Rotavirus spike protein ΔVP8* as a novel carrier protein for conjugate vaccine platform with demonstrated antigenic potential for use as bivalent vaccine

AbstractConjugate vaccine platform is a promising strategy to overcome the poor immunogenicity of bacterial polysaccharide antigens in infants and children. A carrier protein in conjugate vaccines works not only as an immune stimulator to polysaccharide, but also as an immunogen; with the latter generally not considered as a measured outcome in real world. Here, we probed the potential of a conjugate vaccine platform to induce enhanced immunogenicity of a truncated rotavirus spike protein ΔVP8*. ΔVP8* was covalently conjugated to Vi capsular polysaccharide (Vi) of Salmonella Typhi to develop a bivalent vaccine, termed Vi-ΔVP8*. Our results demonstrated that the Vi-ΔVP8* vaccine can induce specific immune responses against both antigens in immunized mice. The conjugate vaccine elicits high antibody titers and functional antibodies against S. Typhi and Rotavirus (RV) when compared to immunization with a single antigen. Together, these results indicate that Vi-ΔVP8* is a potent and immunogenic vaccine candidate, thus strengthening the potential of conjugate vaccine platform with enhanced immune responses to carrier protein, including ΔVP8*.

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Faculty of 1000 evaluation for Head-to-head comparison of humoral immune responses to Vi capsular polysaccharide and Salmonella Typhi Ty21a typhoid vaccines--a randomized trial.

F1000 - Post-publication peer review of the biomedical literature ◽

10.3410/f.718006642.793478204 ◽

2013 ◽

Author(s):

David Murdoch ◽

Gary McAuliffe

Keyword(s):

Immune Responses ◽

Randomized Trial ◽

Capsular Polysaccharide ◽

Salmonella Typhi ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Vi Capsular Polysaccharide ◽

Typhoid Vaccines

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Assessment of Antibody Response Elicited by a 7-valent Pneumococcal Conjugate Vaccine in Pediatric Human Immunodeficiency Virus Infection

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.12.1.165-170.2005 ◽

2005 ◽

Vol 12 (1) ◽

pp. 165-170 ◽

Cited By ~ 28

Author(s):

David Tarragó ◽

Julio Casal ◽

Jesús Ruiz-Contreras ◽

J. Tomás Ramos ◽

Pablo Rojo ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Immune Responses ◽

Conjugate Vaccine ◽

Pneumococcal Conjugate Vaccine ◽

Correlation Coefficients ◽

Antibody Responses ◽

Enzyme Linked Immunosorbent Assay ◽

Immunodeficiency Virus ◽

Vaccine Immunogenicity ◽

Functional Antibodies

ABSTRACT We investigated antibody responses against pneumococci of serotypes 6B, 14, and 23F in 56 children and adolescents with perinatal human immunodeficiency virus (HIV) infection who were vaccinated with 7-valent pneumococcal conjugate vaccine. Overall immune responses differed greatly between serotypes. Correlation coefficients between immunoglobulin G (IgG) measured by enzyme-linked immunosorbent assay (ELISA) and functional antibodies measured by a flow cytometry opsonophagocytosis assay (OPA) varied with serotype and time points studied. After 3 months of administering a second PCV7 dose we got the highest correlation (with significant r values of 0.754, 0.414, and 0.593 for serotypes 6B, 14, and 23F, respectively) but no significant increase in IgG concentration and OPA titers compared to the first dose. We defined a responder to a serotype included in the vaccine with two criteria: frequency of at least twofold OPA and ELISA increases for each serotype and frequency of conversion from negative to positive OPA levels. Responders varied from 43.9% to 46.3%, 28.5% to 50.0%, and 38.0% to 50.0% for serotypes 6B, 14, and 23F, respectively, depending on the response criterion. The present research highlights the importance of demonstrating vaccine immunogenicity with suitable immunological endpoints in immunocompromised patients and also the need to define how much antibody is required for protection from different serotypes, since immunogenicity differed significantly between serotypes.

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Conjugate-like immunogens produced as protein capsular matrix vaccines

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1425005112 ◽

2015 ◽

Vol 112 (10) ◽

pp. E1143-E1151 ◽

Cited By ~ 19

Author(s):

Ann Thanawastien ◽

Robert T. Cartee ◽

Thomas J. Griffin ◽

Kevin P. Killeen ◽

John J. Mekalanos

Keyword(s):

T Cell ◽

Immune Responses ◽

Protective Immunity ◽

The Elderly ◽

Covalent Attachment ◽

Carrier Protein ◽

Elderly Age ◽

Conjugate Vaccines ◽

Age Cohorts ◽

Polysaccharide Antigens

Capsular polysaccharides are the primary antigenic components involved in protective immunity against encapsulated bacterial pathogens. Although immunization of adolescents and adults with polysaccharide antigens has reduced pathogen disease burden, pure polysaccharide vaccines have proved ineffective at conferring protective immunity to infants and the elderly, age cohorts that are deficient in their adaptive immune responses to such antigens. However, T-cell–independent polysaccharide antigens can be converted into more potent immunogens by chemically coupling to a “carrier protein” antigen. Such “conjugate vaccines” efficiently induce antibody avidity maturation, isotype switching, and immunological memory in immunized neonates. These immune responses have been attributed to T-cell recognition of peptides derived from the coupled carrier protein. The covalent attachment of polysaccharide antigens to the carrier protein is thought to be imperative to the immunological properties of conjugate vaccines. Here we provide evidence that covalent attachment to carrier proteins is not required for conversion of T-independent antigens into T-dependent immunogens. Simple entrapment of polysaccharides or a d-amino acid polymer antigen in a cross-linked protein matrix was shown to be sufficient to produce potent immunogens that possess the key characteristics of conventional conjugate vaccines. The versatility and ease of manufacture of these antigen preparations, termed protein capsular matrix vaccines (PCMVs), will likely provide improvements in the manufacture of vaccines designed to protect against encapsulated microorganisms. This in turn could improve the availability of such vaccines to the developing world, which has shown only a limited capacity to afford the cost of conventional conjugate vaccines.

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Immunogenicity of a Heptavalent Conjugate Pneumococcal Vaccine Administered Concurrently with a Combination Diphtheria, Tetanus, Five-Component Acellular Pertussis, Inactivated Polio, and Haemophilus influenzae Type b Vaccine and a Meningococcal Group C Conjugate Vaccine at 2, 3, and 4 Months of Age

Clinical and Vaccine Immunology ◽

10.1128/cvi.00315-09 ◽

2009 ◽

Vol 17 (3) ◽

pp. 311-316 ◽

Cited By ~ 14

Author(s):

S. J. Moss ◽

A. C. Fenton ◽

J. Toomey ◽

A. Grainger ◽

R. Borrow ◽

...

Keyword(s):

Immune Responses ◽

Haemophilus Influenzae ◽

Conjugate Vaccine ◽

Capsular Polysaccharide ◽

Geometric Mean ◽

Haemophilus Influenzae Type ◽

Type B ◽

Term Infants ◽

Meningococcal Group ◽

Pneumococcal Serotype

ABSTRACT The immunogenicities of conjugate pneumococcal vaccines have been demonstrated when they are administered at 2, 3, and 4 months of age. There is a paucity of data on the immunogenicity of this vaccine when it is administered concurrently with other vaccines in the primary immunization schedule of the United Kingdom. We immunized 55 term infants at 2, 3, and 4 months of age with the seven-valent pneumococcal conjugate vaccine (PCV7), the meningococcal group C conjugate (MCC) vaccine, and the diphtheria, tetanus, five-component acellular pertussis, inactivated polio, and Haemophilus influenzae type b (DTaP5/IPV/Hib-TT) vaccine. The immune responses to the H. influenzae type b (Hib), MCC, and tetanus vaccines were measured at 2, 5, and 12 months of age; and the immune responses to PCV7 were measured at 2 and 5 months and then either at 12 months or following a 4th dose of PCV7. There were increases in the geometric mean concentrations (GMCs) of all antigens postimmunization. Greater than or equal to 90% of the infants achieved putatively protective levels postimmunization for all vaccine antigens except pneumococcal serotype 6B and Hib. The GMCs of the PCV7 serotypes increased following a 4th dose, although one infant had not reached putative levels of protection against serotype 6B. In conclusion, when infants were vaccinated according to the schedule described above, they had lower postprimary immunization responses to Hib, meningococcus group C capsular polysaccharide, and pneumococcal serotype 6B than the responses demonstrated by use of the other schedules. Despite this finding, there was a good response following a 4th dose of PCV7.

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Evidence of Extended Thermo-Stability of Typhoid Polysaccharide Conjugate Vaccines

Microorganisms ◽

10.3390/microorganisms9081707 ◽

2021 ◽

Vol 9 (8) ◽

pp. 1707

Author(s):

Fang Gao ◽

Kay Lockyer ◽

Alastair Logan ◽

Sarah Davis ◽

Barbara Bolgiano ◽

...

Keyword(s):

Conjugate Vaccine ◽

Structural Changes ◽

Capsular Polysaccharide ◽

Elevated Temperatures ◽

Storage Temperature ◽

Molecular Size ◽

Cold Chain ◽

Conjugate Vaccines ◽

Vi Capsular Polysaccharide ◽

Thermo Stability

Typhoid conjugate vaccines (TCV) are effective in preventing enteric fever caused by Salmonella enterica serovar Typhi in Southeast Asia and Africa. To facilitate vaccination with the Vi capsular polysaccharide–tetanus toxoid conjugate vaccine, Typbar TCV, and allow it to be transported and stored outside a cold chain just prior to administration, an extended controlled-temperature conditions (ECTC) study was performed to confirm the quality of the vaccine at 40 °C for 3 days at the end of its shelf-life (36 months at 2–8 °C). Studies performed in parallel by the vaccine manufacturer, Bharat Biotech International Limited, and an independent national control laboratory (NIBSC) monitored its stability-indicating parameters: O-acetylation of the Vi polysaccharide, integrity of the polysaccharide–protein conjugate, and its molecular size and pH. ECTC samples stored at 40 °C and 45 °C in comparison with control samples stored at 4 °C and 55 or 56 °C, were shown to have stable O-acetylation and pH; only very slight increases in the percentage of free saccharide and corresponding decreases in molecular size were observed. The deoxycholate method for precipitating conjugated polysaccharide was very sensitive to small incremental increases in percentage of free saccharide, in line with storage temperature and duration. This extended ECTC study demonstrated minimal structural changes to the Vi polysaccharide and conjugate vaccine and a stable formulation following extended exposure to elevated temperatures for the desired durations. This outcome supports the manufacturer’s ECTC claim for the vaccine to be allowed to be taken outside the cold chain before its administration.

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Effect of O Acetylation of Neisseria meningitidis Serogroup A Capsular Polysaccharide on Development of Functional Immune Responses

Infection and Immunity ◽

10.1128/iai.70.7.3707-3713.2002 ◽

2002 ◽

Vol 70 (7) ◽

pp. 3707-3713 ◽

Cited By ~ 99

Author(s):

David S. Berry ◽

Freyja Lynn ◽

Che-Hung Lee ◽

Carl E. Frasch ◽

Margaret C. Bash

Keyword(s):

Immune Responses ◽

Neisseria Meningitidis ◽

Conjugate Vaccine ◽

Essential Role ◽

Capsular Polysaccharide ◽

Enzyme Linked Immunosorbent Assay ◽

Dramatic Reduction ◽

Mouse Immunization ◽

Human Sera ◽

Inhibition Studies

ABSTRACT The importance of O-acetyl groups to the immunogenicity of Neisseria meningitidis serogroup A polysaccharide (PS) was examined in studies using human sera and mouse immunization. In 17 of 18 postimmunization human sera, inhibition enzyme-linked immunosorbent assay indicated that the majority of antibodies binding to serogroup A PS were specific for epitopes involving O-acetyl groups. Studies with mice also showed an essential role for O-acetyl groups, where serum bactericidal titers following immunization with de-O-acetylated (de-O-Ac) conjugate vaccine were at least 32-fold lower than those following immunization with O-Ac PS-conjugate vaccine and 4-fold lower than those following immunization with native capsular PS. Inhibition studies using native and de-O-Ac PS confirmed the specificity of murine antibodies to native PS. The dramatic reduction in immunogenicity associated with removal of O-acetyl groups indicates that O acetylation is essential to the immunogenic epitopes of serogroup A PS. Since levels of bactericidal antibodies are correlated with protection against disease, O-acetyl groups appear to be important in protection.

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Immune Responses to an Oral Typhoid Vaccine Strain That Is Modified to Constitutively Express Vi Capsular Polysaccharide

The Journal of Infectious Diseases ◽

10.1086/421469 ◽

2004 ◽

Vol 190 (3) ◽

pp. 565-570 ◽

Cited By ~ 51

Author(s):

Carol O. Tacket ◽

Marcela F. Pasetti ◽

Marcelo B. Sztein ◽

Sofie Livio ◽

Myron M. Levine

Keyword(s):

Immune Responses ◽

Vaccine Strain ◽

Capsular Polysaccharide ◽

Typhoid Vaccine ◽

Vi Capsular Polysaccharide

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Immune Responses in U.S. Military Personnel Who Received Meningococcal Conjugate Vaccine (MenACWY) Concomitantly with Other Vaccines Were Higher than in Personnel Who Received MenACWY Alone

Clinical and Vaccine Immunology ◽

10.1128/cvi.00267-16 ◽

2016 ◽

Vol 23 (8) ◽

pp. 672-680 ◽

Cited By ~ 6

Author(s):

Michael P. Broderick ◽

Sandra Romero-Steiner ◽

Gowrisankar Rajam ◽

Scott E. Johnson ◽

Andrea Milton ◽

...

Keyword(s):

Immune Responses ◽

Conjugate Vaccine ◽

Military Personnel ◽

Randomized Clinical Trials ◽

Content Type ◽

Immunological Responses ◽

Bactericidal Antibody ◽

Functional Antibodies ◽

Serum Bactericidal Antibody Assay ◽

The Military

ABSTRACTImmunological responses to vaccination can differ depending on whether the vaccine is given alone or with other vaccines. This study was a retrospective evaluation of the immunogenicity of a tetravalent meningococcal conjugate vaccine for serogroups A, C, W, and Y (MenACWY) administered alone (n= 41) or concomitantly with other vaccines (n= 279) to U.S. military personnel (mean age, 21.6 years) entering the military between 2006 and 2008. Concomitant vaccines included tetanus/diphtheria (Td), inactivated polio vaccine (IPV), hepatitis vaccines, and various influenza vaccines, among others; two vaccine groups excluded Tdap and IPV. Immune responses were evaluated in baseline and postvaccination sera forNeisseria meningitidisserogroups C and Y 1 to 12 months (mean, 4.96 months) following vaccination. Functional antibodies were measured by using a serum bactericidal antibody assay with rabbit complement (rSBA) and by measurement of serogroup-specific immunoglobulin G (IgG) antibodies. The percentage of vaccinees reaching threshold levels (IgG concentration in serum, ≥2 μg/ml; rSBA titer, ≥8) corresponding to an immunologic response was higher postvaccination than at baseline (P< 0.001). Administration of MenACWY along with other vaccines was associated with higher geometric means of IgG concentrations and rSBA titers than those measured 4.60 months after a single dose of MenACWY. In addition, higher percentages of vaccinees reached the immunological threshold (range of odds ratios [ORs], 1.5 to 21.7) and more of them seroconverted (OR range, 1.8 to 4.8) when MenACWY was administered with any other vaccine than when administered alone. Additional prospective randomized clinical trials are needed to confirm the observed differences among groups in the immune response to MenACWY when given concomitantly with other vaccines to U.S. military personnel.

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