Description
Background
Often contribution of an adjuvant to vaccine efficacy is shown in studies using one or up to three different doses. The suboptimal vaccine dose is determined in a prior dose finding study or based on literature. In either case, reproducibility is a problem, which affects the window to show improvement by the adjuvant. Another limitation is that these studies provide information within a limited dose range. Statistical analysis is restricted to comparing the groups, while interpolation would predict for a wider dose range. However, more doses are required for such an approach. Using multiple doses and fewer (1-2) animals per dose requires a different housing strategy. Historically, groups in challenge studies are housed separately, since non-protected placebo-animals may re-infect protected vaccinated animals. Here we tested the cationic adjuvant CAF09 in combination with a whole inactivated virus (WIV) vaccine against influenza H7N9 in a dose-response study.
Methods
20 ferrets were allocated to 4 cages of 5 ferrets. Vaccines were administered twice, three weeks apart with 5 different doses ranging from 0.94 – 15 µg HA with 2Log steps. Two cages received the H7N9 WIV only and the other two cages the CAF09 adjuvanted variant. Two weeks after last vaccination ferrets were intra-tracheally challenged with H7N9 influenza and ferrets were sacrificed after 5 days.
Results
Ferrets vaccinated with the vaccine alone show a clear dose-response on functional antibody titers clinical parameters, virus replication and pathology of the lung. The adjuvanted vaccine showed a dose-response on antibody titers after first vaccination, but all doses reached a plateau after booster vaccination. The adjuvanted-vaccine also provided near to complete protection at the lowest doses and full protection at the highest doses.
Conclusions
Thus, the dose-response approach using mixed dose-groups shows a clear dose-dependent effect of the vaccine alone and an immune potentiating effect and a strong contribution to the efficacy of the CAF09 adjuvant. However, the study design can be further improved by including a few lower doses and a placebo, such that also for the adjuvanted vaccine suboptimal effects are obtained. Moreover, re-infection of ferrets by using mixed dose-groups does not seem to play a role, since clear dose-response effects are visible for virus replication.
This study is a proof of concept of the dose-response approach, a strategy that provides results over a wider range of doses using a similar or lesser number of animals as single or multiple dose comparison studies, respectively. This allows for better investigation of adjuvant contribution and further on better clinical study design.
| Choose primary session | Vaccines and antivirals |
|---|---|
| Choose secondary Session | Virus host cell interaction |
