HSV-1 and HSV-2 are DNA viruses that belong to Alphaherpesvirinae, a subfamily of the Herpesviridae family. Both viruses, transmitted across epithelial mucosal cells, as well as through skin interruptions, migrate to nerve tissues, where they persist in a latent state. HSV-1 predominates in orofacial lesions and it is typically found in the trigeminal ganglia, whereas HSV-2 is most commonly found in the lumbosacral ganglia. Nevertheless these viruses can infect both orofacial areas and the genital tract 7.

In recent years, genital herpes has become an increasing common sexually transmitted infection 212. From the late 1970s, HSV-2 seroprevalence in the US has increased by 30%, resulting that one out of five adults is infected 213.

Comparing the developing countries, substantially higher rates of HSV2 have been observed in sub-Saharan Africa, where prevalence in adults ranges from 30% to 80% in women and from 10% to 50% in men, finally more than 80% of female commercial sex workers are infected 12. In South America, available data are mainly for women, in whom HSV2 prevalence ranges from 20% to 40%. Prevalence in the general population of Asian countries shows lower values, from 10% to 30% 312.

HSV seroprevalence in patients attending STD clinics varies from 17% in Italy (6% in the general population) to 40% in Australia (14% in pregnant women) 1415.

Age and sex are important risk factors associated with the acquisition of genital HSV-2 infection. In fact, the prevalence of HSV infection is very low in childhood and early adolescence but it rises with age, reaching the maximum around 40 years 2.

Regarding sex, serological surgery have confirmed that infection is more frequent in women than in men in the general population of US (23,1% in women versus 11,2% in men) and other countries, although in Italy, the seroprevalence is slightly higher in men (6,7%) than in women (4,9%). It is probably due to the younger age of the female group, as well as to the low number of sexual partners for these women, may explain the results 71617. In fact the strongest association with HSV-2 infection appears related to the number of sexual partners.

The specific geographic distribution can also influence the difference in HSV-2 prevalence 14. In fact, the seroprevalence found in a STD clinic in Northern Italy is lower than that found among STD clinic attendees in US, Australia and in a previous Italian study, but it is comparable with that found in similar populations within United Kingdom and New Zealand 14. In addition, ethnicity, poverty, cocaine abuse, earlier onset of sexual activity, sexual behaviour and bacterial vaginosis can facilitate a woman's risk of infection before pregnancy 11819.

Regarding pregnant population, there is a high prevalence of genital herpes. Among Italian pregnant women, the 7.6% seroprevalence observed in Rome is consistent respect to the 8.4% seroprevalence found in Northern Italy in a similar setting 17. Nevertheless it is lower than that reported among pregnant women in other countries 3420. For example, in US, approximately 22% of pregnant women are infected with HSV-2, 10% are at risk of acquisition of genital HSV from their infected partners (during periods of asymptomatic viral shedding) and 2% of women acquire genital herpes during pregnancy, placing their newborn at risk for herpes infection 81021. In Italy, the number of women who acquire HSV infection during pregnancy is about 3% 22. The acquisition of genital herpes during pregnancy has been associated with spontaneous abortion, intrauterine growth retardation, preterm labour, congenital and neonatal herpes infections 23. The risk of neonatal infection varies from 30% to 50% for HSV infections that onset in late pregnancy (last trimester), whereas early pregnancy infection carries a risk of about 1% 24. When primary HSV infection occurs during late pregnancy, there is not adequate time to develop antibodies needed to suppress viral replication before labour. Transmission of HSV from mother to foetus during pregnancy is uncommon; about 85% of perinatal transmission occurs during the intrapartum period 25. Moreover, studies in HIV-infected pregnant women show that co-infection with HSV increases significantly the risk of perinatal HIV transmission above all in women who had a clinical diagnosis of genital herpes during pregnancy 26.

The newborn could be also infected by HSV-1, that may represent almost one-third of all new genital HSV diagnoses 1. An increasing proportion of genital herpes infections due to HSV-1 is particularly evident among college-age populations (16–21 years) of the Midwest (US), where it reached about 78% in 2001 (31% a decade earlier) 6. This result suggested that there is a risk of HSV-1 transmission to newborn when these young women become pregnant and that oral-genital contact is a risk factor for HSV-1 6. HSV-1 infection during childhood has declined so that more adolescents and young adults are HSV seronegative when becoming sexually active 8. This would explain the observed increase in HSV-1 first time infection of the genital tract in this age group.

Genital HSV infection may be symptomatic or asymptomatic. Symptomatic infection is generally described as genital herpes and include primary, first-episode and recurrent herpes outbreaks. Primary genital herpes is usually the most serious event for the individual, especially in pregnancy, since it can cause the most severe neonatal disease. Moreover, it is defined as first-episode of genital herpes where the patient has no antibody against HSV-1 and HSV-2 2.

Primary symptomatic genital herpes, that occurs after an incubation of a period of 2–20 days, is usually important and prolonged (up to 21 days) 211. Within women it causes blistering and ulceration of the external genitalia and cervix leading to vulval pain, dysuria, vaginal discharge and local lymphadenopathy 9. Vesicular and ulcerative lesions of the internal thigh, buttocks, perineum or in perianal skin are also been observed. In men the lesions typically develop on the glans, but also on the penis, internal thigh, buttocks or in perianal skin. Both in man and in woman primary infection may be complicated by systemic symptoms such as fever, headache and myalgia (38% in men, 68% in women) and occasionally meningitis and by autonomic neuropathy resulting in urinary retention, mainly in women 911. Meningitis has been found in 42% of primary HSV-2, 12% of primary HSV-1 infections and 1% of recurrent infections 11. Nevertheless, pre-existing HSV-1 antibodies can alleviate clinical manifestations of subsequently acquired HSV-2 1. In some cases, systemic clinical findings may be the only presenting symptoms of infection and in more than half of patients, primary infection goes unnoticed 9.

The most important HSV infection during pregnancy is the primary genital HSV infection, although, in the majority of pregnant women, the first manifestation of genital herpes is not a primary infection 9.

Primary HSV infections in pregnant women can result in more severe diseases than that in non-pregnant ones. In particular, gingivostomatitis and vulvovaginitis herpetica tend towards dissemination. As a result, women can develop disseminated skin lesions associated with visceral involvement such as hepatitis, encephalitis, thrombocytopenia, leucopoenia and coagulopathy 9. Although disseminated HSV infection is uncommon in pregnancy, the mortality is about 50%. In particular, pregnant women with primary mucous membrane infection during the third trimester, have an increased risk for dissemination and they could transmit HSV to their babies during vaginal delivery 9.

Recurrent episodes of HSV infection are characterized by the presence of antibody against the same HSV type and the herpes outbreaks are usually mild (7–10 days) with less severe symptoms than the first episode. Prodromal symptoms (itching, tingling, neuralgia) may occur hours or days before a recurrent herpes episode 227. The great majority of recurrent genital herpes is due to HSV-2 because this virus reactivates more frequently than HSV-1 279.

The apparently asymptomatic phases between clinical outbreaks of genital herpes are important, since HSV can reactivate periodically in latently infected cells of sensory ganglia travelling via the neuronal axons back to the genital mucosa, without clinical signs or symptoms. This mechanism is known as asymptomatic virus shedding 211. The majority of sexual HSV transmission occurs during asymptomatic periods because the patients are unaware of asymptomatic virus shedding 28. Moreover, asymptomatic shedding has been shown to be higher in women with HSV-2 infection compared with those with HSV-1 (7% versus 2% respectively) 2.

Although there is a small risk of vertical transmission, recurrent genital herpes must be regarded as the most common cause of neonatal infections and the passage through an infected birth canal is the most probable route of transmission 9. In recurrent infections associated with clinical symptoms, the risk of neonatal disease is reduced dramatically by caesarean section 1029. Transmission of HSV by women with asymptomatic viral shedding is of greater significance, since neonates mostly acquire infection without being recognized 9.

The high rate of undiagnosed or asymptomatic HSV infections complicate the prevention 7. In order to avoid the majority of neonatal herpes cases, identification of the at-risk mother is the goal. The first and most important step is the determination of the pregnant women serostatus to establish their susceptibility to the infection during early pregnancy 8. However, current recommendations of the American College of Obstetricians and Gynecologists (ACOG) do not include universal testing because at the present time, type-specific serologic tests are not widely available and their reliability is questionable 850. The most effective measure to prevent perinatal herpes infections is to avoid viral exposure to the neonate when primary genital herpes develops in late pregnancy whereas the risk of severe neonatal infection is small in recurrent episodes 9. A history of HSV infection in all pregnant women and their partner should be obtained at the first prenatal visit 475068. Women with a negative personal history of HSV and especially those with a positive history in the male partner, should be strongly advised to have no oral and sexual intercourse at the time of recurrence in order to avoid infection (in particular during the third trimester of gestation) 950. Moreover, use of condoms throughout pregnancy should be recommended to minimize the risk of viral acquisition, although the male partner has no active lesions 950. However, condoms are not a complete barrier for the genital region 7. Prophylactic administration of acyclovir or valacyclovir in the third trimester of pregnancy should be provided to all pregnants with frequent genital herpes outbreaks and with active genital HSV infection near term or at the time of delivery 784142435069. A careful examination of the vulva, vagina and cervix should be performed on any woman who presents signs or symptoms of HSV infection at the onset of labour. Artificial rupture of membranes should be avoided 850. All pregnants who have a suspected active genital HSV infection or prodromal symptoms of HSV infection should undergo caesarean section, although membranes are intact 50. On the contrary, when genital herpes lesions are not present, caesarean delivery is not required but lesions should be covered with an occlusive dressing before vaginal delivery 4750. It is important to remember that foetal scalp electrodes monitoring during labour and vacuum or forceps delivery should be used only if necessary, since these practices appear to increase the risk of HSV transmission 850.

Neonates, born to women with active genital lesions, with a confirmed or suspected HSV infection should be isolated, managed with contact precautions to avoid direct contact with skin and mucosal lesions, excretions, body fluids and immediately treated with intravenous acyclovir 950. Since neonatal herpes can also be acquired postnatally, postpartum women, family members and nursery personnel with active herpetic lesions of the mouth, skin or breast should take necessary precautionary measures to prevent direct contact with the neonate and/or should be excluded from the neonatal unit until the lesions are fully healed 9.

The development of vaccines against herpesviruses has major public health importance in both immunocompetent and immunocompromised populations. Because these viruses establish latent infections capable of subsequent reactivation, both immunotherapeutic and prophylactic vaccine strategies are needed.

About prophylactic vaccines, partially effective prophylactic vaccines may still be useful if they shift the threshold of infection, or if they prevent or improve disease. They could reduce HSV2 incidence by preventing infection or by reducing the shedding or clinical recurrences in a HSV2-infected individual. On the other hand, these vaccines could increase HSV2 incidence reducing symptomatic signs of disease without effect on viral shedding. In particular, the Chiron-gD2gB2-MF59 vaccine provided only temporary protection lasting a few months, whereas the GlaxoSmithKline (GSK)-gD2-alum-MPL prophylactic vaccine had no effect in men or HSV1 positive women although in HSV1 seronegative women the risk of HSV2 infection and disease was reduced. A further trial of the GSK vaccine in HSV1 negative women is ongoing 70.

Numerous approaches including subunit vaccines, peptide vaccines, live virus vectors and DNA vaccine technology have been used in developing both prophylactic and therapeutic vaccines, since several antiviral therapies are available to control disease and spread, but these are not completely effective and do not affect latent virus 71.

A range of vaccine formulations has been devised, largely as a result of the rapid growth in knowledge in molecular microbiology and genetic engineering, including live and inactivated whole virus vaccines and subunit vaccines consisting of recombinant viral glycoproteins in various adjuvants 72.

Although animal studies on vaccination strategies to prevent genital and neonatal herpes may be promising, clinical trials of HSV-2 vaccines in humans have failed to prove efficacy. In a previous study, an HSV-2 glycoprotein D vaccine using alummorpholine (MPL) as adjuvant, induced protection from clinical disease (73%) and overall HSV-2 transmission (about 40%) 73. Nevertheless, the protective effect of the MPL vaccine was seen only in women who were HSV-1 and HSV-2 seronegative and there was no protection among men or among HSV-1 seropositive women 3.

In conclusion, many prophylactic and therapeutic vaccination approaches have been explored but no effective vaccine is presently available.