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

^{*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

^{*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

^{*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

Table 3a: Summary of Studies Reporting Outcome A – Prevention of Disease

Table 3b: Summary of Studies Reporting Outcome B – Severity of Disease

^{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 5th 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 3rd 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 3rd day that becomes vesicular by 5-7th 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 11th 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 2nd and 3rd week. By the end of the 3rd 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)

^{1. 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.}

^{2. 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.}

^{3. Extra ocular muscle paresis event in one person 8 days after second MVA-BN vaccination; deemed “probably related” by investigators.}

^{4. Sarcoidosis event in one person during the 6 months follow up period; deemed “related” because causal relationship with vaccine could not be ruled out.}

^{5. 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.}

^{6. 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

^{1. 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).}

^{2. “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)}

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Table 5: Summary of Evidence for Outcomes of Interest

Explanations

a. Geometric mean titer is an indirect measure of efficacy.

b. 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.

c. 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.

d. Seroconversion rate is an indirect measure of efficacy.

e. 95% CI includes the potential for both meaningful benefit as well as meaningful harm.

f. 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.

g. 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.

h. Small sample size.

i. 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)

j. 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.

k. 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.

l. There are some concerns with selection bias.

m. Indirect comparison of naively pooled single-arm studies compared to a historical control.

n. Fragility suspected based on few events.

o. 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.

p. 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.

q. 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.

r. 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.

s. Number of participants is not large enough to capture myopericarditis events.

t. “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.

u. 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.

v. Number of decimal places increased to more accurately present lower limit of confidence interval.