<p>Hepatitis C virus continues to be a major global health burden, infecting 58&#xa0;million people and claiming 300,000 lives yearly. At present, no vaccine exists to prevent this disease. Viral attachment and entry are major targets of adaptive humoral responses. However, viral proteins responsible for cell attachment and entry of HCV are the glycoproteins E1 and E2, which are highly glycosylated, leading to the evasion of HCV from the humoral immune response. In this study, HCV pseudoparticles (HCVpp) were produced by transfecting 293T cells with three vectors required to assemble infectious pseudo-particles. The vaccine (HCVNeura A) was generated by hydrolysis of sialic acid residues from glycoproteins on HCVpp by using α2–3,6,8,9 Neuraminidase A (Neura A). In vivo study was performed. Results suggest that deglycosylation of hepatitis C virus pseudoparticles (HCVpp) by α2–3,6,8,9 Neuraminidase A elicited an immune response that recognizes E1E2. The resulting vaccine (HCVNeura A) was immunogenic as demonstrated by the induction of high titers of HCVpp neutralizing antibodies. In a mouse model, active immunization with HCVNeura A effectively protected the Huh7.5 cell line from HCVpp damage. In short, hydrolysis of sialic acid residues from glycoproteins on HCVpp by Neura A elicits the production of protective neutralizing antibody and effectively inhibits infection of Huh7.5 cell line by HCVpp. Similar experiments were also performed using Endo H and PNGase F. However, no protective effect was found (results not shown). This strategy opens a new direction for vaccine design should facilitate the development of vaccines against HCV and other infectious particles. HCV infects 58 million annually, causing 300,000 deaths worldwide. No vaccine exists despite decades of research, making prevention challenging. Viral attachment and entry are major targets of adaptive humoral responses. However, viral proteins responsible for cell attachment and entry of HCV are the glycoproteins E1 and E2, which are highly glycosylated, leading to the evasion of HCV from the humoral immune response. For the first time, we invent a novel effective &amp; practical vaccine (HCVNeura A) by hydrolysis of sialic acid residues from glycoproteins on HCVpp by using α2–3,6,8,9 Neuraminidase A (Neura A), leading to the production of protective neutralizing antibody and effectively inhibits infection of Huh7.5 cell line by HCVpp. This strategy opens a new direction for vaccine design. In fact, the research has already yielded encouraging results, with a patent secured in Taiwan and applications pending in the USA, EU, China, and Hong Kong.</p>