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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
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
- 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 (IMVAMUNE™) 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 (IMVAMUNE™) 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 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.