Herpes Simplex Virus Vaccines

Clinical Description

The clinical illness caused by HSV is determined by the site of infection, age, host immune status, and whether the infection is primary or recurrent.

Primary genital herpes classically presents with vesicular lesions that progress to painful ulcerative skin lesions. The lesions appear on mucosal and keratinized epithelium of the cervix, external genitalia, perineum, anus, buttocks, and/or thighs, and often with systemic symptoms (fever, malaise, and myalgias). However, over 80% of patients with primary infections are asymptomatic, lacking clinical findings, and may not be recognized as genital herpes. ^, Symptomatic individuals may have nonpathognomonic prodromal symptoms including tingling, burning, itching, erythematous patches, and small skin fissures. Recurrent infections tend to have prodromal symptoms prior to the eruption of vesiculoulcerative skin lesions. Lesions appear on the perineum, thighs, and/or buttocks; most recurrent infections are asymptomatic with only subclinical viral shedding in the genital tract. As a result of asymptomatic or unrecognized infections, many individuals are unaware of their diagnosis, which leads to the high rate of transmission. While HSV-1 and HSV-2 cause clinically indistinguishable primary genital infections, those caused by HSV-1 reactivate less frequently, resulting in significantly fewer episodes of recurrent genital infection than HSV-2. Notably, the opposite is true for oral–labial HSV infections.

Common oral–facial infections are generally caused by HSV-1, and are often mild or unrecognized in early childhood. Herpes gingivostomatitis is characterized by oral pain, fever, and vesiculoulcerative lesions throughout the mouth and pharynx. Herpes pharyngitis is less severe than gingivostomatitis, with lesions generally limited to the tonsils and pharynx. Symptomatic oral–facial reactivations most commonly result in herpes labialis, often referred to as “cold sores” or “fever blisters,” and present with prodromal symptoms (tingling, itching, burning, or pain) before the development of the vesicular lesions along the vermilion border of the lip, although lesions can sometimes occur on the nose, chin, cheek, or oral mucosa. HSV can also cause other skin infections, including herpes gladiatorum, herpes rugbiorum, eczema herpeticum, herpetic whitlow, and potentially life-threatening HSV infections among individuals with skin disorders. ^,

HSV ocular infections may be primary or recurrent, caused by either direct contact or nerve route transmission, and are usually unilateral involving the conjunctiva, cornea, or retina. Conjunctivitis is the most common ocular HSV infection. The distinguishing feature of corneal infection is dendritic or geographic ulcers. Individuals with concerns for an ocular infection should be evaluated promptly by an ophthalmologist and treated immediately due to the risk of blindness. Beyond the newborn period, HSV encephalitis is almost always caused by reactivation of HSV-1 and typically involves the temporal cortex. Symptoms include fever, headache, confusion, expressive aphasia, altered levels of consciousness, and focal neurologic deficits. Mollaret meningitis, on the other hand, is a recurrent, self-limiting aseptic meningitis primarily attributed to HSV-2 orolabial or genital infections.

Perinatal HSV infections are life threatening and most commonly result from mother-to-infant transmission. The clinical manifestations are variable but broadly fall into one of three patterns of disease: (a) disease localized to the skin, eyes, or mouth (SEM); (b) encephalitis; or (c) disseminated infection with or without encephalitis. Prompt recognition and early initiation of antiviral therapy are imperative in reducing morbidity and mortality.

HSV infections in the immunocompromised host, particularly those with compromised cellular immunity such as seen with AIDS, may be more severe and life threatening. ^,

Virology and Viral Antigens

HSV is comprised of four components: a double-stranded DNA genome consisting of a long (UL) and short arm (US), an icosahedral capsid, a protein tegument layer, and a lipid envelope. The double-stranded DNA genome consists of approximately 152 kilobases with inverted repeats that encode at least 84 different proteins, and resides within an icosadeltahedral capsid of approximately 162 capsomeres surrounded by a tightly adherent tegument and then an outer lipid bilayer envelope containing at least 12 viral glycoproteins (gB, gC, gD, gE, gG, gH, gI, gJ, gK, gL, gM, and gN) ( Fig. 30.1 ). The envelope glycoproteins are responsible for binding and entering the host epithelial cell and are the major targets for humoral immunity. Antibodies to glycoprotein B (gB), glycoprotein C (gC), glycoprotein D (gD), or glycoprotein H (gH)/glycoprotein L (gL) contribute to inhibiting the absorption or neutralizing of HSV in vitro; antibodies to gB or gD are responsible for inhibiting neuron-to-keratinocyte spread in a cell culture system. CD4 and CD8 cellular responses can be induced by a wide array of HSV proteins including glycoproteins (gB, gC, gD, gE, and gH), structural capsid and tegument proteins (gene products of UL 7, UL21, UL25, UL26, UL29,UL47, UL48, UL49, and the proteins VP5, VP11/12, VP13/14, VP16, VP22, and ICP8), and nonstructural proteins (ICP0, ICP4, and ICP27 and the gene product of UL50). HSV-1 and HSV-2 have 50% homology. Importantly, type-specific glycoproteins G (gG-1 and Gg-2) distinguish the two viruses. This difference forms the basis for the current type-specific serological tests to determine whether an individual is infected with HSV-1, HSV-2, or both.

Pathogenesis as It Relates to Prevention

Infection is initiated once an individual's abraded skin or mucosa is exposed to HSV, leading to binding of HSV to the epithelial cell's surface receptors and resulting in cellular fusion. Once the capsid is inside the host epithelial cell, viral DNA is transported to the nucleus of the host cell where HSV replicates. Progeny virions invade sensory nerve endings and undergo retrograde transport to establish latency in the dorsal root ganglia. It is important to note that hematogenous spread does not play an important role in the pathogenesis of infection except in the host with an immature or compromised immune system. During the initial infection, innate and adaptive humoral and cellular immune responses inhibit viral replication and allow for control of the acute disease. However, despite these responses, the virus is still able to establish latency in the sensory nerve ganglia and periodically reactivate at times of physical or emotional stress, producing virions that are transported to the periphery via anterograde axonal spread. Peripheral replication can either result in symptomatic recurrent infection or asymptomatic viral shedding. The ability to establish latency in the sensory nerve ganglia for the entire lifetime of an individual and the ability of HSV to cause asymptomatic viral shedding poses a challenge for vaccine development. The most successful vaccine would not only prevent primary infection but also prevent the establishment of latency, reduce the frequency and severity of recurrences, decrease viral shedding, and most importantly prevent person-to-person transmission.