Rabies is a highly preventable viral disease which takes at least 59,000 human lives a year. Caused by the rabies virus, it causes viral encephalitis that is progressive and rapidly fatal. Rabies is estimated to cost, in financial terms, approximately US$ 8.6 billion per year.
The disease has been named a Neglected Tropical Disease (NTD) by the World Health Organization (WHO). In other words, it is one of several infectious diseases that affect mainly poor populations in the absence of proper sanitary measures, because of their close daily association with infectious vectors. The WHO has declared 2030 a target year to wipe out human rabies contracted from dogs.
This will require vigorous prevention, diagnosis, and control of this disease, using a unified approach. One of the pillars of this strategy is pre-exposure prophylaxis (PrEP) with rabies vaccine.
Another is post-exposure prophylaxis (PEP) vaccination, the single measure that has saved hundreds of thousands of lives following exposure. Almost 30 million people receive PEP every single year around the world.
Finally, dog vaccination is a central tenet of preventive programs intended to end dog rabies and dog-mediated human rabies worldwide by 2030.
Image Credit: BT PORNCHAI/Shutterstock.com
The vaccine
The first rabies vaccine to be successfully used was developed by Louis Pasteur and Emile Roux, being a live attenuated injectable rabies vaccine. based on nerve tissue homogenates, this has been replaced by modern, concentrated, purified cell culture and embryonated egg-based rabies vaccines (CCEEVs) and human diploid cellular vaccines.
The rabies vaccine is grown on three different types of cells in the laboratory. This includes human cells, chick embryo cells, and fetal monkey lung cells. The virus is grown in the cells, purified, inactivated, and then used to prepare the vaccine.
The vaccine, when used in a timely fashion and at the right dose, is 100% effective in preventing rabies.
The vaccine can be administered with equal efficacy by intramuscular or intradermal use both before and after exposure, but the former requires more expensive equipment and a higher dose. The dermis of the skin contains abundant antigen-presenting cells that are responsible for a strong immune response, thus allowing intradermal vaccination to be both cost-sparing and dose-sparing.
The vaccine vial contains one dose of the vaccine, either 0.5 or 1.0 mL, for intramuscular use. However, with intradermal microinjection technology, this can be used for 4-10 doses, at 0.1 mL Each, reducing the cost per dose, provided manufacturers shift to providing technology for intradermal rather than intramuscular administration.
With intradermal PEP, higher numbers of patients can lead to a reduction in the number of vaccine vials needed by up to 85%. Even if the first or second dose of the vaccine has been taken intramuscularly, the next can be given intradermally with an equal protective effect.
The vaccine appears to be safe in pregnancy and lactation, for immunocompromised individuals, along with routine childhood vaccinations, with other inactivated vaccines such as against Japanese encephalitis, and with live vaccines like the measles-mumps-rubella vaccines.
Pre-exposure prophylaxis
PrEP requires three doses of the rabies vaccine over one month, according to traditional protocols. However, the 2018 recommendations by the WHO include just two visits, each of which has two intradermal microinjections – one in each arm – on days 0 and 7, where day 0 is the first day of injection. Alternatively, two doses may be given intramuscularly on days 0 and 7.
Post-exposure prophylaxis
PEP is conventionally given over 4-5 doses, often in combination with rabies immunoglobulins (RIG), if given to an unvaccinated individual. The WHO 2018 guidelines do recommend a six-microinjection schedule here as well, on days 0, 3, and 7.
PEP is recommended for all bites and contacts with animal saliva unless the skin is completely intact (without any abrasion whatever). The exposed skin must be thoroughly washed with soap and water.
In all other cases, even where the skin has been scratched but is not bleeding, washing of the wound must be followed by immediate PEP. If the bite or scratch has pierced the skin, or if the mucous membrane or broken skin of any part of the body has been exposed to animal saliva, or if bat exposure has occurred, RIG administration is also recommended. The animal’s vaccination status should not be taken into consideration unless such information is known to be foolproof.
Combined strategies
If PrEP has been given, however, PEP can be given in the form of a set of four intradermal booster injections at different sites is sufficient to activate immune memory cells and elicit a much more rapid immune response after exposure.
The individual, in this case, will also not require RIG, which must be infiltrated around the wound, and is mostly unavailable in remote and rural settings in most low-and-middle-income countries (LMICs).
More recent research suggests that three visits, each with two doses of PrEP over a total of 12 years, may be as effective as the PrEP-PEP combination in high-endemicity, low-resource settings. This schedule is more feasible in such situations as it can be incorporated into the EPI.
A one- or two-visit PrEP schedule with two microinjections per dose may also offer the same benefits when coupled with a single visit for PEP if exposure occurs.
Benefits of combination strategies
The benefits include better adherence and lower costs. Further studies are going on to explore the safety and efficacy of single-visit PrEP and PEP, which would be most useful in high-risk groups. There is a need to evaluate the effect of repeated bites and longer intervals between boosters to establish current promising findings.
PEP without PrEP is slower-acting, time-sensitive and time-consuming, while PrEP increases the likelihood of survival in bitten individuals, particularly in case of so-called ‘category 3 exposure’ (eg, transdermal bites/scratches) when RIG is unavailable.”
British Medical Journal Researchers
Some scientists have gone so far as to credit PrEP with protection when exposure has not been followed by PEP, or when the latter was delayed or incomplete.
Cost-effectiveness
It is regrettable, perhaps, that with a known highly effective vaccine approach, the WHO does not recommend the use of PrEP in expanded immunization programs (EPI) citing the lack of cost-effectiveness. The Philippines and Peru had three-visit PrEP for children in highly endemic areas.
Both were then shut down. The Philippines cited vaccine shortages, which shows the need to upscale rabies vaccine production worldwide. Lacking this, manufacturers will target high-income countries whose travelers use PrEP before they begin journeys to endemic spots.
However, researchers have shown that in areas with an annual incidence of bites of 2.6%, that is, where just under half the children may expect to be exposed by the age of 15 years, PrEP may be as cost-effective as the other vaccines included in EPIs with the use of intradermal injections, new schedules, and the ability to target high-risk groups.
Moreover, if entire countries shift to PrEP, economies of scale kick in, which could favor production for endemic LMICs over the long term. The use of less expensive manufacturing technologies such as micro facilities, and vaccines that are shelf-stable with lower packaging volume, could drive this shift.
Canine rabies
Rabies among dogs could be eliminated by enforcing dog vaccination, which would immediately prevent 99% of cases among humans if extended to at least 60-70% of dogs. This requires political will and continuing support, one way of which might be to link human and dog vaccination campaigns for rabies over the next few years.
Conclusion
With a bite risk of 0.3%–1.5% among travelers in highly endemic zones, PrEP became the norm. Meanwhile, as one child dies of rabies every 20 minutes, the overwhelming majority in endemic areas of the world, the debate continues as to the cost-effectiveness of PrEP among those living there as opposed to those simply visiting.
The availability of less costly, more stable, vaccines, more efficient injection devices and schedules, and above all, the need to avoid discriminatory medical practices, seems to compel a worldwide drive towards the eradication of rabies through vaccination.
References: