Tim Rosa, PharmD

Carnivorous mammals and bats are the primary vectors of the rabies virus and are responsible for viral persistence—a global burden that effects more than 50,000 individuals annually thru zoonotic transmission.

 Contact with infected carriers provide transfer of the virus within their saliva to broken skin or mucosa membranes. Transmission from bites or scratches can be fatal if prophylactic measures are not taken.

The pathogenesis of rabies exposure depends on the mode of transmission. After exposure, the rabies virus contained in the saliva is introduced into the muscle and subcutaneous tissue, in which the virial glycoprotein can bind to nicotinic acetylcholine receptors (ACh) and enter the host cell.

 Risk of transmission can be 50 times higher with a canine bite versus scratches because muscle tissue contains high density ACh receptors.

After transmission, the virus remains close to the site of exposure with an incubation period that usually lasts 20 to 90 days and rarely longer than 1 year. The first of 2 viral replications occur in the muscle tissue prior to crossing the neuromuscular junction and into the motor neurons. The second replication follows in the spinal cord and enters the central nervous system prior to widespread dissemination.

 century theorized local injection with human rabies immunoglobulin (HRIG) at the wound site provided better effects at neutralizing the virus.

This approach would prevent the virus from propagating and spreading to neuronal axon. In addition, the effects of passive immunity create an immunological bridge until the active vaccine can adequately produce virus-neutralizing antibodies.

 Dose determination by Cabasso et al, in 1971 intended to investigate the optimal range of HRIG that promotes sufficient antibody response without interference of active immunity induced by the rabies vaccine.

 All subjects were seronegative and divided into groups receiving weight-based dosing in units per kilogram (IU/kg) of 10, 20 or 40 IU/kg, in conjunction with the rabies vaccine. Additionally, 1 group only received 40 UI/kg HRIG and 1 received only vaccine. Serum neutralizing titers (SNT) were obtained and presented as geometric mean titers (GMT), with ratios of 1:2 representing passive immunity.

Significant findings after 24 hours in the 10 UI/kg group determined that SNT were barely detectable and well below the GMT. Although titers continued to rise until day 40, early levels of circulating antibodies levels did not promote protective levels. The researchers concluded this to be a probable result of the rabies vaccine.

The 40 UI/kg groups produced a GMT of 1:11 after 24 hours and continued to rise until day 13 consistent with promoting early protection of circulating antibodies. However, slight declines were apparent on days 23 and 30, indicating interference with active immune response.

The 20 UI/kg group produced a GMT of 1:6, half that of 40 UI/kg, and sufficient to promote protective antibody levels that continued to rise through day 40. The GMT on day 40 was 1:111, twice that of the 40 UI/kg group and slightly below the vaccine alone. This is relevant in determining no interference of an active immune response and what is still recommended by the World Health Organization (WHO).

Recognition of potential exposure and HRIG administration can provide serum antibodies within 24 hours that persists up to 24 days, diminishing prophylaxis failure.

 The vaccine alone does not produce neutralizing antibodies above the minimum titer of 0.5 UI/ml needed within the first week—the basis of the WHO recommendation of prompt administration into and around the wound site for a local protective effect. Allowing HRIG to neutralize rabies viral antibodies prior to transferring into the immunoprotected environment of the peripheral nerve cell.

Limitations of injections at the wound site are due to compartment syndrome, and the remainder may be injected into upper arm, lateral thigh, and gluteal muscle.

 Furthermore, when vaccine administration has already occurred after 7 days, HRIG may interfere with active immune response.

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Nigg AJ, Walker PL. Overview, prevention, and treatment of rabies. Pharmacotherapy. 2009 Oct;29(10):1182-95.

Hemachudha T, Laothamatas J, Rupprecht CE. Human rabies: a disease of complex neuropathogenetic mechanisms and diagnostic challenges. Lancet Neurol. 2002 Jun;1(2):101-9.

Jackson AC. Rabies. Neurol Clin. 2008 Aug;26(3):717-26.

Hanna K, Cruz MC, Mondou E, Corsi E, Vandeberg P. Safety and neutralizing rabies antibody in healthy subjects given a single dose of rabies immune globulin caprylate/chromatography purified. 

Cabasso VJ, Loofbourow JC, Roby RE, Anuskiewicz W. Rabies immune globulin of human origin: preparation and dosage determination in non-exposed volunteer subjects. Bull World Health Organ. 1971;45(3):303-15.

Khawplod P, Wilde H, Chomchey P, Benjavongkulchai M, Yenmuang W, Chaiyabutr N, Sitprija V. What is an acceptable delay in rabies immune globulin administration when vaccine alone had been given previously? Vaccine. 1996 Apr;14(5):389-91.

Articles

Early experiments through the 19th century theorized local injection with human rabies immunoglobulin at the wound site provided better effects at neutralizing the virus.

Human Rabies Immunoglobulin Post-Exposure Prophylaxis

Regulating immune homeostasis is an essential function of the spleen. This lymphopoietic organ contains a quarter of the body’s lymphoid tissue involved in opsonization, in which invading bacterial particles are targeted and phagocytized.

The loss of blood filtering through the spleen diminishes the triggering effect of innate and adaptive immunity that aids in protecting the body against infection, inducing a patient’s vulnerability to invasive infections caused by encapsulated bacteria (eg, 

 accounts for more than 50% of infections in individuals with loss or impairment of splenetic function, resulting in high post-splenectomy mortality rates commonly observed in the first 2 years.

Patients can be aided by health care providers with preventable measures to reduce the chance of infectious risk. This includes determining the appropriateness of vaccinations, timing, the number of doses as decided by previous vaccination history, adverse reactions, patient age, and diagnosis.

 have been identified, each encompassed in a polysaccharide capsule differing in their antigenic variation.

: 23-valent pneumococcal polysaccharide vaccine (PPSV23) and 13-valent pneumococcal conjugate vaccine (PCV13).

PPSV23 contains antigens from 23 serotypes most commonly responsible for 85%-90% of cases of pneumococcal disease, whereas PCV13 carriers 12 of the 13 serotypes contained in PPSV23.

 Vaccine design differs in the number of serotypes covered and the addition of a covalently conjugated protein carrier to PCV13. Each elicit immunity through a B-cell mediated immunity differing in T-cell interactions.

Purified polysaccharide antigens induced by PPSV23 generate a T-independent activation of B-cells, leading to a poor immune response, lacking memory cells with modest affinity of mostly IgM antibodies that tend to wane over time. Conjugation of a carrier protein to the polysaccharide in PCV13 T-dependent activation of B-cells promotes specific antigens with a higher affinity to elicit a more robust and longer lasting immunity.

The Advisory Committee on Immunization Practices (ACIP) recommends routine use of PCV13 in addition to PPSV23 for adults with immunocompromising conditions such as functional or anatomic asplenia. PCV13 has been used in pediatric immunization since 2010, an identical formulation of 7 serotypes in PCV7 with an additional 6 antigens.

Routine use of PCV7 in pediatric immunizations resulted in significant reduction in invasive pneumococcal disease (IPD) with an indirect effect benefiting adults. Although, the serotypes not included in PCV7 remained high in certain immunocompromised populations. 

Among immunocompromised cases of IPD, 50% of the serotypes are contained in PCV13, and 21% in PPSV23. Immunogenic studies comparing antibody responses to PCV13 and PPSV23 was the basis for approval by the FDA in 2011.

Evaluating immunological response in adults, Jackson LA et al compared baseline opsonophagocytic activity (OPA) antibodies commonly associated as an adequate threshold for vaccine-induced protection. PCV13 compared to PPSV23 a month after vaccination demonstrated a statistically significant higher mean OPA titers in PCV13 for 8 of the 12 common serotypes. 

Persistence of immunity 1 year after vaccination declined in both groups. However, OPA remained above pre-vaccination baseline in the PCV13 group, providing an enhanced immunogenicity and support the potential for improved clinical efficacy.

Vaccination is the mainstay in the prevention of infectious disease. Asplenia, regardless of etiology, puts patients at higher risk for serious or life-threatening infections due to encapsulated bacteria, and patients should be educated on the management of possible risks.  

 (bacteremia, meningitis, and pneumonia) place a high burden on adults in the United States. ACIP recommendations are based on the potential benefits outweighing harm due to IPD, providing broader protection of serotypes through use of both pneumococcal vaccines.

1. Kuchar, E., Miśkiewicz, K. and Karlikowska, M. (2015), A review of guidance on immunization in persons with defective or deficient splenic function. Br J Haematol, 171: 683-694.

2. Bonanni P, Grazzini M, Niccolai G, et al. Recommended vaccinations for asplenic and hyposplenic adult patients. 

3. Hayward S, Thompson LA, McEachern A. Is 13-Valent Pneumococcal Conjugate Vaccine (PCV13) Combined With 23-Valent Pneumococcal Polysaccharide Vaccine (PPSV23) Superior to PPSV23 Alone for Reducing Incidence or Severity of Pneumonia in Older Adults? A Clin-IQ. 

4. Clutterbuck EA, Lazarus R, Yu LM, et al. Pneumococcal conjugate and plain polysaccharide vaccines have divergent effects on antigen-specific B cells. 

5. Jackson LA, Gurtman A, van Cleeff M, et al. Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine compared to a 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine-naive adults. 

6. Centers for Disease Control and Prevention (CDC). Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP). 

Patients can be aided by health care providers with preventable measures to reduce the chance of infectious risk.