Randomized Controlled Ferret Study to Assess the Direct Impact of 2008-09 Trivalent Inactivated Influenza Vaccine on A(H1N1)pdm09 Disease Risk

被引:13
作者
Skowronski, Danuta M. [1 ,2 ]
Hamelin, Marie-Eve [3 ,4 ]
De Serres, Gaston [3 ,4 ,5 ]
Janjua, Naveed Z. [1 ,2 ]
Li, Guiyun [1 ]
Sabaiduc, Suzana [1 ,2 ]
Bouhy, Xavier [3 ]
Couture, Christian [6 ]
Leung, Anders [7 ]
Kobasa, Darwyn [7 ,8 ]
Embury-Hyatt, Carissa [9 ]
de Bruin, Erwin [10 ]
Balshaw, Robert [1 ,2 ,11 ]
Lavigne, Sophie [6 ]
Petric, Martin [1 ,2 ]
Koopmans, Marion [10 ,12 ]
Boivin, Guy [3 ,4 ]
机构
[1] British Columbia Ctr Dis Control, Vancouver, BC, Canada
[2] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada
[3] Univ Hosp Ctr Quebec, Quebec City, PQ, Canada
[4] Univ Laval, Quebec City, PQ, Canada
[5] Natl Inst Hlth Quebec, Inst Natl Sante Publ Quebec, Quebec City, PQ, Canada
[6] Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ, Canada
[7] Publ Hlth Agcy Canada, Winnipeg, MB, Canada
[8] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada
[9] Canadian Food Inspect Agcy, Winnipeg, MB, Canada
[10] Natl Inst Publ Hlth & Environm, Rijksinst Volksgezondheid Milieu RIVM, CIDC, Lab Infect Dis Res Diagnost & Screening, NL-3720 BA Bilthoven, Netherlands
[11] Simon Fraser Univ, Burnaby, BC V5A 1S6, Canada
[12] Erasmus MC, Virosci Dept, Rotterdam, Netherlands
基金
加拿大健康研究院;
关键词
H1N1; 2009; VACCINE; PANDEMIC INFLUENZA; VIRUS-INFECTION; PROTECTIVE EFFICACY; ANTIBODY-RESPONSE; IMMUNE-RESPONSES; NWS VIRUS; IMMUNIZATION; ASSOCIATION; EXPRESSION;
D O I
10.1371/journal.pone.0086555
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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-naive 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-naive, 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.
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页数:13
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