ACIP Evidence to Recommendations for Rabies Pre-exposure prophylaxis with a 2-dose Schedule

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Question: Should a 2-dose pre-exposure prophylaxis (PrEP) series involving HDCV* or PCECV† intramuscular (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(s): [0, 7, 21/28 days] rabies vaccine PrEP schedule

Outcome: 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. PrEP should be considered for persons who participate in the following: 1) Work with research-grade high concentration rabies virus or rabies virus that could inadvertently be aerosolized because of laboratory manipulation, 2) activities that might lead to unrecognized exposures (e.g., from a nick in PPE while interacting with bats) for which a person would not know to seek PEP, 3) frequent interaction with animals that might inflict recognized exposures like scratches or bites (e.g., work as a veterinary technician), and 4) international travel to canine-rabies endemic regions where PEP may not be easily accessible.

The ACIP has recommended PrEP for decades; in 2008, the ACIP recommended a 3-dose [0, 7, 21/28 days] intramuscular (IM) rabies vaccine series. However, many persons recommended to receive PrEP, do not receive it.  Data published since the 2008 recommendations support fewer vaccine doses for rabies PrEP; a 2-dose series was recently adopted by the World Health Organization.

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 States1. Many persons have increased risk for rabies because of occupational or recreational activities. However, only unusual cases of human rabies have occurred in vaccinated persons underscoring the importance of PrEP for preventing human rabies in the United States

-Worldwide, the World Health Organization estimates that 59,000 people die from rabies each year2. Travel-associated human rabies cases have occurred among persons in the United States. CDC’s Yellow Book states that children who travel to canine-rabies endemic regions are at a particular risk for rabies. It mentions their inquisitive nature, inability to read behavioral cues from dogs, and increased likelihood for severe bites to high-risk anatomic regions due to short stature in recommending rabies PrEP for travelers to canine rabies endemic regions, including children3

Benefits and Harms

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

Out of 264 persons receiving a 2-dose primary rabies vaccination series, 100% achieved a titer level at or above 0.5 IU/mL when measured 2-to-3 weeks following the second dose. Similarly, 100% of 264 persons receiving a 3-dose primary series achieved a titer level at or above 0.5 IU/mL when measured 2-to-3 weeks following the third dose. This data indicates the 2-dose PrEP rabies vaccine series is just as efficacious as the 3-dose PrEP rabies vaccine series. Since the desirable anticipated effects are the same, the added benefit of the 2-dose series for this outcome is minimal
How substantial are the undesirable anticipated effects? Minimal

The workgroup reviewed safety data compiled from VAERS reports for HDCV4 and PCECV vaccines5,6, the package inserts7,8, 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. Safety from a 2-dose versus a 3-dose PrEP series was therefore not evaluated in the grading of recommendations analysis
Do the desirable effects outweigh the undesirable effects? Favors both -The target antibody titer, 0.5 IU/mL, is achieved 2-3 weeks after both the 2-dose and 3-dose rabies PrEP vaccine series
What is the overall certainty of this evidence for the critical outcomes? Effectiveness of the intervention:
Moderate		 The critical outcome was immunogenicity. There was moderate certainty (level 2) of the evidence. Unclear reporting of randomization and allocation concealment (risk of bias) resulted in a decrease from level 1 to level 2.
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 – The target population would likely appreciate a shorter series that requires fewer vaccines, is less expensive, and provides the same primary immunogenicity as the current 3-dose series

-If a 2-dose series is introduced, educational material may be helpful. This material could stress the role of PrEP and explain that immunogenicity of the 2-dose series is comparable to that of a 3-dose series.

-KAP surveys may be considered to monitor the perception of the target population to the proposed recommendation. Misconceptions identified could then be addressed
Is there important uncertainty about or variability in how much people value the main outcomes? No important uncertainty or variability The target population values protection from acquiring rabies. A large number of people in the United States receive rabies post-exposure prophylaxis each year because of concern for rabies.

Acceptability

Acceptability
Criteria Work Group Judgements Evidence Additional Information
Is the intervention acceptable to key stakeholders? Yes A shorter series would be appreciated by clinical providers, public health officials, and patients who all prefer a simpler vaccine schedule that is less expensive than the current schedule.  Travelers are known to schedule clinic appointments shortly before scheduled travel, i.e., without enough time to receive the 3-dose PrEP schedule which requires at least 21 days9,10. It will be easier to fit appointments for 2 vaccines than for 3 vaccines, before travel and before the start of high-risk activities

Resource Use

Resource Use
Criteria Work Group Judgements Evidence Additional Information
Is the intervention a reasonable and efficient allocation of resources? Yes The reimbursement price for a rabies vaccine dose is approximately $331.  Additional costs are variable depending on the location where PrEP is given (e.g., emergency room versus occupational health/travel clinic). Unpublished CDC and Minnesota Department of Health data suggest total cost of a 3-dose rabies PrEP series may range from $1100-$350011
Some persons who require rabies PrEP because of occupational risk, pay out-of-pocket for it. For example, veterinary blogs indicate that even with subsidized costs, receiving the 3-dose rabies PrEP can be onerous to veterinary students. A 2-dose series would be less expensive for all persons for whom the ACIP recommends a 2-dose rabies PrEP series, including travelers who always pay out-of-pocket for travel-associated vaccines.
Estimated cost of a 3-dose vaccination series is ~$1800 more than that for a 2-dose vaccination series
 -Fewer costs to the patient would be associated with the shorter series, thereby making the intervention a reasonable and efficient allocation of resources to all populations for whom it is indicated

-Rabies vaccine shortages have occurred in the U.S. A shorter vaccine schedule may prevent shortages from impacting PrEP administration

-Rabies PrEP is often not covered by medical insurances or workplaces; out-of-pocket costs are high

Equity

Equity
Criteria Work Group Judgements Evidence Additional Information
What would be the impact on health equity? Probably increased Many who receive rabies PrEP incur personal costs, including those who require these for occupational risks. Such persons are known to not be receive PrEP, possibly, because of costs. Travelers pay out-of-pocket for rabies PrEP as well.  Equity may increase if the series was more affordable A shorter series could potentially make the PrEP series more accessible to persons who would not otherwise have been able to afford the costs.

Feasibility

Feasibility
Criteria Work Group Judgements Evidence Additional Information
Is the intervention feasible to implement? Yes -No barriers are expected to implement this shorter series. With a 3-dose series, stakeholders often find it difficult to ensure all 3 doses are administered before travel or work. Implementing a shorter series will be easier to implement and is feasible.

-Management challenges are expected to be equivocal to those currently faced when deviations in the schedule occur

Balance of consequences

Desirable consequences probably 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 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.

Additional considerations

This series is shorter than the current series for immunogenicity up to 3 years; beyond that, additional studies are needed in order to confirm that immunogenicity persists.  Until then, recipients should follow the titer and booster recommendations for their risk category.

This above language was approved for immunocompetent persons. No rabies vaccine titer is indicated for such persons after completion of the rabies PrEP series. For persons with altered immunity, the same series is recommended, but a titer is needed after completion of the PrEP series; a rabies antibody titer no sooner than 1 week after completion of the series (but ideally 2-3 weeks after 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

Pros:

-Certain people will only need a 2-dose series of PrEP (e.g., persons who only have a risk for rabies for a period <3 years)

-Robust data indicates people are adequately protected for rabies exposures through the 3-year time point after completion of a 2-dose primary series, and do not need to receive the 3rd dose before traveling or beginning a job that requires rabies PrEP

-The rabies workgroup believes more people who are at-risk and recommended by ACIP to receive PrEP will be vaccinated because of the fewer doses and resulting lower costs

Cons:

-Care will need to be taken that persons whose risk for rabies persists beyond 3 years, follow the recommendations for a booster or titer (i.e., Recommendation #2)

References

  1. 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.
  2. Hampson K, Coudeville L, Lembo T, et al. Estimating the global burden of endemic canine rabies. PLoS Negl Trop Dis. 2015 Apr 16;9(4):e0003709. doi: 10.1371/journal.pntd.0003709. Erratum in: PLoS Negl Trop Dis. 2015 May;9(5):e0003786. PMID: 25881058; PMCID: PMC4400070.
  3. Wallace RM, Petersen BW, and Shlim DR. Travel-Related Infectious Diseases. CDC Yellow Book Chapter 4(78). https://wwwnc.cdc.gov/travel/yellowbook/2020/travel-related-infectious-diseases/rabies
  4. 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.
  5. 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.
  6. 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
  7. https://www.fda.gov/media/75709/download
  8. https://www.fda.gov/files/vaccines%2C%20blood%20%26%20biologics/published/Package-Insert—RabAvert.pdf
  9. Yates JA, Rao SR, Walker AT, et al. Global TravEpiNet Consortium. Characteristics and preparation of the last-minute traveler: analysis of vaccine usage in the Global TravEpiNet Consortium. J Travel Med. 2019 Sep 2;26(6):taz031. doi: 10.1093/jtm/taz031. PMID: 31044254; PMCID: PMC6736758.
  10. Walker XJ, Barnett ED, Wilson ME, et al. Boston Area Travel Medicine Network (BATMN). Characteristics of Travelers to Asia Requiring Multidose Vaccine Schedules: Japanese Encephalitis and Rabies Prevention. J Travel Med. 2015 Nov-Dec;22(6):403-9. doi: 10.1111/jtm.12237. Epub 2015 Sep 29. PMID: 26420372.
  11. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-02/24-25/03-Rabies-Rao-508.pdf
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