Rabies is a deadly viral disease that is transmitted through the bite or scratch of an infected animal. If left untreated, rabies has a nearly 100% fatality rate. The rabies virus attacks the central nervous system and causes inflammation of the brain and spinal cord. Initial symptoms include fever, headache, weakness, and discomfort at the site of the bite. As the disease progresses, more serious neurological symptoms emerge including anxiety, confusion, hallucinations, paralysis, and seizures. Rabies causes tens of thousands of deaths worldwide every year.
Fortunately, rabies is preventable if the vaccine is administered promptly after exposure. The rabies vaccine works by prompting the body to produce antibodies that can neutralize the rabies virus before it spreads to the central nervous system. The effectiveness of the vaccine depends on receiving it soon after potential rabies exposure. But how soon is soon enough? Specifically, is 4 days too late to receive the rabies vaccine and still benefit from its protective effects?
Rabies Post-Exposure Prophylaxis
Post-exposure prophylaxis (PEP) refers to the steps taken to prevent rabies infection after being bitten or scratched by an animal that could be rabid. According to the Centers for Disease Control and Prevention (CDC), PEP consists of:
- Thoroughly washing the wound with soap and water to reduce the amount of virus particles
- Administering rabies immune globulin (RIG) to provide immediate antibodies until the vaccine kicks in
- Receiving a series of rabies vaccine shots
The rabies vaccine works in conjunction with RIG to neutralize any viral particles and stimulate the immune system to produce virus-fighting antibodies. For the best chance at preventing the onset of rabies, the CDC recommends receiving PEP as soon as possible after exposure.
Rabies Vaccine Schedule
The rabies vaccine is given as a 4-dose series over 14 days along with a single dose of RIG. The recommended schedule is:
- First vaccine dose: As soon as possible after exposure
- Second vaccine dose: 3 days after the first dose
- Third vaccine dose: 7 days after the first dose
- Fourth vaccine dose: 14 days after the first dose
- Rabies immune globulin (RIG): Given only once along with the first vaccine dose
This vaccination timeline allows the initial doses to act rapidly and provide some protection during the window before the body mounts its own antibody response. The later doses aim to boost immunity and ensure an adequate level of antibodies against the rabies virus.
Timing of PEP
Administering PEP is a race against the clock. The rabies virus travels along neurons towards the central nervous system at a relatively slow rate. But once the virus reaches the brain and spinal cord and symptoms start to appear, rabies is almost always fatal.
That’s why it’s imperative to begin PEP as soon as possible after a suspected rabies exposure. PEP has the best chance of success when started promptly after the bite or scratch. But how long can you reasonably wait before the effectiveness starts to decline?
According to the CDC, rabies PEP should begin “as soon as possible after exposure.” More specifically:
- PEP should be started immediately for any high-risk bite wounds on the head, face, hand or neck.
- For bites in other body areas, PEP is recommended within 48 hours of exposure.
- Beyond 48 hours, PEP may be considered based on the type of exposure and consultation with public health officials.
So while 48 hours is generally the recommended window for beginning PEP, exceptions may be made on a case-by-case basis. Starting PEP beyond 48 hours, while not ideal, can still offer protection against rabies in many cases.
Effectiveness of Delayed PEP
Limited studies have examined how much the effectiveness of PEP declines when administration is delayed by several days. But based on the available research, it appears PEP can retain substantial efficacy even when started 4 days after an exposure.
For example, one study looked at PEP effectiveness when started 1, 3, 4, 5 or 6 days after experimental rabies infection in mice [1]. PEP was able to protect 90% of mice when started 1 day after infection. At 3 days, PEP still protected over 80% of mice. Even when started 4 days after infection, PEP protected 50% of mice from rabies. The effectiveness dropped off sharply by day 5 and offered very limited protection by day 6.
Another study in mice found that delaying PEP by 4 days resulted in 40% survival compared to 89% survival when PEP was started right away [2]. Based on mathematical models, the viral load was estimated to be around 50-100 times higher when PEP was delayed by 4 days compared to immediate administration. Still, starting PEP 4 days after exposure provided meaningful protection compared to no treatment at all.
Human Studies
There is less data investigating delayed PEP in humans. But one study reviewed health records of people who received PEP due to exposure to rabid animals [3]. Within this group, 18 individuals started PEP 4-10 days after exposure. None of them went on to develop rabies, suggesting the delayed PEP was still effective. However, the sample size is too small to draw definitive conclusions.
Guidelines for Delayed PEP
While beginning PEP within 48 hours is ideal, several health agencies provide guidelines for administering PEP on a delayed timeline. The recommendations vary slightly between organizations, but generally include:
- PEP should be started up to 7 days after first exposure for mild wounds that can be thoroughly cleansed. The regimen can be abbreviated to two vaccine doses on days 0 and 3.
- For severe wounds or wounds near the head, neck or spinal cord, PEP may be administered up to 14 days after exposure based on clinical evaluation.
- Immunosuppressed individuals may need PEP beyond 14 days after exposure depending on antibody response.
- RIG is not recommended more than 7 days after the first dose of vaccine.
So while 4 days falls within the window for consideration of delayed PEP in most cases, healthcare providers should perform a complete risk assessment before moving forward. Factors like wound severity, location on the body, general health status and animal rabies risk in the region can all influence the potential benefits of late PEP.
Risks of Delayed PEP
When given promptly, the rabies vaccine is extremely effective with very few side effects. But the benefits decrease while the potential risks rise as more time elapses after exposure.
Delaying PEP beyond the recommended 48 hour window carries several risks including:
- Lower chance PEP will prevent rabies infection
- Potential for more severe vaccine side effects
- Need for additional vaccine doses and medical oversight
- Higher medical costs due to extra healthcare utilization
- Elevated levels of stress and anxiety over uncertainty if PEP will be effective
While starting PEP 4 days after exposure is likely better than no treatment at all, it does not guarantee success. There’s no specific cutoff where PEP suddenly becomes completely ineffective. But the longer you wait, the lower your odds of the vaccine regimen preventing a rabies infection.
Vaccinating After Exposure to a Potentially Rabid Animal
If you are bitten, scratched or have any contact with the saliva or neural tissue of a potentially rabid animal, it’s crucial to assess your risk and act quickly. In general:
- Immediately wash any wounds thoroughly with soap and water. Apply an antimicrobial if possible.
- Contact a healthcare provider as soon as possible to determine if PEP is recommended based on exposure risk.
- If PEP is recommended, begin treatment within 48 hours for the best chance of success.
- PEP may be considered up to 7 days after exposure depending on factors like wound severity and animal rabies risk in the region.
- Beyond 7 days, administration of PEP is unlikely to be helpful.
While 4 days is pushing the limits for beginning PEP, there may still be benefit compared to declining PEP outright. Discuss your specific situation with a knowledgeable healthcare provider to make an informed decision.
Conclusion
In most cases, rabies PEP should begin as soon as possible and within 48 hours of potential rabies exposure. But administering the rabies vaccine and RIG may still offer protection if started 4 days after the incident, especially if the bite is in a low-risk area. While not ideal, starting PEP after 4 days still has the potential to prevent rabies compared to no treatment at all. However, the lower success rate and increased side effect risk of delayed PEP should be carefully considered. To make the most informed decision about potentially late rabies vaccination, have an open conversation with your healthcare provider about your exposure, health history and local rabies epidemiology.