Abstract
Tularemia, also known as rabbit fever, is a severe zoonotic disease in humans caused by the gram-negative bacterium Francisella tularensis (Ft). While there have been a number of attempts to develop a vaccine for Ft, few candidates have advanced beyond experiments in inbred mice. We report here that a prime-boost strategy with aerosol delivery of recombinant live attenuated candidate Ft S4ΔaroD offers significant protection (83% survival) in an outbred animal model, New Zealand White rabbits, against aerosol challenge with 248 cfu (11 LD50) of virulent type A Ft SCHU S4. Surviving rabbits given two doses of the attenuated strains by aerosol did not exhibit substantial post-challenge fevers, changes in erythrocyte sedimentation rate or in complete blood counts. At a higher challenge dose (3,186 cfu; 139 LD50), protection was still good with 66% of S4ΔaroD-vaccinated rabbits surviving while 50% of S4ΔguaBA vaccinated rabbits also survived challenge. Pre-challenge plasma IgG titers against Ft SCHU S4 corresponded with survival time after challenge. Western blot analysis found that plasma antibody shifted from predominantly targeting Ft O-antigen after the prime vaccination to other antigens after the boost. These results demonstrate the superior protection conferred by a live attenuated derivative of virulent F. tularensis, particularly when given in an aerosol prime-boost regimen.
Highlights
We have previously reported that isogenic mutants (S4ΔaroD and S4ΔguaBA) of SCHU S4 protected rabbits against respiratory tularemia better than Live Vaccine Strain” (LVS) when given as a single vaccination by scarification, protection was not complete [35]
We have previously shown that a single vaccination by scarification with deletion mutants of SCHU S4 outperformed LVS in the outbred rabbit model of lethal aerosol SCHU S4 challenge
28 days post-challenge; body temperature and weight were tracked until day 18–21, when rabbits had returned to baseline values
Summary
Twenty rabbits were divided into three groups of 6 rabbits with 2 rabbits used as mock-vaccinated rabbits. In all three prime-boost groups, significant (p < 0.0002) protection was seen with 83% of rabbits surviving in the APAB group and 50% of rabbits surviving in both the APSB and SPAB groups when compared with mockvaccinated and historical controls (Fig 2A). Beginning on day 4 substantial weight loss (defined as 5%) was seen in the mock-vaccinated group that continued to decline until the rabbits succumbed (Fig 2C). In mock-vaccinated rabbits (which includes historical controls) there was a sharp rise in ESR on days 4 and 6 post-infection; these values were significantly higher than baseline (p < 0.0001) (Fig 4A). Similar to what we had observed with the first prime-boost study, rabbits in the vaccine groups at either challenge dose had less fever and weight loss post-challenge compared to the mock-vaccinated rabbits (Fig 5B and 5C).
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