The development of protective herpes simplex virus (HSV) vaccines has been an ongoing challenge for decades. Many vaccine candidates are under development, including DNA, modified mRNA, protein subunit, killed virus, and attenuated live virus vaccines.
The herpes simplex virus exists as 2 biologically distinct serotypes, HSV-1 and HSV-2, which differ mainly by their transmission mode, says the U.S. CDC.
"A vaccine against HSV infection would not only help to promote and protect the health and wellbeing of millions of people, particularly women, worldwide, it could also potentially have an impact on slowing the spread of HIV," Dr. Meg Doherty, director of the WHO's global HIV, hepatitis and sexually transmitted infections programs, commented in a WHO statement published on May 1, 2020.
Herpes Vaccine Candidates
Clinical researchers have been developing herpes vaccines in clinical trials to test therapeutic (intended to reduce viral shedding in people who are already infected with HSV) and preventive (designed to prevent infection) vaccine candidates.
HSV529 (HSV15) is a vaccine candidate classified as a replication-defective virus, meaning the virus possesses all the wild-type HSV virus components except two proteins UL5 and UL29, involved in viral DNA replication. This phase 1/2 study was last updated on September 18, 2020, by Sanofi Pasteur.
EXD-12 is a vaccine candidate currently in preclinical testing for safety and efficacy as both a prophylactic and therapeutic vaccine for both Herpes Simplex Virus-1, HSV-1, and Herpes Simplex Virus-2, HSV-2.
Delta gD-2 (∆gD-2) is a vaccine candidate based on an HSV-2 virus genetically deleted for glycoprotein D (gD-2).
NanoVax is an adjuvant platform used to develop a vaccine candidate to protect against the two viruses that can cause genital herpes.
GSK’s Simplirix HerpeVac was in a double-blind, randomized, controlled phase 3 clinical study to assess the prophylactic efficacy and safety of gD-Alum/MPL vaccine in the prevention of genital herpes disease in young women who are herpes simplex virus (HSV)-1 and -2 seronegative. Last updated during August 2018.
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Herpes Vaccines - Pre-Clinical Development
RVx-201 HSV-2 vaccine candidate is designed to have a specific degree of attenuation through specifically designed mutations in the ICP0 protein.
Herpes Vaccine Development News
January 11, 2021 - A press release by Rational Vaccines herpes focused on the study published in the Journal of Virology on November 23, 2020, demonstrates that the vaccine candidate, RVX10, offered robust protection against ocular herpes simplex virus 1 (HSV-1) infection in vaccinated mice found that the company's RVX101 vaccine candidate used to immunize a unique mouse line (does not generate much of a neutralizing antibody response to the virus) was shown to provide highly protective immunity and prevent herpes-associated neovascularization. This robust efficacy was correlated with CD8+ T cells since depleting these cells after vaccination but before challenge with HSV-1 eliminated any efficacy realized by the vaccine.
November 30, 2020 - In this systematic review of Medline, EMBASE, and PubMed studies, there were 16 articles deemed relevant comprising both animal and human studies (301 patients) regarding the use of the Bacillus Calmette‐Guérin (BCG) vaccine’s off‐target effects that might impact the recurrence of HSV infections. In non-randomized human studies (that failed to control for a placebo effect), BCG vaccination appeared beneficial in 78 percent of adults with recurrent herpes genitalis or labialis, with 37 percent being recurrence‐free for an extended period, 41 percent experiencing less frequent or severe episodes, and only 22 percent reported no change. This clinical benefit is consistent with the findings of immunological sub‐studies. In the two studies restricted to recurrent herpes labialis, 94 percent appeared to benefit from BCG.
November 23, 2020 - Study published by American Society for Microbiology: Collectively, the study suggests CD8+ T cells significantly contribute to the host adaptive immune response to HSV-1 challenge following vaccination with an attenuated virus, but multiple factors are involved in cornea pathology in response to ocular virus challenge. The current study shows that in the near absence of anti-HSV-1 antibody, vaccinated mice are protected from subsequent challenge with wild-type HSV-1 as measured by survival. The efficacy is lost following depletion of CD8+ T cells. Whereas increased survival and reduction in virus replication were observed in vaccinated mice challenged with HSV-1, cornea pathology was mixed with a reduction in neovascularization but no opacity change.
November 23, 2020 - Study published by The Lancet: The Visby Medical Sexual Health Test is a rapid, easy-to-use, single-use, point-of-care device to detect C trachomatis, N gonorrhoeae, and T vaginalis infections showed excellent sensitivity and specificity and could represent an important advance in the development of rapid diagnostics for sexually transmitted infections and other infectious diseases.
November 9, 2020 - MedicalResearch.com Interview with Gary E. Pickard, Ph.D., Professor of Neuroscience, School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln.
November 6, 2020 - Study published by Nature: The R2 non-neuroinvasive HSV-1 vaccine affords protection from genital HSV-2 infections in a guinea pig model. The use of live-attenuated HSV vaccines that robustly replicate in mucosal tissues but are ablated for neuroinvasion offers a promising approach for HSV vaccines. The study found that vaccinating guinea pigs with the modified live virus significantly increased virus-combating antibodies. When challenged with a virulent strain of herpes simplex virus, the vaccinated animals displayed fewer genital lesions, less viral replication, and less of the viral shedding that most readily spreads the infection to others.
November 3, 2020 - Protection against herpes simplex virus type 2 infection in a neonatal murine model using a trivalent nucleoside-modified mRNA in lipid nanoparticle vaccine. Neonatal herpes is a dreaded complication of genital herpes infection in pregnancy. We recently compared two vaccine platforms for preventing genital herpes in female mice and guinea pigs. We determined that HSV-2 glycoproteins C, D, and E expressed using nucleoside-modified mRNA in lipid nanoparticles provided better protection than the same antigens produced as baculovirus proteins and administered with CpG and alum.
September 25, 2020 - Study: Cell entry of enveloped viruses requires specialized viral proteins that mediate fusion with the host membrane by substantial structural rearrangements from a metastable pre- to a stable postfusion conformation. This metastability renders the herpes simplex virus 1 (HSV-1) fusion glycoprotein B (gB) highly unstable such that it readily converts into the postfusion form, thereby precluding structural elucidation of the pharmacologically relevant prefusion conformation.
September 24, 2020 - Study review: When studying animals, the BCG vaccine is a potential, safe, affordable, and readily available candidate intervention to decrease the high burden of disease associated with HSV infection and recurrences, but properly controlled randomized trials are required.
September 15, 2020 - Dr. Roach: HSV diagnosis doesn’t need to doom love life.
August 18, 2020 - A new study evaluated HSV gene editing in a well-established mouse model, using adeno-associated virus (AAV)-delivered meganucleases as a potentially curative approach to treat latent HSV infection. Here we show that AAV-delivered meganucleases, but not CRISPR/Cas9, mediate highly efficient HSV gene editing, eliminating over 90% of latent virus from superior cervical ganglia. The levels of HSV elimination observed in these studies, if translated to humans, would likely significantly reduce HSV reactivation, shedding, and lesions.
August 14, 2020 - Research study: HVEM signaling promotes protective antibody-dependent cellular cytotoxicity vaccine responses to herpes simplex viruses.
July 27, 2020 - Vaccines against Genital Herpes: Where Are We? Because of the high burden of genital herpes, HSV vaccines have been developed, but none have been very successful. This review discusses the current status of genital herpes vaccine development.
July 27, 2020 - In a mice study, these researchers compared protection by the HSV-2 mRNA vaccine against genital HSV-1 and HSV-2 infection. Mice infected with either virus were totally protected from genital disease. Importantly, in two experiments, the mRNA vaccine prevented HSV invasion of the dorsal root ganglia, the site of virus latency, in 39/40 (97.5%) mice infected with either HSV-1 or HSV-2. They conclude that the HSV-2 trivalent mRNA vaccine provides potent protection against HSV-1 and HSV-2 genital infection and is a promising vaccine candidate for human trials.
July 24, 2020 - Over 65% of young people have their first sexual activity unexposed to herpes but risk catching it in adulthood, stated a new study. This research found fewer people are being exposed to HSV-1, also known as oral herpes, in their youth.
July 23, 2020 - Study: Tetrameric glycoprotein complex gH/gL/gQ1/gQ2 is a promising vaccine candidate for human herpesvirus 6B. HHV 6 is a group of various viruses belonging to the herpes virus family. HHV-6B causes a disease called exanthema subitum or roseola infantum in children and infants. It is one of the most common causes of emergency hospitalization in children up to 3 years of age. HHV6B tetramer or gH/GL/gQ1/gQ2 is a protein on the surface of the HHV6 virus that interacts with the human CD134 (a protein present on T cells) to gain entry into host cells. As viruses are intracellular parasites, they need a living cell to survive.
July 21, 2020 - The story of Rational Vaccines' pursuit of a therapeutic vaccine for genital herpes may go down as one of the strangest and most controversial chapters in the history of drug or vaccine development.
July 17, 2020 - This article sheds light on the molecular and structural interactions between HHV-6B tetramer and its host receptor along with their neutralizing antibodies, and their affinities, competition, and binding modes based on the HHV-6B tetramer structure are described. Our findings provide molecular and structural bases for a comprehensive understanding of these interactions and relationships.
July 16, 2020 - Herpes simplex virus type 1 in Europe: a systematic review, meta-analyses, and meta-regressions. The results showed that more than two-thirds (67.4%) of tEurope'spopulation tested positive for HSV-1, which is far lower than the historical level of universal infection in childhood in other parts of the world, such as Africa. Around 32.5% of children and 74.4% of adults were infected in Europe. The results also showed that half of the first-episode genital herpes cases in Europe were already due to HSV-1 instead of HSV-2 infection.
July 9, 2020 - Meta-analytic approach for transcriptome profiling of herpes simplex virus type 1.
June 13, 2020 - Study: 'In this review, I have briefly described some of the models available and then more thoroughly describe the guinea pig model of acute and recurrent genital herpes infections. As discussed, the guinea pig model most closely mimics human disease and provides several important endpoints for evaluating vaccines and antivirals.'
March 3, 2020 - Tissue-resident T cell-derived cytokines eliminate herpes simplex virus-2–infected cells.
May 22, 2020 - Study: Assess the properties and efficacy of an R2 vaccine derived from the alpha-herpesvirus, pseudorabies virus (PRV), in pigs. We demonstrate that the PRV R2 vaccine does not invade the porcine peripheral nervous system within detection limits. Furthermore, after a single intranasal vaccination, R2 conferred protection to pigs subsequently challenged with a virulent PRV field strain (NIA-3). These findings support that the R2 vaccine design is non-neuroinvasive and is an effective vaccine in the context of a natural host.
May 19, 2020 - Genocea Biosciences, Inc. announced it has entered into a material transfer agreement and exclusive license option with Shionogi & Co., Ltd. to develop a novel HSV-2 vaccine using Genocea’s proprietary HSV-2 antigens from the GEN-003 program.
May 7, 2020 - This model recapitulates clinical responses to natural infection and the rgD-2 vaccine trial outcomes and suggests that ΔgD-2 may prove protective in HSV-1-seropositive hosts.
May 6, 2020 - Newly published research is the first to show in a lab model that the herpes simplex virus HSV-1 might cause Alzheimer's. In the study, scientists found that mini 3D models of the human brain, when infected with the virus that causes cold sores, developed hallmarks of Alzheimer's, including amyloid plaque-like formations and neuroinflammation.
May 1, 2020 - The WHO issued a statement saying, 'About half a billion people worldwide live with genital herpes. Several billion have an oral herpes infection, new estimates show, highlighting the need to improve awareness and scale-up services to prevent and treat herpes.'
March 17, 2020 - Lessons learned from prior vaccine studies and select candidate vaccines are discussed, including a trivalent nucleoside-modified mRNA vaccine that our laboratory is pursuing.
March 2, 2020 - WSU researchers recently published a study in the American Society for Microbiology’s journal mSphere that is the first to identify how one of the virus’ proteins acts as a critical signaler for the virus to succeed in infecting a cell.
April 27, 2020 - Study: Based on our revised annotation of 201 viral transcripts and 284 ORFs, we extended the existing nomenclature to include all our novel viral gene products. This did not involve any renaming of previously described viral gene products. Our nomenclature thereby explains the gene expression of most viral ORFs in the context of different transcript isoforms, uORF, and uoORFs. This will facilitate functional studies on the viral gene products and their transcriptional and translational regulation.
February 11, 2020 - Study: Current Antivirals and Novel Botanical Molecules Interfering With Herpes Simplex Virus Infection.
February 6, 2020 - Study: Intramuscular vaccination of mice with the human herpes simplex virus type-1(HSV-1) VC2 vaccine, but not its parental strain HSV-1 (F), confers full protection against lethal ocular HSV-1 (McKrae) pathogenesis.
January 10, 2020 - Sanofi announced Phase 1 and 2 studies were posted. The study's primary objectives are: To describe the safety profile of different investigational vaccine regimens against herpes simplex virus type 2 (HSV-2).To evaluate the efficacy of the investigational vaccine regimens concerning the frequency of herpes simplex virus (HSV) deoxyribonucleic acid (DNA) detection in the genital area (shedding rate) following a 2 dose vaccine schedule; the proportion of participants free of HSV genital recurrence at 6 months after the 2-dose vaccine schedule.
January 8, 2020 - Candel Therapeutics announced the acquisition consolidates a next-generation herpes drug development platform and manufacturing expertise that can be tailored to multiple tumor types and indications.
December 17, 2019 - Immune responses to an HSV-2 polynucleotide immunotherapy COR-1 in HSV-2 positive subjects: A randomized double-blinded phase I/IIa trial. This study confirms the previously demonstrated safety of COR-1 in humans and indicates a potential for the use of COR-1 as a therapy to reduce viral shedding in HSV-2 infected subjects.
December 10, 2019 - A recent study provides new insights into the early stages of a Herpes Simplex Virus 1 (HSV-1) infection. It serves as a general blueprint for investigating heterogeneous cell states in virus infection.
December 5, 2019 - A recent study said ‘a large burden of Human Immunodeficiency Virus (HIV) is likely attributable to a Herpes Simplex Virus type 2 (HSV-2) infection.
November 21, 2019 - Cornell University researchers hoping to learn ‘what’ switches this life-long virus between latent and lytic stages may have found the ‘hidden’ answer to this question.
November 18, 2019 - Global and regional estimates of the contribution of herpes simplex virus type 2 infection to HIV incidence: a population attributable fraction analysis using published epidemiological data. A large burden of HIV is likely to be attributable to HSV-2 infection, even if the effect of HSV-2 infection on HIV had been imperfectly measured in studies providing adjusted RR estimates, potentially because of residual confounding. The contribution is likely to be greatest in areas where HSV-2 is highly prevalent, particularly in Africa. New preventive interventions against HSV-2 infection could not only improve the quality of life of millions of people by reducing the prevalence of herpetic genital ulcer disease but could also have an additional, indirect effect on HIV transmission.
September 20, 2019 - A new herpes simplex 2 virus vaccine study in animals reported an experimental vaccine developed at the University of Pennsylvania had prevented genital lesions in 98 percent of mice and guinea pigs tested. Friedman and colleagues just published a paper in Science Immunology in which they describe the trivalent herpes vaccine that they developed and its efficacy in animal models. This trivalent vaccine protected mice and guinea pigs from developing genital lesions and reduced viral shedding. Neutralizing antibody and CD4+ T cell responses were detected in immunized mice.
July 23, 2019 – A patent was issued on February 19, 2019, which protects the use of BlueWillow Biologics’ unique NanoVax adjuvant platform to develop a vaccine that protects against HSV-1 and HSV-2.
July 23, 2019 - X-Vax Technology, Inc. announced that it had raised $56 million in an upsized Series A financing with participation from strategic and institutional investors, including Johnson & Johnson Innovation – JJDC, Inc. Proceeds from the financing will be used to advance X-VAX's lead program, a vaccine candidate against herpes, called ∆gD-2 (delta gD-2), for further development and production, including a Phase 1 clinical study.
June 15, 2019 – A new study published in Nature on June 12, 2019, by Yale researchers offered insights that could lead to a better genital herpes therapeutic vaccine.
May 2, 2019 - Numerous epidemiological, clinical, and immunological studies demonstrate that BCG vaccination impacts subsequent infections' immune response resulting in reduced morbidity and mortality. Important lines of evidence indicating that BCG protects against viral pathogens come from experimental studies in mice showing that BCG offers protection against various DNA and RNA viruses, including herpes and influenza viruses. Recently, BCG's effect on an experimental viral infection in humans has been demonstrated. These effects are thought to be mediated via the induction of innate immune memory and heterologous lymphocyte activation, resulting in enhanced cytokine production, macrophage activity, T-cell responses, and antibody titers.
April 17, 2019 - Therapeutic Mucosal Vaccination of Herpes Simplex Virus 2-Infected Guinea Pigs with Ribonucleotide Reductase 2 (RR2) Protein Boosts Antiviral Neutralizing Antibodies and Local Tissue-Resident CD4+ and CD8+ TRM Cells Associated with Protection against Recurrent Genital Herpes.
March 27, 2019 - Research article: Duration of protection from live attenuated vs. sub unit HSV-2 vaccines in the guinea pig model of genital herpes: Reassessing efficacy using endpoints from clinical trials.
January 22, 2019 - Study: Vaccine-induced antibodies target sequestered viral antigens to prevent ocular HSV-1 pathogenesis, preserve vision, and preempt productive neuronal infection.
November 22, 2018 - Study: The live attenuated prophylactic HSV vaccine, VC2, was effective in the guinea pig model of genital HSV-2. Its decreased ability to infect neural tissues provides advantages over other live attenuated vaccines. The live attenuated prophylactic HSV vaccine, VC2, was effective in the guinea pig model of genital HSV-2. Its decreased ability to infect neural tissues provides advantages over other live attenuated vaccines.
August 11, 2018 - Herpes simplex virus‐2 dynamics as a probe to measure the extremely rapid and spatially localized tissue‐resident T‐cell response.
October 28, 2015 - Global and Regional Estimates of Prevalent and Incident Herpes Simplex Virus Type 1 Infections in 2012.
Russian Herpes Vaccine
Vitagerpavac is the only multivalent vaccine globally for treating chronic herpesvirus infection (HCV) of types I and II. The vaccine was developed at the Research Institute of Virology. DI. Ivanovsky RAMS has been used in the Russian Federation for over 15 years.
According to the CDC, the spread of HSV- 1 generally occurs by direct contact, usually involving saliva, and most commonly appears as cold sores in or around the mouth, And HSV-2 infections usually occur after sexual contact, leading to recurring, often painful, genital sores in up to a third of people infected. And there is no cure for herpes.
On July 16, 2020, new research published in the journal BMJ Global Health found fewer people are being exposed to herpes simplex type 1 – also known as oral herpes – in their childhood. The prevalence amongst the population in Europe is falling by 1% per year. The results also showed that half of the first-episode genital herpes cases in Europe were already due to HSV-1 instead of HSV-2 infection.
About 13% of the world’s population aged 15 to 49 years were living with herpes simplex virus type 2 infection in 2016, the latest year for which data is available. In 2016, two-thirds of the world's population under 50 — about 3.7 billion people — had herpes simplex virus type 1, which most commonly appears as cold sores in or around the mouth.
Genital herpes infections play a significant role in spreading HIV globally, WHO researchers said.
If a vaccine program for HSV were implemented today and the vaccine was 100% efficacious and utilized by 100% of the target population, the annualized present value of the QALYs gained would be 28,000, says the NIH.
Using committee assumptions of less-than-ideal efficacy and utilization and including time and monetary costs until a vaccine program is implemented, the annualized present value of the QALYs gained would be 7,500.
Most of the disease burden is associated with genital and CNS infections due to the large number of genital infections and the serious, chronic sequelae associated with the relatively fewer CNS HSV disease cases.
The NIH estimates that there are 500,000 new oral infections with HSV each year in the United States. These infections occur in people between 1 and 44 years of age. There are approximately 20,000 new ocular infections with HSV each year. These occur in people between 1 and 84 years of age.
There are approximately 1,500 cases of central nervous system infection with HSV each year. The incidence was assumed to be highest in children between 5 and 14 years of age. It was also assumed that there are 300,000 new cases of genital HSV infections occurring primarily in people between 15 and 34 years of age.
There are also 1,500 new cases of neonatal HSV infections each year, says the CDC.
Certain antiviral drugs, including acyclovir and valaciclovir, can control outbreaks, but they don’t cure a herpes infection, says the CDC.
Herpes and HIV
People with HSV-2 infection are at least three times more likely to become infected with HIV if exposed. Thus, HSV-2 likely plays a substantial role in spreading HIV globally. Women are more susceptible to both HSV-2 and HIV.
Women living in the WHO Africa Region have the highest HSV-2 prevalence and exposure to HIV – putting them at the greatest risk of HIV infection.
Herpes Antiviral Treatments
Most herpes simplex virus infections are self-limited, and treatment is not always indicated or necessary. However, antiviral therapy shortens the symptoms and may prevent dissemination and transmission.
Antiviral medications, such as acyclovir, famciclovir, and valacyclovir, can reduce the severity and frequency of symptoms but cannot cure the infection. About 500 million people worldwide live with genital herpes, and several billion have an oral herpes infection, said the WHO on May 1, 2020.
Treatment of herpes labialis and herpes genitalis generally consists of episodic courses of oral acyclovir, valacyclovir, and ganciclovir. Complicated HSV infections, cutaneous and/or visceral dissemination, neonatal HSV infection, and severe infections in those who are immunocompromised should be treated promptly with intravenous acyclovir, says the CDC.
Patients who are immunocompromised and have recurrent HSV infections, acyclovir-resistant HSV strains have been identified, and treatment with intravenous foscarnet or cidofovir may be used.
Content sources: The WHO, US CDC, WHO, NIH, research papers, ClinicalTrials.gov, and the Precision Vaccinations news network. Content is fact-checked by healthcare providers, such as Dr. Robert Carlson.