Scielo RSS <![CDATA[Vaccimonitor]]> vol. 18 num. 2 lang. es <![CDATA[SciELO Logo]]> <![CDATA[<b>Enfoques mucosales en vacunologia de Neisseria</b>]]> Meningococcal B strains accounts for some 72% and 28% of meningococcal diseases in infants and toddlers in Europe and the USA, respectively. Nevertheless, meningococcal diseases are rare in Cuba owing to the wide spread program on antimeningococcal vaccination in the country. Finlay Institute is one of the pioneering organizations in Neisseria Vaccinology mainly by its contribution to N. meningitidis serogroup B outer membrane-based bivalent vaccine, VA-MENGOC-BC™. This vaccine was given intramuscularly in more than 60 million doses corresponding 10.7 millions of them to Cuban young adults, children, and infants. However, most dangerous or commensally Neisseria strains enter and establish in the mucosa, where the secretory (S) IgA is the main specific guardian and is mainly induced by mucosal routes. However, few mucosal vaccines exist principally due to the absent of mucosal adjuvants. We develop a Finlay Adjuvant (AF) platform based in outer membrane vesicles (Proteoliposome, PL) and its derivate Cochleate (Co). AFPL1 derived from serogroup B N. meningitidis is a potent Th1/CTL driving parenteral adjuvant. AFCo1 is a potent mucosal adjuvant. Therefore, we sought to go deeper in the possible mucosal cross recognition between N. meningitidis serogroups and Neisseria species and explore a concurrent mucosal and parenteral immunization strategy (SinTimVaS) in order to develop suitable mucosal vaccines. Experiments were conducted in Balb/c or C57Bl6 mice with mucosal and systemic immunization using AFCo1 and AFPL1. Human sera and saliva were also analyzed for cross cognition. Mucosal cross recognition at SIgA level in human saliva between N. meningitidis serogroups B, A, C, Y, and W135 were observed. This SIgA cross recognition response was also observed between pathogenic (N. meningitidis serogroup B, N. gonorrhoeae) and non-pathogenic strains (N. flava, N. lactamica). The possible influence of meningococcal vaccination against Gonorrhea was also explored. A proprietary Single Time Vaccination Strategy combining simultaneous mucosal and parenteral doses was developed. N. meningitidis and N. gonorrhoeae show significant cross immune response, and mucosal immunization with AFCo1 to obtain immunity against both strains may be a useful strategy to combat both infections in humans. Single Time Vaccination Strategy could be important to increased human vaccination coverage and herd immunity protecting both systemic and mucosal environments. <![CDATA[<b>Nueva generación de Vacunas Conjugadas Antimeningococica</b>: Fundamentos y Posibilidades a escala Mundial]]> The serogroup distribution of Neisseria meningitidis strains implicated in invasive disease varies geographically and temporally. Monovalent serogroup C conjugate vaccines have successfully reduced serogroup C disease in countries where they are used. However, combinations containing multiple serogroups are needed to fully address disease prevention. GlaxoSmithKline Biologicals’ combined serogroups C, Y and Haemophilus influenzae type b conjugate vaccine (Hib-MenCY-TT) has been shown to be immunogenic and well tolerated in infants. The novel Hib-MenCY-TT vaccine has the potential to prevent approximately 90% of non-serogroup B disease in the US. Several manufacturers have investigated tetravalent ACWY conjugate vaccines. One ACWY conjugate vaccine has been licensed for use 2-55 year olds, but the immunogenicity in infants was reduced. Results of other ACWY vaccines using different protein conjugates have shown higher immunogenicity in infants. The next generation of combination meningococcal conjugate vaccines has potential to further reduce morbidity and mortality due to N. meningitidis, provided they are safe and immunogenic in infants and toddlers. A Hib-MenCY-TT vaccine could substantially reduce meningococcal disease in the US, while tetravalent ACWY conjugate vaccines have the potential to provide coverage across age strata against four of the five major serotypes implicated in invasive meningococcal disease. <![CDATA[<b>Las vacunas conjugadas contra la enfermedad meningococica causadas por los serogrupos A, C, W-135, Y</b>]]> Review the current evidence on available and candidate quadrivalent meningococcal conjugate vaccines. Methods: A comprehensive overview of data on the currently available A-C-W135-Y meningococcal vaccine and the results of late stage development of novel quadrivalent candidate vaccines were reviewed. Conclusions: Licensure of highly effective meningococcal C conjugate vaccines represented an enormous progress in the possibility of controlling meningococcal C disease. The unpredictable changing serogroup epidemiology of meningococcal disease emphasizes the need of developing combination conjugate vaccines, containing more than one meningococcal polysaccharide, to broaden protection against the disease. A quadrivalent meningococcal vaccine (A-C-W135-Y) conjugated to diphtheria toxoid is available only in United States and Canada for use in persons 2-55 years of age. However, in infants (the age group with the highest incidence rates of disease) the vaccine proved to be not immunogenic and is therefore not licensed for use in children younger than 2 years.A novel tetravalent meningococcal vaccine (A-C-W135-Y) conjugated to a non-toxic diphtheria mutant toxin (CRM-197) is being evaluated in Phase III trials and has demonstrated to be immunogenic and well tolerated in all age groups, including infants, representing, at last, a real possibility of a broader protection against meningococcal disease. <![CDATA[<b>El ácido siálico N-acetilado es inmunogénico e induce anticuerpos protectores contra Neisseria meningitidis</b>]]> Recently, we showed that monoclonal antibodies (mAbs) that are reactive with derivatives of polysialic acid containing de-N-acetylated neuraminic acid (Neu) residues are protective against N. meningitidis group B strains (Moe et al. 2005, Infect Immun 73:2123; Flitter et al., in preparation). In addition, we found that fully de-N-acetylated PSA (i.e. poly alpha 2,8 Neu) conjugated to tetanus toxoid (DeNAc) elicits IgM and IgG antibodies of all subclasses in mice that bind to group B strains, activate human complement deposition, are protective in an infant rat model of meningococcal bacteremia and are bactericidal against group C strains (Moe et al, in press). We show here that anti-DeNAc mAbs, DA1 and DA2 (both IgM), are reactive with polysaccharides containing Neu, bind to group B, C, W135 and Y but not X strains grown in chemically defined media (CDM). However, when the group X strain is grown in CDM supplemented with human plasma, DA2 binds. Also both mAbs mediate bactericidal activity against B, C, W135, and X strains with human complement. The esults suggests that N. meningitidis express and/or acquire zwitterionic de-N-acetyl sialic acid antigens that can be the target of protective antibodies. <![CDATA[<b>Nueva generación de vacunas antimeningococica basadas en vesículas de membrana externa</b>]]> With the development of conjugate vaccines, Neisseria meningitidis serogroup B (MenB) will remain the major cause of meningitis, as it is not covered by vaccination. In order to develop a vaccine able to confer a broad cross-protection against invasive MenB strains, we have developed a new generation of outer-membrane vesicles (OMVs) based on the over-expression of well conserved minor outer membrane proteins (OMPs) and the presence of high percentage of detoxified LOS. <![CDATA[<b>Respuesta inmune mucosal inducida por proteoliposoma y cocleato derivados de N. meningitidis serogrupo B.</b>]]> Mucosal vaccination offers attractive advantages to conventional systemic vaccination. Most pathogens enter or establish infection at mucosal surfaces. This represents an enormous challenge for vaccine development. Nevertheless, the availability of safe and effective adjuvants that function mucosally is the major limitation. Therefore, we investigated the impact of mucosal immunization with the Neisseria meningitidis B proteoliposome (AFPL1, Adjuvant Finlay Proteoliposome 1) and its-derived cochleate (Co, AFCo1). They contain multiple PAMPs as immunopotentiators and have delivery system ability as well as Th1 polarization activity. Groups of female mice were immunized by nasal, oral, intravaginal, or intramuscular routes with three doses with AFPL1/AFCo1 alone or containing ovalbumin or glycoprotein (g) D2 from Herpes Simplex Virus type 2 (HSV-2). High levels of specific IgG antibodies were detected in sera of mice vaccinated with either route. However, specific IgA antibodies were produced in saliva and vaginal wash only following mucosal delivering. The polarization to a Th1 pattern was confirmed by testing the induction of IgG2a/IgG2c antibody, positive delayed-type hypersensitivity reactions, and gIFN production. Additionally, AFCo1gD2 showed practically no vaginal HSV-2 replication and 100% protection against lethal vaginal HSV-2 challenge. In conclusion, the results support the use of AFCo1 as potent Th1 adjuvant for mucosal vaccines, particularly for nasal route. <![CDATA[<b>Respuesta inmune sistémica y mucosal contra Neisseria meningitidis B inducida por estrategia de vacunación simultánea mucosal y parental</b>]]> Immunization is one of the most successful and cost-effective health interventions ever. Immunization have been helping to reduce child mortality, improving maternal health and combating infectious diseases. In spite of its, undisputed past success and promising future, however, immunization remains an unfinished agenda because of them inadequate coverage. Several factors have been largely responsible of a difficulty to attain immunization coverage and have been recognized as a problems of current vaccines, such as: the number of dose, excessive use of parenteral route, a small number of adjuvants approve for use in human, higher reactogenicity and unavailability against intracellular pathogens, infected or altered cells and scanty feasibility to combined more than one antigen in the same formulation. For bacterial meningitis WHO estimates that 1.2 million cases occur annually and Neisseria meningitidis is the etiological agent in more than 40% of these cases although some meningococcal vaccines are available. To bear in mind these principals problems, a novel protocol for vaccination against N. meningitidis called Single Time Vaccination Strategy (SinTimVaS) is proposed. Using female BALB/c mice, we induce systemic and mucosal immune responses against N. meningitidis with only one parenteral and one mucosal dose at the same time, employing the Finlay Adjuvants derivate from N. meningitidis, AFPL1 and AFCo1, respectively. In conclusion, SinTimVaS could increase the vaccination coverage and reduce the time-cost of vaccine campaigns, adding the possibility to increase the herd immunity by mucosal specific response induction. <![CDATA[<b>Inmunización nasal con AFCo1 induce en ratones respuesta inmune a N. gonorrhoea</b>]]> Neisseria gonorrhoeae infections are common sexually transmitted diseases. Increased antibiotic-resistant of N. gonorrhoeae strains were reported. N. meningitidis is another human restricted bacterium transmitted through mucosa. However, the induction of systemic specific IgG antibody against some proteins between the two species is known, but the mucosal immune response to these pathogens is not clear. We hypothesized that N. meningitidis could induce immune response against N. gonorrhoeae. Therefore, serogroup B Proteoliposome (PL) was transformed into AFCo1 (Adjuvant Finlay Cochleate 1) and used for nasal immunization of C57Bl/6 mice. The specific IgG and IgG subclasses against both antigens in sera and vaginal extraction were measured by ELISA. Specific proliferation (3H incorporation) of spleen cells and lymph node recall in vitro with PL or N. gonorrhoeae total antigens was measured. Serum and vaginal extraction anti N. meningitidis and N. gonorrhoeae IgG as well as the induction of specific IgG subclasses were detected. N. gonorrhoeae induces specific proliferation of spleen, cervical lymph node (cLN), and mediestinal (meLN) cells from immunized mice. In conclusion, AFCo1 induce anti N. meningitidis immune responses that recognized N. gonorrhoeae antigens in mice. <![CDATA[<b>Inmunización intranasal con AFCo1 induce respuesta inmune de memoria, sistemica y mucosal en ratones neonatal</b>]]> Neonates have a poorly developed immune system. Respiratory pathogens cause disease during early periods of live. Consequently, it is important to develop protective vaccines that induce immunity and immunological memory against respiratory pathogens early in life. Intranasal (i.n.) route could be an effective via for immunization. Therefore, we explored the effectiveness of AF (Adjuvant Finlay) PL1 (Proteoliposome) from Neisseria meningitidis serogroup B and its derivate Cochleate (AFCo1) by nasal route in neonatal mice. They were immunized i.n. 3 times 7 days apart and anti PL systemic and mucosal antibody response were measured by ELISA. In addition, a prime-boost strategy was used to evaluate the humoral immune response in neonate mice. The 3 doses of AFPL1 or AFCo1 induced significant levels of anti PL IgG antibodies in comparison whit control, but AFCo1 (2017 U/mL) was significantly higher than AFPL1 (1107 U/mL). AFCo1 and AFPL1 induced a predominant Th1 pattern with IgG2a/IgG1 >1 by i.n. immunization and AFCo1 induced a high anti PL IgA saliva response in saliva. Interestingly, one nasally prime at 7 days of born and a memory one boost i.n. dose 9 weeks later with AFCo1 or AFPL1 showed similar specific IgG levels and IgG2a/IgG1 relation than 3 i.n. doses in adult mice. In conclusion, these results represent the first report of neonatal intranasal vaccination using AFCo1 capable to induce systemic and mucosal immunity and priming for memory. <![CDATA[<b>Actividad opsonofagocítica contra meningococos del grupo B</b>: ¿Un correlato de protección adicional contra la enfermedad meningococica?]]> Opsonophagocytic activity and serum bactericidal activity against group B meningococci were compared in sera from three vaccine groups given two different outer membrane vesicles vaccines separately or in combination. Opsonophagocytic activity defined more responders and revealed more cross-reactivity against heterologous strains than observed with serum bactericidal activity, and it showed the highest correlation with IgG-binding to live meningococci. Determination of opsonophagocytic activity may therefore be a valuable laboratory supplement to serum bactericidal activity for monitoring protection against group B meningococcal disease. <![CDATA[<b>Los complejos Chaperonina(MSP63)inducen anticuerpos de reacciones cruzadas, bactericidas y opsonofagocítica</b>]]> Alteration of the native structure of antigens can lead to the loss of protective epitopes. Our previous results showed that separation of the meningococcal outer membrane proteins in native conditions revealed the existence of protein complexes that could be relevant for the development of new vaccine formulations. The aim of this work was to analyse the immunogenic characteristics of a highly conserved 700 kDa chaperonin complex (CxChap) detected and purified by using high resolution clear native electrophoresis. Analysis of the anti-CxChap serum by Western-blotting revealed the presence of antibodies against the MSP63 but also against the macrophage infectivity potentiator-like protein (MIP), which is coopurified with the chaperonin complex. Antibodies raised by immunisation with CxChap chaperonin complex show bactericidal and opsonophagocytic activity. <![CDATA[<b>Dinámicas de las interacciones de Neisseria meningitidis con las barreras celulares y los efectores inmunes</b>]]> Neisseria meningitidis outer membrane (OM) adhesins, Opa and Opc are known to exert significant influence on bacterial adhesion and invasion properties. They are also likely to affect the dynamics of cellular barrier penetration as they target human receptors that are subject to upregulation under inflammatory conditions. As some of the targeted receptors are also expressed on immune cells, it is possible that the OM proteins, when presented on bacteria or in OM vesicle vaccines, have the additional capacity to modulate host immune responses. In our recent studies, in vitro model systems were used to further explore these possibilities. The studies illustrated that the major human receptors targeted by Opa and Opc, i.e. CEACAMs and integrins, when upregulated by inflammatory cytokines, encourage enhanced cellular adhesion, invasion and barrier traversal. Tissue infiltration by fully capsulate bacteria via Opa proteins was also observed for piliated Opa+ meningococci. Other studies indicate that Opc increases meningococcal resistance to serum-mediated killing by binding to the complement regulatory molecule vitronectin. In addition, although adverse immunomodulatory effects have been reported for Opa-expressing gonococci and meningococcal OMVs, our studies indicate that interactions with CD4+ T cell expressed CEACAM1 does not offer immunomodulatory properties to meningococci. <![CDATA[<b>Adjuvantes:Un componente esencial de las vacunas de Neisseria</b>]]> Adjuvants may be classified into delivery systems and immune potentiator or modulator molecules based on their mechanism of action. Neisseria vaccines containing traditional adjuvants such as aluminium salts have existed for long time, but meningitis caused by Neisseria meningitidis serogroups, particularly serogroup B, continues to be a global health problem. Novel strategies have applied in silico and recombinant technologies to develop "universal" antigens (e.g. proteins, peptides and plasmid DNA) for vaccines, but these antigens have been shown to be poorly immunogenic even when alum adjuvanted, implying a need for better vaccine design. In this work we review the use of natural, detoxified, or synthetic molecules in combination with antigens to activate the innate immune system and to modulate the adaptive immune responses. In the main, antigenic and imune potentiator signals are delivered using nano-, micro-particles, alum, or emulsions. The importance of interaction between adjuvants and antigens to activate and target dendritic cells, the bridge between the innate and adaptive immune systems, will be discussed. In addition, nasal vaccine strategies based on the development of mucosal adjuvants and Neisseria derivatives to eliminate the pathogen at the site of infection provide promising adjuvants effective not only against respiratory pathogens, but also against pathogens responsible for enteric and sexually transmitted diseases.