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Heterologous Immunity

Infection with various pathogens such as Influenza virus, Respiratory Syncytial Virus (RSV), HIV, Hepatitis B Virus (HBV), Hepatitis C virus (HCV), Dengue Virus (DENV), Zika Virus (ZikaV), West Nile Virus (WNV), Poliovirus, and Epstein-Barr Virus (EBV), for example, leads to variable outcomes with respect to self-clearance, severe pathology, mortality and/or persistence of infection.  It has been shown that this variability is, in part, due to the variability in the prior exposures to foreign antigens and pathogens.  

Not only prior exposure to pathogens, but also prior vaccinations can elicit heterologous immunity.  Vaccines such as Vaccinia (smallpox vaccine), BCG (Bacille Calmette Guerin, for tuberculosis), Measles (for measles virus), OPV (oral polio vaccine), and DTP (for diphtheria, tetanus, and pertussis) which have been very effective in preventing the targeted infection, have been shown to also have heterologous effects in preventing infections with unrelated pathogens.  

For example, small pox vaccination has protective effects in multiple diseases other than small pox, such as papillomas, chronic skin disorders, eyes, ear, nose and throat disorders, measles, scarlet fever, whooping cough, and syphilis.  Smallpox vaccination is also associated with a reduced risk of infectious disease hospitalizations. Prior immunization with small pox vaccine may also provide an individual with some degree of protection to subsequent Human Immunodeficiency Virus (HIV) infection.  In support, it was noted that the worldwide termination of smallpox vaccination in 1980 may have partially allowed the HIV epidemic to explode.

BCG vaccination for tuberculosis has been shown to reduce infant mortality due to childhood infections such as respiratory infections and sepsis unrelated to tuberculosis (TB). Immunization with BCG has also been shown to reduce the incidence of allergic diseases, and autoimmune/inflammatory diseases such as type I diabetes and multiple sclerosis. Removal of the infant BCG vaccination programs due to decline in TB cases has been shown to be correlated with increased incidence of respiratory infections, melanoma, lymphoma, atopic dermatitis, asthma etc.

Measles vaccine given to infants has been shown to reduce childhood mortality by infections other than measles by 30–86% in studies from different countries. Similarly, oral polio vaccine, used widely to eradicate polio has been shown to reduce mortality by 19% (range 5–32%) in children <5 years of age independent of its effect on polio. Furthermore, in a randomized clinical trial, vaccination with OPV and BCG at birth demonstrated 32% (0–57%) lower infant mortality than BCG alone.

Heterologous immunity has been shown commonly among closely related pathogens, e.g., different subtypes of influenza A viruses and Dengue viruses, different members of the same family such as within flaviviruses and picornaviruses, and among unrelated pathogens including parasites, protozoa, bacteria, and viruses.

Experimental and clinical evidence have clearly demonstrated that heterologous immunity or cross-reactivity of killer immune cells is not an isolated or accidental phenomenon, but rather a fundamental attribute of adaptive immunity, forming an integral part of the host defense system against pathogens under natural conditions.

In the elderly, this memory pool can become exhausted due to underlying sub-clinical infections.  In the senescent immune system of the elderly where antigen-specific lymphocytes have become anergic and/or exhausted, they don't respond to a specific vaccine. Mobilizing cross-reactive adaptive immunity by a heterologous therapeutic vaccine is the ultimate strategy to induce effective protective immunity in the elderly.

AlloPrime® creates a large pool of non-exhausted memory Th1 cells and cross-reactive memory killer cells which can be readily activated upon exposure to non-related pathogens, providing a novel means to provide elderly with universal protection from viral infection. 

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