Article

An Adjuvanted Herpes Simplex Virus Type 2 (HSV-2) Subunit Vaccine Elicits a T Cell Response In Mice and Is an Effective Therapeutic Vaccine In Guinea Pigs.

Genocea Biosciences, Inc., Cambridge, MA 02140.
Journal of Virology (Impact Factor: 4.44). 01/2013; 87(7). DOI: 10.1128/JVI.02745-12
Source: PubMed

ABSTRACT

Immunotherapeutic herpes simplex virus 2 (HSV-2) vaccine efficacy depends upon the promotion of antigen-specific immune responses
that inhibit reactivation or reactivated virus, thus controlling both recurrent lesions and viral shedding. In the present
study, a candidate subunit vaccine, GEN-003/MM-2, was evaluated for its ability to induce a broad-spectrum immune response
in mice and therapeutic efficacy in HSV-2-infected guinea pigs. GEN-003 is comprised of HSV-2 glycoprotein D2 (gD2ΔTMR340-363) and a truncated form of infected cell polypeptide 4 (ICP4383-766), formulated with Matrix M-2 (MM-2) adjuvant (GEN-003/MM-2). In addition to eliciting humoral immune responses, CD4+ and CD8+ T cells characterized by the secretion of multiple cytokines and cytolytic antigen-specific T cell responses that were able
to be recalled at least 44 days after the last immunization were induced in immunized mice. Furthermore, vaccination with
either GEN-003 or GEN-003/MM-2 led to significant reductions in both the prevalence and severity of lesions in HSV-2-infected
guinea pigs compared to those of phosphate-buffered saline (PBS) control-vaccinated animals. While vaccination with MM-2 adjuvant
alone decreased recurrent disease symptoms compared to the PBS control group, the difference was not statistically significant.
Importantly, the frequency of recurrent viral shedding was considerably reduced in GEN-003/MM-2-vaccinated animals but not
in GEN-003- or MM-2-vaccinated animals. These findings suggest a possible role for immunotherapeutic GEN-003/MM-2 vaccination
as a viable alternative to chronic antiviral drugs in the treatment and control of genital herpes disease.

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    • "However , only a small subset of candidates achieved sterile immunity as defined by complete protection against viral replication at the site of infection, prevention of dorsal root ganglia infection and absence of recurrent genital shedding of virus or HSV DNA[52]. While previous work has mostly focused on neutralizing antibody responses, T cell immunogens such as ICP4 can enhance systemic CD8 + T cell responses, and adding ICP4 to a gD2 subunit vaccine reduced the number of recurrent lesions and genital viral shedding in guinea pigs[53]. We show here that adding two recently discovered targets of the human T cell response, UL19 and UL25, to gD2 and formulating the recombinant proteins as a stable emulsion with the potent TLR4 agonist GLA, induced not only potent CD4 and antibody responses, but surprisingly also primed polyfunctional CD8 T cells which could be recalled by HSV-2 infection. "
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    ABSTRACT: Background/objectives: There is currently no licensed prophylactic or therapeutic vaccine for HSV-2 infection. Methods: We developed a novel preclinical vaccine candidate, G103, consisting of three recombinantly expressed HSV-2 proteins (gD and the UL19 and UL25 gene products) adjuvanted with the potent synthetic TLR4 agonist glucopyranosyl lipid A (GLA) formulated in stable emulsion. The vaccine was tested for immunogenicity and efficacy in pre-clinical models for preventative and therapeutic vaccination. Results: Vaccination of mice with G103 elicited antigen-specific binding and neutralizing antibody responses, as well as robust CD4 and CD8 effector and memory T cells. The T cell responses were further boosted by subsequent challenge with live virus. Prophylactic immunization completely protected against lethal intravaginal HSV-2 infection in mice, with only transient replication of virus in the genital mucosa and sterilizing immunity in dorsal root ganglia. Supporting the use of G103 therapeutically, the vaccine expanded both CD4 and CD8 T cells induced in mice by previous infection with HSV-2. In the guinea pig model of recurrent HSV-2 infection, therapeutic immunization with G103 was approximately 50% effective in reducing the number of lesions per animal as well as the overall lesions score. Conclusions: Taken together, the data show that G103 is a viable candidate for development of a novel prophylactic and therapeutic HSV-2 vaccine.
    No preview · Article · Nov 2015 · Vaccine
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    • " calculated via GraphPad Prism and Microsoft Excel software . The endpoint titer was defined as the reciprocal of the serum dilution resulting in an OD 405 equal to twice the background . Antibody - mediated neutralization of HSV - 2 / Gal infectivity was determined via a β - galactosidase ( β - gal ) colorimetric assay , as described previously ( Skoberne et al . , 2013 ) . The resultant optical density was measured at 590 nm , and neutralizing antibody titer was defined as the reciprocal of the plasma or serum dilution that produced a 50% reduction in the OD 590 of the virus control ."
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    ABSTRACT: Reactivation of latent herpes simplex virus 2 (HSV-2) infections can be characterized by episodic recurrent genital lesions and/or viral shedding. We hypothesize that infected (HSV-2 pos) asymptomatic individuals have acquired T cell responses to specific HSV-2 antigen(s) that may be an important factor in controlling their recurrent disease symptoms. Our proteomic screening technology, ATLAS™, was used to characterize the antigenic repertoire of T cell responses in infected (HSV-2 pos) and virus-exposed seronegative (HSV-2 neg) subjects. T cell responses, determined by IFN-γ secretion, were generated to gL, UL2, UL11, UL21, ICP4, ICP0, ICP47 and UL40 with greater magnitude and/or frequency among cohorts of exposed HSV-2 neg or asymptomatic HSV-2 pos individuals, compared to symptomatic recurrent HSV-2 pos subjects. T cell antigens recognized preferentially among individuals who are resistant to infection or who are infected and have mild or no clinical disease may provide new targets for the design of vaccines aimed at treating and/or preventing HSV-2 infection.
    Full-text · Article · Aug 2014 · Virology
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    ABSTRACT: Vaccines are the most cost-effective means of preventing infectious diseases and have the potential to be used in a therapeutic capacity for the treatment of numerous chronic diseases and cancer. The majority of available vaccines function by eliciting antibodies that can neutralize toxins or opsonize the pathogen leading to elimination by professional phagocytes. However, there are many infectious and non-infectious diseases for which there are no available vaccines or the current antibody-mediated vaccines offer insufficient protection. There is emerging evidence that successful protection for these conditions requires the stimulation of T cell responses in addition to antibody. Genome/proteome-wide screening of pathogens to identify appropriate antibody targets for inclusion in vaccines has become widely used in recent years. However, the application of high-throughput proteomic screening approaches to identify T cell antigens has substantially lagged behind, primarily due to the lack of methods to identify full protein targets of T cell immunity across a broad human population. In this review, we will discuss some of the significant advances that have been made in high-throughput identification of T cell antigens for the development of novel efficacious vaccines.
    No preview · Article · Jun 2013 · Vaccine
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