Herpes simplex virus (HSV) is a highly prevalent human pathogen existing in two primary types: HSV-1, often associated with oral lesions, and HSV-2, the predominant cause of genital herpes infections. The World Health Organization estimates that approximately 3.7 billion individuals under the age of 50 carry HSV-1 globally, and an additional 491 million people aged 15 to 49 have HSV-2 infection. Despite decades of research, there is currently no licensed vaccine available to prevent or cure infection by either HSV-1 or HSV-2.
Current Status of Licensed Herpes Vaccines
As of late 2025, no regulatory body, including the U.S. Food and Drug Administration or the European Union, has authorized a vaccine for public use against herpes simplex virus. Vaccine candidates have been in development for decades, but none have successfully navigated all required clinical trial phases. Past attempts, such as certain subunit vaccines, failed to demonstrate sufficient efficacy against HSV-2, though some showed partial protection against HSV-1 acquisition. The current standard of care relies on antiviral medications like acyclovir and valacyclovir, which suppress viral replication during active outbreaks and reduce the severity and frequency of symptoms. These treatments do not eliminate the virus or provide a cure for the lifelong infection.
Preventive and Therapeutic Vaccine Goals
Research teams are pursuing two distinct goals with current vaccine development efforts, targeting different patient populations.
Preventive (Prophylactic) Vaccines
The first is the preventive, or prophylactic, vaccine, designed for individuals who have never been infected with HSV. The objective is to generate an immune response strong enough to prevent the initial acquisition of the virus and the subsequent establishment of latency. Success in this area would drastically reduce the incidence of new infections globally.
Therapeutic Vaccines
The second approach involves therapeutic vaccines, aimed at treating individuals already living with a chronic HSV infection. These vaccines are intended to boost the body’s existing immune response to control recurrence. The primary goal is to reduce the frequency and severity of symptomatic outbreaks and minimize asymptomatic viral shedding, which lowers the risk of transmission.
Biological Challenges in Vaccine Creation
The herpes virus possesses unique biological mechanisms that create significant hurdles for vaccine developers, complicating the generation of effective immunity. The most significant challenge is the virus’s ability to establish latency, traveling along nerves to hide within the sensory nerve ganglia. In this dormant state, the virus is invisible to circulating immune cells and renders most antiviral drugs ineffective.
HSV has also evolved sophisticated strategies to actively evade the host’s immune system, making a protective response difficult to generate. The virus can suppress the presentation of its own antigens to immune cells, for instance, by interfering with mechanisms like MHC class I presentation. Natural infection itself does not result in sterilizing immunity, as the virus frequently reactivates despite the presence of virus-specific antibodies and T-cells. Therefore, a successful vaccine must elicit an immune response superior to the protection gained from a natural infection.
Notable Vaccine Candidates in Development
Despite the difficulties, several promising vaccine candidates are advancing through the clinical trial pipeline, utilizing cutting-edge technologies. Moderna is developing mRNA-1608, a therapeutic vaccine candidate for HSV-2 that has progressed into Phase I/II clinical trials. This mRNA platform is designed to generate a robust immune response by inducing both neutralizing antibodies and strong cell-mediated immunity.
Another notable candidate is BioNTech’s BNT163, a prophylactic mRNA-based vaccine that encodes for three key HSV-2 glycoproteins and is currently in Phase I development. However, other efforts have recently faced setbacks, highlighting the persistent challenges in this field. For example, GSK’s therapeutic candidate, GSK3943104, was discontinued after a Phase I/II trial concluded it did not meet its primary efficacy goal of reducing lesions in patients with recurrent genital herpes. Other approaches include live-attenuated vaccines, such as Rational Vaccines’ VC2, which targets both HSV-1 and HSV-2 and is currently undergoing clinical studies.