Abstract
Smallpox (variola virus) is a bioweapon concern. Monkeypox is a growing zoonotic poxvirus threat. These problems have resulted in extensive efforts to develop potential therapeutics that can prevent or treat potentially lethal poxvirus infections in humans. Monoclonal antibodies (mAbs) against smallpox are a conservative approach to this problem, as the licensed human smallpox vaccine (vaccinia virus, VACV) primarily works on the basis of protective antibody responses against smallpox. Fully human mAbs (hmAbs) against vaccinia H3 (H3L) and B5 (B5R), targeting both the mature virion (MV) and extracellular enveloped virion (EV) forms, have been developed as potential therapeutics for use in humans. Post-exposure prophylaxis was assessed in both murine and rabbit animal models. Therapeutic efficacy of the mAbs was assessed in three good laboratory practices (GLP) studies examining severe combined immunodeficiency mice (SCID) given a lethal VACV infection. Pre-exposure combination hmAb therapy provided significantly better protection against disease and death than either single hmAb or vaccinia immune globulin (VIG). Post-exposure combination mAb therapy provided significant protection against disease and death, and appeared to fully cure the VACV infection in ≥50% of SCID mice. Therapeutic efficacy was then assessed in two rabbit studies examining post-exposure hmAb prophylaxis against rabbitpox (RPXV). In the first study, rabbits were infected with RPVX and then provided hmAbs at 48 hrs post-infection, or 1 hr and 72 hrs post-infection. Rabbits in both groups receiving hmAbs were 100% protected from death. In the second rabbitpox study, 100% of animal treated with combination hmAb therapy and 100% of animals treated with anti-B5 hmAb were protected. These findings suggest that combination hmAb treatment may be effective at controlling smallpox disease in immunocompetent or immunodeficient humans.
Highlights
Smallpox is a highly lethal viral infection affecting humans (30% mortality) [1] which can spread rapidly through a population
We show efficacy of the human monoclonal antibody (mAb) (hmAbs) in protecting severe combined immunodeficiency mice (SCID) mice against vaccinia virus (VACV) infection both pre-exposure and post-exposure in studies run under good laboratory practices (GLP) regulations (US FDA 21 CFR part 58)
We have shown that a combination of anti-H3 hV26 and anti-B5 h101 has significantly better protective efficacy than vaccinia immune globulin (VIG) against lethal VACV infection of SCID mice when treatments were provided before infection [36]
Summary
Smallpox is a highly lethal viral infection affecting humans (30% mortality) [1] which can spread rapidly through a population. Renewed fears that smallpox might be deliberately released in an act of bioterrorism have led to resurgence in the study of treatment of smallpox infection. Individuals ,35 years old (approximately 50% of the population) have not been vaccinated against smallpox, leaving them highly susceptible in the event of an outbreak. There is substantial interest in better therapeutics for the treatment of the rare but severe side effects of the smallpox vaccine. There is interest in therapeutics for treatment of other poxviruses, such as monkeypox, which is transmitted among rodent populations. A monkeypox outbreak occurred for the first time in the USA in 2003 [5,6,7,8]
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