Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Use of JYNNEOS® (orthopoxvirus) vaccine booster (Policy Questions 3 and 4)

Table 1.1: Policy Question 3 and PICO

Table 1: Policy Question and PICO
Policy question:	Should persons who are at continued risk for occupational exposure to more virulent orthopoxviruses such as variola virus or monkeypox virus receive a booster dose of JYNNEOS® every two years after the primary JYNNEOS® series?
Population	Persons who are at risk for occupational exposure to variola virus or monkeypox virus
Intervention	Booster with JYNNEOS® 2 years after primary series
Comparison	No vaccine booster after JYNNEOS® primary series
Outcomes	Prevention of disease Severity of disease Serious adverse events Myo-/ peri- carditis

Table 1.2: Policy Question 4 and PICO

Table 1: Policy Question and PICO
Policy question:	Should persons who are at continued risk for occupational exposure to replication-competent orthopoxviruses like vaccinia virus or cowpox virus receive a booster dose of JYNNEOS® at least every 10 years after the primary JYNNEOS® series?
Population	Persons who are at risk for occupational exposure to replication competent orthopoxviruses like vaccinia virus or cowpox virus
Intervention	Booster with JYNNEOS® at least every 10 years
Comparison	No vaccine booster after JYNNEOS® primary series
Outcomes	Prevention of disease Severity of disease Serious adverse events Myo-/ peri- carditis

Table 2: Outcomes and Rankings

Table 2: Outcomes and Rankings
Outcome	Importance^*	Included in evidence profile
Prevention of disease	Critical	Yes
Severity of disease	Critical	Yes
Serious adverse events**	Critical	Yes
Myo-/ peri- carditis	Important	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 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 source
RCT data
NCT02038881 Overton3 Overton et al. 2020	Phase II, Randomized, Open-label	USA	Mean 35 SD 6.7	87	31	27	Safety and immunogenicity in HIV+ patients	Bavarian Nordic
Observational data for the intervention
NCT00686582 Von Sonnenburg 3	Phase II, non-randomized, open-label	Germany	Mean 34.6 SD 10.2	304	92	NA	Safety and immunogenicity	Bavarian Nordic
Observational data for the comparison
VRC 201 Parrino1 Parrino 2007	Phase I/Ib randomized, placebo controlled, double-blinded trial	USA	Mean and SD NR, adults	77	NA	19	Immunogenicity, safety, Dryvax challenge, cell mediated/humoral immune responses	NIAID
NCT00437021 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	NA	67	Safety and immunogenicity	NIAID
NCT01668537 Greenburg4 2014	Phase II, Randomized, Double-blind, Multicenter	USA	Mean 27.7 SD 6.28	651	NA	327	Safety and immunogenicity	Bavarian Nordic
NCT00879762 Frey3 Troy et al. 2015 Frey et al. 2014	Phase II, randomized, double blinded	USA	Mean 26.5 SD NR	91	NA	45	Safety and immunogenicity	NIAID
NCT00316602 Greenburg2 Greenberg 2015	Phase II, non-randomized, open-label	USA and Mexico	Mean 27.7 SD 6.11	632	NA	632	Safety and immunogenicity in people with atopic dermatitis	NIAID and Bavarian Nordic
NCT00914732 Frey4 Troy et al. 2015 Frey et al. 2015	Phase II, randomized, triple blinded	USA	Mean 27.2 SD 4.6	523	NA	167	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	NA	60	Safety and immunogenicity in HIV positive patients	NIAID
NCT01144637 Overton2 Overton et al. 2018	Randomized, Double-Blind, Placebo-Controlled Phase III Trial	USA	Mean 27.7 SD 6.3	4005	NA	4005	immunogenicity, safety, and tolerability	Bavarian Nordic and BARDA
NCT00189917 von Sonnenburg2 Darsow et al. 2016 Von Sonnenburg et al. 2014	Open-label, Controlled Phase I Pilot Study	Germany	Mean NR SD NR	60	NA	60	Safety and immunogenicity	NIAID and Bavarian Nordic
NCT00133575 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	NA	10	Safety and immunogenicity and surrogate efficacy (Dryvax challenge)	NIAID
NCT01913353 Pittman Pittman 2019	Phase 3, open-label, randomized clinical trial	U.S. military, stationed in Korea	Mean 23.5 SD 4.67	433	NA	220	Immunogenicity, Surrogate efficacy (ACAM2000 challenge), Adverse events	Bavarian Nordic, US Army Medical Research Institute of Infectious Diseases
NCT01827371 Frey5 Anderson et al. 2020 Jackson et al. 2017	Phase II, Randomized, Open-Label	USA	Mean 27.4 SD 5.3	435	NA	115	Safety and immunogenicity	NIAID
NCT00082446 Frey1 Frey 2007 Sano 2009	Phase I, randomized, partially blinded, placebo controlled clinical trial	USA	Mean 24.8 SD 3.8	90	NA	30	Immunogenicity, Cell-mediated immunity, Surrogate efficacy (Dryvax challenge), Adverse events	NIAID
NCT00316589 Overton1 Overton et al. 2015	Phase II, Multicenter, Open-label, Controlled	USA	Mean 37.5 SD 8.0	579	NA	439	Safety and immunogenicity	HHS and NIAID
NCT00189959 Pokorny Von Kremplehuber et al. 2010	Phase II, Double-blind, randomized, Dose-finding Study	Switzerland	Mean 23.3 SD 3.0	165	NA	55	Safety and immunogenicity	NIAID and Bavarian Nordic
Vollmar Vollmar et al. 2005	Phase 1, randomized, double-blinded and open-label	Germany	Mean 32.8	68	NA	16	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 data
NCT00316589 Overton3 Overton et al. 2015	Age: Mean 35 SD 6.7 HIV positive vaccinia naïve adults	31	27	No vaccine booster after MVA-BN primary series	Geometric mean titer: Mean 3.56 titer units more (1.84 more to 6.89 more) Seroconversion rate: RR = 1.00 (0.94 to 1.06); 0 fewer per 1,000 (from 60 fewer to 60 more)	Serious risk of bias due to high attrition rate in the per protocol population
Observational data for the intervention
NCT00686582 Von Sonnenburg 3	Mean 34.6 SD 10.2 Healthy vaccinia naïve adults	75	NA	NA	From pooled all observational studies (comparison and intervention): Among intervention: 74/75 (99%) seroconverted Among Comparison: 3326/3539 (94%) seroconverted Seroconversion rate: RR 1.05 (1.02 to 1.08); 47 more per 1,000 (from 19 more to 75 more)
Observational for the comparison
NCT00437021 Frey 2 Frey et al. 2013 Troy et al. 2015	Mean 24.7 SD 4.2 Healthy vaccinia naïve adults	NA	63	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate.
NCT01668537 Greenburg4 2014	Mean 27.7 SD 6.28 Healthy vaccinia naïve adults	NA	297	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate.
NCT00316602 Greenburg2 Greenberg 2015	Mean 26.5 SD NR Healthy vaccinia naïve adults and vaccinia naïve adults with atopic dermatitis	NA	451	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate.
NCT00914732 Frey4 Troy et al. 2015 Frey et al. 2015	Mean 27.7 SD 6.11 Healthy vaccinia naïve adults	NA	148	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate.
NCT00189904 Greenburg1 Greenberg et al. 2013	Mean 37.9 SD NR Healthy vaccinia naïve adults and HIV + vaccinia naïve adults	NA	60	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate.
NCT01144637 Overton2 Overton et al. 2018	Mean 27.7 SD 6.3 Healthy vaccinia naïve adults	NA	1906	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate.
NCT00189917 von Sonnenburg2 Darsow et al. 2016 Von Sonnenburg et al. 2014	Mean NR SD NR Healthy vaccinia naïve adults and vaccinia naïve adults with a history of atopic dermatitis, active atopic dermatitis or allergic rhinitis	NA	56	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate.
NCT01913353 Pittman Pittman 2019	Mean 23.5 SD 4.67 Healthy vaccinia naïve adults	NA	185	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate.
NCT00082446 Frey1 Frey 2007 Sano 2009	Mean 24.8 SD 3.8 Healthy vaccinia naïve adults	NA	15	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate.
NCT00316589 Overton1 Overton et al. 2015	Mean 37.5 SD 8.0 Healthy vaccinia naïve adults and HIV + vaccinia naïve adults	NA	298	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate.
NCT00189959 Pokorny Von Kremplehuber et al. 2010	Mean 23.3 SD 3.0 Healthy vaccinia naïve adults	NA	52	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate.
Vollmar Vollmar et al. 2005	Mean 32.8 Healthy vaccinia naïve adult males	NA	16	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate.

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)
No data available for this outcome.

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)
RCT
NCT00316589 Overton3 Overton et al. 2015	Age: Mean 35 SD 6.7 HIV positive vaccinia naïve adults	31	27	No vaccine booster after MVA-BN primary series	Not estimable No serious adverse events were recorded among the intervention or comparison groups	Serious risk of bias due to high attrition rate in the per protocol population
Observational intervention
NCT00686582 Von Sonnenburg 3	Mean 34.6 SD 10.2 Healthy vaccinia naïve adults	75¹	NA	NA	Not estimable Among intervention: 0/75 (0%) had vaccine-related SAEs Among comparison: 3/5265 (0.1%) had vaccine related SAEs
Observational comparison
Parrino 1	Mean and SD NR Healthy vaccinia naïve adults	NA	19	No vaccine booster after TBC-MVA primary series	Pooled studies. See observational intervention for effect estimate.
Frey 2	Mean 24.7 SD 4.2 Healthy vaccinia naïve adults	NA	67	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate.
Greenburg 4	Mean 27.7 SD 6.28 Healthy vaccinia naïve adults	NA	327	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate.
Frey 3	Mean 26.5 SD NR Healthy vaccinia naïve adults	NA	45	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate.
Greenburg 2	Mean 26.5 SD NR Healthy vaccinia naïve adults and vaccinia naïve adults with atopic dermatitis	NA	632	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate. 1 SAE² was recorded for a participant, a healthy vaccinia naïve adult, in this comparison group
Frey 4	Mean 27.7 SD 6.11 Healthy vaccinia naïve adults	NA	167	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate.
Greenburg 1	Mean 37.9 SD NR Healthy vaccinia naïve adults and HIV + vaccinia naïve adults	NA	60	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate.
Overton 2	Mean 27.7 SD 6.3 Healthy vaccinia naïve adults	NA	3003	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate.
Von Sonnenburg 2	Mean NR SD NR Healthy vaccinia naïve adults and vaccinia naïve adults with a history of atopic dermatitis, active atopic dermatitis or allergic rhinitis	NA	60	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate.
Seaman/Wilck	Mean 25.2, SD=3.7 Healthy vaccinia naïve adults	NA	10	No vaccine booster after Acambis MVA primary series	Pooled studies. See observational intervention for effect estimate.
Pittman	Mean 23.5 SD 4.67 Healthy vaccinia naïve US military soldiers	NA	220	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate.
Frey 5	Mean 27.4 SD 5.3 Healthy vaccinia naïve adults	NA	116³	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate. 1 SAE³ was recorded for a participant in this comparison group
Frey 1	Mean 24.8 SD 3.8 Healthy vaccinia naïve adults	NA	30	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate.
Overton 1	Mean 37.5 SD 8.0 Healthy vaccinia naïve adults and HIV + vaccinia naïve adults	NA	439	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate. 1 SAE⁴ was recorded for a participant, an HIV positive vaccinia naïve adult, in this comparison group
Pokorny	Mean 23.3 SD 3.0 Healthy vaccinia naïve adults	NA	54⁵	No vaccine booster after MVA-BN primary series	Pooled studies. See observational intervention for effect estimate.
Vollmar Vollmar et al. 2005	Mean 32.8 Healthy vaccinia naïve adult males	NA	16	MVA-BN	Pooled studies. See observational intervention for effect estimate.

N=75 is the reported number at risk for those at risk for serious adverse events. Reasons for attrition not reported
Extra ocular muscle paresis event in one person 8 days after second MVA-BN vaccination; deemed probably related by investigators.
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.
One person missing all symptom data.

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)
RCT
NCT00316589 Overton3 Overton et al. 2015	Age: Mean 35 SD 6.7 HIV positive vaccinia naïve adults	31	27	No vaccine booster after MVA-BN primary series	Not estimable No myopericarditis events were recorded among the intervention or comparison groups	Serious risk of bias due to high attrition rate in the per protocol population

Table 4: GRADE Summary of Findings

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							№ of patients		Effect		Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	JYNNEOS® OPXV vaccine primary series followed by a JYNNEOS® booster every 2 years	JYNNEOS® OPXV vaccine primary series	Relative (95% CI)	Absolute (95% CI)	Certainty	Importance
A. Prevention of disease (assessed with: Geometric mean titer)
1^1,2	randomized trials	serious^a	not serious	very serious^b,c	not serious^d	none	26	20	–	mean 3.56 titer units more (1.84 more to 6.89 more)	Level 4 VERY LOW	CRITICAL
A. Prevention of disease (assessed with: seroconversion rate)
1^1,2	randomized trials	serious^a	not serious	very serious^b,c	serious^d,e	none	26/26 (100.0%)	20/20 (100.0%)	RR 1.00 (0.94 to 1.06)	0 fewer per 1,000 (from 60 fewer to 60 more)	Level 4 VERY LOW	CRITICAL
A. Prevention (assessed with: seroconversion rate)
12^{3,4,5,6,7,8,9,10,11,12,13,14,15,16, 17,18,19,20,21,22,23,24,25,26,27,28,29,30, 31,32,33, 39}	observational studies	very serious^f	serious^g	PQ3: serious^h PQ4: very serious^h	seriousⁱ	none	74/75 (98.7%)	3326/3539 (94.0%)	RR 1.05 (1.02 to 1.08)	47 more per 1,000 (from 19 more to 75 more)	Level 4 VERY LOW	CRITICAL
C. Serious adverse events (assessed with: vaccine related SAE rate)
1^1,2	randomized trials	not serious	not serious	serious^c	very serious^j	none	0/31 (0.0%)	0/27 (0.0%)	not estimable		Level 4 VERY LOW	CRITICAL
C. Serious adverse events (assessed with: vaccine related SAE rate)
17^{3,4,5,6,7,8,9,10,11,12,13,14,15,16, 17,18,19,20,21,22,23,24,25,26,27,28,29,30, 31,32,33,34,35,36,37,38,39}	observational studies	very serious^f	serious^g	serious^h	serious^k	none	0/75 (0.0%)	3/5265 (0.1%)	not estimable		Level 4 VERY LOW	CRITICAL
D. Myo-/pericarditis (assessed with: myo-/pericarditis event rate)
1^1,2	randomized trials	serious^l	not serious	serious^c	very serious^j	none	0/31 (0.0%)	0/27 (0.0%)	not estimable		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	Certainty
Prevention of disease	Critical	Yes	Very low
Severity of disease	Important	Yes	NA (No data available)
Serious adverse events	Critical	Yes	Very low
Myo-/pericarditis	Critical	Yes	Very low
Minor adverse events	Not important	No	N/A

Explanations

High attrition rate in per protocol population.
Immunogenicity as assessed with GMT is an indirect measure of efficacy.
Available intervention data gives a booster at day 84. Indirect evidence for 2 year booster.
There is one study with a small sample size.
95% CI suggests there may be the potential for benefit or harm.
Many studies have serious concerns for risk of bias. Observational data has a higher risk for bias there were some concerns in a few studies for attrition and timing of outcome ascertainment.
Only one study contributes data to the intervention. Others contribute data to the comparison. Can’t assess inconsistency for intervention.
PQ3: Downgrade for indirectness because the comparisons are between studies. PQ4: h. Downgrade for indirectness because the comparisons are between studies. Further downgrade for indirectness because 2-year booster data is indirect data for 10-year booster data.
Though the confidence interval is small, the number of participants in the intervention group is small and therefore may not provide a precise estimate.
Study population is very small and would be poor at estimating the rate of rare outcomes.
Few people in the intervention group. Wide confidence interval.
High attrition rate and unclear information about randomization procedure.

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Content source: National Center for Immunization and Respiratory Diseases