AtheroVax: a peptide vaccine with a therapeutic effect in animal model of chronic inflammation

Abstract

Abstract Background Inflammation is a driver of atherosclerosis, but inflammatory mediators are essential components of the immune response. AtheroVax targets only pathogenic forms of sTNFR2 while preserving the membrane-bound (wild-type) TNFR2 and its contributions to a non-pathogenic immune response. We hypothesize that the vaccine mediated clearance of sTNRF2 will be more specific and offers long-term treatment options. The aim of this study is to investigate the therapeutic effect of an sTNFR2-targeting peptide (14 amino acid) vaccine, AtheroVax, in a rat model of acetic acid-induced colitis. Methods Two studies were conducted. In the first study 100 male outbred white Wistar rats (age 8 weeks, weight ~250 g) were used to evaluate a subcutaneous (SQ) injections of human sTNFR2 peptide sequence. In the second study 80 rats were used to evaluate SQ injections of the rat sTNFR2 sequence. After the adaptation period, the animals were randomly divided into treatment groups. In study 1, group A (n = 30), phosphate-buffered saline (PBS), group B (n = 30), 25 μg of alum diluted in PBS, group C (n = 30), 25 μg of alum + 25 μg of peptide diluted in PBS, and group D (n = 10) no colitis controls. In study 2, group A (n = 25), phosphate-buffered saline (PBS), group B (n = 25), 25 μg of alum + 25 μg of rat sTNFR2 peptide, group C (n = 30), 25 μg of alum + 75 μg of rat sTNFR2 peptide, and group D (n = 5) no colitis controls. The animals were kept under standard vivarium conditions (temperature 22±2°C, relative humidity 50±5%, light/dark cycles 12 h/12 h). Animals were fed ad libitum standard laboratory chow and water under the supervision of trained personnel. Results The short 14 amino acid peptides administered prior to initiating colitis significantly improved the course of colitis in both studies by significantly (p<0.05) reducing weight loss, fever, bleeding and diarrhea, and disease severity as well as providing a survival benefit (p<0.05) in rats with colitis. AtheroVax also significantly (p<0.001) reduced serum levels of TNF-α and IL-6. Histopathology evaluation reveals preservation of colon cellular architecture in vaccinated animals in both studies. Immunohistochemistry and examination of spleen and lymph nodes provides supporting evidence of the vaccine protection from chronic inflammation. Conclusion Our studies have shown that AtheroVax may be an effective therapeutic candidate for reducing chronic inflammation. These pre-clinical findings will provide a basis to further evaluate this novel vaccine in follow-up pre-clinical studies. A vaccine limiting the progression of atherosclerosis will greatly contribute to the reduction in morbidity and mortality from cardiovascular disease.