Randomized controlled ferret study to assess the direct impact of 2008-09 trivalent inactivated influenza vaccine on A(H1N1)pdm09 disease risk.
During spring-summer 2009, several observational studies from Canada showed increased risk of medically-attended, laboratory-confirmed A(H1N1)pdm09 illness among prior recipients of 2008-09 trivalent inactivated influenza vaccine (TIV). Explanatory hypotheses included direct and indirect vaccine effects. In a randomized placebo-controlled ferret study, we tested whether prior receipt of 2008-09 TIV may have directly influenced A(H1N1)pdm09 illness. Thirty-two ferrets (16/group) received 0.5 mL intra-muscular injections of the Canadian-manufactured, commercially-available, non-adjuvanted, split 2008-09 Fluviral or PBS placebo on days 0 and 28. On day 49 all animals were challenged (Ch0) with A(H1N1)pdm09. Four ferrets per group were randomly selected for sacrifice at day 5 post-challenge (Ch+5) and the rest followed until Ch+14. Sera were tested for antibody to vaccine antigens and A(H1N1)pdm09 by hemagglutination inhibition (HI), microneutralization (MN), nucleoprotein-based ELISA and HA1-based microarray assays. Clinical characteristics and nasal virus titers were recorded pre-challenge then post-challenge until sacrifice when lung virus titers, cytokines and inflammatory scores were determined. Baseline characteristics were similar between the two groups of influenza-naïve animals. Antibody rise to vaccine antigens was evident by ELISA and HA1-based microarray but not by HI or MN assays; virus challenge raised antibody to A(H1N1)pdm09 by all assays in both groups. Beginning at Ch+2, vaccinated animals experienced greater loss of appetite and weight than placebo animals, reaching the greatest between-group difference in weight loss relative to baseline at Ch+5 (7.4% vs. 5.2%; p = 0.01). At Ch+5 vaccinated animals had higher lung virus titers (log-mean 4.96 vs. 4.23pfu/mL, respectively; p = 0.01), lung inflammatory scores (5.8 vs. 2.1, respectively; p = 0.051) and cytokine levels (p>0.05). At Ch+14, both groups had recovered. Findings in influenza-naïve, systematically-infected ferrets may not replicate the human experience. While they cannot be considered conclusive to explain human observations, these ferret findings are consistent with direct, adverse effect of prior 2008-09 TIV receipt on A(H1N1)pdm09 illness. As such, they warrant further in-depth investigation and search for possible mechanistic explanations.
British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada ; University of British Columbia, Vancouver, British Columbia, Canada.
Danuta M
DM
Skowronski
Centre Hospitalier Universitaire de Québec [University Hospital Centre of Québec], Québec, Canada ; Laval University, Québec, Canada.
Marie-Eve
ME
Hamelin
Centre Hospitalier Universitaire de Québec [University Hospital Centre of Québec], Québec, Canada ; Laval University, Québec, Canada ; Institut National de Santé Publique du Québec [National Institute of Health of Québec], Québec, Canada.
Gaston
G
De Serres
British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada ; University of British Columbia, Vancouver, British Columbia, Canada.
Naveed Z
NZ
Janjua
British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada.
Guiyun
G
Li
British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada ; University of British Columbia, Vancouver, British Columbia, Canada.
Suzana
S
Sabaiduc
Centre Hospitalier Universitaire de Québec [University Hospital Centre of Québec], Québec, Canada.
Xavier
X
Bouhy
Institut universitaire de cardiologie et pneumologie de Québec, Québec, Québec, Canada.
Christian
C
Couture
Public Health Agency of Canada, Winnipeg, Manitoba, Canada.
Anders
A
Leung
Public Health Agency of Canada, Winnipeg, Manitoba, Canada ; Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada.
Darwyn
D
Kobasa
Canadian Food Inspection Agency, Winnipeg, Manitoba, Canada.
Carissa
C
Embury-Hyatt
Laboratory for Infectious Disease Research, Diagnostics and Screening, Centre for Infectious Disease Control (CIDC), Rijksinstituut voor Volksgezondheid en Milieu (RIVM) [National Institute of Public Health and the Environment], Bilthoven, The Netherlands.
Erwin
E
de Bruin
British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada ; University of British Columbia, Vancouver, British Columbia, Canada ; Simon Fraser University, Burnaby, British Columbia, Canada.
Robert
R
Balshaw
Institut universitaire de cardiologie et pneumologie de Québec, Québec, Québec, Canada.
Sophie
S
Lavigne
British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada ; University of British Columbia, Vancouver, British Columbia, Canada.
Martin
M
Petric
Laboratory for Infectious Disease Research, Diagnostics and Screening, Centre for Infectious Disease Control (CIDC), Rijksinstituut voor Volksgezondheid en Milieu (RIVM) [National Institute of Public Health and the Environment], Bilthoven, The Netherlands ; Viroscience Department, Erasmus MC, Rotterdam, The Netherlands.
Marion
M
Koopmans
Centre Hospitalier Universitaire de Québec [University Hospital Centre of Québec], Québec, Canada ; Laval University, Québec, Canada.
Guy
G
Boivin
D000704:Analysis of Variance; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005289:Ferrets; D006386:Hemagglutination Tests; D007150:Immunohistochemistry; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology / Q000472:pathogenicity*; D007252:Influenza Vaccines / Q000009:adverse effects* / Q000627:therapeutic use; D046228:Microarray Analysis; D009500:Neutralization Tests; D009976:Orthomyxoviridae Infections / Q000209:etiology* / Q000517:prevention & control; D015164:Vaccines, Inactivated / Q000009:adverse effects* / Q000627:therapeutic use
D000914:Antibodies, Viral; D007252:Influenza Vaccines; D015164:Vaccines, Inactivated