Herpes Simplex Virus: Why No Vaccine or Cure Yet? All You Need to Know.

History

Oral herpes is believed to have initially appeared at least 2,000 years ago. One of the first known descriptions of an infection that may have been caused by herpes comes from a renowned Greek physician named Herodotus, who lived in the Roman Empire during the 1st century AD. Some scholars even believe William Shakespeare alluded to herpes infections by mentioning “blisters plagues” in his famous play, Romeo and Juliet. However, the word “herpes” was not coined until well after Shakespeare’s death. 

The English physician Richard Boulton first used the word “herpes” in his book System of Rational and Practical Chirurgery, which was published in 1713. Later, in 1736, a French physician named John Astruc described a case of genital herpes. Astruc’s work was translated into English in 1754. Shortly afterwards, herpes came to be thought of as a vocational disease that afflicted prostitutes. (A vocational disease is an illness caused by a person’s occupation.)   

Despite the fact that physicians and scientists had known of herpes for nearly two millennia, it was not until the 20th century that experiments were conducted to try and determine the exact nature of the disease. Some of the first experiments involved infecting rabbits with herpes. During the 1940s, the cause of herpes was definitively identified as a virus. 

A major breakthrough in the history of treating herpes occurred during the 1960s when A.J. Nahmias and W.R. Dowdle reported that oral and genital herpes were caused by different strains of HSV. Medical professionals at the time began experimenting with several antiviral medications to help fight against herpes infections. At first, little progress was made, but by the mid-1970s, the first antiviral therapy for neonatal infection was invented. In 1981, an antiviral drug named acyclovir was approved by the FDA. Acyclovir quickly became one of the most effective drugs used to treat herpes [5]. However, its effectiveness is limited.

Epidemiology

HSV-1 infections occur worldwide in all seasons and affect men and women equally. The infection prevalence is high in low- and middle-income countries. Several countries in South America and Africa (especially Sub-Saharan Africa) have seroprevalence rates of over 90% [7].

People at greater risk of contracting the infection include newborns, children at daycare centers, adolescents, wrestlers, and healthcare workers. 

• Adolescents are at risk of acquiring either oral or genital infections when they first become sexually active.
• Athletes like wrestlers are more susceptible to skin and eye infections because they may have direct contact with their opponents’ oral secretions when they wrestle. 
• Healthcare workers are at risk of exposure to infections while treating infected people. 
• Neonates or newborns can acquire HSV during the time of delivery [6].

MENA region

HSV-1 is quite prevalent in the Middle East and North Africa (MENA) region. As of 2019, the pooled seroprevalence of the infection in adults in MENA was over 90%. Interestingly, seroprevalence increases with age. Children are at the lowest risk (60.5%), while those over the age of 30 are at the highest risk (94.3%) [7].

Asia

In Asia, around 75% of adults and 50% of children are seropositive for HSV-1. The seroprevalence rate increased with age. It is 60% greater in people over 60 years of age than in those who are younger than 20 years. China has one of the highest seroprevalence rates among Asian countries, with 93% of adults testing positive for HSV [8].

USA

According to data collected from the Centers for Disease Control and Prevention (CDC), about 11.9% of people in the US between the ages of 14 and 49 have HSV-2-inflicted genital herpes. About 47.8% are infected with HSV-1. Both of these infections are more common in women than in men. About 71.7% of Mexican-Americans have HSV-1, and about 34.6% of the non-Hispanic Black population in the country are infected with HSV-2 [10].

Canada

HSV-2 seroprevalence in Canada is around 10%. This number accounts for 44.5% of all sexually transmitted infections. Additionally, 60.7% of all HIV-positive people in the country are coinfected with HSV-2. 

South America

HSV-2 is also quite prevalent in South America and the Caribbean, with around 20% of the general population having the infection. Female sex workers have the highest seroprevalence (74.8%), followed by male sex workers and men who have sex with transgender people. The combined infection rate among these last two groups is 54.6%. 

Like other regions, the HSV-2 seroprevalence in South America and the Caribbean increased with age. It was 9.6% for those less than 10 years of age and about 38.4% for those over the age of 40. The good news is that there has been a gradual decline in seroprevalence rates in the region by 2% over the last three decades [12]. 

Australia and New Zealand

The pooled mean seroprevalence in Australia and New Zealand is around 15.4% among the general population. About 27.8% of them are men who have sexual relations with other men [2].

Sub-Saharan Africa  

Sub-Saharan Africa has an HSV-2 seroprevalence of around 37%, greater than pooled mean seroprevalences in other parts of the world. Approximately 25% of the population in Western Africa, 35.8% in Southern Africa, 41.9% in Eastern Africa, and 52.4% in Central Africa are seropositive for HSV-2 infection. 

The pooled mean seroprevalence among women is higher than among men in all of these regions. It was highest for people between the ages of 40 and 50, followed by those over 50. The younger population (those less than 20 years of age) has the lowest seroprevalence, followed by those between 20 and 30. In women, the seroprevalence rate increased with age [11].

How is it spread?

Oral Herpes (Herpes Simplex type 1, HSV-1)

People with oral herpes are less likely to get reinfected; however, they are still susceptible to contracting genital herpes. Oral herpes is contagious and can spread from person to person, either through direct or indirect contact. 

• Direct oral contact could involve kissing an infected person.
• Indirect contact involves touching contaminated objects or surfaces (including active sores in or around the mouth of an infected person) and subsequently touching the mouth with infected fingers. It also involves eating food contaminated with the infected person’s saliva.
• Oral sex, which involves oral-genital contact, can cause genital herpes [1].

Genital Herpes (Herpes Simplex type 2, HSV-2)

Genital herpes can spread in the following ways:

• Genital herpes is spread mainly during sexual activity that involves direct contact with genital or anal surfaces, open sores, or other bodily fluids.
• It can also be transmitted by a mother to her newborn at the delivery time as the infant comes into contact with maternal genital secretions contaminated with HSV [3].

Biology of the disease

Oral Herpes (HSV-1)

The HSV-1 virus can enter the body through breaks in the skin. Once inside the body, it begins to replicate in the epidermis and epithelial cells of the skin located near the site of contact. Eventually, the virus travels to clusters of nerve cells nearby (sensory ganglia), where it continues to replicate. It travels along the neural pathways and can remain latent for a long time, only to reappear years later. This is why herpes is a lifelong infection that has no cure. 

When a latent herpes infection gets reactivated, the virus begins to replicate in the sensory ganglia and is then transported back to the epithelial cells of the skin. Here, it continues to replicate, periodically causing the characteristic blisters or ulcers to appear [6]. 

Genital Herpes (HSV-2)

HSV-2 virus replicates and spreads in the genital epidermal cells that produce keratin, resulting in painful ulcers. The infection can spread to nerve endings and is transported to the dorsal root ganglia (sensory root nerve cells that transmit sensory information like temperature, pressure, touch from the surface of our body to our spinal cords). When HSV-2 infiltrates the dorsal root ganglia, the herpes infection can stay latent for a long time. The virus can become reactivated in the ganglia and transported back to the genital tract via axons in the nervous system. It then starts replicating in the genital epidermal cells. This is how genital herpes symptoms recur throughout one’s lifetime [13]. 

Symptoms

Oral Herpes (HSV-1)

The incubation period for an HSV-1 infection is two to 12 days [6]. In most cases, people with oral herpes do not show any symptoms. However, some people develop painful blisters or open sores in and around their mouths. Other common symptoms include irritation or a burning sensation around the mouth. These symptoms can recur periodically in different frequencies and vary from one person to another [1].

Genital Herpes (HSV-2)

It takes 4 to 7 days for lesions to appear on the genitals after exposure to HSV-2. People with genital herpes can have symptoms ranging from severe to mild. Some people even show no symptoms whatsoever. Symptomatic HSV-2 infections are characterized by blisters on the genital or anal regions, which usually resolve in 2 to 3 weeks. 

Other common symptoms include:

• Fever
• Headache
• Body pains
• Swollen lymph nodes
• Pain or burning sensation while passing urine

It is uncommon for symptoms of  HSV-1 to reappear frequently. HSV-2, on the other hand, often produces lifelong bouts of blisters. Over time, however, the severity of the symptoms usually decreases [1,3].

What makes herpes infections reappear? 

The herpes virus remains in an infected person’s body for a lifetime. It gets reactivated in response to specific triggers, including:

• Emotional distress
• Infectious diseases
• Fever
• High doses of steroids 
• Surgical procedures
• Radiotherapy
• Sun exposure (UV light exposure) [4].

Complications

Here is a list  of some of the possible complications of HSV infections:

• HSV-2 makes the infected person three times more vulnerable to HIV infections. A person with HIV and HSV-2 infection is more likely to spread HIV infection to others.
• In rare cases, HSV-2 infections can cause disseminated infection. This involves viral invasion causing damage to cells and tissues of the body.
• Neonatal infections can happen when the mother acquires HSV towards the end of her gestation period.
• Although rare, HSV-1 can cause encephalitis or eye infections [1].

Diagnosis

Similar to other infectious diseases, HSV infections are clinically diagnosed in a laboratory through different diagnostic methods. Some of the common ones include:

• Polymerase Chain Reaction (PCR): A PCR assay is the preferred diagnostic method to detect HSV infection in the presence of active lesions. It is accurate and has about a 95% sensitivity rate. It is also effective in distinguishing between HSV-1 and HSV-2.
• Serologic Tests (Blood tests): If there are no active lesions on the patient’s body and PCR results are negative, then serological tests can help diagnose herpes. Medical professionals are advised to repeat serological testing in infected individuals since it may take between 2 weeks and 6 months for antibodies to form after initial exposure [14].  
• Viral culture: Herpes viral culture looks for cytopathic effects in the selected cell line, which usually takes between 24 and 48 hours to appear.  This method is less sensitive compared to PCR, and the sensitivity depends on the quantity of infection found in the sample collected [6]. 
• Tzanck smear: This test is performed by scraping the blisters on the patient’s body. Although it is a simple, rapid, and inexpensive diagnostic technique, it has lower sensitivity and specificity compared to a viral culture or PCR-based test. Also, a Tzanck smear cannot distinguish between HSV-1 and HSV-2 infections [9]. 

Treatment

There are no FDA-approved vaccines for HSV. Supportive care can reduce the severity of the illness and the frequency of the appearance of symptoms. Treatment should be initiated as early as possible to decrease the rate of transmission and symptom duration. Some antiviral drugs, such as acyclovir, famciclovir, and valacyclovir, are used to treat people infected with HSV; however, their effectiveness is limited [1,14].  

In pregnant women, suppressive therapy, which involves taking antiviral drugs regularly, can help reduce the risk of active lesions during delivery. It also reduces the risk of recurrence by almost 75% [14].

Prevention

The following preventive measures can, to a certain extent, help protect against HSV infections:

• Avoid oral contact, including kissing and oral sex with people who are infected or suspected of having oral herpes.
• Avoid eating contaminated food or sharing objects contaminated with the saliva of people who are infected or suspected to be infected.
• Avoid having sexual intercourse with a person who is infected or suspected to be infected.
• Use condoms consistently.
• Male circumcision can provide life-long protection (at least to some degree) against HSV-2 infection.
• People with genital herpes or suspected of having genital herpes should consider getting screened for HIV infection [1].
• It is advisable for pregnant women to abstain from sexual contact with partners who have or are suspected of having herpes.
• Healthcare workers involved in obstetrics should make it a practice to examine pregnant women for herpes and herpetic lesions before delivery. If the woman is found to be infected with HSV, a cesarean procedure can be performed at a hospital to reduce the risk of neonatal infections [3].

There is ongoing research to advance the diagnosis, treatment, and prevention of herpes simplex virus infections. In December 2022, the CDC issued a request for a new type of serological test to improve HSV-2 diagnosis. 

Why is there no herpes vaccine?

A new clinical trial is underway to find an effective Herpes (HSV-2) vaccine. One of the biggest challenges in developing a herpes vaccine is that the virus can stay dormant in infected people for a long time. Vaccines work by introducing a milder form of the disease-causing agent into the body and training the immune system to fight back. With herpes, an individual’s immune system may or may not react to the vaccine immediately, rendering the vaccine ineffective.  

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