT01913353
Pittman
Pittman 2019
Mean age 23.5 y
Healthy vaccinia naïve adults
220
213
ACAM2000
Not estimable,
0/220 participants developed myo-/pericarditis in the intervention group.
0/213 developed myo-/pericarditis in the comparison group
Serious concerns because of open-label trial designNCT00082446
Frey 1
Frey 2007
Sano 2009
Mean age 24.8 y
Healthy vaccinia naïve adults
30
15
Dryvax
Not estimable,
0/30 participants developed myo-/pericarditis in the intervention group.
0/13 developed myo-/pericarditis in the comparison group
Not seriousVRC 201
Parrino1
Parrino 2007
Mean age NR
Healthy vaccinia naïve adults
18
21
Dryvax
Not estimable,
0/19 participants developed myo-/pericarditis in the intervention group.
0/19 participants developed myo-/pericarditis in the comparison group
Very serious because unknown how many people were monitored for myopericarditis and when in the trial, this was startedObservational data for the interventionNCT00437021
Frey 2
Frey et al. 2013
Troy et al. 2015
Age: Mean 24.7
SD 4.2
Healthy vaccinia naïve adults
67
NA
NA
NA10 participants developed myo-/pericarditis in the intervention groupNCT01668537
Greenburg4
2014
Age: Mean 27.7
SD 6.28
Healthy vaccinia naïve adults
327
NA
NA
NA10 participants developed myo-/pericarditis in the intervention groupNCT00879762
Frey3
Troy et al. 2015
Frey et al. 2014
Age: Mean 26.5
SD NR
Healthy vaccinia naïve adults
45
NA
NA
NA10 participants developed myo-/pericarditis in the intervention groupNCT00316602
Greenburg2
Greenberg 2015
Age: Mean 27.7
SD 6.11
Healthy vaccinia naïve adults and**Vaccinia naïve adults with atopic dermatitis**
623
NA
NA
NA10 participants developed myo-/pericarditis in the intervention groupNCT00316524
von Sonnenburg1
Zitzman-Roth et al. 2015
Age: Mean 29.8
SD 9.07
Healthy vaccinia naïve adults
183
NA
NA
NA10 participants developed myo-/pericarditis in the intervention groupNCT00189904
Greenburg1
Greenberg et al. 2013
Age: Mean 37.9
SD NR
HIV negative vaccinia naïve adults and **HIV positive vaccinia naive adults**
60
NA
NA
NA10 participants developed myo-/pericarditis in the intervention groupNCT01144637
Overton2
Overton et al. 2018
Age: Mean 27.7
SD 6.3
Healthy vaccinia naïve adults
3003
NA
NA
NA1**1 participant developed possible myopericarditis2 in the intervention group**NCT00189917
von Sonnenburg2
Darsow et al. 2016
Von Sonnenburg et al. 2014
Age: Mean NR
SD NR
Healthy vaccinia naïve adults and **adults with either history of atopic dermatitis, active atopic dermatitis, or allergic rhinitis**
60
NA
NA
NA10 participants developed myo-/pericarditis in the intervention groupNCT00133575
Seaman/Wilck
Seaman et al. 2010
Wilck et al. 2010
Age: Mean 25.2, SD=3.7
Healthy vaccinia naïve adults
10
NA
NA
NA10 participants developed myo-/pericarditis in the intervention groupNCT02038881
Overton3
Overton et al. 2020
Age: Mean 35
SD 6.7**HIV positive vaccinia naïve adults**
58
NA
NA
NA10 participants developed myo-/pericarditis in the intervention groupNCT00316589
Overton1
Overton et al. 2015
Age: Mean 37.5
SD 8.0
Healthy vaccinia naïve adults and **HIV positive vaccina naïve adults**
439
NA
NA
NA10 participants developed myo-/pericarditis in the intervention groupNCT00189959
Pokorny
Von Kremplehuber et al. 2010
Age: Mean 23.3
SD 3.0
Healthy vaccinia naïve adults
54
NA
NA
NA10 participants developed myo-/pericarditis in the intervention group
There was no available comparison data from the systematic review. An effect estimate was calculated using intervention data from 12 naively pooled observational studies reporting myopericarditis after MVA vaccine administration (data from systematic review) and comparison data from one study reporting myopericarditis rate after ACAM2000 administration (Source: ACAM2000 package insert, FDA). Risk ratio 0.040 (0.004 to 0.310), 5 fewer events of myo-/pericarditis per 1000 (from 6 fewer to 5 fewer).
“One individual in Group 3 experienced symptoms indicating possible acute pericarditis according to protocol criteria (chest pain worsening when lying down) (Table 3). A thorough cardiac examination, including auscultation, ECG, Troponin I testing and echocardiography did not confirm the diagnosis. The echocardiography did not reveal any signs of pericardial effusion, pericardial rub, ECG changes suggestive of pericarditis, Troponin I increased or decreased exercise capacity. A detailed laboratory examination revealed a positive serology for Coxsackie B virus in temporal relation to the reported chest pain, suggesting a possible acute viral infection as the potential cause of the symptoms.”  Overton 2008 (#106)
Policy Question 1: Should JYNNEOS® be recommended for research and clinical laboratory personnel performing diagnostic testing for orthopoxviruses* and for designated response teams# at risk for occupational exposure to orthopoxviruses?
Certainty assessment
No of patients
Effect
Certainty
ImportanceNo of studies
Study design
Risk of bias
Inconsistency
Indirectness
Imprecision
Other considerations
JYNNEOS OPXV vaccine primary series
ACAM2000 OPXV vaccine primary series
Relative
(95% CI)
Absolute
(95% CI)A. Prevention of disease (assessed with: geometric mean titer)21,2,3,4,5,6
randomized trials
not serious
not serious
seriousa,b
not serious
none
213
199
–
MD **1.62 titer units higher**
(1.32 higher to 1.99 higher)c
Level 2
Moderate
CRITICALA. Prevention of disease (assessed with: seroconversion rate)21,2,3,4,5,6
randomized trials
not serious
not serious
seriousb,d
seriouse
none
213/213 (100.0%)
192/199 (96.5%)
**RR 1.02**
(0.99 to 1.05)
**19 more per 1,000**
(from 10 fewer to 48 more)
Level 3
Low
CRITICALB. Severity of disease (assessed with: maximum lesion area)17
randomized trials
seriousf
not serious
not seriousg
very seriouse,h
none
15/15 (100.0%)i
8/8 (100.0%)
**RR 1.00**
(0.83 to 1.20)
**0 fewer per 1,000**
(from 170 fewer to 200 more)
Level 4
Very low
IMPORTANTC. **Serious adverse events (SAE) (assessed with: vaccine associated serious adverse event rate)**31,2,3,4,5,6,7
randomized trials
not serious
not serious
not serious
very seriousj
none
0/269 (0.0%)
1/245 (0.4%) k
**RR 0.33**
(0.01 to 7.70)
**3 fewer per 1,000**
(from 4 fewer to 27 more)
Level 3
Low
CRITICALC. **Serious adverse events (SAE) (assessed with: vaccine related serious adverse event rate)**158,9,10,11,12,13,14,15,16,17,
18,19,20,21,22,23,24,25,26,27,
28,29,30,31,32,33,34,35,36,
37,38,39,40
observational studies
seriousl
not serious
seriousm
seriousn
none
4/5237 (0.1%) o,p
3/873 (0.3%) q,r
**RR 0.22**
(0.05 to 0.99)
**3 fewer per 1,000**
(from 3 fewer to 0 fewer)
Level 4
Very low
CRITICALD. Myo-/pericarditis (assessed with: myo-/pericarditis event rate)31,2,3,4,5,6,7
randomized trials
not serious
not serious
not serious
very seriouss
none
0/269 (0.0%)
0/245 (0.0%)
not estimable

Level 3
Low
IMPORTANTD. Myo-/pericarditis (assessed with: myo-/pericarditis event rate)1214,15,16,17,18,19,20,21,22,23,24,
25,26,27,28,29,30,31,32,33,
34,35,36,37,38,39
observational studies
seriousl
not serious
seriousm
not serious
none
1/4938 (0.0%) t
5/875 (0.6%) u
**RR 0.040**
(0.004 to 0.310)v
**5 fewer per 1,000**
(from 6 fewer to 4 fewer)
Level 4
Very low
IMPORTANT
Table 5: Summary of Evidence for Outcomes of Interest
Table 5: Summary of Evidence for Outcomes of Interest
Outcome
Importance
Included in profile
CertaintyPrevention of disease
Critical
Yes
ModerateSeverity of disease
Important
Yes
Very lowSerious adverse events
Critical
Yes
LowMyo-/pericarditis
Critical
Yes
LowMinor adverse events
Not important
No
N/A
Explanations
Geometric mean titer is an indirect measure of efficacy.
Frey study used Dryvax in the comparison group. For the immunogenicity outcomes we do not feel there would be a significant difference between the two live vaccines.
In order to calculate a mean difference and 95% CI, geometric mean data were transformed to arithmetic mean. The effect estimate was then transformed to geometric mean difference, which you see here.
Seroconversion rate is an indirect measure of efficacy.
95% CI includes the potential for both meaningful benefit as well as meaningful harm.
Concerns for risk of bias due to attrition. The two groups that contributed data to the intervention and comparison for this outcome lost between 11 and 21% of participants at the time this outcome was assessed.
The ideal measure of disease severity is take maximum lesion area. This study, Parrino et al. 2007, reports the proportion of participants with an attenuated take lesion. Clinical difference between categorical (proportion of participants with attenuated take) vs. continuous measurement (take maximum lesion area) is minimal. We feel this won’t affect indirectness. See Parrino et al. 2007 for a description of lesion attenuation criteria.
Small sample size.
Additionally, for this outcome there are data from single-arm observational studies that provide data for the intervention. These data were not included in the GRADE table because there are no available comparison data in these studies. We naively pooled intervention data from 2 single-arm studies: 42/171 (24.6%) participants who received an MVA [0, 28] primary vaccine series (either MVA-BN or Acambis MVA “ACAM3000”) developed an attenuated take lesion after live vaccinia vaccine challenge (either ACAM2000 or Dryvax). Among the other participants in the two studies, 38/171 (22.2%) developed a full take lesion and 89/171 (52.0%) developed no take lesion. (Pittman et al. 2007, Seaman et al. 2010, Wilck et al. 2010)
The sample size is small and does not meet the optimal size to assess this outcome and suggest fragility of the estimate. Also, the 95% CI includes the potential for meaningful harm.
One vaccine-related SAE was experienced after Dryvax administration in the comparison group. The SAE was characterized by severe elevated liver enzymes 84 days after the first Dryvax vaccine. This was reported in the Parrino et al. 2007 study. This SAE was deemed “possibly related to vaccination.” No other information is available.
There are some concerns with selection bias.
Indirect comparison of naively pooled single-arm studies compared to a historical control.
Fragility suspected based on few events.
Serious adverse events were defined according to the standard FDA definition including: death, life-threatening illness, hospitalization (initial or prolonged), disability or permanent damage, congenital anomaly/birth defect, required intervention to prevent permanent impairment or damage, and other serious medical events. In addition, data was collected about any smallpox vaccine-specific adverse event: postvaccinial encephalitits, eczema vaccinatum, progressive vaccinia, and generalized vaccinia.
Vaccine related serious adverse events in the intervention group: 1) Extra ocular muscle paresis event in one person 8 days after second MVA-BN vaccination; deemed probably related by investigators. 2) Sarcoidosis event in one person during the 6 month follow up period; deemed related because causal relationship with vaccine could not be ruled out. 3) Acute myocardial infarction event in one person 117 days after the first MVA-BN dose. Deemed related to vaccination because no other reasonable etiology was found. 4) Pneumonia and pleurisy event in one person 1 day after second MVA-BN dose. Deemed “possibly but unlikely” to be associated with vaccination.
Vaccine related serious adverse events from historical data for the comparison. 1) One participant developed severe somatization disorder that was deemed definitely related to vaccination with ACAM2000. 2) One participant developed abnormal ECG changes that was deemed possibly related to vaccination. 3) One participant developed increased cardiac enzymes that was deemed probably related to vaccination. Reference: Rosenthal, S., Merchlinsky, M., & Chowdhury, M. (2007). VRBPAC Background Document: ACAM200 (Live vaccinia Virus Smallpox Vaccine). Trial number H-400-009.
Comparison data was drawn from historical data. In a phase III clinical trial for ACAM2000, 3/873 (0.34%) developed vaccine related serious adverse events after ACAM2000 administration.
Number of participants is not large enough to capture myopericarditis events.
“One individual in Group 3 experienced symptoms indicating possible acute pericarditis according to protocol criteria (chest pain worsening when lying down). A thorough cardiac examination, including auscultation, ECG, Troponin I testing and echocardiography did not confirm the diagnosis. The echocardiography did not reveal any signs of pericardial effusion, pericardial rub, ECG changes suggestive of pericarditis, Troponin I increase or decreased exercise capacity. A detailed laboratory examination revealed a positive serology for Coxsackie B virus in temporal relation to the reported chest pain, suggesting a possible acute viral infection as the potential cause of the symptoms.” Overton ET, Lawrence SJ, Wagner E, et al. Immunogenicity and safety of three consecutive production lots of the non replicating smallpox vaccine MVA: A randomized, double blind, placebo controlled phase III trial. *PLoS ONE [Electronic Resource]. 2018;13(4):e0195897.*
No comparison data was available from the systematic review. Comparison is drawn from historical data, a study reporting myopericarditis rate after ACAM2000 administration. Source: ACAM2000 package insert, FDA.
Number of decimal places increased to more accurately present lower limit of confidence interval.References
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