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  2. WHO
  3. WHO COMMISSIONED GLOBAL REVIEW PUBLISHED IN 1993 S. Sridhar et al. A systematic literature review of missed opportunities for immunization in low- and middle-income countries, Vaccine 32 (2014) MISSED OPPORTUNITIES to vaccinate an estimated 30% of children and women
  4. TODAY’S SCENARIO FOR VACCINATING WOMEN is GLOOMY ……….. WHAT SHOULD BE OUREMPHASIS  Health worker knowledge  Access and vaccine service availability;  Cost and service quality; and Use of all opportunities;
  5.  All women of childbearing age should be evaluated for the possibility of pregnancy before immunisation2  Immunisation history should be taken at first antenatal visit  LIVE VIRAL VACCINES are contraindicated during pregnancy, but risk is largely theoretical2 2. Guidelines for Vaccinating Pregnant Women, Recommendations of the Advisory Committee on Immunization Practices (ACIP) December 2012 GUIDELINES
  6.  WOMEN WHO HAVE INADVERTENTLY RECEIVED LIVE VACCINE DURING PREGNANCY SHOULD NOT BE COUNSELED TO TERMINATE THE PREGNANCY FOR TERATOGENIC RISK3  Non pregnant women should delay pregnancy for at least 4 week  Inactivated viral vaccines, bacterial vaccines and toxoids are safe in pregnancy Immunization in Pregnancy and Breast-Feeding, Part 3 Recommended Immunization, Canadian Immunization Guide GUIDELINES
  7.  Breast feeding women can be immunised safely  Pregnant women should be offered the influenza vaccine during the season Immunization in Pregnancy and Breast-Feeding, Part 3 Recommended Immunization, Canadian Immunization Guide GUIDELINES
  8. Vaccines help keep a woman and her growing family healthy! Maternal Vaccination – CDC, September, 2016 Available from; accessed on 26-12-2016
  9. Chickenpox Vaccination for Women
  10. PREGNANCY AND CHICKENPOX Varicella infection during the 1st & 2nd trimester may increase the risk for congenital varicella syndrome.5 1st & 2nd Trimester Varicella infection during the 3rd trimester may lead to maternal pneumonia.5 3rd Trimester Newborns whose mothers develop chickenpox from 5 days before to 2 days after delivery are at risk of chickenpox shortly after birth5 Perinatal Varicella 5. Ronald F Lamont et al. BJOG 2011;118:1155–1162
  11. CONGENITAL VARICELLA SYNDROME  Varicella infection in the first or early second trimester of pregnancy could lead to “Congenital Varicella Syndrome" in the fetus5.  Primary VZV infection during pregnancy may result in:  intrauterine infection in about 25% of the cases5  congenital anomalies can be expected in approximately 12% of infected fetuses5Clinical features Reports6 Sauerbrei and Wutzler [3] % Enders and Miller [6] % Skin lesions 73 72 Neurologic defects or diseases 62 48 Eye diseases 52 44 Limb hypoplasia 46 72 Intrauterine retardation 23 Muscle hypoplasia 20 24 Gastrointestinal abnormalitiesa 19 20 Genitourinary abnormalities 12 - Affections of internal organs 13 - Developmental delay 12 - Defects of cardiovascular system 8 - Defects of other organs 7 - 5. Ronald F Lamont et al. BJOG 2011;118:1155–1162 6. Michael Paul Tan et al. Reproductive Toxicology 21 (2006) 410–420
  12. 1. Classic cicatricial scarring is visualized in an infant with congenital varicella syndrome7. 2. The right lower leg has significant bone and muscle hypoplasia. The classic cicatricial scarring is also visualized7. 3. Infant aged 14 months with herpes zoster in the classic dermatomal pattern. There was a maternal history of varicella at 28 weeks of pregnancy7. 4. Newborn with varicella acquired from the mother in the perinatal period7. 7. Candice K. Smith at al. Fetal & Neonatal Medicine 14 (2009) 209–217
  13. MATERNAL PNEUMONIA  Maternal pneumonia is a complication in about 10–20% of cases of Varicella infection during 3rd trimester of pregnancy, resulting in a higher mortality and morbidity than in non pregnant adults  Pregnant women with VZV pneumonia should be hospitalized for monitoring and administered antiviral therapy, because up to 40% of women may need mechanical ventilation  Mortality in severe cases is estimated to be 3–14%  The risk for pneumonia also increases with increasing gestational age 3rd Trimester Ronald F Lamont et al. BJOG 2011;118:1155–1162
  14.  Newborns whose mothers develop chickenpox rash from 5 days before to 2 days after delivery are at risk for chickenpox shortly after birth, with the chance of death as high as 30%8 8. PRENATAL VARICELLA
  15. PREVENTION OF VARICELLA INFECTION Woman of childbearing age9 The best way to protect against chickenpox is to get the chickenpox vaccine. (1-3 months prior pregnancy)9 Pregnant woman who is not protected against chickenpox9 Vaccination of close contacts is the most effective way to protect a pregnant woman against chickenpox9. Postpartum As soon as a pregnant woman delivers her baby, she should be vaccinated against chickenpox with 1st dose and the second dose at the 6-8-week post- partum visit9 9.
  16. Seroprevalence of antibodies against varicella increased with age1 0 10 20 30 40 50 60 70 80 90 100 1–5 6–10 11–15 16–20 21–30 31–40 %seroprevalence Age group (years) Varicella is most common in adolescents and adults in tropical regions4 Reports from South India showed that nearly 30% of adolescents >15 years of age may be susceptible to varicella5 Studies conducted in the Uttar Pradesh region:2,3 • 4.4–15.8% of patients hospitalised with acute viral encephalitis had anti-VZV antibodies Study conducted across four sites across India (Kolkata, Lucknow, Mumbai, Bangalore):1 • Overall anti-VZV seroprevalence: 68.22% • Seroprevalence increased with age, with a significant proportion of adolescents susceptible to infection Owing to the high disease burden in India,it’s important to protect against Varicella VZV, varicella zoster virus 1. Lokeshwar MR et al. Indian Pediatr 2000; 37: 714–9; 2. Beig FK et al. Int J Infect Dis 2010; 14: e141–6; 3. Jain P et al. Jpn J Infect Dis 2014; 67: 197–203; 4. World Health Organization. Wkly Epidemiol Rec 2014; 89: 265–87; 5. Verma R et al. Hum Vaccin 2011; 7: 874–7.
  17. VARICELLA VACCINATION  100% sero-conversion with 2 doses of VarilrixTM in healthy adults10  1 dose: 85% seroconversion  2 doses: 100% seroconversion and 4 fold rise in GMTs  Proven Safety and efficacy in 53 clinical trials in >10000 individuals10 10. H W Kreth et al. Biodrugs 2008; 22 (6): 387-402 VarilrixTM (Varicella Vaccine Live)
  18. Recommendations for Chickenpox Vaccination  2 doses for all older than 12 months recommended by:  Indian Academy of Pediatrics#  Advisory Committee on Immunization Practices/Centre for Disease Control & Prevention *  American Academy of Pediatrics^ # IAP Guidebook * MMWR, June 22, 2007; 56(RR-4):1-40 ^ Prevention of Varicella: Recommendations for Use of Varicella Vaccines in Children, Including a Recommendation for a Routine 2-Dose Varicella Immunization Schedule Committee on Infectious Diseases Pediatrics 2007;120;221
  20. Measles, Mumps and Rubella  Measles illness during pregnancy leads to increased rates of premature labor, spontaneous abortion, and low birth weight among affected infants and also birth defects11  Mumps developed in women during the first trimester of pregnancy, leads to an increased risk for fetal death11  Rubella developed in women during preganancy may lead to Congential Rubella syndrome11 11. CDC MMWR1998 ; 47: 2-6
  21. Congenital Rubella Syndrome  Congenital Rubella Syndrome is the most serious feature of rubella  It arises when pregnant women become infected with the rubella virus in the early stages of pregnancy  Infection of the foetus occurs when the rubella virus spreads from the placenta and enters the foetal circulation CDC pink book (
  22. Incidence of Congenital Rubella Syndrome (CRS)  CRS is estimated to affect up to 85% of infants born to women infected with rubella during the first trimester of pregnancy  Over 100,000 cases per year of CRS occur in the developing world alone#  Congenital Rubella Syndrome is associated with spontaneous abortion, premature delivery and stillbirth4 4. # IAP Guidebook 40k.cases CRS…occur in INDIA
  23. CONGENITAL RUBELLA SYNDROME- MANIFESTATIONS Consequence of CRS12 Incidence (%) Hearing Impairment 60 Heart Defect 45 Microcephaly 27 Cataracts 25 Low Birth Weight (<2500g) 23 Mental Retardation 13 12. Scott R Lambert, Br J Ophthalmol 2007;91:1418–1419
  24. A. A child with expanded or acute congenital rubella syndrome who had hepatosplenomegaly, thrombocytopenia, cataracts, deafness, Congenital heart disease and mental retardation. Also Cutis marmorata, a peculiar mottling common in infants and young children with congenital rubella syndrome13 B. CRS patient showing cataracts13 13. MA South et al. Teratology 31:297-307 (1985)
  25. Rubella in Delhi: In-utero Infection and Congenital Rubella Syndrome  A section of women (5-10%) unexposed to natural or vaccinated rubella virus remain susceptible and add the burden of CRS in society by contracting rubella infection during pregnancy as can be seen from the significant correlation between the in-utero infection cases and CRS in new-borns 1) I. Gandhoke, et al.; Indian Journal of Medical Microbiology; Vol. 26, Issue 4; 2008 RUBELLA INFECTION IS THE MAJOR CAUSE OF BIRTH OF DEFORMED BABY
  26. Rubella Vaccine or combined MMR vaccine?  CDC EMPHASIZES on the use of Combined MMR vaccine for any indication  CDC: Potential additional benefit of protection against measles and mumps 1CDC MMRW 1998 ; 47: 2-6
  27. MMR Vaccination  The MMR vaccine prevents measles, mumps and rubella**  MMR Vaccine [PriorixTM - Measles, Mumps and Rubella vaccine (live)] is highly immunogenic after one dose, with reported seroconversion rates of:  98.7% for measles14  95.5% for mumps14  99.5% for rubella14 14. Priorix Prescribing information **
  28. MMR Vaccination Recommendations 2 doses for all older than 12 months recommended by…  Indian Academy of Pediatrics#  Advisory Committee on Immunization Practices/Centre for Disease Control & Prevention**  American Academy of Pediatrics^^ ** # IAP Guidebook, Committee on Infectious Diseases ^^Age for Routine Administration of the Second Dose of Measles-Mumps-Rubella Vaccine Committee on Infectious Diseases Pediatrics
  29. Cervarix® 2-dose schedule (9-14 years)
  30. PUBLIC HEALTH RATIONALE FOR 2-DOSE DEVELOPMENT  Delivering a 3-dose schedule to adolescents has proven challenging  The most important challenges are related to:  Implementation  Affordability™® Cervarix 2-dose for 9-14 years old girls. HPV, human papillomavirus Unmet need in Private Market There is an unmet need for an easier-to-implement and more affordable HPV vaccine schedule to improve convenience and compliance.
  31. This principle is independent of dosing schedule (2 or 3) 9-14 years Cannot be assessed Not ethical in <15 years; challenging feasibility Assessed Immune response 2x higher than older age group Efficacy Inferred 9-14 years Assessed Immune response not inferior to older age group Efficacy Inferred 15-25 years Efficacy Immunogenicity Assessed CIN2+, CIN3+, 6 & 12M persistent infection Assessed 3-dose 3-dose 2-dose Development BACKGROUND: EFFICACY AND IMMUNOBRIDGING Cannot be assessed Not ethical in <15 years; challenging feasibility
  33. 2-dose for girls aged 9-14 years old demonstrated non-inferior immune response to HPV-16 and 18 compared with 3-dose 15-25 years old. Natural infection = subjects who had cleared infection had GMTs of 29.8 (HPV-16) and 22.6 EL.U/mL (HPV-18) in Study HPV-008 [Paavonen J et al. Lancet 2007;369:2161–70]. Plateau = GMTs at the plateau level in Study HPV-007 (Month 45–50 time point, females aged 15–25 years) were 397.8 (HPV-16) and 297.3 EL.U/mL (HPV-18) [HPV-007 Study Group et al. Lancet 2009;374:1975–85]. ATP, according-to-protocol; CI, confidence interval; ELISA, enzyme-linked immunosorbent assay; GMT, geometric mean titres; HPV, human papillomavirus 1.Romanowski B, et al.. Hum Vaccin Immunother. 2015;12:1,20-29 • Antibody kinetics similar in both groups (ELISA, 9-14 vears & 15-25 years) • GMTs above plateau level seen in subjects with sustained protection (HPV-001/007) • GMTs above levels elicited after natural infection (control arm HPV-008) • All subjects seropositive from Month 7 to 60 HPV-16 HPV-18
  34. HPV-070: Safety profile with 2-dose and 3-dose  Incidence of local solicited symptoms and general solicited symptoms (per subject) during the 7-day post-vaccination period (TVC) 3 4 HPV, human papillomavirus; TVC, total vaccination cohort Puthanakit et al JID 2016:214:525-36 Reactogenicity & safety for 2-dose compared 3-dose were assessed up to M13 All groups showed clinically acceptable safety profile
  35. Clinical Summary on 2 Dose Development = Immunogenicity (4 yr follow up) (Vaccine and non vaccine type) =Safety = Duration of protection (21 years at least) = Efficacy (93.2% in naieve girls) (Inferred by Immunobridging) 3 Dose in 15-25 years old 2 Dose in 9-14 years old= New Indicated age group of Cervarix® : 9-45 years old. 1.Romanowski B, et al.. Hum Vaccin Immunother. 2015;12:1,20-29 2. Puthanakit et al JID 2016:214:525-36. Cervarix PI"
  36. Cervarix® 2D demonstrated superior immune response as compared to a 2 D or 3D of q-HPV in 9-14 years old. 2.5 times 3 times 3 times 5.5 times 2 Dose 3 Dose • HPV 16 •HPV 18 2 Dose HEAD TO HEAD COMPARISON of Two vaccine IMMUNE RESPONSE ATP, according to protocol; ED, mean effective dose; GMT, geometric mean titre; HPV, human papillomavirus; PBNA, pseudovirion-based neutralisation assay - Leung et al. Hum Vaccin Immunother. 2015 Jul3;11(7):1689-702
  37. • 2-dose development of Cervarix® consistently demonstrates high immunogenicity versus a 3-dose schedule1-2 – Non-inferiority of the antibody response against HPV-16 and -18 up to 5 years – Comparable antibody responses to non-vaccine types 31 and 45 up to at least 48 months – Comparable T- and B-cell responses induced by the 2-dose schedule and the 3-dose schedule • Modeling predicts this immunity will last at least 21 years1 • The safety profile of the 2-dose schedule remains similar 1-2-3 • The immune response elicited by Cervarix® In a 2-dose schedule is superior to that of Gardasil in 2-dose and 3-dose schedule in 9-14 year-old girls3 CONCLUSIONS HPV, human papillomavirus; PBNA, pseudovirion-based neutralisation assay 1.Romanowski B, et al.. Hum Vaccin Immunother. 2015;12:1,20-29; 2. Puthanakit et al JID 2016:214:525-36. 3.Leung et al. Hum Vaccin Immunother. 2015 Jul 3;11(7):1689-702

Notes de l'éditeur

  1. Varilrix also.. Efficacy and immuno Mmr and not rubella Efficacy, immuno of mmr vaccine
  2. Therefore, from a public health perspective, there is significant unmet need for an easier to implement and more affordable HPV vaccination schedule.
  3. The concept of immunobridging is that if the immune response in the 9 to 14 year old population is non-inferior to that seen in the 15 to 25 year old population then the efficacy of the vaccine can be inferred from 9 to 14 years of age. This principle is independent of whether a 2- or 3-dose schedule is used.
  4. From the study results, we will focus on the comparison of the immunogenicity and safety of the 2-dose schedule (0-6M) in 9 to 14 year olds using the current formulation, versus the 3-dose schedule in 15 to 25 year olds. The antibody kinetics up to Month 60 are similar in both groups, both for HPV-16 and HPV-18. The GMTs remained above the plateau level seen in subjects with sustained protection in trials HPV-001 and -007. This GMT plateau level already being well above the levels elicited by natural infection, as was observed in the PATRICIA trial. All subjects were seropositive from Month 7 all the way through to the 60-month time point. We should note here that the 2-dose schedule (M0,6) using the licensed formulation elicited an immune response in adolescents that was non-inferior to the 3-dose schedule in young women, therefore the 40/40 formulation was not justified and results obtained with this formulation will not be presented in this training course.
  5. Last, but not least, the safety profiles of the 2-dose schedule and the 3-dose schedule were evaluated in the HPV-070 study. This graph demonstrates the incidence of local solicited symptoms and general solicited symptoms per subject during the 7-day post vaccination period in the total vaccinated cohort, showing that the safety profiles of the two schedules is comparable. When we look more in detail at this safety graph, what can be observed is that the percentage of subjects with symptoms of fatigue, gastro-intestinal events, headache and myalgia were lower in the 2-dose group. § The reactogenicity and safety for the 2-dose schedule compared to the 3-dose schedule were assessed up to Month 13 and both groups showed a clinically acceptable safety profile, in the 9 to 14 year old and the 15 to 25 year old populations, respectively.
  6. Now having seen all the key data for a 2-dose schedule in young adolescents, the data from studies HPV-048 up to Month 60 and HPV-070 at Month 7 and 13 consistently demonstrate that § the immunogenicity of a 2-dose Cervarix® schedule is non-inferior to a 3-dose schedule. § The antibody response to HPV-16 and -18 and to non-vaccine types 31 and 45 with a 2-dose schedule is comparable to the 3-dose schedule and is sustained up to at least 48 months, as illustrated by the study 048. § Consistent with the antibody results, the 2-dose schedule induced T- and B-cell responses that are comparable to the 3-dose schedule. § The neutralising antibody assay results and the avidity index suggest that not only the quantity but also the quality of the 2-dose response is in line with that of the 3-dose schedule The safety profile is similar both with the 2- and 3-dose groups. § In addition to this, the results from the independent study conducted in Mexico are consistent with the findings of the GSK trials, supporting the 2-dose schedule for Cervarix® in young adolescents. § The comparative trial HPV-071 demonstrated the superiority of the antibody response against HPV-16 and -18 at M7 with Cervarix® 2-dose compared to Gardasil™given in both 2- and 3-dose schedules.