Clinical And Vaccine Immunology[JOURNAL]
Sun
200 papers
Heat Shock Proteins in Histoplasma and Paracoccidioides.
Cleare LG, Zamith-Miranda D, Nosanchuk JD
Clin Vaccine Immunol · 2017 Nov · PMID 28903987 · Full text
Heat shock proteins (Hsps) are highly conserved biomolecules that are constitutively expressed and generally upregulated in response to various stress conditions (biotic and abiotic). Hsps have diverse functions, categor...
Heat shock proteins (Hsps) are highly conserved biomolecules that are constitutively expressed and generally upregulated in response to various stress conditions (biotic and abiotic). Hsps have diverse functions, categorizations, and classifications. Their adaptive expression in fungi indicates their significance in these diverse species, particularly in dimorphic pathogens. and species are dimorphic fungi that are the causative agents of histoplasmosis and paracoccidioidomycosis, respectively. This minireview focuses on the pathobiology of Hsps, with particular emphasis on their roles in the morphogenesis and virulence of and and the potential roles of active and passive immunization against Hsps in protection against infection with these fungi.
Merozoite Surface Protein 1 from Plasmodium falciparum Is a Major Target of Opsonizing Antibodies in Individuals with Acquired Immunity against Malaria.
Jäschke A, Coulibaly B, Remarque EJ … +2 more , Bujard H, Epp C
Clin Vaccine Immunol · 2017 Nov · PMID 28877929 · Full text
Naturally acquired immunity against malaria is largely mediated by serum antibodies controlling levels of blood-stage parasites. A limited understanding of the antigenic targets and functional mechanisms of protective an...
Naturally acquired immunity against malaria is largely mediated by serum antibodies controlling levels of blood-stage parasites. A limited understanding of the antigenic targets and functional mechanisms of protective antibodies has hampered the development of efficient malaria vaccines. Besides directly inhibiting the growth of parasites, antibodies can opsonize merozoites and recruit immune effector cells such as monocytes and neutrophils. Antibodies against the vaccine candidate merozoite surface protein 1 (MSP-1) are acquired during natural infections and have been associated with protection against malaria in several epidemiological studies. Here we analyzed serum antibodies from semi-immune individuals from Burkina Faso for their potential (i) to directly inhibit the growth of blood stages and (ii) to opsonize merozoites and to induce the antibody-dependent respiratory burst (ADRB) activity of neutrophils. While a few sera that directly inhibited the growth of blood stages were identified, immunoglobulin G (IgG) from all individuals clearly mediated the activation of neutrophils. The level of neutrophil activation correlated with levels of antibodies to MSP-1, and affinity-purified MSP-1-specific antibodies elicited ADRB activity. Furthermore, immunization of nonhuman primates with recombinant full-size MSP-1 induced antibodies that efficiently opsonized merozoites. Reversing the function by preincubation with recombinant antigens allowed us to quantify the contribution of MSP-1 to the antiparasitic effect of serum antibodies. Our data suggest that MSP-1, especially the partially conserved subunit MSP-1, is a major target of opsonizing antibodies acquired during natural exposure to malaria. Induction of opsonizing antibodies might be a crucial effector mechanism for MSP-1-based malaria vaccines.
Anthrax Vaccine Precipitated Induces Edema Toxin-Neutralizing, Edema Factor-Specific Antibodies in Human Recipients.
Dumas EK, Gross T, Larabee J … +11 more , Pate L, Cuthbertson H, Charlton S, Hallis B, Engler RJM, Collins LC, Spooner CE, Chen H, Ballard J, James JA, Farris AD
Clin Vaccine Immunol · 2017 Nov · PMID 28877928 · Full text
Edema toxin (ET), composed of edema factor (EF) and protective antigen (PA), is a virulence factor of that alters host immune cell function and contributes to anthrax disease. Anthrax vaccine precipitated (AVP) contains...
Edema toxin (ET), composed of edema factor (EF) and protective antigen (PA), is a virulence factor of that alters host immune cell function and contributes to anthrax disease. Anthrax vaccine precipitated (AVP) contains low but detectable levels of EF and can elicit EF-specific antibodies in human recipients of AVP. Active and passive vaccination of mice with EF can contribute to protection from challenge with spores or ET. This study compared humoral responses to ET in recipients of AVP ( = 33) versus anthrax vaccine adsorbed (AVA; = 66), matched for number of vaccinations and time postvaccination, and further determined whether EF antibodies elicited by AVP contribute to ET neutralization. AVP induced higher incidence (77.8%) and titer (229.8 ± 58.6) of EF antibodies than AVA (4.2% and 7.8 ± 8.3, respectively), reflecting the reported low but detectable presence of EF in AVP. In contrast, PA IgG levels and ET neutralization measured using a luciferase-based cyclic AMP reporter assay were robust and did not differ between the two vaccine groups. Multiple regression analysis failed to detect an independent contribution of EF antibodies to ET neutralization in AVP recipients; however, EF antibodies purified from AVP sera neutralized ET. Serum samples from at least half of EF IgG-positive AVP recipients bound to nine decapeptides located in EF domains II and III. Although PA antibodies are primarily responsible for ET neutralization in recipients of AVP, increased amounts of an EF component should be investigated for the capacity to enhance next-generation, PA-based vaccines.
Protective Vaccine Efficacy of the Complete Form of PPE39 Protein from Mycobacterium tuberculosis Beijing/K Strain in Mice.
Kim A, Hur YG, Gu S … +1 more , Cho SN
Clin Vaccine Immunol · 2017 Nov · PMID 28877927 · Full text
The aim of this study was to evaluate the protective efficacy of MTBK_24820, a complete form of PPE39 protein derived from a predominant Beijing/K strain of in South Korea. Mice were immunized with MTKB_24820, Bacilli...
The aim of this study was to evaluate the protective efficacy of MTBK_24820, a complete form of PPE39 protein derived from a predominant Beijing/K strain of in South Korea. Mice were immunized with MTKB_24820, Bacilli Calmette-Guérin (BCG), or adjuvant prior to a high-dosed Beijing/K strain aerosol infection. After 4 and 9 weeks, bacterial loads were determined and histopathologic and immunologic features in the lungs and spleens of the -infected mice were analyzed. Putative immunogenic T-cell epitopes were examined using synthetic overlapping peptides. Successful immunization of MTBK_24820 in mice was confirmed by increased IgG responses ( < 0.05) and recalled gamma interferon (IFN-γ), interleukin-2 (IL-2), IL-6, and IL-17 responses ( < 0.05 or < 0.01) to MTBK_24820. After challenge with the Beijing/K strain, an approximately 0.5 to 1.0 log reduction in CFU in lungs and fewer lung inflammation lesions were observed in MTBK_24820-immunized mice compared to those for control mice. Moreover, MTBK_24820 immunization elicited significantly higher numbers of CD4 T cells producing protective cytokines, such as IFN-γ and IL-17, in lungs and spleens ( < 0.01) and CD4 multifunctional T cells producing IFN-γ, tumor necrosis factor alpha (TNF-α), and/or IL-17 ( < 0.01) than in control mice, suggesting protection comparable to that of BCG against the hypervirulent Beijing/K strain. The dominant immunogenic T-cell epitopes that induced IFN-γ production were at the N terminus (amino acids 85 to 102 and 217 to 234). Its vaccine potential, along with protective immune responses , may be informative for vaccine development, particularly in regions where the Beijing/K-strain is frequently isolated from TB patients.
Chlamydia trachomatis: the Persistent Pathogen.
Witkin SS, Minis E, Athanasiou A … +2 more , Leizer J, Linhares IM
Clin Vaccine Immunol · 2017 Oct · PMID 28835360 · Full text
is an obligate intracellular bacterium whose only natural host is humans. Although presenting as asymptomatic in most women, genital tract chlamydial infections are a leading cause of pelvic inflammatory disease, tubal f...
is an obligate intracellular bacterium whose only natural host is humans. Although presenting as asymptomatic in most women, genital tract chlamydial infections are a leading cause of pelvic inflammatory disease, tubal factor infertility, and ectopic pregnancy. has evolved successful mechanisms to avoid destruction by autophagy and the host immune system and persist within host epithelial cells. The intracellular form of this organism, the reticulate body, can enter into a persistent nonreplicative but viable state under unfavorable conditions. The infectious form of the organism, the elementary body, is again generated when the immune attack subsides. In its persistent form, ceases to produce its major structural and membrane components, but synthesis of its 60-kDa heat shock protein (hsp60) is greatly upregulated and released from the cell. The immune response to hsp60, perhaps exacerbated by repeated cycles of productive infection and persistence, may promote damage to fallopian tube epithelial cells, scar formation, and tubal occlusion. The chlamydial and human hsp60 proteins are very similar, and hsp60 is one of the first proteins produced by newly formed embryos. Thus, the development of immunity to epitopes in the chlamydial hsp60 that are also present in the corresponding human hsp60 may increase susceptibility to pregnancy failure in infected women. Delineation of host factors that increase the likelihood that will avoid immune destruction and survive within host epithelial cells and utilization of this knowledge to design individualized preventative and treatment protocols are needed to more effectively combat infections by this persistent pathogen.
Mother-Newborn Pairs in Malawi Have Similar Antibody Repertoires to Diverse Malaria Antigens.
Boudová S, Walldorf JA, Bailey JA … +12 more , Divala T, Mungwira R, Mawindo P, Pablo J, Jasinskas A, Nakajima R, Ouattara A, Adams M, Felgner PL, Plowe CV, Travassos MA, Laufer MK
Clin Vaccine Immunol · 2017 Oct · PMID 28835359 · Full text
Maternal antibodies may play a role in protecting newborns against malaria disease. parasite surface antigens are diverse, and protection from infection requires allele-specific immunity. Although malaria-specific antib...
Maternal antibodies may play a role in protecting newborns against malaria disease. parasite surface antigens are diverse, and protection from infection requires allele-specific immunity. Although malaria-specific antibodies have been shown to cross the placenta, the extent to which antibodies that respond to the full repertoire of diverse antigens are transferred from the mother to the infant has not been explored. Understanding the breadth of maternal antibody responses and to what extent these antibodies are transferred to the child can inform vaccine design and evaluation. We probed plasma from cord blood and serum from mothers at delivery using a customized protein microarray that included variants of malaria vaccine target antigens to assess the intensity and breadth of seroreactivity to three malaria vaccine candidate antigens in mother-newborn pairs in Malawi. Among the 33 paired specimens that were assessed, mothers and newborns had similar intensity and repertoire of seroreactivity. Maternal antibody levels against vaccine candidate antigens were the strongest predictors of infant antibody levels. Placental malaria did not significantly impair transplacental antibody transfer. However, mothers with placental malaria had significantly higher antibody levels against these blood-stage antigens than mothers without placental malaria. The repertoire and levels of infant antibodies against a wide range of malaria vaccine candidate antigen variants closely mirror maternal levels in breadth and magnitude regardless of evidence of placental malaria. Vaccinating mothers with an effective malaria vaccine during pregnancy may induce high and potentially protective antibody repertoires in newborns.
Combined Action of Human Commensal Bacteria and Amorphous Silica Nanoparticles on the Viability and Immune Responses of Dendritic Cells.
Malachin G, Lubian E, Mancin F … +2 more , Papini E, Tavano R
Clin Vaccine Immunol · 2017 Oct · PMID 28835358 · Full text
Dendritic cells (DCs) regulate the host-microbe balance in the gut and skin, tissues likely exposed to nanoparticles (NPs) present in drugs, food, and cosmetics. We analyzed the viability and the activation of DCs incuba...
Dendritic cells (DCs) regulate the host-microbe balance in the gut and skin, tissues likely exposed to nanoparticles (NPs) present in drugs, food, and cosmetics. We analyzed the viability and the activation of DCs incubated with extracellular media (EMs) obtained from cultures of commensal bacteria (, ) or pathogenic bacteria (, ) in the presence of amorphous silica nanoparticles (SiO NPs). EMs and NPs synergistically increased the levels of cytotoxicity and cytokine production, with different nanoparticle dose-response characteristics being found, depending on the bacterial species. and EMs plus NPs at nontoxic doses stimulated the secretion of interleukin-1β (IL-1β), IL-12, IL-10, and IL-6, while and EMs plus NPs at toxic doses stimulated the secretion of gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), IL-4, and IL-5. On the contrary, and EMs induced cytokines only when they were combined with NPs at toxic concentrations. The induction of maturation markers (CD86, CD80, CD83, intercellular adhesion molecule 1, and major histocompatibility complex class II) by commensal bacteria but not by pathogenic ones was improved in the presence of noncytotoxic SiO NP doses. DCs consistently supported the proliferation and differentiation of CD4 and CD8 T cells secreting IFN-γ and IL-17A. The synergistic induction of CD86 was due to nonprotein molecules present in the EMs from all bacteria tested. At variance with this finding, the synergistic induction of IL-1β was prevalently mediated by proteins in the case of EMs and by nonproteins in the case of EMs. A bacterial costimulus did not act on DCs after adsorption on SiO NPs but rather acted as an independent agonist. The inflammatory and immune actions of DCs stimulated by commensal bacterial agonists might be altered by the simultaneous exposure to engineered or environmental NPs.
Equine Arteritis Virus Elicits a Mucosal Antibody Response in the Reproductive Tract of Persistently Infected Stallions.
Carossino M, Wagner B, Loynachan AT … +8 more , Cook RF, Canisso IF, Chelvarajan L, Edwards CL, Nam B, Timoney JF, Timoney PJ, Balasuriya UBR
Clin Vaccine Immunol · 2017 Oct · PMID 28814389 · Full text
Equine arteritis virus (EAV) has the ability to establish persistent infection in the reproductive tract of the stallion (carrier) and is continuously shed in its semen. We have recently demonstrated that EAV persists wi...
Equine arteritis virus (EAV) has the ability to establish persistent infection in the reproductive tract of the stallion (carrier) and is continuously shed in its semen. We have recently demonstrated that EAV persists within stromal cells and a subset of lymphocytes in the stallion accessory sex glands in the presence of a significant local inflammatory response. In the present study, we demonstrated that EAV elicits a mucosal antibody response in the reproductive tract during persistent infection with homing of plasma cells into accessory sex glands. The EAV-specific immunoglobulin isotypes in seminal plasma included IgA, IgG1, IgG3/5, and IgG4/7. Interestingly, seminal plasma IgG1 and IgG4/7 possessed virus-neutralizing activity, while seminal plasma IgA and IgG3/5 did not. However, virus-neutralizing IgG1 and IgG4/7 in seminal plasma were not effective in preventing viral infectivity. In addition, the serological response was primarily mediated by virus-specific IgM and IgG1, while virus-specific serum IgA, IgG3/5, IgG4/7, and IgG6 isotype responses were not detected. This is the first report characterizing the immunoglobulin isotypes in equine serum and seminal plasma in response to EAV infection. The findings presented herein suggest that while a broader immunoglobulin isotype diversity is elicited in seminal plasma, EAV has the ability to persist in the reproductive tract, in spite of local mucosal antibody and inflammatory responses. This study provides further evidence that EAV employs complex immune evasion mechanisms during persistence in the reproductive tract that warrant further investigation.
Impact of Poxvirus Vector Priming, Protein Coadministration, and Vaccine Intervals on HIV gp120 Vaccine-Elicited Antibody Magnitude and Function in Infant Macaques.
Phillips B, Fouda GG, Eudailey J … +16 more , Pollara J, Curtis AD, Kunz E, Dennis M, Shen X, Bay C, Hudgens M, Pickup D, Alam SM, Ardeshir A, Kozlowski PA, Van Rompay KKA, Ferrari G, Moody MA, Permar S, De Paris K
Clin Vaccine Immunol · 2017 Oct · PMID 28814388 · Full text
Despite success in reducing vertical HIV transmission by maternal antiretroviral therapy, several obstacles limit its efficacy during breastfeeding, and breast-milk transmission is now the dominant mode of mother-to-chil...
Despite success in reducing vertical HIV transmission by maternal antiretroviral therapy, several obstacles limit its efficacy during breastfeeding, and breast-milk transmission is now the dominant mode of mother-to-child transmission (MTCT) of HIV in infants. Thus, a pediatric vaccine is needed to eradicate oral HIV infections in newborns and infants. Utilizing the infant rhesus macaque model, we compared 3 different vaccine regimens: (i) HIV envelope (Env) protein only, (ii) poxvirus vector (modified vaccinia virus Ankara [MVA])-HIV Env prime and HIV Env boost, and (iii) coadministration of HIV Env and MVA-HIV Env at all time points. The vaccines were administered with an accelerated, 3-week-interval regimen starting at birth for early induction of highly functional HIV Env-specific antibodies. We also tested whether an extended, 6-week immunization interval using the same vaccine regimen as in the coadministration group would enhance the quality of antibody responses. We found that pediatric HIV vaccines administered at birth are effective in inducing HIV Env-specific plasma IgG. The vaccine regimen consisting of only HIV Env protein induced the highest levels of variable region 1 and 2 (V1V2)-specific antibodies and tier 1 neutralizing antibodies, whereas the extended-interval regimen induced both persistent Env-specific systemic IgG and mucosal IgA responses. Antibody-dependent cell-mediated cytotoxicity (ADCC) antibodies in plasma were elicited by all vaccine regimens. These data suggest that infant immunizations beginning at birth are effective for the induction of functional HIV Env-specific antibodies that could potentially protect against breast milk transmission of HIV and set the stage for immunity prior to sexual debut.
Effect of Vaccine-Elicited Antibodies on Colonization of Neisseria meningitidis Serogroup B and C Strains in a Human Bronchial Epithelial Cell Culture Model.
Vianzon V, Illek B, Moe GR
Clin Vaccine Immunol · 2017 Oct · PMID 28794055 · Full text
Capsular polysaccharide-protein conjugate vaccines protect individuals from invasive disease and decrease carriage, which reduces spread of the organism in the population. In contrast, antibodies elicited by plain polysa...
Capsular polysaccharide-protein conjugate vaccines protect individuals from invasive disease and decrease carriage, which reduces spread of the organism in the population. In contrast, antibodies elicited by plain polysaccharide or protein antigen-based meningococcal (Men) vaccines have little or no effect on decreasing carriage. In this study, we investigated the mechanism by which vaccine-induced human immunoglobulin G (IgG) antibodies affect colonization by meningococcal serogroup B (MenB) or C (MenC) strains using a human bronchial epithelial cell culture model (16HBE14o-). Fluorescence microscopy showed that bacteria colonizing the apical side of 16HBE14o- monolayers had decreased capsular polysaccharide on the bacterial surface that resulted from shedding the capsule and not decreased production of polysaccharide. Capsular polysaccharide shedding depended on the presence of 16HBE14o- cells and bacteria but not direct adherence of the bacteria to the cells. Treatment of bacteria and cells with postimmunization MenC-conjugate IgG or murine anti-MenB polysaccharide monoclonal antibodies (MAbs) inhibited capsule shedding, microcolony dispersal, and invasion of the 16HBE14o- cell monolayer. In contrast, the IgG responses elicited by immunization with MenC polysaccharide (PS), MenB outer membrane vesicle (OMV)-based, or factor H binding protein (FHbp)-based vaccines were not different than preimmune IgG or no-treatment response. The results provide new insights on the mechanism by which high-avidity anticapsular antibodies elicited by polysaccharide-conjugate vaccines affect meningococcal colonization. The data also suggest that any effect on colonization by IgG elicited by OMV- or FHbp-based vaccines may involve a different mechanism.
Immunogenicity of Nontypeable Haemophilus influenzae Outer Membrane Vesicles and Protective Ability in the Chinchilla Model of Otitis Media.
Winter LE, Barenkamp SJ
Clin Vaccine Immunol · 2017 Oct · PMID 28768669 · Full text
Outer membrane vesicles (OMVs) produced by Gram-negative bacteria are enriched in several outer membrane components, including major and minor outer membrane proteins and lipooligosaccharide. We assessed the functional a...
Outer membrane vesicles (OMVs) produced by Gram-negative bacteria are enriched in several outer membrane components, including major and minor outer membrane proteins and lipooligosaccharide. We assessed the functional activity of nontypeable (NTHi) OMV-specific antisera and the protective ability of NTHi OMVs as vaccine antigens in the chinchilla otitis media model. OMVs were purified from three HMW1/HMW2-expressing NTHi strains, two of which were also engineered to overexpress Hia proteins. OMV-specific antisera raised in guinea pigs were assessed for their ability to mediate killing of representative NTHi in an opsonophagocytic assay. The three OMV-specific antisera mediated killing of 18 of 65, 24 of 65, and 30 of 65 unrelated HMW1/HMW2-expressing NTHi strains. Overall, they mediated killing of 39 of 65 HMW1/HMW2-expressing strains. The two Hia-expressing OMV-specific antisera mediated killing of 17 of 25 and 14 of 25 unrelated Hia-expressing NTHi strains. Overall, they mediated killing of 20 of 25 Hia-expressing strains. OMVs from prototype NTHi strain 12 were used to immunize chinchillas and the course of middle ear infection was monitored following intrabullar challenge with the homologous strain. All control animals developed culture-positive otitis media, as did two of three HMW1/HMW2-immunized animals. All OMV-immunized animals, with or without supplemental HMW1/HMW2 immunization, were completely protected against otitis media. NTHi OMVs are the first immunogens examined in this model that provided complete protection with sterile immunity after NTHi strain 12 challenge. These data suggest that NTHi OMVs hold significant potential as components of protective NTHi vaccines, possibly in combination with HMW1/HMW2 proteins.
A Combination of Recombinant Mycobacterium bovis BCG Strains Expressing Pneumococcal Proteins Induces Cellular and Humoral Immune Responses and Protects against Pneumococcal Colonization and Sepsis.
Goulart C, Rodriguez D, Kanno AI … +4 more , Converso TR, Lu YJ, Malley R, Leite LCC
Clin Vaccine Immunol · 2017 Oct · PMID 28768668 · Full text
Pneumococcal diseases remain a substantial cause of mortality in young children in developing countries. The development of potentially serotype-transcending vaccines has been extensively studied; ideally, such a vaccine...
Pneumococcal diseases remain a substantial cause of mortality in young children in developing countries. The development of potentially serotype-transcending vaccines has been extensively studied; ideally, such a vaccine should include antigens that are able to induce protection against colonization (likely mediated by interleukin-17A [IL-17A]) and invasive disease (likely mediated by antibody). The use of strong adjuvants or alternative delivery systems that are able to improve the immunological response of recombinant proteins has been proposed but poses potential safety and practical concerns in children. We have previously constructed a recombinant BCG strain expressing a pneumococcal surface protein A (PspA)-PdT fusion protein (rBCG PspA-PdT) that was able to induce an effective immune response and protection against sepsis in a prime-boost strategy. Here, we constructed two new rBCG strains expressing the pneumococcal proteins SP 0148 and SP 2108, which confer IL-17A-dependent protection against pneumococcal colonization in mouse models. Immunization of mice with rBCG 0148 or rBCG 2108 in a prime-boost strategy induced IL-17A and gamma interferon (IFN-γ) production. The combination of these rBCG strains with rBCG PspA-PdT (rBCG Mix), followed by a booster dose of the combined recombinant proteins (rMix) induced an IL-17A response against SP 0148 and SP 2108 and a humoral response characterized by increased levels of IgG2c against PspA and functional antibodies against pneumolysin. Furthermore, immunization with the rBCG Mix prime/rMix booster (rBCG Mix/rMix) provides protection against pneumococcal colonization and sepsis. These results suggest the use of combined rBCG strains as a potentially serotype-transcending pneumococcal vaccine in a prime-boost strategy, which could provide protection against pneumococcal colonization and sepsis.
N-Terminal Pfs230 Domain Produced in Baculovirus as a Biological Active Transmission-Blocking Vaccine Candidate.
Lee SM, Wu CK, Plieskatt JL … +3 more , Miura K, Hickey JM, King CR
Clin Vaccine Immunol · 2017 Oct · PMID 28747311 · Full text
Transmission-blocking vaccines have the potential to accelerate malaria parasite elimination by inducing antibodies that block parasite transmission from humans to mosquitoes. Pfs230, a gametocyte surface protein involve...
Transmission-blocking vaccines have the potential to accelerate malaria parasite elimination by inducing antibodies that block parasite transmission from humans to mosquitoes. Pfs230, a gametocyte surface protein involved in gamete function, has long been a promising candidate. Due to the large size (3,135 amino acids), complex domains, and repeating 6-cysteine (6-Cys) motifs with a multitude of disulfide bonds, the feasibility of expression of a full-length protein has been difficult. A priority focus, therefore, has been on the generation of single domains, including N-terminal fragments. Here we utilized a heterologous expression system, baculovirus, to produce an N-terminal domain of Pfs230 (Pfs230C1). Pfs230C1 (amino acids 443 to 731) with a polyhistidine affinity tag was expressed in Super Sf9 cells. Since the native host lacks glycosylation machinery, a single N585Q mutation was made to eliminate potential N-linked glycosylation. The expressed protein, purified by nickel affinity, ion exchange, and size exclusion chromatography to >90% purity, was present in monomeric form with an observed mass of 33,510 Da (matching oxidized form). Peptide mapping and disulfide analysis confirmed the proper formation of predicted disulfide bonds. Antibodies, generated against Pfs230C1 in mice, bound to the gametocyte in an immunofluorescence assay (IFA) and demonstrated functional activity in both the standard membrane feeding assay (SMFA) and the exflagellation assay (EXA). The biochemical, biophysical, and immunological results reported herein support the continued advancement of an N-terminal Pfs230 antigen (Pfs230C1) as a component of a transmission-blocking vaccine. Our results also support the continued use of the scalable baculovirus expression system for the generation of complex proteins.
Assignment of Weight-Based Antibody Units for Four Additional Serotypes to a Human Antipneumococcal Standard Reference Serum, 007sp.
Goldblatt D, McKeen A, Burbidge P … +5 more , McElhiney S, McLaughlin L, Johnson A, Rauh M, Giardina PC
Clin Vaccine Immunol · 2017 Sep · PMID 28724524 · Full text
The pneumococcal enzyme-linked immunosorbent assay (ELISA) reference standard serum, lot 89SF, had been in use since 1990 and was replaced with a new reference standard serum, 007sp, in 2013. This serum was generated und...
The pneumococcal enzyme-linked immunosorbent assay (ELISA) reference standard serum, lot 89SF, had been in use since 1990 and was replaced with a new reference standard serum, 007sp, in 2013. This serum was generated under an FDA-approved clinical protocol where 278 adult volunteers were immunized with the 23-valent unconjugated polysaccharide vaccine Pneumovax II and a unit of blood was obtained twice within 120 days following immunization. Pooled serum was prepared from the plasma, filled at 6 ml per vial, and lyophilized. Five independent laboratories participated in bridging the serotype-specific IgG assignments of 89SF to 007sp to establish equivalent reference values for 13 pneumococcal capsular serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) using the WHO reference ELISA. A subsequent follow-up study established equivalent reference values for an additional seven serotypes (8, 10A, 11A, 12F, 15B, 22F, 33F). In this study, three laboratories assigned weight-based IgG concentrations in micrograms per milliliter of serum to 007sp for four additional serotypes: 2, 9N, 17F, and 20A. This study completes the assignment of serotypes for 89SF to 007sp. In addition, the IgG antibody assignments for a 12-member WHO quality control (QC) serum panel were extended to cover the four additional serotypes. Agreement was excellent, with a concordance correlation coefficient ( ) of >0.996 when values from each laboratory were compared to the assigned values for the 12 WHO QC sera. The 007sp preparation has replaced 89SF as the pneumococcal reference standard. Sufficient quantities of 007sp are projected to be available for the next 25 years.
Rubella Surveillance and Diagnostic Testing among a Low-Prevalence Population, New York City, 2012-2013.
Isaac BM, Zucker JR, Giancotti FR … +4 more , Abernathy E, Icenogle J, Rakeman JL, Rosen JB
Clin Vaccine Immunol · 2017 Sep · PMID 28701468 · Full text
The New York City Department of Health and Mental Hygiene (DOHMH) receives clinical and laboratory reports for rubella. Because rubella immunoglobulin M (IgM) assays may produce false-positive results and rubella infecti...
The New York City Department of Health and Mental Hygiene (DOHMH) receives clinical and laboratory reports for rubella. Because rubella immunoglobulin M (IgM) assays may produce false-positive results and rubella infections may be asymptomatic, interpretation of positive IgM results can be challenging. Rubella reports received by DOHMH in 2012 to 2013 were reviewed. The rubella IgM testing purpose was determined through case investigation. Results of IgM testing by indirect enzyme-linked immunosorbent assay (ELISA) and capture enzyme immunoassay (EIA) were compared to determine positive predictive value (PPV) and specificity. DOHMH received 199 rubella reports; 2 were true cases. Of all reports, 77.9% were tested for rubella IgM erroneously, 19.6% were tested for diagnostic purposes, 2.0% had unknown test purpose, and 0.5% were not tested. PPV of indirect ELISA was 6% overall, 14% for diagnostic tests, and 0% for tests ordered erroneously. PPV of capture EIA was 29% overall, 50% for diagnostic tests, and 0% for tests ordered erroneously. Overall, specificity was 52% for indirect ELISA and 85% for capture EIA. Limiting rubella IgM testing to patients for whom rubella diagnosis is suspected and using a more specific IgM assay have the potential to reduce false-positive rubella IgM results.
The Cross-Species Mycobacterial Growth Inhibition Assay (MGIA) Project, 2010-2014.
Brennan MJ, Tanner R, Morris S … +13 more , Scriba TJ, Achkar JM, Zelmer A, Hokey DA, Izzo A, Sharpe S, Williams A, Penn-Nicholson A, Erasmus M, Stylianou E, Hoft DF, McShane H, Fletcher HA
Clin Vaccine Immunol · 2017 Sep · PMID 28701467 · Full text
The development of a functional biomarker assay in the tuberculosis (TB) field would be widely recognized as a major advance in efforts to develop and to test novel TB vaccine candidates efficiently. We present prelimina...
The development of a functional biomarker assay in the tuberculosis (TB) field would be widely recognized as a major advance in efforts to develop and to test novel TB vaccine candidates efficiently. We present preliminary studies using mycobacterial growth inhibition assays (MGIAs) to detect BCG vaccine responses across species, and we extend this work to determine whether a standardized MGIA can be applied in characterizing new TB vaccines. The comparative MGIA studies reviewed here aimed to evaluate robustness, reproducibility, and ability to reflect responses. In doing so, they have laid the foundation for the development of a MGIA that can be standardized and potentially qualified. A major challenge ahead lies in better understanding the relationships between protection, growth inhibition, and the immune mechanisms involved. The final outcome would be a MGIA that could be used with confidence in TB vaccine trials. We summarize data arising from this project, present a strategy to meet the goals of developing a functional assay for TB vaccine testing, and describe some of the challenges encountered in performing and transferring such assays.
Dose Selection for an Adjuvanted Respiratory Syncytial Virus F Protein Vaccine for Older Adults Based on Humoral and Cellular Immune Responses.
Falloon J, Talbot HK, Curtis C … +9 more , Ervin J, Krieger D, Dubovsky F, Takas T, Yu J, Yu L, Lambert SL, Villafana T, Esser MT
Clin Vaccine Immunol · 2017 Sep · PMID 28679495 · Full text
This is the second phase 1 study of a respiratory syncytial virus (RSV) vaccine containing RSV fusion protein (sF) adjuvanted with glucopyranosyl lipid A (GLA) in a squalene-based 2% stable emulsion (GLA-SE). In this ran...
This is the second phase 1 study of a respiratory syncytial virus (RSV) vaccine containing RSV fusion protein (sF) adjuvanted with glucopyranosyl lipid A (GLA) in a squalene-based 2% stable emulsion (GLA-SE). In this randomized, double-blind study, 261 subjects aged ≥60 years received inactivated influenza vaccine (IIV), a vaccine containing 120 μg sF with escalating doses of GLA (1, 2.5, or 5 μg) in SE, or a vaccine containing 80 μg sF with 2.5 μg GLA in SE. Subjects receiving 120 μg sF with 2.5 or 5 μg GLA were also randomized to receive IIV or placebo. Immunity to RSV was assessed by detection of microneutralizing, anti-F immunoglobulin G, and palivizumab-competitive antibodies and F-specific gamma interferon enzyme-linked immunosorbent spot assay T-cell responses. Higher adjuvant doses increased injection site discomfort, but at the highest dose, the reactogenicity was similar to that of IIV. Significant humoral and cellular immune responses were observed. The 120 μg sF plus 5.0 μg GLA formulation resulted in the highest responses in all subjects and in older subjects. These results confirm previous observations of vaccine tolerability, safety, and immunogenicity and were used to select the 120 μg sF plus 5.0 μg GLA formulation for phase 2 evaluation. (This study has been registered at ClinicalTrials.gov under registration no. NCT02289820.).
A Cation-Binding Surface Protein as a Vaccine Antigen To Prevent Moraxella catarrhalis Otitis Media and Infections in Chronic Obstructive Pulmonary Disease.
Murphy TF, Brauer AL, Johnson A … +3 more , Wilding GE, Koszelak-Rosenblum M, Malkowski MG
Clin Vaccine Immunol · 2017 Sep · PMID 28659326 · Full text
is an exclusively human respiratory tract pathogen that is a common cause of otitis media in children and respiratory tract infections in adults with chronic obstructive pulmonary disease. A vaccine to prevent these infe...
is an exclusively human respiratory tract pathogen that is a common cause of otitis media in children and respiratory tract infections in adults with chronic obstructive pulmonary disease. A vaccine to prevent these infections would have a major impact on reducing the substantial global morbidity and mortality in these populations. Through a genome mining approach, we identified AfeA, an ∼32-kDa substrate binding protein of an ABC transport system, as an excellent candidate vaccine antigen. Recombinant AfeA was expressed and purified and binds ferric, ferrous, manganese, and zinc ions, as demonstrated by thermal shift assays. It is a highly conserved protein that is present in all strains of Immunization with recombinant purified AfeA induces high-titer antibodies that recognize the native protein. AfeA expresses abundant epitopes on the bacterial surface and induces protective responses in the mouse pulmonary clearance model following aerosol challenge with Finally, AfeA is expressed during human respiratory tract infection of adults with chronic obstructive pulmonary disease (COPD). Based on these observations, AfeA is an excellent vaccine antigen to be included in a vaccine to prevent infections caused by .
Identification of an Atypical Enzootic Bovine Leukosis in Japan by Using a Novel Classification of Bovine Leukemia Based on Immunophenotypic Analysis.
Nishimori A, Konnai S, Okagawa T … +8 more , Maekawa N, Goto S, Ikebuchi R, Nakahara A, Chiba Y, Ikeda M, Murata S, Ohashi K
Clin Vaccine Immunol · 2017 Sep · PMID 28659325 · Full text
Bovine leukemia is classified into two types: enzootic bovine leukosis (EBL) and sporadic bovine leukosis (SBL). EBL is caused by infection with bovine leukemia virus (BLV), which induces persistent lymphocytosis and B-c...
Bovine leukemia is classified into two types: enzootic bovine leukosis (EBL) and sporadic bovine leukosis (SBL). EBL is caused by infection with bovine leukemia virus (BLV), which induces persistent lymphocytosis and B-cell lymphoma in cattle after a long latent period. Although it has been demonstrated that BLV-associated lymphoma occurs predominantly in adult cattle of >3 to 5 years, suspicious cases of EBL onset in juvenile cattle were recently reported in Japan. To investigate the current status of bovine leukemia in Japan, we performed immunophenotypic analysis of samples from 50 cattle that were clinically diagnosed as having bovine leukemia. We classified the samples into five groups on the basis of the analysis and found two different types of EBL: classic EBL (cEBL), which has the familiar phenotype commonly known as EBL, and polyclonal EBL (pEBL), which exhibited neoplastic proliferation of polyclonal B cells. Moreover, there were several atypical EBL cases even in cEBL, including an early onset of EBL in juvenile cattle. A comparison of the cell marker expressions among cEBL, pEBL, and B-cell-type SBL (B-SBL) revealed characteristic patterns in B-cell leukemia, and these patterns could be clearly differentiated from those of healthy phenotypes, whereas it was difficult to discriminate between cEBL, pEBL, and B-SBL only by the expression patterns of cell markers. This study identified novel characteristics of bovine leukemia that should contribute to a better understanding of the mechanism underlying tumor development in BLV infection.
The Pneumococcal Serotype 15C Capsule Is Partially O-Acetylated and Allows for Limited Evasion of 23-Valent Pneumococcal Polysaccharide Vaccine-Elicited Anti-Serotype 15B Antibodies.
Spencer BL, Shenoy AT, Orihuela CJ … +1 more , Nahm MH
Clin Vaccine Immunol · 2017 Aug · PMID 28637806 · Full text
As a species, (the pneumococcus) utilizes a diverse array of capsular polysaccharides to evade the host. In contrast to large variations in sugar composition and linkage formation, O-acetylation is a subtle capsular mod...
As a species, (the pneumococcus) utilizes a diverse array of capsular polysaccharides to evade the host. In contrast to large variations in sugar composition and linkage formation, O-acetylation is a subtle capsular modification that nonetheless has a large impact on capsular shielding and recognition of the capsule by vaccine-elicited antibodies. Serotype 15B, which is included in the 23-valent pneumococcal polysaccharide vaccine (PPV23), carries the putative O-acetyltransferase gene The coding sequence of contains eight consecutive TA repeats [(TA)]. Replication slippage is thought to result in the addition or loss of TA repeats, subsequently causing frameshift and truncation of WciZ to yield a nonacetylated serotype, 15C. Using sensitive serological tools, we show that serotype 15C isolates whose contains seven or nine TA repeats retain partial O-acetylation, while serotype 15C isolates whose contains six TA repeats have barely detectable O-acetylation. We confirmed by inhibition enzyme-linked immunosorbent assay that (TA) serotype 15C is ∼0.1% as acetylated as serotype 15B, while serotype 15X is nonacetylated. To eliminate the impact of genetic background, we created isogenic serotype 15B, (TA) serotype 15C, and 15BΔ (15X) strains and found that reduction or absence of WciZ-mediated O-acetylation did not affect capsular shielding from phagocytes, biofilm formation, adhesion to nasopharyngeal cells, desiccation tolerance, or murine colonization. Sera from PPV23-immunized persons opsonized serotype 15B significantly but only slightly better than serotypes 15C and 15X; thus, PPV23 may not result in expansion of serotype 15C.
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