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Strategic Plan for HERPES 

SIMPLEX VIRUS Research 

September 2023
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TABLE OF CONTENTS 

EXECUTIVE SUMMARY .................................................................................................................................. 2

INTRODUCTION............................................................................................................................................. 4

STRATEGIC PRIORITY 1: Improve Fundamental Knowledge of HSV Biology, Pathogenesis, and 

Epidemiology ................................................................................................................................................ 5

Objective 1.1: Enhance Fundamental Knowledge of HSV Biology............................................................ 6

Objective 1.2: Characterize Host and Pathogen Drivers that Underlie Dynamics of HSV Latency and 

Reactivation .............................................................................................................................................. 7

Objective 1.3: Improve Understanding of Diverse Pathophysiology of HSV Infection............................. 7

Objective 1.4: Explore Epidemiology and Co-infection Associated with HSV Infection ........................... 9

Objective 1.5: Improve and Develop New in vitro and in vivo Models that Reflect Human Disease.....10

STRATEGIC PRIORITY 2: Accelerate Research to Improve HSV Diagnosis................................................... 10

Objective 2.1: Support Innovative Technologies that can be Utilized in Diverse Clinical Settings to 

Expand Testing Availability ..................................................................................................................... 11

STRATEGIC PRIORITY 3: Improve Strategies to Treat and Cure HSV........................................................... 12

Objective 3.1: Advance the Development of Long-Acting Treatment Strategies...................................13

Objective 3.2: Evaluate the Safety and Efficacy of Treatment Strategies in Diverse Populations and Age 

Groups..................................................................................................................................................... 13

Objective 3.3: Identify Strategies for Working Toward Elimination of HSV or Development of a 

Functional Cure....................................................................................................................................... 14

STRATEGIC PRIORITY 4: Advance Research to Prevent HSV Infection........................................................ 15

Objective 4.1: Advance the Development of Promising Vaccines and Multipurpose Prevention 

Technologies (MPTs)............................................................................................................................... 15

Objective 4.2 Support Clinical Trials to Test Therapeutics and Vaccines ...............................................16

CONCLUSION............................................................................................................................................... 19

APPENDICES ................................................................................................................................................ 20

APPENDIX 1: NIH HSV Working Group Members ................................................................................... 20

APPENDIX 2: NIH-Supported HSV Research Resources.......................................................................... 21

APPENDIX 3: Analysis of Public Comments to Request for Information (RFI)........................................23

Specific Themes from RFI Responses.................................................................................................. 24

Cross-cutting Themes.......................................................................................................................... 25
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EXECUTIVE SUMMARY

Herpes simplex virus (HSV) 1 and 2 are among the most common viral infections in the U.S., with up to

80% of people between the ages of 14 and 49 infected with HSV-1 and more than 10% infected with 

HSV-2.

1

Infection with HSV can result in a diverse range of symptoms and pathology that can lead to 

lifelong complications. 

2

To date, there are no HSV vaccines approved by the U.S. Food and Drug Administration (FDA). While 

research advances have resulted in several therapeutics, the effectiveness of these treatments in 

reducing symptoms and viral transmission varies widely. In addition, current treatment strategies 

require active virus replication, making them ineffective against latent HSV infection. The National 

Institutes of Health (NIH) recognizes that the development of commercially available HSV vaccines, 

therapeutics and diagnostics to improve public health and well-being requires a multi-pronged effort 

building upon advances in HSV research. 

To advance research to understand and address HSV infection, the NIH has established the Strategic 

Plan for Herpes Simplex Virus Research. This plan aligns with ongoing national efforts, including the 

Sexually Transmitted Infections (STI) National Strategic Plan, and provides the framework for HSV 

research aligned with four priorities (Figure 1): 

• Strategic Priority 1: Improve fundamental knowledge of HSV biology, pathogenesis, and

epidemiology

• Strategic Priority 2: Accelerate research to improve HSV diagnosis

• Strategic Priority 3: Improve strategies to treat and cure HSV

• Strategic Priority 4: Advance research to prevent HSV infection

These strategic priorities encompass interdependent activities that combine the efforts of the research 

community with those in public health and clinical medicine to develop interventions to reduce the 

health consequences of HSV. 

1 McQuillan G, Kruszon-Moran D, Flagg EW, Paulose-Ram R. Prevalence of herpes simplex virus type 1 and type 2 in 

persons aged 14–49: United States, 2015–2016. NCHS Data Brief, no 304. Hyattsville, MD: National Center for 

Health Statistics. 2018. https://www.cdc.gov/nchs/data/databriefs/db304.pdf 2 https://www.cdc.gov/std/treatment-guidelines/herpes.htm
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Figure 1. The mission of the NIH Strategic Plan for Herpes Simplex Virus Research is to improve diagnostic tools, prevention 

strategies, and treatments to reduce the public health impact of HSV. This mission will be achieved through four strategic 

priorities. Priority 1: Improve fundamental knowledge of HSV biology, pathogenesis, and epidemiology. Priority 2: Accelerate 

research to improve HSV diagnosis. Priority 3: Improve strategies to treat and cure HSV. Priority 4: Advance research to prevent 

HSV infection. The strategic priorities will be supported by existing tools and resources, such as the current body of research, 

diagnostics, treatment and prevention strategies, and public health policies.
 

 

 

 

 

 

 

 

 

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INTRODUCTION 

Figure 2. Negative-stained transmission 

electron microscopic image of herpes 

simplex virions. Image credit: Centers 

for Disease Control and Prevention 

In the U.S., an estimated 50% to 80% of people ages 14-49 have been 

infected with HSV-1 while more than 10% have been infected with 

HSV-2 . Clinical manifestations of HSV infections can result in 

significant complications. HSV is one of the leading causes of 

infectious blindness worldwide and can also impact the central 

nervous system (CNS) resulting in dangerous inflammation of the 

brain or spinal cord. Neonatal herpes, if left untreated, has a case 

fatality rate of 60% . Individuals from disadvantaged populations bear 

a higher burden of HSV infection, which may contribute to disparities 

in long-term health. Asymptomatic cases of HSV are also extremely 

common, and those who are asymptomatic continue to shed the virus 

and can transmit it to close contacts. There is currently no cure for 

HSV, so individuals remain infected and may need to continue 

treatment for recurrences and complications for the rest of their 

lives. 

5

4

3

One of the challenges in treating HSV infections is the diverse nature of clinical manifestations of 

disease. In many cases, symptomatic infection with HSV can lead to the development of herpetic lesions 

that present as oral labial herpes (cold sores) or genital herpes. These infectious lesions are common 

sources of disease spread. HSV can also result in diverse and distinct pathology in other tissues of the 

body, including ocular keratitis, meningitis, or encephalitis. Most cases of HSV encephalitis are due to 

HSV-1, while most cases of HSV meningitis are due to HSV-2. 

HSV infection predominantly occurs through contact with infected tissue of oral or genital mucosal 

surfaces that are shedding virus. Infection may also occur in other areas of the body if the skin is 

damaged and comes in contact with infectious virus. Once in the host, the virus can then transition to a 

quiescent state, called latency, actively suppressing the expression of genes that could lead to detection 

by the human immune system. In this manner, the virus can exist for extended periods of time in the 

body without causing symptoms. Once a “trigger” for transition out of latency occurs, HSV reverts into 

its active, or lytic state. Known triggers for virus reactivation include stress, sunlight, immune 

suppression, and a variety of other factors. 

The vacillating nature of the HSV infection cycle and often asymptomatic nature of infection present 

challenges in diagnosis and treatment. Recent studies have shown that live virus is shed without the 

presence of clinically evident classic herpetic lesions. As such, the development and improvement of 

serologic and point-of-care diagnostics continues to be a research priority. There are currently no 

licensed vaccines for HSV-1 or HSV-2. HSV infections are primarily treated with antivirals such as 

acyclovir (or valacyclovir), which can reduce the frequency and intensity of outbreaks of herpetic lesions 

if started early during the lytic cycle. A prophylactic vaccine that can prevent infection or a therapeutic 

3 https://www.cdc.gov/nchs/data/databriefs/db304.pdf 

4 https://www.cdc.gov/std/treatment-guidelines/herpes.htm 5 https://pubmed.ncbi.nlm.nih.gov/28153513/ 

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vaccine for individuals who are already infected with HSV that could reduce recurrences and/or 

shedding would be a crucial tool in mitigating the public health impact of herpes simplex viruses. 

The public health impact of HSV-1 and HSV-2 underscores the need for advancing research efforts to 

understand and thoroughly characterize HSV biology, pathogenesis, and epidemiology toward the 

development of commercially available vaccines, therapeutics and diagnostics. To address and 

coordinate efforts to facilitate HSV research, an NIH-wide HSV Working Group, led by the National 

Institute of Allergy and Infectious Diseases (NIAID), was established. This group consists of scientific and 

policy experts from NIAID, the National Institute on Mental Health (NIMH), the National Institute of 

Neurological Disorders and Stroke (NINDS), the National Institute on Aging (NIA), the National Institute 

on Minority Health and Health Disparities (NIMHD), the Eunice Kennedy Shriver National Institute of 

Child Health and Human Development (NICHD), and the National Eye Institute (NEI). To seek broad 

public input on scientific areas of interest in HSV research, NIH issued a Request for Information (RFI). 

The results of the RFI are summarized in Appendix 3 and suggestions were incorporated into the plan as 

appropriate. 

To advance NIH HSV research objectives, the NIH HSV Working Group organized this plan into four 

strategic priorities: (1) improving fundamental knowledge of HSV biology, pathogenesis, and 

epidemiology; (2) accelerating research to improve HSV diagnosis; (3) improving strategies to treat and 

cure HSV; and (4), advancing research to prevent HSV infection. These interdependent priorities form 

the framework of the NIH strategy to advance our understanding of HSV-1 and HSV-2 and help 

accelerate the development of safe and effective interventions to reduce the public health impact of 

HSV-1 and HSV-2. 

STRATEGIC PRIORITY 1: Improve Fundamental Knowledge of HSV

Biology, Pathogenesis, and Epidemiology 

Strategic Priority 1: Improve Fundamental Knowledge of HSV Biology, Pathogenesis, and 

Epidemiology 

Objective 1.1: 

Objective 1.2: 

Objective 1.3: 

Objective 1.4: 

Objective 1.5: 

Enhance Fundamental Knowledge of HSV Biology 

Characterize Host and Pathogen Drivers that Underlie Dynamics of HSV Latency 

and Reactivation 

Improve Understanding of Diverse Pathophysiology of HSV Infection 

Explore Epidemiology and Co-infection Associated with HSV Infection 

Improve and Develop New in vitro and in vivo Models that Reflect Human Disease 

Although HSV is extremely common worldwide, considerable gaps remain in the fundamental 

understanding of HSV. These include our understanding of the basic components of HSV biology, 

pathophysiology, and the host and pathogen drivers that sustain virus latency or drive reactivation. NIH 

will continue to support research guided by the objectives below toward advancing the understanding of 

the basic biology of the HSV viruses that will accelerate advances in diagnostics, vaccine development, 

and efforts toward a cure. 

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Objective 1.1: Enhance Fundamental Knowledge of HSV Biology

• Mechanisms of HSV entry into host cells: HSV can utilize various modes of entry based on cell

types infected. HSV can directly fuse with the host plasma membrane, or it can utilize endocytic

pathways that are either pH-dependent or -independent. The fusion of the viral envelope with

the host cell membrane is a crucial step in infectivity. Continued support for research

characterizing this process will be a critical asset for the development of vaccines and

therapeutics. If the initial entry of HSV into the host cell can be blocked, infection cannot be

established.

• Mechanisms of replication: Replication of viral DNA is carried out by several viral-encoded

proteins. The newly replicated viral genomes are packaged into preformed capsids in the

nucleus, and the viral proteins and the envelope acquired as newly infectious virions exit from

the cell. The HSV viral replication process is the target for many of the currently approved HSV

therapeutics. Continued investigations of the complex processes of HSV virus replication and

viral assembly will be important for the elucidation of new possible targets for HSV therapeutics.

• Mechanisms of HSV trafficking in the nervous system: HSV can infect both the peripheral and

central nervous systems. After initial infection of epithelial cells, HSV can enter neurons in the

skin or mucosa at the primary site of infection. The virus is then transported to clusters of

neurons in the peripheral nervous system, called the trigeminal or dorsal root ganglia, where it

can establish a life-long latent infection. Upon reactivation in the ganglia, HSV is transported

back to the periphery where they cause lesions on the lips or genitals. In rare cases, HSV can also 

spread from ganglia to the brain which can lead to severe neurological conditions, although the 

precise mechanisms by which this occurs remain unknown. Additional research to elucidate the 

basic biological mechanisms of HSV trafficking in the nervous system can lead to novel strategies 

for preventing HSV dissemination in the nervous system.

• Fundamental aspects of immune response: Several components of the HSV virion, including the

viral nucleic acid and viral proteins, have been shown to trigger immune responses to HSV,

including activation of type 1 interferon (IFN), HSV-specific antibodies, T cells, natural killer (NK)

cells, dendritic cells (DC), as well as other immune mechanisms. Investigators are working to

define HSV epitopes that are recognized by T cells in the mucosal surface (at the site of infection

and reactivation) and to understand the role of these cells in disease prevention, viral

reactivation, and pathogenesis. Additional studies are needed to better characterize the complex 

consequences of the host immune response to HSV in multiple areas of the body including the 

CNS, where a strong inflammatory response to the virus can be particularly detrimental. Such 

investigations support the identification of potential correlates of protection and enable 

researchers to better understand the role of the immune system in viral latency, disease 

progression, and ultimate severity of disease.

• HSV transmission: Transmission of HSV occurs through contact with an individual who is infected 

and shedding the virus. This may occur in individuals who are either symptomatic or

asymptomatic for HSV. In neonatal HSV, transmission can occur either in utero, during delivery,

or just after birth. Although many features that lead to HSV transmission are understood,
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continued research is needed to further elucidate specific aspects of the transmission process, 

including the amount of virus required for transmission, and understanding of the specific 

features of transmission. 

• Identify biomarkers of disease: Biomarkers have the potential to predict susceptibility to HSV

disease states and may be leveraged to predict which patients are more likely to have severe

HSV or to have frequent recurrences. To identify new markers of disease, efforts will need to

leverage advanced -omics approaches (e.g., transcriptomics, proteomics, metabolomics, etc.)

that can compare the level of gene expression, proteins, or metabolites in patients with or

without specific manifestations of HSV disease. Applying comprehensive systems biology

analyses of the data generated using these approaches can accelerate research and illuminate

new mechanisms that may lead to development of novel drugs or therapeutics.

Objective 1.2: Characterize Host and Pathogen Drivers that Underlie Dynamics of HSV 

Latency and Reactivation 

Objective 1.3: Improve Understanding of Diverse Pathophysiology of HSV Infection

• Encephalitis and meningitis: In addition to infecting the skin, mucosa, and peripheral neurons

and ganglia, both HSV-1 and HSV-2 can cause inflammation in the brain and spinal cord (the

central nervous system or CNS), known as encephalitis and meningitis, respectively (Figure 3).

Herpes simplex encephalitis (HSE) accounts for 10-20% of all sporadic encephalopathies, and if it

• Strategies of immune evasion: HSV uses multiple strategies to avoid detection and clearance by

the immune system and sustain infection through cycles of latency and reactivation. For

example, during active infection, HSV can inhibit presentation of viral proteins to T cells,

hampering their ability to respond to the virus. In addition, HSV can express molecules to bind to

HSV-specific antibodies, limiting their activity. Once in the latent phase, the HSV genome

expresses latency-associated transcripts (LATs) that help establish viral latency and may

facilitate avoiding detection by the immune system. Continued advancements to characterize

HSV immune evasion during both HSV latency and reactivation will be critical towards the

development of strategies that interfere with these immune evasion processes.

• External and host-derived factors that drive HSV reactivation: The specific triggers that initiate

reactivation of latent HSV to the lytic state continue to be of significant scientific interest.

Although the specific triggers of reactivation remain unclear, several factors have been

implicated in this process. Stress on a host organism can lead to immune suppression and has

been linked to HSV reactivation. In addition, intrinsic host-derived factors related to the immune

response may result in a predisposition to reactivation. Cellular transcription factors that are

involved in reactivation of HSV, and loss of nerve growth factor (NGF) may also be sources of

reactivation of the virus. Identifying specific factors that are responsible for HSV reactivation will

help identify individuals at high-risk or predisposed to reactivation as well as strategies to

counteract this process and resulting HSV pathology.
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goes untreated with antiviral agents, the mortality rate is as high as 70%6.Neonates and 

immunosuppressed individuals are at especially high risk for serious HSV-related CNS

complications. Previous research has suggested that pathology in HSE may be due to both virus 

replication and the immune response to the infection. However, the specific roles for each of 

these mechanisms remain unclear. In addition, the virus or host mechanisms that drive

reactivated HSV to spread to the CNS or make people more susceptible to CNS invasion require 

further characterization. Advancing the understanding of CNS pathology of HSV will be 

important for intervention strategies that result in better long-term outcomes for patients with 

HSE. 

6 https://pubmed.ncbi.nlm.nih.gov/26387515/

• Herpetic Keratitis: HSV can also infect multiple tissues of the eye. HSV keratitis (HSV-mediated

inflammation of the cornea) is a leading cause of blindness worldwide and recurrent HSV

keratitis is not uncommon. HSV keratitis can take three primary forms: epithelial, stromal, and

rarely, endothelial. Epithelial and stromal keratitis result from infection of specific layers of the

cornea and can lead to vision impairment. Endothelial keratitis is caused by an immune

response to HSV infection and can have severe adverse effects on vision. HSV can also cause

uveitis, retinitis, and progressive retinal necrosis. Continued research is needed to evaluate HSV

ocular pathology and investigate strategies to improve these clinical outcomes.

Figure 3. Diverse pathophysiology of HSV 

infection. HSV passed to the child during the 

perinatal period can lead to life-threatening 

symptoms, such as blood pressure instability, 

shock, lethal encephalitis, and blood clotting 

(left). HSV infection in adults can negatively 

impact the central nervous system (CNS), causing 

encephalitis, meningitis, and post-infectious

neurodegeneration (right).

• Development of neurodegenerative disorders: HSV, similar to a number of other viral

pathogens, has been associated with the future development and/or progression of

neurodegenerative disorders that can lead to dementia (i.e., Alzheimer’s Disease and Related

Dementias). However, whether these outcomes are directly related to direct viral infection or

due to secondary effects of inflammatory responses remain unclear. Brain inflammation

triggered by the reactivation of latent HSV may lead to neurodegeneration or accelerate the

progression of previously existing neurodegenerative disease states. In addition, several recent

epidemiologic studies have suggested that HSV-1 infection may be correlated with an increased

risk of Alzheimer’s Disease. Further research is needed to elucidate associations between HSV
 

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NIH Strategic Plan for HSV Research 

and the development of neurodegenerative disorders and determine pathological mechanisms 

that lead to more adverse outcomes. 

• Neonatal: Neonatal HSV disease can be caused by HSV-1 or HSV-2. A pregnant person infected 

with HSV can transmit the virus to the child, and this risk increases with primary infection. Most 

neonatal transmissions from a pregnant person to a child are caused by HSV-2. Although HSV 

can be transmitted before, during, and after birth, transmission occurring during birth is the 

most common cause of neonatal HSV. Neonatal HSV infections can be classified into three 

primary manifestations: localized skin/eye/mouth disease; disseminated infections with multiple 

organ system involvement; or CNS disease. In the decades since antivirals became available, 

morbidity and mortality of neonatal HSV have decreased significantly, but CNS and especially 

disseminated neonatal HSV may still be devastating. The development of diagnostics for use at 

labor and delivery combined with and vaccines and therapeutics to prevent the neonatal 

transmission of HSV will be critical tools to combatting HSV infection and pathology in neonates. 

Objective 1.4: Explore Epidemiology and Co-infection Associated with HSV Infection 

• Investigate the prevalence and determinants of HSV susceptibility among populations 

experiencing health disparities: Although HSV has been shown to disproportionately affect 

historically marginalized populations, an understanding of the various determinants of health 

that influence HSV infection is limited. In the U.S., HSV disparities can exist based on factors 

related to social determinants of health including race or ethnicity, geography, environment, 

and socioeconomic status. HSV-1 prevalence is highest among Mexican American persons while 

Black persons have nearly a 3-fold higher HSV-2 prevalence compared to Mexican American and 

non-Hispanic White persons7

. In addition, individuals from intersectional, multiple marginalized 

identities, including living in rural settings or identifying as a sexual or gender minority, may be 

at an even higher risk for HSV acquisition. Further research is needed to evaluate the interplay 

of various determinants of health and contexts that lead to adverse outcomes related to HSV 

infection in populations experiencing health disparities. 

• Investigate impact of health disparities on HSV prevalence in different populations: Although 

HSV has been shown to disproportionately affect certain groups, including historically 

marginalized populations, the social determinants of these health disparities remain largely 

unknown and may differ based on HSV subtype. Mexican Americans have a higher prevalence of 

HSV-1 compared to other racial/ethnic groups, while non-Hispanic Black Americans have nearly 

a 4-fold higher prevalence of HSV-2 compared to non-Hispanic White Americans. In addition, the 

prevalence of HSV-2 infection among females is twice that of males.8 Further research is needed 

to characterize the disparities in HSV infection prevalence in historically marginalized 

populations, including sexual and gender minorities and people living in rural areas of the U.S. 

• Address complex epidemiologic synergy of HIV and HSV co-infection: Prior to the availability of 

highly active antiretroviral therapy (HAART) for individuals with HIV, genital HSV was widely 

7 https://pubmed.ncbi.nlm.nih.gov/29442994/ 

8 https://www.cdc.gov/nchs/data/databriefs/db304.pdf 

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recognized as a cofactor in enhancing sexual acquisition of HIV. However, people co-infected 

with HIV and HSV with undetectable HIV viral load due to HAART appear to be no more likely to 

transmit HIV than those without HSV. Therefore, the impact of HSV as a cofactor expanding the 

HIV epidemic has been reduced due to the successful implementation of public health strategies 

to test for and treat HIV. However, genital HSV may continue to amplify HIV transmission in 

persons not yet recognized to have HIV infection or not engaged in HIV care. New and improved 

strategies to prevent and treat HSV infection may help to reduce the risk of HIV transmission in 

HSV serodiscordant couples (one person is HSV positive and one is HSV negative) and may have 

the additional benefit of mitigating HIV spread globally. 

Objective 1.5: Improve and Develop New in vitro and in vivo Models that Reflect Human 

Disease 

• In vivo animal models: Although currently available animal models provide valuable insight into 

HSV infection, many HSV vaccine candidates showing promise in animal models are less 

successful when tested in humans. The most common animal models in HSV research are the 

mouse, guinea pig, and rabbit. Lesser used models include the cotton rat and rhesus macaques. 

Developing and improving animal models that recapitulate human disease is crucial for basic 

research and for evaluating therapeutics, vaccines, and microbicides. 

• Tissue culture, explant models, and organoids: Tissue culture and ex vivo explant models are 

valuable tools to characterize critical features of the HSV life cycle. Cell lines have long been 

used to evaluate the lytic stage of an HSV infection. However, recent advances in explant 

models, where a small section of tissue can be removed from an organism and multiple 

differentiated cell types can be studied ex vivo, have enabled researchers to explore reactivation 

of HSV from the latent to the lytic phase. The benefit of this system over a traditional tissue 

culture model is that multiple tissue types can be investigated under experimental conditions. 

Advances in the explant models have permitted some modeling of the latent phase of these 

viruses. Organoids are three dimensional masses of cells derived from stem cells that resemble 

an organ. These can be used to investigate multiple cell type responses to experimental 

conditions and are highly valuable in investigating the mechanisms underlying observed or 

phenotypic effects caused by infection. Continued efforts in developing animal models, ex vivo, 

and in vitro tissue culture models and organoid models have the potential to more accurately 

model HSV infection in humans. 

STRATEGIC PRIORITY 2: Accelerate Research to Improve HSV Diagnosis 

Strategic Priority 2: Accelerate Research to Improve Diagnosis 

Objective 2.1: Support Innovative Technologies that can be Utilized in Diverse Clinical Settings to 

Expand Testing Availability 

The lack of reliable and accurate diagnostics continues to be a challenge in the effort to prevent and 

treat HSV. To address these ongoing challenges, NIH will continue to prioritize the advancement of 

fundamental research to support the development of better diagnostics. Improvement of serologic tests 

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and point-of-care diagnostics will be important tools to facilitate the development of treatment and 

vaccination strategies to prevent HSV transmission. To be most effective, improvements in diagnostics 

may also need to be paired with strategies to improve communication on the importance of testing and 

diagnosis of HSV to both individuals and medical providers. 

Objective 2.1: Support Innovative Technologies that can be Utilized in Diverse Clinical 

Settings to Expand Testing Availability 

• Support development of accurate and sensitive serologic tests for screening and diagnosis:

Improving the accuracy of serologic tests is essential for improving diagnosis of infection in both 

asymptomatic and symptomatic individuals. Serologic tests, which detect antibodies to HSV 

circulating in the blood, are currently not included in standard sexually transmitted infection 

(STI) screening panels, due to their potential for indicating a false positive test result. A serologic 

test that uses the Western blot assay has less potential for false positives and is considered the 

“gold standard” for HSV infection diagnosis. This test, however, is only commercially available 

from one source. Historically, the Western blot has not been a technology that is easily 

amenable to point of care (POC) testing or for conversion to a commercial platform allowing for 

wide distribution and low cost. Thus, the Western blot assay is mostly used as a confirmatory 

test for those who can access and afford it. Serologic tests could likely be improved through 

better understanding of the immune response to HSV and introduction of state-of-the-art

technologies and diagnostic platforms. In addition, efforts could be made in the conversion of 

the Western blot assay into a more accessible and affordable test. Development of novel, 

accurate serologic tests will likely be the foundation for not only clinical screening to prevent 

transmission, but also the design of needed surveillance programs for adult HSV infection, 

neonatal herpes, and other diseases and syndromes associated with HSV infection. 

• Support development of diagnostic assays for CNS complications of HSV that do not rely on 

cerebrospinal fluid (CSF) sampling: Brain injury caused by HSE proceeds at a rapid pace, and the 

survival and neurological outcome of patients with HSE is dependent upon immediate treatment 

with antiviral medication. HSE diagnosis currently involves a polymerase chain reaction for viral 

DNA in CSF, which requires a painful spinal puncture to patients and sometimes repeated CSF 

sampling. Further complicating this issue is the fact that HSE symptoms are often nonspecific, 

which means that many physicians fail to perform CSF testing before permanent brain injury has 

been observed on magnetic resonance imaging. A sensitive screening test for HSE which utilizes 

a more accessible blood sample (as opposed to CSF) would substantially reduce morbidity and 

mortality caused by the CNS complications of HSV infection.
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• Improve performance of point-of-care diagnostic assays: Current strategies for HSV diagnosis

include direct detection of HSV genetic material (usually through a nucleic acid amplification test

(NAAT)) or culture of the virus from a clinical specimen. These tests can usually discriminate 

between HSV-1 and HSV-2. However, HSV can only be detected if the patient is shedding the 

virus. Therefore, these tests are generally only performed when lesions, such as genital ulcers, 

are evident and around suspicion for HSV infection. These tests usually require several days 

turnaround for results. An ideal diagnostic would be one that could be performed at the site 

where the patient seeks care. These tests are referred to as PoC tests, and can yield an answer in 

a timely manner, usually in an hour or less (Figure 4). The ideal test would not only be able to 

detect HSV but would also distinguish between HSV-1 and HSV-2. 

Figure 4. Goals of Point-of-care (POC) testing. POC 

testing allows increased access to diagnostic tools, 

decreased time between diagnosis and treatment, 

and improved treatment and prevention outcomes.

• Continuation of efforts to develop a PoC test that can accurately identify and differentiate

between the leading causes of genital ulcers (HSV, Treponema pallidum [the cause of syphilis],

and mpox virus) would assist in the diagnosis and clinical management of each infection. The

development of PoC tests is particularly important to diagnose HSV shedding in a pregnant

individual in the delivery room, facilitating earlier treatment of neonates or allowing the choice

of a cesarean delivery to minimize the potential for transmission.

STRATEGIC PRIORITY 3: Improve Strategies to Treat and Cure HSV 

Strategic Priority 3: Improve Strategies to Treat and Cure HSV

Objective 3.1: Advance the Development of Long-Acting Treatment Strategies

Objective 3.2: Evaluate the Safety and Efficacy of Treatment Strategies in Diverse Populations 

and Age Groups

Objective 3.3: Identify Strategies for Reducing the Effects of HSV or Functional Cure

Although existing regimens are relatively effective if started early, there continues to be an urgent need 

to identify safe and effective treatments across the spectrum of HSV disease. The most promising current 

therapeutic options require active virus replication, rendering them ineffective against latent infection. In 

addition, the best available treatments only partially reduce transmission of the virus to uninfected 

partners. NIH will continue to support efforts to treat and cure HSV, including the development of longacting treatment strategies and novel strategies to target latent HSV. In addition, NIH will support the 
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efforts to evaluate treatments through appropriate clinical trials in diverse groups to ensure that 

research findings can be generalizable to the entire population. 

Objective 3.1: Advance the Development of Long-Acting Treatment Strategies 

• Develop novel HSV treatments: Current strategies to treat HSV rely primarily on the use of

nucleoside analogs that function by inhibiting the HSV polymerase during viral replication.

Current first line antivirals are acyclovir, valacyclovir, and famciclovir. Second line therapies,

cidofovir and foscarnet, are used in cases of drug resistance to the first line therapies, and their

use is limited by significant toxicities. Although successful at mitigating some of the damaging

sequelae of HSV, current treatment strategies are not effective at elimination of infection and

only partially reduce virus shedding. As a result, many individuals still transmit the virus to close

contacts despite taking daily antivirals or suffer from relapse after stopping therapy. In addition,

long-term use of these treatments in those who are immunocompromised can lead to the

development of drug resistance. To combat this, further research is needed towards the

development of novel antivirals that can synergize with current regimens to enhance their

function and potentially treat resistant infections and reduce shedding. This may include

targeting certain viral enzymes important for virus binding, entry, or replication. In addition to

antivirals, studies have suggested that individual HSV monoclonal antibodies (mAbs) can confer

levels of protection and neutralization of HSV, indicating that mAbs may be a promising strategy 

to treat or prevent HSV infection. Further studies are needed to identify and evaluate mAbs that 

may function in synergy with current strategies to treat or prevent HSV infection.

• Advance treatment strategies for reduced sequelae of HSV encephalitis, including role of antiinflammatory medications: The neurological impact of HSV infection has been well documented

and can lead to severe organ disease, including brain injury due to herpes simplex encephalitis

(HSE). HSV can also cause inflammation of the optic nerve, or optic neuritis, and this can lead to

reduced vision or blindness. CNS pathology is attributable to a combination of viral replication

and immune mediated responses to the infection. Once HSV infection is established in the brain,

components of the adaptive immune response, including T and B cells, drive immune responses

that are integral in controlling infection. However, these responses, if not carefully modulated,

can lead to dangerous inflammatory responses in the brain. Therefore, in addition to standard

treatment strategies for HSV including acyclovir, additional immunomodulatory strategies may

be necessary to treat HSV in these circumstances. In animals, multiple broad-acting

immunosuppressive treatments have been tested including broad-acting corticosteroids or

inhibitors of key inflammatory pathways, such as Toll-like receptor (TLR) pathways. These

treatments may be able to modulate the pathophysiology associated with encephalitis and have

not been shown to interfere with standard HSV treatments, such as acyclovir.

Objective 3.2: Evaluate the Safety and Efficacy of Treatment Strategies in Diverse 

Populations and Age Groups 

• Immunocompromised individuals at high-risk for disease: In individuals who are

immunocompromised, such as HIV patients not on Highly Active Antiretroviral Therapy (HAART),
 

 

 

 

 

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transplant recipients, or people who have severe congenital immune disorders, HSV 

pathophysiology can be much more severe and potentially life-threatening. 

Immunocompromised individuals are also much more susceptible to HSV reactivation, with 

more severe symptoms that are slower to heal or respond to therapy. Although standard 

treatment regimens including acyclovir are considered viable treatment options for these 

populations, patients may develop infections that are resistant to acyclovir. Although antivirals 

can be used for prophylaxis or treatment in these populations, further research is needed to 

identify and develop additional treatment options for immunosuppressed or 

immunocompromised individuals. Treatments for this population that could keep the virus in its 

latent phase could save significant morbidity as lytic lesions in this population are often long 

lasting and severe. 

• Advance investigation of HSV treatment strategies in populations with health disparities:

Although HSV has been shown to disproportionately affect disadvantaged populations, such as

racial or ethnic minorities, the social determinants of these health disparities and their impact

on HSV treatment remain largely unknown. Improved understanding of determinants that

impact HSV infection will be critical to develop better treatment strategies that are culturally or

contextually adapted and to conduct more representative clinical trials as new treatments

become available. As part of this effort, developing strategies to improve healthcare access and

quality in low-resource clinical and community settings is a priority. Improving the HSV care

continuum in diverse populations and settings will enhance the ability to assess individuals at

high risk for HSV, evaluate HSV treatment efficacy, and improve dissemination of best practices

among populations experiencing health disparities.

• Treatment in those who are pregnant and in neonates: Pregnant individuals are at high risk for

passing on infection to their child. Delivery by cesarean reduces risk of transmission from the

pregnant individual to the infant, as does treatment to suppress the virus in pregnant people

with a history of HSV. In pregnant individuals who are shedding HSV near delivery, it is

important to determine whether the individual has a primary or recurrent HSV infection. This

distinction may impact the risk of neonatal infection and its management. Identification of

pregnant people who are shedding HSV at or near delivery may also allow earlier treatment of

neonates and prevent establishment of HSV infection.

Objective 3.3: Identify Strategies for Working Toward Elimination of HSV or 

Development of a Functional Cure 

• Establish strategies to target latent HSV: While antiviral therapy can reduce HSV reactivation,

currently available antiviral drugs have not been shown to completely prevent reactivation or

eliminate latent virus. Although full eradication of the virus from the body, or sterilizing cure,

may not be feasible in the short-term, efforts to achieve a “functional cure,” or sustained

suppression of viral shedding without the need for recurring treatment, may be achievable.

During latency, HSV actively suppresses gene expression that render traditional treatment

strategies, such as DNA polymerase inhibitors, ineffective. Therefore, strategies need to be

advanced to specifically target HSV in the latent state. This may include either directly targeting

and inactivating HSV or achieving a similar goal by completely suppressing reactivation of latent

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virus through gene editing technologies (e.g., CRISPR/Cas, meganucleases). Advancing these 

strategies and exploring new mechanisms to decrease HSV reactivation will be key steps

towards the goal of functionally reducing the effects of HSV infection.

STRATEGIC PRIORITY 4: Advance Research to Prevent HSV Infection

Strategic Priority 4: Advance Research to Prevent HSV Infection

Objective 4.1: Advance the Development of Promising Vaccines and Multipurpose Prevention 

Technologies (MPT)

Objective 4.2: Support Clinical Trials to Test Therapeutics and Vaccines

Effective prevention of HSV requires a multi-pronged effort building upon advances in HSV research. 

Promising HSV prevention strategies must be comprehensively tested in diverse populations and age 

groups and must be paired with enhanced strategies for diagnosis to target and treat high-risk groups.

This is particularly important for infected pregnant individuals, who are at high risk for vertical 

transmission to the child. NIH will continue to support the development and testing of safe and effective 

HSV prevention candidates and strategies, including the advancement and testing of prophylactic 

vaccines to prevent HSV infection. 

Objective 4.1: Advance the Development of Promising Vaccines and Multipurpose 

Prevention Technologies (MPTs)

Currently there are no FDA-approved HSV vaccines, though multiple candidates are in development for 

either prophylactic or therapeutic use. The goal of a prophylactic vaccine is to prevent HSV acquisition. 

Alternatively, a therapeutic vaccine would be intended for patient with an existing HSV infection to elicit 

an immune response to reduce the frequency of viral reactivation and lesion outbreaks and to reduce 

viral shedding. This approach aligns with the WHO Preferred Product Characteristics for Herpes Simplex 

Virus Vaccines9

, a document which NIAID helped develop. In addition to vaccines, efforts are also 

ongoing to advance multipurpose prevention technologies, products developed with multiple active 

drugs to simultaneously to prevent HIV, other STIs or unintended pregnancy. To advance these 

priorities, research efforts are ongoing to:

• Identify correlates of protection for HSV-1 and HSV-2: Characterizing immune responses and

correlates of protection can help speed discovery and testing of promising HSV vaccine

candidates. While correlates of immune protection have not been conclusively elucidated for

either HSV-1 or HSV-2, current studies suggest that neutralizing antibodies specific to proteins

on the viral surface correlate with protection against HSV in mice and guinea pigs. Similarly, a

recent NIAID-funded Phase 3 vaccine trial identified IgG antibodies specific to HSV-1

glycoprotein D as the first human correlate of protection against genital herpes caused by this

virus. Research identifying the correlates of protection observed against both HSV-1 and HSV-2

9 https://www.who.int/publications/i/item/9789241515580
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in humans will facilitate understanding the effectiveness of protection offered in vaccines 

targeted against both virus types. 

• Advance the development of vaccines:

o Attenuated and replication-deficient virus: Attenuated and replication-deficient 

vaccines contain a version of HSV that is weakened in the laboratory to trigger a strong 

HSV-specific immune response, yet not cause disease. There are currently several

different approaches for live attenuated vaccines under development for both HSV-1 

and HSV-2, and multiple candidates are being explored as both preventative and 

therapeutic vaccines. 

o DNA/RNA: This strategy employs a multivalent approach wherein the immune system is 

exposed to multiple HSV antigens. Researchers have previously advanced the use of 

plasmid DNA (pDNA) vaccines for HSV therapeutic vaccine development, and while 

preclinical studies were promising, clinical trials were unsuccessful at reducing recurrent 

outbreaks. Other groups have had initial success with messenger RNA (mRNA) lipid 

nanoparticle vaccines, a platform similar to those used by some SARS-CoV-2 vaccines to 

prevent COVID-19. 

o Protein subunit: Protein subunit approaches for HSV involve a trivalent subunit vaccine 

targeting three glycoproteins on the HSV surface and have demonstrated promise in 

non-human primates and guinea pigs. An intranasal two-component vaccine against two

HSV-2 glycoproteins in an oil-in-water nanoemulsion adjuvant has shown both 

therapeutic and prophylactic potential in animal models. 

• Advance the development of Multipurpose Prevention Technologies (MPTs): MPTs are

interventions that are being developed for vaginal or rectal use to prevent HIV infections, other 

STIs including HSV, and unintended pregnancies, if contraception is a desired component. There 

are a variety of MPT formulations such as gels, films, or intravaginal rings. The active drug 

products have included antivirals, antimicrobials, and monoclonal antibodies. 

Objective 4.2 Support Clinical Trials to Test Therapeutics and Vaccines

• Leverage infrastructure to evaluate efficacy of HSV prevention and treatment strategies: The 

development of safe and effective vaccines and treatments for HSV requires comprehensive and 

rigorous clinical testing. NIH will continue to leverage its robust clinical trial infrastructure to

advance clinical research for promising therapeutic and vaccine candidates for HSV (Box 1). 

• Advance and test treatment strategies for pregnant individuals: Studies suggest that some 

pregnant individuals with primary HSV infections develop protective responses against HSV 

transmission. Researchers are investigating whether giving HSV-specific antibodies to pregnant 

people provides additional benefit to prevent neonatal HSV when combined with other current 

strategies. The development of new antivirals or vaccines for HSV prevention, treatment, or 

both that can be safely administered to pregnant individuals are additional avenues of research 

to protect the neonate.
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NIH Strategic Plan for HSV Research

• Develop strategies to vaccinate and treat diverse populations: A successful vaccination 

campaign will depend not only on the development of safe and effective vaccines, but also 

reliable strategies to facilitate equitable vaccination uptake among all populations. This is 

particularly important in areas with high risk of HSV disease acquisition and transmission.

Lessons learned from previous vaccination efforts, including COVID-19, can inform strategies for 

deploying and encouraging uptake of HSV vaccines when new vaccine candidates become 

available. These lessons include collaborative community partnership, appropriate 

representation, information communication and dissemination strategies for vaccine safety and 

efficacy to facilitate access to vaccines among populations experiencing health disparities. NIH 

will continue to support efforts to improve the future availability and uptake of HSV vaccines to 

diverse populations.
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Box 1. A portfolio analysis describing NIH support for HSV prevention and treatment strategies from fiscal year (FY) 2016 – 2022. 

NIH funding (in millions) shows a steady increase from $6.11m in FY 2016 to $14.39m in FY 2022 with a slight decrease in FY 21. 

Number of preclinical and early clinical research projects for HSV prevention and treatment strategies for FY 2016 – 2022 

followed the same trend. Types of interventions supported are prophylactic and therapeutic vaccines, antivirals, monoclonal 

antibodies, behavioral, and multipurpose prevention technologies (MPTs). Clinical research topics focused on prevention 

treatment, women’s health, neurological health, eye health, neonatal health, and co-infection. The method and analysis used 

for this search criteria are described below*.

*Data for this analysis were collected from NIH REPORTER on 7/31/2023. Search criteria were: Fiscal Year: 2022, 2021, 2020, 2019, 2018, 2017, 

2016; Text Search: (“genital herpes" OR "herpes simplex virus" OR "herpes simplex viruses" OR "herpes simplex" OR "HSV" OR "HSV-1" OR "HSV2" OR "HSV-1" OR "HSV-2") AND (treat OR treats OR treatment OR treatments OR prevent OR prevents OR prevention OR preventions OR 

preventing OR therapy OR therapies OR therapeutic OR therapeutics OR vaccine OR vaccines OR vaccinate OR vaccinates OR vaccination OR 

vaccinations OR antiviral OR antivirals OR antimicrobial OR antimicrobials OR antibody OR antibodies OR drug OR drugs OR medicine OR 

medicines OR medication OR medications OR cure OR cures OR remedy OR remedies) NOT ("herpes zoster" OR cancer OR glioblastoma OR 

glioma OR gliomas OR oncolytic OR "oHSV" OR zoster OR "high-speed videoendoscopy" OR "dysphonia" OR "human greater saphenous vein" OR 

"voice tremor"); Limit To: Project Title, Project Abstracts; NIH Spending Category: Bioengineering. Biotechnology, Clinical Research, Clinical Trials 

and Supportive Activities, Immunization, Infectious Diseases, Sexually Transmitted Infections, Nanotechnology, Vaccine Related, Eye Disease and 

Disorders of Vision, Pediatric, Mental Health, Behavioral and Social Science, Social Determinants of Health, Neurosciences, Prevention, Women's 

Health. 
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CONCLUSION

The NIH Herpes Simplex Virus Strategic Plan establishes research priorities for NIH in its efforts to 

respond to the ongoing threat of HSV. This plan serves as a framework for research efforts to address

this critical public health threat and aligns with goals and priorities in the Sexually Transmitted Infections 

National Strategic Plan. NIH will continue to support basic research and advance translational studies 

toward the development and testing of improved diagnostics, therapeutics, and vaccines to detect, 

treat, and prevent HSV. NIH also will continue to work with partners to advance these efforts and to 

enhance health communication and outreach strategies to support availability and uptake, particularly 

in high-risk populations. Through this combined effort of improving the reliability and availability of 

diagnostics and the development and testing of safe and effective vaccines and therapeutics, NIH is 

leading the biomedical research response to reduce the persistent personal and public health impacts of 

HSV. 
 

 

 

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APPENDICES 

APPENDIX 1: NIH HSV Working Group Members 

IC Last Name First Name Position 

NIAID Azeez Olumayowa Health Science Policy Analyst, Policy, Planning and 

Evaluation Branch, OD 

NIAID Bushar Nicholas Chief, Policy, Planning and Evaluation Branch, OD 

NIAID Challberg Mark Health Scientist Administrator 

NIAID Chen Ray Physician 

NIAID Cohen Jeffrey Physician 

NIAID Connolly Kristie Health Scientist Administrator 

NIAID Davis Mindy Health Science Administrator 

NIAID Deal Carolyn Chief, Enteric and Sexually Transmitted Infections Branch 

NIAID Deckhut Alison Chief, Basic Immunology Branch 

NIAID Dempsey Walla Program Officer 

NIAID Drew Jessi Contractor, Policy, Planning and Evaluation Branch, OD 

NIAID Gautam Rajeev Health Scientist, Program Officer 

NIAID Glock Jonathan Program Officer 

NIAID Grace Beth Senior Financial Analyst 

NIAID Greenstone Heather Health Scientist Administrator 

NIAID Hiltke Thomas Program Officer 

NIAID Miers Sarah Program Analyst 

NIAID Mulach Barbara Director, Office of Scientific Coordination and Program 

Operations 

NIAID Newman Lori Medical Officer 

NIAID Schmit Ginny Health Science Policy Analyst, Policy, Planning and 

Evaluation Branch, OD 

NIAID Shaffer Meredith Scientific Program Specialist 

NIAID Zwerski Sheryl Scientific Program Director 

NIA Maric Maja Program Director 

NICHD Yates Franklin Medical Officer 

NIMH Chai Mindy Chief, Science Policy and Evaluation Branch 

NIMH Fox Meredith Director, Office of Science Policy, Planning, and 

Communications 

NIMH Rao Vasudev Program Officer 

NIMHD Herren Olga Program Officer 

NINDS Daley Will Program Director, Neuronal Environment Cluster 

NINDS Torborg Christine Health Science Policy Analyst 

NEI McKie George Program Officer 

20 
Resource Name Description 

BEI Resources Repository 

Central repository that supplies organisms and reagents to the 

broad community of microbiology and infectious diseases 

researchers 

Bioinformatics Resource Centers Collects, archives, updates, and integrates research data with 

user-friendly interfaces and computational analysis tools 

NIAID Clinical Genomics Program Provides centralized resources to be used for genomics and 

related research 

Genomic Centers forInfectious 

Disease Resources 

Provides innovative application of genomic technologies and 

rapid, cost-efficient production of high-quality genome 

sequences for pathogens and hosts 

Infectious Disease Clinical Research 

Consortium 

A clinical trials research consortium that prioritizes vaccines, 

diagnostics, and other interventions to test in clinical trials 

ImmPort Platform toshare and analyze immunology datagenerated from 

human and animal models 

Immune Epitope Database and 

Analysis Resource Immune Epitope 

Database and Analysis Resource 

Database with detailed information for more than 1,000,000 

unique immune epitopes (antibody/B cell and T cell) related to 

infectious and immune mediated diseases 

ImmuneSpace 

Powerful data management and analysis engine for the HIPC 

program that enables integrative analyses and visualization of

human immunological data 

Interventional AgentDevelopment 

Services tofacilitate preclinical development oftherapeutics and 

new in vivodiagnostics forinfectious disease–causing pathogens 

and/or toxins 

NIAID Adjuvant Development 

Program 

The goal of the adjuvant development program is to establish 

and expand the availability of novel vaccine adjuvants that 

researchers can use for preclinical vaccine development inboth 

infectious and immune mediated diseases 

NIAID Adjuvant Discovery Program 

NIAID plays a leading role in the discovery, development, and 

characterization of new vaccine adjuvants that may be used to: 

improve the efficacy of current vaccines; design new or 

improved vaccines for existing and emerging infectious diseases; 

and develop vaccines to treat allergies, autoimmune diseases, 

and cancer 

NIH Tetramer Core Facility Produces and distributes major histocompatibility complex 

tetramers and related reagents to the research community 

Phase IClinical Trial Units for 

Therapeutics 

Supports design, development, implementation, andconduct of 

Phase I clinical trials against viral (other than HIV), bacterial, 

parasitic, and fungal pathogens 

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NIH Strategic Plan for HSV Research 

APPENDIX 2: NIH-Supported HSV Research Resources 

21 
 

 

 

 

 

 

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Resource Name Description 

Preclinical Models of Infectious 

Disease Program 

Provides development, screening, and efficacy testing in 

preclinical infectious diseases models, including traditional lab 

species, nonhuman primates, and non-traditional models 

Structural Genomics Centers for 

Infectious Diseases 

Applies state-of-the-art technologies/methodologies to 

characterize 3-D atomic structures of molecules to support 

infectious disease research 

Therapeutic Development Services: 

Biopharmaceutical Product 

Development Services 

Offers services for biotechnology products, such as planning, 

product characterization, process development, formulation, 

Good Manufacturing Practice, and Chemistry, Manufacturing 

and Control documentation 

Therapeutic Development Services: 

Interventional Agent Development 

Services 

Facilitates development of therapeutics, including lead 

identification and development, chemistry and manufacturing, 

toxicology, and pharmacokinetics 

Vaccine Adjuvant Compendium 

Displays adjuvant characteristics or metadata defined through 

NIAID-supported adjuvant studies, helps vaccine developers 

identify suitable adjuvants for vaccine indications 

Offers services for vaccine and adjuvant development such as 

assay development, non-clinical immunogenicity and efficacy 

studies, clinical and non-clinical sample testing and safety and 

toxicity testing 

Vaccine Development Services: 

Vaccine Testing Services 

Vaccine Development Services: 

Vaccine Manufacturing Services 

Feasibility, Gap Analysis, and Product, Development Plan 

Support, Product Optimization, Process Development and 

Formulation Studies, Product Release Assay Development 

including Potency Assays, Pilot and cGMP Manufacture, Audits 

and Regulatory Activities and Documentation 

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APPENDIX 3: Analysis of Public Comments to Request for Information (RFI)

The National Institutes of Health (NIH) developed the Strategic Plan for Herpes Simplex Virus Research 

to serve as a foundation for the research and medical communities to continue to work together to 

develop interventions that will enable us to reduce the health consequences of HSV infection. 

To solicit input from the public, NIH released the Request for Information (RFI): Inviting Comments and 

Suggestions on a Framework for the NIH HSV Strategic Plan (NOT-AI-23-042), which was open for 

comments from April 21, 2023, to June 21, 2023. The RFI gathered input from the research community, 

advocacy groups, the public, and other interested stakeholders on significant knowledge gaps and 

barriers, resource deficiencies, and areas of emerging technologies relevant to HSV research. The 

responses to the RFI were reviewed and incorporated in the plan as appropriate.

Comments were requested on, but not limited to, the following topics in HSV research: 

• Significant research gaps and/or barriers not identified in the outlined strategic priorities 

• Necessary resources critical to advancing research in the outlined strategic areas

• Emerging scientific advances or techniques that may accelerate research related to the outlined 

priorities 

• Approaches to advance treatment and prevention, and identify future priority areas for new 

clinical research

In response to the RFI, NIH received 105 submissions, underscoring the significant interest in advancing 

HSV research. Overall, the respondents indicated support of the plan’s outlined priorities, suggested 

new or adapted scientific priorities, and offered personal experiences providing insight into living with 

HSV infection. To respect the personal nature of many of these submissions, a summary of themes that 

emerged from an analysis of the RFI responses is provided. Figure 5 shows the top ten most frequently

cited topics from the RFI responses. 

Figure 5: Ten most frequently mentioned topics of interest from RFI responses. To the right are the number of responses across 

all topics, indicating areas of interest. Note, each of the 105 respondents were able to provide comments on multiple topics.

20

21

25

26

33

33

34

34

36

38

Include HSV on Universal STI Panel

Increased Funding

Address and Reduce Social Stigma

Neurological Impacts

Pregnancy Health / Transmission to Neonate

Transmission Concerns

Vaccine Development

Mental Health Impacts, Depression, Suicidality

Public Health Education

Need for Better Diagnostics
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NIH Strategic Plan for HSV Research

Specific Themes from RFI Responses

Basic HSV Biology, Pathogenesis and Epidemiology

Respondents supported continued investigations into HSV epidemiology and basic HSV biology, 

including viral mechanisms of entry, viral replication, viral assembly and egress, immune response to 

infection, as well as investigation into whether HSV pathogenesis differs by gender. Respondents also 

suggested the need for research to further identify and explain differences in HSV infectivity, shedding 

and transmission. 

Neurological Impacts of HSV

Support for further investigations of the neurological impacts of HSV was a common theme across

responses. This included investigations into the link between HSV and Alzheimer's disease/dementia and 

other conditions. Comments mentioned the importance of treating acute and chronic HSV infection to 

reduce the risk of progression to other conditions including neurodegenerative diseases. Neuropathic 

pain and neuropathic itch were frequently suggested as areas that may benefit from more investigation.

Mental Health Impacts of HSV

For people living with HSV, there can be significant impacts on mental health such as depression and the 

societal stigma surrounding infection. Numerous comments noted a lack of recognition by the medical 

community of these impacts. Respondents offered suggestions to assess the mental and social impact of 

the viruses on those living with HSV such as measuring the mental health cost (e.g., quality-adjusted life 

year QALY). Many expressed interest in the research community investigating how reducing the 

prevalence of HSV could impact the prevalence and cost of HIV burden of disease. Another suggestion 

was to model the impact of HSV infection on social well-being (e.g., how many working 

days/months/years lost to stress, anxiety, and pain). 

HSV Models of Infection 

Another area that was highlighted in the comments was the need for continued development of robust 

models of human peripheral ganglia or other human neuronal models. Respondents felt that 

investigators’ work in this area has not been sufficiently coordinated, and that researchers have not 

received sufficient support. As such, there are few efforts to directly compare infection models or to 

invest in the development of models to better recreate the complex cellular environment where HSV 

establishes latency. Others suggested that the development of improved, reliable animal models for 

predicting immunological outcomes should be developed and emphasized the importance of rigorous 

comparisons between models. 

HSV Diagnostics 

Several respondents commented on the need for improved sensitivity and specificity of diagnostic tests, 

including decreasing the high number of false positives/negatives. In addition, respondents supported 

efforts to improve access to the current Western Blot test and increased emphasis on developing 

specific and sensitive at-home tests. Respondents were also interested in the development of point of 

care (PoC) diagnostics that can detect HSV from sampling of skin and mucosal sites without evidence of 

herpetic lesions (i.e., asymptomatic individuals). One commenter noted that universal screening of 

people of childbearing age would help determine the risk for neonatal infection. Additionally screening 

of neonates for both symptomatic or asymptomatic infection would be important since subclinical 

infection could result in short- or long-term neurological sequelae in a newborn. 

As part of an overall emphasis on improving HSV diagnosis, several respondents indicated that HSV 

testing should be included in routine STI screening panels. There was sentiment that the current United 

States Preventive Services Task Force (USPSTF) recommendations to not test asymptomatic people for 
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NIH Strategic Plan for HSV Research

HSV, and the subsequent adverse impact on routine screening for HSV has led to poor clinical care and 

the deprioritization of HSV as a health issue. 

HSV Preventative and Therapeutic Treatments

Respondents indicated that development of an HSV cure should be the highest priority for the field. As 

part of this effort, commenters noted that there is a need to increase resources for clinical trials

investigating interventions. Specifically, more funding should be allocated for investigations into 

prophylactic vaccine candidates. 

Preventing HSV shedding was also an area of significant focus. Many indicated that the treatment, 

pritelivir, should be available for all, not just those who are immunocompromised. In addition, 

respondents suggested that therapeutic approaches for those for whom current therapies have little to 

no effect be expanded and barriers of access to all therapies be decreased. Commentors also suggested 

that multipurpose prevention therapies (MPTs) containing acyclovir or a monoclonal antibody that 

prohibits HSV transmission, should be further developed and brought to market.

Many respondents suggested that there is also a need for research on HSV suppression during 

pregnancy, including epidemiological studies that demonstrate the effectiveness of treating HSV 

infection during pregnancy to improve maternal and fetal outcomes. It also was suggested that 

researchers investigate outbreaks triggered by hormonal changes in women. Resources for coupling 

evaluation of PoC diagnostics for pregnant individuals during delivery with post-exposure prophylaxis 

(PEP) in exposed newborns should be prioritized. 

HSV Clinical Research

Several respondents noted that clinical trials should be broadly advertised, engaging community 

members to promote inclusive participation. Incorporating social sciences into HSV research was also 

suggested to help identify issues related to vaccine hesitancy, burden of disease, appropriate education 

for physicians providing counseling to HSV positive individuals, etc. Some respondents suggested 

implementation of community advisory boards consisting of people living with herpes and other 

stakeholders for all HSV clinical trials.

Cross-cutting Themes

HSV Research Funding and Support

Many comments stated that funding for HSV research across all areas should be increased. Respondents 

noted the need for additional government funding for the development of prophylactic vaccines, 

pointing out that pharmaceutical companies are working extensively on therapeutic HSV vaccines. Other 

commenters noted that funding should be provided to small organizations in areas that recruit for 

diverse clinical trial participants. Another response indicated that funding opportunities should be 

provided to researchers and trainees from underrepresented groups across all disciplines to better 

understand HSV. 

HSV Research Collaborations 

Enhanced research collaboration was another theme that emerged from the responses. There was

interest in improving and emphasizing scientific collaboration in the HSV field, including the sharing and 

depositing of reagents in existing NIAID or other reagent repositories and coordinating

workshops/meetings that bring HSV researchers together. Respondents also expressed the importance 

of collaborative efforts in improving strategies to manage HSV diagnoses (e.g., holistic practitioners, 

mental health providers, etc.). Further, results from clinical studies investigating other infections, such 

as HIV, should be shared to provide data on virologic outcomes for those coinfected with HSV.
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NIH Strategic Plan for HSV Research

Additionally, responders indicated that more NIH programs and staff should be dedicated to HSV 

research and treatment, and that a program dedicated to a single virus and its diseases be modeled 

after the Division of AIDS. Respondents also requested more collaboration across NIH Institutes, 

Centers, and Offices (ICOs) and noted the need for multidisciplinary expertise in virology, immunology, 

epidemiology, statistics, mathematical modeling, and clinical trial design to stimulate advances in the 

HSV field. Because there are few clinical researchers dedicated to the study of HSV, some suggested it 

would be beneficial to implement novel and other funding strategies (e.g., Request for Applications 

(RFAs) and Request for Proposals (RFPs) across NIH ICOs to encourage participation. Junior and new 

researchers should also be incentivized to join the field.

HSV Public Health Education 

Respondents suggested clinical advances in diagnosis need to be accompanied by the development of 

new and widely disseminated educational materials for providers. These materials would enable them 

to provide more effective and compassionate counseling for those who test positive for HSV and 

support referral of patients to mental health providers. Several individuals stated that physicians regard 

HSV as a mere skin condition rather than a complex disease with nervous system involvement. 

Neuropathic pain and neuropathic itch are frequently unrecognized as HSV symptoms by physicians, and 

many respondents suggested education among physicians in these areas. Others expressed the need for 

education for providers and the public on asymptomatic transmission of HSV. 

Many respondents indicated that HSV-related stigma amongst the patient, professional, and scientific 

communities and has stymied scientific progress. The burden of HSV impact disproportionately affects 

women and minorities, and because of the stigma around this disease, there are screening guidelines 

that are paternalistic and not patient-centered. Respondents suggested that herpes should be 

rebranded as a public health epidemic. Increasing awareness is critical for public health education and 

reducing stigma. 

HSV surveillance

Finally, respondents indicated the need for improved HSV surveillance. Surveillance tools that could 

provide the scientific and medical communities with a clearer, more nuanced picture of the burden of 

HSV include population-based surveys, opportunistic and sentinel surveillance, and case-based 

reporting.
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