A Virus-Like Particle-Based Vaccine Selectively Targeting Soluble TNF-α Protects from Arthritis without Inducing Reactivation of Latent Tuberculosis

Abstract

Neutralization of the proinflammatory cytokine TNF-α by mAbs or soluble receptors represents an effective treatment for chronic inflammatory disorders such as rheumatoid arthritis, psoriasis, or Crohn’s disease. In this study, we describe a novel active immunization approach against TNF-α, which results in the induction of high titers of therapeutically active autoantibodies. Immunization of mice with virus-like particles of the bacteriophage Qβ covalently linked to either the entire soluble TNF-α protein (Qβ-C-TNF1–156) or a 20-aa peptide derived from its N terminus (Qβ-C-TNF4–23) yielded specific Abs, which protected from clinical signs of inflammation in a murine model of rheumatoid arthritis. Whereas mice immunized with Qβ-C-TNF1–156 showed increased susceptibility to Listeria monocytogenes infection and enhanced reactivation of latent Mycobacterium tuberculosis, mice immunized with Qβ-C-TNF4–23 were not immunocompromised with respect to infection with these pathogens. This difference was attributed to recognition of both transmembrane and soluble TNF-α by Abs elicited by Qβ-C-TNF1–156, and a selective recognition of only soluble TNF-α by Abs raised by Qβ-C-TNF4–23. Thus, by specifically targeting soluble TNF-α, Qβ-C-TNF4–23 immunization has the potential to become an effective and safe therapy against inflammatory disorders, which might overcome the risk of opportunistic infections associated with the currently available TNF-α antagonists.

Immunochemical termination of self-tolerance

“…In addition, anti-TNF-␣ antibodies (17,18) and soluble chimeric TNF-␣ receptors (19,20) are widely used in the treatment of autoimmune disease, and a number of approaches are being pursued to develop TNF-␣-specific vaccines for clinical use. The latter include recombinant TNF-␣ molecules containing foreign immunodominant T-helper epitopes, TNF-␣ fusions to virus-like particles of the bacteriophage Q ␤ , and keyhole limpet hemocyanin-TNF-␣ heterocomplexes (4,21,22).…”

Targeting IL-12/IL-23 by Employing a p40 Peptide-Based Vaccine Ameliorates TNBS-Induced Acute and Chronic Murine Colitis

“…Virus-like particles induce potent B-cell responses even in the absence of adjuvants (30,31), and as carrier proteins, they are preferable to other proteins. More recently, cytokine peptide-based virus-like particle vaccines are being investigated by chemically conjugating synthesized cytokine peptides to bacteriophage Qβ virus-like particles (33). Compared with the vaccines that are currently being investigated, the p40 vaccine used in the present study has unique advantages: (1) it uses a small peptide, avoiding possible cross-reaction with other self proteins; (2) it is highly antigenic, eliciting longlasting specific antibodies without the use of an adjuvant owing to its virus-like particle feature; (3) it is a recombinant protein, making it easier to prepare and to control the quality of the vaccine than those by chemical coupling (33); (4) the safety of the vaccine carrier HBcAg has been confirmed in a phase I clinical trial for a malaria vaccine used in humans (34), making this vaccine even more attractive for human use.…”

A Virus-Like Particle-Based Anti-Nerve Growth Factor Vaccine Reduces Inflammatory Hyperalgesia: Potential Long-Term Therapy for Chronic Pain

“…Using this approach to vaccine design, we have previously demonstrated that levels of neutralizing Ab responses against self-proteins can be induced that are high enough to show therapeutic effectiveness in mice (31)(32)(33)(34)(35). We have also demonstrated that efficacy established in animal models can be translated into efficacy in humans (47,48).…”

“…To test the feasibility of this concept, we generated a vaccine comprising mature NGF covalently conjugated to a virus-like particle (VLP) carrier derived from the bacteriophage Qb. We have previously validated this approach both preclinically and clinically for other Ags (30)(31)(32)(33)(34)(35).…”