Herpes Simplex Virus (HSV), comprising types HSV-1 and HSV-2, is a highly prevalent infection that establishes a permanent presence in the human nervous system. Globally, over 3.7 billion people under the age of 50 are estimated to have HSV-1, while nearly 500 million people aged 15–49 have HSV-2, which is the primary cause of genital herpes. Current treatments, which include antiviral drugs like acyclovir and valacyclovir, are limited to suppressive therapy that manages symptoms and reduces the frequency and intensity of outbreaks. These medications cannot eliminate the latent virus hiding in the nerve cells, meaning the possibility of recurrence and transmission remains. This fundamental challenge has driven researchers to pursue two distinct, more permanent solutions that could transform the treatment landscape and ultimately lead to a cure.
Defining the Goalposts: Sterilizing Cure vs. Functional Cure
Scientists working toward a permanent solution for HSV operate with two different definitions of a “cure,” each requiring a unique approach. A sterilizing cure represents the complete eradication of the virus from the body. This ambitious goal involves physically removing the viral DNA, known as the latent episome, from the infected nerve cells where it resides.
The virus hides in sensory nerve clusters, specifically the dorsal root ganglia, making it invisible to the immune response. Achieving a sterilizing cure means accessing these protected neurons and excising the viral genome without damaging the host’s DNA.
A functional cure, conversely, focuses on permanent viral control rather than elimination. In this scenario, the HSV DNA remains dormant within the nerve cells, but the therapy prevents it from reactivating, replicating, or shedding. This approach aims to eliminate both symptomatic recurrences and asymptomatic viral shedding, which is the main driver of transmission.
Therapeutic vaccines drive the pursuit of a functional cure, while gene editing techniques are dedicated to achieving a sterilizing cure.
Gene Editing: Targeting the Latent Virus
The most direct path toward a sterilizing cure involves gene editing tools, such as meganucleases and CRISPR/Cas9, to target the latent HSV genome. Researchers at the Fred Hutchinson Cancer Center are employing these systems for this precise genetic task. The meganuclease enzyme is engineered to make two specific cuts in the double-stranded DNA of the herpes virus.
Making two cuts causes irreparable damage, preventing the virus from repairing itself or reactivating. The body’s natural DNA repair mechanisms then recognize this damaged viral DNA as foreign material and dispose of it. The key challenge is delivering these editing tools specifically to the infected neurons scattered throughout the sensory ganglia.
To overcome this hurdle, scientists use harmless, modified viruses called adeno-associated virus (AAV) vectors to carry the gene editing instructions. These vectors are injected into the bloodstream, travel to the nerve clusters, and release their payload inside the infected cells, where the tools begin excising the latent HSV DNA.
In pre-clinical mouse models, this gene editing approach has shown remarkable success, eliminating 90% or more of the HSV-1 infection in the nerve tissue. Specifically, one study demonstrated a 97% reduction of HSV-1 in a mouse model of genital infection. This high level of viral reduction is considered sufficient to prevent future outbreaks and stop transmission entirely.
Therapeutic Vaccines and Immune System Training
Therapeutic vaccines focus on a functional cure by strengthening the body’s existing defenses against HSV. These vaccines are administered to people who already have the virus, aiming to train the immune system to maintain permanent control over the latent infection. This strategy is distinct from traditional prophylactic vaccines, which prevent infection in uninfected individuals.
The goal is to induce a potent, long-lasting T-cell response, the primary defense mechanism against herpesvirus reactivation. The effectiveness of a therapeutic vaccine correlates with the strength of T-cell immunity, specifically CD4+ and CD8+ subsets. These cells must be strategically deployed to the mucosal sites where the virus attempts to re-emerge and shed.
By stimulating a robust cellular immune response, the vaccine seeks to significantly reduce both symptomatic recurrences and asymptomatic viral shedding. Reducing shedding is a public health priority, as it is the main way the virus is transmitted. Several candidates are in development, including protein subunit vaccines like GEN-003, which has demonstrated a reduction in genital shedding and lesion rates in early trials.
Modern approaches, including mRNA-based vaccines from companies like Moderna and BioNTech, are also being developed. These platforms target multiple viral proteins simultaneously to elicit a broader and more durable immune memory, relying on generating a sustained presence of virus-specific T-cells at the site of potential viral reactivation.
The Current State of Clinical Trials
Progress toward both a sterilizing and a functional cure has moved into active development, placing several candidates on the pathway to human use. The gene editing approach, exemplified by the work from Fred Hutch, is currently in advanced pre-clinical safety testing and refinement. Researchers are streamlining the delivery vector to reduce potential side effects on the liver and nerves before moving to human clinical trials.
The transition from successful animal models to human trials is complex, requiring rigorous regulatory alignment to ensure safety and effectiveness. Success depends on the safe and efficient systemic delivery of the meganuclease payload to every infected nerve cluster.
On the vaccine front, several candidates are further along in the clinical pipeline, having entered Phase 1 and Phase 2 trials. Moderna’s mRNA-1608 launched its Phase 1 study to evaluate safety and immunogenicity, with estimated completion in mid-2025. Other candidates, like GEN-003, have shown positive results in Phase 2 trials, demonstrating a statistically significant reduction in viral shedding and lesion rates.
These clinical trial results offer optimism, confirming that both gene editing and immune-training strategies can reduce the viral burden. Each step forward, whether in advanced pre-clinical testing or early-stage human trials, brings the possibility of a permanent solution closer to reality.