Rabies virus protection issues and therapy

Rabies remains a serious and usually fatal disease in many countries. The World Health Organization (WHO) estimates that approximately 10 million people worldwide require medical treatment against rabies each year after being exposed to an animal suspected of having rabies. In the United States of America (USA), there are close to 40,000 post-exposure prophylaxis treatments administrated each year, which represents about 100 million dollars in costs for treatment, health care, education and prevention. Current rabies exposure immune prophylaxis includes a new treatment product tested in Phase 2 and 3 clinical trials in Israel. This product is now sold in 10 countries and should soon be available in the USA. Results of comparison clinical trials show it to be as efficacious as other human immunoglobulin G (IgG) products. In animals, there have been no documented cases in North America of rabies in vaccinated, truly immunized dogs and cats for two decades, although the disease still exists among wildlife and feral companion animal species. While most pet dogs are vaccinated for rabies, fewer cats have historically been vaccinated until recent laws have required it. The Rabies Challenge Fund (RCF) research studies are now at years 6 and 7 post-vaccination, and the initial challenge phase results showed the vaccinates to be protected from rabies. Abbreviations: AE: Adverse Events; CNS: Central Nervous System; CVB: Center for Veterinary Biologics; ELISA: Enzyme-Linked Immunosorbent Assay; CFR: Code of Federal Regulations; IgG: Immunoglobulin G; MLV: Modified Live Virus; RCF: Rabies Challenge Fund; RVNA: Rabies Virus Neutralizing Titer; RFFIT: Rapid Fluorescent Focus Inhibition Test; USA: United States of America; USDA: United States Department of Agriculture; WHO: World Health Organization. Introduction Countless animals have been vaccinated routinely and repeatedly for rabies and the other common serious infectious viral and bacterial diseases, without obvious untoward effects [1-4]. But, veterinarians still need to be aware of the potential for adverse events (AE) and determine what constitutes “acceptable” harm [1-3]. Vaccines typically contain immunologic adjuvants which act to accelerate, prolong, or enhance antigen-specific immune responses when used together with specific vaccine antigens [5,6]. While vaccine adjuvants are incorporated into vaccines to enhance their immunogenicity, this increases the risk of autoimmune and inflammatory adverse events following vaccination [5]. For the killed vaccines available for human and veterinary use, potent adjuvants are included to produce a more sustained humoral immune response and compete favorably with the longer protection typically afforded by modified-live virus (MLV) products. But, these adjuvants may also induce adverse effects [1,5-17]. Discussion Although killed or inactivated products make up about 15% of the veterinary biologicals used, they have been associated with 85% of the post-vaccination reactions, mainly because of the acute adverse responses induced by the adjuvants used in companion animal, wildlife and livestock species [1,10,16-18]. Several years ago, an “allkilled” combination vaccine for dogs was marketed, but some users encountered minor problems with discoloration and local reactions at the injection site, and the product was withdrawn. Ringworm and chlamydia vaccines introduced for use in cats are advertised as having the safety advantage of a killed product [1]. This debate about the relative merits and safety of killed versus MLV vaccines has been ongoing, and was hotly debated in a comparison of the risks, costs, and convenience of killed versus modified live human polio vaccines [19]. Documented AE from the adjuvants used in human vaccines, especially those containing aluminum and thimerosal (mercury salt), continue to appear in the literature [11-16]. Adverse events associated with vaccine adjuvants Adjuvants have been used safely in human and veterinary medicine for decades, especially those containing aluminum salts, monophosphoryl lipid A, and squalene in animal vaccines [20-27]. In 2012, investigators from China determined that four botanical polysaccharide preparations, namely Astragalus, Echinacea, wolfberry and kelp, acted as immunopotentiators/adjuvants in mice and dogs when added to veterinary rabies vaccines [28]. Nevertheless, as cited above, adjuvants can also produce numerous AE. Experimental studies have shown that simultaneous administration of even two-three adjuvants can overcome genetic resistance to autoimmunity [15]. Because vaccines are viewed as inherently safe and non-toxic, toxicity studies are often excluded from their regulatory safety assessment. Children are especially at risk being more vulnerable to toxicity than adults; and they are regularly exposed to more vaccine adjuvants than adults. Adjuvants impact the central nervous system at all levels and can do so by changing gene expression [13]. Further, it is now known that the neuro-immune axis, heavily targeted by adjuvants, plays a key role in brain development and immune function [12,13,15,24]. Correspondence to: W. Jean Dodds, DVM; Hemopet, 938 Stanford Street, Santa Monica, CA 90403, USA, Tel: 714-891-2022 Ext 115, E-mail: [email protected]