National Center for Emerging and Zoonotic Infectious Diseases

PEP vaccine series: Change to the series for healthy 

and immunocompromised persons

Meeting of the Advisory Committee on Immunization 

Practices 

June 24, 2021

Agam Rao, MD

Lead, ACIP Rabies Workgroup
Post-exposure prophylaxis (PEP) for persons who 

have not previously received PEP or PrEP

Rabies Vaccine 

Human Rabies 

Immunoglobulin 

(RIG)

Day 0 Days 3, 7, 14

Rabies Vaccines 
Features of an improved PEP schedule

 Effectiveness unchanged from currently recommended series

 Fewer doses than the current 4-dose schedule

 Completed sooner than the current schedule 

 Intramuscular vaccine schedule

 Robust data supporting its use
Updated WHO recommendations for PEP in healthy 

persons

 WHO
Question: What is the data for changing PEP 

schedule?
Systematic review for Kessels et al

• Objective: Inform 2018 WHO update 

for rabies PEP schedules by evaluating

• Immunogenicity and 

effectiveness of PEP schedules of 

reduced dose and duration

• New evidence on effective PEP 

protocols for special populations

• Effect of changing routes of 

administration (ID or IM) during a 

single course of PEP on the 

immunogenicity of PEP
WG considerations

 Current ACIP PEP schedules have not been problematic

 Cost considerations less critical 

 Expectations for ideal data if changes proposed

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High seroconversion rate (~100%) 

Effectiveness for all population types

Large number of subjects 

Impact of RIG on antibody levels considered

Vaccines used in the US

Route of administration can be converted to an intramuscular 

recommendation

If PEP was administered after an exposure, animal causing exposure was 

confirmed rabid
Schedules reviewed

Author/Year Schedule, vaccine, 

& participants

Results Reported limitations

Shantavasinkul

2010

-ID [0, 3, 7 days] with and 

without eRIG+ TRC

-4 site each day

-PVRV* (3 arms)

-N= 131

1) RVNA >0.5 IU/mL

2) Increased immunogenicity 

with 4-site than with TRC

1) Healthy subjects only

2) Rabies was not lab-confirmed in 

biting animals

Sudarshan 

2012

-ID [0, 3, 7 days]

-4 site each day

-PCEC* or PVRV(2 arms)

-N= 80 (40 in each arm)

1) All with RVNA >0.5 IU/mL

2) 1 year after series, 79% of 

PCECV with RVNA >0.5 

IU/mL and remainder 

boosted; 8 had inadequate

1) Healthy adult subjects only 

2) Small sample size

3) Did not evaluate vaccine + RIG

4) Observational data re: PCEC

Naranya2015 -ID [0, 3, 7 days]

-4-site each day

-PCEC* or PVRV

-N= 90 (45 in PCEC arm)

1) PCEC group with RVNA >0.5 

IU/mL on days 14, 90, 365

2) With or without eRIGhad 

similar GMT

1) Not tested in children or pregnant / 

lactating persons

2) Rabies was not lab-confirmed in 

biting animals

3) Observational data re: PCEC titers

*PVRV: Purified Vero Cell Rabies Vaccine (cell culture vaccine believed to be equally efficacious to HDCV and PCECV)
Main study that informed WHO recommendations

Author/Year Schedule, vaccine, 

& participants

Results Reported limitations

Tarantola

2019

-ID [0, 3, 7 days]

-2 site each day

-PVRV

-N= 2,805 (1739 from 

confirmed rabid animals; 

of these, only 129 got 3 

dose series)

1) No significant 

difference in deaths 

after 4-dose vs. 3-dose 

series but low power

2) Can be shortened with 

“no detectable added 

risk” with limitation in 

power

1) Low power for the outcome of 

importance

2) Vaccine used is not available in the 

U.S. but is believed to be equally 

efficacious

3) Study conducted in Cambodia, 

potentially not representative of 

U.S. population

4) Data is encouraging but more data 

is needed

*PVRV: Purified Vero Cell Rabies Vaccine (cell culture vaccine believed to be equally efficacious to HDCV and PCECV
WG conclusions

 More studies are needed before a change can be proposed to the current 

4-dose IM series

 Studies for consideration should involve

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Large number of subject

Variety of populations (e.g., children of all ages)

Vaccines licensed in U.S.

Either IM schedule or ID that can be confidently extrapolated to a 

proposed IM schedule

Evaluation of the impact of RIG on antibody titers

Titers in human subjects after vaccination and confirmation of rabies 

in the offending animal
Clinical guidance

Inactivated vaccines in immunocompromised persons

 No safety concerns

 Immune response may be inadequate

 Options for pre-exposure prophylaxis (PrEP)

• Delay PrEP until no longer immunocompromised or consider 

avoiding activities for which rabies PrEP is indicated

• Administer PrEP per recommendations for healthy persons but 

virus neutralizing antibody titers should be checked (and booster if 

lower than the minimum antibody titer threshold)
2008 rabies post-exposure prophylaxis for 

immunocompromised persons

 Avoid immunosuppressive agents during administration of PEP unless 

essential for the treatment of other conditions

 When PEP is administered to immunocompromised persons

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One or more serum samples tested for rabies virus neutralizing antibody to 

ensure acceptable antibody response

Upon consultation with public health, booster doses typically given until 

adequate titers are reached
2008 ACIP recommendations versus 2010 Update

 2008 ACIP recommendations

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5-dose series was recommended series

Same PEP series for healthy persons and immunocompromised

Titer check after completion of series was only recommended for 

immunocompromised persons (similar to previous ACIP recs)

 2010 Update: Prompted by a shortage in rabies vaccines and provided 

updated recommendations for the PEP schedule

Data assessed and 4-dose PEP series found to be effective

4-dose series replaced 5-dose series for healthy persons only
WG considerations about immunocompromised

 For immunocompromised, ACIP recommends titer check after PEP series

 More vaccine doses (and more titer checks) may be indicated accordingly

 Since titer check is needed regardless of schedule, offering it with the 

fourth dose, i.e., sooner than current guidance, has advantages

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Spare some persons unnecessary additional doses

Schedule recommendations for healthy and immunocompromised 

persons would be similar 

• Immunocompromised persons would still need titer to confirm 

adequate response

• No negative impact on patient care
Proposed clinical guidance (no vote needed)

 Titers for immunocompromised persons should still be checked after 

completion of PEP series (as has always been recommended)

 Titer should be checked with fourth dose and decisions about additional 

doses made accordingly

 Expedited titer checks occur when clinicians contact the lab where the 

titer check is occurring and indicate the importance for clinical decisionmaking

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Titer check can often be completed within 48 hours

Clinician request is needed so that facility is aware
Acknowledgements

 Susan Moore

 Deborah Briggs

 Katie Brown

 Sally Slavinski

 Matt Zahn

 David Shlim

 James Stevermer

 Elizabeth Barnett

 Karl Hess

 Sharon Frey

 Lynn Bahta

 Michael Pentella

 Pedro Moro

 Kristina Angelo

 Eun-Chung Park

 Robin Levis

 Paula Agger

 Greg Moran
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?