Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Use of JYNNEOS® (orthopoxvirus) vaccine heterologous for those who received ACAM2000 primary series

About

CDC vaccine recommendations are developed using an explicit evidence-based method based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

Table 1: Policy Question 5 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 orthopoxviruses
Intervention
Booster with JYNNEOS®
Comparison
Booster with ACAM2000
Outcomes
a. Prevention of disease
b. Severity of disease
c. Serious adverse events
d. Myo-/ peri- carditis

Table 2: Outcomes and Rankings

Outcome Importance* Included in evidence profile
Prevention of disease Critical Yes
Severity of disease Important Yes
Serious adverse events** Critical Yes
Myo-/ peri- carditis Critical Yes
Minor 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 encephalitis, eczema vaccinatum, progressive vaccinia, and generalized vaccinia.

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 source
RCT
VRC-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 NIAID
Observational data for the intervention
NCT00316524
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 Nordic
NCT00189904
Greenburg1
Greenberg et al. 2013
Phase I/II, non-randomized, open-label USA Mean 37.9
SD NR
151 91 NA Safety and immunogenicity NIAID
NCT00857493
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 Nordic
Vollmar
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

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 intervention
NCT00316524
von Sonnenburg1
Zitzman-Roth et al. 2015
Mean 29.8
SD 9.07
58 NA NA NA
No comparison data from systematic review1
NCT00189904
Greenburg1
Greenberg et al. 2013
Mean 37.9
SD NR
193 NA NA NA
No comparison data from systematic review1
NCT00857493
Greenburg 3
Greenburg et al. 2016
Mean 35.8
SD NR
82 NA NA NA
No comparison data from systematic review1

1. 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

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 intervention
VRC-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)

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
VRC-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 intervention
NCT00316524
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 review1,2
NCT00189904
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 review1,2
NCT00857493
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
Vollmar
Vollmar et al. 2005
Mean 32.8
Healthy vaccinia naïve adult males
18 NA NA Pooled studies. See observational intervention for effect estimate.

1. 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.

2. 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

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
VRC-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 intervention
NCT00316524
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 review1,2
NCT00189904
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 review1,2
NCT00857493
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

1. 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.

2. 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.

References in this table:123456789

Certainty assessment № of patients Effect Certainty Importance
№ 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
CRITICAL
B. 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
IMPORTANT
C. 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
CRITICAL
C. 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
CRITICAL
D. 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
IMPORTANT
D. 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

Outcome Importance Included in profile Certainty
Prevention of disease Critical Yes Very low
Severity of disease Important Yes Very low
Serious adverse events Critical Yes Low
Myo-/pericarditis Critical Yes Very low
Minor adverse events Not important No N/A

Explanations

a. Risk of bias due to lack of comparison data.

b. Seroconversion rate is an indirect measure of prevention.

c. Small sample size, no comparison.

d. Attrition rate was variable across study groups. One group lost 17% of participants.

e. Small sample size, fragility of estimate.

f. In the protocol it is unclear how serious adverse events were assessed.

g. Sample size is small, too small to detect rare adverse events.

h. Observational data was included in the evidence profile for this outcome because the effect estimate for the randomized trials was not estimable.

i. 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.

j. 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.

k. 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.

l. 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.

m. Sample size is small, too small to detect rare events of myopericarditis after JYNNEOS®.

n. Intervention data was drawn from 3 observational studies included in the systematic review. 0/349 (0.00 %) participants developed myo-/pericarditis.

o. 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.

View the complete list of GRADE evidence tables‎

  1. 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.
  2. 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.
  3. 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.
  4. A Randomized, Double-blind, Placebo-controlled Study on Immunogenicity and Safety of MVA-BN (IMVAMUNE™) Smallpox Vaccine in Healthy Subjects. https://clinicaltrials.gov/show/NCT00316524; 2006.
  5. 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 (IMVAMUNE™) smallpox vaccine in 18-55 year old healthy subjects. http://www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2005-001781-14-DE; 2006.
  6. 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.
  7. 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.
  8. 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 challenge in vaccinia-naive and vaccinia-immune individuals. Vaccine; 2007.
  9. 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.