The Herpes Simplex Virus (HSV) exists in two types: HSV-1, commonly associated with oral herpes, and HSV-2, the leading cause of genital herpes. Both types are highly prevalent globally, and once contracted, the virus remains in the body for life. As of 2024, no commercially available medication offers a permanent, sterilizing cure that completely eradicates the virus from the nervous system. Research is intensely focused on finding a cure due to the significant health and economic burden HSV places on millions worldwide.
Existing Antiviral Management Strategies
The current standard of care for managing HSV infection relies on FDA-approved antiviral medications such as acyclovir, valacyclovir, and famciclovir. These drugs function as guanine analogues, mimicking a natural building block of viral DNA. Virus-infected cells utilize these analogues during replication; once incorporated, the compound acts as a chain terminator, preventing the synthesis of new viral DNA.
This mechanism stops the virus from multiplying, shortening the duration and severity of active outbreaks. Valacyclovir and famciclovir are prodrugs, converted into their active forms (acyclovir and penciclovir) only after absorption, which improves their bioavailability compared to older drugs. While highly effective at suppression, these treatments must be taken consistently, either episodically for outbreaks or daily for suppressive therapy. They serve as management tools to reduce recurrence and lower the risk of transmission, but they do not eliminate the latent virus.
The Search for a Cure: Gene Editing and Latency Disruption
The fundamental challenge in curing herpes lies in its ability to establish latency, where the viral DNA lies dormant within the sensory nerve ganglia, hidden from the immune system and existing antiviral drugs. Researchers are pursuing a sterilizing cure by targeting this latent virus to physically remove or disable the viral genome. Gene editing technologies, most notably CRISPR/Cas9, represent a major strategy for achieving this eradication.
One promising approach involves delivering molecular “scissors” directly to the infected nerve cells. Scientists at the Fred Hutch Cancer Center have demonstrated success in preclinical mouse models using an experimental gene therapy employing a meganuclease enzyme. This enzyme is designed to recognize and make precise cuts in two distinct locations on the HSV DNA, destroying the viral genetic material.
The meganuclease is carried to the nerve ganglia via a delivery vehicle, typically a modified, non-pathogenic adeno-associated virus (AAV) vector. In recent studies, this targeted therapy successfully eliminated 90% or more of the latent HSV-1 DNA in mouse models of both oral and genital infection. By excising the viral DNA from the host’s nerve cells, this method aims to achieve a permanent, single-dose cure, eliminating the potential for future outbreaks and asymptomatic viral shedding.
Therapeutic Vaccines and Immune System Modulation
A separate research path focuses on achieving a functional cure, which involves using the body’s own defenses to keep the virus permanently suppressed. Therapeutic vaccines are designed to treat already infected individuals, differing from prophylactic (preventative) vaccines. They aim to significantly boost the existing immune response, primarily by enhancing T-cell mediated immunity.
The goal is to train the immune system to maintain constant surveillance over the nerve ganglia, preventing the latent virus from reactivating and causing symptoms or transmission. Moderna’s candidate, mRNA-1608, leverages messenger RNA technology to instruct the body’s cells to produce specific HSV proteins that trigger a powerful T-cell response. This candidate is currently being evaluated in Phase 1/2 clinical trials.
The path for therapeutic vaccines is challenging, evidenced by the recent discontinuation of a Phase II trial for candidate GSK3943104 after it failed to meet its primary efficacy goal. Despite setbacks, the immune modulation strategy remains viable. Even a vaccine that does not eradicate the virus but drastically reduces recurrence and shedding would offer a significant improvement over current daily antiviral medications. The hope is that a powerful, targeted T-cell response could provide a “functional cure,” where the infection remains undetectable and non-transmissible.
Realistic Timelines for Clinical Trials
The transition of a promising scientific discovery to a commercially available treatment is a rigorous, multi-year process governed by clinical trial phases. The most advanced gene editing approaches, which have shown success in animal models, are still in the preclinical stage and have not yet entered human trials. Before a gene therapy can be tested in humans, researchers must complete extensive safety and dosing studies to meet regulatory requirements.
Candidates like the therapeutic vaccine mRNA-1608 are further along, currently progressing through Phase 1 and 2 trials to assess safety, optimal dosage, and initial efficacy. Phase I trials focus on safety in a small group, Phase II evaluates effectiveness and side effects, and Phase III involves thousands of participants to confirm efficacy and monitor for rare side effects. Successfully completing all three phases and gaining regulatory approval typically takes many years, often a decade or more from the first human trial. Therefore, while the potential for a cure is greater than ever, a widely available treatment stemming from current research is realistically still several years away.