Yale investigators have shown that the combination of a vaccine and a medicated cream is a promising strategy to dramatically reduce the recurrence of genital herpes.
Their study, co-led by researchers at the University of Pennsylvania and University of Cincinnati Children’s Hospital Medical Center, was published in the journal npj Vaccines.
Herpes simplex virus (HSV) type 2, which causes genital herpes, is very common, affecting more than 400 million people worldwide.
There’s no cure and efforts to develop a vaccine have had limited success.
The research team tested a novel vaccine strategy, known as prime and pull, in guinea pigs infected with genital herpes.
The “prime” involves a vaccine that generates a response to the virus from T cells, highly specialized immune cells.
The “pull” consists of a cream containing imiquimod, a medication commonly used to treat genital warts.
Applied to the affected area, the cream attracts key immune cells to the site of infection where they can block the virus from spreading and causing herpes lesions.
The study showed that the effect of the combination therapy was far greater than either the vaccine or cream alone.
“It’s the first time that a study has shown that prime-and-pull strategy can block existing recurrent disease,” said co-corresponding author Akiko Iwasaki, the Waldemar Von Zedtwitz Professor of Immunobiology at Yale School of Medicine.
“Development of a therapeutic HSV vaccine is a high priority.
Our exciting results have encouraged us and, hopefully others, to pursue this strategy with more vaccines,” said co-corresponding author David Bernstein, professor of pediatrics and former director of the Division of Infectious Diseases at Cincinnati Children’s Hospital.
The study team gave three rounds of treatment to the animals, noting that the strategy worked rapidly and beginning with the first round.
This strategy, if developed into a therapy for humans, could be a game changer for individuals with recurrent infections or resistance to standard antiviral treatment, said Iwasaki.
Active herpes infection causes painful lesions that are physically and emotionally harmful to affected people, she noted.
Herpes simplex virus type 1 (HSV-1) is a member of the Alphaherpesviridae subfamily.
Its structure is composed of linear dsDNA, an icosahedral capsid that is 100 to 110 nm in diameter, with a spikey envelope.
In general, the pathogenesis of HSV-1 infection follows a cycle of primary infection of epithelial cells, latency primarily in neurons, and reactivation. HSV-1 is responsible for establishing primary and recurrent vesicular eruptions, primarily in the orolabial and genital mucosa.
HSV-1 infection has a wide variety of presentations, including orolabial herpes, herpetic sycosis (HSV folliculitis), herpes gladiatorum, herpetic whitlow, ocular HSV infection, herpes encephalitis, Kaposi varicelliform eruption (eczema herpeticum), and severe or chronic HSV infection. Antiviral therapy limits the course of HSV infection.
Risk factors for HSV-1 infection differ depending on the type of HSV-1 infection. In the case of orolabial herpes, risk factors include any activity that exposes one to an infected patient’s saliva, for example, shared drinkware or cosmetics, or mouth to mouth contact.
The major risk factor for herpetic sycosis is close shaving with a razor blade in the presence of an acute orolabial infection.
Risk factors for herpes gladiatorum include participation in high-contact sports such as rugby, wrestling, MMA, and boxing.
Risk factors for herpetic whitlow include thumb sucking and nail biting in the presence of orolabial HSV-1 infection in the child population, and medical/dental profession in the adult population (although HSV-2 most commonly causes herpetic whitlow in adults).
A major risk factor for herpes encephalitis is mutations in the toll-like receptor (TLR-3) or UNC-93B genes. It has been postulated that these mutations inhibit normal interferon-based responses.
The major risk factor for eczema herpeticum is skin barrier dysfunction. This can be seen in atopic dermatitis, Darier disease, Hailey-Hailey disease, mycosis fungoides, and all types of ichthyosis.
The increased risk is also associated with mutations in the filaggrin gene, which is seen in atopic dermatitis and ichthyosis vulgaris. Pharmaceutical risk factors for eczema herpeticum include the use of topical calcineurin inhibitors such as pimecrolimus and tacrolimus.
Risk factors for severe or chronic HSV infection include immunocompromised states such as transplant recipients (solid organ or hematopoietic stem cells), HIV infection, or leukemia/lymphoma patients.
HSV-1 is typically spread through direct contact with contaminated saliva or other infected bodily secretions, as opposed to HSV-2, which is spread primarily by sexual contact. HSV-1 begins to replicate at the site of infection (mucocutaneous) and then proceeds to travel by retrograde flow down an axon to the dorsal root ganglia (DRG).
It is in the DRG that latency is established.
This latency period allows the virus to remain in a non-infectious state for a variable amount of time before reactivation. HSV-1 is sly in its ability to evade the immune system via several mechanisms. One such mechanism is inducing an intercellular accumulation of CD1d molecules in antigen presenting cells.
Normally, these CD1d molecules are transported to the cell surface, where the antigen is presented resulting in the stimulation of natural killer T-cells, thus promoting immune response.
When CD1d molecules are sequestered intercellularly, the immune response is inhibited. HSV-1 has several other mechanisms by which it down-regulates various immunologic cells and cytokines.
Treatment / Management
For the treatment of orolabial herpes, the current recommendation is oral valacyclovir (2 grams twice daily for one day). If the patient has frequent outbreaks, chronic suppression is warranted.
For chronic suppression of immunocompetent patients, oral valacyclovir 500 mg daily (for patients with less than ten outbreaks per year) or oral valacyclovir 1 gram by mouth daily (for patients with greater than 10 outbreaks a year) is recommended.
For the treatment of eczema herpeticum, it is recommended to use 10 to 14 days of either acyclovir (15 mg/kg with a 400 mg maximum) 3 to 5 times daily or Valacyclovir 1 gram by mouth twice a day.
For immunocompromised patients with severe and chronic HSV, treatment is aimed at chronic suppression. For chronic suppression of immunocompromised patients, oral acyclovir 400 to 800 2 to 3 times daily, or oral valacyclovir 500 mg twice daily is recommended.
More information:npj Vaccines, DOI: 10.1038/s41541-019-0129-1
Provided by Yale University