Rabies is a zoonotic viral disease that poses a significant public health challenge globally, with a particularly severe impact in regions such as Asia and Africa. The disease is caused by the Lyssavirus of the Rhabdoviridae family, a highly neurotropic virus that is typically transmitted through the saliva of infected animals. Among these animals, dogs are the most common vectors, contributing to the majority of human rabies cases. Despite being a preventable disease through timely vaccination and appropriate wound management, rabies continues to cause approximately 59,000 deaths annually. This high mortality rate is largely attributable to delayed or inadequate post-exposure prophylaxis (PEP), which is critical in preventing the onset of symptoms and eventual fatality after exposure.^1-4

The public health burden of rabies is exacerbated in low-resource settings where access to vaccines and medical care may be limited. Children under the age of 15 are disproportionately affected, highlighting the need for targeted interventions in this vulnerable population. Furthermore, rabies control requires a multifaceted approach that includes not only vaccination of humans but also mass vaccination of animal reservoirs, particularly dogs, to reduce the incidence of transmission.^5-7

In recent years, there have been significant advancements in rabies vaccination protocols and guidelines for managing animal bites. These updates aim to improve the efficacy of both pre-exposure prophylaxis (PrEP) for high-risk individuals and post-exposure prophylaxis (PEP) for those potentially exposed to the virus. Newer vaccines and immunoglobulins, including monoclonal antibodies, have been developed to enhance immune responses and provide longer-lasting protection. Additionally, updated guidelines emphasize the importance of immediate and thorough wound care, along with timely administration of vaccines and rabies immunoglobulins.^8-11

This review seeks to provide a comprehensive analysis of these recent advances and updated guidelines. By synthesizing the latest research and recommendations, the review aims to offer healthcare professionals, policymakers, and the general public a detailed understanding of effective rabies prevention and control strategies. The goal is to mitigate the impact of rabies worldwide, moving closer to the elimination of this deadly disease.

Rabies remains a critical public health issue, endemic in over 150 countries worldwide, with the vast majority of cases concentrated in Asia and Africa. According to the World Health Organization (WHO), an alarming 95% of rabies-related deaths occur in these regions. This high incidence rate is attributed to various factors, including large populations of stray dogs, limited access to healthcare, and insufficient implementation of rabies control measures. Particularly concerning is the impact on children under the age of 15, who represent a significant portion of these fatalities. This demographic's vulnerability underscores the urgent need for targeted interventions and educational programs to protect pediatric populations from rabies.

Regional Statistics14-16

• Asia: Asia accounts for 59.6% of global rabies cases. The high prevalence in this region can be attributed to dense human and animal populations, particularly in countries like India and China, where dog-mediated rabies is widespread.

• Africa: Africa is responsible for 36% of global rabies cases. Similar to Asia, challenges such as large populations of stray dogs, inadequate healthcare infrastructure, and limited access to vaccines contribute to the high incidence of rabies in this region.

• India: Within Asia, India is a critical focal point for rabies, accounting for 59.9% of rabies deaths in the region and 35% of deaths worldwide. This statistic highlights the urgent need for effective rabies control measures in India, including mass vaccination of dogs, improved access to post-exposure prophylaxis (PEP), and public education campaigns to raise awareness about rabies prevention.

   

Despite the high burden of rabies in many parts of the world, certain regions have successfully eliminated the disease through rigorous control measures. Countries such as Australia, Taiwan, Cyprus, Japan, Ireland, New Zealand, the United Kingdom, Finland, and various islands in the Western Pacific have been declared rabies-free. These successes are often due to comprehensive vaccination programs, strict animal control policies, and natural geographical barriers like water bodies that prevent the spread of the virus. In India, the Lakshadweep and Andaman and Nicobar Islands are also rabies-free, demonstrating that with concerted effort, rabies can be controlled and eliminated.

Pathogenesis and Transmission15-18

Understanding the pathogenesis and transmission dynamics of rabies is crucial for developing effective prevention and control strategies. Rabies transmission primarily occurs through bites from infected animals. When a rabid animal bites, virus-laden saliva enters the body through broken skin or mucous membranes. This method of transmission is particularly effective because the virus has a direct entry point to begin its infection process.

Common Modes of Transmission

• Direct Bites: The most prevalent mode of transmission. Rabies is typically transmitted through the bite of a rabid animal, which introduces the virus into the victim’s body.

• Licks: On broken skin or mucous membranes. Although less common than bites, licks from rabid animals can also transmit the virus if there is a break in the skin or if the saliva comes into contact with mucous membranes.

• Scratches: From infected animals. Scratches can introduce the virus if the rabid animal's saliva contaminates the wound.

   

Uncommon Modes of Transmission

• Aerosol Transmission: Inhalation of virus-laden particles. This mode is rare but possible in specific settings, such as laboratories where high concentrations of the virus might be present.

• Organ Transplantation: Transmission through the transplantation of infected organs. Although extremely rare, there have been documented cases of rabies transmission through organ transplants from undiagnosed infected donors.

• Ingestion: Rare cases involving the ingestion of infected tissues, usually related to traditional medicinal practices. This mode of transmission is uncommon and typically associated with specific cultural practices.

   

The rabies virus cannot penetrate intact skin and requires an entry point, such as a bite wound or abrasion. Once the virus enters the body, it travels along peripheral nerves at a rate of 200-400 mm per day to reach the central nervous system (CNS). This neurotropic movement is facilitated by the virus's ability to hijack the host's nervous system transport mechanisms. In the CNS, the virus replicates extensively, causing encephalitis, which is the hallmark of rabies infection. This inflammation of the brain leads to severe neurological symptoms and is ultimately fatal if not treated promptly. After replicating in the CNS, the virus spreads centrifugally to various organs, including the salivary glands, which are crucial for further transmission to other hosts.

Clinical Presentation of Rabies19,20

The clinical course of rabies in humans is a dire progression that can be divided into two distinct stages: the prodromal stage and the paralytic stage. Each stage presents a unique set of symptoms that escalate in severity, ultimately leading to the patient's death if not managed promptly.

Prodromal Stage

The prodromal stage, which typically lasts 3-4 days, marks the initial phase of rabies infection in humans. During this period, patients often present with non-specific symptoms that can be easily mistaken for other viral infections. Common symptoms include fever, headache, malaise, and localized pain or paresthesia at the site of the animal bite. These initial symptoms are often accompanied by neurological manifestations such as agitation, anxiety, and excitation, which reflect the virus's early impact on the central nervous system (CNS).

One of the hallmark signs of the prodromal stage is the development of aerophobia (fear of air drafts) and photophobia (fear of light). These symptoms are indicative of the heightened sensory responses associated with rabies and can be distressing for the patient. The presence of these symptoms, along with a history of animal exposure, should prompt immediate medical evaluation for rabies.

Paralytic Stage

Following the prodromal stage, the disease rapidly progresses to the paralytic stage, typically within 2-3 days. This stage is characterized by severe neurological symptoms that are often unmistakable. One of the most notable and distressing symptoms is severe hydrophobia (fear of water), which leads to painful spasms in the throat muscles whenever the patient attempts to drink. This symptom is nearly pathognomonic for rabies and is a critical diagnostic indicator.

In addition to hydrophobia, patients in the paralytic stage exhibit difficulty swallowing, hypersalivation, and convulsions. These symptoms are a result of extensive viral replication in the CNS and subsequent inflammation. The disease progresses rapidly during this stage, often leading to coma and death within a few days. The rapid progression and severity of symptoms underscore the importance of early intervention and prophylactic treatment following potential exposure to the rabies virus.

Diagnosis of Rabies21,22

Diagnosing rabies in humans relies heavily on clinical observation and the patient's history of potential exposure to rabid animals. Given the characteristic symptoms such as hydrophobia and aerophobia, clinicians can often suspect rabies based on clinical presentation alone. However, confirmatory laboratory tests are essential to establish a definitive diagnosis.

Confirmatory Laboratory Tests

1. Antigen Detection: This method involves using immunofluorescence to detect rabies virus antigens in skin biopsies. The nape of the neck is a preferred site for these biopsies due to the high likelihood of detecting viral antigens in nerve-rich tissues.

2. Virus Isolation: Rabies virus can be isolated from various bodily fluids, including saliva, cerebrospinal fluid (CSF), and other secretions. This method helps in identifying the presence of the virus in the patient's body.

3. Histopathological Examination: Post-mortem analysis of brain tissues can reveal Negri bodies, which are eosinophilic, intracytoplasmic inclusions found in neurons infected with the rabies virus. The presence of Negri bodies is a definitive marker of rabies infection.

These diagnostic tools are crucial for confirming rabies, particularly in cases where clinical symptoms are ambiguous or where there is a need to differentiate rabies from other neurological disorders. Prompt and accurate diagnosis is essential for initiating appropriate post-exposure prophylaxis and for managing the disease in exposed individuals.

Treatment and Management of Rabies^21-23

Rabies is almost invariably fatal once clinical symptoms appear, making prevention through vaccination and immediate post-exposure prophylaxis (PEP) critical. The cornerstone of rabies management is to prevent the onset of symptoms through prompt and appropriate post-exposure measures. However, once clinical signs manifest, the focus shifts to supportive care to alleviate symptoms and prevent complications.

Preventive Measures

• Vaccination: Pre-exposure prophylaxis (PrEP) is recommended for high-risk individuals such as veterinarians, animal handlers, and travelers to endemic areas. Post-exposure prophylaxis (PEP) should be initiated immediately after potential exposure, involving wound cleansing, rabies immunoglobulin (RIG) administration, and a series of rabies vaccinations.

   

Supportive Care

Once clinical rabies develops, the treatment is palliative and focuses on maintaining patient comfort and managing symptoms:

• Isolation: Patients with rabies should be placed in a quiet, dimly lit room to minimize external stimuli that can trigger spasms and exacerbate symptoms. Isolation also helps prevent further agitation and potential harm to the patient and caregivers.

• Sedation and Pain Management: Use of sedatives, such as morphine, is crucial in managing anxiety, agitation, and pain. Sedation helps reduce the frequency and severity of spasms and convulsions, providing some relief to the patient.

• Muscle Relaxants: To control spastic contractions and muscle spasms, muscle relaxants may be administered. These medications can help ease the painful spasms associated with hydrophobia and other neurological symptoms.

• Hydration and Nutrition: Ensuring proper hydration and nutrition is vital, as patients often have difficulty swallowing (dysphagia) and may refuse to drink due to hydrophobia. Intravenous fluids and parenteral nutrition may be necessary to maintain hydration and provide essential nutrients.

• Monitoring and Support: Continuous monitoring for respiratory and cardiac complications is essential. Respiratory support, including mechanical ventilation, may be required if the patient develops respiratory failure. Cardiac monitoring helps detect and manage any arrhythmias or other cardiac issues that may arise.

   

Effective management of rabies hinges on prevention through timely vaccination and post-exposure prophylaxis. Once clinical symptoms appear, the prognosis is grim, and treatment becomes primarily supportive. Providing a calm environment, managing pain and anxiety with sedatives, controlling muscle spasms, and ensuring hydration and nutrition are critical components of care. Continuous monitoring and support for respiratory and cardiac functions are also essential. Understanding and implementing these treatment protocols can help healthcare providers offer the best possible care to patients afflicted with this devastating disease.

Guidelines on Animal Bite Management^23-27

Given the fatal nature of rabies, prompt and appropriate management of animal bites is essential, particularly in endemic areas. The following guidelines provide a comprehensive approach to assessing and managing animal bites to prevent the onset of rabies.

Assessing Vaccination Status

One of the first steps in managing an animal bite is to assess and document the vaccination status of the biting animal. This is crucial as it can influence the post-exposure prophylaxis (PEP) strategy. If there is any uncertainty or lack of documentation regarding the animal’s vaccination status, it is safer to proceed with full PEP. This precautionary measure helps ensure that the risk of rabies infection is minimized.

Provoked vs. Unprovoked Bites

All animal bites should be treated as potential rabies exposures, irrespective of whether the bite was provoked or unprovoked. Provoked bites, such as those occurring when an animal is disturbed or threatened, may present a lower risk of rabies compared to unprovoked bites. However, the distinction does not eliminate the need for PEP. Given the high fatality rate of rabies, it is prudent to consider PEP for all bites.

Bites by Wild Animals

Bites from wild animals are particularly concerning and should be treated as Category III exposures. This category warrants immediate PEP due to the higher likelihood of rabies transmission. Wild animals, including bats, foxes, and raccoons, are known reservoirs of the rabies virus, and their bites pose a significant risk.

Human-to-Human Transmission

Although extremely rare, there have been instances of potential human-to-human transmission of rabies, primarily through organ transplants. In such cases, PEP may be administered as a precautionary measure to prevent the spread of the virus. This approach underscores the importance of vigilance and precaution in managing potential rabies exposures.

Categories of Exposure

Rabies exposure is categorized based on the type of contact with the suspect animal:

1. Category I: Touching or feeding animals, contact of intact skin with animal secretions.

   • Treatment: Counsel the patient and wash the area with soap and water to minimize any risk.

2. Category II: Nibbling of uncovered skin, minor scratches without bleeding.

   • Treatment: Immediate PEP with vaccination to prevent rabies infection.

3. Category III: Single or multiple transdermal bites, licks on broken skin, mucous membrane contamination, contact with bats.

   • Treatment: Immediate PEP with Rabies Immunoglobulin (RIG) and vaccination to provide immediate protection and initiate an immune response.

      

Local Wound Management

Proper wound management is critical in reducing the risk of rabies infection following an animal bite:

• Do’s:

  • Wash the wound immediately with soap and running water for at least 15 minutes to reduce viral load.

  • Apply antiseptics such as povidone-iodine or alcohol to disinfect the wound.

  • Infiltrate RIG into and around the wound for Category III exposures to neutralize the virus locally.

• Don’ts:

  • Do not touch wounds with bare hands to avoid further contamination.

  • Avoid applying irritants such as soil, chilies, oil, lime, or herbs, as they can exacerbate tissue damage and do not neutralize the virus.

  • Do not cauterize wounds, as this can cause additional tissue damage and does not effectively kill the virus.

     

Passive Immunization

Rabies Immunoglobulins (RIG)

• Human RIG (HRIG): Administered at 20 IU/kg, commonly available at 150 IU/ml. It provides immediate passive immunity by neutralizing the virus at the wound site.

• Equine RIG (ERIG): Administered at 40 IU/kg, commonly available at 300 IU/ml. ERIG is an alternative to HRIG, especially in regions where HRIG is unavailable.

   

RIG should be infiltrated into and around the wound. If the volume of RIG is insufficient, it can be diluted with sterile saline. Importantly, RIG should not be injected intramuscularly away from the wound site as this could suppress the vaccine-induced antibody production.

Rabies Monoclonal Antibodies (R-Mab)

• Fully Human R-Mab (e.g., Rabishield): Administered at 3.33 IU/kg. It offers a lower risk of adverse reactions and easier infiltration compared to other forms of RIG.

• Murine R-Mab: Administered at 40 IU/kg. Although effective, it is less preferred due to a higher risk of immunogenicity.

   

Active Immunization (ARV)

Intramuscular (IM) Regimens

• Essen Regimen: Consists of 5 doses administered on days 0, 3, 7, 14, and 28. This regimen is widely used and provides robust protection against rabies.

• Zagreb Regimen: Consists of 4 doses—two on day 0 (one in each deltoid or thigh site) and one each on days 7 and 21. This regimen is an alternative that reduces the number of clinic visits required.

   

Intradermal (ID) Regimens

• Updated Thai Regimen: Involves 2-site ID injections on days 0, 3, 7, and 28. This regimen is cost-effective and has been shown to be equally efficacious as IM regimens.

• WHO 2018 Approved ID PEP: Involves 2-site ID injections on days 0, 3, and 7. This regimen is recommended for use in specific contexts where vaccine availability and cost are significant concerns.

   

General Guidelines for ARV

The WHO recommends intradermal vaccines to address issues of vaccine availability and cost. Only vaccines approved by the Drug Controller General of India (DCGI) for ID use should be utilized. The following guidelines should be followed:

• Dosage:

  • IM: Full vial (0.5/1 ml) per dose.

  • ID: 0.1 ml per site, ensuring a visible and palpable bleb.

  • Vaccines with adjuvants should not be used for ID administration.

• Storage:

  • Keep sealed and reconstituted vaccines at 2-8°C.

  • Discard any reconstituted vaccine that is unused after 6-8 hours to maintain efficacy and safety.

     

Modern Anti-Rabies Vaccines in India

India has several modern anti-rabies vaccines available, including:

1. Abhayrab: Purified Vero Cell Rabies Vaccine (PVRV) by Human Biologicals Institute, Hyderabad.

2. Rabipur/Chirorab: Purified Chick Embryo Cell Vaccine (PCEC) by Novartis/Sanofi/Aventis/Bharat Biotech.

3. Rabivax-S: PVRV by Serum Institute of India, Pune.

4. Vaxirab-N: Purified Duck Embryo Vaccine (PDEV) by Zydus Alidac, Ahmedabad.

5. Rabio: Chromatographically PVRV by Prosper Channel Lifesciences India Pvt Ltd, Delhi.

6. Rabirix: Chromatographically PVRV by Bharat Biotech, Hyderabad.

    

Pre-Exposure Prophylaxis (PrEP)

PrEP is recommended for individuals at high risk of rabies exposure, such as laboratory staff, veterinarians, animal handlers, and wildlife officers. It is also advisable for travelers to rabies-endemic areas and children living in or visiting such regions.

• Regimens:

  • Immunologically Naive: 2-site ID or 1-site IM on days 0 and 7.

  • Immunodeficiency: Individual evaluation with an additional dose between days 21-28, plus complete PEP including RIG in case of exposure.

     

Booster Vaccination and Monitoring

High-Risk Professionals

• Monitoring: Serum samples should be taken every six months to monitor antibody levels.

• Boosters: Administer boosters if antibody titres fall below 0.5 IU/ml to maintain protective immunity.

Other Professions

• Monitoring: Serum samples every two years.

• Boosters: Administer boosters if titres fall below 0.5 IU/ml.

   

Routine boosters are not required for the general public in areas of risk.

PEP in Case of Re-Exposure

Local Wound Treatment

Local wound treatment is essential for all re-exposure cases. Immediate washing and disinfection of the wound significantly reduce the risk of rabies transmission.

Active Immunization

• 1-site ID on days 0 and 3, or

• 4-sites ID on day 0, or

• 1-site IM on days 0 and 3.

   

RIG is generally not required for re-exposure cases, except for immunocompromised individuals who may not mount an adequate immune response.

Managing animal bites effectively is critical to preventing rabies. This involves a thorough assessment of the bite, immediate wound care, appropriate use of passive and active immunization, and ongoing monitoring and booster vaccination for high-risk individuals. By following these guidelines, healthcare providers can significantly reduce the risk of rabies and protect public health.

Rabies remains a critical public health challenge, especially in regions with high dog populations and insufficient vaccination coverage. Despite its preventability, the disease continues to cause significant mortality due to gaps in timely and appropriate prophylactic measures. Recent advancements in vaccination protocols, the development of monoclonal antibodies, and updated management guidelines have markedly enhanced the prevention and control of rabies. To effectively reduce the global burden of this fatal disease, public health initiatives must prioritize comprehensive education, robust vaccination campaigns, and ensuring widespread accessibility to post-exposure prophylaxis (PEP). These efforts are essential to mitigate the impact of rabies and move towards its eventual eradication.

1. Rabies. Available from: https://www.sciencedirect.com/topics/immunology-and-microbiology/rabies

2. Rabies. Available from: https://www.who.int/news-room/fact-sheets/detail/rabies

3. Rabies virus. Available from: https://www.sciencedirect.com/topics/medicine-and-dentistry/rabies-virus

4. Fooks AR, Banyard AC, Horton DL, Johnson N, McElhinney LM, Jackson AC. Current status of rabies and prospects for elimination. Lancet. 2014 Oct 11;384(9951):1389-99.

5. Lodha L, Manoor Ananda A, Mani RS. Rabies control in high-burden countries: role of universal pre-exposure immunization. Lancet Reg Health Southeast Asia. 2023 Aug 1;19:100258.

6. Rabies. Available from: https://www.woah.org/en/disease/rabies/

7. Rabies. Available from: https://www.who.int/news-room/fact-sheets/detail/rabies

8. Rabies Pre-exposure Prophylaxis. Available from: https://www.health.state.mn.us/diseases/rabies/risk/preexposure.html

9. Fooks AR, Banyard AC, Ertl HCJ. New human rabies vaccines in the pipeline. Vaccine. 2019 Oct 3;37 Suppl 1(Suppl 1)

10. Natesan K, Isloor S, Vinayagamurthy B, Ramakrishnaiah S, Doddamane R, Fooks AR. Developments in Rabies Vaccines: The Path Traversed from Pasteur to the Modern Era of Immunization. Vaccines (Basel). 2023 Mar 29;11(4):756.

11. Post-exposure Prophylaxis. Available from: https://www.cdc.gov/rabies/hcp/prevention-recommendations/post-exposure-prophylaxis.html

12. Pattnaik P, Mahal A, Mishra S, Alkhouri A, Mohapatra RK, Kandi V. Alarming Rise in Global Rabies Cases Calls for Urgent Attention: Current Vaccination Status and Suggested Key Countermeasures. Cureus. 2023 Dec 13;15(12)

13. Rabies. Available from: https://www.who.int/news-room/fact-sheets/detail/rabies

14. Jane Ling MY, Halim AFNA, Ahmad D, Ramly N, Hassan MR, Syed Abdul Rahim SS, et al. Rabies in Southeast Asia: a systematic review of its incidence, risk factors and mortality. BMJ Open. 2023 May 10;13(5)

15. Jane Ling MY, Halim AFNA, Ahmad D, et al. Rabies in Southeast Asia: a systematic review of its incidence, risk factors and mortality. BMJ Open. 2023;13