ADCC at the interface between innate and adaptive immunity against herpes simplex virus

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Vaccines represent a major accomplishment of biomedical science in controlling many infectious diseases. However, over the past decades vaccine development against herpes has been hampered by a knowledge gap about what type of immune responses are effective in preventing herpes infection. At X-VAX, we believe that a new approach may hold the key to defeating herpes: inducing antibody-dependent cell-mediated cytotoxicity (ADCC) to flag infected cells for destruction by natural immune cells. ADCC has already revolutionized cancer therapy; it is one of the primary mechanisms of antitumor activity of monoclonal antibodies such as rituximab.

As vaccination depends on stimulation of a specific immune response, how can a vaccine candidate that induces ADCC potentially help us to fight herpes simplex virus (HSV)? The following provides an overview of the body’s two immune systems, and then reviews how ADCC combines the power of these two systems.

First and second line of defense

Our immune system protects us from the invasion of a wide range of organisms that include viruses. This immunity consists of two distinct systems: Innate (natural) immunity is the defense system with which we were born, and adaptive (acquired) immunity is the immune system that develops with exposure to various microbes. Simply stated, after the body’s natural physical barriers, defense against invading microbes is mediated by rapid, non-specific innate immunity followed by highly specific, longer-term adaptive immunity.

The innate immune system is the first line of defense as it responds rapidly, activating the body’s non-specific defense mechanisms to combat invaders identified as foreign or “non-self”. The innate immune cell repertoire includes tissue-resident cells such as macrophages, and cells which circulate via blood and the lymphoid system, such as natural killer cells.

In contrast, adaptive immunity is the second line of defense and characterized by two types of lymphocytes, T and B cells. These cells may be slower to respond but the response is highly specific to the invading organism with the ability to develop immunological memory with readiness to mount a rapid defense against subsequent infections by the same organism. The adaptive immune system consists of two main mechanisms: cell-mediated and humoral.

The cell-mediated immune response of the adaptive immune system involves T cells. Cytotoxic (killer) T cells recognize infected cells based on specific proteins (antigens) and bring about their destruction. T cells also use signaling molecules known as cytokines to orchestrate other immune cells moving to the site of infection and destroy infected cells. The humoral immune response of the adaptive immune system involves B cells and is also called antibody-mediated immunity.

The humoral immune system deals with invading microorganisms that are freely circulating, or outside infected cells. B cells generate specific antibodies that bind to a recognized antigen on the surface of a virus. If this antibody binding is able to thwart mechanisms needed for viral attachment and entry into the body’s cells, then it is called a neutralizing antibody. Vaccine strategies frequently seek to generate neutralizing antibodies to prevent viruses from entering cells and infecting the host. However, once a virus has entered the body’s cells, it can evade these neutralizing antibodies.

Antibody-dependent cell-mediated cytotoxicity (ADCC)

If a virus does evade neutralization and successfully invades the body’s cells, the virus is replicated inside the cell and some of the viral proteins are expressed on the surface of the infected cell. When this happens, a broad array of non-neutralizing antibodies can recognize and bind to those surface viral proteins. Now that the infected cells are flagged by specific antibodies, non-specific natural killer cells of the innate immune system identify the flagged cell as foreign or “non-self” and can in turn bind through their Fc receptors to these antibodies. After binding, Fc receptor activation triggers natural killer cells to release cytotoxic agents that cause the death of the infected cell and thereby block cell-to-cell viral spread – which is why these non-neutralizing ADCC antibodies are also called Fc receptor activating antibodies. ADCC is an example of cooperation between the potent antiviral action of the innate immune system with the diversity and specificity of the adaptive immune system.

ADCC against herpes simplex virus

It has become evident that some viruses including herpes simplex virus have evolved mechanisms to evade the body’s immune systems, and that the presence of neutralizing antibodies alone does not always predict protection. In fact, according to data from the World Health Organization, more than 50% of all people under the age of 50 are infected with HSV-1, and multiple attempts to prevent HSV infection with vaccines that elicit neutralizing antibodies have failed. A role for ADCC in herpes simplex control has been suggested by a study of newborns with HSV infections: High anti-HSV ADCC antibody levels of their HSV-infected mother were associated with an absence of disseminated herpes infection in their infants.1

For our vaccine candidate ∆gD-2 (delta gD-2), we deleted the gene that encodes the glycoprotein D protein on the surface of the HSV-2 virus. With it, we removed the source of an immunodominant neutralization response and thereby a key evasion mechanism – thereby unleashing an ADCC response in preclinical models that may prove to be effective in not only the prevention but also the treatment of herpes disease.

ADCC mechanism of immunity

ADCC mechanism of immunity

1 Kohl, S et al., Neonatal antibody-dependent cellular cytotoxic antibody levels are associated with the clinical presentation of neonatal herpes simplex virus infection. The Journal of Infectious Diseases. 1989;160(5), 770-776.