Genital Herpes Vaccine Development PDF

Genital herpes vaccine development Jasper Joye Disclaimer This presentation is based solely on my own views and interpretations. The content and opinions expressed herein do not necessarily represent the views or policies of GSK. This presentation is intended for informational purposes only and i...

Genital herpes vaccine development Jasper Joye Disclaimer This presentation is based solely on my own views and interpretations. The content and opinions expressed herein do not necessarily represent the views or policies of GSK. This presentation is intended for informational purposes only and is not endorsed by or affiliated with GSK. Genital herpes vaccine development 1. Disease overview 2. Why do we need a genital herpes vaccine? 3. What kind of vaccines could be developed to manage HSV? 4. What has been done in the past? 5. Immune evasion mechanism 6. Where are we now in genital herpes vaccine development? 1. Disease overview 1. Viral Biology 2. Epidemiology and global burden 3. Natural history 1. 2. 3. 4. 5. Pathogenesis Transmission, risk factors, and options for prevention Clinical presentation Stigmatizing consequences HIV co-infection 04 December 2023 4 1.1 Viral Biology Family Herpesviridae • Over a 100 known Herpes viruses, of which 8 are clinically relevant • All have latency potential through complex immune evasion mechanisms and establishment of reservoirs Group Virus Growth cycle Latency Alpha HSV1 HSV2 VZV Short sensory nerve ganglia, cranial nerve ganglia Beta CMV HHV-6 HHV-7 Long lymphoreticular tissue, secretory gland, kidneys, and other tissues cells Gamma EBV KSHV Variable lymphoid B cells 1. 2. 04 December 2023 Cohen JI, Introduction to Herpesviridae, in: Mandell, Douglas, and Bennett, eds. Principles and Practice of Infectious Diseases. 8th ed. Saunders/Elsevier; 2015: 1707-12. Christopher J. Burrell, Colin R. Howard, Frederick A. Murphy, Fenner and White's Medical Virology (Fifth Edition) Chapter 17 - Herpesviruses, Academic Press, 2017: 237-261. 5 1.1 Viral Biology Herpes Simplex Virus ▪ Herpes Simplex Virus (HSV) is a human α-herpesvirus of two types, HSV-1 and HSV-2 ▪ HSV-1 causes more oral infections (herpes labialis) whilst HSV-2 is more associated with genital disease (herpes genitalis) although HSV-1 genital herpes incidence is on the rise. ▪ The overall sequence homology between HSV-1 and HSV-2 is about 50%. ▪ Capable of infecting nerve ganglia and preventing viral clearance by the immune system. (=latency) 6 1.1 Viral Biology Surface glycoprotein ▪ HSV (both 1 & 2) have at least 12 virus-encoded glycoproteins in its lipid envelope ▪ gD is the immunodominant epitope ▪ Several glycoproteins play an important role in key viral functions (receptor binding, cell entry, envelope formation) 7 1.2. Epidemiology and global burden Epidemiology HSV-1 HSV-2 • estimated 491 million (13%) people aged 15 to 49 years worldwide were living with the HSV-2 infection Prevalence of HSV-2 infection was estimated to be highest in Africa (44% in women and 25% in men), followed by the Americas (24% in women and 12% in men) Prevalence was also shown to increase with age, though the highest numbers of people newlyinfected were adolescents. • • In 2016, an estimated 3.7 billion people under the age of 50 (67% of the population) had HSV-1 infection (oral or genital) 122 million to 192 million people aged 1549-years were estimated to have genital HSV-1 infection (varied substantially by region) Most genital HSV-1 infections are estimated to occur in the Americas, Europe and Western Pacific, where HSV-1 continues to be acquired well into adulthood 31 May 2022 / Confidential 8 1.2. Epidemiology and global burden Global prevalence of HSV-2 An estimated 491 million people aged 15–49 (13%) worldwide have HSV-2 infection, Europe ♀ 10.7 ♂ 5.3 Americas ♀ 24.0 ♂ 11.6 - >85% undiagnosed - 60% of diagnosed are treated - Prevalence of HSV-2 infection was estimated to be highest in Africa (44% in women and 25% in men), followed by the Americas (24% in women and 12% in men) - Prevalence was also shown to increase with age, though the highest numbers of people newly-infected were adolescents. W Pacific ♀ 14.6 ♂ 7.1 Middle E ♀ 7.6 ♂ 2.8 Africa ♀ 43.9 ♂ 25.4 SE Asia ♀ 9.6 ♂ 7.2 James et al. Bull WHO 2020;98:315-329 Schiffer JT & Corey L.; 2015; Saunders/Elsevier 04 December 2023 9 Comparison of Burden of HSV1 and HSV 2 infection 95% of all burden of disease of genital herpes is caused by HSV-2 HSV 1 HSV 2 Sex Almost equal Double burden among women Age highest prevalence 2024 years highest prevalence 2024 years Average number of days spent with GUD symptoms 10 days with GUD 46 days with GUD Looker KJ, Johnston C,Welton NJ, et al. The global and regional burden of genital ulcer disease due to herpes simplex virus: a natural history modelling study. BMJ Global Health. 2020;5:e001875. doi:10.1136/ 10 1.2. Epidemiology and global burden Global burden of genital herpes 10-15% recognized infection HSV-2 seroprevalence 85-90% unrecognized and/or asymptomatic infection 1. Fanfair RN et al. Sex Transm Dis, 2013. 40(11):860-4. 2. Genital Herpes – CDC Fact Sheet https://www.cdc.gov/std/herpes/stdfact-herpes-detailed.htm [accessed NOV 2021] 04 December 2023 11 1.3. Natural history Pathogenesis 1. Inoculation of virus to mucosa or small skin break 2. Replication initiated in nucleated cells of dermis and epidermis 3. Sensory nerve endings become infected via axon to sacral ganglia 4. Latency is established at sacral ganglia 5. Reactivation – viral release from sensory neurons into genital tract a. Clinical Symptoms b. Asymptomatic Shedding 1. 2. Schiffer, J. T., & Corey, L. (2009). New concepts in understanding genital herpes. Current infectious disease reports, 11(6), 457-464. Image from: https://www.drawittoknowit.com/course/immunology/glossary/immunology-microbiology/herpes-simplex-viruses-1-2 [accessed NOV 2021] 04 December 2023 12 1.3. Natural history Clinical presentation HSV infection Increased risk of HIV infection Neonatal infection CDC. STI Treatment Guidelines 2021. Genital Herpes. Herpes - STI Treatment Guidelines (cdc.gov) [accessed NOV 2021] Invasive disease (immunocompromised patients) Retinitis Vertical transmission Meningitis Mental and sexual health impairment Pain Recurrences 13 1.3. Natural history Clinical presentation • Clinical manifestations of HSV infection depend on the anatomic site involved, the age and the immune status of the host • Severity vary from subclinical shedding to overwhelming sepsis or encephalitis • Both viral subtypes can cause genital and orofacial infections, and infections caused by the two subtypes are clinically indistinguishable 14 1.3. Natural history Clinical presentation Constitutional symptoms • fever, headache, myalgias and malaise are common Atypical presentations • Sexual Exposure 4-7 days may include small erosions and fissures, as well as dysuria or urethritis without lesions Primary Infection 2-3 weeks New lesions appear and existing lesions progress to vesicles and pustules -> coalesce into ulcers before crusting then healing Healed lesions HSV1: 1-2/yr HSV-2: 4-5/yr Prodrome: Pain, tingling, burning, paresthesias Skin lesions 5-10 days More severe among immunocompromised Long term mental, sexual, and social impairment Recurrence 15 1. 2. WHO Guidelines for the Treatment of Genital Herpes Simplex Virus, 2016. https://www.who.int/reproductivehealth/publications/rtis/genital-HSV-treatment-guidelines/en/ [accessed NOV 2021] Schiffer, J. T., & Corey, L. (2009). New concepts in understanding genital herpes. Current infectious disease reports, 11(6), 457-464 15 1.3. Natural history Viral shedding ▪ Viral shedding results from HSV replication in the genital skin and mucosa ▪ Shedding can be symptomatic or asymptomatic1-3 o ~80% of HSV-2 seropositive people do not know that they are infected * *** * * ****** o ~80% of new HSV-2 infections acquired from persons who do not know that they have genital herpes ▪ HSV-shedding occurs frequently1-3 ▪ In a 3-month period, 52 of 53 (98%) of persons not aware of having HSV-2 had either lesions, viral shedding, or both ▪ Subclinical shedding are much more frequent for genital HSV-2 infection than for genital HSV-1 infection4 1. Wald A, et al. Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons. N Engl J Med 2000; 342:844–50; 2. Tronstein E,, et al. Genital shedding of herpes simplex virus among symptomatic and asymptomatic persons with HSV-2 infection. JAMA 2011; 305:1441–9; 3. CDC – Sexually Transmitted Diseases Treatment Guidelines – Genital HSV infections https://www.cdc.gov/std/tg2015/herpes.htm (accessed Oct 2020); 4. Engelberg R, Carrell D, Krantz E, et al. Natural history of genital herpes simplex virus type 1 infection. Sex 16 Transm Dis 2003;30:174–7. 1.3. Natural history Transmission, risk factors, and options for prevention Antiviral medication HSV Positive Reactivation and shedding of virus Shedding is most likely the key determinant of transmission 1. 2. 3. 4. 5. Condom Transmission via Direct skin or mucosal contact Sexual activity Vaginal birth delivery Median time to transmission among discordant couples – 3 months (24 sexual acts) Transmission occurs in 80% time during asymptomatic shedding Cesarian Section HSV Negative Risk Factors: Biological: Females Behavioral: Multiple sexual partners Younger age of first intercourse Intercourse with sex workers Previous STI Schiffer JT and Correy L, Herpes Simplex Virus, in: Mandell, Douglas, and Bennett, eds. Principles and Practice of Infectious Diseases. 8th ed. Saunders/Elsevier; 2015: 1713-30. Schiffer, J. T., & Corey, L. (2009). New concepts in understanding genital herpes. Current infectious disease reports, 11(6), 457-464 Wald A, et al. Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons. N Engl J Med 2000; 342:844–50; Tronstein E,, et al. Genital shedding of herpes simplex virus among symptomatic and asymptomatic persons with HSV-2 infection. JAMA 2011; 305:1441–9; Engelberg R, Carrell D, Krantz E, et al. Natural history of genital herpes simplex virus type 1 infection. Sex Transm Dis 2003;30:174–7. 17 1.3. Natural history Strong synergy exists between HSV-2 and HIV ▪ HSV-2 infection can at least double the risk for sexually-acquired HIV infection1 because o genital herpes provides a port of entry for HIV o recruit HIV target cells to the sites of epithelial infection ▪ HIV infection increases the risk for HSV-2 transmission and increases the disease severity1 ▪ In Africa, one third of HIV infections are attributable to HSV-2 infections2 1. Schiffer, J. T., & Corey, L. (2009). New concepts in understanding genital herpes. Current infectious disease reports, 11(6), 457-464 2. WHO. First global and regional estimates of HIV infections attributablle to HSV infection. https://www.who.int/reproductivehealth/hiv-hsv2-infections/en/ [accessed NOV 2021] 18 1.3. Natural history Stigmatizing consequences Beyond the pain and discomfort of genital and systemic HSV symptoms, genital HSV infection can have important effects on sexual relationships and quality of life. Genital herpes is often stigmatizing, and the social consequences of the infection can have profound effects on sexual health and well-being, especially for adolescents and young adults1. “it’s not a disease that kills you, the stigma is the problem” “my GP doesn’t know all these details” “Prefer to stay miserable than other people having to have it” “there are moments I have an outbreak and I wanna die” “Need to arrange sex life around blisters” “For the rest of my life I feel shit” “I have anxiety attacks, I am neurotic” “I am shy to talk about this” “I stayed with him because I have this, and don’t want to be alone” Among women newly diagnosed with GH, 34% qualified as “clinical cases” for depression, and 64% had anxiety. A majority reported feeling ashamed and worried about having an outbreak or giving herpes to someone else. 19 2. Why do we need a genital herpes vaccine? • • • • • Prevention of genital ulcer disease (both HSV-1 and HSV-2) Prevention of transmission – protecting sexual partners Prevention of neonatal herpes Interruption of HIV epidemic Prevention of encephalitis, keratitis & herpes labialis 04 December 2023 20 3. What kind of vaccines could be developed to manage HSV? WHO preferred product characteristics for herpes simplex virus vaccines • “Existing tools for prevention or treatment of HSV are unlikely to have an impact on the incidence and prevalence of genital herpes at the population level. HSV vaccines might, therefore, be the only affordable and accessible option to achieve this goal, especially in LMICs but also in HICs.” • WHO describes 2 potential kinds of HSV vaccines: - Prophylactic: vaccines to prevent infection by HSV-1 and HSV-2 Therapeutic: vaccines to reduce disease severity and reduce reactivation of infection, including shedding of HSV that can be transmitted to others WHO preferred product characteristics for herpes simplex virus vaccines. 14MAY2019 04 December 2023 21 3. What kind of vaccines could be developed to manage HSV? Prophylactic HSV vaccines • Vaccine given to prevent infection with HSV-1 or HSV-2. • Need to be administered before exposure to the virus - HSV-2: before the first sexual contact HSV-1: during infancy • Most useful in low to middle income countries (LMIC) (HIV acquisition) WHO preferred product characteristics for herpes simplex virus vaccines. 14MAY2019 04 December 2023 22 3. What kind of vaccines could be developed to manage HSV? Therapeutic HSV vaccines • • • • Vaccine given to treat genital herpes signs and symptoms Can only be administered to genital herpes infected patients Most useful in high income countries (HIC) Current focus of vaccine industry (clinical development, clinical trial design, availability of participants) WHO preferred product characteristics for herpes simplex virus vaccines. 14MAY2019 04 December 2023 23 3. What kind of vaccines could be developed to manage HSV? Gottlieb SL et al, Vaccine 2017. https://doi.org/10.1016/j.vaccine.2017.10.084 04 December 2023 24 3. What does the ideal genital herpes vaccine look like? Prophylactic vs therapeutic vaccines Prophylactic vaccine Therapeutic vaccine Advantages Disadvantages - Reduces BoD Reduces HIV acquisition risk Greatest impact LMIC Established immunization platforms could be used to deliver vaccine - - Reduces BoD Quicker/less costly development Impact in LMIC although less Better alternative than current treatment - - - - WHO preferred product characteristics for herpes simplex virus vaccines. 14MAY2019 Large clinical trials (>10000 participants) Pediatric population Only small portion of infected individuals know they have genital herpes but still transmit Potentially only impact on symptoms but not on transmission No existing immunization platforms Potentially no impact on HIV acquisition 04 December 2023 25 5. Where are we now in genital herpes vaccine development? Candidates already in clinical development Candidate Platform Phase NCT number BioNTech mRNA I NCT05432583 Moderna mRNA I/II NCT06033261 GSK Recombinant protein, adjuvant I/II NCT05298254 www.clinicaltrials.gov 04 December 2023 26 5. Where are we now in genital herpes vaccine development? Global priority 04 December 2023 27