HSV-1 and HSV-2 are among the most common human pathogens globally, establishing lifelong infections in a vast majority of the population. HSV-1 is primarily associated with oral herpes, while HSV-2 generally causes genital herpes; however, both can cause lesions in either location. The virus persists by establishing a dormant state in nerve cells, leading to periodic outbreaks. This presents a profound public health challenge, driving the search for treatments that move beyond symptom management to offer a functional or sterilizing cure. Current research focuses on overcoming the virus’s ability to hide and preventing its transmission, marking a shift from traditional antiviral approaches.
Current Antivirals and Their Limitations
The current standard of care relies on nucleoside analog antiviral medications, such as acyclovir, valacyclovir, and famciclovir. These drugs inhibit the viral DNA polymerase, the enzyme necessary for viral replication. The compounds are converted into an active form inside the infected cell, where they are incorporated into the growing viral DNA strand, effectively halting replication. While effective at controlling the acute, lytic phase of the infection, these antivirals do not eliminate the virus from the body. Their primary limitation is the inability to target the virus during its latent phase, when the viral genome lies dormant within the sensory nerve ganglia, necessitating lifelong management and allowing for periodic reactivation.
Targeting Latency and Viral Persistence
The greatest challenge in developing a herpes cure is the virus’s ability to establish latency, where the viral DNA remains dormant in nerve cells. New strategies focus on either physically removing the viral DNA or forcing the virus out of dormancy so it can be killed. This aims for a “functional cure” (stopping reactivation) or a “sterilizing cure” (eliminating the virus entirely).
Gene Editing (CRISPR/Cas9)
One promising avenue involves gene editing technologies, particularly CRISPR/Cas9. This system uses a guide RNA molecule to direct the Cas9 enzyme to specific sequences within the viral DNA. Researchers design these guides to cleave the HSV genome, leading to its destruction or neutralization within the neuron. Studies show that CRISPR/Cas9 can effectively target and modify latent HSV-1 genomes in models, reducing the virus’s ability to reactivate.
Latency Reversal Agents (LRAs)
An alternative strategy uses latency reversal agents (LRAs), compounds designed to induce the dormant virus to exit latency. Forcing the virus into its active, or lytic, phase makes it vulnerable to existing or new antiviral medications. This process is complex because the virus maintains latency through epigenetic mechanisms, such as DNA methylation, which suppress viral gene expression.
The success of these interventions hinges on solving the challenge of drug delivery. Treatments must cross the blood-brain barrier and travel to the sensory nerve ganglia, such as the trigeminal ganglia for HSV-1. Nanoparticle-based delivery systems, including lipid-based nanocarriers, are being explored to safely transport gene-editing components or LRAs directly to the infected nerve cells.
Strategies for Herpes Vaccine Development
Vaccine research pursues two distinct goals: preventing infection (prophylactic vaccines) and reducing severity and transmission in those already infected (therapeutic vaccines). Prophylactic vaccines aim to block the virus from establishing a latent infection. Therapeutic vaccines seek to boost the host immune system to better control the virus in the latent reservoir, reducing outbreaks and viral shedding.
Several technological platforms are utilized for these candidates:
- Subunit vaccines use specific viral proteins, such as glycoproteins, to stimulate an immune response. While safe, they have struggled to induce the broad immunity needed against HSV.
- Live-attenuated vaccines use a weakened form of the virus that replicates minimally. These are generally more immunogenic than subunit vaccines but require careful engineering to ensure safety and prevent latency establishment.
- Messenger RNA (mRNA) technology is the newest platform, similar to COVID-19 vaccines. mRNA vaccines instruct cells to produce key herpes proteins, inducing strong antibody and T-cell responses.
The advantage of mRNA vaccines, such as Moderna’s mRNA-1608, is their speed of development and potential for high immunogenicity. This platform can be easily modified to target multiple viral components simultaneously and is being developed for both prophylactic and therapeutic use.
Tracking Progress in Clinical Trials
The journey from discovery to treatment involves rigorous, multi-stage clinical trials to systematically test a candidate’s safety, dosage, and efficacy. Phase 1 trials focus on safety and dosage in a limited number of healthy volunteers. Phase 2 involves a larger group to assess efficacy and continue monitoring safety. Phase 3 trials are large-scale studies confirming effectiveness and comparing the new treatment to the current standard of care before regulatory approval.
Several promising candidates are currently advancing through this pipeline. Moderna’s mRNA-1608 is in a combined Phase 1/2 trial as a therapeutic vaccine for individuals infected with HSV-2. BioNTech’s BNT163 is in a Phase 1 trial, focused on preventing HSV-2 infection in uninfected adults (prophylactic use). Beyond vaccines, therapeutic agents are also progressing; for instance, Assembly Biosciences’ ABI-5366, a helicase primase inhibitor, is in Phase 1a/1b trials as a long-acting antiviral. Although some candidates, like GSK’s therapeutic vaccine GSK3943104, have failed in Phase 2 trials, these setbacks provide valuable data that informs future strategies.