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Background

Immune Responses of Healthy Subjects to a Single Dose of Intramuscular Inactivated Influenza A/Vietnam/1203/2004 (H5N1) Vaccine After Priming With an Antigenic Variant. Nega Ali Goji, M.D., Carrie Nolan, N.P., Heather Hill, M.S., CCRC, Mark Wolf, Ph.D., Thomas Rowe, M.S., John J Treanor, M.D.

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  1. Immune Responses of Healthy Subjects to a Single Dose of Intramuscular Inactivated Influenza A/Vietnam/1203/2004 (H5N1) Vaccine After Priming With an Antigenic Variant. Nega Ali Goji, M.D., Carrie Nolan, N.P., Heather Hill, M.S., CCRC, Mark Wolf, Ph.D., Thomas Rowe, M.S., John J Treanor, M.D. University of Rochester Medical Center, Rochester, NY, EMMES Corporation, Rockville, MD, Southern Research Institute, Birmingham, AL

  2. Background • Non-adjuvanted, inactivated subvirion H5N1 vaccine required two 90 mcg doses to elicit neutralizing antibody in more than half of subjects • In one study, a third dose of inactivated A/Duck/Singapore/97 (H5N3) vaccine 16 months after a priming series resulted in significant boosting (Stephenson, 2003) • Pre-priming might generate better immunity, allowing a single dose strategy in face of emerging pandemic. However, any emergent pandemic virus will likely represent antigenic variant from the priming virus • We took advantage of a previous study evaluating a baculovirus recombinant H5 A/HK/156/97 (clade 3) vaccine performed in 1998 to evaluate effect of boosting with a single dose of subvirion A/VN/1203/04 (clade 1) vaccine.

  3. 128 64 Neutralizing GMT 32 16 8 Vaccine administered at visit S1 and S3 Neutralizing antibody responses to rH5 A/HK/156 vaccine Treanor Vaccine 19:1732, 2001

  4. Objectives • Determine the ability of a clade 3 H5 recombinant vaccine to prime for immune responses to a subsequent clade 1 H5 subvirion vaccine in healthy adults • Comparison of responses in H5 primed subjects to those of H5 naïve subjects • Determine the safety of revaccination with a clade 1 vaccine in primed subjects

  5. Methods • Subjects: participants in 1998 study who received a clade 3 rH5 vaccine baculovirus-expressed recombinant H5 vaccine (A/HK/156/97, Clade 3) • Vaccine: single 90 mcg dose of subvirion rgA/Vietnam/1203/04 x PR8 (clade 1) vaccine • Safety diary card x 7 days, all adverse events recorded over 56 days • Serum HAI and MN antibody tested at days 0, 28, and 56 • Results compared to responses to one (primary analysis) or two (secondary analysis) 90 mcg doses of clade 1 vaccine in naïve subjects

  6. Placebo 25 ug x 2 45 ug x 2 90 ug x 2 90 ug x 1 + 10 ug x 1 Evaluation of priming with an antigenic variant: schematic of study design 1998 2005 UR-98012 A/HK/156/97 rH5 DMID 05-0043 Healthy recipients of any rH5 rgA/VN/1203/04 H5-PRIMED Placebo excluded 90 ug x 1 37 subjects 147 subjects DMID 04-063 rgA/VN/1203/04 Vaccine 19:1732, 2001 H5-NAIVE 90 ug x 2 103 subjects NEJM 354:1343, 2006 CLADE 3 CLADE 1

  7. Demographics H5 NAIVE (DMID 04-063) n=103 H5 PRIMED (DMID 05-0043) n=37 White Black Asian Pacific Islander Multiracial Hispanic Female Age (median, range) 84 (82%) 11 (11%) 8 (8%) 0 (0%) 0 (0%) 13 (13%) 55 (54%) 38 (18-64) 35 (95%) 2 (5%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 23 (62%) 42 (33-51)

  8. Rates and severity of side effects after 1 (D1) or 2 doses (D2) in naïve subjects and after one dose in H5 vaccine-primed (PR) subjects

  9. H5 NAIVE H5 PRIMED 256 256 DMID 05-0043 DMID 04-063 128 128 64 64 GMT HAI Antibody GMT HAI Antibody 32 32 64.0 16 16 27.7 48.2 8 8 5.2 13.3 5.1 4 4 90 mcg 90 mcg 90 mcg Serum hemagglutination-inhibition (HAI) titers following one or two doses of H5 vaccine in naïve subjects or following a single dose in H5 vaccine-primed subjects

  10. H5 NAIVE H5 PRIMED 256 256 DMID 04-063 DMID 05-0043 128 128 64 64 93.8 GMT NT Antibody GMT NT Antibody 32 32 68.9 16 16 22.9 8 8 8.3 6.4 5.1 4 4 90 mcg 90 mcg 90 mcg Serum neutralizing (NT) antibody responses following one or two doses of H5 vaccine in naïve subjects or following a single dose in H5 vaccine-primed subjects

  11. Rates of serum HAI and NT antibody responses and proportion achieving a titer of 1:40 or greater after one or two doses of H5 vaccine in naïve subjects or after one dose in H5 vaccine-primed subjects Percent >1:40 (95% CI) Percent responding* (95% CI) Result 28 days after: Dose 1 Dose 2 Dose 1 Group H5 naïve H5 primed HAI 23 (15, 33) 43 (33, 54) 68 (50, 82) NT 10 (5, 18) 41 (32, 52) 76 (59, 88) HAI 24 (16, 34) 44 (34, 55) 70 (53, 84) NT 11 (6, 19) 42 (33, 53) 76 (59, 88) * Response defined as 4-fold or greater increase in titer from baseline. For the HAI assay, a response also must achieve a titer of 1:40 or greater

  12. Effect of the priming dose of recombinant H5 vaccine administered in 1998 on responses to 90 mcg of H5 vaccine in 2006 Response to a single dose of H5 vaccine in 2006 NT HAI 1998 Priming Dose 25 ug x 2 45 ug x 2 90 ug x 2 90 ug/10 ug Response* n (%) 7 (58%) 6 (86%) 5 (63%) 7 (70%) Response* n (%) 10 (83%) 6 (86%) 7 (88%) 9 (90%) N 12 7 8 10 GMT 63.5 155.1 42.1 48.7 GMT 195.6 304.5 174.5 134.5 * Response defined as 4-fold or greater increase in titer from baseline. For the HAI assay, a response also must achieve a titer of 1:40 or greater

  13. Relationship between response in 1998 and response in 2005 Response to a single dose of H5 vaccine in 2006 NT HAI Response to rH5 in 1998^ No Yes Response* n (%) 17 (63%) 8 (80%) Response* n (%) 22 (81%) 10 (100%) N 27 10 GMT 44.3 172.5 GMT 67.7 226.3 ^ Response in 1998 was defined as 4-fold or greater increase in MN titer to a titer of 1:80 or greater, accompanied by positive WB * Response defined as 4-fold or greater increase in titer from baseline. For the HAI assay, a response also must achieve a titer of 1:40 or greater

  14. Memory B cell responses of primed subjects in study DMID 05-043

  15. Conclusions • The antibody responses to a single dose of non-adjuvanted vaccine support the hypothesis that previous vaccination with a clade 3 H5 vaccine primed for responses to a clade 1 H5 vaccine • Antibody responses to a single booster dose exceeded those seen after two doses in naïve subjects, and were better than those seen with the original recombinant vaccine. The reasons for such vigorous responses to revaccination are unclear: • Revaccination was well tolerated, with a side effect profile similar to vaccination of naïve subjects.

  16. Conclusions • Further studies to evaluate different priming schedules and to verify priming between clade 1 and clade 2 viruses are needed • If the results were confirmed in larger studies, then pre-pandemic vaccination programs could be considered for some populations (first responders, HCW, military)

  17. Acknowledgements University of Rochester Carrie Nolan Diane O’Brien Mhorag Hay Dave Topham John Treanor Southern Research Institute Tom Rowe EMMES Corporation Mark Wolff Ken Wilkins Heather Hill DMID Roland Levandowski Linda Lambert Shy Shorer

  18. Response of healthy adults to a third dose of subvirion H5 vaccine (study DMID 04-090) 64 32 GMT HAI antibody 16 8 Vaccine 4 0 208 28 180 56 Study day

  19. Alignment of A/Hong Kong/156/97 and A/Vietnam/1203/04 H5 Hemagglutinins EID 11:1515-1521, 2005

  20. Antigenic relatedness of clade 3 and clade 1 viruses EID 11:1515-1521, 2005

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