A fresh approach to beat genital herpes

There is no vaccine for herpes. However, based on ground-breaking research from the University of Gothenburg in Sweden, Simplexia has developed a novel and unique vaccine approach to stop  genital herpes virus by locking down the virus as it tries to spread between cells.

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A novel strategy The Simplexia approach Support for the Simplexia approach The scientific rationale
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A novel strategy to develop a vaccine against HSV-2

Although several vaccine approaches have been tested in humans, none of them has led to a licensed vaccine. Simplexia offers a novel and unique approach to develop a vaccine against HSV-2 infection.

Vaccination – A Global Priority

Herpes virus infections are lifelong, incurable, often stigmatizing, and no existing interventions can effectively prevent them at the population-level. Vaccine development is a global WHO priority and fits several of the UN’s 17 Sustainable Development Goals.

Prevention is better than treatment

The therapeutic options available, such as oral antiviral drugs, only treat symptoms. Furthermore, they are only partially effective in reducing the effects of infection and the risk of transmission between partners. Oral antiviral drugs can be effective, reducing symptoms of HSV-2 by 70-80%. However, compliance can be a problem for suppressive treatment. Antiviral drugs have no effect or poor effect on recurrent HSV-2 meningitis, neonatal infections during childbirth, and do not reduce the risk of acquiring HIV, which is associated with HSV-2 infection. Continuous therapy with anti-herpesvirus medications is less than 50% effective in reducing transmission between partners. Even individuals without symptoms can transmit HSV-2. Approximately 20% of persons who test positive for HSV-2 do not show typical signs of infection. Untested, infected but symptom-free individuals may transmit the virus to partners without being aware of the risk. The development of one or more herpes simplex virus (HSV) vaccines has therefore been identified by the World Health Organization as an important goal for sexual and reproductive health (SRH) worldwide.

The Simplexia Approach

Cross-reactive immune responses from a prior HSV-1 infection do not provide protection against subsequent HSV-2 infection. Several human vaccine trials using cross-reactive antigens found on both HSV-1 and -2 virus have failed. Therefore, Simplexia’s vaccine is based on a type-specific protein of HSV-2, gG-2. Simplexia has developed a soluble version of the membrane-bound region of gG2 (mgG2) as an HSV-2 vaccine antigen.

Illustration of HSV-1 and HSV-2

Schematic illustration of HSV-1 and HSV-2

Virus-DNA is located inside the virus particle and protected by a shell of proteins. Other viral proteins are embedded in the envelope of the viral particle. Most of the proteins, here illustrated by glycoprotein gD and gB, are similar between HSV-1 and HSV-2 and illustrated in green and yellow color. In contrast, the glycoprotein G2, illustrated in red, is specific for HSV-2.

Genital mucosa cells are infected

The HSV-2 infect the genital mucosa and the nerve cells

The genital mucosa cells are infected with HSV-2 and the viral DNA penetrates into the nucleus of the cell and replicate. Viruses are leaving the mucosa cell membrane and infect the nerve endings and further transported to the nerve cell body where HSV-2 become dormant.

The route of HSV-2

The route of HSV-2 after reactivation from the nerve cell to the mucosa cells

Periodically virus is reactivated from the nerve cell body and transported back to the genital mucosa cells giving blisters and genital lesions (1) or leaving the mucosa cells without symptoms (2).

The importance of glycoprotein G

The glycoprotein G of HSV-2 is important for release of virus from infected cells

When glycoprotein G of HSV-2 is present, viruses are released from the infected cells and can be transmitted to a partner. When the gG-2 protein is lacking, viruses are trapped at the cell membrane and cannot be transmitted to a partner.

A prophylactic vaccine

A prophylactic vaccine

A prophylactic vaccine stops the infection to the nerve endings. HSV-2 cannot infect the individual.

A therapeutic vaccine

A therapeutic vaccine

A therapeutic vaccine stops HSV-2 in nerve cell body and/or the transport of virus within the nerve cell. As HSV-2 does not reach the genital mucosa, no symptoms are recognized and no viruses can be transmitted to a partner.

The rationale for using protein gG-2

Cross-reactive antibodies elicited after an HSV-1 infection are not protective against HSV-2 infection

Usually, the individual is infected with HSV-1 in early childhood. After the HSV-1 infection, antibodies designated as a Y in speckled yellow or green color are elicited against the envelope HSV-1 proteins, exemplified by gB-1 protein (yellow) and gD-1 protein (green). Most of these antibodies are cross-reactive, i.e., antibodies binding to gB-1 and gD-1 also bind to gB-2 and gD-2 on HSV-2. Cross-reactive HSV-1 antibodies do not protect from an HSV-2 infection. This observation is the rationale to use the HSV-2 specific protein gG-2 as a vaccine against HSV-2 infection.

Schematic illustration of HSV-1 and HSV-2

Virus-DNA is located inside the virus particle and protected by a shell of proteins. Other viral proteins are embedded in the envelope of the viral particle. Most of the proteins, here illustrated by glycoprotein gD and gB, are similar between HSV-1 and HSV-2 and illustrated in green and yellow color. In contrast, the glycoprotein G2, illustrated in red, is specific for HSV-2.

The HSV-2 infect the genital mucosa and the nerve cells

The genital mucosa cells are infected with HSV-2 and the viral DNA penetrates into the nucleus of the cell and replicate. Viruses are leaving the mucosa cell membrane and infect the nerve endings and further transported to the nerve cell body where HSV-2 become dormant.

The route of HSV-2 after reactivation from the nerve cell to the mucosa cells

Periodically virus is reactivated from the nerve cell body and transported back to the genital mucosa cells giving blisters and genital lesions (1) or leaving the mucosa cells without symptoms (2).

The glycoprotein G of HSV-2 is important for release of virus from infected cells

When glycoprotein G of HSV-2 is present, viruses are released from the infected cells and can be transmitted to a partner. When the gG-2 protein is lacking, viruses are trapped at the cell membrane and cannot be transmitted to a partner.

A prophylactic vaccine

A prophylactic vaccine stops the infection to the nerve endings. HSV-2 cannot infect the individual.

A therapeutic vaccine

A therapeutic vaccine stops HSV-2 in nerve cell body and/or the transport of virus within the nerve cell. As HSV-2 does not reach the genital mucosa, no symptoms are recognized and no viruses can be transmitted to a partner.

Cross-reactive antibodies elicited after an HSV-1 infection are not protective against HSV-2 infection

Usually, the individual is infected with HSV-1 in early childhood. After the HSV-1 infection, antibodies designated as a Y in speckled yellow or green color are elicited against the envelope HSV-1 proteins, exemplified by gB-1 protein (yellow) and gD-1 protein (green). Most of these antibodies are cross-reactive, i.e., antibodies binding to gB-1 and gD-1 also bind to gB-2 and gD-2 on HSV-2. Cross-reactive HSV-1 antibodies do not protect from an HSV-2 infection. This observation is the rationale to use the HSV-2 specific protein gG-2 as a vaccine against HSV-2 infection.

Illustration of HSV-1 and HSV-2

Genital mucosa cells are infected

The route of HSV-2

The importance of glycoprotein G

A prophylactic vaccine

A therapeutic vaccine

The rationale for using protein gG-2

Support for the Simplexia approach

In contrast to the successes achieved with the herpes zoster “shingles” vaccines, an effective vaccine for HSV has remained elusive. Although several vaccine approaches have been tested in humans, none of them has led to a licensed vaccine. In spite of promising results in pre-clinical studies in animal models, earlier candidates that have been tested in clinical trials have achieved only partial success.

Nevertheless, the herpes zoster vaccine has shown that protein subunit vaccines can be effective at stimulating an immune response against viral proteins and protecting against recurrent disease.

The scientific rationale

Simplexia has therefore chosen a novel approach to vaccine development for genital herpes based on research from the University of Gothenburg and from earlier pre-clinical and clinical data.

Type-specific antigen

Unlike other HSV-2 glycoproteins mgG-2 has low sequence homology with its HSV-1 counterpart and has been shown to only induce an HSV-2 type specific antibody response. In fact, the mgG-2 protein has been used for several years as a type-specific antigen for HSV-2 specific diagnosis. Since gG2 is unique for HSV-2, vaccination with Simplexia's vaccine is not affected by previous HSV-1 infection.

Role in release of virus from cells

Virus studies using an mgG-2-negative HSV-2 mutant show that mgG-2 is involved in the extracellular release of infectious particles. Although glycoprotein gG2 is not essential for replication in cultured cells it is important for the exit of HSV-2 virus from cells and intact mgG-2 in clinical HSV-2 isolates is of importance for human infection, as mgG-2-negative HSV-2 isolates are rarely detected.

Stimulates proliferation of T-cells in infected patients

Proliferative helper T-cells responses are seen in HSV-2 infected patients after stimulation with gG2 protein, with greater responses seen in asymptomatic than symptomatic individuals.

Protects against disease in challenge model

Vaccination of mice with either mgG2 or Simplexia’s soluble version of mgG2 protects mice against genital HSV-2 infection in a laboratory challenge model.