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David J Lewis,
Carol A Fraser,
Abdel N Mahmoud,
Rebecca C Wiggins,
Maria Woodrow,
Alethea Cope,
Chun Cai, Rafaela Giemza,
Simon A Jeffs,
Maria Manoussaka,
Tom Cole,
Martin P Cranage,
Robin J Shattock,
Charles J Lacey
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ABSTRACT: 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. TRIAL REGISTRATION: ClinicalTrials.gov NCT00637962.
PLoS ONE 01/2011; 6(9):e25165. · 4.09 Impact Factor
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ABSTRACT: Bacille Calmette Guérin substrain Moreau Rio de Janeiro is an attenuated strain of Mycobacterium bovis that has been used extensively as an oral tuberculosis vaccine. We assessed its potential as a challenge model to study clinical and immunological events following repeated mycobacterial gut infection. Seven individuals received three oral challenges with approximately 10(7) viable bacilli. Clinical symptoms, T-cell responses and gene expression patterns in peripheral blood were monitored. Clinical symptoms were relatively mild and declined following each oral challenge. Delayed T-cell responses were observed, and limited differential gene expression detected by microarrays. Oral challenge with BCG Moreau Rio de Janeiro vaccine was immunogenic in healthy volunteers, limiting its potential to explore clinical innate immune responses, but with low reactogenicity.
Vaccine 07/2010; 28(33):5427-31. · 3.77 Impact Factor
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David J M Lewis,
Zhiming Huo,
Susan Barnett,
Ingrid Kromann, Rafaela Giemza,
Eva Galiza,
Maria Woodrow,
Birgit Thierry-Carstensen,
Peter Andersen,
Deborah Novicki,
Giuseppe Del Giudice,
Rino Rappuoli
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ABSTRACT: 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.
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.
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.
PLoS ONE 01/2009; 4(9):e6999. · 4.09 Impact Factor
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Christine Sadorge,
Anna Ndiaye,
Nathalie Beveridge,
Schale Frazer, Rafaela Giemza,
Nathalie Jolly,
Julie Johnson,
Helen Liddy,
Catherine A Cosgrove,
Paola Allavena,
Alberto Mantovani,
Stéphane Béchet,
Annick Fontaine-Thompson,
George E Griffin,
Francis Dupont,
Philippe J Sansonetti,
David J M Lewis
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ABSTRACT: Twenty-eight adults received between 10(2) and 10(8)colony forming units of live Shigella dysenteriae type-1 vaccine SC599, attenuated by deletion of invasion (icsA), iron chelation (ent, fep) and shiga toxin A-subunit (stxA) genes, followed by ciprofloxacin on day 4. Dose-independent diarrhea or change in bowel habit was seen in 3 subjects, without dysentery, vaccinaemia or serious adverse events. Hematology and biochemical parameters were unchanged. Doses of 10(5) or greater induced dose-independent SD1 lipopolysaccharide-specific antibody secreting cell (ASC) responses. Geometric mean number of IgA ASCs per 10(6) PBMCs for 10(5), 10(6), 10(7) and 10(8) groups were respectively 41, 8.8, 26 and 8.5. Serum antibody responses were seen in three subjects. SC599 appears immunogenic with maximum tolerated dose greater than 10(8)CFU.
Vaccine 03/2008; 26(7):978-87. · 3.77 Impact Factor
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ABSTRACT: 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.
Infection and Immunity 05/2006; 74(4):2449-52. · 4.16 Impact Factor
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Zhiming Huo,
Ruchi Sinha,
Edel A McNeela,
Ray Borrow, Rafaela Giemza,
Catherine Cosgrove,
Paul T Heath,
Kingston H G Mills,
Rino Rappuoli,
George E Griffin,
David J M Lewis
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ABSTRACT: Thirty-six healthy volunteers received either a single intramuscular injection of Neisseria meningitidis serogroup C polysaccharide (MCP)-CRM197 conjugate vaccine in alum or two nasal insufflations 28 days apart of the same vaccine powder, without alum, mixed with chitosan. Nasal immunization was well tolerated, with fewer symptoms reported than after intramuscular injection. The geometric mean concentrations of MCP-specific immunoglobulin G (IgG) after one nasal immunization were 3.25 microg/ml in naïve subjects and 14.4 microg/ml in subjects previously immunized parenterally, compared with 4.30 microg/ml in naïve subjects immunized intramuscularly. The geometric mean titer of serum bactericidal antibody (SBA) rose 24-fold after two nasal immunizations in naïve subjects and was comparable to parenteral immunization (1,080 versus 1,625). All subjects achieved SBA titers associated with protection after two nasal immunizations: even those with titers of <8 at entry. A single nasal immunization boosted the SBA titer to > or =128 in 96% of previously immunized subjects, and two immunizations achieved this level in 92% of naive subjects. MCP-specific IgG levels were approximately 70% IgG2 and approximately 20% IgG1 after nasal or intramuscular immunization. Increases in CRM197-specific IgG and diphtheria toxin-neutralizing activity were observed after nasal or intramuscular immunization, with balanced IgG1/IgG2 and higher IgG4. Significant MCP-specific secretory IgA was detected in nasal wash only after nasal immunization and predominantly on the immunized side. Simple nasal insufflation of existing MCP-CRM197 conjugate vaccines in chitosan offers an inexpensive but effective needle-free prime and boost against serogroup C N. meningitidis and diphtheria.
Infection and Immunity 12/2005; 73(12):8256-65. · 4.16 Impact Factor
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Kingston H G Mills,
Catherine Cosgrove,
Edel A McNeela,
Amy Sexton, Rafaela Giemza,
Inderjit Jabbal-Gill,
Anne Church,
Wu Lin,
Lisbeth Illum,
Audino Podda,
Rino Rappuoli,
Mariagrazia Pizza,
George E Griffin,
David J M Lewis
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ABSTRACT: Subunit intranasal vaccines offer the prospect of inducing combined systemic-mucosal immunity against mucosally transmitted infections such as human immunodeficiency virus. However, although human studies have demonstrated the induction of active immunity, secretory immunoglobulin A (sIgA) responses are variable, and no study has demonstrated protection by accepted vaccine-licensing criteria as measured by direct toxin-neutralizing activity. Using the genetically inactivated mutant diphtheria toxoid CRM(197) in a bioadhesive polycationic polysaccharide chitosan delivery system, we found that a single nasal immunization was well tolerated and boosted antitoxin neutralizing activity in healthy volunteers, which could be further boosted by a second immunization. The neutralizing activity far exceeded accepted protective levels and was equivalent to that induced by standard intramuscular vaccine and significantly greater than intranasal immunization with CRM(197) in the absence of chitosan. A striking but unexpected observation was that although unilateral intranasal immunization induced circulating antitoxin antibody-secreting cells, a nasal antitoxin sIgA response was seen only after the second immunization and only in the vaccinated nostril. If these data are reproduced in larger studies, an intranasal diphtheria vaccine based on CRM(197)-chitosan could be rapidly licensed for human use. However, a restricted sIgA response suggests that care must be taken in the priming-boosting strategy and clinical sampling techniques when evaluating such vaccines for the induction of local mucosal immunity.
Infection and Immunity 03/2003; 71(2):726-32. · 4.16 Impact Factor
