Expression of human CEACAM1 in transgenic mice limits the Opa-specific immune response against meningococcal outer membrane vesicles

Zariri, Afshin; Dijken, Harry van; Hamstra, Hendrik-Jan; Flier, Michiel van der; Vidarsson, Gestur; Putten, Jos P. M. van; Boog, Claire J. P.; Dobbelsteen, Germie van den; Ley, Peter van der

doi:10.1016/j.vaccine.2013.07.069

Cited by 11 publications

(10 citation statements)

References 44 publications

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“…Furthermore, there was no reduction of cross-reactivity in an H44/76 mutant devoid of all four Opa genes compared to wildtype H44/76 (Fig. 3), perhaps related to the fact that CEACAM1-humanized mice display a reduced humoral response toward Opa proteins (32). Thus, Opa proteins do not appear to contribute substantially to the strong cross-reactivity patterns among N. meningitidis isolates, at least following natural infection.…”

Section: Discussionmentioning

confidence: 92%

Sterilizing Immunity Elicited by Neisseria meningitidis Carriage Shows Broader Protection than Predicted by Serum Antibody Cross-Reactivity in CEACAM1 -Humanized Mice

et al. 2015

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bNeisseria meningitidis asymptomatically colonizes the human upper respiratory tract but is also the cause of meningitis and severe septicemia. Carriage or disease evokes an immune response against the infecting strain. Hitherto, we have known little about the breadth of immunity induced by natural carriage of a single strain or its implications for subsequent infectious challenge. In this study, we establish that transgenic mice expressing human CEACAM1 support nasal colonization by a variety of strains of different capsular types. Next, we nasally challenged these mice with either of the N. meningitidis strains H44/76 (serogroup B, ST-32) and 90/18311 (serogroup C, ST-11), while following the induction of strain-specific immunoglobulin. When these antisera were tested for reactivity with a diverse panel of N. meningitidis strains, very low levels of antibody were detected against all meningococcal strains, yet a mutually exclusive "fingerprint" of high-level cross-reactivity toward certain strains became apparent. To test the efficacy of these responses for protection against subsequent challenge, CEACAM1-humanized mice exposed to strain 90/18311 were then rechallenged with different N. meningitidis strains. As expected, the mice were immune to challenge with the same strain and with a closely related ST-11 strain, 38VI, while H44/76 (ST-32) could still colonize these animals. Notably, however, despite the paucity of detectable humoral response against strain 196/87 (ST-32), this strain was unable to colonize the 90/18311-exposed mice. Combined, our data suggest that current approaches may underestimate the actual breadth of mucosal protection gained through natural exposure to N. meningitidis strains. N eisseria meningitidis is the causative agent of meningococcal meningitis and septicemia. Both manifestations of invasive meningococcal disease (IMD) primarily affect infants and toddlers and are characterized by a rapid course of progression (1). The fatality rate is particularly high in meningococcal sepsis, and treatment options are limited, especially when patients present in hospitals with late-stage disease (2). Therefore, preemptive measures such as vaccination are pivotal in the defense against this human-specific pathogen.Although mainly recognized because of its devastating invasive potential, N. meningitidis bacteria are normal inhabitants of the human upper respiratory tract, as about 10% of the general population carry these bacteria in their throats (3, 4). Overall, progression into disease is uncommon and is limited to certain hypervirulent lineages of this diverse species (5, 6). One key aspect in meningococcal virulence is the polysaccharide capsule, which shields the bacteria against the bactericidal activities of the host through phagocytosis and the complement system and which allows for their survival and multiplication in the blood. In order to overcome this protective function, immunoglobulin specific for surface antigens is required to facilitate Fc receptor-mediated phagocytosis and ser...

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Section: Discussionmentioning

confidence: 92%

Sterilizing Immunity Elicited by Neisseria meningitidis Carriage Shows Broader Protection than Predicted by Serum Antibody Cross-Reactivity in CEACAM1 -Humanized Mice

et al. 2015

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“…Since capsular polysaccharide is an essential virulence factor for many pathogenic bacteria, its removal has the additional benefit of rendering the production strains safer to handle. Many outer membrane antigens function by binding to some host receptor or ligand, and it has recently been found that in such cases their immunogenicity is reduced by this interaction [127, 156, 160]. By using mutants, which no longer bind their natural human ligand through small alterations in the binding site, one can increase their protective capacity.…”

Section: Omv Process Developmentmentioning

confidence: 99%

Outer membrane vesicles as platform vaccine technology

Pol

Stork

Ley

2015

Biotechnology Journal

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288

241

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Outer membrane vesicles (OMVs) are released spontaneously during growth by many Gram‐negative bacteria. They present a range of surface antigens in a native conformation and have natural properties like immunogenicity, self‐adjuvation and uptake by immune cells which make them attractive for application as vaccines against pathogenic bacteria. In particular with Neisseria meningitidis, they have been investigated extensively and an OMV‐containing meningococcal vaccine has recently been approved by regulatory agencies. Genetic engineering of the OMV‐producing bacteria can be used to improve and expand their usefulness as vaccines. Recent work on meningitis B vaccines shows that OMVs can be modified, such as for lipopolysaccharide reactogenicity, to yield an OMV product that is safe and effective. The overexpression of crucial antigens or simultaneous expression of multiple antigenic variants as well as the expression of heterologous antigens enable expansion of their range of applications. In addition, modifications may increase the yield of OMV production and can be combined with specific production processes to obtain high amounts of well‐defined, stable and uniform OMV particle vaccine products. Further improvement can facilitate the development of OMVs as platform vaccine product for multiple applications.

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“…However, other reports have shown that the binding of host molecules to vaccine targets can result in the induction of the antibodies directed against parts of the vaccine target that are not involved in the binding to the complement regulatory protein. This phenomenon can be overcome by the use of mutated bacterial proteins that are no longer able to bind their host target protein (Rossi et al, 2013; Zariri et al, 2013; Costa et al, 2014; Granoff et al, 2016). Therefore, the use of mutated complement evasion molecules that no longer bind to their host target proteins should be considered in the design of microbial vaccines that aim to elicit antibodies that block binding of the host complement regulator to the pathogen.…”

Section: Complement Evasion Molecules As Vaccine Targetsmentioning

confidence: 99%

Hijacking Complement Regulatory Proteins for Bacterial Immune Evasion

2016

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The human complement system plays an important role in the defense against invading pathogens, inflammation and homeostasis. Invading microbes, such as bacteria, directly activate the complement system resulting in the formation of chemoattractants and in effective labeling of the bacteria for phagocytosis. In addition, formation of the membrane attack complex is responsible for direct killing of Gram-negative bacteria. In turn, bacteria have evolved several ways to evade complement activation on their surface in order to be able to colonize and invade the human host. One important mechanism of bacterial escape is attraction of complement regulatory proteins to the microbial surface. These molecules are present in the human body for tight regulation of the complement system to prevent damage to host self-surfaces. Therefore, recruitment of complement regulatory proteins to the bacterial surface results in decreased complement activation on the microbial surface which favors bacterial survival. This review will discuss recent advances in understanding the binding of complement regulatory proteins to the bacterial surface at the molecular level. This includes, new insights that have become available concerning specific conserved motives on complement regulatory proteins that are favorable for microbial binding. Finally, complement evasion molecules are of high importance for vaccine development due to their dominant role in bacterial survival, high immunogenicity and homology as well as their presence on the bacterial surface. Here, the use of complement evasion molecules for vaccine development will be discussed.

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Expression of human CEACAM1 in transgenic mice limits the Opa-specific immune response against meningococcal outer membrane vesicles

Cited by 11 publications

References 44 publications

Sterilizing Immunity Elicited by Neisseria meningitidis Carriage Shows Broader Protection than Predicted by Serum Antibody Cross-Reactivity in CEACAM1 -Humanized Mice

Sterilizing Immunity Elicited by Neisseria meningitidis Carriage Shows Broader Protection than Predicted by Serum Antibody Cross-Reactivity in CEACAM1 -Humanized Mice

Outer membrane vesicles as platform vaccine technology

Hijacking Complement Regulatory Proteins for Bacterial Immune Evasion

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