Immunity to Bodetella pertussis. Kingston Mills. Trinity Biomedical Sciences Institute Trinity College Dublin, Ireland

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1 Immunity to Bodetella pertussis Kingston Mills Trinity Biomedical Sciences Institute Trinity College Dublin, Ireland

2 Correlates / mechanisms of immunity Vaccine/ Infection Efficacy in Children Efficacy in mice Protect Against IgG (ELISA) Th2 Antibody Subclass wp or Infection ap 7-85% (4% 5yrs) 9-95% High Disease, Infection & Transmission IgG2a/c (mouse) Opsonizing Medium Disease IgG1 (mouse) Toxin neutralizing Innate immune (DC, Mθ, ILCs, NK, γδ) Antibody Tfh T T RM Y B cell Neutrophils Macrophages

3 IL-5 (pg/ml) IFN- (ng/ml) T cell responses Consistency across species Mouse Human Baboon Convalescent wp ap Th2 Mouse strain Redhead and Mills, I&I Conv wp ap Mills et al Buisman et al Mascart et al Mertosola et al Ausiellio et al De Magistis, Pizza and Rappuoli Infection and wp, and more variably ap, also induce Warfel & Merkl PNAS 214

4 Log 1 CFU / Lung Natural immunity induced by infection with B. pertussis is mediated by and IL-12 IFNγ DC IL-1β / IL-23 IL-17 Murine respiratory infection model B. Pertussis infected IFN-γR -/- Days post challenge B. Pertussis infected Wild type IFN-γR -/- low dose Bp IL-17 KO WT Days post challenge Mahon et al J Exp Med. 186(11): Ross et al. PLoS Pathog. 213;9(4):e13264.

5 % Protected after the fifth dose of DTaP, the odds of acquiring pertussis increased by an average of 42% per year Our findings highlight the need to develop new pertussis-containing vaccines that will provide long-lasting immunity. 1 Extrapolated from Klein, NEJM 212, McGirr & Fisman, Pediatrics Years since last vaccination Suggests ap are poor at inducing Immunological memory

6 Mechanisms of Immunological memory Ag Antigen-induced differentiation of naïve T/B Effector T / plasma T/B T Dendritic cell Tn T CM T EM T RM CD44 lo CD62L hi Naïve T cell CD44 hi CD62L hi Central memory T cell CD44 hi CD62L lo Effector memory T cell CD69 + CD13 + Tissue resident memory T cell T FH B cell B T follicular helper cell Y CXCR5 + PD-1 + Naive B cell Plasma cell

7 IL-21 A b s o lu te n u m b e rs / S p le e n T follicular helper (Tfh) Facilitate germinal center formation, B cell activation, antibody production & generation of long-term memory B cell responses. Secrete IL-21 and IL-4/IFNγ Induced during infection Induction influenced by adjuvants T FH B cell T FH in spleen of B. pertussis infected mice C D 4 + C X C R 5 + P D -1 + T fh c e lls D a y s P o s t In fe c tio n CD4 + CXCR5 + PD-1 + Day 7 Day T follicular helper cell Y CXCR5 + PD-1 + Naive B cell Plasma cell IFN-γ

8 Vaccine Tissue resident memory (T RM ) Innate immune (DC, Mθ, ILCs, DC NK, γδ) Naive T cell Tfh Lymph Node Naive B cell Y Effector & Effector & B Plasma cell Reside locally in mucosal tissues to provide the front line of defense against pathogens Derived from precursors that entered tissues during the effector phase of immune responses & remained poised within this compartment (i.e. maintain memory) A potential role in vaccine-induced immunity against microbes that infect mucosal tissues Spleen + other lymphoid tissue T EM T eff Infected lung Primed lung T CM T RM T RM (poised) infection IFN-γ? Neutrophil Macrophage

9 Cell x1^5 Cells x1 5 Immunization with wp induces superior effector memory T (T EM ) than an ap vaccine Spleen day of challenge 5 4 T CM Day Immune responses & CFU T EM Naive ap wp

10 wp vaccine Effector / T/B Tfh / T RM ap vaccine Effector Th2/ Antibody DC Naive T cell Effector / DC Naive T cell Effector Th2 / T T Lymph Node Tfh Naive B cell B Lymph Node Tfh Naive B cell B Spleen + other lymphoid tissue T EM T eff Infected lung Primed lung Spleen + other lymphoid tissue Infected lung Primed lung T CM T RM T RM (poised) infection IFN-γ? Neutrophil Macrophage

11 Adjuvants: activate innate immunity Bacteria STING Higgins and Mills, Curr Infect Dis Rep, (21)

12 Macropahges / Lung IFN- (ng/ml) Log 1 CFU / Lung Log 1 CFU / Lung Immunization with an experimental ap + TLR9 agonist, CpG, is as effective as wp against B. pertussis challenge ap vaccine rpt (1 μg) + FHA (2.5 μg) + alum or CpG protection mediated by Day PBS ap+ wp ap+ alum CpG Immune responses CFU PBS ap + alum ap + CpG wp Days Post Infection ** *** WT PBS WT ap + CpG IFN -/- ap + CpG *** Days Post Infection TLR agonist DC IL-12 IFNγ Macrophage 1 WT WT IFN- -/- PBS ap + CpG Ross et al. PLoS Pathog. 213;9(4):e13264.

13 Novel TLR2 agonist and antigen from B. pertussis BP kda lipoprotein from B. pertussis. A TLR2 agonist. Immunostimulatory in vitro and in vivo Antigenic component of B. pertussis immune responses to Bp1569 in infected mice. TLR1 BP1569 TLR2 LP1569 Synthetic lipopeptide version of BP1569. Activates dendritic that promote and responses. Adjuvant activity in vivo DC NFκB Pro-inflammatory cytokines: IL-6, IL-1, IL-12p4, TNFα

14 Prime / boost with an experimental acellular pertussis vaccine + TLR2 agonist induces sterilizing immunity in trachea Log 1 CFU / Trachea L o g 1 C F U / L u n g IL -1 7 (p g /m l) Log 1 antibody IF N - (n g /m l) Prime Boost PBS PBS ap + Alum ap + Alum ap + Alum ap + LP1569 ap+ LP1569 ap + LP1569 Ag/adj Dose FHA, rpt:.2 μg/mouse LP1569: 5 μg/mouse Alum: 1 μg/mouse P B S a P + a lu m, a P + a lu m a P + a lu m, a P + T L R 2 a a P + T L R 2 a, a P + T L R 2 a 6 L u n g s Trachea *** M e d iu m F H A P r n ** IF N 2 IL *** *** *** P B S a P /a lu m a P /a lu m a P / P B S a P /a lu m a P / a P / IgG 2a Days Post Challenge 1 ** ** PBS ap/alum ap/alum ap/lp156 PBS ap/alum ap/lp1569 ap/lp156 Mucosal Immunol. 215 May;8(3):67-17 and Allen et al unpublished

15 A rationally designed pertussis vaccine based on established correlates of Immunity? Vaccine/ Infection Efficacy in Children Efficacy in mice IgG (ELISA) Th2 Opson Ab B / Tfh T / T RM ap 7-85% Medium wp or Infection 9-95% High ap + novel adjuvants (PAMPs)? High ??

16 Conclusions Current ap vaccines administered with alum as the adjuvant have suboptimal efficacy and in particular induction of long term immunity Fail to induce appropriate immunological memory Fail to induce appropriate T cell responses, including, circulating Tfh and lung T RM Possible solutions Booster immunization with a reformulated vaccine (e.g. add new adjuvant to existing Tdap for preschool/adolescent booster) 3 rd generation paediatric ap vaccine with /Tfh/T RM inducing adjuvant (+/- alum) needed to address resurgence of pertussis

17 Mieszko Wilk Alicja Misiak Martina Gogarty Caroline Sutton Mathilde Raverdeau Conor Finlay Joseph DeCourcey Mark Lynch Heather Kavanagh Aideen Allen Roisin McManus Sarah Edwards Niamh McGuinness Lydia Dyck Aoife McGinley Shauna Quinn Robert Walsh Enterprise Ireland Sarah Higgins Pádraig Ross Lisa Mielke Neil Marshall Mark Ryan Liz Ryan Bernard Mahon Collaborators Marina Lynch Aisling Dunne