Herpes Simplex Virus (HSV) is one of the most common viral infections worldwide, persisting lifelong in the host. It is caused by two distinct types: HSV-1, which traditionally causes oral herpes (cold sores) but is increasingly linked to genital herpes, and HSV-2, the primary cause of genital herpes lesions. Global prevalence is high, with an estimated 3.8 billion people under 50 carrying HSV-1, and over 520 million people aged 15 to 49 infected with HSV-2.
Current treatments, such as the antiviral drugs acyclovir and valacyclovir, only manage active outbreaks by interfering with viral replication. These medications reduce the severity and duration of symptomatic episodes and suppress recurrence, but they do not eliminate the latent virus residing in the sensory nerve ganglia. Because existing drugs cannot offer a cure, there is a significant need for a vaccine that can either prevent initial infection or functionally cure the disease by eliminating or silencing the latent virus.
Defining the Vaccine Goals
Researchers are pursuing two fundamentally different functional goals for an HSV vaccine: prophylactic and therapeutic. A prophylactic vaccine is designed to prevent initial infection in individuals who have never been exposed to the virus. Success requires stimulating a strong, durable neutralizing antibody response. These antibodies must block the virus from entering host cells at the mucosal surface and prevent it from migrating to the sensory nerve ganglia, stopping the establishment of lifelong latency.
The second goal is a therapeutic vaccine, intended for individuals already infected with HSV-1 or HSV-2. This approach aims to significantly reduce the frequency and severity of recurrent outbreaks, rather than eliminating the latent virus. Therapeutic vaccines boost the host’s existing immune response by stimulating potent cellular immunity, specifically virus-specific T cells. This T cell response is necessary to better contain the virus within the nerve tissue and minimize viral shedding, which is the main driver of transmission.
Diverse Scientific Strategies in Development
The search for an effective HSV vaccine involves multiple platforms, each attempting to present viral components to the immune system. Subunit vaccines represent a traditional approach, focusing on specific viral surface proteins like glycoprotein D (gD) and glycoprotein B (gB), which are essential for viral entry. These candidates are safer because they contain no viral genetic material, but they often require specialized adjuvants to provoke a robust immune response. Past gD-based subunit vaccines failed to prevent HSV-2 infection in large-scale human trials, suggesting a single-protein approach may be insufficient to overcome the virus’s complex evasion mechanisms.
A newer strategy involves the use of mRNA and DNA vaccines, similar to those deployed against COVID-19. These vaccines deliver genetic instructions for the body’s own cells to manufacture one or more viral antigens. Producing the antigens internally generates a comprehensive and durable immune response that includes both neutralizing antibodies and potent T cells. For example, BioNTech’s candidate BNT163 encodes three different HSV-2 glycoproteins to induce a broad immune response.
Live-attenuated vaccines, which use a weakened version of the virus, are also being explored because they can induce a broad immune response mimicking natural infection. This platform presents a safety challenge due to the risk that the attenuated virus might establish latency or mutate back to a more virulent form. The most advanced, potentially curative strategy is a gene therapy approach that directly targets latent viral DNA in the sensory neurons. This involves using a viral vector to deliver gene-editing enzymes, specifically meganucleases, which cut and degrade the herpes DNA. Preclinical studies have demonstrated a reduction of up to 97% of latent HSV DNA in animal models.
Current Status of Clinical Trials
The journey from concept to licensed vaccine involves a rigorous, multi-phase clinical trial process: Phase I (safety and immunogenicity), Phase II (efficacy and dose-ranging), and Phase III (large-scale trials). Currently, no HSV vaccine has successfully navigated this entire pathway to gain regulatory approval.
The most notable progress is seen in mRNA vaccine candidates. Moderna’s mRNA-1608, a therapeutic vaccine for people already infected with HSV-2, is currently in a fully enrolled Phase 1/2 clinical trial. This study assesses the vaccine’s safety and its ability to reduce recurrent genital herpes lesions. BioNTech is also advancing its prophylactic mRNA candidate, BNT163, which is in a Phase 1 trial to evaluate safety and immune responses in healthy volunteers.
Despite the new technologies, the development path remains challenging, as evidenced by recent setbacks. Pharmaceutical company GSK recently discontinued its therapeutic subunit vaccine candidate (GSK3943104) after it failed to meet the primary efficacy objective in a Phase 1/2 trial. This discontinuation highlights the difficulty of creating an immune response capable of controlling a virus highly skilled at evading the body’s defenses. The current timeline suggests that the earliest a successful candidate could move through the final stages of testing and regulatory review would still be several years away.