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

February 24, 2021

Agam Rao, MD

CAPT, US Public Health Service

Poxvirus and Rabies Branch

Centers for Disease Control and Prevention
Rabies antibody response

▪ Target response, i.e., ≥ minimum antibody titer, 0.5 IU/mL, regardless of 

series

– Children

– Pregnant women

– Persons ≥ 65 years of age

▪ Persons with altered immunity

– Efficacy can be a concern

– Titer check after primary series (and boosters until ≥ 0.5 IU/mL) 
Rabies vaccines licensed in U.S.

▪ Been used in the U.S. for decades

▪ No change in favorable safety profile

Biologic Product 

name

Manufacturer Administration Potency

Human 

diploid cell 

vaccine 

(HDCV)

Imovax Sanofi Pasteur intramuscularly

≥2.5 IU of 

rabies 

antigen

Purified 

chick 

embryo cell 

vaccine 

(PCECV)

RabAvert Bavarian 

Nordic intramuscularly

≥2.5 IU of 

rabies 

antigen
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
Adherence to ACIP PrEP recommendations*

▪ Veterinary students: 100% (required for clinics)

▪ Laboratory personnel: 100% (required)

▪ Animal control: 78.5%

▪ Veterinary technicians/staff: 69.3% (in other published studies, 30-40% adherence)

▪ Wildlife biologists: ~50%

▪ Other risk groups: ?

▪ Travelers: ?

*Some results from unpublished CDC data; Blanton 

et al.

Includes data obtained from ~2,000 persons 

Survey sent to members of professional 

organizations who were certified providers and 

were likely more compliant with the ACIP recs 

than persons not captured by the survey
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 all those for whom rabies vaccine PreP is recommended?

Population Persons 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
Problem: Rabies and PrEP

▪ Rabies is nearly always fatal

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

▪ PrEP critically important to some persons

– Unusual exposures (e.g., aerosolized) or high concentration virus

– Unrecognized exposures

– Frequent exposure to potentially rabid animals

– Travel abroad to canine-rabies endemic regions without quick PEP access
Primary immunogenicity of PrEP for rabies

▪ Rabies modern cell culture vaccines are effective

▪ ACIP has recommended PrEP for decades

▪ Noncompliance among some for whom it is recommended

– Out-of-pocket costs

– Some occupations do not require it

– Insufficient time to complete 3-dose series before international travel
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 for evidence: effectiveness Moderate certainty of evidence (Level 2) due to 

concerns for risk of bias
PrEP costs

▪ Reimbursement price for vaccine 

dose: $331*(Source: CMS/ASP)

▪ Additional costs are variable 

depending on location PrEP is 

administered 

▪ We estimate $1100- $3500 for 

PrEP series

(3 vaccines + additional costs)

Figure: Location of pre-exposure vaccine administration by occupation 

in the United States; not shown is PrEP received in Emergency 

Departments which was the location for PrEP in 2% of respondents 

(Source: Blanton et al, unpublished data from CDC survey)
Proportion of PrEP costs that are out-of-pocket

Vaccination indication # reporting 

insurance would 

cover at least part 

of cost

Booster Titer

# reporting 

employer would 

cover at least 

part of cost

Booster Titer

# reporting 

EITHER would 

cover at least part 

of the cost

Booster Titer

Veterinary professionals 25% 25% 20% 40% 25% 30%

Animal control 50% 40% 54% 20% 60% 60%

Animal rehabilitationists 25% 33% 12% 20% 25% 40%

Source: Unpublished CDC data; Blanton et al
EtR: Policy question #1

Domains WG interpretation

Target population sentiments: uncertainty about 

or variability in how much people value outcomes?

No: Target population values “protection” from rabies 

and there is likely no important variability

Acceptability to stakeholders? Yes: Shorter schedule preferred by patients & providers

Reasonable and efficient allocation of resources? Yes: Cost savings and because rabies vaccine shortages 

have occurred in U.S.

Impact on equity? Probably reduced because of decreased costs

Feasible to implement? Yes: Shorter series than current series
EtR: Policy question #1

Domains WG interpretation

Target population sentiments: Does the target 

population feel desirable effects are large relative 

to undesirable effects

Probably yes

• Data supports high costs incurred by PrEP

recipients

• Persons who should receive PrEP for travel are 

known to not receive it because <21 days from 

clinic appointment to 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 immunocompetant 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 those in the #3 risk category of people who 

receive PreP?

Population

Persons 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
Problem: Long-term immunogenicity for rabies

▪ Immunology suggests that anamnestic response to an exposure occurs

▪ WHO approved 2-dose series (no booster or titers)

▪ Rabies is nearly 100% fatal

▪ WG opted for most cautious route 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

• Booster at day 21 is equivalent to current 3-dose 

series and is known to provide long-term 

immunogenicity 

• 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)
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

• Booster provides reassurance that outweighs any 

inconvenience

Target population sentiments: uncertainty about 

or variability in how much people value outcomes?

No: Target population values “protection” from rabies 

and there is likely no important variability

Acceptability to stakeholders? Yes: Stakeholders accustomed to accommodating third 

dose of rabies vaccine and will find it acceptable to 

have booster as an option

Reasonable and efficient allocation of resources? Yes: Cost savings
Costs of titer compared to booster 

▪ Titer: Cost ~$50-$75* + cost of blood draw / clinic appointment

▪ Booster: ~$331 for cost of booster + additional costs

*KSU website and word of mouth
EtR: Policy question #2

Domains WG interpretation

Impact on equity? Don’t know: some PrEP costs are out-of-pocket; 

because titer is offered as option, inequity could be 

resolved by choosing that option

Feasible to implement? Yes: Administrators could opt to schedule booster dose 

at the time of primary vaccination
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
Clinical guidance scenarios

Time (in years)

Days [0, 7 days]

2-dose PrEP

Year 3

Rabies 

exposure

To be cautious:

PEP = RIG + vaccine IM[0, 3, 7, 14 days]

No titer or 

booster
Clinical guidance scenarios

Time (in years)

Days [0, 7 days] 

2-dose PrEP

Year 3

Traveling again No titer or 

booster These situations currently are handled 

on case-by-case basis 
Acknowledgements

▪ Rabies WG

▪ Ryan Wallace

▪ Jesse Blanton

▪ Doug Campos-Outcalt

▪ Rebecca Morgan

▪ Florence Whitehill

▪ Jessica MacNeil

▪ 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?
Implications of proposed changes

Risk 

group

Population Primary 

immunog

enicity

Implications Long-term 

immunogenicity

Implications

#1 Research laboratorians

Diagnostic laboratorians

#2 Bat biologists

#3 Animal care professionals in 

terrestrial rabies regions

Animal care professionals in 

non-terrestrial rabies regions, 

students, spelunkers, 

persistent travelers

Short-term animal care 

professionals and persons 

without sustained risk for 

rabies

Titer every 6 months

IM [0, 7 

days]

Fewer vaccine doses 

but equivalent 

efficacy

Makes sense to 

consider all 

laboratorians equally

Titer check ever 6 

months1

Titer check every 2 

years2

No change

No change

Fewer vaccine doses 

and/or fewer titer checks

Same number of vaccine 

doses OR instead of 3rd

vaccine, a titer

No additional vaccine 

and no titers

Titer once (1-3 

years after 

primary series)

OR

Booster no sooner 

than day 21 and no 

later than year 3
PrEP Policy Question #1

Table 3a: 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 cointerventions would have influenced the outcome.
PrEP Policy Question #1

Table 3b: 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, 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, SD 12.9 371 364 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 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, 

SD 1.33

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

Vodopija, 1986 NR 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. 
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

20 No comparison1 PCEC, IM Not able to 

calculate2

8/9 Minimal concerns

Soentjens, 

2019

Median 29.0, NR 183 No comparison1 HDCV, IM Not able to 

calculate2

8/9 Minimal 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.
Reminder: proposed changes

Highlighted: Proposed 

changes to 2008 ACIP 

recommendations 

Red box: Today’s votes 

Primary 

immunogenicity 

Long-term 

immunogenicity 

#1 risk group

(i.e., laboratorians) IM [0, 7 days] Titers every 6 months 

after primary series

#2 risk group

(i.e., persons who 

handle bats or enter 

high density bat 

environments)

IM [0, 7 days] Titers every 2 years after 

primary series

#3 risk group (i.e., 

veterinarians, vet 

assistants, animal 

handlers, vet students, 

travelers etc.)

IM [0, 7 days]

Titer once at 2 years after 

primary series

OR

Booster once no sooner 

than day 21 and no later 

than 3 yearsȽ