Herpes Simplex Virus (HSV) is one of the most common human pathogens, with HSV-1 causing most oral herpes and HSV-2 being the primary cause of genital herpes. The World Health Organization estimates that billions of people worldwide are infected with HSV-1, and hundreds of millions are infected with HSV-2. Despite decades of research, a vaccine that either prevents infection or eliminates the virus remains unavailable. This failure stems from the unique biological strategy the virus employs to persist in the human body.
The Biological Obstacle: Latency and Immune Evasion
The fundamental difficulty in creating a herpes vaccine lies in the virus’s ability to establish a lifelong latent infection. Following the initial infection at a mucosal surface, the virus travels along the nerve fibers, a process called retrograde axonal transport. The virus then reaches the cell bodies of neurons in the sensory ganglia, such as the trigeminal ganglia for HSV-1 and the sacral ganglia for HSV-2, where it essentially goes into hiding.
Within the neuron, the viral DNA circularizes and exists as a non-replicating structure called an episome. During this latent phase, the virus significantly represses the expression of most of its genes, making it nearly invisible to the immune system’s surveillance mechanisms. The immune system, particularly T-cells, cannot clear the infection because the virus is not actively reproducing or presenting a full set of viral proteins on the cell surface. This neuronal sanctuary shields the virus from circulating antibodies and cellular immune responses that would otherwise target an active infection.
Prophylactic vs. Therapeutic: Defining the Vaccine Goal
Researchers must contend with two distinct and challenging goals for a herpes vaccine, each requiring a fundamentally different immunological approach. The prophylactic vaccine aims to prevent the infection from ever establishing itself in an uninfected individual. This strategy requires inducing a robust and sustained antibody response at the mucosal surface—the entry point of the virus—to neutralize the virus before it can reach the nerve endings.
The therapeutic vaccine, conversely, is designed for individuals already living with the virus. Its goal is not to cure the infection but to significantly reduce the frequency and severity of recurrent outbreaks and viral shedding. Achieving this requires a potent, cell-mediated immune response, specifically T-cell activation. This response must be strong enough to recognize and suppress the dormant virus within the nerve ganglia before it can reactivate.
Current Research Efforts and Promising Candidates
Current research focuses on overcoming the latency obstacle and generating powerful immune responses at the infection site. Newer platforms like messenger RNA (mRNA) vaccines, similar to those used against COVID-19, are being explored for their potential to elicit both strong antibody and T-cell responses. Moderna’s candidate, mRNA-1608, is a trivalent vaccine targeting three different glycoproteins on the HSV-2 surface, aiming to induce both neutralizing antibodies and cell-mediated immunity.
Other approaches include subunit vaccines, which use only specific viral proteins to stimulate an immune response, and live-attenuated vaccines, which are weakened forms of the virus designed to replicate briefly without causing disease. BioNTech’s BNT163 is an mRNA candidate focused on prophylactic prevention, while other groups are developing replication-defective viruses. These varied strategies represent a concerted global effort to solve the dual challenge of blocking initial entry and managing established latency.
Managing Herpes Today: Existing Antiviral Treatments
While a vaccine remains under development, the infection is currently managed using daily oral antiviral medications. Commonly prescribed drugs, such as Acyclovir and Valacyclovir, work by interfering with the virus’s ability to replicate its DNA. These medications are effective at limiting viral spread during an active outbreak, thereby speeding up the healing of lesions and reducing symptoms.
Valacyclovir is a prodrug of Acyclovir, meaning it is converted into the active compound in the body, which results in higher bioavailability and less frequent dosing for patients. By inhibiting the viral DNA polymerase, these treatments stop the virus from multiplying during its active, lytic phase. However, these drugs do not target the latent form of the virus residing in the nerve cells, which is why treatment must be continued to suppress future outbreaks.