Program Schedule

LB-2
Avian Influenza A/H7N9 Vaccine Mixed with MF59 Adjuvant at the Point-of-Use.  A Randomized Clinical Trial of a Pandemic Threat Response

Session: Oral Abstract Session: Late Breaker Oral Abstracts
Saturday, October 11, 2014: 10:40 AM
Room: The Pennsylvania Convention Center: 105-AB
Background: An avian H7N9 influenza outbreak has caused morbidity with high mortality in China since 2013.  To compare the safety and immunogenicity of H7N9 vaccine with or without MF59 adjuvant, we conducted a phase 2 clinical trial at four NIAID-funded Vaccine and Treatment Evaluation Units (VTEUs).

Methods: Healthy adults aged 19-64 years were given influenza A/Shanghai/2/13 (H7N9) inactivated virus vaccine IM on days 0 and 21 at nominal antigen (Ag) doses of 3.75, 7.5, 15, or 45µg.  Field site mixing of Ag with MF59 (9.75 mg squalene/0.25ml) was performed for both, one or neither of the 2 doses.  Key study outcomes were antibody (Ab) titers on d42, vaccine-related serious adverse events, and solicited local and systemic symptoms post-vaccination.  B and T cells assays were performed on a subset of 37 participants.  ClinicalTrials.gov # NCT01938742.

Results: 700 subjects were enrolled.  Hemagglutination inhibition (HAI) and neutralizing Ab (NAb) were minimal after 2 doses of unadjuvanted vaccine or 1 dose of adjuvanted vaccine (any Ag dose).  For 3.75 µg + MF59, d42 HAI seroconversion (SC; 4-fold titer rise to >40) occurred in 60% (95% CI, 50-70); and geometric mean titer (GMT) was 35 (95% CI, 26-47).  Higher doses of Ag did not increase response.  For NAb, the 3.75 µg + MF59 group had a day 42 SC rate of 84% (95% CI, 76-91) with a GMT of 85 (95% CI, 69-104).  Mixing adjuvant with only the first of 2 15 µg doses was comparable to 2 adjuvanted 15 µg doses.  Recent seasonal flu vaccination and aging attenuated Ab responses.  Ab responses correlated with d8 Ab-secreting B cells (ASC; r=0.43; p=0.01) and CD4+ICOS+CXC3+CXCR5+ T follicular helper cells (TFH; r=0.57; p<0.001) in blood, but not d0 memory B cells.  TFH recognized H7 Ag, produced IL21, and trended higher with MF59.  There were no vaccine-related serious adverse events and reactogenicity was mostly mild with more frequent local symptoms seen with adjuvanted doses.

Conclusion: Point-of-use mixing and administration of 2 doses of H7N9 vaccine (3.75 µg) with MF59 produced d42 SC in 60% of subjects.  D8 ASC and CD4 TFH levels correlated with d42 HAI Ab response.  The study indicates potential value in this rapid response tactic against H7N9.  Remaining questions include Ab duration and protective efficacy.

Mark J. Mulligan, MD, FIDSA1, David Bernstein, MD2, Patricia Winokur, MD3, Richard Rupp, MD4, Lilin Lai, MD5, Evan J. Anderson, MD6, Nadine Rouphael, MD7, Michelle Dickey, CNP2, Jack T. Stapleton, MD8, Srilatha Edupuganti, MD9, Paul W. Spearman, MD, FIDSA10, Sarah Kabbani, MD, FIDSA5, Dilek Ince, MD11, Diana L. Noah, PhD12, Heather Hill, MS13, Abbie R. Bellamy14 and DMID 13-0032 H7N9 Vaccine Study Group, (1)Medicine, Infectious Diseases, Emory, Atlanta, GA, (2)Cincinnati Children's Hospital Medical Center, Cincinnati, OH, (3)University of Iowa, Iowa City, IA, (4)University of Texas Medical Branch, Galveston, TX, (5)Emory University Hope Clinic, Atlanta, GA, (6)Pediatrics and Medicine, Emory University School of Medicine, Atlanta, GA, (7)Emory University, Atlanta, GA, (8)University of Iowa and Iowa City VAMC, Iowa City, IA, (9)Infectious Diseases, Emory University School of Medicine, Decatur, GA, (10)Emory University School of Medicine, Atlanta, GA, (11)Division of Infectious Diseases, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, (12)Southern Research Institute, Birmingham, AL, (13)EMMES Corporation, Rockville, MD, (14)Emmes Corp, Rockville, MD

Disclosures:

M. J. Mulligan, None

D. Bernstein, Genocea: Research Contractor, Research support

P. Winokur, None

R. Rupp, None

L. Lai, None

E. J. Anderson, None

N. Rouphael, None

M. Dickey, None

J. T. Stapleton, None

S. Edupuganti, None

P. W. Spearman, None

S. Kabbani, None

D. Ince, None

D. L. Noah, None

H. Hill, None

A. R. Bellamy, None

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