Herpes Simplex Virus (HSV) is a widespread global health concern. It manifests as two types: Herpes Simplex Virus type 1 (HSV-1), commonly associated with oral herpes, and Herpes Simplex Virus type 2 (HSV-2), the primary cause of genital herpes. While many infections are asymptomatic, both types can lead to painful, recurring lesions and pose significant public health challenges. Developing an effective vaccine against HSV remains an important public health objective.
The Biological Challenge of an HSV Vaccine
Developing a vaccine against the Herpes Simplex Virus presents complex biological hurdles, primarily due to the virus’s unique life cycle and its strategies for evading the immune system. A major challenge is HSV’s ability to establish latency, where it retreats into nerve cells, such as the trigeminal ganglion for HSV-1 and the dorsal root ganglia for HSV-2. In this dormant state, the virus remains largely inaccessible to immune surveillance, making it difficult for the body’s defenses to eliminate the infection.
Even during active infection, HSV employs various mechanisms to suppress the immune response. The virus interferes with immune signaling pathways, including Toll-like receptors and the production of interferons. Viral proteins, particularly glycoprotein D (gD) on the virus surface, contribute to immune evasion and facilitate viral proliferation. These evasion tactics mean an effective vaccine must prevent initial infection and address the virus’s ability to establish and reactivate from latency.
Prophylactic vs Therapeutic Vaccine Goals
HSV vaccine development pursues two goals: prophylactic or therapeutic. A prophylactic vaccine aims to prevent uninfected individuals from acquiring HSV. It would block initial infection, preventing the virus from establishing latency in nerve cells.
In contrast, a therapeutic vaccine is for people already infected with HSV. Its objective is not to cure the infection, but to mitigate its effects. This includes reducing outbreak frequency and severity, lessening viral shedding, and lowering transmission risk. This distinction influences vaccine candidate design and evaluation.
Current Vaccine Candidates and Research
Current HSV vaccine research explores various scientific approaches, each aiming to overcome the virus’s complex biological challenges. Promising avenues include mRNA vaccines, subunit vaccines, and gene-editing therapies. These diverse strategies reflect efforts to develop effective prevention and treatment options.
mRNA Vaccines
mRNA vaccine technology has gained prominence, with companies like Moderna and BioNTech leading development. Moderna’s candidate, mRNA-1608, is designed as a therapeutic vaccine for individuals already infected with HSV-2, aiming to induce robust antibody and cell-mediated immune responses. It is in a fully enrolled Phase 1/2 clinical trial with 300 participants who have recurrent genital herpes, with results anticipated by June 2025. The mRNA platform allows rapid development and scalable manufacturing, potentially offering cross-protection against HSV-1.
BioNTech is also advancing an mRNA-based vaccine, BNT163, as a prophylactic measure to prevent HSV-2 infection. This candidate encodes three specific HSV-2 glycoproteins intended to block viral entry and spread, and counteract immune-suppressing properties. A Phase 1 clinical trial for BNT163 began in December 2022, enrolling 108 healthy volunteers without symptomatic genital herpes, with estimated completion in October 2026. This technology instructs the body’s cells to produce viral proteins, training the immune system to recognize and fight the virus.
Subunit Vaccines
Subunit vaccines, which use specific viral proteins to trigger an immune response, have been a long-standing area of HSV vaccine research. Historically, recombinant glycoprotein D (gD) from HSV-2 has been a focus, with some candidates showing limited success, particularly against HSV-1 genital infection rather than HSV-2. More recently, GSK pursued a therapeutic HSV vaccine candidate, GSK3943104, which progressed to a Phase 1/2 clinical trial. However, in September 2024, GSK announced this candidate did not achieve its primary efficacy objective and will not move to Phase 3 studies, though data collection continues for further insights.
Gene-Editing Therapies
Gene-editing technologies are another approach, spearheaded by researchers at the Fred Hutch Cancer Center. Their work focuses on developing a potentially curative gene therapy using gene-editing molecules, specifically meganucleases, delivered by adeno-associated virus (AAV) vectors. This method targets latent HSV DNA within nerve cells, aiming to cut and damage viral genes so severely that the virus cannot repair itself, allowing the body to eliminate it. Pre-clinical studies in mouse models have demonstrated significant reductions in latent HSV DNA, achieving 90% or more elimination of HSV-1 in facial infections and up to 97% in genital infections, alongside a decrease in viral shedding. The research team has also simplified the treatment, using a single vector and meganuclease to improve safety and production.
The Role of Antiviral Medications
Antiviral medications currently serve as the primary treatment for managing Herpes Simplex Virus infections, in the absence of a cure or widely available vaccine. These drugs, including acyclovir, valacyclovir, and famciclovir, function by interfering with the virus’s ability to replicate, reducing the severity and duration of outbreaks. They are nucleoside analogs that mimic natural building blocks of DNA, and are selectively activated by viral enzymes within infected cells. Once activated, they inhibit the viral DNA polymerase, preventing the virus from synthesizing new genetic material and reproducing.
These medications are not a cure for HSV, as they do not eliminate the latent virus in nerve cells, but they are effective in managing symptoms and reducing recurrent episodes. For active outbreaks, antivirals can shorten healing time and lessen pain, with treatment being most effective when initiated within 48 hours of symptom onset. For frequent or severe outbreaks, daily suppressive therapy can significantly reduce recurrences, often by about 75%.
Beyond managing symptoms, suppressive antiviral therapy also lowers the risk of HSV transmission. Studies indicate continuous daily treatment can reduce asymptomatic viral shedding, decreasing the likelihood of spreading the virus to sexual partners. While these medications provide relief and control, they highlight the ongoing need for a vaccine that could offer more comprehensive prevention or a cure for HSV.