GENEVA Two-thirds of the world's population under 50 have the highly infectious herpes virus that causes cold sores around the mouth, the World Health Organization said on Wednesday, in its first estimate of global prevalence of the disease. 
 
 More than 3.7 billion people under the age of 50 suffer from the herpes simplex virus type 1 (HSV-1), usually after catching it in childhood, according to a the WHO study. 
 
 That is in addition to 417 million people in the 17-49 age range who have the other form of the disease, HSV-2, which causes genital herpes. 
 
 HSV-1 normally causes mouth ulcers rather than genital infection, but it is becoming an increasing cause of genital infection too, mainly in rich countries. 
 
 That is because improved hygiene in rich countries is lowering HSV-1 infection rates in childhood, leaving young people more at risk of catching it via oral sex when they become sexually active. 
 
 HSV-2 can increase the risk of catching and spreading HIV, the disease that causes AIDS. Little is known about any link between HSV-1 and HIV/AIDS, although it can lead to other serious complications such as encephalitis. 
 
 "We really need to accelerate the development of vaccines against herpes simplex virus, and if a vaccine designed to prevent HSV-2 infection also prevented HSV-1, it would have far reaching benefits," said Sami Gottlieb, a WHO medical officer. 
 
 Nathalie Broutet, also a WHO medical officer, said the U.S. National Institutes of Health and companies including GlaxoSmithKline Plc were involved in trials to determine whether a therapeutic or preventative vaccine was preferable. 
 
 Gottlieb said GSK had previously abandoned a vaccine trial after finding the product was not effective against HSV-2, although it did show some efficacy against HSV-1. 
 
 "That was interesting and promising and gave a proof of concept that these vaccines can be developed. There's a lot of work ongoing and we're hopeful that we'll have an HSV vaccine in the future," she said. 
 
 Several phase-1 and phase-2 trials were underway, she said. Genocea Biosciences Inc recently dropped work on a pneumonia vaccine in favor of its more promising work on genital herpes. 
 
 (Reporting by Tom Miles; Editing by Gareth Jones) 

 Two-thirds of the world's population has the virus that causes cold sores, the World Health Organization said Wednesday. 
 
 That's 3.7 billion people under the age of 50 with the pesky and incurable herpes virus. 
 
 But it causes more than cold sores. 
 
 The herpes simplex 1 virus (HSV-1) can also cause sores on the genitals — and oral sex is becoming a leading way it's being transmitted, the WHO reported in the Public Library of Science journal PLoS ONE. 
 
 "The global burden of HSV-1 infection is huge," the WHO research team writes. 
 
 "An estimated 140 million people aged 15-49 years were calculated to have prevalent genital HSV-1 infection globally in 2012," they wrote. 
 
 That means two kinds of incurable herpes viruses are causing sexually transmitted infections in the populations. 
 
 HSV-2 is traditionally called genital herpes, and it's the kind most people think of as causing sexually transmitted infections. HSV-1, while annoying and sometimes painful, is usually caught in childhood and often via kisses. 
 
 "The new estimates highlight the crucial need for countries to improve data collection for both HSV types and sexually transmitted infections in general," said Dr. Marleen Temmerman, director of WHO's Department of Reproductive Health and Research. 
 
 In the Americas, WHO estimates that 49 percent of women, or 178 million women, have HSV-1 and 39 percent of men, or 142 million, do. 
 
 That's the region with the lowest rates. In Africa, 87 percent of people have HSV-1 while it's close to 60 percent in Southeast Asia. 
 
 Both viruses cause painful and recurring blisters and both can spread even if someone doesn't have skin blisters. Both can be treated with the same antiviral drugs but the drugs just control the virus - they cannot cure an infection. 
 
 At least once scientific study suggests that humans caught herpes viruses from chimpanzees. 

 Abstract Background Herpes simplex virus type 1 (HSV-1) commonly causes orolabial ulcers, while HSV-2 commonly causes genital ulcers. However, HSV-1 is an increasing cause of genital infection. Previously, the World Health Organization estimated the global burden of HSV-2 for 2003 and for 2012. The global burden of HSV-1 has not been estimated. Methods We fitted a constant-incidence model to pooled HSV-1 prevalence data from literature searches for 6 World Health Organization regions and used 2012 population data to derive global numbers of 0-49-year-olds with prevalent and incident HSV-1 infection. To estimate genital HSV-1, we applied values for the proportion of incident infections that are genital. Findings We estimated that 3709 million people (range: 3440–3878 million) aged 0–49 years had prevalent HSV-1 infection in 2012 (67%), with highest prevalence in Africa, South-East Asia and Western Pacific. Assuming 50% of incident infections among 15-49-year-olds are genital, an estimated 140 million (range: 67–212 million) people had prevalent genital HSV-1 infection, most of which occurred in the Americas, Europe and Western Pacific. Conclusions The global burden of HSV-1 infection is huge. Genital HSV-1 burden can be substantial but varies widely by region. Future control efforts, including development of HSV vaccines, should consider the epidemiology of HSV-1 in addition to HSV-2, and especially the relative contribution of HSV-1 to genital infection. 
 
 Citation: Looker KJ, Magaret AS, May MT, Turner KME, Vickerman P, Gottlieb SL, et al. (2015) Global and Regional Estimates of Prevalent and Incident Herpes Simplex Virus Type 1 Infections in 2012. PLoS ONE 10(10): e0140765. https://doi.org/10.1371/journal.pone.0140765 Editor: Neal A. DeLuca, University of Pittsburgh School of Medicine, UNITED STATES Received: August 12, 2015; Accepted: September 30, 2015; Published: October 28, 2015 This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication Data Availability: All relevant data are within the paper and its Supporting Information files. Funding: This work was funded by the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (http://www.who.int/reproductivehealth/hrp/en/). WHO commissioned the study, advised as required during the study, co-ordinated data requests, helped with redrafts, and approved the manuscript submission. KJL had full access to all the data in the study and had final responsibility for the decision to submit for publication. KJL received funding from the National Institute for Health Research (NIHR) Health Protection Research Unit (HPRU) in Evaluation of Interventions, Health Protection Scotland and Sexual Health 24 during the course of this study. ASM received funding from the National Institutes of Health (NIH P01-A1-030731-23) during the study. These funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors alone are responsible for the views expressed in this article and they do not necessarily represent the views, decisions or policies of the institutions with which they are affiliated. Competing interests: The authors have declared that no competing interests exist. 
 
 Introduction Herpes simplex virus type 1 (HSV-1) is a highly infectious virus which is primarily transmitted by oral-oral contact and causes orolabial herpes (notably “cold sores”) in those infected[1]. The virus is highly prevalent and endemic throughout the world[2,3]. The majority of HSV-1 infections occur during childhood and infection is never cleared[1], with lifelong potential for symptomatic or asymptomatic viral shedding episodes[4,5]. In rare cases, infection can lead to more serious complications, such as encephalitis. In developed country settings, HSV-1 is the most common identified cause of sporadic encephalitis in children and adults[6,7]. HSV-2, by contrast, is almost entirely sexually transmitted, and is therefore most closely associated with genital herpes[1]. However, HSV-1 has the potential to be transmitted through oral sex to cause genital infection[1]. In a number of developed settings (e.g., the USA, Western Europe, Australia and New Zealand) there is evidence that the proportion of first episode genital herpes that is due to HSV-1 has increased, particularly among young people[8–13]. It is thought that decreases in rates of childhood infection over time[14], combined with increases in the frequency of oral sex in these populations, are driving this trend[15]. Women are more likely to acquire genital herpes than men, and this holds true for both HSV-1 and HSV-2[9,11,16,17]. The natural history of genital infection differs for the two viral types. Although first episode genital herpes is clinically indistinguishable between HSV-1 and HSV-2, subsequent recurrences are milder and much less frequent for HSV-1[5,18,19]. Neonatal herpes, a rare but devastating illness with high morbidity and mortality, can be caused by both HSV-1 and HSV-2[20]. However, a study of more than 58,000 live births showed that when mothers shed genital HSV at delivery, HSV-1 may be more likely than HSV-2 to be transmitted to the neonate[21]. In one study in Canada from 2000–2003, 63% of neonatal herpes cases were due to HSV-1[22]. This is one of a growing number of epidemiological studies that suggests that the impact of HSV-1 genital infections is widely underappreciated. It is known that HSV-2 increases HIV susceptibility and infectiousness[23–28]. The association between HSV-1 and HIV is unknown. Determining the proportion of HSV-1 infection that is oral versus genital is difficult. Standard type-specific serological tests measure the presence of IgG antibodies to distinguish HSV-1 and HSV-2 infections, but can only tell us whether an individual is infected and not the site of infection[29]. Viral shedding (both symptomatic and asymptomatic) occurring at the site of infection can be detected by a variety of methods. However, viral shedding is episodic. This means that viral shedding studies may not detect viral presence without multiple samples being taken from each person over time[30]. Nevertheless, type-specific viral detection studies remain the most accurate way to assess the site of infection. Quantifying the overall burden of HSV-1 infection, the burden of genital HSV-1, and the relative contribution of HSV-1 versus HSV-2 to genital herpes allows us to appropriately target prevention and treatment resources and tailor prevention counselling. In addition, such data can guide appropriate development of future interventions. The World Health Organization (WHO) has generated estimates of the global burden of HSV-2 twice: for 2003[16] and for 2012[17]. The global burden of HSV-1 infection has never been estimated to our knowledge. In this paper we present first WHO estimates of the burden of prevalent (existing) and incident (new) HSV-1 infection in 0–49 year olds for 2012 both globally and by WHO region. We also estimate the burden of genital HSV-1 infection in those aged 15–49 years. 
 
 Methods The method of estimation was multi-step and very similar to the method used to generate HSV-2 prevalence and incidence[16,17]. First we searched PubMed and EMBASE databases for studies reporting HSV-1 prevalence (any language) published from 2005 onwards that met our selection criteria. For search terms used see S1 Document. HSV-1 prevalence was defined as the percentage of individuals with type-specific IgG antibodies to HSV-1 cross-sectionally. Reference lists of key publications were also searched. Data from publications published before 2005 and extracted previously[3,16] were included if the selection criteria were met. The key inclusion criteria were: some detail of study location and some information on age. Studies were excluded if participants were selected on the basis of having a medical condition. The rationale for this was that prevalence in such individuals may not be generalizable to the general population. For further details of the selection criteria see S1 Document. Only prevalence values from general populations were retained for the analyses. Data from specialised study populations such as men who have sex with men, STI clinic attendees and commercial sex workers were not used. Studies where enrolment was based on a particular minority subpopulation, for example, elderly Latino people in the Sacramento area, USA, were also not used. Specific regional criteria for use in the estimates were also applied depending on data availability by sex and study year for each region. In particular, only those prevalence values from studies from 2000 onwards were used, except for Africa and South-East Asia, where prevalence values from 1995 onwards were used due to poor data availability. Next we pooled raw HSV-1 prevalence values for general populations by age for each of the 6 WHO regions (and by sex where data availability permitted this). The WHO regions are as follows: the Americas, Africa, Eastern Mediterranean, Europe, South-East Asia and Western Pacific (S1 Table). Pooling was done for the following age ranges: 0–4; 5–9; 10–14; 15–19; 20–24; 25–29; 30–34; 35–39; 40–44 and 45–49 years. A sample size of 20 or more was required for pooling. All prevalence values were adjusted for test sensitivity and specificity prior to pooling[31–33]. Lastly we fitted a model[34] to the pooled HSV-1 prevalence values to estimate smoothed HSV-1 prevalence and calibrate HSV-1 incidence, which were then applied to population sizes for 2012[35] to generate the regional burdens of HSV-1 infection at any site. We estimated the burden of genital HSV-1 infection by assigning values for the proportion of incident HSV-1 infections from age 15 years that are genital from existing literature. This proportion is difficult to determine, and to our knowledge, only two studies have been carried out to estimate it. In a prospective US study of HSV-2 seronegative individuals aged 17–79 years who were “high-risk” or in HSV-2 serodiscordant relationships, 19 had incident HSV-1 infections, of which 12 were symptomatic and the site of infection could be determined. Overall, 50% (6/12) of symptomatic incident HSV-1 infections were associated with genital lesions; the remaining symptomatic individuals had either orolabial lesions or pharyngitis[36]. In a more recent study of HSV seronegative women aged 18–30 years in the control arm of the HERPEVAC Trial for Women in the USA, with 127 total incident HSV-1 infections, 85% (28/33) of symptomatic incident HSV-1 infections were associated with either genital disease or both oral and genital disease[13]. We found no studies to estimate this proportion outside of the USA. Uncertainty bounds around the estimates were computed which accounted for uncertainty in the underlying prevalence data. For a detailed description of the model and estimates calculation see S1 Document. 
 
 Ethics Statement It was not necessary to seek ethical approval for this study as this study is an analysis of existing published prevalence data and as such did not involve human participants directly. Correspondingly, no patient records or patient information were accessed. 
 
 Discussion An estimated 3709 million people globally aged 0–49 years were infected with prevalent HSV-1 in 2012. Assuming 50% of incident infections among 15-49-year-olds are genital, an estimated 140 million people were infected with prevalent genital HSV-1. The number of HSV-1 infections was highest for Africa, South-East Asia and Western Pacific, which had the largest population sizes. However, the majority of genital HSV-1 infections were in the Americas, Europe and Western Pacific, where HSV-1 infection continued to increase after adolescence. The prevalence of genital HSV-1 was highest for the Americas, which had the lowest HSV-1 prevalence on entering adolescence of all 6 regions. Taken together with estimates of HSV-2 infection among adults globally, which were all considered to be genital, our new estimates of HSV-1-associated genital infection suggested that 544 million people had genital infection due to either viral type worldwide in 2012, assuming half of incident HSV-1 infections in adults are genital. This figure could be as high as 633 million people, if 85% of incident HSV-1 infections in adults are genital, as suggested in a recent prospective study(13). It is unclear how much of this infection is recognized, as only about 10–20% of HSV-2 infections are diagnosed[14,38,39] and the analogous proportion for HSV-1 is unknown. In adults and adolescents, genital herpes due to HSV-1 is associated with less frequent symptomatic disease recurrences than HSV-2[5,18,19]. Thus, disease burden will vary by region not only by the number of people with genital herpes, but also the relative proportions caused by HSV-2 versus HSV-1. Although the burden of genital HSV-2 is high in Africa and moderate in South-East Asia, the available data suggest that genital HSV-1 is currently less likely to be an important public health problem in these regions. This is because HSV-1 acquisition here appeared to be high prior to adolescence and thus sexual debut, thereby protecting individuals in these regions from genital disease. However, the prevalence data on which the estimates were based were extremely sparse. For Africa, only one pooled prevalence estimate was available, with the remainder of the prevalence data for fitting coming from single studies. Genital HSV-1 could be much higher than estimated if HSV-1 infection continued after adolescence in these regions. Additionally, regional estimates could mask very different patterns of infection, including higher genital HSV-1, in individual countries or in specific settings. Our estimates of HSV-1 are considerably hampered by small numbers of studies across all regions, and by issues of small sample size, quality of data and generalizability within studies. Estimates of the burden of genital HSV-1 are severely hampered by lack of data on the proportion of incident HSV-1 infection from adolescence that is genital. We attempted to account for this uncertainty by generating two sets of estimates for genital HSV-1: the first assuming a value of 50% for this proportion[36], and the second assuming a value of 85%[13]. These values are the best available, but based on very small samples and only US populations. In addition, the site of new HSV-1 infection can only be determined for symptomatic people, and a large proportion of infections are asymptomatic. The estimates assume that the proportions of new HSV-1 infections that are genital versus oral are the same for both symptomatic and asymptomatic people. If new genital HSV-1 infections are more likely than new oral HSV-1 infections to be symptomatic, the estimated proportion of all incident HSV-1 infections that are genital may be inflated. This proportion may also vary considerably by region, setting, age and sex, although this variability may be less important for regions like Africa and South-East Asia with apparently little HSV-1 acquisition after early adolescence. Although we computed uncertainty bounds around the estimates, these are unlikely to fully account for all variation in underlying prevalence, most notably because reliable bounds for the African estimates could not be calculated. Consideration of the estimate reliability in light of these important issues should accompany interpretation and application of these estimates. Recent changes in the pattern of HSV-1 infection, i.e., decreasing rates of oral HSV-1 infection in childhood and increasing sexual transmission of HSV-1, mean that there may be cohort effects in prevalence data whereby older individuals have experienced higher historic rates of childhood infection and lower rates of sexual transmission. In the National Health and Nutrition Examination Surveys (NHANES) in the USA, the only nationally-representative general population surveys of HSV-1 prevalence repeated over a number of years, HSV-1 seroprevalence has been declining since the first surveys (1988–1994) and is continuing to decrease, with the largest decreases observed for adolescents[14,40]. We used only data from 2000 onwards (with the exception of Africa and South-East Asia), which minimized the influence of cohort effects to some extent. However this would not have removed the effect of all ongoing HSV-1 trends in the Americas and potentially other settings. The model in effect enables us to fit a function to smooth out observed prevalence, and then estimate the number of incident infections that would result from the fitted function, assuming that over the short period of one year prevalence does not change. Impact and recommendations This is the first attempt to calculate the global burdens of all HSV-1 and genital HSV-1, and hence the first attempt to quantify the extent to which genital HSV-1 presents a public health problem across different regions. To date, prevention and control efforts against genital herpes have focussed almost exclusively on HSV-2. We show that this strategy is likely to be currently appropriate for Africa and South-East Asia, where genital HSV-1 infection is probably not a public health issue at this time. However, for other regions, most notably the Americas, Europe and Western Pacific, such a strategy would fail to address a substantial burden of genital HSV-1 infection. In addition to the consequences of genital HSV-1 infection, orolabial HSV-1 infection is important in its own right. Symptomatic recurrent orolabial herpes can range from a mere annoyance to severe disease in the setting of immunocompromise. In addition, HSV-1 is one of the most common causes of sporadic encephalitis, which is rare but devastating, with high morbidity and associated costs[6,7] and HSV-1 also contributes to neonatal infections and deaths. Patterns of HSV-1 and HSV-2 infection, and their relative contribution to genital disease, are a product of multiple interactions. These include: different routes of transmission, different risk profiles by age, and the role of cross-immunity. Decreases in childhood HSV-1 infection and increases in orogenital sex have the potential to introduce genital HSV-1 as a public health issue in those regions where it is currently minimally present, since decreasing childhood-acquired immunity to HSV-1 (oral HSV-1 otherwise seems to protect against genital HSV-1) means more adults are at risk of acquiring genital HSV-1 through oral sex. Since HSV-1 infection does not seem to follow HSV-2[37], interventions that decrease HSV-2 infection could potentially lead to an increase in genital HSV-1, while a decrease in HSV-1 could lead to an increase in HSV-2 disease[36]. Other considerations for control programmes include: genital herpes due to HSV-1 is less likely to recur compared with HSV-2; the risk of neonatal herpes seems to be higher for HSV-1 than for HSV-2; and genital HSV-1 could in theory enhance HIV acquisition in a similar way to HSV-2 although the association is not understood. Despite the limited availability of data informing these estimates, we hope to increase understanding of the global scope of HSV-1 infection, and guide development of future prevention efforts. In a recent Phase III trial, an HSV vaccine based on glycoprotein D2 failed to prevent HSV-2 infection and disease, but, encouragingly, did show significant efficacy against HSV-1-related infection and disease[41]. Efforts to develop new HSV vaccines are advancing[42]. There are currently a number of HSV vaccine candidates in the development pipeline, with several therapeutic (vaccines which work in those already infected to reduce viral shedding and disease) and prophylactic vaccines in Phase I and II trials, in conjunction with substantial advances in delivery systems, adjuvants and stimulation of mucosal immunity[42]. These estimates lay the groundwork for determining the potential impact of a vaccine against HSV and informing important vaccine characteristics. For the Americas, Europe and the Western Pacific, a vaccine would need to target both HSV types to prevent genital herpes. In Africa and South-East Asia, a vaccine targeting HSV-2 infection would address genital herpes but would need to be effective in the presence of HSV-1 infection if targeted to adolescents or would need to be an infant vaccine. In summary, these WHO estimates show an enormous burden of HSV-1 globally, with regional variation in the age at which HSV-1 is acquired. Increased data on the epidemiology of HSV-1 are needed to strengthen the robustness of these estimates and provide a clearer picture in all regions as to how HSV-1 differs by age and sex. Furthermore, an improved understanding of the interaction between HSV-1 and HSV-2 at different anatomic sites on protective immunity is needed. Genital HSV-1 acquisition is lowest in regions such as Africa with the highest HIV rates, but understanding how HSV-1 affects HIV spread is critical given how common this infection is globally. It is hoped these estimates will be used to develop appropriate prevention messages, manage and counsel patients with symptomatic genital herpes, develop improved treatment regimens and diagnostic tests, and ultimately, develop HSV vaccines. 
 
 Acknowledgments The authors thank Professor Anna Wald (University of Washington) for valuable input, Dr Gretchen Stevens (World Health Organization) for statistical advice, Dr Fujie Xu (Centers for Disease Control and Prevention) for helpful discussion, Jessica Ho (World Health Organization) for helping with population data, Sharanya Rajagopal (University of Washington) for advising on meta-analysis in Stata, and the reviewers who made helpful suggestions for improving the manuscript. KJL, MTM, KMET and PV thank the National Institute for Health Research (NIHR) Health Protection Research Unit (HPRU) in Evaluation of Interventions for research support. 
 
 Author Contributions Conceived and designed the experiments: KJL LMN. Performed the experiments: KJL. Analyzed the data: KJL ASM MTM KMET PV SLG LMN. Contributed reagents/materials/analysis tools: KJL ASM MTM KMET PV. Wrote the paper: KJL ASM MTM KMET PV SLG LMN. Contributed to the ongoing progress and direction of the research: KJL ASM MTM KMET PV SLG LMN. Provided technical expertise and input: KJL ASM MTM KMET PV SLG LMN.
– In its first ever global assessment of the prevalence of the herpes virus that causes cold sores, the World Health Organization reports in the journal PLoS ONE that two in three humans under the age of 50 are infected with the incurable virus. That's an estimated 3.7 billion people. The WHO had previously done the same assessment for herpes simplex virus type 2, aka genital herpes, and found that 417 million people ages 17-49 have it. HSV-1, by contrast, is transmitted by oral-oral contact (often via childhood kisses, notes NBC News) and causes cold sores. "However, HSV-1 is an increasing cause of genital infection," they write, with the prevalence of genital HSV-1 being highest in the Americas. Reuters explains why: "Improved hygiene in rich countries" is reducing the number of infections that occur during childhood, and pushing more into young adulthood, where HSV-1 is transferred via oral sex (so not oral-oral but oral-genital). "We really need to accelerate the development of vaccines against herpes simplex virus," one WHO medical officer says. There are currently multiple phase-1 and phase-2 trials, with Genocea Biosciences halting its work on a pneumonia vaccine to focus on genital herpes. As for HSV-1, the WHO estimates that the Americas have the lowest infection rates: 49% of women and 39% of men. That number jumps to nearly 60% in Asia and a whopping 87% in Africa, reports NBC News. (This newborn almost died when a hospital visitor with HSV-1 kissed her.)