The herpes simplex virus (HSV) is a highly prevalent pathogen globally, existing in two primary forms, and is responsible for lifelong infections. As of today, there is no widely licensed or Food and Drug Administration (FDA)-approved vaccine available to either prevent initial infection or treat an existing Herpes Simplex Virus type 1 (HSV-1) or type 2 (HSV-2) infection. Medical efforts currently focus on managing symptoms and reducing the frequency of outbreaks using antiviral medications. However, research is actively progressing on multiple vaccine candidates that aim to change the landscape of HSV management and prevention.
The Distinction Between HSV-1 and HSV-2
Herpes Simplex Virus is categorized into two distinct types, HSV-1 and HSV-2. HSV-1 is traditionally associated with oral herpes, resulting in cold sores around the mouth. HSV-2 is most commonly linked to genital herpes, causing lesions in the genital and anal regions. The location of the lesions is not exclusive, as HSV-1 has become a frequent cause of new genital herpes cases, particularly in younger populations. Both viruses establish a permanent, latent infection in the nervous system, complicating both treatment and vaccine design.
Prophylactic Vaccine Efforts
Prophylactic vaccines are designed for individuals who have never been infected with the herpes simplex virus. The primary aim of these preventative candidates is to achieve “sterilizing immunity,” meaning the body’s immune response completely blocks the virus before it can infect the nerve cells and enter a latent state. Many current candidates leverage new technologies, such as messenger RNA (mRNA) platforms, which instruct the body’s cells to produce specific viral proteins to stimulate an immune response. BioNTech’s BNT163 is an mRNA vaccine candidate currently in Phase 1 clinical trials, designed to prevent genital lesions caused by HSV-2 and potentially HSV-1. This vaccine encodes three specific glycoproteins from the HSV-2 virus.
Another approach involves subunit vaccines, which utilize only fragments of the viral proteins, such as glycoproteins, often combined with an adjuvant. Replication-defective virus vaccines are also under investigation; these are genetically modified versions of the virus that can infect cells but are unable to replicate efficiently.
Therapeutic Vaccine Development
Therapeutic vaccines are intended for individuals who are already infected with HSV-1 or HSV-2. The purpose of these vaccines is to manage the chronic disease by strengthening the host’s existing immune response. The major goals are to reduce the frequency and severity of recurrent outbreaks and lessen viral shedding, thereby decreasing the risk of transmission.
These vaccines often focus on boosting the cellular immune response, particularly the T-cells, which control the virus. Moderna’s mRNA-1608, for instance, is an mRNA vaccine candidate being studied in Phase 1/2 clinical trials for its therapeutic potential in adults with recurrent HSV-2. Pharmaceutical companies are also exploring recombinant protein vaccines, such as GSK’s candidate, which is in Phase 1/2 trials. These vaccines use specific viral proteins combined with potent adjuvants to provoke a more robust T-cell reaction against the infected cells. Therapeutic vaccines could offer a long-term strategy for minimizing the disruptive effects of recurrent herpes outbreaks.
Biological Hurdles in Vaccine Creation
The primary biological challenge in developing an effective herpes vaccine lies in the virus’s ability to establish latency within the host’s nervous system. After initial infection, HSV travels along the nerve fibers and establishes a permanent, dormant presence in the sensory nerve cell clusters known as ganglia. In this latent state, the viral genome exists without actively producing infectious virus particles.
The immune system is unable to completely clear the virus from these protected nerve cells. Specialized tissue-resident T-cells help suppress the virus and prevent frequent reactivation, but they cannot eradicate the viral DNA. Another hurdle is the complexity of the viral envelope, which is studded with multiple glycoproteins that the virus uses to enter host cells and evade immune detection. A successful vaccine must generate a broad and durable neutralizing antibody response against these various proteins to prevent initial entry into epithelial cells and subsequent invasion of the nervous system.