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)

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 orthopoxviruses
Intervention	Vaccination with JYNNEOS®
Comparison	Vaccination with ACAM2000
Outcomes	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 orthopoxviruses
Intervention	Vaccination with JYNNEOS®
Comparison	Vaccination with ACAM2000
Outcomes	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 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 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
NCT01913353 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 Diseases
NCT00082446 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	NIAID
VRC 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	NIAID
Observational data for the intervention
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	67	NA	Safety and immunogenicity	NIAID
NCT01668537 Greenburg4 2014	Phase II, Randomized, Double-blind, Multicenter	USA	Mean 27.7 SD 6.28	651	327	NA	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	45	NA	Safety and immunogenicity	NIAID
NCT00316602 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 Nordic
NCT00914732 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 Nordic
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	183	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	60	NA	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	3003	NA	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	60	NA	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	10	NA	Safety and immunogenicity and surrogate efficacy (Dryvax challenge)	NIAID
NCT01827371 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	NIAID
NCT02038881 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 Nordic
NCT00316589 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 NIAID
NCT00189959 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 Nordic
Vollmar 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 data
NCT01913353 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 data
VRC 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 5^th 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 3^rd 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 3^rd day that becomes vesicular by 5-7^th 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 11^th 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 2^nd and 3^rd week. By the end of the 3^rd 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)
RCT
NCT01913353 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 design
NCT00082446 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 serious
VRC 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.
Obs
NCT00437021 Frey 2 Frey et al. 2013 Troy et al. 2015	Age: Mean 24.7 SD 4.2 Healthy vaccinia naïve adults	67	NA	NA	NA² 0 participants had vaccine related SAEs in the intervention group
NCT01668537 Greenburg4 2014	Age: Mean 27.7 SD 6.28 Healthy vaccinia naïve adults	327	NA	NA	NA² 0 participants had vaccine related SAEs in the intervention group
NCT00879762 Frey3 Troy et al. 2015 Frey et al. 2014	Age: Mean 26.5 SD NR Healthy vaccinia naïve adults	45	NA	NA	NA² 0 participants had vaccine related SAEs in the intervention group
NCT00316602 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	NA² 0 participants had vaccine related SAEs in the intervention group
NCT00316524 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	NA² 0 participants had vaccine related SAEs in the intervention group
NCT01144637 Overton2 Overton et al. 2018	Age: Mean 27.7 SD 6.3 Healthy vaccinia naïve adults	3003	NA	NA	NA² 0 participants had vaccine related SAEs 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	NA² 0 participants had vaccine related SAEs in the intervention group
NCT00133575 Seaman/Wilck Seaman et al. 2010 Wilck et al. 2010	Age: Mean 25.2, SD=3.7 Healthy vaccinia naïve adults	10	NA	NA	NA² 0 participants had vaccine related SAEs in the intervention group
NCT01827371 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	NA² 0 participants had vaccine related SAEs in the intervention group
NCT00316589 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	NA² 0 participants had vaccine related SAEs in the intervention group
Vollmar Vollmar et al. 2005	Age: Mean 32.8 Healthy vaccinia naïve adult males	16	NA	NA	NA² 0 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)
RCT
NCT01913353 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 design
NCT00082446 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 serious
VRC 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 started
Observational data for the intervention
NCT00437021 Frey 2 Frey et al. 2013 Troy et al. 2015	Age: Mean 24.7 SD 4.2 Healthy vaccinia naïve adults	67	NA	NA	NA¹ 0 participants developed myo-/pericarditis in the intervention group
NCT01668537 Greenburg4 2014	Age: Mean 27.7 SD 6.28 Healthy vaccinia naïve adults	327	NA	NA	NA¹ 0 participants developed myo-/pericarditis in the intervention group
NCT00879762 Frey3 Troy et al. 2015 Frey et al. 2014	Age: Mean 26.5 SD NR Healthy vaccinia naïve adults	45	NA	NA	NA¹ 0 participants developed myo-/pericarditis in the intervention group
NCT00316602 Greenburg2 Greenberg 2015	Age: Mean 27.7 SD 6.11 Healthy vaccinia naïve adults and Vaccinia naïve adults with atopic dermatitis	623	NA	NA	NA¹ 0 participants developed myo-/pericarditis in the intervention group
NCT00316524 von Sonnenburg1 Zitzman-Roth et al. 2015	Age: Mean 29.8 SD 9.07 Healthy vaccinia naïve adults	183	NA	NA	NA¹ 0 participants developed myo-/pericarditis 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	NA¹ 0 participants developed myo-/pericarditis in the intervention group
NCT01144637 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	NA¹ 0 participants developed myo-/pericarditis in the intervention group
NCT00133575 Seaman/Wilck Seaman et al. 2010 Wilck et al. 2010	Age: Mean 25.2, SD=3.7 Healthy vaccinia naïve adults	10	NA	NA	NA¹ 0 participants developed myo-/pericarditis in the intervention group
NCT02038881 Overton3 Overton et al. 2020	Age: Mean 35 SD 6.7 HIV positive vaccinia naïve adults	58	NA	NA	NA¹ 0 participants developed myo-/pericarditis in the intervention group
NCT00316589 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	NA¹ 0 participants developed myo-/pericarditis in the intervention group
NCT00189959 Pokorny Von Kremplehuber et al. 2010	Age: Mean 23.3 SD 3.0 Healthy vaccinia naïve adults	54	NA	NA	NA¹ 0 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							№ of patients		Effect		Certainty	Importance
№ 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)	Certainty	Importance
A. Prevention of disease (assessed with: geometric mean titer)
2^1,2,3,4,5,6	randomized trials	not serious	not serious	serious^a,b	not serious	none	213	199	–	MD 1.62 titer units higher (1.32 higher to 1.99 higher)c	Level 2 Moderate	CRITICAL
A. Prevention of disease (assessed with: seroconversion rate)
2^1,2,3,4,5,6	randomized trials	not serious	not serious	serious^b,d	serious^e	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	CRITICAL
B. Severity of disease (assessed with: maximum lesion area)
1⁷	randomized trials	serious^f	not serious	not serious^g	very serious^e,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	IMPORTANT
C. Serious adverse events (SAE) (assessed with: vaccine associated serious adverse event rate)
3^{1,2,3,4,5,6,7}	randomized trials	not serious	not serious	not serious	very serious^j	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	CRITICAL
C. Serious adverse events (SAE) (assessed with: vaccine related serious adverse event rate)
15^{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, 37,38,39,40}	observational studies	serious^l	not serious	serious^m	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	CRITICAL
D. Myo-/pericarditis (assessed with: myo-/pericarditis event rate)
3^{1,2,3,4,5,6,7}	randomized trials	not serious	not serious	not serious	very serious^s	none	0/269 (0.0%)	0/245 (0.0%)	not estimable		Level 3 Low	IMPORTANT
D. Myo-/pericarditis (assessed with: myo-/pericarditis event rate)
12^{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	serious^l	not serious	serious^m	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	Certainty
Prevention of disease	Critical	Yes	Moderate
Severity of disease	Important	Yes	Very low
Serious adverse events	Critical	Yes	Low
Myo-/pericarditis	Critical	Yes	Low
Minor 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

Pittman, P. R., Hahn, M., Lee, H. S., Koca, C., Samy, N., Schmidt, D., Hornung, J., Weidenthaler, H., Heery, C. R., Meyer, T. P. H., Silbernagl, G., Maclennan, J., Chaplin, P.. Phase 3 Efficacy Trial of Modified Vaccinia Ankara as a Vaccine against Smallpox. New England Journal of Medicine; 2019.
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Content source: National Center for Immunization and Respiratory Diseases