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A Cholera Conjugate Vaccine Containing O-specific Polysaccharide (OSP) of V. cholerae O1 Inaba and Recombinant Fragment of Tetanus Toxin Heavy Chain (OSP:rTTHc) Induces Serum, Memory and Lamina Proprial Responses against OSP and Is Protective in Mice.

Sayeed MA, Bufano MK, Xu P, Eckhoff G, Charles RC, Alam MM, Sultana T, Rashu MR, Berger A, Gonzalez-Escobedo G, Mandlik A, Bhuiyan TR, Leung DT, LaRocque RC, Harris JB, Calderwood SB, Qadri F, Vann WF, Kováč P, Ryan ET - PLoS Negl Trop Dis (2015)

Bottom Line: Intestinal lamina proprial IgA responses targeting OSP occurred following intradermal vaccination.We found no appreciable change in immune responses when the conjugate vaccine was administered in the presence or absence of immunoadjuvant alum.Development of an effective cholera conjugate vaccine that induces high level and long-term immune responses against OSP would be beneficial, especially in young children who respond poorly to polysaccharide antigens.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Center for Vaccine Sciences, International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh.

ABSTRACT

Background: Vibrio cholerae is the cause of cholera, a severe watery diarrhea. Protection against cholera is serogroup specific. Serogroup specificity is defined by the O-specific polysaccharide (OSP) component of lipopolysaccharide (LPS).

Methodology: Here we describe a conjugate vaccine for cholera prepared via squaric acid chemistry from the OSP of V. cholerae O1 Inaba strain PIC018 and a recombinant heavy chain fragment of tetanus toxin (OSP:rTTHc). We assessed a range of vaccine doses based on the OSP content of the vaccine (10-50 μg), vaccine compositions varying by molar loading ratio of OSP to rTTHc (3:1, 5:1, 10:1), effect of an adjuvant, and route of immunization.

Principle findings: Immunized mice developed prominent anti-OSP and anti-TT serum IgG responses, as well as vibriocidal antibody and memory B cell responses following intramuscular or intradermal vaccination. Mice did not develop anti-squarate responses. Intestinal lamina proprial IgA responses targeting OSP occurred following intradermal vaccination. In general, we found comparable immune responses in mice immunized with these variations, although memory B cell and vibriocidal responses were blunted in mice receiving the highest dose of vaccine (50 μg). We found no appreciable change in immune responses when the conjugate vaccine was administered in the presence or absence of immunoadjuvant alum. Administration of OSP:rTTHc resulted in 55% protective efficacy in a mouse survival cholera challenge model.

Conclusion: We report development of an Inaba OSP:rTTHc conjugate vaccine that induces memory responses and protection against cholera in mice. Development of an effective cholera conjugate vaccine that induces high level and long-term immune responses against OSP would be beneficial, especially in young children who respond poorly to polysaccharide antigens.

No MeSH data available.


Related in: MedlinePlus

Serum IgG responses at different time points against (A) O-specific polysaccharide (OSP) and (B) tetanus toxoid (TT) in various vaccine cohorts following intramuscular (IM) or intradermal (ID) immunization with various doses (based on OSP component) and/or loading ratios of OSP to TTHc, with or without adjuvant alum.Mice were immunized on days 0, 21, and 42. Responder frequency reflects a 15-fold increase over baseline for anti-OSP IgG, and 30-fold increase for anti-TT IgG. An asterisk denotes a statistically significant difference (P<0.05) in the mean response from baseline (day 0) level.
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pntd.0003881.g003: Serum IgG responses at different time points against (A) O-specific polysaccharide (OSP) and (B) tetanus toxoid (TT) in various vaccine cohorts following intramuscular (IM) or intradermal (ID) immunization with various doses (based on OSP component) and/or loading ratios of OSP to TTHc, with or without adjuvant alum.Mice were immunized on days 0, 21, and 42. Responder frequency reflects a 15-fold increase over baseline for anti-OSP IgG, and 30-fold increase for anti-TT IgG. An asterisk denotes a statistically significant difference (P<0.05) in the mean response from baseline (day 0) level.

Mentions: We found a significant increase in OSP (Fig 3A) and tetanus (Fig 3B)-specific IgG responses in serum of mice who received Inaba OSP-rTTHc vaccine intramuscularly or intradermally. These responses were comparable at different doses and molar ratios of OSP to TThc, with no major increase afforded when the vaccine was administered in the presence of alum. Significant responses (P<0.05) against OSP and TTHc were found in all cohorts of mice after a single immunization of vaccine when compared to baseline (day 0) levels, with responses being detectable within 7 days of first immunization in many cohorts. No antigen-specific responses were detected in mice immunized with alum alone. We found no significant increase in serum IgM or IgA responses in any vaccine cohort. In general, immune responses were comparable across all the vaccine cohorts, although anti-OSP responses rose more rapidly in mice immunized with 20 μg of OSP (5:1) compared to responses in mice immunized with 10 μg or 50 μg. Anti-TT responses were highest in mice immunized intradermally, with a significant boosting increase following the third immunization (Fig 3B). Following immunization with OSP:rTTHc, we found no significant induction of antibody targeting the squarate moiety used to attach OSP to carrier (Fig 4). We detected low level vibriocidal responses in vaccinated animals (Fig 5).


A Cholera Conjugate Vaccine Containing O-specific Polysaccharide (OSP) of V. cholerae O1 Inaba and Recombinant Fragment of Tetanus Toxin Heavy Chain (OSP:rTTHc) Induces Serum, Memory and Lamina Proprial Responses against OSP and Is Protective in Mice.

Sayeed MA, Bufano MK, Xu P, Eckhoff G, Charles RC, Alam MM, Sultana T, Rashu MR, Berger A, Gonzalez-Escobedo G, Mandlik A, Bhuiyan TR, Leung DT, LaRocque RC, Harris JB, Calderwood SB, Qadri F, Vann WF, Kováč P, Ryan ET - PLoS Negl Trop Dis (2015)

Serum IgG responses at different time points against (A) O-specific polysaccharide (OSP) and (B) tetanus toxoid (TT) in various vaccine cohorts following intramuscular (IM) or intradermal (ID) immunization with various doses (based on OSP component) and/or loading ratios of OSP to TTHc, with or without adjuvant alum.Mice were immunized on days 0, 21, and 42. Responder frequency reflects a 15-fold increase over baseline for anti-OSP IgG, and 30-fold increase for anti-TT IgG. An asterisk denotes a statistically significant difference (P<0.05) in the mean response from baseline (day 0) level.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4495926&req=5

pntd.0003881.g003: Serum IgG responses at different time points against (A) O-specific polysaccharide (OSP) and (B) tetanus toxoid (TT) in various vaccine cohorts following intramuscular (IM) or intradermal (ID) immunization with various doses (based on OSP component) and/or loading ratios of OSP to TTHc, with or without adjuvant alum.Mice were immunized on days 0, 21, and 42. Responder frequency reflects a 15-fold increase over baseline for anti-OSP IgG, and 30-fold increase for anti-TT IgG. An asterisk denotes a statistically significant difference (P<0.05) in the mean response from baseline (day 0) level.
Mentions: We found a significant increase in OSP (Fig 3A) and tetanus (Fig 3B)-specific IgG responses in serum of mice who received Inaba OSP-rTTHc vaccine intramuscularly or intradermally. These responses were comparable at different doses and molar ratios of OSP to TThc, with no major increase afforded when the vaccine was administered in the presence of alum. Significant responses (P<0.05) against OSP and TTHc were found in all cohorts of mice after a single immunization of vaccine when compared to baseline (day 0) levels, with responses being detectable within 7 days of first immunization in many cohorts. No antigen-specific responses were detected in mice immunized with alum alone. We found no significant increase in serum IgM or IgA responses in any vaccine cohort. In general, immune responses were comparable across all the vaccine cohorts, although anti-OSP responses rose more rapidly in mice immunized with 20 μg of OSP (5:1) compared to responses in mice immunized with 10 μg or 50 μg. Anti-TT responses were highest in mice immunized intradermally, with a significant boosting increase following the third immunization (Fig 3B). Following immunization with OSP:rTTHc, we found no significant induction of antibody targeting the squarate moiety used to attach OSP to carrier (Fig 4). We detected low level vibriocidal responses in vaccinated animals (Fig 5).

Bottom Line: Intestinal lamina proprial IgA responses targeting OSP occurred following intradermal vaccination.We found no appreciable change in immune responses when the conjugate vaccine was administered in the presence or absence of immunoadjuvant alum.Development of an effective cholera conjugate vaccine that induces high level and long-term immune responses against OSP would be beneficial, especially in young children who respond poorly to polysaccharide antigens.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Center for Vaccine Sciences, International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh.

ABSTRACT

Background: Vibrio cholerae is the cause of cholera, a severe watery diarrhea. Protection against cholera is serogroup specific. Serogroup specificity is defined by the O-specific polysaccharide (OSP) component of lipopolysaccharide (LPS).

Methodology: Here we describe a conjugate vaccine for cholera prepared via squaric acid chemistry from the OSP of V. cholerae O1 Inaba strain PIC018 and a recombinant heavy chain fragment of tetanus toxin (OSP:rTTHc). We assessed a range of vaccine doses based on the OSP content of the vaccine (10-50 μg), vaccine compositions varying by molar loading ratio of OSP to rTTHc (3:1, 5:1, 10:1), effect of an adjuvant, and route of immunization.

Principle findings: Immunized mice developed prominent anti-OSP and anti-TT serum IgG responses, as well as vibriocidal antibody and memory B cell responses following intramuscular or intradermal vaccination. Mice did not develop anti-squarate responses. Intestinal lamina proprial IgA responses targeting OSP occurred following intradermal vaccination. In general, we found comparable immune responses in mice immunized with these variations, although memory B cell and vibriocidal responses were blunted in mice receiving the highest dose of vaccine (50 μg). We found no appreciable change in immune responses when the conjugate vaccine was administered in the presence or absence of immunoadjuvant alum. Administration of OSP:rTTHc resulted in 55% protective efficacy in a mouse survival cholera challenge model.

Conclusion: We report development of an Inaba OSP:rTTHc conjugate vaccine that induces memory responses and protection against cholera in mice. Development of an effective cholera conjugate vaccine that induces high level and long-term immune responses against OSP would be beneficial, especially in young children who respond poorly to polysaccharide antigens.

No MeSH data available.


Related in: MedlinePlus