By Marie Rosenthal, MS
The Advisory Committee on Immunization Practices (ACIP) recently harmonized the schedule for pre-exposure prophylaxis (PrEP) of rabies vaccination to provide the same schedule for children as adults.
In February, the ACIP recommended a two-dose intramuscular (IM) rabies vaccine series—given on days 0 and 7—in immunocompetent people 18 years of age and older for whom rabies PrEP is indicated.
The ACIP also recommended an IM booster dose of rabies vaccine—as an alternative to a titer check—for immunocompetent adults who have a sustained elevated risk for recognized rabies exposures beyond three years, such as laboratory workers, veterinary staff and others who work with animals. The booster dose should be administered no sooner than day 21 but no later than three years after the two-dose PrEP series.
The previous 2008 recommendations required three doses of PrEP over the course of 21 to 28 days. Extending the timing of the third booster dose can be a cost-effective option, especially for some traveling to a rabies endemic country, because people can wait until they return for the booster dose, experts said.
On June 24, the ACIP voted unanimously to make these same recommendations for children younger than 18 years of age.
PrEP should be administered to children who are at elevated risk for rabies exposure, such as those who travel to a canine rabies endemic country, explained Sharon Frey, MD, FACP, FIDSA, the chair of the ACIP Rabies Work Group. Dr. Frey is a professor and the clinical director for the Center for Vaccine Development, Division of Infectious Diseases, Allergy and Immunology at Saint Louis University School of Medicine.
Although bats are the most common source of rabies exposure in the United States, dogs are the most common source of rabies in many other countries, and children are at a particularly high risk for dog bites, explained Agam K. Rao, MD, a medical officer at the CDC’s National Center for Emerging and Zoonotic Infectious Diseases. In addition, they are more likely to receive multiple and severe bites, particularly to the head and neck.
Rabies immune globulin (RIG), which is used for post-exposure prophylaxis (PEP) is not always available in developing countries, and rabies vaccines may not be readily available, especially in rural areas, she explained.
There was no reason to maintain separate recommendations, Dr. Rao told the ACIP because children mount a good immune response to the primary series, and titers may even stay higher longer in children. “Since boost-ability is not a concern for adults, it should not be a concern for children,” she told the committee.
There could be problems if the schedules are not harmonized, she added. When people were following the 2008 recommendations, if the three-dose series could not be completed within 28 days before leaving the United States, people did not receive any PrEP before traveling, so there could be cases where parents would be vaccinated but not children, who are at greater risk, she explained.
And the schedules were the same in 2008.
About 170,000 doses of PrEP are given in the United States each year, mostly to travelers, but also to veterinary staff, animal control officers, laboratory personnel, wildlife biologists and others, according to Dr. Rao.
Although there was no vote about PEP, the committee heard a presentation on PEP and new formulations of RIG, which provides passive immunity before vaccine-induced humoral immunity occurs. RIG is given as part of PEP to people who did not receive PrEP or have never had PEP, according to Dr. Rao.
The ACIP has been recommending 20 IU/kg of RIG within the first seven days of initiation of a rabies vaccine. RIG should be given around the wound and the remaining administered intramuscularly in a different location than the vaccine. RIG could be diluted for large or multiple wounds.
In 2018, the World Health Organization modified its recommendations, saying RIG should only be given around the wound and the remaining should not be given in an IM injection.
There are several reasons for this change, Dr. Rao explained.
The supply of RIG in some countries is limited and very expensive, and less than 2% of people with serious wounds receive RIG.
Because dog bites are the most common cause of rabies in many of these countries, wounds are large and the maximum infiltration of RIG around a wound is sufficient, and the benefits of IM RIG administration are limited.
The WHO recommended that RIG be prioritized to high-risk exposures, people with multiple bites, deep wounds and bites to highly innervated body parts. In addition, severely immunocompromised people and those with confirmed or probable rabies or who had a bat exposure should also be prioritized.
The ACIP Rabies Work Group reviewed the 2018 position statement to see whether the United States should consider similar changes.
The group found that the data cited by the WHO were limited, and the issues in the United States were different. There was no difficulty obtaining RIG in the United States, so there was no need to limit its use.
In addition, the most common rabies exposure in the United States is from bats, and those bites tend to be very small or barely visible, so very little RIG would be administered at the wound site.
Therefore, an IM injection of the remaining product could be of benefit: Data suggest that IM RIG is detected in sera 24 hours later, according to Dr. Rao.
Dr. Rao also gave an update on the newly licensed RIG products available in the United States: HyperRab by Grifols and Kedrab by Kedrion Biopharma.
Both RIG products are prepared from plasma of donors who were hyperimmunized with rabies vaccine.
HyperRab was licensed in 2018 and is indicated for PEP along with rabies vaccine. HyperRab is a higher concentration formulation of what used to be HyperRab S/D, which is no longer distributed by the manufacturer. HyperRab has a greater concentration of anti-rabies virus antibodies within each milliliter of volume, so less volume is needed when administering PEP.
“A more concentrated product could be preferable for small bites, such as bat bites,” Dr. Rao said.
“Given differences in potency between products, oversight is needed to ensure that the correct volume is administered for a particular product,” she added.
Under certain circumstances, if a larger volume is needed, HyperRab can be diluted with dextrose 5% in water, rather than normal saline, and clinicians should be made aware of this.
Kedrab was licensed in 2017 and is similar to other RIG products, licensed as part of PEP.
“Kedrab and HyperRab actually make up most of the market share for rabies immune globulin,” Dr. Rao said.
She said production and manufacturing processes have improved for RIG products, and their safety and efficacy are similar; therefore, the work group does not recommend one over the other.
“As far as selection of a RIG product goes, the indications are the same for all of them. A more concentrated product could potentially be preferable for small wounds, like what is involved with those from a bat bite,” Dr. Rao said. “Given the differences in potency between the products, oversight is obviously needed to ensure that the correct volume is administered for a particular product. There could be errors made and twice the volume inadvertently administered if care is not taken to recognize the fact that one is more concentrated.
“It’s really up to individual facilities to decide which product they want to stock,” she said. “We’ve learned that facilities typically just stock one product.”
