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HPV vaccines: who and when to vaccinate

HPV vaccines: who and when to vaccinate. Margaret Stanley Department of Pathology Cambridge. OUTLINE OF PRESENTATION. Immune response in the natural history of HPV infections Prophylactic vaccines rationale and immune mechanisms Who and when to vaccinate before exposure

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HPV vaccines: who and when to vaccinate

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  1. HPV vaccines: who and when to vaccinate Margaret Stanley Department of Pathology Cambridge

  2. OUTLINE OF PRESENTATION • Immune response in the natural history • of HPV infections • Prophylactic vaccines rationale and immune mechanisms • Who and when to vaccinate • before exposure • ? post exposure

  3. Immunity is a partnership • Innate no memory, not antigen specific • activated by cell death • Innate immunity kick starts adaptive immunity • by activating antigen presenting cells (APC) • Adaptive memory antigen specific • lymphocytes key players • humoral immunity • antibody mediated • neutralises extracellular pathogens • prevents re-infection • cell mediated immunity • cytotoxic effectorcells • kill infected cells

  4. Type 1/Th1 Cell mediated CD4+ T cells help killers Killer T cells Activated macrophages* Cytokines* Natural killer cells* Type 2/Th2 Humoral CD4+ T cells help B cells make antibody Non cytotoxic Antibody IgM, IgG, IgA, IgE Adaptive immune responses *innate effectors enhanced and activated by adaptive responses

  5. Natural Course of Genital HPV Infection HrHPVs 12-18months LrHPVs 4-9months Time infection Seroconversion Antibody to L1 Immune Response CMI First Lesion Virological clearance DNA-ve Viral persistence DNA+ve LSIL/HSIL Productive viral infection, DNA+ve low grade lesions DNA-ve

  6. Antibody responses in natural infections are slow and weak only 50-60% of women sero-convert Why are antibody responses so poor? No viraemia HPV does not lyse keratinocytes no inflammation no pro-inflammatory cytokines poor activation of Langerhans cells and stromal dendritic cells Free virus particles are shed from mucosal surfaces with poor exposure to APC

  7. OUTLINE OF PRESENTATION • Immune response in the natural history • of HPV infections • Prophylactic vaccines rationale and immune mechanisms • Who and when to vaccinate • before exposure • ? post exposure

  8. Why might vaccines generating neutralising antibody be effective prophylactically ? • Systemic immunisation with infectious Cotton • tail rabbit papillomavirus (CRPV) • did not induce visible papillomas • generated serum neutralising antibody • immunised rabbits were protected against • viral challenge Shope RE 1937 Immunisation of rabbits to infectious papillomatosis J Exp Med 65 607-24

  9. HPV vaccines are sub-unit vaccines made of virus like particles: VLPs Making VLPs: molecular “cut and paste” “cut” the L1 gene from the virus DNA “paste” into the DNA of another microbe such as yeast or baculovirus grow the recombinant microbe in large amounts – as it grows it makes the L1 protein The chemistry of this protein is such that it self assembles into a virus like particle - an empty protein shell without DNA The VLP is morphologically and immunologically identical to the HPV virus particle HPV 16 L1 VLPs

  10. VLP vaccines: mechanisms • 3 key players in the induction • of the antibody response • Dendritic cells (antigen presenting cells) in the • muscle • T lymphocytes in the lymph node • B lymphocytes in the lymph node

  11. Immune Response to HPV Vaccines:A Proposed Mechanism1–5 1. Stanley M. Vaccine. 2005 [Epub ahead of print].2. Batista FD, Neuberger MS. EMBO Journal. 2000;19:513–520. 3. Tyring SK. Curr Ther Res. 2000;61:584–596.4. Roden RB, Hubbert NL, Kirnbauer R, et al. J Virol. 1996;70:3298–3301. 5. Chen XS, Garcea RL, Goldberg I, et al. MolCell. 2000;5:557–567.

  12. Th2 cell help for B lymphocytes is crucial • to • Class switching – determines the type (IgG,etc) • and amount of antibody secreted • dictated by the Th2 cytokines – these in turn • are regulated by • antigen type • antigen dose • The generation of memory and the efficiency • of the response to recall antigen • under the control of memory Th2 cells

  13. B cell memory and long term antibody persistence Amanna et al Imm Revs 2006 211:320

  14. VLP vaccines generate high levels of antibody to HPV L1 Why are they so immunogenic? • Delivered intramuscularly • rapid access of VLPs to blood vessels • and local lymph nodes • potent activators of APC • induce good T helper responses for B cells

  15. OUTLINE OF PRESENTATION • Immune response in the natural history • of HPV infections • Prophylactic vaccines rationale and immune mechanisms • Who and when to vaccinate • before exposure • ? post exposure

  16. Natural Course of Genital HPV Infection infection Seroconversion Average time 9mo First Lesion Immune Response Sustained clinical remission Active Growth (3-6 Mo.) Late Stage Host Containment (3-6 Mo.) DNA-ve Sero-ve Persistent or recurrent disease

  17. Quadrivalent HPV Vaccine Phase III Adolescent Immunogenicity StudyNeutralizing Anti-HPV GMTs* at Month 7 Females 10–15 Years of Age Males 10–15 Years of Age Females 16–23 Years of Age *GMT = geometric mean titers • Block SL, Nolan T, Sattler C, et al. Pediatrics. 2006: 118.2135-45

  18. Age Specific Neutralizing HPV-6 Antibodies 1 Month Post-Vaccination1 PPE population* Neutralizing anti-HPV 6 GMTs at month 7 Immunogenicity Bridge Efficacy Program 1600 1500 1300 1100 Serum cLIA GMT with 95% CI, mMU/mL 900 700 500 Females Only Males + Females 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Age at Enrollment (Years) *Inclusive of five study protocols; all GMTs measured using cLIA 1. Data on file, MSD.

  19. Demonstration of Immune Memory with an Antigen Challenge at Month 601 HPV 16 10,000 Immune memory demonstrated after immune challenge 1000 Anti-HPV response(GMT Levels with 95% CI[log10 scale]) Quadrivalent HPV Vaccine n=78 100 10 Placebo (Sero (–) and PCR (–)) n=70 ↴ 0 2 3 7 12 18 24 30 36 54 6 60 61 Months 60+1week Vaccination on day 0, at two and six months Immune challenge at 60 months • Similar results seen with HPV 18, 6, and 11 *In subjects naïve to the relevant HPV type from day 1 through month 60 1. Data on file, MSD.

  20. OUTLINE OF PRESENTATION • Immune response in the natural history • of HPV infections • Prophylactic vaccines rationale and immune mechanisms • Who and when to vaccinate • before exposure • ? post exposure

  21. Natural Course of Genital HPV Infection infection Seroconversion Average time 9mo First Lesion Immune Response Sustained clinical remission DNA-ve Sero+ve Active Growth (3-6 Mo.) Late Stage Incubation (1-6 Mo.) Host Containment (3-6 Mo.) DNA-ve Sero-ve Persistent or recurrent disease

  22. Gardasil Phase III HPV-Naïve Modified Intention To Treat Population Endpoint HPV vaccine Placebo % 95% C.I cases cases Efficacy n=9342 n=9400 • HPV 16/18-related • CIN 3 or AIS • HPV 16/18-related CIN3 • HPV 16/18-related AIS 0 0 0 52 47 9 100 100 100 93, 100 92, 100 49, 100 Mean follow up 2 years Subjects are counted once per applicable row. www.fda.gov/ohrms/dockets/ac/06/slides/2006-4222s-index.htm

  23. Quadrivalent HPV Vaccine Yields Higher Neutralizing Anti-HPV Antibodies in Baseline Seropositive Subjects Vaccine: naive recipient Scale 3000 Placebo: naive recipient 2000 Vaccine: seropositive and PCR negative recipient 10 Placebo: seropositive and PCR negative recipient 1000 100 Geometric Mean Titer (mMU/mL) Log 10 1 0 7 12 18 30 42 48 Months These results suggest that women who were baseline HPV sero-positive had a booster response to the vaccination.

  24. Natural Course of Genital HPV Infection infection Seroconversion Average time 9mo First Lesion Immune Response Sustained clinical remission Active Growth (3-6 Mo.) Late Stage Incubation (1-6 Mo.) Host Containment (3-6 Mo.) DNA+ve Sero+ve DNA+ve Sero-ve Persistent or recurrent disease

  25. OUTLINE OF PRESENTATION • Immune response in the natural history • of HPV infections • Prophylactic vaccines rationale and immune mechanisms • Who and when to vaccinate • before exposure • ? post exposure

  26. Is there cross-protection? Evidence for cross-protection against incident infection with HPV 45 and 31 after vaccination with Cervarix Harper etal Lancet April 6th 2006 Cross neutralising antibodies to HPV 45 and 31 generated after immunisation with Gardasil Titres of these cross-neutralising antibodies are 1-2 logs lower than the dominant type specific neutralising antibody Smith JF et al IPV Prague Sept 3 2006 Abstract PL 1-6

  27. Prophylactic HPV L1 VLP vaccines Efficacy >90% for persistent infection 100% for disease (5 years post vaccination) in subjects naïve for vaccine HPV types Immunogenic high antibody concentrations up to 1000x > than in natural HPV infection Duration of vaccine induced antibody levels protection maintained over 5 years Safe no vaccine related serious adverse events identified in the trials to date (70,000 women)

  28. Protection for this generation

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