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Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Use of JYNNEOS® (orthopoxvirus) vaccine heterologous for those who received ACAM2000 primary series										Related Pages
										Table 1: Policy Question 5 and PICO
Table 1: Policy Question and PICO
Policy question:
**Should persons who are at continued risk for occupational exposure to orthopoxviruses, and who received an ACAM2000 primary vaccination, receive a booster dose of JYNNEOS® as an option to a booster dose of ACAM2000?**Population
Persons who are at risk for occupational exposure to orthopoxvirusesIntervention
Booster with JYNNEOS®Comparison
Booster with ACAM2000Outcomes
Prevention of disease
Severity of disease
Serious adverse events
Myo-/ peri- carditisTable 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 sourceRCTVRC-203
Parrino 2
Parrino et al. 2007
Phase I/Ib randomized, placebo controlled, double-blinded trial
USA
Mean 47.2
SD 8.6
75
22
30
Immunogenicity of TBC-MVA, safety, Dryvax challenge, cell mediated/humoral immune responses
NIAIDObservational data for the interventionNCT00316524
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
200
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
91
NA
Safety and immunogenicity
NIAIDNCT00857493
Greenburg 3
Greenburg et al. 2016
Randomized, Double-Blind, Placebo Controlled Phase II Trial
USA
Mean 35.8
SD NR
120
58
NA
Safety and immunogenicity
NIAID and Bavarian NordicVollmar
Vollmar 2006
Phase 1, randomized, double-blinded and open-label
Germany
Mean 32.8
68
18
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)Observational data for the interventionNCT00316524
von Sonnenburg1
Zitzman-Roth et al. 2015
Mean 29.8
SD 9.07
58
NA
NA
NA
No comparison data from systematic review1NCT00189904
Greenburg1
Greenberg et al. 2013
Mean 37.9
SD NR
193
NA
NA
NA
No comparison data from systematic review1NCT00857493
Greenburg 3
Greenburg et al. 2016
Mean 35.8
SD NR
82
NA
NA
NA
No comparison data from systematic review1
No comparison data. Intervention data: 272/333 (81.68 %) participants from 3 studies seroconverted 14 days after booster with MVA.
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)Observational data for the interventionVRC-203
Parrino 2
Parrino et al. 2007
Mean 47.2
SD 8.6Healthy vaccinia experienced adults
20
28
Dryvax
No comparison data available. Intervention data from the systematic review: 20/20 (100%) of vaccinia experienced participants developed an attenuated take lesion after Dryvax challenge following booster with MVA vaccine.
Serious risk of bias. Attrition rate was variable across study groups. One group lost 17% of participants.
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)RCTVRC-203
Parrino 2
Parrino et al. 2007
Mean 47.2
SD 8.6
Healthy vaccinia experienced adults
22
28
Dryvax
Not estimable.
No participant in either the intervention or comparison group had a vaccine related SAE.
Serious risk of bias. Attrition rate was variable across study groups. One group lost 17% of participants.Observational data for the interventionNCT00316524
von Sonnenburg1
Zitzman-Roth et al. 2015
Mean 29.8
SD 9.07
Healthy vaccinia experienced adults
200
NA
NA
Not estimable, no comparison data available from systematic review1,2NCT00189904
Greenburg1
Greenberg et al. 2013
Mean 37.9
SD NR
Healthy vaccinia experienced adults and **vaccinia experienced adults with HIV**
91
NA
NA
Not estimable, no comparison data available from systematic review1,2NCT00857493
Greenburg 3
Greenburg et al. 2016
Mean 35.8
SD NR
Healthy vaccinia experienced adults
58
NA
NA
Not estimable, no comparison data available from systematic review1,2Vollmar
Vollmar et al. 2005
Mean 32.8
Healthy vaccinia naïve adult males
18
NA
NA
Pooled studies. See observational intervention for effect estimate.
Intervention data was drawn from 4 observational studies included in the systematic review. 0/367 (0.00 %) participants from 4 studies developed vaccine related serious adverse events. Comparison data was drawn from historical data. In a phase III clinical trial for ACAM2000 enrolling participants with previous smallpox vaccination 3/1371 (0.22%) developed vaccine related serious adverse events after ACAM2000 administration. No smallpox vaccine-specific serious adverse event was recorded.
Vaccine related serious adverse events from historical data for the comparison. 1) One participant developed chest pain that was deemed possibly related to vaccination with ACAM2000. 2) One participant developed atrial fibrillation that was deemed possibly related to vaccination. 3) One participant developed chest discomfort that was deemed possibly related to vaccination. Reference: Rosenthal, S., Merchlinsky, M., & Chowdhury, M. (2007). VRBPAC Background Document: ACAM200 (Live vaccinia Virus Smallpox Vaccine). Trial number H-400-012.
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)RCTVRC-203
Parrino 2
Parrino et al. 2007
Mean 47.2
SD 8.6
Healthy vaccinia experienced adults
22
28
Dryvax
Not estimable.
No participant in either the intervention or comparison group developed myo-/pericarditis
Serious risk of bias. Attrition rate was variable across study groups. One group lost 17% of participants.Observational interventionNCT00316524
von Sonnenburg1
Zitzman-Roth et al. 2015
Mean 29.8
SD 9.07
Healthy vaccinia experienced adults
200
NA
NA
Not estimable, no comparison data available from systematic review1,2NCT00189904
Greenburg1
Greenberg et al. 2013
Mean 37.9
SD NR
Healthy vaccinia experienced adults and **vaccinia experienced adults with HIV**
91
NA
NA
Not estimable, no comparison data available from systematic review1,2NCT00857493
Greenburg 3
Greenburg et al. 2016
Mean 35.8
SD NR
Healthy vaccinia experienced adults
58
NA
NA
Not estimable, no comparison data available from systematic review1,2
Intervention data was drawn from 3 observational studies included in the systematic review. 0/349 (0.00 %) participants developed myo-/pericarditis. Comparison data was drawn from historical data. In a phase III clinical trial for ACAM2000 enrolling participants with previous smallpox vaccination, 0/1371 (0.00%) developed myo-/pericarditis after ACAM2000 administration.
Reference for historical data: Rosenthal, S., Merchlinsky, M., & Chowdhury, M. (2007). VRBPAC Background Document: ACAM200 (Live vaccinia Virus Smallpox Vaccine). Trial number H-400-012.
Policy Question 2: Should JYNNEOS® be recommended for healthcare personnel who administer ACAM2000 or care for patients after vaccination with replication-competent orthopoxviruses?
Certainty assessment
No of patients
Effect
Certainty
ImportanceNo of studies
Study design
Risk of bias
Inconsistency
Indirectness
Imprecision
Other considerations
a booster dose of JYNNEOS®
a booster dose of ACAM2000
Relative
(95% CI)
Absolute
(95% CI)A. Prevention of disease (assessed with: seroconversion rate)31,2,3,4,5,6,7
observational studies
seriousa
not serious
seriousb
seriousc
none
No comparison data available. Intervention data from the systematic review: 272/333 (81.68 %) participants from 3 studies seroconverted 14 days after booster with MVA.
Level 4
VERY LOW
CRITICALB. Severity of disease (assessed with: take maximum lesion area)18
observational studies
seriousa,d
not serious
not serious
very seriouse
none
No comparison data available. Intervention data from the systematic review: 20/20 (100%) of vaccinia experienced participants developed an attenuated take lesion after Dryvax challenge following booster with MVA vaccine.
Level 4
VERY LOW
IMPORTANTC. Serious adverse events (assessed with: vaccine related serious adverse event rate)18
randomized trials
seriousf
not serious
not serious
very seriousg
none
0/22 (0.0%)
0/28 (0.0%)
not estimable

Level 4
VERY LOW
CRITICALC. Serious adverse events (assessed with: vaccine related serious adverse event rate)41,2,3,4,5,6,7,9
observational studiesh
not serious
not serious
seriousi
very seriousg
none
0/367 (0.0%)j
3/1371 (0.2%)k
RR 0.53
(0.03 to 10.32)
1 fewer per 1,000
(from 2 fewer to 22 more)
Level 4
VERY LOW
CRITICALD. Myo-/pericarditis (assessed with: myo-/pericarditis event rate)18
randomized trials
very seriousl
not serious
not serious
very seriousm
none
0/22 (0.0%)
0/28 (0.0%)
not estimable

Level 4
VERY LOW
IMPORTANTD. Myo-/pericarditis (assessed with: myo-/pericarditis event rate)31,2,3,4,5,6,7
observational studies
not serious
not serious
seriousi
very seriousm
none
0/349 (0.0%)n
0/1371 (0.0%)o
not estimable

Level 4
VERY LOW
IMPORTANT
**RR:** risk ratio;**CI:** confidence interval
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
Very lowSeverity of disease
Important
Yes
Very lowSerious adverse events
Critical
Yes
LowMyo-/pericarditis
Critical
Yes
Very lowMinor adverse events
Not important
No
N/A
Explanations
Risk of bias due to lack of comparison data.
Seroconversion rate is an indirect measure of prevention.
Small sample size, no comparison.
Attrition rate was variable across study groups. One group lost 17% of participants.
Small sample size, fragility of estimate.
In the protocol it is unclear how serious adverse events were assessed.
Sample size is small, too small to detect rare adverse events.
Observational data was included in the evidence profile for this outcome because the effect estimate for the randomized trials was not estimable.
Single-arm studies contribute data to the intervention, but no available data for the comparison from the systematic review. Downgraded for indirectness because historical data was used for comparison.
Intervention data was drawn from 3 observational studies included in the systematic review. 0/349 (0.00 %) participants from 3 studies developed vaccine related serious adverse events.
Comparison data was drawn from historical data. In a phase III clinical trial for ACAM2000 enrolling participants with previous smallpox vaccination 3/1371 (0.22%) developed vaccine related serious adverse events after ACAM2000 administration. No smallpox vaccine-specific serious adverse event was recorded.
Assessment of myo-/pericarditis was initiated late in the study at the request of FDA. Very few subjects could be evaluated at that point. It was unclear how many subjects were evaluated.
Sample size is small, too small to detect rare events of myopericarditis after JYNNEOS®.
Intervention data was drawn from 3 observational studies included in the systematic review. 0/349 (0.00 %) participants developed myo-/pericarditis.
Comparison data was drawn from historical data. In a phase III clinical trial for ACAM2000 enrolling participants with previous smallpox vaccination, 0/1371 (0.00%) developed myo-/pericarditis after ACAM2000 administration.References
Greenberg, R. N., Hay, C. M., Stapleton, J. T., Marbury, T. C., Wagner, E., Kreitmeir, E., Roesch, S., von Krempelhuber, A., Young, P., Nichols, R., Meyer, T. P., Schmidt, D., Weigl, J., Virgin, G., Arndtz-Wiedemann, N., Chaplin, P.. A Randomized, Double-Blind, Placebo-Controlled Phase II Trial Investigating the Safety and Immunogenicity of Modified Vaccinia Ankara Smallpox Vaccine (MVA-BN R) in 56-80-Year-Old Subjects. PLoS ONE [Electronic Resource]; 2016.
A Study to Evaluate Safety and Immunogenicity of One and Two Doses of IMVAMUNE® Smallpox Vaccine in 56-80 Year Old Vaccinia-experienced Subjects. https://clinicaltrials.gov/show/NCT00857493; 2009.
Zitzmann-Roth, E. M., von Sonnenburg, F., de la Motte, S., Arndtz-Wiedemann, N., von Krempelhuber, A., Uebler, N., Vollmar, J., Virgin, G., Chaplin, P.. Cardiac safety of Modified Vaccinia Ankara for vaccination against smallpox in a young, healthy study population. PLoS ONE [Electronic Resource]; 2015.
A Randomized, Double-blind, Placebo-controlled Study on Immunogenicity and Safety of MVA-BN (IMVAMUNETM) Smallpox Vaccine in Healthy Subjects. https://clinicaltrials.gov/show/NCT00316524; 2006.
A partially randomized, partially double-blind, placebo-controlled Phase II non-inferiority study to evaluate immunogenicity and safety of one and two doses of MVA-BN (IMVAMUNETM) smallpox vaccine in 18-55 year old healthy subjects. http://www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2005-001781-14-DE; 2006.
Bavarian Nordic, , National Institute of Allergy and Infectious Diseases, . Safety, Tolerability and Immune Response of IMVAMUNE (MVA-BN)Smallpox Vaccine in HIV Infected Patients. 2005.
Greenberg, R. N., Overton, E. T., Haas, D. W., Frank, I., Goldman, M., von Krempelhuber, A., Virgin, G., Bädeker, N., Vollmar, J., Chaplin, P.. Safety, immunogenicity, and surrogate markers of clinical efficacy for modified vaccinia Ankara as a smallpox vaccine in HIV-infected subjects. J Infect Dis; Mar 1 2013.
Parrino, J., McCurdy, L. H., Larkin, B. D., Gordon, I. J., Rucker, S. E., Enama, M. E., Koup, R. A., Roederer, M., Bailer, R. T., Moodie, Z., Gu, L., Yan, L., Graham, B. S.. Safety, immunogenicity and efficacy of modified vaccinia Ankara (MVA) against Dryvax<sup></sup> challenge in vaccinia-naive and vaccinia-immune individuals. Vaccine; 2007.
Vollmar J, Arndtz N, Eckl KM, et al. Safety and immunogenicity of IMVAMUNE, a promising candidate as a third generation smallpox vaccine. Vaccine. 2006;24(12):2065-70.Top of Page
							
					
						Page last reviewed:  May 26, 2022					Content source: 	National Center for Immunization and Respiratory Diseases homeACIP Home
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