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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, 2021Agam 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 profileBiologicProduct
nameManufacturer Administration Potency
Human
diploid cell
vaccine
(HDCV)Imovax Sanofi Pasteur intramuscularly≥2.5 IU of
rabies
antigen
Purified
chick
embryo cell
vaccine
(PCECV)RabAvertBavarian
Nordicintramuscularly≥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*Some results from unpublished CDC data; Blanton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
EtRfor 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 effectsMinimal; 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 effectsProbably 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
inmost settings in most settingsX
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 pre -
exposure prophylaxis ( PrEP ) is indicatedRecommendation
EtRfor 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 ?
PopulationPersons in the #3 risk category for whom rabies vaccine PrEP is
recommended
InterventionDay 21 -year 3 rabies vaccine booster after [0, 7 days] rabies
vaccine PrEP schedule
ComparisonNo 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 effectsModerate
•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 effectsProbably 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 3Rabies
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 3Traveling againNo titer or
boosterThese 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 PathologyQuestions?
Implications of proposed changes
Risk
groupPopulation Primary
immunog
enicityImplications Long -term
immunogenicityImplications
#1 Research laboratorians
Diagnostic laboratorians
#2 Bat biologists
#3Animal 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
rabiesTiter every 6 months
IM [0, 7
days]Fewer vaccine doses
but equivalent
efficacyMakes sense to
consider all
laboratorians equallyTiter check ever 6
months1
Titer check every 2
years2No 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 titersTiter 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
yearAge (years) N
interventionN
comparisonVaccine Risk Ratio
[95% CI]Study limitations
(Risk of Bias)
Endy , 2019 Mean 32.4,
Range 18 -5922 24 PCEC, IM, ID 1.00
[0.89, 1.12]Some concerns1
Soentjens ,
2019Median 29.0,
Range NR242 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 -interve ntions would
have influenced the outcome.
2Method of randomization and allocation not reported. Study did not blind participants or healthcare personnel; however, unlik elythat co -
interventions would have influenced the outcome .
PrEP Policy Question #1
Table 3b: Summary of Observational Studies Reporting Outcome
Authors last name, pub
yearAge (years) N
interventionN
comparisonVaccine Risk Ratio [95%
CI]1Study 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]47/9 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]49/9 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 -
6260 59 PCEC, IM, ID 1.00 [0.96, 1.05]49/9 No concerns
Sabchareon, 1999 Mean 10,
SD 1.33190 190 HDCV, IM 1.00 [0.99, 1.01] 7/9 Minimal concerns
Vodopija , 1986 NR 49 46 HDCV, PCEC,
IM1.00 [0.94, 1.06]49/9 No concerns
1Data from observational studies, where intervention and comparison data were taken from the same people at different time poi nts, 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 we re 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 yearAge (years) N intervention N comparison Comparator
vaccineRisk Ratio
[95% CI]Study limitations (Study
quality3)
Endy , 2019 Mean 32.4,
Range 18 -5920 No comparison1PCEC, IM Not able to
calculate28/9 Minimal concerns
Soentjens ,
2019Median 29.0, NR 183 No comparison1 HDCV, IM Not able to
calculate28/9 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