The Herpes Simplex Virus (HSV), comprising types 1 (HSV-1) and 2 (HSV-2), is one of the most widespread human pathogens globally, infecting billions. Approximately two-thirds of the world’s population under age 50 have HSV-1, which often causes oral herpes, while hundreds of millions have HSV-2, the primary cause of genital herpes. Despite this high prevalence, a widely available, FDA-approved vaccine for the prevention or treatment of HSV does not currently exist. The complex biology of the virus has historically stalled development, but several promising candidates are now moving through the clinical trial pipeline.
The Current Status of Herpes Vaccines
Current medical management for herpes relies on antiviral medications like acyclovir and valacyclovir. These drugs suppress active viral replication during an outbreak, effectively managing symptoms and reducing the frequency of recurrent episodes. However, antivirals do not eliminate the virus from the body. They also do not guarantee the cessation of viral shedding, meaning transmission can still occur even when a person is asymptomatic.
A vaccine aims for a more definitive outcome than antivirals, such as sterilizing immunity or a functional cure. Sterilizing immunity means complete prevention of infection. A functional cure, often the goal of therapeutic vaccines, would significantly reduce outbreaks and viral shedding, preventing disease and transmission without eliminating the virus. New technologies are reigniting the field following the failure of previous vaccine candidates.
Scientific Hurdles in Vaccine Development
Creating an effective herpes vaccine is complicated primarily by the virus’s ability to establish latency. Following initial infection, the virus travels up nerve endings to hide dormant in the sensory nerve ganglia. From this protected location, the virus is largely invisible to the immune system, which is why the body cannot clear the infection naturally.
The virus also employs mechanisms to evade immune detection, complicating vaccine design. To combat HSV effectively, a vaccine must generate a strong, specific immune response, particularly robust T-cell mediated immunity. T-cells are crucial because they patrol the nerves and skin to contain the virus when it attempts to reactivate. Previous vaccine attempts focused only on neutralizing antibodies, which failed because they did not address the virus hidden in the nerve tissue.
Key Candidates and Clinical Trial Progress
Research now focuses on novel vaccine platforms, including messenger RNA (mRNA) and live-attenuated technologies, to overcome biological hurdles. One prominent candidate is Moderna’s mRNA-1608, an mRNA vaccine targeting HSV-2 designed to induce both a strong antibody response and cell-mediated immunity. This candidate is currently undergoing Phase 1 clinical trials to assess its safety and the immune response generated in adults with recurrent genital herpes. The initial phase of this trial is expected to be completed in mid-2025.
BioNTech is also developing an mRNA-based preventative vaccine, BNT163, which encodes for three different HSV-2 glycoproteins to block viral entry and spread. BNT163 is in a Phase 1 clinical study to test its safety and immunogenicity in adults who do not have symptomatic genital herpes. A live-attenuated vaccine, such as RatioVaccines’ VC2, represents another approach, using a weakened form of the virus that cannot establish a latent infection.
The path to approval is structured through three main phases:
- Phase 1 focuses on safety and determining the correct dosage in a small group of people.
- Phase 2 trials, involving hundreds of participants, test the vaccine’s effectiveness and continue to monitor safety.
- Phase 3 involves thousands of participants to confirm efficacy, compare it to existing treatments or placebo, and track long-term side effects.
While candidates like mRNA-1608 and BNT163 are progressing in early phases, moving successfully through Phase 3 and receiving FDA approval typically takes several years.
Distinguishing Preventative and Therapeutic Goals
Herpes vaccine research is divided into two distinct objectives: preventative (prophylactic) and therapeutic. A preventative vaccine is intended for individuals who have never been infected with HSV. Its goal is to block the initial infection entirely, protecting uninfected people from contracting the virus. The BioNTech candidate, BNT163, is an example of this preventative approach.
A therapeutic vaccine is designed for people already infected with HSV. Its purpose is not to eliminate the virus, but to reduce the frequency and severity of outbreaks and decrease viral shedding. This approach is considered a more realistic initial goal, given the high number of infected people worldwide and the difficulty in achieving sterilizing immunity. Moderna’s mRNA-1608 candidate is being developed with a therapeutic focus.