Herpes Simplex Virus (HSV), comprising types 1 and 2, is one of the most widespread infections globally, affecting billions of people. Over 3.7 billion individuals under the age of 50 are estimated to be infected with HSV-1, which is the main cause of oral herpes and an increasing cause of genital herpes. HSV-2, the primary cause of genital herpes, affects approximately 520 million people aged 15 to 49 worldwide. Current antiviral treatments are effective at managing outbreaks but cannot eliminate the virus or offer a cure. This high prevalence and the virus’s nature as a lifelong infection create an urgent need for an effective vaccine to curb transmission and reduce the associated disease burden.
The Current Reality of Availability
The central question for many is when a herpes vaccine will be available for public use. The straightforward answer is that no commercially available vaccine for HSV-1 or HSV-2 exists today. Despite decades of research, an effective prophylactic or therapeutic vaccine has not yet been authorized by major regulatory bodies like the U.S. Food and Drug Administration. Development is progressing through the various stages of clinical trials, a rigorous process that takes many years. A commercially available vaccine is likely several years away, contingent on the successful outcome of late-stage trials. Candidates currently in Phase 1 or Phase 2 must successfully complete the large-scale Phase 3 trials before they can be submitted for regulatory approval. This timeline is complicated by recent setbacks, such as a major therapeutic vaccine candidate from GSK failing its primary efficacy endpoint in a Phase 2 trial in September 2024.
Defining the Two Vaccine Goals
Researchers are pursuing two distinct goals in the development of a herpes vaccine: prevention and therapy. These two aims target different populations and require fundamentally different scientific strategies. The first approach is the Prophylactic Vaccine, designed to protect uninfected individuals from ever acquiring the virus. It works by training the immune system to recognize the virus before the initial infection, aiming for “sterilizing immunity” that blocks viral entry at the mucosal surface.
The second approach is the Therapeutic Vaccine, given to people who are already infected with HSV. The goal is not to cure the infection, but to significantly reduce the frequency and severity of outbreaks, as well as decrease viral shedding to limit transmission. Because the virus establishes a lifelong, latent infection in nerve cells, a therapeutic vaccine must focus on boosting the cellular immune response to control viral reactivation. Conversely, a prophylactic vaccine primarily focuses on eliciting a potent antibody response to neutralize the virus upon initial exposure.
Key Hurdles in Vaccine Development
The primary biological challenge is the virus’s ability to establish latency by hiding within sensory nerve cells, such as the dorsal root ganglia. After the initial infection, the virus travels up the nerve axon and settles in the neuron, where it enters a dormant state. In this form, the viral genome exists as a circular episome that expresses few viral proteins, allowing it to remain invisible to the body’s immune system or current antiviral drugs.
Another significant hurdle is generating a sufficiently robust and localized mucosal immune response at the site of infection. The virus enters the body through mucosal surfaces, and a protective vaccine needs to create high levels of neutralizing antibodies and T-cells in that specific area. However, the immune response generated by systemic vaccination often fails to reach the necessary concentration of immune cells at the mucosal barrier to block the virus completely.
The virus has also evolved sophisticated mechanisms for immune evasion, which complicates the training of the immune system. For instance, HSV produces a protein called ICP-47, which interferes with the host cell’s ability to present viral antigens to cytotoxic T-lymphocytes (CTLs). This mechanism prevents the full activation of the cell-mediated immune response, making it difficult for vaccines to elicit the strong T-cell response needed to control the infection.
Promising Candidates and Clinical Progress
Despite the complex biological challenges, a number of innovative vaccine candidates are advancing through the clinical trial process, offering renewed hope. These candidates employ various scientific strategies, including subunit, live-attenuated, and messenger RNA (mRNA) technologies. The clinical trial process is divided into three main phases: Phase 1 tests safety in a small group, Phase 2 tests efficacy and optimal dosing, and Phase 3 confirms efficacy and monitors side effects in thousands of participants.
One of the most closely watched candidates is Moderna’s mRNA-1608, a prophylactic vaccine currently in Phase 1 trials. This vaccine uses a trivalent approach, targeting three different glycoproteins—gC, gD, and gE—on the surface of the HSV-2 virus. It aims to induce both a strong antibody and a cellular T-cell response. The Phase 1 trial is expected to be completed in mid-2025, which will determine its safety and the strength of the immune response before it can progress to larger trials.
Other efforts focus on entirely new scientific mechanisms, such as the gene therapy research being conducted at the Fred Hutch Cancer Center. This preclinical approach aims to achieve a functional cure by using a gene-editing tool to directly target and eliminate the latent viral DNA buried within the nerve cells. While this is a promising strategy, it has not yet entered human clinical trials and would need to clear the rigorous regulatory process before becoming available. The recent failure of the therapeutic candidate from GSK underscores the high-risk nature of this research, but the diversity of approaches in the pipeline suggests researchers are continuing to explore every avenue to solve this challenging public health problem.