Abstract
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.
Highlights
During spring-summer 2009, several observational studies from Canada reported that prior receipt of the 2008–09 trivalent inactivated influenza vaccine (TIV) was associated with increased risk of medically-attended, laboratory-confirmed A(H1N1)pdm09 illness, with estimated risk or odds ratios of 1.4–2.5 compared to those unvaccinated [1]
Antibody Response Individual hemagglutination inhibition (HI), MN and ELISA assay results are displayed concurrently for pre-shipment, day 0, 28, 49 and 54/63 time points, for the four vaccinated and four placebo animals sacrificed at Ch+5 in Table S4, and for the 12 animals per group sacrificed at day 63 in Table S5 for vaccinated animals and Table S6 for placebo animals
Total influenza A ELISA antibody was significantly higher among vaccine compared to placebo animals at both scheduled sacrifices (Table 1)
Summary
During spring-summer 2009, several observational studies from Canada reported that prior receipt of the 2008–09 trivalent inactivated influenza vaccine (TIV) was associated with increased risk of medically-attended, laboratory-confirmed A(H1N1)pdm illness, with estimated risk or odds ratios of 1.4–2.5 compared to those unvaccinated [1]. Two small ferret studies reported no TIV effect on virus replication in nasal or lung specimens [14,15] but, where clinical outcomes have been assessed, several studies have shown consistent albeit non-significant trend toward greater weight loss and worsening of severity indicators in vaccinated ferrets [16,17,18,19] All of these ferret studies to date, have suffered from small sample size, typically comparing #5 animals per group in total
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