Tularemia vaccine: Safety, reactogenicity, "Take" skin reactions, and antibody responses following vaccination with a new lot of the Francisella tularensis live vaccine strain - A phase 2 randomized clinical Trial

Abstract

Background: Tularemia is caused by Francisella tularensis, a gram-negative bacterium that has been weaponized as an aerosol. For protection of personnel conducting biodefense research, the United States Army required clinical evaluation of a new lot of tularemia live vaccine strain manufactured in accordance with Current Good Manufacturing Practices.

Methods: A phase 2 randomized clinical trial compared the new lot (DVC-LVS) to the existing vaccine that has been in use for decades (USAMRIID-LVS). The vaccines were delivered by scarification to 228 participants. Safety, reactogenicity, take and/or antibody levels were assessed on days 0, 1, 2, 8, 14, 28, 56, and 180.

Principal results: Both vaccines were safe and had acceptable reactogenicity profiles during six months of follow-up. There were no serious or grade 3 and 4 laboratory adverse events. Moderate systemic reactogenicity (mostly headache or feeling tired) was reported by ∼23% of participants receiving either vaccine. Injection site reactogenicity was mostly mild itchiness and pain. The frequencies of vaccine take skin reactions were 73% (95% CI, 64, 81) for DVC-LVS and 80% (95% CI, 71, 87) for USAMRIID-LVS. The 90% CI for the difference in proportions was -6.9% (-16.4, 2.6). The rates of seroconversion measured by microagglutination assay on days 28 or 56 were 94% (95% CI, 88, 98; n=98/104) for DVC-LVS and 94% (95% CI, 87, 97; n=103/110) for USAMRIID-LVS (p=1.00). Day 14 sera revealed more rapid seroconversion for DVC-LVS relative to USAMRIID-LVS: 82% (95% CI, 73, 89) versus 55% (95% CI, 45, 65), respectively (p<0.0001).

Major conclusions: The DVC-LVS vaccine had similar safety, reactogenicity, take and antibody responses compared to the older USAMRIID vaccine, and was superior for early (day 14) antibody production. Vaccination take was not a sensitive surrogate for seroconversion in a multi-center study where personnel at five research clinics performed assessments. ClinicalTrials.gov identifier NCT01150695.

Keywords: Bacterial; Francisella tularensis; LVS; Take; Tularemia; Vaccine.

Conflict of interest statement

The authors had no conflicts of interest to report.

Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1. CONSORT diagram

The diagram details the dispositions for all participants who were enrolled and screened, and for eligible participants who were randomized and vaccinated. 1All enrolled and vaccinated subjects are included in the safety data analyses. 2The intention to treat (ITT) analysis population for the immunogenicity analyses includes all subjects. 3The per protocol (PP) analysis population for the immunogenicity analyses include subjects who met all inclusion and exclusion criteria, whose visits 7 and 8 were within protocol-specified windows (between days 26–30 and 49–63, respectively) and who contributed both pre- and post-vaccination blood samples for testing for which valid results were reported. Fourteen of the 228 subjects randomized and vaccinated were excluded from the per protocol immunogenicity analyses.

Figure 2. Digital Photographs of Representative Scarification Sites Categorized as Takes, by Study Visit

For selected days post-scarification, vaccine scarification sites and one saline scarification site are shown. The appearances of scarification sites for the two study vaccines were similar and so vaccine groups are not specified here. Take was defined as the development of an erythematous papule, vesicle, and/or eschar with or without underlying induration by days 7–9 as assessed by the VTEUs’ staffs.

Figure 3. Antibody Responses in the Microagglutination Antibody Assay. A

Proportions of subjects seroconverting (achieving a 4-fold or greater rise from day 0 baseline) by study group and study day. B. Geometric mean titers by study group and study day.