Potent Adjuvant Activity of Cationic Liposome-DNA Complexes for Genital Herpes Vaccines

Abstract

Development of a herpes simplex virus (HSV) vaccine is a priority because these infections are common. It appears that potent adjuvants will be required to augment the immune response to subunit HSV vaccines. Therefore, we evaluated cationic liposome-DNA complexes (CLDC) as an adjuvant in a mouse model of genital herpes. Using a whole-virus vaccine (HVAC), we showed that the addition of CLDC improved antibody responses compared to vaccine alone. Most important, CLDC increased survival, reduced symptoms, and decreased vaginal virus replication compared to vaccine alone or vaccine administered with monophosphoryl lipid A (MPL) plus trehalose dicorynomycolate (TDM) following intravaginal challenge of mice. When CLDC was added to an HSV gD2 vaccine, it increased the amount of gamma interferon that was produced from splenocytes stimulated with gD2 compared to the amount produced with gD2 alone or with MPL-alum. The addition of CLDC to the gD2 vaccine also improved the outcome following vaginal HSV type 2 challenge compared to vaccine alone and was equivalent to vaccination with an MPL-alum adjuvant. CLDC appears to be a potent adjuvant for HSV vaccines and should be evaluated further.Herpes simplex virus type 1 (HSV-1) and HSV-2 are two members of the HSV family of alphaherpesviruses, which establish lifelong latent infection in sensory neurons and lead to chronic herpes disease. HSV-1 infection causes facial/ocular disease, while HSV-2 is the leading cause of genital herpes, although both viruses can be found at oral and genital sites. Indeed, the incidence of HSV-1 genital disease is increasing and approximates that of HSV-2 in certain countries (17). Approximately 45 million people in the United States (20 to 30%) have genital herpes infection, and new infections occur at a rate of 1 million per year (17,29). One of the most serious complications of genital herpes occurs when the virus is transmitted from mother to neonate. Infection of the neonate causes significant morbidity and mortality, even with proper antiviral therapy (25). Genital herpes infection also increases the risk of acquiring human immunodeficiency virus (HIV) infection and increases shedding of HIV in genital lesions (5, 40).HSV-2 infection induces both humoral and T-cell-mediated immunity; however, the mechanisms that contribute to longterm control of genital herpes are not understood and could be different from those that will protect against primary infection or disease. Studies from animal models of HSV infection and human studies indicate that high levels of neutralizing antibodies, innate immunity natural killer (NK) cells, interferon (IFN), and macrophages contribute to protection from HSV infection, but the major determinants of HSV protection are both CD8 ϩ and especially CD4 ϩ T cells (7,9,23,27,30,31). Clearance of virus from recurrent lesions is also more closely correlated to T-cell immunity. Thus, when a recurrent lesion occurs, mononuclear cells, primarily CD4 ϩ T cells, infiltrate the lesion as early as 2 days after formation and ...

Effects of herpes simplex virus type 2 glycoprotein vaccines and CLDC adjuvant on genital herpes infection in the guinea pig

“…We had previously shown that CLDC improved the efficacy of the gD2 (306) vaccine while CLDC alone was not protective [16], [26]. In the experiments presented here, we compared the gD2 (306) to a further truncated form of gD2 (285)) as well as to a gD2 (285) + gB2 + gH2/gL2 and to a vaccine without gD2 (gB2 + gH2/gL2) when administered with CLDC.…”

“…We elected to evaluate these vaccine candidates with Cationic Lipid DNA Complexes (CLDC) as the adjuvant as we had previously shown that this adjuvant appeared to be more effective than MPL/Alum, the adjuvant used in recent clinical trials of a gD2 vaccine [3], when evaluated in mouse and guinea pig models of genital HSV-2 infection [16, 26]. The cationic liposomes facilitate endocytosis and direct delivery of the plasmid DNA to the endosomal compartment thus increasing binding of nucleic acids to endosomal toll-like receptors [27].…”

Application of Innate Immune Molecules for a New Class of Drugs: Infection, Inflammation and Beyond

“…The cationic liposome-DNA complex containing CpG motifs (CLDC) seems to have great potential to be used for vaccines. Bernstein et al showed that the CLDC greatly improved the immunogenicity of a herpes vaccine [13]. Thus, better approaches using TLR9 agonists in combination with other devices are still appearing.…”

A cationic liposome–DNA complexes adjuvant (JVRS-100) enhances the immunogenicity and cross-protective efficacy of pre-pandemic influenza A (H5N1) vaccine in ferrets

“…JVRS-100 is comprised of cationic liposome–DNA complexes (CLDC) and was developed as an adjuvant for vaccines against infectious diseases and as an immunomodulator for cancer therapy (Bernstein et al, 2009; Chang et al, 2009; Lay et al, 2009; Zaks et al, 2006). It has been demonstrated that the addition of CLDC to influenza vaccines can induce robust CD4 + Th1 response and predominant IgG2a/c antibody responses in mice (Chang et al, 2009; Dong et al, 2012; Hong et al, 2010; Lay et al, 2009).…”