Author(s): David Shlim

Prior to the coronavirus disease 2019 (COVID-19) pandemic, few topics in travel medicine prompted more concern and questions than the prevention of rabies in travelers. Rabies prevention presents unique issues for the travel medicine clinician, because it is the one infectious disease that can be prevented, either through a combination of pre- and postexposure immunizations or through postexposure treatment with rabies immune globulin (RIG) and vaccine. Prevention is possible because the time of the bite can almost always be recognized, and immunoprophylactic intervention can stop clinical disease from developing. The seeming complexity of the issues surrounding wound care, timing of administration, deviations from standard schedules, the cost of preexposure immunization, and the difficulty of finding vaccine and RIG while traveling can make the travel medicine practitioner’s head spin.

The good news is that we have developed a method of preventing rabies encephalitis that is virtually 100% effective. The challenges that remain are the lack of availability of RIG in many areas of the world, the expense of both pre- and postexposure care, and the ongoing endemicity of rabies in street dogs in many areas. To keep the travel medicine approach to rabies prevention in perspective, 1–2 cases of rabies are reported in travelers per year, in contrast to >50,000 rabies deaths in resource-poor, low- and middle-income countries.

The 2-dose Preexposure Rabies Vaccine Schedule

World Health Organization Recommendations

In 2017—partly to address the lack of progress in decreasing rabies in the world—a World Health Organization (WHO) expert committee endorsed a 2-dose rabies preexposure immunization schedule in place of the previous 3-dose schedule. The committee was hoping to make preexposure immunization more affordable and convenient for local people, and more desirable and feasible for travelers. The seemingly sudden announcement spurred national health agencies to do their own research and decide whether to harmonize with WHO, or stick to their own recommendations. Conclusions so far have varied around the world.

WHO also endorsed the use of wound-only administration of RIG, in which an anatomically appropriate dose (not to exceed the weight-calculated amount) of RIG is injected around the wound, but where the remaining calculated dose is not administered intramuscularly. This idea was based on the thinking that RIG is most valuable at the site of the wound, and little additional RIG makes its way into the bloodstream. The further rationale behind this approach is that it leaves hard-to-obtain and expensive RIG available to treat more people. But measurable amounts of RIG are detected in the blood after its intramuscular administration, and whether this is critical to prevention of rabies encephalitis is not really known.

Advisory Committee on Immunization Practices Guidance

In the United States, the Advisory Committee on Immunization Practices (ACIP) convened a working group to evaluate similar questions to those considered by WHO. In 2021, ACIP voted to approve a 2-dose preexposure rabies immunization series, with the proviso that either a third dose be given within 3 years, or a serological test be performed to document seroconversion. Although the working group felt that “boostability” likely will extend beyond 3 years, there were no data yet available to support this.

In addition, and in contrast to WHO recommendations, ACIP elected to retain the current guidance of calculating RIG dose based on patient weight, administering an amount feasible around the wound and delivering the rest into muscle. This raises the question of whether Americans will receive the ACIP-recommended full RIG dose in countries that have adopted WHO’s wound-only RIG administration guidance. This might be yet another reason for recommending preexposure prophylaxis.

After a high-risk exposure, travelers who received 2 (or 3) doses of rabies vaccine before travel need to receive 2 more doses of rabies vaccine, 3 days apart. Conversely, unimmunized travelers exposed to rabies and other lyssaviruses will require—according to US standards—a series of 4 or 5 doses of rabies vaccine intramuscularly over a 2- to 4-week period, and infiltration of RIG. Because human and equine RIG often are unavailable in low- and middle-income countries, preexposure rabies immunization can facilitate the traveler’s access to adequate postexposure rabies prophylaxis.

In the United States, however, where a single dose of rabies vaccine can exceed $400, cost has been a deterrent to preexposure prophylaxis. Although the new ACIP guidelines have reduced the associated inconvenience of 3 pretravel clinic visits extending over several weeks to just 2 visits 7 days apart, the high price might influence a traveler’s decision about whether to accept preexposure prophylaxis. Even when modern cell-culture rabies vaccine was first introduced in the early 1980s, at approximately $45 per dose, many people already considered the vaccine too expensive.

Intradermal Preexposure Rabies Immunization

Intradermal (ID) rabies immunization began almost as soon as the intramuscular (IM) human diploid cell vaccine (HDCV) was manufactured. By reconstituting the 1.0 mL of vaccine in the vial, practitioners could draw up approximately eight 0.1-mL doses. One problem was that the entire vial had to be used within a few hours of reconstituting, meaning that a provider had to either be working in a busy clinic or lining up groups of people (e.g., families) for rabies immunization all at the same time.

Early studies of the immune response to ID rabies vaccine, using HDCV and later, other rabies vaccines, were uniformly encouraging. Virtually 100% of vaccinees seroconverted. A 1982 statement by ACIP reviewed data on >1,500 vaccinees and declared, “It appears that, with this vaccine, the 0.1-mL ID regimen is an acceptable alternative to the currently approved 1.0-mL IM regimen for preexposure prophylaxis.” ACIP called upon manufacturers to produce a product with appropriate packaging and labeling.

In 1986, the Mérieux Institute (now Sanofi Pasteur) received approval to market a 0.1-mL dose in an individual syringe. Sharing reconstituted vials of 1.0 mL between patients remained off-label. Although the new product solved the logistical problem of providing individual travelers with an ID dose, the cost of the prepackaged ID dose was still 75% of the full 1.0-mL IM dose.

ACIP continued to endorse the concept of ID preexposure rabies immunization in a 1999 statement on rabies prevention. Three lots of a prepackaged rabies ID vaccine were recalled in 2000, however, for having a potency that fell below the specification level before the expiration date. In 2001, the ID rabies vaccine was withdrawn from the market. Since then, authorities in the United States have not recommended sharing 1.0-mL vials for ID rabies immunization because the manufacturer has not applied to the US Food and Drug Administration for the appropriate packaging and labeling. This lack of endorsement of ID preexposure immunization has frustrated some travel medicine professionals.

With 2 decades more experience in using ID preexposure rabies immunization, the concept is now well accepted and routinely used in many parts of the world; ID administration remains off-label in the United States, however, due to the aforementioned packaging issues. Some clinics relying on preexposure ID dosing require vaccinated travelers to have a titer drawn after the series is completed to confirm seroconversion. This may save some money, but requires an additional clinic visit and even more time before travel.

Postexposure Prophylaxis

A wide variety of postexposure vaccine regimens are now used around the world, some of which use multisite intradermal vaccine doses. From the point of view of the traveler, perhaps the best strategy would be to try to use postexposure regimens that are approved in the traveler’s home country, which could create the most confidence and make it easier to complete at home any regimens initiated abroad.

Prevention: The Best Medicine

I recently noticed that travelers are almost never bitten a second time in their entire lives, and experienced travelers and expatriates, including most travel medicine professionals, are never bitten at all. This led me to believe that it might be possible to educate travelers on how to avoid bites by making them better aware of animal behaviors and to keep their distance.

Perhaps greater emphasis on bite prevention should become a priority during the pretravel visit. As travel medicine professionals, we can analyze our own behaviors in avoiding bites and transmit that information to travelers. Avoiding bites altogether would be the best way to help reduce anxiety-ridden travel and urgent telephone calls to obtain postexposure immunization in resource-poor settings.

. . . perspectives chapters supplement the clinical guidance in this book with additional content, context, and expert opinion. The views expressed do not necessarily represent the official position of the Centers for Disease Control and Prevention (CDC).