INFECTIOUS DISEASES DEPARTMENT AIDS REFERENCE CENTRE Vaccination schedule of HIV patients: an update BREACH symposium, Nov 30 2018 N. Dauby, Ch. Martin CHU Saint-Pierre, Brussels 1
Plan 1. Mechanisms of defective vaccine response during HIV infection 2. Vaccine schedule : current recommandations and recent data 3. Vertically-infected young adults : a special population
Pathways to antibody production : role of germinal centers Linterman & Hill 2016
Vaccine response in HIV-infected subjects : mechanisms of dysfunction T Follicular Helpter T cells (Tfh) dysfunction HIV-infected Different phenotype B cell dysfunction Exhausted & activated B cells Lower response to proliferation Persistent Immune activation on ART Lower rate of seroconversion after vaccination Lower persistance of vaccine-specific antibody
15 HIV+ on cart 3.6 years on ART CD4 711/µL CD4/CD8 ratio 1.6 5 Healthy donors
Higher % of Tfh Higher expression of SLAM & ICOS Higher level of cell death at baseline
Predictors of serological responses to trivalent influenza vaccine in HIV+ subjects on ART Negative correlation scd25 CD38+HLA-DR+ICOS+Ki-67+PD-1+ (% of ptfh) CD38+HLA-DR ICOS Ki-67+PD-1+ (% of ptfh) IL-21 Positive correlation CD38+HLA-DR+ICOS+Ki-67+PD-1 (% of ptfh) CD38 HLA-DR ICOS+Ki-67+PD-1 (% of ptfh) CD38 HLA-DR (% of CD8) TCM (% of CD4) De Armas JCI insight 2017
Early cart preserves both B and Tfh compartments Early ART Chronic ART Memory B cells Tfh cells Moir et al Blood 2010 Planchais et al J Immunol 2018
Plan 1. Mechanisms of defective vaccine response during HIV infection 2. Vaccine schedule : current recommandations and recent data 3. Vertically-infected young adults : a special population
10
New CSS/HGR recommendations: pending Categories: Announced changes: Actively recommended (A) Risk dependant (R) Standard indications (S) Contraindication (CI) -appearance of MenACWY, MenB, inactivated Zoster -MenC/MenACWY: switch S R -HPV: switch R A -MMR: switch R S -VZV: switch R A 11
New CSS/HGR recommendations: pending Categories: Announced changes: Actively recommended (A) Risk dependant (R) Standard indications (S) Contraindication (CI) -appearance of MenACWY, MenB, inactivated Zoster -MenC/MenACWY: switch S R -HPV: switch R A -MMR: switch R S -VZV: switch R A 12
Review Clin Infect Dis 2014 Med follow-up 9mo-9years Med 40 pts/study 13
Measles immunization (MMR) 10 children studies, 2 adults studies Metaanalyse 5 children studies 68% still protected>2y 40% >5y Adult data: 95% still protected if immunized during childhood (= before HIV) 43% still protected 1y after vaccination if vaccinated during adulthood 14
Measles immunization (MMR) Metaanalyse 5 children studies 68% still protected>2y 40% >5y 10 children studies, 2 adults studies Nadir CD4 T cells count predicts functionnal responses to immunisations in chronic HIV infection, even after years of suppressive antiviral therapy Adult data: 95% still protected if immunized during childhood (= before HIV) 43% still protected 1y after vaccination if vaccinated during adulthood Lange et al. AIDS 2003, 17:2015 2023 15
Respect Innovation Engagement Solidarity Quality 16 16
Tetanos immunization in HIV infected children Only children data (241 pts- 8 studies- 76% retro) 67-90% still protected >2 y 78% still protected >4 y Meta analyse (prosp studies): 74% still protected >2 y, 43% >4 y ccl: probably booster/10 y ok Adult data? 17
Duration of TT seroprotection using linear regression in HIV-negative population Estimated half life : 11 years 95% population protected 64 years after vaccination 0.01 IU/ml Log10 (ATA)= α+β*years after vaccination α : log [ATA] at time of immunization β : decay rate [ATA] Hammarlund CID 2016
Anti-TT Antibodies persistance after immunization in HIV-infected adults N= 66 T½ (anti-tt Ab decay) 4 years [IC95%, 2,7-7,7] Gobert C et al, unpublished data
Yellow Fever Vaccine 20
Veit et al. Clin Infect Dis 2017 247 pts < Swiss HIV Cohort Primovaccination after HIV diagnosis - 83% with VL<400 cop/ml - med CD4=536/mm 3 Overall - baseline sero+ 46% (!) - 1 year 95% - 5 years 86% - 10 years 75% VL<400 cop/ml - baseline sero+ 46% (!) - 1 year 99% - 5 years 99% - 10 years 100%
First results of CHU Saint-Pierre YF study: preliminary! N= 230 patients Age: med 43 y F 56% HIV mode acq: Ht 75% MSM 19% 7% received YFV before HIV received YFV when HIV+ From SSA 75% 93% >10 y in YF endemic countries: 84% pts/ travel 1 mo (med 3x) 22
Immunovirological parameters At time of vaccination - med CD4 564/mm³ - med HIV VL<20 - nadir CD4 230/mm³ But nadir CD4<200: 41% AIDS event in 20% (mostly before YFV) At NT determination -med CD4 650 -med HIV VL <20 Med time between YFV and Ab determination «delay» : 63 mo (3-455) Med time with ART during delay: 100% 23
Results and analysis NT 1/10 80% NT < 10 20% Risk factors for non-protection: -YFV before or after HIV diagnosis p= 0.0283 -Age/ Sex/ ethnicity/ HIV acquisition mode p=ns -Med CD4 at time of vaccination p=0.0386 -Cat CD4 at time of vaccination>500 versus <500/mm³ p=ns -Med VL at time of vaccination p=0.0008 -Cat VL at time of vaccination <50 versus >50/ml p=0.02 -Nadir CD4 p= NS -Immunovirological parameters at NT determination p=ns -Time under ART during delay YFV-NT determination p<0.0001 24
Plan 1. Mechanisms of defective vaccine response during HIV infection 2. Vaccine schedule : current recommandations and recent data 3. Vertically-infected young adults : a special population
Young vertically-infected subjects & vaccine response SIV-model of vertical infection (Xu J Immunol 2018) Profound impact on germinal centers Tfh development Limited B cells expansion & proliferation High rate of (un)structured treatment interruption (Rakhmanina JIAS 2016) CD4+ T cells, Tfh & memory B cells preservation require sustained viral control (Adland AIDS 2018, Muema PLoS One 2017) Meta analysis indicate lower seroconversion rate & antibody persistance What about vertically infected subjects entering adults care?
Vertical transmission is a risk factor for measles seronegativity CHU Saint-Pierre Cohort Retrospective study Measles seronegativity in vertically infected subjects 67.7% vs 15.4% (OR 7.7, 95% CI 3.3-18.3) Median age : 19 years Majority had 2 doses PENTA Guidelines : Retest Measles serology every 3-5 years Dauby HIV Med 2018
High proportion of rubella seronegativity in perinatally-infected women of childbearing age Retrospective study Perinatally-infected women of childbearing age (n=29) Age-matched HIV-infected subjects non-vertical infection (n=58) No difference in Born outside Belgium Sub-Saharan Africa origin VL, CD4 and nadir CD4 Rubella seronegativity (WHO cut off ; 10 IU/ml) 34% (10/29) vs 7,16% (4/58) (p=0.03) Majority of vertically-infected women had received > 1 dose of MMR (median=2) Beum AB et al, manuscript in preparation
Conclusions Chronic HIV infection alters B cells, Tfh phenotype & functions compromising GC dynamics that lead to efficient long lived vaccine response Early treatment is critical to preserve those functions Vaccine schedule should be tailored & serological testing considered in : Vertically infected adults Low nadir CD4 count Long duration of uncontrolled VL 29
Acknowledgements Pr Corazza C. Nagant Dr Sigi Van Den Wijngaert Funding Association d aide à la recherche médicale André Vésale BREACH Pr De Wit Dr Konopnicki Dr Libois Dr Genotte Dr Martin Dr Gérard Dr Payen Dr Semaille Dr De Rouffignac Marc Delforge
Thank You! Respect Innovation Engagement Solidarity Quality 31