ACIP Evidence to Recommendations for Booster Dose of Rabies Vaccine After the 2-dose Pre-exposure Prophylaxis Schedule

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Question: Should an IM booster dose of rabies vaccine (HDCV* or PCECV§) be recommended as an alternative to a titer check no sooner than day 21 and no later than 3 years after the 2-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 risk category #3

Intervention: Day 21 to year 3 rabies vaccine booster after [0, 7 days] rabies vaccine PrEP schedule with HDCV* or PCECV§

Comparison(s): No rabies vaccine booster after [0, 7 days] rabies vaccine PrEP schedule with HDCV* or PCECV§

Outcome: Long-term Immunogenicity

*Human diploid cell vaccine
†Purified chick embryo cell vaccine

Background:

Rabies is an acute, progressive encephalomyelitis that is nearly always fatal once symptoms begin. Rabies pre-Exposure prophylaxis (PrEP) is an important component of preventing human rabies in the United States. It does not negate the need for post-exposure prophylaxis (PEP), but simplifies PEP for persons who are at a higher risk for rabies than the general U.S. population, and is believed to provide some protection if PEP is inadvertently not sought or delayed. A 2-dose primary series is proposed for those persons for whom PrEP is indicated; robust data confirms an anamnestic response is elicited 3 years after the 2-dose PrEP schedule but there is no data evaluating whether an anamnestic response occurs later than 3 years.

For persons at elevated risk of unrecognized exposures (i.e., risk categories 1 and 2), the ACIP recommends serial titer checks at specific time intervals; this infers long-term immunogenicity. For persons at elevated risk of only recognized exposures (i.e., risk category 3), serial titers are not needed. This is because serial titers are intended for persons with unrecognized exposures. Data indicates that a 1-time titer check 1-3 years after the 2-dose primary series is an indicator of long-term immunogenicity1,2. Some people may have rabies antibody titers ≥ 0.5 IU/mL, the minimum acceptable rabies antibody titer. For those persons, no further action is needed. For those with a titer <0.5 IU/mL, a booster rabies vaccine is needed. As an alternative to the titer check, a booster can be obtained straight away; A booster at day 21/28 is equivalent to the 2008 ACIP 3-dose rabies PrEP series3 and is known to provide long-term immunogenicity. Booster doses beyond those days may provide additional options.

Of note, in the coming years, long-term immunogenicity of the 2-dose series beyond 3 years, is expected. Depending on those findings, this proposed recommendation for a booster may no longer be indicated and could be re-assessed by an ACIP committee.

Problem

Problem
Criteria Work Group Judgements Evidence Additional Information
Is the problem of public health importance? Yes

-Rabies is nearly always fatal when symptoms begin

-Approximately 5,000 animals test positive for rabies each year in the United States4. Many persons have increased risk for rabies because of occupational or recreational activities, most of which require long-term immunogenicity

-Persons in the #3 risk category require long-term immunogenicity (e.g., career veterinarians).  While it is possible that the 2-dose [0, 7 days] IM series provides long-term immunogenicity on its own, in the absence of data confirming this, a titer check to determine if a booster is needed OR a booster straight away, provide added assurance for this nearly 100% fatal illness.

 Allowing for the option of a booster straight away is important because for some persons in the target population, it is preferable to bypass the titer guidance for a booster.  The costs may differ for a titer versus a booster but additionally, time may be a consideration5:  Some may not want to obtain a titer, only to receive a result that indicates a booster is necessary; they may prefer to proceed directly to a booster. Others, however, may prefer only receiving the minimum number of vaccinations needed; these persons may like to get a booster vaccination only if a titer suggests it would be beneficial.

 

Providing more than one option for long-term immunogenicity may increase the number of people who are adequately vaccinated. The time intervals that the booster or titer can be received allows for flexibility and prevents the target population from being delayed in traveling or working.

Benefits and Harms

Benefits and Harms
Criteria Work Group Judgements Evidence Additional Information
How substantial are the desirable anticipated effects? Moderate

An anamnestic response to vaccine challenge occurred for 100% of persons who received rabies vaccine booster at the 1 year and 3 year time points. These time points are markers of long-term immunogenicity.

 We suspect that persons who receive the 2-dose [0, 7 days] series will still be able to mount an anamnestic response many years later.  However, rabies is nearly 100% fatal.  In the absence of human data beyond the 3 year time point, the potential harm inflicted if our suspicion is incorrect results in moderate desirable anticipated effects of a booster.
How substantial are the undesirable anticipated effects? Minimal

-The workgroup reviewed safety data compiled from VAERS reports for HDCV6 and PCECV7,8 vaccines, the package inserts9,10 and 25 trials published since the 2008 ACIP recommendations. No change in the safety profile were identified; these rabies vaccines have been used for decades and have a favorable safety profile.

-A booster dose is not believed to result in more adverse events; in fact, adverse events are believed to decrease as more rabies vaccines are administered

 HDCV and PCECV rabies vaccines are considered safe
Do the desirable effects outweigh the undesirable effects? Favors interventional The benefits of ensuring long-term immunogenicity outweigh the minimal risks associated with the booster dose
What is the overall certainty of this evidence for the critical outcomes? Effectiveness of the intervention:
Low		 The critical outcome was immunogenicity. Using the GRADE approach, there was low certainty that a booster after the [0, 7 days] IM schedule provides better long-term immunogenicity than the 2-dose series without a booster
Safety was not a critical outcome and not assessed using  GRADE because HDCV and PCECV have been used for decades and the safety profile is considered favorable.

Values

Values
Criteria Work Group Judgements Evidence Additional Information
Does the target population feel that the desirable effects are large relative to undesirable effects? Probably yes No research evidence identified The target population likely wants to ensure they have long-term immunogenicity for rabies.  Given the limited data that a 2-dose series alone will provide long-term immunogenicity, we expect that the benefits of a titer or a booster outweigh any inconvenience associated with receiving the booster dose.  The target population may value the decreased anxiety of acquiring rabies that a booster or titer provides.
Is there important uncertainty about or variability in how much people value the main outcomes? No important uncertainty or variability The target population likely desire a PrEP series that provides long-term immunogenicity. There is no important uncertainty or variability on that desire because the target population is at increased risk for exposure to this life-threatening infection

Acceptability

Acceptability
Criteria Work Group Judgements Evidence Additional Information
Is the intervention acceptable to key stakeholders? Yes Stakeholders are invested in ensuring the target population has long-term immunogenicity for rabies. They are accustomed to accommodating for a third dose of rabies vaccine because the 2008 ACIP recommended PrEP schedule involved 3 doses2. Stakeholders will find it acceptable to have both a booster dose option and a titer option

Resource Use

Resource Use
Criteria Work Group Judgements Evidence Additional Information
Is the intervention a reasonable and efficient allocation of resources? Yes The cost of a 3-dose series is more than that of a 2-dose series.  However, because this option will be typically favored over the titer check option by persons whose occupations cover the cost, there will not be undue burden on the target population who opts for this. Occupations that cover the cost of the booster are accustomed to high costs for rabies PrEP and might find skipping straight to booster efficient for their clinic practices over a titer check followed, potentially, by a booster dose.

Equity

Equity
Criteria Work Group Judgements Evidence Additional Information
What would be the impact on health equity? Don’t know The option for a titer check 1-3 years after completion of the 2-dose PrEP series could be less expensive for some persons; the titer check may reveal a level ≥ 0.5 IU/mL which requires no further intervention. However, for some persons, the titer may be < 0.5 IU/mL; these persons will require a booster vaccination (~$331 for booster + additional costs associated with venue where vaccine is administered) as well11. The costs of a titer followed by a booster is expected to be more than that of preceding directly to a booster and much more than a titer check alone (~$50-75 + cost of blood draw / clinic appointment). If these costs are incurred by occupational supervisors, there may be no impact on health equity
It is not known how many people might require a booster vaccination after a titer is checked. For this reason, the impact of the options for long-term immunogenicity is unknown

Feasibility

Feasibility
Criteria Work Group Judgements Evidence Additional Information
Is the intervention feasible to implement? Yes Administrators of the booster are accustomed to accommodating multiple doses of pre-exposure prophylaxis beyond a [0, 7 days] series.  They will have no difficulty with feasibility of a booster dose after a 2-dose series because the 2008 ACIP recommendations required 3 doses of rabies vaccine2 and these recommendations call for 3 rabies vaccines as well

Balance of consequences

Desirable consequences clearly outweigh undesirable consequences in most settings

Is there sufficient information to move forward with a recommendation? Yes.

Policy options for ACIP consideration

ACIP recommends the intervention

Draft recommendation

ACIP recommends an intramuscular booster dose of rabies vaccine, as an alternative to a titer check, for immunocompetent persons 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.

Additional considerations

This above language was approved for immunocompetent persons. No rabies vaccine titer is indicated for such persons after completion of the booster dose. For persons with altered immunity, the same booster recommendation applies, but a titer is needed after completion of the booster. The rabies antibody titer should be collected no sooner than 1 week after completion of the booster (but ideally 2-3 weeks after it) and it should be ≥ 0.5 IU/mL. If it is not, an additional dose should be administered followed by another titer check. If two such additional doses fail to achieve the minimum acceptable antibody titer, public health authorities should be consulted for case-specific guidance.

Final deliberation and decision by the ACIP

Final ACIP recommendation

ACIP recommends the intervention.

Additional ACIP considerations

If persons are not compliant with this recommendation,

  1. And they have not yet had an exposure, they can have the option of “catching up” by obtaining a random titer after 3 years.
    • If the titer is ≥ the minimum antibody titer by RFFIT testing set by ACIP (i.e., 0.5 IU/mL), the person is considered pre-immunized for the purposes of managing any future rabies exposures. No further titers or boosters are needed and they are considered to have long-term immunogenicity. Any future exposures would require only 2 doses of rabies vaccine for post exposure prophylaxis, [0, 7 days].
    • If the titer is < the minimum antibody titer by RFFIT testing set by ACIP (i.e., 0.5 IU/mL), the person can receive booster doses until the post-booster titer is ≥ 0.5 IU/mL. At that point, they will be considered pre-immunized for the purposes of managing any future rabies exposures.  No further titers or boosters are needed. Both immunocompetent persons and those with altered immunity would require a titer check after completion of booster doses administered greater than 3 years after the 2-dose primary PrEP series. Any future exposures would require only 2 doses of rabies vaccine for post exposure prophylaxis, [0, 7 days].
  1. And they are identified at the time they need PEP because of an exposure >3 years after the primary series:
    • The person would not be considered “previously immunized” even though they very well may have titers ≥0.5 IU/mL before the exposure occurred. The person would receive RIG + 4 doses of rabies vaccine which is indicated for persons who are not previously immunized who require rabies post-exposure prophylaxis. No risks are expected with the extra vaccine doses or the RIG that this person would receive.

References

  1. Soentjens P, Andries P, Aerssens A, et al. Preexposure intradermal rabies vaccination: a non-inferiority trial in healthy adults on shortening the vaccination schedule from 28 to 7 days . Clin Infect Dis 2018; 68:  707-14. PMID:29939243https://doi.org/10.1093/cid/ciy513
  2. Strady A, Lang J, Lienard M, Blondeau C, Jassaud R, Plotkin SA. Antibody persistence following preexposure regimens of cell-culture rabies vaccines: 10-year follow-up and proposal for a new booster policy. J Infect Dis 1998;177:1290-5.  PMID:9593014 https://doi.org/10.1086/515267
  3. Manning SE, Rupprecht CE, Fishbein D, et al. Human rabies prevention—United States, 2008: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep 2008;57(RR-3):1–28
  4. Ma X, Monroe BP, Wallace RM, et al. Rabies surveillance in the United States during 2019. J Am Vet Med Assoc. 2021 Jun 1;258(11):1205-1220. doi: 10.2460/javma.258.11.1205. PMID: 33978439.
  5. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-02/24-25/03-Rabies-Rao-508.pdf
  6. Moro PL, Woo EJ, Paul W et al. Post-Marketing Surveillance of Human Rabies Diploid Cell Vaccine (Imovax) in the Vaccine Adverse Event Reporting System (VAERS) in the United States, 1990‒2015. PLoS Negl Trop Dis. 2016 Jul 13;10(7):e0004846. doi: 10.1371/journal.pntd.0004846. PMID: 27410239; PMCID: PMC4943633.
  7. Moro PL, Lewis P, Cano M. Adverse events following purified chick embryo cell rabies vaccine in the Vaccine Adverse Event Reporting System (VAERS) in the United States, 2006-2016. Travel Med Infect Dis. 2019 May-Jun;29:80-81. doi: 10.1016/j.tmaid.2018.10.016. Epub 2018 Oct 26. PMID: 31203930; PMCID: PMC6946544
  8. Dobardzic A, Izurieta H, Woo EJ, Iskander J, Shadomy S, Rupprecht C, Ball R, Braun MM. Safety review of the purified chick embryo cell rabies vaccine: Data from the Vaccine Adverse Event Reporting System (VAERS), 1997-2005. Vaccine. 2007 May 22;25(21):4244-51. doi: 10.1016/j.vaccine.2007.02.075. Epub 2007 Mar 15. PMID: 17382435
  9. https://www.fda.gov/media/75709/download
  10. https://www.fda.gov/files/vaccines%2C%20blood%20%26%20biologics/published/Package-Insert—RabAvert.pdf
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