National Center for Emerging and Zoonotic Infectious Diseases

Summary of Evidence to Recommendations 

Frameworks for Use of JYNNEOS®

Advisory Committee on Immunization Practices

November 3, 2021

Agam Rao, MD 

CAPT, US Public Health Service

Poxvirus and Rabies Branch

Centers for Disease Control and Prevention
Reminder: 5 PICO questions

▪ 1 and 2: Primary vaccination with JYNNEOS® in at-risk populations

▪ 3 and 4: Booster after primary JYNNEOS® series in person with 

continued* occupational risk

▪ 5: Change from booster with ACAM2000 to booster with JYNNEOS® for 

those who received ACAM2000 primary series

* Continued risk refers to persistent risk due to occupational work performed. Designated public health and 

healthcare worker response teams approved by public health authorities are not at “continued risk” because 

they are vaccinated for the purposes of preparedness
Evidence to Recommendations (EtR) 

Frameworks 1 and 2: Primary vaccination 

with JYNNEOS®
Problem: Primary vaccination

▪ Orthopoxvirus infections cause morbidity and mortality 

▪ Several populations are at occupational risk 

– Research laboratory personnel

– Clinical laboratory personnel performing diagnostic testing for orthopoxviruses

– Designated response team members

– Select healthcare personnel who administer ACAM2000 or care for patients 

infected with replication competent orthopoxviruses

▪ ACAM2000 is currently recommended by the ACIP 

– Benefits to having more than one effective vaccine

– Provides options
PICO #1

Policy question: Should JYNNEOS® be recommended for research laboratory 

personnel*, clinical laboratory personnel performing diagnostic testing for 

orthopoxviruses†, and designated response team members§

at risk for occupational exposure to orthopoxviruses?

Population Clinical laboratory personnel performing diagnostic testing for orthopoxviruses and 

designated response teams

Intervention Vaccination with JYNNEOS®

Comparison Vaccination with ACAM2000

Outcome

a) Prevention of disease

b) Severity of disease

c) Serious adverse events

d) Myo-/ peri- carditis 

*Research laboratory personnel are those who directly handle 1) cultures or 2) animals contaminated or infected with replication-competent vaccinia virus, recombinant 

vaccinia viruses derived from replication-competent vaccinia strains (i.e., those that are capable of causing clinical infection and producing infectious virus in humans), or 

other orthopoxviruses that infect humans (e.g., monkeypox, cowpox, and variola). 

†Clinical laboratory personnel who perform routine chemistry, hematology, and urinalysis testing, including for suspect or confirmed patients with Orthopoxvirus

infections, are not included in this recommendation as their risk for exposure is very low

§Public health authorities, at their own discretion, may approve a cohort of healthcare and/or public health personnel to receive primary vaccination against 

Orthopoxviruses for preparedness purposes (e.g., first responders who might participate in a smallpox or monkeypox outbreak)
PICO #1

Policy question: Should JYNNEOS® be recommended for research laboratory 

personnel*, clinical laboratory personnel performing diagnostic testing for 

orthopoxviruses†, and for designated response team members§

at risk for occupational exposure to orthopoxviruses?

Population Clinical laboratory personnel performing diagnostic testing for orthopoxviruses and 

designated response teams

Intervention Vaccination with JYNNEOS®

Comparison Vaccination with ACAM2000

Outcome

a) Prevention of disease

b) Severity of disease

c) Serious adverse events

d) Myo-/ peri- carditis 

*Research laboratory personnel are those who directly handle 1) cultures or 2) animals contaminated or infected with replication-competent vaccinia virus, recombinant 

vaccinia viruses derived from replication-competent vaccinia strains (i.e., those that are capable of causing clinical infection and producing infectious virus in humans), or 

other orthopoxviruses that infect humans (e.g., monkeypox, cowpox, and variola). 

†Clinical laboratory personnel who perform routine chemistry, hematology, and urinalysis testing, including for suspect or confirmed patients with Orthopoxvirus

infections, are not included in this recommendation as their risk for exposure is very low

§Public health authorities, at their own discretion, may approve a cohort of healthcare and/or public health personnel to receive primary vaccination against 

Orthopoxviruses for preparedness purposes (e.g., first responders who might participate in a smallpox or monkeypox outbreak)

Assesses efficacy

Assesses safety

Assesses safety
Domain: Benefits and harms

▪ How substantial are the desirable anticipated effects

▪ How substantial are the undesirable anticipated effects

▪ Do the desirable effects outweigh the undesirable effects?

▪ What is the overall certainty of the evidence for the outcomes?
Benefits

How substantial are the desirable anticipated effects?

Minimal Small Moderate Large Don’t know Varies 

▪ JYNNEOS® is not a replicating virus so there is no potential spread to others

▪ FDA found JYNNEOS® to be non-inferior to ACAM2000 for immunogenicity

▪ Evidence table for outcome A, prevention of disease, suggests there may be 

a small benefit of JYNNEOS® compared to replicating orthopoxvirus vaccines
Outcome A: Prevention of disease

Certainty assessment No of patients Effect

No of Certainty Importance

studies

Study 

design Risk of bias Inconsistency

Indirectnes

s

Imprecisio

n

Other 

considerati

ons

JYNNEOS 

OPXV 

vaccine 

primary 

series

ACAM2000 

OPXV 

vaccine 

primary 

series

Relative

(95% CI)

Absolute

(95% CI)

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 

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. 
Harms

▪ JYNNEOS® is a non-replicating virus; serious adverse events reported from 

ACAM2000 have been attributed to uncontrolled replication

▪ There are fewer contraindications to JYNNEOS ® compared to ACAM2000

▪ Evidence tables

– Randomized controlled trials (RCTs) and pooled observational data indicate 

fewer adverse events with JYNNEOS

– Too few subjects enrolled in the RCTs to adequately assess 

– Pooled observational data was reassuring and included many more subjects
Summary of outcome C: Serious Adverse Events

Certainty assessment No of patients Effect

No of Certainty Importance

studies

Study 

design Risk of bias Inconsistency

Indirectness Imprecision

Other 

considerati

ons

JYNNEOS® 

OPXV 

vaccine 

primary 

series

ACAM2000 

OPXV 

vaccine 

primary 

series

Relative

(95% CI)

Absolute

(95% CI)

C. Serious adverse events (SAE) (assessed with: vaccine associated SAE 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 SAE rate)

15 

8,9,10,11,12,13,1

4,15,16,17,18,19,

20,21,22,23,24,25

,26,27,28,29,30,3

1,32,33,34,35,36,

37,38,39, 40

observation

al studies 

serious l not serious serious m serious n 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 
Outcome D: Myo-/pericarditis

Certainty assessment No of patients Effect

Certainty Importanc

No eof 

studies

Study 

design Risk of bias Inconsistency

Indirectnes

s

Imprecisio

n

Other 

considerati

ons

JYNNEOS 

OPXV 

vaccine 

primary 

series

ACAM2000 

OPXV 

vaccine 

primary 

series

Relative

(95% CI)

Absolute

(95% CI)

D. Myo-/pericarditis (assessed with: CDC definition of myocarditis 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 

CRITICAL 

D. Myo-/pericarditis (assessed with: myo-/pericarditis event rate)

12 

14,15,16,17,18,1

9,20,21,22,23,24,

25,26,27,28,29,3

0,31,32,33,34,35,

36,37,38,39

observation

al 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 

CRITICAL 

See extra slides for footnotes
Benefit/Harm ratio

Do the desirable effects outweigh the undesirable effects?

Favors intervention Favors comparison Favors both Favors neither Unclear

▪ Benefits small but harms are minimal

▪ The desirable effects therefore outweigh the undesirable effects

▪ The intervention is favored
Benefits and Harms

What is the overall certainty of this evidence for the critical outcomes?

Effectiveness of the intervention

No studies found 4 (very low) 3 (low) 2 (moderate) 1 (high)

▪ Prevention of disease is the only critical outcome that assessed effectiveness 

of the intervention

▪ After considering GMT and SCR data together, we have moderate certainty 

that there is a small increase in disease prevention provided by JYNNEOS® 

compared to ACAM2000
Outcome A: Prevention of disease

Certainty assessment No of patients Effect

No of Certainty Importance

studies

Study 

design Risk of bias Inconsistency

Indirectnes

s

Imprecisio

n

Other 

considerati

ons

JYNNEOS 

OPXV 

vaccine 

primary 

series

ACAM2000 

OPXV 

vaccine 

primary 

series

Relative

(95% CI)

Absolute

(95% CI)

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 

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. 
Benefits and Harms

What is the overall certainty of this evidence for the critical outcomes?

Safety of the intervention

No studies found 4 (very low) 3 (low) 2 (moderate) 1 (high)

▪ Evidence table indicated fewer serious adverse events and cases of myocarditis after 

JYNNEOS® primary series vs. ACAM2000 primary series

▪ However, there is low certainty in these estimates 
Summary of outcome C: Serious Adverse Events

Certainty assessment No of patients Effect

No of Certainty Importance

studies

Study 

design Risk of bias Inconsistency

Indirectness Imprecision

Other 

considerati

ons

JYNNEOS® 

OPXV 

vaccine 

primary 

series

ACAM2000 

OPXV 

vaccine 

primary 

series

Relative

(95% CI)

Absolute

(95% CI)

C. Serious adverse events (SAE) (assessed with: vaccine associated SAE 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 SAE rate)

15 

8,9,10,11,12,13,1

4,15,16,17,18,19,

20,21,22,23,24,25

,26,27,28,29,30,3

1,32,33,34,35,36,

37,38,39, 40

observation

al studies 

serious l not serious serious m serious n 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 
Outcome D: Myo-/pericarditis

Certainty assessment No of patients Effect

Certainty Importanc

No eof 

studies

Study 

design Risk of bias Inconsistency

Indirectnes

s

Imprecisio

n

Other 

considerati

ons

JYNNEOS 

OPXV 

vaccine 

primary 

series

ACAM2000 

OPXV 

vaccine 

primary 

series

Relative

(95% CI)

Absolute

(95% CI)

D. Myo-/pericarditis (assessed with: CDC definition of myocarditis 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 

CRITICAL 

D. Myo-/pericarditis (assessed with: myo-/pericarditis event rate)

12 

14,15,16,17,18,1

9,20,21,22,23,24,

25,26,27,28,29,3

0,31,32,33,34,35,

36,37,38,39

observation

al 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 

CRITICAL 

See extra slides for footnotes
Domain: Values

▪ Does target population feel that the desirable effects are large relative to 

undesirable effects?

▪ Is there important uncertainty about or variability in how much people 

value the main outcomes?
Values

Does the target population feel that the desirable effects are large relative to 

undesirable effects

No Probably no Uncertain Probably yes Yes Varies

▪ In 2015, CDC surveyed 275 healthcare personnel in the Democratic 

Republic of Congo (DRC) to evaluate the target populations values

– 99% of respondents had reported having seen a monkeypox case

– >75% were not interested in ACAM2000, many citing adverse events, potential 

for autoinoculation, and not wanting a vaccine scar

– 98% were interested in JYNNEOS®

▪ The U.S. target population has made multiple requests for this vaccine
Values

Is there important uncertainty about or variability in how much people value the main 

outcomes

Important Possibly important Probably no No important No known

uncertainty uncertainty or important uncertainty or undesirable

or variability variability uncertainty or variability outcomes

variability 

▪ No research identified but stakeholders expected to value immunity; 2-dose 

JYNNEOS® found to be non-inferior to ACAM2000 for immunogenicity by FDA

▪ Will take longer (from first vaccination) before person given JYNNEOS® is 

considered fully vaccinated compared to person given ACAM2000; 2-doses of 

JYNNEOS® administered over 28 days but only one vaccination for ACAM2000
Domain: Acceptability

Is the intervention acceptable to key stakeholders

No Probably no Uncertain Probably yes Yes Varies

▪ Ease of finding provider; no absences from work to travel to provider who 

can give the vaccine because any many more providers will be comfortable 

administering a subcutaneous injection

▪ Non-replicating virus so no risk of transmission to others, particularly to 

immunocompromised persons and those with eczema

▪ Adverse events expected to be more rare
Domain: Resource Use

Is the intervention a reasonable and efficient allocation of resources

No Probably no Uncertain Probably yes Yes

▪ JYNNEOS®, like ACAM2000, would be provided from HHS’ Strategic 

National Stockpile (SNS) free-of-cost 

▪ Even in cases where employers do not cover the cost of clinic 

appointments, there may be similar clinic costs associated with JYNNEOS® 

and ACAM2000 vaccinations. This is because in some clinics, patients 

return for in-person clinic appointments on multiple days after ACAM2000 

vaccination (e.g., days 3, 7 and sometimes many times afterwards) to 

perform dressing changes and assess the “take” site
Domain: Equity

What would be the impact on health equity?

Reduced Probably Reduced Probably no impact Probably increased

Increased Varies Don’t know

▪ For some vaccine recipients, cost of clinic appointments is absorbed by the 

employer. There would be no change in those costs

▪ There would be fewer costs and challenges associated with identifying a 

provider to provide the vaccine which occurs for ACAM2000; some 

persons needing ACAM2000 currently travel to a provider willing to 

administer the vaccine and in the process, incur personal expenses for 

hotel and mileage
Domain: Feasibility

Is the intervention feasible to implement

No Probably no Uncertain Probably yes Yes Varies 

▪ Potentially the same number (or possibly fewer) clinic visits with JYNNEOS®

▪ Less difficulty getting on a vaccination schedule because more providers 

willing to administer subcutaneous injection

▪ JYNNEOS®, once thawed/refrigerated, is good for 6 months; thawed 

ACAM2000 is good for 18 months

▪ Shipping conditions are the same for both JYNNEOS® and ACAM2000 and the 

6 month window allows ample time for providers to schedule vaccinations
Summary of EtR #1

Domains Domains Domains

Benefits: How 

substantial are the 

desired anticipated 

effects

Small Values: Does the 

target population feel 

desirable effects are 

large

Yes Impact on 

health equity

Increased

Harms: How 

substantial are 

undesirable 

anticipated effects?

Minimal Is there important 

uncertainty about or 

variability in values?

Probably 

not

Feasible to 

implement?

Yes

Benefit / Harm: Favors 

intervention

Acceptable to 

stakeholders?

Yes Balance of consequences: 

Desirable consequences 

probably outweigh 

undesirable 

consequences in most 

settings

Overall certainty of 

the evidence for 

the critical 

outcomes

Effectiveness: 

moderate

Safety: low

Reasonable and 

efficient allocation of 

resources?

Yes
Proposed recommendation 1

The ACIP recommends JYNNEOS® as an alternative to ACAM2000 for 

research laboratory personnel*, clinical laboratory personnel performing 

diagnostic testing for orthopoxviruses†, and for designated response team 

members at risk for occupational exposure to orthopoxviruses§

*Research laboratory personnel are those who directly handle 1) cultures or 2) animals contaminated or infected with replicationcompetent vaccinia virus, recombinant vaccinia viruses derived from replication-competent vaccinia strains (i.e., those that are

capable of causing clinical infection and producing infectious virus in humans), or other orthopoxviruses that infect humans (e.g., 

monkeypox, cowpox, and variola). 

†Clinical laboratory personnel who perform routine chemistry, hematology, and urinalysis testing, including for suspect or 

confirmed patients with Orthopoxvirus infections, are not included in this recommendation as their risk for exposure is very low

§Public health authorities, at their own discretion, may approve a cohort of healthcare and/or public health personnel to receive

primary vaccination against Orthopoxviruses for preparedness purposes (e.g., first responders who might participate in a smallpox 

or monkeypox outbreak)
PICO #2

Policy question: Should JYNNEOS® be recommended for healthcare 

personnel who 1) administer ACAM2000 or 2) care for patients 

infected with replication competent orthopoxviruses*

Population

Healthcare personnel who administer ACAM2000 or care for 

patients after vaccination with replication competent 

orthopoxviruses

Intervention Vaccination with JYNNEOS®

Comparison Vaccination with ACAM2000

Outcome

a) Prevention of disease

b) Severity of disease

c) Serious adverse events

d) Myo-/ peri- carditis 

* For example, those caring for patients enrolled in clinical trials for replication-competent orthopoxvirus vaccines and those 

caring for persons with suspected or confirmed orthopoxvirus infections (e.g., clinicians and environmental services personnel)
Benefits and harms: Identical GRADE table as for EtR #1

Domains Explanation

Benefits: How 

substantial are the 

desired 

anticipated effects

Small Evidence table for outcome A, prevention of disease, 

suggests there is a small benefit of JYNNEOS® compared 

to ACAM2000 for prevention of infection

Harms: How 

substantial are 

undesirable 

anticipated 

effects?

Minimal Evidence tables for the RCTs could not adequately assess 

harms because of the small number of persons enrolled in 

these; however, the observational data is reassuring that 

there JYNNEOS® is either slightly better or similar to 

ACAM2000 for harms

Benefit / Harm: Favors 

intervention

Small benefit and minimal harms favors the intervention, 

i.e., JYNNEOS®

Overall certainty 

of the evidence 

for the critical 

outcomes

Effectiveness: 

moderate

Safety: low

Same certainty levels as for EtR #1 because GRADE tables 

are the same
Values

Does the target population feel that the desirable effects are large relative to 

undesirable effects

No Probably no Uncertain Probably yes Yes Varies

▪ There is no research data to evaluate this but it is believed that some members of 

the population will be interested in vaccination or at least, would like the option of 

being vaccinated even if it is not indicated for the entire population

▪ In the past, when patients were admitted with adverse events from replicating 

orthopoxvirus vaccines, some healthcare workers were anxious

▪ Allowing for these persons to be vaccinated is consistent with the ACIP 

recommendations for ACAM2000
Values

Is there important uncertainty about or variability in how much people value the main 

outcomes

Important Possibly important Probably no No important No known

uncertainty uncertainty or important uncertainty or undesirable

or variability variability uncertainty or variability outcomes

variability 

▪ Because of the low risk, many persons within this population may opt to not be 

vaccinated

▪ Others, however, may (for the factors previously discussed) opt to be vaccinated

▪ There is some variability in how much people value this recommendation, potentially 

indicating it could be recommended by shared clinical decision-making
Acceptability, impact on health equity, and feasibility

Domains Explanation

Acceptable to 

stakeholders?

Yes Ease of finding provider, no absences from work to travel, no 

costs incurred by vaccinee

Reasonable and efficient 

allocation of resources?

Yes • JYNNEOS, like ACAM2000, would be provided from HHS’ 

SNS

• Cost of clinic appointments would presumably be covered 

by employer and supervisors would be supportive

Impact on health equity Increased Decreased costs and challenges for whose who would 

otherwise need to travel to receive an orthopoxvirus vaccine

Feasible to implement? Yes • No research identified but potentially the same number of 

in-person clinic visits (or possibly fewer) than for 

ACAM2000

• Easier to get on provider schedule for subcutaneous 

injection
Summary of EtR #2

Domains Domains Domains

Benefits: How 

substantial are the 

desired anticipated 

effects

Small Values: Does the 

target population feel 

desirable effects are 

large

Probably yes Impact 

on health 

equity

Increased

Harms: How 

substantial are 

undesirable 

anticipated effects?

Minimal Is there important 

uncertainty about or 

variability in values?

Probably 

important 

uncertainty 

or variability

Feasible 

to 

impleme

nt?

Yes

Benefit / Harm: Favors 

intervention

Acceptable to 

stakeholders?

Yes Balance of 

consequences: 

Desirable 

consequences 

probably outweigh 

undesirable 

consequences in most 

settings

Overall certainty of 

the evidence for 

the critical 

outcomes

Effectiveness: 

moderate

Safety: low

Reasonable and 

efficient allocation of 

resources?

Yes
Proposed recommendation #2

The ACIP recommends JYNNEOS®, based on shared clinical decision-making, 

as an alternative to ACAM2000 for healthcare personnel who administer 

ACAM2000 or care for patients infected with replication competent 

orthopoxviruses*

* For example, those caring for patients enrolled in clinical trials for replication-competent orthopoxvirus

vaccines and those caring for persons with suspected or confirmed orthopoxvirus infections (e.g., clinicians and 

environmental services personnel)
EtRs 3 and 4: Booster with JYNNEOS® after 

JYNNEOS® primary series
Problem: Booster

▪ Virulent orthopoxviruses (e.g., variola virus and monkeypox virus)

– Increasing number of laboratories are working with monkeypox virus (e.g., 

primate laboratories

– Work with these typically require personal protective equipment and other 

safeguards; but ensuring long-term immunogenicity through a booster, 

provides an additional level of protection if unintentional breaches occur

▪ Less virulent orthopoxviruses (e.g., vaccinia virus, cowpox virus, and Alaskapox virus)

– Morbidity may be prevented, e.g., A mild case of vaccinia infection occurred in 

a laboratorian in the United States who had not received a booster >10 years 

after his primary ACAM2000 vaccination; these could potentially be prevented 

with the recommended booster

▪ Stakes higher to individual and public health, if virulent orthopoxvirus

infection is acquired; for this reason, boosters historically given more 

frequently for those working with virulent orthopoxviruses
Proposed recommendations for JYNNEOS® compared to those for ACAM

ACAM2000 JYNNEOS®

Population 

recommended

Persons at occupational risk for orthopoxviruses (i.e., diagnostic 

laboratorians, healthcare response teams)

Populations offered Persons who administer ACAM2000 or care for patients with 

infection or after vaccination with replication competent virus

Populations for whom 

booster is recommended 

at specific intervals

Persons who are at continued or sustained risk for 

orthopoxviruses [Note: Response teams are not at continued risk and 

will receive boosters only at the time of a smallpox/monkeypox event]

Frequency of boosters: 

Those working with smallpox 

and monkeypox

Every 3 years (had previously 

been every year)

Every 2 years

Frequency of boosters: 

Those working with less 

virulent orthopoxviruses

At least every 10 years
PICO #3

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® every 2 years after primary series

Comparison No vaccine booster after JYNNEOS primary series

Outcome

a) Prevention of disease

b) Severity of disease

c) Serious adverse events

d) Myo-/ peri- carditis 

* Continued risk refers to persistent risk due to occupational work performed. Designated public 

health and healthcare worker response teams approved by public health authorities are not at 

“continued risk” because they are vaccinated for the purposes of preparedness

Assesses efficacy

Assesses safety

Assesses safety
PICO #4

Policy question: Should persons who are at continued risk for 

occupational exposure to less virulent 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 less virulent 

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

Outcome

a) Prevention of disease

b) Severity of disease

c) Severe adverse events

d) Myo-/ peri- carditis 
Summary of Benefits and Harms Domain for PICOs 3 & 4

Benefits and harms domains

Benefits: How substantial are the desired 

anticipated effects

Small: The evidence tables show a small increase in 

disease prevention after JYNNEOS booster to the 

JYNNEOS primary series; boosters may provide 

reassurance of continued protection from inadvertent 

exposures

Harms: How substantial are undesirable 

anticipated effects?

Minimal: No serious adverse events or myopericarditis 

observed among those who received JYNNEOS booster 

dose 2 years after the primary series

Benefit / Harm: Favors intervention

Overall certainty of the evidence for the critical 

outcomes

Effectiveness: very low

Safety: very low
Certainty assessment Noof patients Effect

No Certainty Importance of 

studies Study design Risk of bias Inconsistency

Indirectness Imprecision

Other 

consideratio

ns

JYNNEOS® 

OPXV 

vaccine 

primary 

series 

followed by 

a JYNNEOS® 

booster 

every 2 years

JYNNEOS® 

OPXV 

vaccine 

primary 

series

Relative

(95% CI)

Absolute

(95% CI)

A. Prevention of disease (assessed with: Geometric mean titer)

1 1,2 randomized 

trials 

serious a not serious serious b,c very 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 serious b,c very 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)

13 

3,4,5,6,7,8,9,10,1

1,12,13,14,15,16,

17,18,19,20,21,2

2,23,24,25,26,27,

28,29,30,31,32,3

3,39

observation

al studies 

serious f serious g #3: serious h

#4: very 

serious

serious i 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 

Policy Questions #3 and #4: Outcome A: Prevention
Policy Questions #3 and #4

Outcome C: Serious adverse events

Certainty assessment No of patients Effect

Certainty Importanc

No eof 

studies

Study 

design Risk of bias Inconsistency

Indirectnes

s

Imprecision

Other 

considerati

ons

JYNNEOS® 

OPXV 

vaccine 

primary 

series 

followed 

by a 

JYNNEOS® 

booster 

every 2 

years

JYNNEOS® 

OPXV 

vaccine 

primary 

series

Relative

(95% CI)

Absolute

(95% CI)

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 

3,4,5,6,7,8,9,10,1

1,12,13,14,15,16,

17,18,19,20,21,2

2,23,24,25,26,27,

28,29,30,31,32,3

3,34,35,36,37,38, 

39

observation

al studies 

serious f not serious serious h serious k none 0/75 (0.0%) 3/5265 

(0.1%) 

not 

estimable

Level 4 

VERY LOW 

CRITICAL 

See slide 47 for footnotes
Policy Questions #3 and #4

Outcome D: Myopericarditis

Certainty assessment No of patients Effect

Certainty Importanc

No eof 

studies

Study 

design Risk of bias Inconsistency

Indirectnes

s

Imprecision

Other 

considerati

ons

JYNNEOS® 

OPXV 

vaccine 

primary 

series 

followed 

by a 

JYNNEOS® 

booster 

every 2 

years

JYNNEOS® 

OPXV 

vaccine 

primary 

series

Relative

(95% CI)

Absolute

(95% CI)

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 

CRITICAL 

c. Available intervention data gives a booster at day 84. Indirect evidence for 2-year booster. 

j. Study population is very small and would be poor at estimating the rate of rare outcomes. 

l. High attrition rate and unclear information about randomization procedure. 
Summary of remaining domains

Domains Explanation Domains

Values: Does the 

target population 

feel desirable 

effects are large

Probably yes Booster may be 

desirable to those who 

want to ensure longterm immunogenicity

Impact 

on 

health 

equity

Probably 

no 

impact

For many, 

employers absorb 

the cost

Is there important 

uncertainty about 

or variability in 

values?

Probably not Stakeholders expected 

to value persistent 

immunity

Feasible 

to 

implem

ent?

Probably 

yes

Need to get a 

booster dose. But 

many clinicians 

can provide subQ

injection

Acceptable to 

stakeholders?

Yes Easy to find caregiver 

to administer vaccine

Balance of consequences: Desirable 

consequences probably outweigh 

undesirable consequences in most 

settings Reasonable and 

efficient allocation 

of resources?

Yes for #3 and 

Probably yes 

for #4

For persons working 

with less virulent 

orthopoxviruses, costs 

of clinic visit likely still 

acceptable
Proposed recommendation 3

The ACIP recommends persons who are at continued risk* for occupational 

exposure to more virulent orthopoxviruses like variola virus or monkeypox 

virus receive booster doses of JYNNEOS every 2 years after the primary 

JYNNEOS series

* Continued risk refers to persistent risk due to occupational work performed. Designated public health and 

healthcare worker response teams approved by public health authorities are not at “continued risk” because 

they are vaccinated for the purposes of preparedness
Proposed recommendation #4

The ACIP recommends persons who are at continued risk* for occupational 

exposure to replication competent orthopoxviruses like vaccinia or cowpox 

receive booster doses of JYNNEOS® after the primary JYNNEOS® series

*Continued risk refers to persistent risk due to occupational work performed
EtR #5: Change from ACAM2000 boosters to 

JYNNEOS® boosters for those who received 

the ACAM2000 primary series 
Problem

▪ Health authorities and JYNNEOS® sponsor are routinely being asked when 

this vaccine will be available

▪ Some laboratory directors have indicated that many of those who receive 

ACAM2000 boosters would like to change to JYNNEOS® if the ACIP 

recommendations explicitly allow for this

– Ease of identifying a clinician who can administer it

– No risk for infection spread to others

– No dressings to manage

– Fewer relative contraindications

▪ Unpublished data from the Democratic Republic of Congo indicates that 

JYNNEOS® is preferred to ACAM2000
PICO #5

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

Outcome

a) Prevention of disease

b) Severity of disease

c) Severe adverse events

d) Myo-/ peri- carditis 

* Continued risk refers to persistent risk due to occupational work performed. Designated public health 

and healthcare worker response teams approved by public health authorities are not at “continued risk” 

because they are vaccinated for the purposes of preparedness

Assesses efficacy

Assesses safety

Assesses safety
Benefits and harms summary:

Domains Explanation

Benefits: How substantial 

are the desired 

anticipated effects

Don’t know Only observational data was available for this outcome

There was no available comparison data so it is 

unknown, from the Evidence table, how substantial the 

desirable anticipated effects are

Harms: How substantial 

are undesirable 

anticipated effects?

Minimal No serious adverse events or myo- / pericarditis cases 

were identified

Benefit / Harm: Unclear We don’t know if there are benefits to administering 

JYNNEOS® boosters compared to ACAM2000 boosters

Overall certainty of the 

evidence for the critical 

outcomes

Effectiveness: 

Very low

Safety: very low

Outcome A RCTs: Serious concerns about risk of bias, 

indirectness, and imprecision 

Outcome C and D RCTs: Serious or very serious concerns 

about risk of bias and very serious concerns about 

imprecision
Policy Question #5

Outcome A: Prevention

Certainty assessment No of patients Effect

Certainty Importanc

No eof 

studies

Study 

design Risk of bias Inconsistency

Indirectnes

s

Imprecisio

n

Other 

considerati

ons

a booster 

dose of 

JYNNEOS

a booster 

dose of 

ACAM2000

Relative

(95% CI)

Absolute

(95% CI)

A. Prevention of disease (assessed with: seroconversion rate)

3 1,2,3,4,5,6,7 observation

al studies 

serious a not serious serious b serious c 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 

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

b. SCR is an indirect measure of prevention. 

c. Small sample size, no comparison. 
Summary: Policy Question #5 

Outcome C: Serious Adverse Events

Certainty assessment No of patients Effect

No of Certainty Importance

studies

Study 

design

Risk of 

bias

Inconsiste

ncy

Indirectne

ss

Imprecisio

n

Other 

considerat

ions

a booster 

dose of 

JYNNEOS

a booster 

dose of 

ACAM200

0

Relative

(95% CI)

Absolute

(95% CI)

C. Serious adverse events (assessed with: vaccine related SAE event rate)

1 8randomize

d trials 

serious f not serious not serious very 

serious g

none 0/22 (0.0%) 0/28 (0.0%) not 

estimable 

Level 4 VERY 

LOW 

CRITICAL 

C. Serious adverse events (assessed with: vaccine related SAE event rate)

3 1,2,3,4,5,6,7 observatio

nal studies

h

not serious not serious serious i very serious 

g

none 0/349 

(0.0%) j

3/1371 

(0.2%) k

RR 0.56

(0.03 to 

10.85) 

1 fewer per 

1,000

(from 2 

fewer to 22 

more) 

Level 4 

VERY LOW 

CRITICAL 

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. 
Policy Question #5

Outcome D: Myo-/pericarditis

Certainty assessment No of patients Effect

Certainty Importanc

No eof 

studies

Study 

design Risk of bias Inconsistency

Indirectnes

s

Imprecision

Other 

considerati

ons

a booster 

dose of 

JYNNEOS

a booster 

dose of 

ACAM2000

Relative

(95% CI)

Absolute

(95% CI)

D. Myo-/pericarditis (assessed with: myo-/pericarditis event rate)

1 8randomized 

trials 

very serious l not serious not serious very serious 

m

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)

3 1,2,3,4,5,6,7 observation

al studies 

not serious not serious serious i very serious 

m

none 0/349 (0.0%) 

n

0/1371 

(0.0%) o

not 

estimable 

Level 4 

VERY LOW 

IMPORTANT 

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. 

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. 
Summary of remaining domains

Domains Domains

Values: Does the 

target population 

feel desirable effects 

are large

Yes: Target populations have made 

multiple requests for this vaccine

Unpublished data from the DRC 

indicates strong interest in JYNNEOS®

Impact on health 

equity

Probably increased: 

No costs with travel 

to find provider

Is there important 

uncertainty about or 

variability in values?

Probably not: Anecdotally, we know 

that some laboratory directors 

anticipate many of their staff to 

change to JYNNEOS® boosters if the 

ACIP explicitly indicates it is 

acceptable

Feasible to 

implement?

Yes: Feasible for CDC 

Drug Services to ship 

and for product to be 

used within the 6 

month time interval 

after that

Acceptable to 

stakeholders?

Yes: Ease of finding provider, no risk of 

transmission to others, no work 

absences due to travel to get vaccine, 

fewer contraindications

Balance of consequences: Desirable 

consequences probably outweigh 

undesirable consequences in most settings

Reasonable and 

efficient allocation of 

resources?

Yes: Would be same as for ACAM2000 

booster
Proposed recommendation #5

The ACIP recommends 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

* Continued risk refers to persistent risk due to occupational work performed. Designated public health and 

healthcare worker response teams approved by public health authorities are not at “continued risk” because 

they are vaccinated for the purposes of preparedness
Proposed clinical guidance

▪ If recipients change from ACAM2000 to JYNNEOS®, recipients should

– Receive subsequent boosters with JYNNEOS®

– Adhere to the booster schedule for JYNNEOS®

▪ Changes from JYNNEOS® to ACAM2000 are expected to occur less frequently
Acknowledgements

▪ Rebecca Morgan

▪ Doug Campos-Outcalt

▪ Florence Whitehill

▪ Brett Petersen 

▪ Pablo Sánchez

▪ Beth Bell 

▪ Wilbur Chen

▪ Mike Merchlinsky

▪ Stuart Isaacs

▪ Jafar Razeq

▪ Andrea McCollum

▪ Joanna Taliano

▪ Michael Townsend

▪ Heike Bailen

▪ Amanda Zarrabian

▪ David Weber

▪ Howard Minkoff

▪ Mark Challberg

▪ Sixun Yang

▪ Clement Meseda

▪ Alonzo García

▪ Jordan Kennedy 

▪ Marissa Pearson

▪ Dana Haberling

▪ Bryan Schumacher

▪ Ramya Natarajan

▪ Christina Hutson

▪ Jee Kim

▪ Todd Smith

▪ Andres Vellasco-Villa

▪ Amber Kunkel

▪ Jesse Bonwitt

▪ James Ellison

▪ Nick Wiese

▪ Modupe Osinabi

▪ Logan Timm

▪ Stephanie Tran

▪ Tiara Harms

▪ Sathesh Panayampalli

▪ Inger Damon

▪ Julian Jolly

▪ Julie Villanueva

▪ Yon Yu

▪ Lisa Hesse

▪ David Kuhar

▪ Mike McNeil

▪ Marie de Perio

▪ Christy Hughes

▪ April Killikelly

▪ Lalita Priyamvada

▪ Whitni Davidson
For more information, contact CDC

1-800-CDC-INFO (232-4636)

TTY: 1-888-232-6348 www.cdc.gov

The findings and conclusions in this report are those of the authors and do not necessarily represent the 

official position of the Centers for Disease Control and Prevention.

National Center for Emerging and Zoonotic Infectious Diseases

Division of High-Consequence Pathogens and Pathology

Questions?
Footnotes for slide 11 and 17

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. 
Footnotes for slide 12 and 18

l. There are some concerns for selection bias. 

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

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. 
Footnotes for slide 40 

a. High attrition rate in per protocol population. 

b. Immunogenicity as assessed with GMT is an indirect measure of efficacy. 

c. Available intervention data gives a booster at day 84. Indirect evidence for 2-year booster. 

d. There is one study with a small sample size. 

e. 95% CI suggests there may be the potential for benefit or harm. 

f. 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. 

g. Only one study contributes data to the intervention. Others contribute data to the comparison. Can't assess inconsistency for

intervention. 

h. This is the only place where the evidence profiles for policy questions #3 and #4 differ. For both #3 and #4: Downgrade for indirectness 

because the comparisons are between studies. PQ #4: Further downgrade for indirectness because 2-year booster data is indirect data for 

10-year booster data. 

i. Though the confidence interval is small, the number of participants in the intervention group is small and therefore may not provide a 

precise estimate. 
Footnotes for slide 42

c. Available intervention data gives a booster at day 84. Indirect evidence for 2-year booster. 

f. Many studies have very serious concerns for risk of bias. Edit: Explain a bit more. More an issue with the fact they are obs. some 

concerns in a few studies for attrition and timing. 

h. Downgrade for indirectness because the comparisons are between studies. 

j. Study population is very small and would be poor at estimating the rate of rare outcomes. 

k. Few people in the intervention group. Wide confidence interval. 
Footnotes for slide 61 

a. High attrition rate in per protocol population. 

b. Immunogenicity as assessed with GMT is an indirect measure of efficacy. 

c. Available intervention data gives a booster at day 84. Indirect evidence for 2-year booster. 

d. There is one study with a small sample size. 

e. 95% CI suggests there may be the potential for benefit or harm. 

f. 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. 

g. Only one study contributes data to the intervention. Others contribute data to the comparison. Can't assess inconsistency for

intervention. 

h. This is the only place where the evidence profiles for policy questions #3 and #4 differ. For both #3 and #4: Downgrade for indirectness 

because the comparisons are between studies. PQ #4: Further downgrade for indirectness because 2-year booster data is indirect data for 

10-year booster data. 

i. Though the confidence interval is small, the number of participants in the intervention group is small and therefore may not provide a 

precise estimate. 
Back-up slides: EtR1 and 2





Policy Questions #1 and #2

Outcome D: Myo-/pericarditis

“One [MVA vaccinated] individual...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 al. 2018)

This event does not meet the CDC case definition for myopericarditis (see Casey et al. 2006), however 

Overton et al. describe this event as “possible acute pericarditis” according to the case definition outlined in 

the study protocol. We chose to include this event in the effect estimate calculation in order to provide a 

conservative estimate. 

Casey C, Vellozzi C, Mootrey GT, et al. Surveillance guidelines for smallpox vaccine (vaccinia) adverse reactions. MMWR Recomm Rep. Feb 3 2006;55(Rr-1):1-

16. 

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. 
Back-up slides: EtR 3 and 4
Policy Questions #3 and #4

Summary of studies contributing data to PQ #3 and #4

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 Vaccines Outcomes Funding 

source

Randomized data

NCT02038881

Overton3

Overton et al. 

2020

Phase II, 

Randomized, 

Open-label

United States Mean 35

SD 6.7

87 31 27 MVA-BN Safety including cardiac outcomes, 

immunogenicity, CD4+ T cell counts 

in HIV+ patients

Bavarian 

Nordic
Policy Questions #3 and #4

Summary of studies contributing data to PQ #3 and #4

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 Vaccines Outcomes Funding 

source

Observational Intervention data

NCT00686582

Von Sonnenburg 3

Bavarian Nordic 

2008

Phase II, nonrandomized, 

open-label

Germany Mean 34.6 

SD 10.2

304 92 NA MVA-BN Safety and immunogenicity Bavarian 

Nordic
Policy Questions #3 and #4

Summary of studies contributing data to PQ #3 and #4

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 Vaccines Outcomes Funding 

source

Observational comparison data

VRC 201

Parrino1

Parrino 2007

Phase I/Ib 

randomized, 

placebo 

controlled, 

double-blinded 

trial

USA Mean and

SD NR,

adults

77 NA 19 TBC-MVA Immunogenicity, safety, Dryvax 

challenge, cell mediated/humoral 

immune responses

NIAID

NCT00437021

Frey 2

Frey et al. 2013

Troy et al. 2015

Phase II, Doubleblind, 

Randomized, 

Dose-finding 

Study

USA Mean 24.7

SD 4.2

208 NA 67 MVA-BN Safety and immunogenicity NIAID

NCT01668537

Greenburg4

2014

Phase II, 

Randomized, 

Double-blind, 

Multicenter 

USA Mean 27.7

SD 6.28

651 NA 327 MVA-BN 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 MVA-BN Safety and immunogenicity NIAID
Policy Questions #3 and #4

Summary of studies contributing data to PQ #3 and #4

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 Vaccines Outcomes Funding 

source

Observational comparison data

NCT00316602

Greenburg2

Greenberg 2015

Phase II, nonrandomized, 

open-label

USA and Mexico Mean 27.7

SD 6.11

632 NA 632 MVA-BN 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 MVA-BN Safety and immunogenicity NIAID and 

Bavarian 

Nordic

NCT00189904

Greenburg1

Greenberg et al. 

2013

Phase I/II, nonrandomized, 

open-label

USA Mean 37.9

SD NR

151 NA 60 MVA-BN Safety and immunogenicity in HIV 

positive patients

NIAID

NCT01144637

Overton2

Overton et al. 2018

Randomized, 

Double-Blind, 

PlaceboControlled Phase 

III Trial

USA Mean 27.7

SD 6.3

4005 NA 4005 MVA-BN immunogenicity, safety, and tolerability Bavarian 

Nordic and 

BARDA
Policy Questions #3 and #4

Summary of studies contributing data to PQ #3 and #4

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 Vaccines Outcomes Funding 

source

Observational comparison data

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 MVA-BN Safety and immunogenicity NIAID and 

Bavarian 

Nordic

NCT00133575

Seaman/Wilck

Seaman et al. 2010

Wilck et al. 2010

Phase I/II, 

randomized, 

double blinded, 

placebocontrolled

USA Mean 25.2, SD=3.7 72 NA 10 ACAM3000* Safety and immunogenicity and 

surrogate efficacy (Dryvax challenge)

NIAID

NCT01913353

Pittman

Pittman 2019

Phase 3, openlabel,

randomized 

clinical trial

U.S. military, 

stationed in 

Korea

Mean 23.5 

SD 4.67

433 NA 220 MVA-BN Immunogenicity,

Surrogate efficacy (ACAM2000 

challenge),

Adverse events

Bavarian 

Nordic, US 

Army Medical 

Research 

Institute of 

Infectious 

Diseases

*ACAM3000, or Acambis MVA, is a modified vaccinia Ankara (MVA) vaccine.
Policy Question #3 and #4

Summary of studies contributing data to PQ #3

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 Vaccines Outcomes Funding 

source

Observational comparison data

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 MVA-BN Safety and immunogenicity NIAID

NCT00082446

Frey1

Frey 2007

Sano 2009

Phase I, 

randomized, 

partially blinded,

placebo 

controlled

USA Mean 24.8

SD 3.8

90 NA 30 MVA-BN 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 MVA-BN Safety and immunogenicity HHS and 

NIAID

NCT00189959

Pokorny

Von Kremplehuber 

et al. 2010

Phase II, Doubleblind, 

randomized, 

Dose-finding 

Study

Switzerland Mean 23.3

SD 3.0

165 NA 55 MVA-BN Safety and immunogenicity NIAID and 

Bavarian 

Nordic
Back-up slides: EtR 5
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 Vaccines Outcomes Funding 

source

Randomized data

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 TBC-MVA

Dryvax

Immunogenicity of TBCMVA, 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 

Germany Mean 29.8

SD 9.07

745 200 NA MVA-BN Safety and immunogenicity NIAID and 

Bavarian 

Nordic

NCT00189904

Greenburg1

Greenberg et al. 

2013

Phase I/II, nonrandomized, openlabelUSA Mean 37.9

SD NR

151 91 NA MVA-BN Safety and immunogenicity NIAID

NCT00857493

Greenburg 3

Greenburg et al. 

2016

Randomized, DoubleBlind, Placebo 

Controlled Phase II Trial

USA Mean 35.8

SD NR

120 58 NA MVA-BN Safety and immunogenicity NIAID and 

Bavarian 

Nordic

Policy Question #3 and #4

Summary of studies contributing data to PQ #3