National Center for Emerging and Zoonotic Infectious Diseases

Summary of Evidence to Recommendations 

Framework for Rabies Pre-Exposure Prophylaxis Vote

Advisory Committee on Immunization Practices

June 24, 2021

Agam Rao, MD

CAPT, US Public Health Service

Poxvirus and Rabies Branch

Centers for Disease Control and Prevention
Recommendations passed

 ACIP recommends a 2-dose [0, 7 days] intramuscular rabies vaccine series 

in immunocompetent persons ≥18 years of age for whom rabies vaccine 

pre-exposure prophylaxis (PrEP) is indicated

 ACIP recommends an intramuscular booster dose of rabies vaccine, as an 

alternative to a titer check, for immunocompetent persons ≥ 18 years of 

age who have sustained and elevated risk for only recognized rabies 

exposures (i.e., those in risk category #3 of rabies PrEP recommendations 

table*). The booster dose should be administered no sooner than day 21 

but no later than 3 years after the 2-dose PrEP series

**Risk category table in next slide
1For questions about 

the disease 

biogeography of the 

region where an 

exposure occurred, 

please contact your 

local or state health 

department

2Bats are reservoirs 

for rabies in all US 

states except Hawaii

3Terrestrial mammals 

are non-bat species 

(e.g., racoons, skunks, 

livestock)
Proposed recommendations for June ACIP vote

 ACIP recommends a 2-dose [0, 7 days] intramuscular rabies vaccine series 

in immunocompetent persons <18 years of age for whom rabies vaccine 

pre-exposure prophylaxis (PrEP) is indicated

 ACIP recommends an intramuscular booster dose of rabies vaccine, as an 

alternative to a titer check, for immunocompetent persons < 18 years of 

age who have sustained and elevated risk for only recognized rabies 

exposures (i.e., those in risk category #3 of rabies PrEP recommendations 

table*). The booster dose should be administered no sooner than day 21 

but no later than 3 years after the 2-dose PrEP series

*Risk category table in previous slide
PrEP in children

 Most common reason: Travel to canine rabies endemic 

countries 

– RIG is not available in some developing countries

– Rabies vaccines may only be available in capital city 

resulting in a delay to PEP administration if travel is to 

rural regions

– Children are at increased risk of multiple and severe bites 

including to face and neck

 Costs: PrEP for travel is typically paid out-of-pocket and can 

be costly because the 2008 ACIP PrEP schedule recommends 

3 doses of vaccine over the course of 21-28 days
Estimated* PrEP use in the United States

 Doses: 170,000 including 500 booster doses

 Categories of people receiving PrEP: 60,535 / year

– Travelers and “other risk groups”: 41,117

– Veterinary technicians: 13,860

– Veterinary students: 3,500

– Animal control: 1,178

– Rabies laboratory personnel: 480

– Wildlife biologists: 400 * Mathematical model based on 

workforce statistics produced by 

Bureau of Labor Statistics and market 

research provided by Bavarian Nordic
Conclusions from presentation about rabies PrEP and 

children during May ACIP meeting

 Primary immunogenicity

– No difference between primary immunogenicity in children compared to 

adults for any given schedule

– One observational study included in GRADE table for 2-dose series 

showed 190 (100%) children aged 5-13 years mounted titers ≥ 0.5 IU/mL 

cut-off after primary series

 Long-term immunogenicity

– Titers in children may stay higher for longer

– Since boostability is not a concern for adults, it should not be a concern 

for children
Impact of 3-dose series on PrEP administration

Time

Day 0

First travel clinic 

appointment

Day 7 Day 10 Day 100

Hypothetical 

exposure

Flight

Rabies PrEP

RIG and 4-dose 

PEP indicated
Impact of 2-dose series* on PrEP administration

Time

Day 0

First travel clinic 

appointment

Day 7 Day 10 Day 100

Hypothetical 

exposure

Flight

Dose 1 

Rabies PrEP 2-dose PEP 

indicated

Dose 2 

Rabies PrEP

*Persons at sustained risk for rabies beyond 3 years, would 

receive titer at 1-3 years (booster if <0.5 IU/mL) or booster no 

sooner than day 21 but no later than year 3 for long-term 

immunogenicity
Implications of not aligning adult and pediatric PrEP

recommendations

 Discordant recommendations

– Parents may get vaccinated but children would not

– Children are believed to be at greater risk than adults but would not 

be vaccinated

 Setting precedent

– No previous rabies PrEP or PEP recommendations have involved a 

different series for adults compared to children

– Differing recommendations would lead to incorrect concern that more 

doses are needed for children than for adults
EtR for policy question #1: Primary 

immunogenicity
PrEP policy question #1

Policy question: Should a two dose pre-exposure prophylaxis (PrEP) series 

involving HDCV* or PCECV† IM [0, 7 days] replace the 3 dose series IM[0, 7, 

21/28 days] for children# for whom rabies vaccine PreP is recommended?

Population Children for whom rabies vaccine PrEP is recommended

Intervention [0, 7 days] rabies vaccine PrEP schedule

Comparison [0, 7, 21/28 days] rabies vaccine PrEP schedule

Outcome Primary immunogenicity 

*Human diploid cell vaccine

† Purified chick embryo cell vaccine

#Persons <18 years of age
Problem: Rabies and PrEP

 Rabies is nearly always fatal

 PrEP is important component of preventing human rabies in U.S.

 Yellow Book specifically mentions children are at a particular risk for rabies

– Inquisitive nature and attraction to animals

– Inability to read behavioral cues from dogs and other animals

– Increased likelihood for severe bites to high-risk anatomic regions (e.g., head 

and face) because of short stature

 Children often travel to canine rabies endemic regions 

 Rabies modern cell culture vaccines are effective
EtR: Policy question #1

Domains WG interpretation

Benefits: How substantial are the desired 

anticipated effects

Minimal; 100% of people seroconvert for proposed and 

for previous schedule

Harms: How substantial are undesirable 

anticipated effects?

Minimal; No expected safety concerns

Benefit / Harm: Do desirable effects outweigh 

undesirable effects?

Favors both

Overall certainty of the evidence for the critical 

outcome(s)?

Moderate certainty of evidence (Level 2) due to 

concerns for risk of bias
PrEP Policy Question #1

Summary of Randomized Control Trial Studies Reporting Outcome

Authors last 

name, pub 

year

Age (years) N 

intervention

N 

comparison

Vaccine Risk Ratio 

[95% CI]

Study limitations 

(Risk of Bias)

Endy, 2019 Mean 32.4, 

Range 18 - 59

22 24 PCEC, IM, ID 1.00 

[0.89, 1.12]

Some concerns1

Soentjens, 

2019

Median 29.0, 

Range NR

242 240 HDCV, ID 1.00 

[0.99, 1.01]

Some concerns2

1Allocation concealment not reported. Study did not blind participants or healthcare personnel; however, unlikely that co-interventions would have influenced the outcome. 2Method of randomization and allocation not reported. Study did not blind participants or healthcare personnel; however, unlikely that co-interventions would have influenced 

the outcome.
PrEP Policy Question #1

Summary of Observational Studies Reporting Outcome

Authors last name, pub year Age (years) N intervention N comparison Vaccine Risk Ratio [95% CI]1 Study limitations (Study quality2)

Ajjan, 1989 Mean 22, 

Range 19-41

72 69 HDCV, IM 1.00 [0.97, 1.03] 9/9 No concerns

Arora, 2004 Mean 26.2, 

Range NR

44 44 HDCV, IM 1.00 [0.96, 1.04] 9/9 No concerns

Briggs, 1996 NR 146 146 HDCV, IM 1.00 [0.99, 1.01] 9/9 No concerns

Cramer 2016 Mean 36.7,

Range 18 – 65

371 364 PCEC, IM 0.99 [0.98, 1.01]4 7/9 Minimal concerns

Hacibektasoglu, 1992 Mean 20, 

Range 18 – 24

30 30 HDCV, IM 0.90 [0.79, 1.03] 9/9 No concerns

Jaijaroensup, 1999 Mean NR,

Range 17 – 22

138 129 PCEC, IM, ID 0.94 [0.87, 1.02]4 9/9 No concerns

Kitala, 1990 NR 37 37 HDCV, IM 1.00 [0.95, 1.05] 8/9 Minimal concerns

Recuenco, 2017 Median 41.0, 

Range 20 - 62

60 59 PCEC, IM, ID 1.00 [0.96, 1.05]4 9/9 No concerns

Sabchareon, 1999 Mean 10,

Range 5 -13

190 190 HDCV, IM 1.00 [0.99, 1.01] 7/9 Minimal concerns

Vodopija, 1986 Mean NR,

Range 19 -25

49 46 HDCV, PCEC, IM 1.00 [0.94, 1.06]4 9/9 No concerns

1Data from observational studies, where intervention and comparison data were taken from the same people at different time points, were analyzed using M-H Risk Ratio random effects procedure. Due to unavailable 

raw data on pairing, a matched analysis was not possible.

2Study quality for observational studies was assessed using the Newcastle Ottawa Scale.

3Age for total study population was not reported in this paper. Numbers in this cell are from the study arm from which data were extracted. 4Studies contained multiple arms relative to the analysis. Risk ratio reflects pooled analysis from eligible arms. 
Sabchareon et al

 HDCV in 190 school children

 After [0, 7 days] series, 100% of children had antibody titers ≥ 0.5 IU/mL

Day

Table from: Sabchareon A, Lang J, Attanath

P et al. A new vero cell rabies vaccine: 

Results of a comparative trial with human 

diploid cell rabies vaccine in children. Clin 

Infec Dis. 1999; 29: 141-9. 
Table 4: Evidence table

Immunogenicity after [0, 7 days] PrEP series with HDCV or PCECV

CI: Confidence interval; RR: Risk ratio

Explanations

a. Method of randomization and allocation not reported in Soentjens 2019 and allocation concealment not reported in Endy 2019. Neither study blinded participants or healthcare personnel; however, unlikely that cointerventions would have influenced the outcome. 

b. Sabchareon 1999 study was conducted among children and the response may be more robust than in adults, which would potentially overestimate the immune response.

Certainty assessment No of patients Effect

Certainty Importance

No of studies Study design Risk of bias Inconsistency Indirectness Imprecision

Other 

consideration

s

[0, 7 days] 

rabies 

vaccine PrEP 

schedule

[0, 7, 21/28 

days] rabies 

vaccine PrEP 

schedule

Relative

(95% CI)

Absolute

(95% CI)

Immunogenicity (RCTs) (follow up: range 2 weeks to 3 weeks; assessed with: titer level above 0.5)

2 1,2 randomized 

trials 

serious a not serious not serious not serious none 264/264 

(100.0%) 

264/264 

(100.0%) 

RR 1.00

(0.99 to 1.01) 

0 fewer per 

1,000

(from 10 

fewer to 10 

more) 

Level 2

Moderate

CRITICAL 

Immunogenicity (observational studies) (follow up range: 2 to 3 weeks, assessed with titer level above 0.5)

10 3,4,5,6,7,8,9,10,11,1

2

observational 

studies 

not serious not serious not serious b not serious strong 

association 

1090/1137 

(95.9%) 

1081/1114 

(97.0%) 

RR 1.00

(0.99 to 1.00) 

0 fewer per 

1,000

(from 10 

fewer to 0 

fewer) 

Level 3

Low

CRITICAL 
EtR: Policy question #1

Domains WG interpretation

Values: Does the target population feel that desirable 

effects are large relative to undesirable effect?

Yes. Desirable effect is being vaccinated from rabies

Values: Is there important uncertainty about or 

variability in how much people value the main 

outcomes?

No. Target population values “protection” of children 

from rabies because this population is at a higher risk 

than adults during travel

Acceptability: Is the intervention acceptable to key 

stakeholders?

Yes. Shorter schedule preferred by patients & 

providers and will enable more children to be 

vaccinated before risky travel

Resource Use: Is the intervention a reasonable and 

efficient allocation of resources?

Yes. Travel vaccination costs are typically out -ofpocket; fewer doses results in lower costs for 

individuals. Also, rabies vaccine shortages have 

occurred in U.S. so using fewer doses will result in 

efficient allocation of resources

Equity: What would be the impact on health equity? Probably increased because of decreased costs

Feasibility: Is the intervention feasible to implement? Yes. Shorter series than current series so it can be 

more easily implemented before travel
Balance of Consequences

Undesirable Undesirable Balance between 

consequences clearly consequences probably desirable and undesirable

outweigh desirable outweigh desirable consequences is closely 

consequences in most consequences in most balanced or uncertain

settings settings

Desirable consequences Desirable consequences There is insufficient evidence

probably outweigh clearly outweigh to determine the balance of

undesirable consequences undesirable consequences consequences

in most settings in most settings

X
Proposed recommendation for vote

ACIP recommends a 2-dose [0, 7 days] intramuscular 

rabies vaccine series in immunocompetent persons 

<18 years of age for whom rabies vaccine preexposure prophylaxis (PrEP) is indicated

Recommendation
EtR for policy question #2: Long-term 

immunogenicity 
PrEP policy question #2

Policy question: Should an IM booster dose of rabies vaccine (*PCECV or 

†HDCV) be recommended as an alternative to a titer check no sooner than 

day 21 and no later than 3 years after the two dose pre-exposure prophylaxis 

(PrEP) series IM [0, 7 days] for children$ in the #3 risk category of people 

who receive PreP?

Population

Children in the #3 risk category for whom rabies vaccine PrEP

is recommended

Intervention Day 21- year 3 rabies vaccine booster after [0, 7 days] rabies 

vaccine PrEP schedule

Comparison No rabies vaccine booster after [0, 7 days] rabies vaccine PrEP

schedule

Outcome Long-term immunogenicity

*Human diploid cell vaccine

† Purified chick embryo cell 

vaccine

$ Persons < 18 years of age
Problem: Long-term immunogenicity for rabies

 Some children may make trips to developing countries (e.g., to visit 

grandparents) beyond 3 years

 Immunology suggests that anamnestic response to an exposure occurs

 WHO approved 2-dose series for this population

 WG opted for very cautious recommendation to ensure long-term 

immunogenicity for [0, 7 days] series

– Strong data for long-term immunogenicity only exists for up to 3 years

– Data shows that titer at ≥ 1 year, is marker of long-term immunogenicity

– WG proposed 

• Titer at 1-3 years (and boost accordingly) OR

• Booster no sooner than day 21 and no later than year 3
Long-term immunogenicity reported in recently 

published article*

 6 persons who received [0, 7 days] IM series, were evaluated after 10-11 

years 

– 3 male; 3 female

– Ages 34-46

– 5 had titers ≥ 0.5 IU/mL

– All had 4-fold increase in titers after booster

 More data expected about long-term immunogenicity of 2-dose series because 

WHO recommendations made in 2018

*De Pijper et al, Long-term memory response after a single intramuscular rabies booster vaccination, 10-24 

years after primary vaccination. Journal of Infectious Diseases. Epub January 2021
EtR: Policy question #2

Domains WG interpretation

Benefits: How substantial are the desired 

anticipated effects

Moderate

• Flexibility in receiving titer check (and only booster if 

indicated) versus a booster over a broad time period, 

i.e., as soon as day 21 and as late as 3 years;100% of 

subjects mounted anamnestic response to booster 

at 1-3 years

Harms: How substantial are undesirable 

anticipated effects?

Minimal; No expected safety concerns

Benefit / Harm: Do desirable effects outweigh 

undesirable effects?

Favors intervention

Overall certainty for evidence: effectiveness Low certainty of evidence (Level 3)
PrEP Policy Question #2

Table 3: Summary of Studies Reporting Outcome

Authors 

last name, 

pub year

Age (years) N intervention N comparison Comparator 

vaccine

Risk Ratio 

[95% CI]

Study limitations (Study 

quality3)

Endy, 2019 Mean 32.4, 

Range 18 - 59

42 No comparison1 PCEC, IM Not able to 

calculate2

8/9 Mild concerns

Soentjens, 

2019

Median 29.0, NR 368 No comparison1 HDCV, IM Not able to 

calculate2

8/9 Mild concerns

1No comparison data available for this policy question available in these studies. 

2No comparison data available to calculate effect estimate.

3Study quality for observational studies was assessed using the Newcastle Ottawa Scale.
Table 4: Evidence table

Duration of immunogenicity after [0, 7 days] PrEP series with HDCV or PCECV

Certainty assessment

Impact Certainty Importance

No of studies Study design Risk of bias Inconsistenc

y

Indirectness Imprecision

Other 

consideratio

ns

Anamnestic response after booster (follow up: range 1 weeks to 3)

2 1,2 observational 

studies 

not serious not serious not serious not serious none A historical control of trial participants receiving 2 doses of rabies 

vaccine resulting in 100% immunogenicity (n=264) at 1-3 weeks 

following vaccination schedule (Endy 2019, Soentjens 2019) : 

410/410 (100%) seroconverstion with booster

Level 3

Low

CRITICAL 

CI: Confidence interval
EtR: Policy question #2

Domain WG interpretation

Target population sentiments: Does 

the target population feel desirable 

effects are large relative to 

undesirable effects

Probably yes

• Stakeholders want to avoid acquiring high-stakes infection; 

children have many more years ahead of them making future 

travel more likely than an older adult who is vaccinated

• Booster provides reassurance that outweighs any inconvenience

Target population sentiments: Is 

there important uncertainty about or 

variability in how much people value 

the main outcome(s)?

No: Target population values “protection” from rabies and there is 

likely no important variability

Acceptability: Is the intervention 

acceptable to stakeholders?

Yes: Stakeholders accustomed to accommodating third dose of rabie 

vaccine and will find it acceptable to have booster as an option, 

particularly given the flexibility for when that booster can be given

Resources: Reasonable and efficient 

allocation of resources?

Yes: Persons who do not have sustained risk for rabies will not requir 

the booster; additionally, because of the flexibility in the time point for 

this booster, it can be arranged at a time when there is no shortage of 

vaccines
EtR: Policy question #2

Domains WG interpretation

Equity: What would be the impact on health 

equity?

Increased: Some PrEPcosts are out-of-pocket. Because 

titer is offered as option, inequity could be resolved by 

choosing that option. Additionally, children without 

sustained risk for rabies will not need booster or titer 

and those who do require it, could defer receiving (and 

paying) up to 3 years later diffusing the costs over a 

longer time period

Feasibility: Is the intervention feasible to 

implement?

Yes: Administrators could opt to schedule booster dose 

at the time of primary vaccination if there is a concern 

for travelers not remembering to receive booster dose
Balance of Consequences

Undesirable Undesirable Balance between 

consequences clearly consequences probably desirable and undesirable

outweigh desirable outweigh desirable consequences is closely 

consequences in most consequences in most balanced or uncertain

settings settings

Desirable consequences Desirable consequences There is insufficient evidence

probably outweigh clearly outweigh to determine the balance of

undesirable consequences undesirable consequences consequences

in most settings in most settings
Proposed recommendation for vote

ACIP recommends an intramuscular booster dose of rabies 

vaccine, as an alternative to a titer check, for 

immunocompetent persons >=18 years who have sustained and 

elevated risk for only recognized rabies exposures (i.e., those in 

risk category #3 of rabies PrEP recommendations table). The 

booster dose should be administered no sooner than day 21 

but no later than 3 years after the 2-dose PrEP series. 

Recommendation
Proposed recommendations for June ACIP vote

 ACIP recommends a 2-dose [0, 7 days] intramuscular rabies vaccine series 

in immunocompetent persons <18 years of age for whom rabies vaccine 

pre-exposure prophylaxis (PrEP) is indicated

 ACIP recommends an intramuscular booster dose of rabies vaccine, as an 

alternative to a titer check, for immunocompetent persons < 18 years of 

age who have sustained and elevated risk for only recognized rabies 

exposures (i.e., those in risk category #3 of rabies PrEP recommendations 

table ∫

). The booster dose should be administered no sooner than day 21 

but no later than 3 years after the 2-dose PrEP series

∫

Risk category table in next slide
1For questions about 

the disease 

biogeography of the 

region where an 

exposure occurred, 

please contact your 

local or state health 

department

2Bats are reservoirs 

for rabies in all US 

states except Hawaii

3Terrestrial mammals 

are non-bat species 

(e.g., racoons, skunks, 

livestock)
Acknowledgements

 Rabies WG

 Doug Campos-Outcalt

 Rebecca Morgan

 Jesse Blanton

 Ryan Wallace

 Brett Petersen

 Florence Whitehill

 James Ellison

 Erin Whitehouse

 Sathesh Panayampalli 
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?