BMS301 Lecture 2 Rabies Virus - Fall 2024

BMS301: Lecture 2: Viral Encephalitis (2): Rabies virus Prof. Eman El-Seidi F A C U L T Y O F M E D I C I N E F a l l 2 0 2 4 gu.edu.eg ...

BMS301: Lecture 2: Viral Encephalitis (2): Rabies virus Prof. Eman El-Seidi F A C U L T Y O F M E D I C I N E F a l l 2 0 2 4 gu.edu.eg  ILOs By the end of the lecture, students should be able to: - Describe the characteristic structure of rabies virus. - Identify the main reservoirs of rabies virus. - Identify the transmission of rabies infection. - Identify pathogenesis and clinical manifestations of rabies infection. - List laboratory diagnosis of rabies in humans and animals. - List post-exposure prophylaxis of rabies. - Identify vaccines. - Identify pre-exposure prophylaxis of rabies. Eman El-Seidi RHABDOVIRIDAE (Rabies virus) Eman El-Seidi  Rabies Virus Structure Bullet-shaped (one flat end & one tapering end) Symmetry: helically coiled nucleoprotein. Genome: negative sense ssRNA Enveloped with protruding spikes (needed for virus attachment to the host cells) Eman El-Seidi  RABIES: Key Facts 1 Serious infectious viral disease causing acute fatal encephalomyelitis. It is a zoonotic viral disease which infects wild & domestic animals: – Bats are the primary reservoir host. – Dogs are responsible for viral transmission to humans in up to 99% of cases in endemic regions, with a small proportion due to transmission via wildlife (e.g., foxes, wolves, bats or racoons). Eman El-Seidi  RABIES: Key Facts 2 Spread to people through animal bites or scratches, largely via saliva. 100% vaccine-preventable. Tens of thousands of deaths every year, mainly in Asia & Africa. 40% of people bitten by rabid animals are children under 15 years. Eman El-Seidi  RABIES: Key Facts 3 Immediate, thorough wound washing with soap & water after contact with a suspect rabid animal is crucial & can save lives as the 1st step of rabies post- exposure prophylaxis (PEP). Elimination is possible by vaccination of dogs & cats and avoidance of animal bites. Eman El-Seidi Main Reservoirs of Rabies Dogs, cats Wild carnivores (e.g., foxes, wolves, racoons,…) Bats Other animals (e.g., cattle, camels & horses) are susceptible but do not transmit the disease. Eman El-Seidi  Transmission Rabid animal bites or scratches inoculate the virus into wounds because rabies virus is present in the saliva of infected animals (e.g., dogs, cats … etc.). Non-bite exposures is very rare, (e.g., recipients of transplanted corneas from infected humans or inhalation of infective aerosols in bat caves or salivary contamination of skin abrasions or wounds). Eman El-Seidi  Pathogenesis  The virus replicates at the site of infection in the cytoplasm of infected nerve cells causing their damage and formation of intra-cytoplasmic inclusion bodies “Negri bodies”. Then, the virus travels along the peripheral nerves to the CNS (no viraemia).  The virus travels retrograde along the peripheral nerves to the salivary glands (to be excreted in saliva) or eyes or kidneys. Eman El-Seidi Consequence of an Exposure to RABV Infection depends on:  Severity (depth) of the wound  Location of the bite(s)  Quantity inoculated (virus load)  Virus genotype  The timeliness (start) of post- exposure prophylaxis (PEP) Probability of developing rabies following a bite by a rabid animal to:  The head: 55%  Upper limb: 22%  Lower limb: 12% Eman El-Seidi  Clinical Manifestations  Incubation Period: 2 weeks – 16 weeks or even longer.  The duration of incubation period depends on: ◦ Distance from the bite site to CNS: shorter in children & with bites in the head & neck longer when bites are in the lower limbs ◦ Severity of bite ◦ Amount of inoculated virus ◦ Immune status of the host  Clinically, 3 distinct phases: Prodromal phase, furious rabies & dumb (paralytic) rabies Eman El-Seidi  Clinical Manifestations  Prodromal phase: Initially, mild fever & pain or paresthesia at the bite site.  As the virus spreads in the CNS → Furious rabies (most common form ~70-80%) The infected person/animal has strange behavior & becomes extremely irritable & aggressive. Brainstem encephalitis with hydrophobia (painful pharyngeal spasms when offered water), aerophobia, hyperactivity & fluctuating consciousness. Death occurs after a few days due to cardio-respiratory arrest.  Dumb (paralytic) rabies (~20-30%): Lastly, ascending flaccid paralysis, starting at the site of bite or scratch with pain in the affected muscles will precede death (from cardiac or respiratory failure). N.B.: Once symptoms develop, rabies is almost always fatal to animals & humans. Eman El-Seidi  Laboratory Diagnosis A. Diagnosis of Human Rabies Infection: No tests are currently available to diagnose rabies infection in humans before the onset of clinical disease. Why?  No viraemia & the virus resides intracellularly (within myocytes or neurons at the site of the bite) & travels to CNS along nerve cells, so it does not stimulate antibodies until late in the infection. Eman El-Seidi  B. Diagnosis of Rabies Disease  In Humans:  Early diagnosis is difficult.  Several tests are necessary to diagnose rabies ante-mortem (before death) in humans, by detection of viral antigens or nucleic acid in saliva, corneal impressions or skin biopsies (obtained from nape of the neck). Eman El-Seidi  B. Diagnosis of Rabies Disease  In Animals (Post-mortem): ABC ◦ Demonstration of Negri bodies in the hippocampus & cerebellum. ◦ Detection of rabies antigen by direct immunofluorescence. ◦ Detection of rabies virus nucleic acid by RT-PCR. ◦ Electron microscopy: Rabies virus is seen as bullet- shaped particles. Eman El-Seidi  Management of Rabies No cure for the clinical disease: Rabies is almost always fatal as antiviral agents; interferons & rabies immunoglobulins fail to treat human cases. Fortunately, rabies infection can be aborted by using preventive therapy in the form of post- exposure prophylaxis (PEP) due to the long incubation period of rabies (~ 2-16 weeks). PEP = local wound treatment + rabies vaccine + rabies immune globulin (RIG). Eman El-Seidi Rabies Post-Exposure Prophylaxis (PEP): Based on Risk of Exposure Eman El-Seidi  High Risk of exposure Less Risk of exposure No Risk Immediate PEP PEP delayed No PEP 1. Unprovoked animal attacks If a bite or mucous Bites by small 2. Bites or scratches from high- membrane exposure rodents (e.g., risk animals (e.g., bats, foxes, was inflicted by a rats, mice, wolves & non-domestic /stray domestic animal with rabbits, guinea dogs or cats) known vaccination pigs and 3. Contact with bats (bite or status and if the hamsters) do non-bite exposure to bats). animal can be not require quarantined for 10 treatment. 4. All bite exposures with days, PEP can be anticipated short incubation withheld based on: Such animals periods (children or in bites in can be infected ❑ If the animal the head & neck and in with rabies extensive/deep bites). survived this period, virus but have rabies is excluded. 5. Human-to-human among never been ❑ If signs of rabies associated with corneas recipients/ Exposure to CSF, saliva, or mucous occurred, animal transmission to membrane of a person should be sacrificed humans. suspected of having rabies. & tested for rabies. Eman El-Seidi  Rabies Post-Exposure Prophylaxis (PEP) Schedule Not previously vaccinated: Previously vaccinated: 1. Emergency care 1. Emergency care 2. Rabies immunoglobulins 2. No RIG (RIG): neutralize some of the 3. Rabies vaccine inoculated virus, providing time for vaccine to stimulate active antibody production. 3. Rabies vaccine Eman El-Seidi  Rabies Post-Exposure Prophylaxis Schedule Not previously vaccinated / Previously vaccinated Emergency care: No sutures Immediate & thorough washing & flushing of all bite wounds or scratches for 15 minutes with soap & water or water alone, even if the person presents long after exposure. Disinfection with detergent, 70% ethanol, iodine. Tetanus prophylaxis & antibiotics. Eman El-Seidi  Rabies Post-Exposure Prophylaxis Schedule Not previously vaccinated Rabies immune globulin (RIG):  Administer as early as possible.  The full dose should be infiltrated into & around the wound(s).  RIG should not be administered in the same syringe or in the same site for administration of vaccine.  Because RIG might partially suppress active production of antibody, no more than the recommended dose calculated by body weight (20 IU/kg body weight) should be given.  RIG is derived from human blood (hRIG) or equine blood (eRIG) with similar clinical effectiveness but hRIG has less adverse events. A single monoclonal antibody (mAB) against rabies has been licensed in India in 2017. Eman El-Seidi Rabies Post-Exposure Prophylaxis Schedule Rabies Vaccine: If Not previously vaccinated: Five doses of rabies cell-derived vaccine; CCEEV (IM or intradermal; ID in deltoid area or thigh) on days 0, 3, 7, 14 and 28. N.B.: when administered by the intradermal (ID) route for either PEP or PrEP, efficacy is equivalent to or higher than of same vaccine administered by IM route. One dose by ID is 0.1 ml while it is 0.5 or 1 ml by IM) Eman El-Seidi  Rabies Post-Exposure Prophylaxis Schedule Rabies Vaccine: If Previously Vaccinated: Two IM or ID doses of rabies cell-derived vaccine; CCEEV (in deltoid area or thigh): one immediately (day 0) & one 3 days later. Eman El-Seidi  Rabies Vaccines Rabies vaccine nature: inactivated virus (i.e., fixed rabies virus inactivated by beta-propiolactone). The deltoid area is the only acceptable site of vaccination for adults & older children. – For younger children, the outer aspect of the thigh may be used. Vaccine should never be administered in the gluteal area (vaccine in fatty tissue induces lower immune response). Eman El-Seidi  Cell-derived rabies vaccines (= Cell Culture & Embryonated Egg-Based Vaccines; CCEEVs)  Current cell-derived rabies vaccines are inactivated vaccines, safe, more immunogenic with less doses, as compared to discontinued crude rabies vaccines. Therefore, inactivated rabies vaccines are used in both PrEP & for PEP.  They include: 1. Human diploid cell rabies vaccine (HDCV): It is the gold standard for rabies vaccines (prepared on human diploid cell culture). 2. Rabies vaccine adsorbed (RVA): prepared on fetal rhesus lung diploid cell culture. 3. Purified Vero cell rabies vaccine: prepared on vero (monkey kidney) cell lines. 4. Purified chick embryo cell vaccine (PCECV): prepared on chicken fibroblasts. Eman El-Seidi  Control of Rabies  Pre-exposure prophylaxis (PrEP): ◦ It is given to high-risk individuals (e.g., rabies laboratory workers, animal handlers, veterinarians) or travelers to at-risk areas where access to medical care is likely to be limited (Egypt is considered a high-risk country for rabies, www.nhs.uk). ◦ Rabies vaccine (HDCV or RVA) is given in 3 doses (0, 7 and 21 or 28) with booster doses if antibody titre falls below 0.5 IU/ml (after obtaining routine serum samples every 6 months-2 years, according to risk).  Vaccination of pets: e.g., dogs & cats.  Control of stray dogs. Eman El-Seidi THANK YOU Eman El-Seidi