Vaccine Development for Respiratory Viruses in Children. James E. Gern MD Professor of Pediatrics and Medicine University of Wisconsin Madison USA

Transcription

1 Vaccine Development for Respiratory Viruses in Children James E. Gern MD Professor of Pediatrics and Medicine University of Wisconsin Madison USA

2 Speaker Disclosure In accordance with the policy of the Thoracic Society of Australia and New Zealand the following presenter has indicated that they have a relationship which in the context of their presentation, could be perceived as a real or apparent conflict of interest but do not consider that it will influence their presentation. The nature of the conflict is listed: Consultant for companies interested in developing new therapies for respiratory viruses Regeneron PREP Biopharma Janssen

3 Which Viruses to Target? Bronchiolitis RSV 33.8 million cases/yr 1 May cause recurrent wheeze and contribute to asthma Treatment limited to palivizumab Costly Requires repeated injections Rhinovirus Wheezing in children 2 years of age Acute exacerbations of asthma, CF, COPD May cause recurrent wheeze and contribute to asthma No specific treatments are available 1 Nair H et al Lancet 2010;375:

4 Successful Vaccines Mimic Natural Immunity Polio Influenza Measles etc.

5 RSV Vaccine: Opportunities and Challenges Opportunities Only 2 RSV serotypes High risk populations have been identified Young Small airways Immune suppressed Genetic variability Challenges High titer antibody is needed for protection At risk = very young = immunologic immaturity Previous FI RSV vaccine accentuated severity of illness (Th2 mechanism)

6 RSV Vaccination in Early Life Live attenuated vaccines 1 Can cause URI symptoms Difficult balance of attenuation vs. immunogenicity Infants age < 4 months have impaired antibody responses to wild type RSV 2 1 Karron R et al Curr Top Microbiol Immunol 2013, 372: Sande C et al Vaccine 2014,

7 Approaches to RSV Vaccination Ruckwardt TJ et al Curr Opin Virol 16:

8 Vaccine Components Antigens Pre fusion F protein Antibodies have greater neutralizing capacity 1 N, G and M2 proteins are also potential targets Adjuvants 2 Age specific effects Animal models: TLR3, TLR3, and TLR9 Synergistic effects T eff vs. T reg Virosomes 3 Viral envelope + TLR2 and TLR4 agonists (P3CSK4 and MPLA respectively) 1 Ngwuta JO et al Sci Transl Med Ruckwardt TJ et al Curr Opin Virol 16: Kamphuis T et al Vaccine 2013;31:

9 RSV Vaccination during Pregnancy Transplacental antibody can modulate risk in the first few months of life 1 This approach has been successful for other infectious diseases Tetanus, pertussis, influenza 1 Chu HY et al J Infect Dis 2014, 210:

10 RV Vaccine: Opportunities and Challenges Opportunities Naturally occurring antibodies are neutralizing Substantial natural protection first few months At risk populations recognized Atopy Asthma, COPD and other chronic lung diseases Challenges ~180 types (likely serologically distinct) RV B probably attenuated Natural immunity has little or no cross protection 1 1 Mitchison DA. Br Med J. 1965;1(5446): Palmenberg A et al, Molecular Protocols, 2014

11 Reduced RV Antibodies are Associated with COPD Exacerations P = 0.01 Yerkovich ST et al BMC Pulm Med :37

12 Rhinovirus Canyon Jean Yves Sgro, IMV website

13

14 Is a Rhinovirus Vaccine Possible? Cross reactivity of capsid proteins Better adjuvants Masking of major epitopes Cross reactive T cell immunity

15 Rhinovirus Neutralization by Antibodies to VP4 RV capsids breathe, exposing internal epitopes of capsid proteins that are more conserved than surface epitopes Vaccination of to N terminus of VP4 Evidence of neutralization Some cross protection Katpally U et al J Virol, 2009;83:

16 Conservation of Amino Acid Sequence of VP1 Among RV A and RV B Katpally U et al J Virol, 2009;83:

17 Conservation of Amino Acid Sequence of VP4/VP2 among RV A and RV B Katpally U et al J Virol, 2009;83:

18 Rhinovirus Neutralization by Antibodies to VP4 Mice inoculated with VP4 peptides Neutralization assay for RV-B14 and RV-A16 Katpally U et al J Virol, 2009;83:

19 Cross Neutralization of Antibodies to VP1 Protein or Peptide Rabbits were immunized with VP1 from two different serotypes (RV B14 or RV A89) Cross neutralization tested in vitro Antibody responses to recombinant proteins were greater than those elicited by peptides Edlmayr J et al Eur Respir J 2011; 37: 44 52

20 Cross Neutralization of Antibodies to RV B and RV B VP1 Protein or Peptide Anti-89VP1 Anti-14VP1 a, 1:2; b, 1:4; c, 1:8; d, 1:16 Edlmayr J et al Eur Respir J 2011; 37: 44 52

21 RV Infections and Immunization Induce Cross Serotype Reactive Antibodies to VP1 Mouse models of intranasal infection and immunization RV1B, either infection or subq with Freund s adjuvant Cross reactive IgG responses to VP1 were detected in serum and BAL IgA responses were relatively weak Neutralizing responses required 2 or more infections McLean GR et al Antiviral Res 95 (2012)

22 Infection with RV1B and/or RV29 Increases RV1B Specific IgG Single Infections Serial Infections McLean GR et al Antiviral Res 95 (2012)

23 Effects of RV1B Immunization on Neutralizing Antibody McLean GR et al Antiviral Res 95 (2012)

24 Cross Serotype Immunity Induced by Immunization with Recombinant VP0 VP0 some highly conserved regions among RV A and RV B species Immunization of mice with recombinant RV A16 VP0 (VP2+VP4) little neutralizing antibody unless coupled with subsequent infection Immunization + Infection Some cross neutralization (RV 1B, RV 29) Some effect on viral clearance Glanville N et al PLOS Pathogens 2013;9:e

25 Immunization with VP0 Leads to More Rapid RV Clearance Immunized with RV-A16 VP0 ± adjuvant Mice infected with RV1B RV1B in lung tissue (qpcr) Glanville N et al PLOS Pathogens 2013;9:e

26 What about RV C? RV A and RV C replicate more rapidly than RV B 1 RV C and RV C are most likely to cause early life wheezing illnesses 2 Wheezing with RV C most closely associated with development of asthma 3 RV C is most likely associated with severe exacerbations of asthma 4 1 Nakagome K et al JACI 2014;134: Lee WM et al AJRCCM 2012;186: Teo et al Cell Host & Microbe 2015;17: Bizzintino et al ERJ 2011; 37:

27 Antibody Responses to RV C Viruses Sera from 63 healthy adults 1 Antibody responses to VP1 of RV A, B and C measured Cross reactivity of antibody responses within species Lower titers of specific antibody to RV C types RV C antibodies also low in children with exacerbations of asthma 2 1 Iwasaki J et al.. PLoS One 2013, 8:e Iwasaki J et al. JACI 2014;134:25-32

28 Reduced PBMC Responses to RV C Clinical isolates from all three species - A16, B52, C15 PBMC from normal volunteers Inoculate (2 X 10 8 RNA copies/100 µl) - Cytokines: TNF, IL 10 - IFN, IFN, IFN - Chemokines: MCP 1, MIP 1, CXCL10 Berry A, Devries M and Jackson D (unpublished)

29 Reduced Cytokine Responses to RV-C IFN-lambda 2

30 Species Effects on RV-Induced Cellular Responses Airway Epithelium PBMC RV-A RV-B RV-C Cytokine Production

31 Virus Bacteria Interactions Many RV infections cause mild illness or are asymptomatic Detection of either bacterial or viral pathogens in nasal secretions is associated with increased risk of wheezing illnesses 1 Do bacterial pathogens increase the severity of viral illnesses? 2 Children (half with asthma): weekly nasal samples tested by PCR for RV and bacterial pathogens Compared to assessment of respiratory symptoms and exacerbations of asthma 1 Bisgaard BMJ 2010 Oct 4;341:c Kloepfer et al J Allergy Clin Immunol 2014

32 Virus Precedes Detection of S. Pneumoniae Kloepfer et al J Allergy Clin Immunol 2014)

33 Combined Infections Increase the Risk for Illness and Exacerbations of Asthma Moraxella Strept Morax only vs. no pathogen Strep only vs. no pathogen Illness RV only vs. no pathogen RV+Morax vs. no pathogen * * RV only vs. no pathogen RV+Strep vs. no pathogen * * RV+Morax vs. RV only * RV+Strep vs. RV only Odds Ratio for Illness Odds Ratio for Illness Morax only vs. no pathogen M. Catarrhalis and RV S. Pneumoniae and RV D. (NA) E. Strep only vs. no pathogen Asthma Exacerbation RV only vs. no pathogen RV+Morax vs. no pathogen * * RV only vs. no pathogen RV+Strep vs. no pathogen * RV+Morax vs. RV only RV+Strep vs. RV only Kloepfer et al J Allergy Clin Immunol 2014 Odds Ratio for Exacerbation Odds Ratio for Exacerbation

34 Conclusions RSV vaccine High titer antibody needed Very young children must be protected Improved vaccine vs. prenatal immunization Rhinovirus: A&C clinically important, about 140 types Studies to date demonstrate some ability to elicit cross neutralization ofrrv A & RV B RV C may be most virulent, but less immunogenic Opportunities for bacterial immunization?

35 Acknowledgments UW Allergy/Immunology NIH Yury Bochkov NIAID: AADCRC (RhinoGen, Kazuyuki Nakagome RG RV A16, ICAC) Shamaila Ashraf NHLBI: COAST UW Institute for Molecular Virology Ann Palmenberg Kelly Watters Holly Basta Jean Yves Sgro Hiba Bashir Robert Lemanske Jr. Dan Jackson Kirsten Kloepfer (IUPUI) Rose Vrtis Tressa Pappas Mike Evans Ron Gangnon Becky Brockman Schneider Kris Grindle Amaziah Coleman Ann Esquivel Alalia Berry