HSV-2 infection follows a complex and dynamic natural history [6,7,8]. After sexual acquisition, the virus establishes lifelong latency in the sacral ganglia of sensory nerves, with periodic reactivation [7, 8]. Clinical expression is highly variable: some persons may remain asymptomatic or have unrecognized infection, whereas others experience recurrent episodes of urogenital symptoms which may or may not include ulcerative genital lesions [6,7,8,9,10]. Recurrences vary in frequency, duration, and severity, ranging from mild and infrequent to persistent and debilitating disease [6, 9, 10, 46,47,48,49,50]. Among immunocompetent persons, the predictors of the frequency and clinical severity of reactivations remain poorly understood [6, 7, 51]. Effective immune control limits viral reactivation and subsequent shedding, whereas immune compromise—such as in untreated people with HIV—is associated with more frequent, prolonged, and severe recurrences [52,53,54].

Most HSV-2 infections are unrecognized and undiagnosed [9, 10, 48], and this diagnostic gap hampers infection control efforts. Educational interventions to improve symptom recognition have shown measurable benefits, with most HSV-2–antibody seropositive persons subsequently able to identify or recall typical episodes of infection once counseled [9, 10, 48]. However, even in the absence of symptoms, HSV-2 can be intermittently shed from the genital mucosa [6, 7], sustaining an unrecognized reservoir of persons who may transmit the virus to sex partners or neonates.

The majority of transmissions occur from persons unaware of their infection and without lesions at the time of contact [55,56,57]. This combination of high prevalence of unrecognized infection, subclinical viral shedding, and transmission in the absence of symptoms limits the effectiveness of symptom-based prevention and underscores the potential role of screening to identify those with otherwise undiagnosed infections, enabling targeted counselling, education, and, where indicated, antiviral suppression.

In 2020, an estimated 25.6 million people aged 15–49 years acquired new HSV-2 infections globally (Fig. 1) [1]. In the same age group, 519.5 million people were living with infection, corresponding to a global prevalence of 13.3% [1]. Sub-Saharan Africa bore the greatest burden, accounting for nearly 10 million new infections—38% of the global total—and having both the highest prevalence and the largest absolute number of people living with infection [1].

Global distribution of annual incident and prevalent HSV-2 infections by World Health Organization region, 2020 [1]. Incident infections denote new cases within the year; prevalent infections denote the number of people living with HSV-2 infection. Abbreviations: HSV-2, herpes simplex virus type 2

HSV-2 prevalence varies substantially by region. The highest prevalence is observed in sub-Saharan Africa (37.3%) [11], followed by Latin America and the Caribbean (21.6%) [15], North America and Australia/New Zealand (approximately 15%) [14, 57, 58], Europe (12.4%) [13], Asia (12.1%) [12], and the Middle East and North Africa (5.1%) [59].

Several epidemiological patterns are consistent across regions. Women have a substantially higher prevalence than men—approximately 50–70% greater [11,12,13,14,15, 57,58,59]—reflecting increased biological susceptibility to infection [60, 61]. Prevalence follows a clear gradient by sexual risk behavior, being highest among female sex workers and men who have sex with men, and lowest in the general population [11,12,13,14,15, 59]. Age-specific prevalence rises rapidly after sexual debut and largely plateaus by the mid-40s [11,12,13,14,15, 57,58,59]. There is also evidence of a cohort effect, with higher incidence observed in certain decades, such as in the United States [57, 62].

Recent studies have reinforced the central role of HSV-2 in both clinically diagnosed genital ulcer disease and laboratory-confirmed genital herpes [1, 2, 11,12,13,14,15, 59]. In 2020, an estimated 187.9 million people aged 15–49 years experienced at least one episode of HSV-2-associated genital ulcer disease, corresponding to a global prevalence of 4.8% [1]. Prevalence was substantially higher in women (6.2%) than in men (3.5%) [1].

The proportion of genital ulcer disease attributable to HSV-2 mirrors its underlying prevalence [1, 2, 11,12,13,14,15]. The highest contribution is observed in sub-Saharan Africa, where HSV-2 accounts for more than half of all genital ulcer disease cases [11]. In Asia and in Latin America and the Caribbean, nearly half of genital ulcer disease cases are attributable to HSV-2 [12, 15], while in Australia, Europe, and Canada the proportion is lower, at around one-quarter [13, 14].

Globally, HSV-2 is the predominant cause of genital herpes [11,12,13,14,15], yet its contribution relative to herpes simplex virus type 1 (HSV-1) has declined in North America, Europe, and Australia over the past three decades [13, 14, 16]. This trend reflects reductions in HSV-2 prevalence in these regions [13, 14,