Two Studies Evaluating the Safety and Immunogenicity of a Live, Attenuated Shigella flexneri 2a Vaccine (SC602) and Excretion of Vaccine Organisms in North American Volunteers

ABSTRACT We report the first community-based evaluation of Shigella flexneri 2a strain SC602, a live, oral vaccine strain attenuated by deletion of the icsA (virG) plasmid virulence gene, given at 104 CFU. The primary objectives of this trial were to determine the safety and immunogenicity of the vaccine and to determine the duration of colonization. Four of 34 volunteers experienced transient fevers, and three reported diarrhea during the first 3 days of the study. Half of the volunteers mounted a positive serum immunoglobulin A (IgA) response to S. flexneri lipopolysaccharide. All but one of the volunteers excreted the vaccine in their stools for 1 to 33 days, and this excretion was often intermittent. Data from the community-based study were supplemented with an inpatient trial in which three volunteers received 103 and nine received 104 CFU. All volunteers who received 103 CFU excreted SC602 and had an IgA antibody-secreting cell response. Two of these had a serum IgA response. Six of the nine volunteers who received 104 CFU excreted SC602. One vaccinee had a transient fever and two met the definition of diarrhea. Six volunteers that received 104 CFU had an antibody-secreting cell response, and four had a serum IgA response. SC602 has now been tested at 104 CFU in a total of 58 volunteers. The cumulative results of these clinical trials, reported here and previously (Coster et al., Infect. Immun. 67:3437-3443, 1999), have demonstrated that SC602 is a substantially attenuated candidate vaccine that can evoke protection against the most severe symptoms of shigellosis in a stringent human challenge model of disease.

Download Full-text

Antigen-Specific Immunoglobulin A Antibodies Secreted from Circulating B Cells Are an Effective Marker for Recent Local Immune Responses in Patients with Cholera: Comparison to Antibody-Secreting Cell Responses and Other Immunological Markers

Infection and Immunity ◽

10.1128/iai.71.8.4808-4814.2003 ◽

2003 ◽

Vol 71 (8) ◽

pp. 4808-4814 ◽

Cited By ~ 64

Author(s):

Firdausi Qadri ◽

Edward T. Ryan ◽

A. S. G. Faruque ◽

Firoz Ahmed ◽

Ashraful Islam Khan ◽

...

Keyword(s):

Immune Responses ◽

Immunoglobulin A ◽

Peripheral Circulation ◽

Secreting Cell ◽

Antibody Secreting Cell ◽

Immunological Responses ◽

B Subunit ◽

Mucosal Infection ◽

Circulating Lymphocytes

ABSTRACT Gut-derived lymphocytes transiently migrate through the peripheral circulation before homing back to mucosal sites and can be detected using an ELISPOT-based antibody secreting cell (ASC) assay. Alternatively, transiently circulating lymphocytes may be cultured in vitro, and culture supernatants may be assayed for antigen-specific responses (antibody in lymphocyte supernatant [ALS] assay). The ALS assay has not been validated extensively in natural mucosal infection, nor has the ALS response been compared to the ASC assay and other cholera-specific immunological responses. Accordingly, we examined immune responses in 30 adult patients with acute cholera in Bangladesh, compared with 10 healthy controls, measuring ALS-immunoglobulin A (IgA), ASC-IgA, and serum and fecal IgA responses to two potent Vibrio cholerae immunogens, the nontoxic B subunit of cholera toxin (CtxB) and lipopolysaccharide (LPS) and a weaker V. cholerae immunogen, the mannose-sensitive hemagglutinin (MSHA). We found significant increases of anti-CtxB, anti-LPS, and anti-MSHA IgA in supernatants of lymphocytes cultured 7 days after onset of cholera using the ALS assay. We found that ALS and ASC responses correlated extremely well; both had comparable sensitivities as the vibriocidal responses, and both procedures were more sensitive than fecal IgA measurements. An advantage of the ALS assay for studying mucosal immune responses is the ability to freeze antibodies in supernatants for subsequent evaluation; like the ASC assay, the ALS assay can distinguish recent from remote mucosal infection, a distinction that may be difficult to make in endemic settings using other procedures.

Download Full-text

A Potent Virus-Specific Antibody-Secreting Cell Response to Acute Enterovirus 71 Infection in Children

The Journal of Infectious Diseases ◽

10.1093/infdis/jiv094 ◽

2015 ◽

Vol 212 (5) ◽

pp. 808-817 ◽

Cited By ~ 7

Author(s):

Kuan-Ying Arthur Huang ◽

Jainn-Jim Lin ◽

Cheng-Hsun Chiu ◽

Shuan Yang ◽

Kuo-Chien Tsao ◽

...

Keyword(s):

Specific Antibody ◽

Cell Response ◽

Enterovirus 71 ◽

Secreting Cell ◽

Antibody Secreting Cell ◽

Virus Specific Antibody ◽

Enterovirus 71 Infection

Download Full-text

Total and Envelope Protein-Specific Antibody-Secreting Cell Response in Pediatric Dengue Is Highly Modulated by Age and Subsequent Infections

PLoS ONE ◽

10.1371/journal.pone.0161795 ◽

2016 ◽

Vol 11 (8) ◽

pp. e0161795 ◽

Cited By ~ 3

Author(s):

Jessica F. Toro ◽

Doris M. Salgado ◽

Rocío Vega ◽

Jairo A. Rodríguez ◽

Luz-Stella Rodríguez ◽

...

Keyword(s):

Specific Antibody ◽

Cell Response ◽

Envelope Protein ◽

Secreting Cell ◽

Antibody Secreting Cell

Download Full-text

Parameters Underlying Successful Protection with Live Attenuated Mutants in Experimental Shigellosis

Infection and Immunity ◽

10.1128/iai.69.2.1072-1083.2001 ◽

2001 ◽

Vol 69 (2) ◽

pp. 1072-1083 ◽

Cited By ~ 10

Author(s):

Maria Lina Bernardini ◽

Josette Arondel ◽

Irene Martini ◽

Awa Aidara ◽

Philippe J. Sansonetti

Keyword(s):

Double Mutant ◽

Wild Type Strain ◽

Shigella Flexneri ◽

Immunoglobulin A ◽

Wild Type ◽

Tissue Destruction ◽

Protective Capacity ◽

Nasal Tissue ◽

Essential Parameter ◽

Iga Response

ABSTRACT Because the use of live attenuated mutants of Shigellaspp. represents a promising approach to protection against bacillary dysentery (M. E. Etherridge, A. T. M. Shamsul Hoque, and D. A. Sack, Lab. Anim. Sci. 46:61–66, 1996), it becomes essential to rationalize this approach in animal models in order to optimize attenuation of virulence in the vaccine candidates, as well as their route and mode of administration, and to define the correlates of protection. In this study, we have compared three strains ofShigella flexneri 5—the wild-type M90T, anaroC mutant, and a double purE aroC mutant—for their pathogenicity, immunogenicity, and protective capacity. Protection against keratoconjunctivitis, induced by wild-type M90T, was used as the protection read out in guinea pigs that were inoculated either intranasally or intragastrically. Following intranasal immunization, the aroC mutant elicited weak nasal tissue destruction compared to M90T and achieved protection correlated with high levels of local anti-lipopolysaccharide immunoglobulin A (IgA), whereas the purE aroC double mutant, which also elicited weak tissue destruction, was not protective and elicited a low IgA response. Conversely, following intragastric immunization, only the M90T purE aroC double mutant elicited protection compared to both the aroC mutant and the wild-type strain. This mutant caused mild inflammatory destruction, particularly at the level of Peyer's patches, but it persisted much longer within the tissues. This could represent an essential parameter of the protective response that, in this case, did not clearly correlate with high anti-lipopolysaccharide IgA titers.

Download Full-text

Specific antibody secreting cell response to bacterial antigens in children with Kawasaki syndrome and healthy controls

Progress in Pediatric Cardiology ◽

10.1016/s1058-9813(06)80016-0 ◽

1992 ◽

Vol 1 (1) ◽

pp. 69

Author(s):

Mary P. Glode ◽

Rose L. Brogden ◽

John F. James ◽

Diane L. Lindflott ◽

James W. Wiggens

Keyword(s):

Specific Antibody ◽

Cell Response ◽

Kawasaki Syndrome ◽

Healthy Controls ◽

Secreting Cell ◽

Antibody Secreting Cell ◽

Bacterial Antigens

Download Full-text

Vaccination against Shigellosis with Attenuated Shigella flexneri 2a Strain SC602

Infection and Immunity ◽

10.1128/iai.67.7.3437-3443.1999 ◽

1999 ◽

Vol 67 (7) ◽

pp. 3437-3443 ◽

Cited By ~ 146

Author(s):

Trinka S. Coster ◽

Charles W. Hoge ◽

Lillian L. VanDeVerg ◽

Antoinette B. Hartman ◽

Edwin V. Oaks ◽

...

Keyword(s):

Shigella Flexneri ◽

Virulence Gene ◽

Enzyme Linked Immunosorbent Assay ◽

Dose Selection ◽

Chromosomal Locus ◽

Antibody Secreting Cell ◽

Severe Diarrhea ◽

Shigella Flexneri 2A ◽

Intercellular Spread ◽

Mild Diarrhea

ABSTRACT The Shigella flexneri 2a SC602 vaccine candidate carries deletions of the plasmid-borne virulence gene icsA(mediating intra- and intercellular spread) and the chromosomal locusiuc (encoding aerobactin) (S. Barzu, A. Fontaine, P. J. Sansonetti, and A. Phalipon, Infect. Immun. 64:1190–1196, 1996). Dose selection studies showed that SC602 causes shigellosis in a majority of volunteers when 3 × 108 or 2 × 106 CFU are ingested. In contrast, a dose of 104 CFU was associated with transient fever or mild diarrhea in 2 of 15 volunteers. All volunteers receiving single doses of ≥104 CFU excreted S. flexneri 2a, and this colonization induced significant antibody-secreting cell and enzyme-linked immunosorbent assay responses against S. flexneri 2a lipopolysaccharide in two-thirds of the vaccinees. Seven volunteers who had been vaccinated 8 weeks earlier with a single dose of 104 CFU and 7 control subjects were challenged with 2 × 103 CFU of virulent S. flexneri 2a organisms. Six of the control volunteers developed shigellosis with fever and severe diarrhea or dysentery, while none of the vaccinees had fever, dysentery, or severe symptoms (P = 0.005). Three vaccinees experienced mild diarrhea, and these subjects had lower antibody titers than did the fully protected volunteers. Although the apparent window of safety is narrow, SC602 is the first example of an attenuated S. flexneri 2a candidate vaccine that provides protection against shigellosis in a stringent, human challenge model.

Download Full-text