Transient Facial Nerve Paralysis (Bell's Palsy) following Intranasal Delivery of a Genetically Detoxified Mutant of Escherichia coli Heat Labile Toxin

BACKGROUND: An association was previously established between facial nerve paralysis (Bell's palsy) and intranasal administration of an inactivated influenza virosome vaccine containing an enzymatically active Escherichia coli Heat Labile Toxin (LT) adjuvant. The individual component(s) responsible for paralysis were not identified, and the vaccine was withdrawn. METHODOLOGY/PRINCIPAL FINDINGS: Subjects participating in two contemporaneous non-randomized Phase 1 clinical trials of nasal subunit vaccines against Human Immunodeficiency Virus and tuberculosis, both of which employed an enzymatically inactive non-toxic mutant LT adjuvant (LTK63), underwent active follow-up for adverse events using diary-cards and clinical examination. Two healthy subjects experienced transient peripheral facial nerve palsies 44 and 60 days after passive nasal instillation of LTK63, possibly a result of retrograde axonal transport after neuronal ganglioside binding or an inflammatory immune response, but without exaggerated immune responses to LTK63. CONCLUSIONS/SIGNIFICANCE: While the unique anatomical predisposition of the facial nerve to compression suggests nasal delivery of neuronal-binding LT-derived adjuvants is inadvisable, their continued investigation as topical or mucosal adjuvants and antigens appears warranted on the basis of longstanding safety via oral, percutaneous, and other mucosal routes

Phase I Randomised Clinical Trial of an HIV-1CN54, Clade C, Trimeric Envelope Vaccine Candidate Delivered Vaginally

We conducted a phase 1 double-blind randomised controlled trial (RCT) of a HIV-1 envelope protein (CN54 gp140) candidate vaccine delivered vaginally to assess immunogenicity and safety. It was hypothesised that repeated delivery of gp140 may facilitate antigen uptake and presentation at this mucosal surface. Twenty two healthy female volunteers aged 18–45 years were entered into the trial, the first receiving open-label active product. Subsequently, 16 women were randomised to receive 9 doses of 100 µg of gp140 in 3 ml of a Carbopol 974P based gel, 5 were randomised to placebo solution in the same gel, delivered vaginally via an applicator. Participants delivered the vaccine three times a week over three weeks during one menstrual cycle, and were followed up for two further months. There were no serious adverse events, and the vaccine was well tolerated. No sustained systemic or local IgG, IgA, or T cell responses to the gp140 were detected following vaginal immunisations. Repeated vaginal immunisation with a HIV-1 envelope protein alone formulated in Carbopol gel was safe, but did not induce local or systemic immune responses in healthy women

Boosting of cellular immunity against Mycobacterium tuberculosis and modulation of skin cytokine responses in healthy human volunteers by Mycobacterium bovis BCG substrain Moreau Rio de Janeiro oral vaccine

Oral immunization of healthy adults with 10(7) CFU BCG Moreau Rio de Janeiro was well tolerated and significantly boosted gamma interferon responses to purified protein derivative, Ag85, and MPB70 from previous childhood intradermal BCG immunization. Oral BCG offers the possibility of a needle-free tuberculosis vaccine and of boosting the protective immunity from intradermal tuberculosis vaccines

Randomised Clinical Trial Investigating the Specificity of a Novel Skin Test (C-Tb) for Diagnosis of <i>M. tuberculosis</i> Infection

<div><p>Background</p><p>Tuberculin skin testing is simple and relatively inexpensive, but the specificity of PPD is affected by BCG vaccination.</p><p>Objective</p><p>Determine optimal dose and specificity of recombinant ESAT-6 and CFP-10 (C-Tb) produced in <i>Lactococcus lactis</i> for diagnosis of <i>M. tuberculosis</i> infection.</p><p>Methods</p><p>In a dose finding phase I trial 0.01 or 0.1 µg preserved and unpreserved C-Tb was injected by Mantoux technique in 38 patients with active tuberculosis and induration responses measured. In a phase II specificity trial in 151 uninfected, BCG vaccinated participants 0.1 µg C-Tb was compared to 2 TU PPD.</p><p>Results</p><p>0.1 µg C-Tb gave a median induration of 15 mm after 2 days. Phenol preservation did not affect the response. The specificity of C-Tb was 99.3% (95% CI 96–100%) regarding indurations ≥5 mm as a positive outcome. This was higher than the specificity of PPD (63% using a cut-off of 5 mm or 92% using a cut-off of 15 mm to adjust for non-specific BCG responses). Local adverse reactions following C-Tb injection included transient itching and discomfort as expected components of the immune response.</p><p>Conclusion</p><p>C-Tb offers a simple and convenient skin test to diagnose <i>M. tuberculosis</i> infection using a single, universal cut-off unaffected by BCG vaccination.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT01033929" target="_blank">NCT01033929</a> and <a href="http://www.clinicaltrials.gov/ct2/show/NCT01241188" target="_blank">NCT01241188</a>.</p></div

Serum and nasal lavage antibody response to LTK63.

<p>Anti-LTK63 specific IgG and IgA in serum (µg/mL, (A)) and nasal lavage (ng/mL, (B)) measured by ELISA. Time course for individual response of Case 1 (left figures) and Case 2 (right figures) shown as blue lines. Response of remainder of group shown as group mean: for Case 1 (closed circles) n = 4; for Case 2 (who received only one dose) n = 15 receiving three doses (closed circles), and n = 4 receiving one dose (open circles). Error bars indicate SEM. Immunization days 0, 28, and/or 56 indicated by broad ticks crossing x-axis.</p