1. Non-Influenza Respiratory Virus Vaccines Larry J. Anderson DVD, NCIRD, CDC Atlanta, GA, USA 41 st National Immunization Conference Kansas City, Missouri

2. Acute Respiratory Infections Children Leading cause of morbidity and mortality ~2 million deaths/year Adults US -- ~1 million cases of community acquired pneumonia/yr US -- 6 th leading cause of death

3. Acute Respiratory Infections Viral agents Respiratory Syncytial Virus (RSV) Influenza virus A and B (Flu A and B) Human parainfluenza viruses 1-4 Adenoviruses Rhinoviruses, Enteroviruses New agents (HMPV, Coronaviruses, Parvoviruses) Bacterial agents S. Pneumonia, H. Influenza, M. Pneumonia, Chlamydia, etc. Gram negatives, M. TB, Legionella, other Unidentified etiology (unknown, undiagnosed)

4. Status of Non-Influenza, Respiratory Virus Vaccines AgentPopulation Live virus Inactivated/subunitStatus Adenovirus Military Recruits YesNoRe-licensure Clinical trials HPIV1, 3 ChildrenYesNo Phase 1 and 2 trials (HPIV 3) HMPVChildrenYesNoPre-clinical RSV Children, Adults YesYes Phase 1 and 2 trials SARS CoV ??Yes Phase 1 trials

5. New Respiratory Virus Vaccines The hope – an RSV vaccine The challenge – how to make a safe and effective vaccine

6. RSV Disease in Infants and Young Children: Washington DC Childrens Hospital Parrot et al. Am J Epidemiol 1973:98

7. Percentage of Respiratory Pathogens among Children <5 yr. Hospitalized with Fever or ARI

8. Estimates of RSV Hospitalizations and Deaths in Infants and Young Children Shay et al JAMA 1999;282:1440 Hospitalizations <1 yr (1980-1996)  Total –73,000-126,000  Bronchiolitis – 51,000- 82,000 yearly  Pneumonia - 22,000- 44,000 yearly Deaths <1 yr (1979- 1997)  Bronchiolitis and pneumonia - 171-510

9. FI-RSV Vaccine Trial, Washington D.C. 1966-67, Kapikian et al. Am J Epidemiolo 1969;89:1699 VaccineAge RSV Infected PneumoniaHospital FI-RSV (15) 6-23 mo 67%60%33% FI-HPIV (48) 48%8%0% FI-RSV (15) >23 mo 36%18%0% FI-HPIV (48) 31%11%2%

10. RSV – General Features Single-stranded, negative sense, nonsegmented RNA virus -- Family Paramyxoviridae –Attachment (G) proteins assist with viral adherence to the host cells –Fusion (F) proteins aid with viral penetration RSV diagram by Dr J Randhawa available at: http://www.bio.warwick.ac.uk/easton/

11. Classic Live RSV Vaccine Development Generate candidate vaccines Chemical mutagenesis Cold adaptation Sequential passage in tissue culture Combinations of above Select temperature sensitive mutant or replication deficient viruses Test candidate vaccines Studies in animals Clinical trials in humans

12. support plasmids ribozyme N P L Encodes full length antigenomic or genomic RNA Vero cells, qualified plaque assay passage transfection Recovery of infectious Virus from cDNA Reverse Genetics T7 promoter T7

13. Developing Live RSV Vaccines With Reverse Genetics Generate Hypotheses Sequence studies of candidate vaccines Functional studies of viral proteins Biology of infection/pathogenesis of disease Test Hypotheses Generate test viruses Tissue culture and animal studies Clinical trials in humans

14. Evolution of Candidate RSV Vaccines VirusGeneration Clinical Trials Cpts 245/955 CP TS Fever, AOM, ?LRI Cpts 530/1009 CP TS Fever, AOM, ?LRI Cpts 245/404 CP TS Nasal congestion Delta SH, NS1, NS2, M2-2 RG Cpts 245/404/1030 dSH RG Safe (?), ?effective – antibody response, re-challenge studies

15. Highly Attenuated Live RSV Candidate Vaccine in Infants Karron et al J. Infect. Dis. 2005;191:1093 # % Infected Days shed (Peak titer/ml) % with Fever/Resp % with Ab response Vaccine- 1 st dose 169410.6 3.5 log pfu 5631 Vaccine- 2 nd dose 164411.8 1.5 log pfu 3144 Placebo-11200170 Placebo-2900440

16. Rate of RSV and Influenza Attributable Deaths, U.S. 1990-1998

17. Other Strategies Insert immune active human genes Up/down regulate viral proteins Insert RSV proteins into other viruses Modify parts of RSV proteins Subunit/inactivated vaccines Other

18. Comments Need – –US population - 1 st RSV than others –Military recruits - adenovirus RSV vaccines –Powerful tools to understand biology of infection and pathogenesis of disease make ~any candidate live, inactivated, or subunit vaccine we want –?what we want