Mucosal Immunity in Healthy Adults after Parenteral Vaccination with Outer‐Membrane Vesicles from<i>Neisseria meningitidis</i>Serogroup B

Davenport, Victoria; Groves, Eleanor; Horton, Rachel Elizabeth; Hobbs, Christopher; Guthrie, Terry; Findlow, Jamie; Borrow, Ray; Næss, Lisbeth Meyer; Oster, Philipp; Heyderman, Robert S.; Williams, Neil

doi:10.1086/590669

Cited by 35 publications

(23 citation statements)

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“…Our findings highlight the importance of the complex interplay between humoral and cell-mediated immunity against meningococci and suggest that OMV-based vaccines have the potential to induce both Th1 and Th2 cytokines, at least as detected in cells from peripheral circulation. Natural immunity against meningococci at the systemic level has been shown to be a balanced Th1/Th2 memory response (52), whereas the mucosal T cell response has been characterized as Th1 polarized (39,44,52). Hence, the results presented here obtained with OMV vaccination are consistent with the picture seen in natural immunity in adults, at least at the systemic level.…”

Section: Discussionsupporting

confidence: 85%

“…In addition, we have demonstrated that crossreactive T cell responses were accompanied by the production of both Th1 and Th2 cytokines measured as IFN-␥, IL-4, and IL-10. Parenteral immunization with OMV vaccines has previously been claimed to induce a Th1-biased response (40,44), but a clear association between any defined cytokine profile and protection against meningococcal disease has not yet been established. It has been suggested that a Th1-skewed immune response can be beneficial by promoting enhanced Fc␥R1 expression on phagocytes, neutrophil mobilization, and intracellular bactericidal activity, whereas a more balanced Th1/Th2 response will be necessary to secure the activation and regulation of essential B cell responses such as IgG and IgA production and opsonophagocytosis (45,46).…”

Section: Discussionmentioning

confidence: 99%

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Cellular Immune Responses in Humans Induced by Two Serogroup B Meningococcal Outer Membrane Vesicle Vaccines Given Separately and in Combination

Oftung

Korsvold

Aase

et al. 2016

Clin Vaccine Immunol

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MenBvac and MeNZB are safe and efficacious outer membrane vesicle (OMV) vaccines against serogroup B meningococcal disease. Antibody responses have previously been investigated in a clinical trial with these two OMV vaccines given separately (25 g/dose) or in combination (12.5 and 12.5 g/dose) in three doses administered at 6-week intervals. Here, we report the results from analyzing cellular immune responses against MenBvac and MeNZB OMVs in terms of antigen-specific CD4 ؉ T cell proliferation and secretion of cytokines. The proliferative CD4؉ T cell responses to the combined vaccine were of the same magnitude as the homologous responses observed for each individual vaccine. The results also showed cross-reactivity in the sense that both vaccine groups receiving separate vaccines responded to both homologous and heterologous OMV antigen when assayed for antigen-specific cellular proliferation. In addition, a multiplex bead array assay was used to analyze the presence of Th1 and Th2 cytokines in cell culture supernatants. The results showed that gamma interferon, interleukin-4 (IL-4), and IL-10 responses could be detected as a result of vaccination with both the MenBvac and the MeNZB vaccines given separately, as well as when given in combination. With respect to cross-reactivity, the cytokine results paralleled the observations made for proliferation. In conclusion, the results demonstrate that cross-reactive cellular immune responses involving both Th1 and Th2 cytokines can be induced to the same extent by different tailor-made OMV vaccines given either separately or in combination with half the dose of each vaccine. N eisseria meningitidis serogroup B vaccines based on outer membrane vesicles (OMVs) from defined serogroup B strains have been shown to be efficacious to control clonal outbreaks in several countries, including Norway, Cuba, and New Zealand (1-3). The PorA protein is the immunodominant antigen in OMV vaccines and elicits protective immune responses (4). PorA shows large sequence variation between strains, and a limitation of OMV vaccines is that they induce mainly strain-specific antibodies (5), but cross-protective antibodies against other B strains have been observed in small children and adults (3, 5). The OMV vaccine MenBvac was developed based on the B:15:P1.7,16 strain representative of the previous meningococcal epidemic in Norway. Based on several clinical trials, this vaccine has been shown to be safe, immunogenic, and to confer protection against meningococcal B disease (6-9). MenBvac has also recently been used to combat an outbreak of serogroup B disease in France demonstrating that OMV vaccines can be efficient against heterologous B strains provided that they are sufficiently immunologically close (10, 11).A similar meningococcal serogroup B OMV vaccine (MeNZB) based on a different strain (B:4:P1.7-2,4) was developed and introduced in 2004 to control the meningococcal epidemic in New Zealand (12)(13)(14) showing more than 70% effectiveness (3). However, in most geographical regions ...

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Cellular Immune Responses in Humans Induced by Two Serogroup B Meningococcal Outer Membrane Vesicle Vaccines Given Separately and in Combination

Oftung

Korsvold

Aase

et al. 2016

Clin Vaccine Immunol

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“…The paradigmatic cellular immune response to mucosal infection involves Th2-regulated IgA production; however, there are examples where Th1 or Th17 responses may be critical determinants of protective immunity against potentially invasive mucosal pathogens (12,13,23,26). Because cholera is prototypical of a noninflammatory, toxin-mediated diarrhea (17), it was plausible that the disease would induce a CD4 ϩ T-cell response skewed predominantly toward a noninflammatory Th2 response to V. cholerae antigens.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have focused on the ratio of Th1/Th2 responses as an important determinant of the mucosal immune response (12,13,26). As shown in Fig.…”

Section: Cytokine Responses Tomentioning

confidence: 99%

Vibrio cholerae O1 Infection Induces Proinflammatory CD4⁺T-Cell Responses in Blood and Intestinal Mucosa of Infected Humans

Kuchta

Rahman

Sennott

et al. 2011

Clin Vaccine Immunol

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Vibrio cholerae O1 is a noninvasive enteric pathogen and serves as a model for studies of mucosal immunity. Although symptomatic V. cholerae infection induces durable protection against subsequent disease, vaccination with oral killed whole-cell V. cholerae stimulates less long-lasting protection against cholera. In this study, we demonstrated that cholera induces an early proinflammatory cellular immune response that results in priming of Th1-and Th17-type cytokine responses to ex vivo antigenic stimulation and an increase in the ratio of Th1 to Th2 CD4 ؉ T-cell responses. Comparable priming of Th1 and Th17 responses, with an increased ratio of Th1 to Th2 CD4 ؉ T-cell responses, was not observed in subjects who received two doses of the oral cholera vaccine Dukoral (a whole-cell cholera toxin B subunit containing [WC-CTB] vaccine). These findings suggest that natural V. cholerae infection induces an early, proinflammatory cellular immune response, despite the apparent lack of clinical signs of inflammation. The failure of the WC-CTB vaccine to activate equivalent, CD4؉ T-cell responses is a potential explanation for the shorter duration of protection following immunization with this vaccine. Additional studies are needed to determine whether these early T-cell-mediated events predict the subsequent duration of immunologic memory.Vibrio cholerae causes 3 million to 5 million cases of diarrhea and over 100,000 deaths annually (2). Organisms colonize the epithelial surface of the small intestine and elaborate cholera toxin (CT), an essential virulence factor for all pandemic strains of V. cholerae (30). Because V. cholerae is a prototypical noninvasive pathogen, it serves as a model for the study of mucosal immunity (17).Natural infection with V. cholerae provides greater than 90% protection against subsequent disease for at least 3 years in U.S. volunteer studies (the maximum period studied) and an average of 3 to 8 years on the basis of epidemiological studies in areas of endemicity (5,19,21). The mechanism(s) of protective immunity against cholera is not well understood but has been hypothesized to depend on anamnestic responses of memory B cells (16,25,35). Consistent with this, our group previously demonstrated that V. cholerae protein antigen-specific memory B cells remain detectable in the circulation for over a year following cholera, after circulating antibody levels have returned to baseline levels. In contrast, memory B-cell responses to lipopolysaccharide, a T-cell-independent antigen, were found to decrease more rapidly after infection (16). Such long-lasting memory B cells against V. cholerae protein antigens could play a role in mediating anamnestic responses and protection against subsequent infection.In contrast, a currently licensed cholera vaccine, Dukoral (a whole-cell CT B subunit [WC-CTB] vaccine), consists of killed V. cholerae O1 supplemented with recombinant cholera toxin B subunit (rCTB) and provides over 60% protection. However, protection wanes by 3 years after vaccination, and the vacc...

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“…PBMC were isolated from 45 ml peripheral venous blood, as previously described (19). Briefly, plasma was separated by centrifugation (400 3 g, 20˚C, 10 min) and discarded.…”

Section: Isolation Of Mononuclear Cellsmentioning

confidence: 99%

Polysaccharide-Specific Memory B Cells Generated by Conjugate Vaccines in Humans Conform to the CD27+IgG+ Isotype–Switched Memory B Cell Phenotype and Require Contact-Dependent Signals from Bystander T Cells Activated by Bacterial Proteins To Differentiate into Plasma Cells

Clarke

Williams

Findlow

et al. 2013

The Journal of Immunology

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The polysaccharides (PS) surrounding encapsulated bacteria are generally unable to activate T cells and hence do not induce B cell memory (BMEM). PS conjugate vaccines recruit CD4+ T cells via a carrier protein, such as tetanus toxoid (TT), resulting in the induction of PS-specific BMEM. However, the requirement for T cells in the subsequent activation of the BMEM at the time of bacterial encounter is poorly understood, despite having critical implications for protection. We demonstrate that the PS-specific BMEM induced in humans by a meningococcal serogroup C PS (Men C)–TT conjugate vaccine conform to the isotype-switched (IgG+CD27+) rather than the IgM memory (IgM+CD27+) phenotype. Both Men C and TT-specific BMEM require CD4+ T cells to differentiate into plasma cells. However, noncognate bystander T cells provide such signals to PS-specific BMEM with comparable effect to the cognate T cells available to TT-specific BMEM. The interaction between the two populations is contact-dependent and is mediated in part through CD40. Meningococci drive the differentiation of the Men C–specific BMEM through the activation of bystander T cells by bacterial proteins, although these signals are enhanced by T cell–independent innate signals. An effect of the TT-specific T cells activated by the vaccine on unrelated BMEM in vivo is also demonstrated. These data highlight that any protection conferred by PS-specific BMEM at the time of bacterial encounter will depend on the effectiveness with which bacterial proteins are able to activate bystander T cells. Priming for T cell memory against bacterial proteins through their inclusion in vaccine preparations must continue to be pursued.

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Mucosal Immunity in Healthy Adults after Parenteral Vaccination with Outer‐Membrane Vesicles fromNeisseria meningitidisSerogroup B

Abstract: Parenteral MenB vaccination selectively reprograms preexisting naturally acquired mucosal immunity. As new-generation protein-based MenB vaccine candidates undergo evaluation, the impact of these vaccines on mucosal immunity in both adults and children will need to be addressed.

Cited by 35 publications

References 50 publications

Cellular Immune Responses in Humans Induced by Two Serogroup B Meningococcal Outer Membrane Vesicle Vaccines Given Separately and in Combination

Cellular Immune Responses in Humans Induced by Two Serogroup B Meningococcal Outer Membrane Vesicle Vaccines Given Separately and in Combination

Vibrio cholerae O1 Infection Induces Proinflammatory CD4⁺T-Cell Responses in Blood and Intestinal Mucosa of Infected Humans

Polysaccharide-Specific Memory B Cells Generated by Conjugate Vaccines in Humans Conform to the CD27+IgG+ Isotype–Switched Memory B Cell Phenotype and Require Contact-Dependent Signals from Bystander T Cells Activated by Bacterial Proteins To Differentiate into Plasma Cells

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Mucosal Immunity in Healthy Adults after Parenteral Vaccination with Outer‐Membrane Vesicles fromNeisseria meningitidisSerogroup B

Abstract: Parenteral MenB vaccination selectively reprograms preexisting naturally acquired mucosal immunity. As new-generation protein-based MenB vaccine candidates undergo evaluation, the impact of these vaccines on mucosal immunity in both adults and children will need to be addressed.

Cited by 35 publications

References 50 publications

Cellular Immune Responses in Humans Induced by Two Serogroup B Meningococcal Outer Membrane Vesicle Vaccines Given Separately and in Combination

Cellular Immune Responses in Humans Induced by Two Serogroup B Meningococcal Outer Membrane Vesicle Vaccines Given Separately and in Combination

Vibrio cholerae O1 Infection Induces Proinflammatory CD4+T-Cell Responses in Blood and Intestinal Mucosa of Infected Humans

Polysaccharide-Specific Memory B Cells Generated by Conjugate Vaccines in Humans Conform to the CD27+IgG+ Isotype–Switched Memory B Cell Phenotype and Require Contact-Dependent Signals from Bystander T Cells Activated by Bacterial Proteins To Differentiate into Plasma Cells

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Vibrio cholerae O1 Infection Induces Proinflammatory CD4⁺T-Cell Responses in Blood and Intestinal Mucosa of Infected Humans