da Silva MA, Converso TR, Gonçalves VM
… +3 more, Leite LCC, Tanizaki MM, Barazzone GC
Clin Vaccine Immunol
· 2017 Aug · PMID 28637805
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Current pneumococcal vaccines are composed of bacterial polysaccharides as antigens, plain or conjugated to carrier proteins. While efficacious against vaccine serotypes, epidemiologic data show an increasing incidence o...Current pneumococcal vaccines are composed of bacterial polysaccharides as antigens, plain or conjugated to carrier proteins. While efficacious against vaccine serotypes, epidemiologic data show an increasing incidence of infections caused by nonvaccine serotypes of The use of pneumococcal surface protein A (PspA) as a carrier protein in a conjugate vaccine could help prevent serotype replacement by increasing vaccine coverage and reducing selective pressure of serotypes. PspA is present in all pneumococcal strains, is highly immunogenic, and is known to induce protective antibodies. Based on its sequence, PspA has been classified into three families and six clades. A PspA fragment derived from family 2, clade 4 (PspA4Pro), was shown to generate antibodies with a broad range of cross-reactivity, across clades and families. Here, PspA4Pro was modified and conjugated to capsular polysaccharide serotype 14 (PS14). We investigated the impact of conjugation on the immune response induced to PspA4Pro and PS14. Mice immunized with the PS14-mPspA4Pro conjugate produced higher titers of anti-PS14 antibodies than the animals that received coadministered antigens. The conjugate induced antibodies with opsonophagocytic activity against PS14-carrying strains, as well as against a panel of strains bearing PspAs from five clades (encompassing families 1 and 2) bearing a non-PS14 serotype. Furthermore, mice immunized with PS14-mPspA4Pro were protected against nasal colonization with a nonrelated strain bearing PspA from clade 1, serotype 6B. These results demonstrate that the cross-reactivity mediated by PspA4Pro is retained following conjugation, supporting the use of PspA4 as a carrier protein in order to enhance pneumococcal vaccine coverage and encourage its further investigation as a candidate in future vaccine designs.
Sears KT, Tennant SM, Reymann MK
… +5 more, Simon R, Konstantopoulos N, Blackwelder WC, Barry EM, Pasetti MF
Clin Vaccine Immunol
· 2017 Aug · PMID 28637804
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Diarrhea is a common illness among travelers to resource-limited countries, the most prevalent attributable agent being enterotoxigenic (ETEC). At this time, there are no vaccines licensed specifically for the preventio...Diarrhea is a common illness among travelers to resource-limited countries, the most prevalent attributable agent being enterotoxigenic (ETEC). At this time, there are no vaccines licensed specifically for the prevention of ETEC-induced traveler's diarrhea (TD), and this has propelled investigation of alternative preventive methods. Colostrum, the first milk expressed after birthing, is rich in immunoglobulins and innate immune components for protection of newborns against infectious agents. Hyperimmune bovine colostrum (HBC) produced by immunization of cows during gestation (and containing high levels of specific antibodies) is a practical and effective prophylactic tool against gastrointestinal illnesses. A commercial HBC product, Travelan, is available for prevention of ETEC-induced diarrhea. Despite its demonstrated clinical efficacy, the underlying immune components and antimicrobial activity that contribute to protection remain undefined. We investigated innate and adaptive immune components of several commercial HBC products formulated to reduce the risk of ETEC-induced diarrhea, including Travelan and IMM-124E, a newer product that has broader gastrointestinal health benefits. The immune components measured included total and ETEC-specific IgG, total IgA, cytokines, growth factors, and lactoferrin. HBC products contained high levels of IgG specific for multiple ETEC antigens, including O-polysaccharide 78 and colonization factor antigen I (CFA/I) present in the administered vaccines. Antimicrobial activity was measured using novel functional assays. HBC greatly reduced ETEC motility in soft agar and exhibited bactericidal activity in the presence of complement. We have identified immune components and antimicrobial activity potentially involved in the prevention of ETEC infection by HBC .
Fischer DD, Kandasamy S, Paim FC
… +10 more, Langel SN, Alhamo MA, Shao L, Chepngeno J, Miyazaki A, Huang HC, Kumar A, Rajashekara G, Saif LJ, Vlasova AN
Clin Vaccine Immunol
· 2017 Aug · PMID 28637803
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Malnutrition leads to increased morbidity and is evident in almost half of all deaths in children under the age of 5 years. Mortality due to rotavirus diarrhea is common in developing countries where malnutrition is prev...Malnutrition leads to increased morbidity and is evident in almost half of all deaths in children under the age of 5 years. Mortality due to rotavirus diarrhea is common in developing countries where malnutrition is prevalent; however, the relationship between malnutrition and rotavirus infection remains unclear. In this study, gnotobiotic pigs transplanted with the fecal microbiota of a healthy 2-month-old infant were fed protein-sufficient or -deficient diets and infected with virulent human rotavirus (HRV). After human rotavirus infection, protein-deficient pigs had decreased human rotavirus antibody titers and total IgA concentrations, systemic T helper (CD3 CD4) and cytotoxic T (CD3 CD8) lymphocyte frequencies, and serum tryptophan and angiotensin I-converting enzyme 2. Additionally, deficient-diet pigs had impaired tryptophan catabolism postinfection compared with sufficient-diet pigs. Tryptophan supplementation was tested as an intervention in additional groups of fecal microbiota-transplanted, rotavirus-infected, sufficient- and deficient-diet pigs. Tryptophan supplementation increased the frequencies of regulatory (CD4 or CD8 CD25 FoxP3) T cells in pigs on both the sufficient and the deficient diets. These results suggest that a protein-deficient diet impairs activation of the adaptive immune response following HRV infection and alters tryptophan homeostasis.
Liu Z, Shao J, Zhao F
… +8 more, Zhou G, Gao S, Liu W, Lv J, Li X, Li Y, Chang H, Zhang Y
Clin Vaccine Immunol
· 2017 Aug · PMID 28592628
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The potential diagnostic value of chemiluminescence immunoassays (CLIAs) has been accepted in recent years, although their use for foot-and-mouth disease (FMD) diagnostics has not been reported. Full-length 3ABC and 2C p...The potential diagnostic value of chemiluminescence immunoassays (CLIAs) has been accepted in recent years, although their use for foot-and-mouth disease (FMD) diagnostics has not been reported. Full-length 3ABC and 2C proteins were expressed in bacteria and purified by affinity chromatography to develop a rapid and accurate approach to distinguish pigs infected with foot-and-mouth disease virus (FMDV) from vaccinated pigs. The recombinant proteins were then used as antigens to develop two CLIAs for the detection of antibodies against nonstructural viral proteins. The diagnostic performance of the two assays was compared by analyzing serum from pigs (naive pigs, = 63; vaccinated, uninfected pigs, = 532; naive, infected pigs, = 117) with a known infection status. The 3ABC-2C CLIA had a higher accuracy rate, with a diagnostic sensitivity of 100% and a diagnostic specificity of 96.5%, than the 3ABC CLIA, which had a diagnostic sensitivity of 95.7% and a diagnostic specificity of 96.0%. The results of the 3ABC-2C CLIA also had a high rate of concordance with those of two commercial FMDV enzyme-linked immunosorbent assay (ELISA) kits used to assess serum collected from 962 pigs in the field (96.2% and 97.8%, respectively). The 3ABC-2C CLIA detected infection in serum samples from infected pigs earlier than the commercial ELISA kits. In addition, the 3ABC-2C CLIA produced results within 15 min. On the basis of these findings, the 3ABC-2C CLIA could serve as the foundation for the development of penside FMD diagnostics and offers an alternative method to detect FMDV infections.
Yu H, Chen K, Sun Y
… +9 more, Carter M, Garey KW, Savidge TC, Devaraj S, Tessier ME, von Rosenvinge EC, Kelly CP, Pasetti MF, Feng H
Clin Vaccine Immunol
· 2017 Aug · PMID 28592627
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The host immune response affects pathogen virulence in infection (CDI). Thus, cytokine responses to CDI likely are associated with disease initiation and progression. Understanding the molecular drivers of inflammation...The host immune response affects pathogen virulence in infection (CDI). Thus, cytokine responses to CDI likely are associated with disease initiation and progression. Understanding the molecular drivers of inflammation and biochemical markers of disease severity is important for developing novel therapies and predicting disease prognosis. In this study, we investigated cytokine production in patients with CDI and evaluated the potential of cytokines to serve as biomarkers for CDI and predictors of disease severity. The systemic cytokine profiles of 36 CDI patients (20 with severe disease) and 8 healthy donors and the toxin-induced cytokine profiles of peripheral blood mononuclear cells (PBMC) were determined. Further, we evaluated glucosyltransferase (GT) activity in regulation of toxin-induced cytokine expression. We found upregulation of the majority of measured cytokines (11/20, 55%) in CDI patients. Interleukin-1β (IL-1β), IL-6, IL-8, IL-17A, and IL-16 were the most upregulated. High serum levels of IL-2 and IL-15 were associated with a poor prognosis in CDI patients, whereas high levels of IL-5 and gamma interferon (IFN-γ) were associated with less severe disease. Both TcdA and TcdB were potent inducers of cytokine responses, as demonstrated by stimulation of a greater number and amount of cytokines. In addition to confirming prior reports on the role of IL-8, IL-1β, and IL-6 in CDI, our data suggest that IL-16 and IL-17A, as well as the IL-1β/Th17 axis, play a key role in driving inflammatory responses in CDI. A functional GT domain of toxins was required for the induction of a majority of cytokines investigated.
van Hooij A, Boeters DM, Tjon Kon Fat EM
… +4 more, van den Eeden SJF, Corstjens PLAM, van der Helm-van Mil AHM, Geluk A
Clin Vaccine Immunol
· 2017 Aug · PMID 28592626
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Although rheumatoid arthritis (RA) is a chronic, persistent autoimmune disease, 10 to 15% of RA patients achieve sustained disease-modifying antirheumatic drug (DMARD)-free remission over time. The biological mechanisms...Although rheumatoid arthritis (RA) is a chronic, persistent autoimmune disease, 10 to 15% of RA patients achieve sustained disease-modifying antirheumatic drug (DMARD)-free remission over time. The biological mechanisms underlying the resolution of persistent inflammation in RA are still unidentified, and there is a lack of prognostic markers. It is well established that increased serum levels of gamma interferon-induced protein 10 (IP-10) are associated with (acute) increased inflammatory responses (e.g., in leprosy). In order to assess the potential of IP-10 as a diagnostic tool for inflammatory episodes of RA, we performed a retrospective study and assessed IP-10 levels in longitudinally banked serum samples obtained from patients upon first diagnosis of RA. The selection consisted of 15 persistent RA patients and 19 patients who achieved DMARD-free sustained remission. IP-10 levels, measured by use of a user-friendly quantitative lateral flow assay (LFA), showed up to 170-fold variation interindividually, and baseline IP-10 levels could not be differentiated between the two patient groups. However, a difference in the change in IP-10 levels between the first and last visits (ΔIP-10) was observed ( = 0.003) between DMARD-free (median ΔIP-10, -662 pg/ml [decrease]) and persistent (median ΔIP-10, 468 pg/ml [increase]) RA patients. Moreover, intraindividual changes in IP-10 levels during the course of disease corresponded to the disease activity score (DAS) ( = 0.05). These data indicate that IP-10 is associated with disease activity and perseverance of RA. The association of IP-10 with DAS indicates that this tool may be a practical diagnostic aid to help in monitoring disease progression in RA patients and may also find applications in other chronic diseases with exacerbated inflammatory episodes.
Mutucumarana CP, Eudailey J, McGuire EP
… +8 more, Vandergrift N, Tegha G, Chasela C, Ellington S, van der Horst C, Kourtis AP, Permar SR, Fouda GG
Clin Vaccine Immunol
· 2017 Aug · PMID 28566336
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Despite the widespread use of antiretrovirals (ARV), more than 150,000 pediatric HIV-1 infections continue to occur annually. Supplemental strategies are necessary to eliminate pediatric HIV infections. We previously rep...Despite the widespread use of antiretrovirals (ARV), more than 150,000 pediatric HIV-1 infections continue to occur annually. Supplemental strategies are necessary to eliminate pediatric HIV infections. We previously reported that maternal HIV envelope-specific anti-V3 IgG and CD4 binding site-directed antibodies, as well as tier 1 virus neutralization, predicted a reduced risk of mother-to-child transmission (MTCT) of HIV-1 in the pre-ARV era U.S.-based Women and Infants Transmission Study (WITS) cohort. As the majority of ongoing pediatric HIV infections occur in sub-Saharan Africa, we sought to determine if the same maternal humoral immune correlates predicted MTCT in a subset of the Malawian Breastfeeding, Antiretrovirals, and Nutrition (BAN) cohort of HIV-infected mothers ( = 88, with 45 transmitting and 43 nontransmitting). Women and infants received ARV at delivery; thus, the majority of MTCT was (91%). In a multivariable logistic regression model, neither maternal anti-V3 IgG nor clade C tier 1 virus neutralization was associated with MTCT. Unexpectedly, maternal CD4 binding-site antibodies and anti-variable loop 1 and 2 (V1V2) IgG were associated with increased MTCT, independent of maternal viral load. Neither infant envelope (Env)-specific IgG levels nor maternal IgG transplacental transfer efficiency was associated with transmission. Distinct humoral immune correlates of MTCT in the BAN and WITS cohorts could be due to differences between transmission modes, virus clades, or maternal antiretroviral use. The association between specific maternal antibody responses and transmission, which is distinct from potentially protective maternal antibodies in the WITS cohort, underlines the importance of investigating additional cohorts with well-defined transmission modes to understand the role of antibodies during HIV-1 MTCT.
Lujan E, Partridge E, Giuntini S
… +2 more, Ram S, Granoff DM
Clin Vaccine Immunol
· 2017 Aug · PMID 28566335
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MenB-FHbp is a meningococcal serogroup B vaccine with two factor H binding protein (FHbp) antigens from subfamilies A and B. For licensure, efficacy was inferred from serum bactericidal antibody (SBA) responses to four r...MenB-FHbp is a meningococcal serogroup B vaccine with two factor H binding protein (FHbp) antigens from subfamilies A and B. For licensure, efficacy was inferred from serum bactericidal antibody (SBA) responses to four reference strains. Only limited information is available on the breadth or duration of protective SBA responses to genetically diverse disease-causing strains. Seventeen health care or laboratory workers were immunized with two ( = 2) or three ( = 15) doses of MenB-FHbp at 0, 2, and 6 months. SBA levels were measured against 14 serogroup B case isolates, including 6 from U.S. college outbreaks and 2 from Quebec during hyperendemic disease. Compared with preimmunization titers, the proportion of subjects with ≥4-fold increases in SBA titer 1 month after 2 doses of vaccine ranged from 35% to 94% for six isolates with FHbp subfamily A and from 24% to 76% for eight isolates with subfamily B FHbp. The respective proportions with ≥4-fold titer increases at 1 month after dose 3 were 73% to 100% and 67% to 100%. At that time point, the proportion of subjects with titers of ≥1:4 (presumed sufficient for short-term protection) ranged from 93% to 100% for all 14 isolates. By 9 to 11 months after dose 3, 50% or fewer of the subjects with follow-up sera had protective titers of ≥1:4 for 4 of 9 isolates tested. Three doses of MenB-FHbp elicited short-term protective SBA responses to diverse disease-causing serogroup B strains. For some strains, serum titers declined to <1:4 by 9 to 11 months, which raises concerns about the duration of broad, long-term protection. (This study has been registered at ClinicalTrials.gov under registration no. NCT02569632.).
Haney DJ, Lock MD, Simon JK
… +2 more, Harris J, Gurwith M
Clin Vaccine Immunol
· 2017 May · PMID 28566334
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Immunologic correlates of protection can be used to infer vaccine efficacy for populations in which challenge trials or field studies are infeasible. In a recent cholera challenge trial (WH Cohen et al, Clinical Infectio...Immunologic correlates of protection can be used to infer vaccine efficacy for populations in which challenge trials or field studies are infeasible. In a recent cholera challenge trial (WH Cohen et al, Clinical Infectious Disease 62: 1329-1335, 2016), 134 North American cholera-naïve volunteers were randomized to receive either the live, attenuated single-dose cholera vaccine CVD 103-HgR or placebo, and titers of vibriocidal antibodies against classical Inaba were assessed 10 days after treatment. Subsequent to the immunologic evaluation, each subject ingested a fixed quantity of virulent O1 El Tor Inaba. Data from this trial suggest that vaccine-induced increase in vibriocidal antibody titer prior to challenge is tightly linked with protection: 51/51 vaccinees with post-vaccination vibriocidal titers >= 2560 were protected against moderate/severe cholera, and 60/62 vaccinees who seroconverted, or experienced a 4-fold or greater increase in vibriocidal titer relative to pre-vaccination levels, were similarly protected. Atypically high vibriocidal titers were observed in some placebo subjects; protection was limited in these individuals and differed substantially from the level of protection experienced by vaccinees with the same post-vaccination titers. Since only 1 of 66 placebo recipients experienced seroconversion, seroconversion was found to be uniquely associated with vaccination and insensitive to the effects of factors that can cause titers to be elevated but are weakly associated with protection. Thus, vibriocidal seroconversion was found to be better than vibriocidal titer for inferring vaccine efficacy in cholera-naïve populations for which studies based upon exposure to are impractical.
Clin Vaccine Immunol
· 2017 Jul · PMID 28515136
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Invasive nontyphoidal (iNTS) infections are commonly associated with infections, but the immunologic basis for this linkage is poorly understood. We hypothesized that infection compromises the humoral and cellular imm...Invasive nontyphoidal (iNTS) infections are commonly associated with infections, but the immunologic basis for this linkage is poorly understood. We hypothesized that infection compromises the humoral and cellular immunity of the host to NTS, which increases the susceptibility of the host to iNTS infection. We prospectively recruited children aged between 6 and 60 months at a Community Health Centre in Blantyre, Malawi, and allocated them to the following groups; febrile with uncomplicated malaria, febrile malaria negative, and nonfebrile malaria negative. Levels of serovar Typhimurium-specific serum bactericidal activity (SBA) and whole-blood bactericidal activity (WBBA), complement C3 deposition, and neutrophil respiratory burst activity (NRBA) were measured. Levels of SBA with respect to Typhimurium were reduced in febrile -infected children (median, -0.20 log10 [interquartile range {IQR}, -1.85, 0.32]) compared to nonfebrile malaria-negative children (median, -1.42 log10 [IQR, -2.0, -0.47], = 0.052). In relation to SBA, C3 deposition on Typhimurium was significantly reduced in febrile -infected children (median, 7.5% [IQR, 4.1, 15.0]) compared to nonfebrile malaria-negative children (median, 29% [IQR, 11.8, 48.0], = 0.048). WBBA with respect to Typhimurium was significantly reduced in febrile -infected children (median, 0.25 log10 [IQR, -0.73, 1.13], = 0.0001) compared to nonfebrile malaria-negative children (median, -1.0 log10 [IQR, -1.68, -0.16]). In relation to WBBA, Typhimurium-specific NRBA was reduced in febrile -infected children (median, 8.8% [IQR, 3.7, 20], = 0.0001) compared to nonfebrile malaria-negative children (median, 40.5% [IQR, 33, 65.8]). infection impairs humoral and cellular immunity to Typhimurium in children during malaria episodes, which may explain the increased risk of iNTS observed in children from settings of malaria endemicity. The mechanisms underlying humoral immunity impairment are incompletely understood and should be explored further.
Clin Vaccine Immunol
· 2017 Jul · PMID 28515135
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From experimental models and the analyses of patients, it is well documented that antigen-specific T cells are critical for protection against infection. Effective vaccines require both targeting to the pathogen and an...From experimental models and the analyses of patients, it is well documented that antigen-specific T cells are critical for protection against infection. Effective vaccines require both targeting to the pathogen and an immune stimulant to induce maturation of appropriate immune responses. While a great number of antigens have been examined as vaccine candidates against various species, few have advanced to human or canine clinical trials. With emphasis on antigen expression, in this minireview we discuss some of the vaccine platforms that are currently being explored for the development of vaccines. It is clear that the vaccine platform of choice can have a significant impact upon the level of protection induced by particular antigens, and we provide and highlight some examples for which the vaccine system used has impacted the protective efficacy imparted.
Bannantine JP, Campo JJ, Li L
… +6 more, Randall A, Pablo J, Praul CA, Raygoza Garay JA, Stabel JR, Kapur V
Clin Vaccine Immunol
· 2017 Jul · PMID 28515134
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Johne's disease, a chronic gastrointestinal inflammatory disease caused by subspecies , is endemic in dairy cattle and other ruminants worldwide and remains a challenge to diagnose using traditional serological methods....Johne's disease, a chronic gastrointestinal inflammatory disease caused by subspecies , is endemic in dairy cattle and other ruminants worldwide and remains a challenge to diagnose using traditional serological methods. Given the close phylogenetic relationship between subsp. and the human pathogen , here, we applied a whole-proteome protein array to identify seroreactive and diagnostic subsp. antigens. A genome-scale pairwise analysis of amino acid identity levels between orthologous proteins in subsp. and showed an average of 62% identity, with more than half the orthologous proteins sharing >75% identity. Analysis of the protein array probed with sera from subsp. -infected cattle showed antibody binding to 729 proteins, with 58% of them having ≥70% identity to subsp. orthologs. The results showed that only 4 of the top 40 seroreactive antigens were orthologs of previously reported subsp. antigens, revealing the existence of a large number of previously unrecognized candidate diagnostic antigens. Enzyme-linked immunosorbent assay (ELISA) testing of 20 subsp. recombinant proteins, representing reactive and nonreactive orthologs, further confirmed that the array has utility as a screening tool for identifying candidate antigens for Johne's disease diagnostics. Additional ELISA testing of field serum samples collected from dairy herds around the United States revealed that MAP2942c had the strongest seroreactivity with Johne's disease-positive samples. Collectively, our studies have considerably expanded the number of candidate subsp. proteins with potential utility in the next generation of rationally designed Johne's disease diagnostic assays.
Urakami A, Sakurai A, Ishikawa M
… +9 more, Yap ML, Flores-Garcia Y, Haseda Y, Aoshi T, Zavala FP, Rossmann MG, Kuno S, Ueno R, Akahata W
Clin Vaccine Immunol
· 2017 Jul · PMID 28515133
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Virus-like particles (VLPs) are noninfectious multiprotein structures that are engineered to self-assemble from viral structural proteins. Here, we developed a novel VLP-based vaccine platform utilizing VLPs from the chi...Virus-like particles (VLPs) are noninfectious multiprotein structures that are engineered to self-assemble from viral structural proteins. Here, we developed a novel VLP-based vaccine platform utilizing VLPs from the chikungunya virus. We identified two regions within the envelope protein, a structural component of chikungunya, where foreign antigens can be inserted without compromising VLP structure. Our VLP displays 480 copious copies of an inserted antigen on the VLP surface in a highly symmetric manner and is thus capable of inducing strong immune responses against any inserted antigen. Furthermore, by mimicking the structure of the immature form of the virus, we altered our VLP's dynamics and enhanced its immunogenicity. We used the circumsporozoite protein (CSP) of the malaria parasite as an antigen and demonstrated that our VLP-based vaccine elicits strong immune responses against CSP in animals. The sera from immunized monkeys protected mice from malaria infection. Likewise, mice vaccinated with CSP-containing VLPs were protected from an infectious sporozoite challenge. Hence, our uniquely engineered VLP platform can serve as a blueprint for the development of vaccines against other pathogens and diseases.
Gu XX, Plotkin SA, Edwards KM
… +8 more, Sette A, Mills KHG, Levy O, Sant AJ, Mo A, Alexander W, Lu KT, Taylor CE
Clin Vaccine Immunol
· 2017 Jul · PMID 28490424
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Since the middle of the 20th century, vaccines have made a significant public health impact by controlling infectious diseases globally. Although long-term protection has been achieved with some vaccines, immunity wanes...Since the middle of the 20th century, vaccines have made a significant public health impact by controlling infectious diseases globally. Although long-term protection has been achieved with some vaccines, immunity wanes over time with others, resulting in outbreaks or epidemics of infectious diseases. Long-term protection against infectious agents that have a complex life cycle and antigenic variation remains a key challenge. Novel strategies to characterize the short- and long-term immune responses to vaccines and to induce immune responses that mimic natural infection have recently emerged. New technologies and approaches in vaccinology, such as adjuvants, delivery systems, and antigen formulations, have the potential to elicit more durable protection and fewer adverse reactions; together with systems, these technologies have the capacity to model and accelerate vaccine development. The National Institute of Allergy and Infectious Diseases (NIAID) held a workshop on 19 September 2016 that focused on waning immunity to selected vaccines (for , serovar Typhi, , influenza, mumps, and malaria), with an emphasis on identifying knowledge gaps, future research needs, and how this information can inform development of more effective vaccines for infectious diseases.
Venge P, Eriksson AK, Douhan-Håkansson L
… +1 more, Pauksen K
Clin Vaccine Immunol
· 2017 Jul · PMID 28468981
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The distinction between bacterial and viral causes of infections of the respiratory tract is a major but important clinical challenge. We investigated the diagnostic performance of human neutrophil lipocalin (HNL) in res...The distinction between bacterial and viral causes of infections of the respiratory tract is a major but important clinical challenge. We investigated the diagnostic performance of human neutrophil lipocalin (HNL) in respiratory tract infections compared to those of C-reactive protein (CRP) and procalcitonin (PCT). Patients were recruited from the emergency department and from a primary care unit ( = 162). The clinical diagnosis with regard to bacterial or viral cause of infection was complemented with objective microbiological/serological testing. HNL was measured in whole blood after preactivation with the neutrophil activator formyl-methionine-leucine-phenylalanine (fMLP) (B-HNL), and CRP and PCT were measured in plasma. Head-to-head comparisons of the three biomarkers showed that B-HNL was a superior diagnostic means to distinguish between causes of infections, with areas under the concentration-time curve (AUCs) of receiver operating characteristic (ROC) analysis for HNL of 0.91 (95% confidence interval [CI], 0.83 to 0.96) and 0.92 (95% CI, 0.82 to 0.97) for all respiratory infections and for upper respiratory infections, respectively, compared to 0.72 (95% CI, 0.63 to 0.80) and 0.68 (95% CI, 0.56 to 0.79) for CRP, respectively ( = 0.001). In relation to major clinical symptoms of respiratory tract infections (cough, sore throat, stuffy nose, and signs of sinusitis), AUCs varied between 0.88 and 0.93 in those patients with likely etiology (i.e., etiology is likely determined) of infection, compared to 0.63 and 0.71 for CRP, respectively, and nonsignificant AUCs for PCT. The diagnostic performance of B-HNL is superior to that of plasma CRP (P-CRP) and plasma PCT (P-PCT) in respiratory tract infections, and the activity specifically reflects bacterial challenge in the body. The rapid and accurate analysis of HNL by point-of-care technologies should be a major advancement in the diagnosis and management of respiratory infections with respect to antibiotic treatment.
Nixon CE, Park S, Pond-Tor S
… +9 more, Raj D, Lambert LE, Orr-Gonzalez S, Barnafo EK, Rausch KM, Friedman JF, Fried M, Duffy PE, Kurtis JD
Clin Vaccine Immunol
· 2017 Jul · PMID 28468980
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Naturally acquired antibodies to schizont egress antigen 1 (PfSEA-1A) are associated with protection against severe malaria in children. Vaccination of mice with SEA-1A from (PbSEA-1A) decreases parasitemia and prolong...Naturally acquired antibodies to schizont egress antigen 1 (PfSEA-1A) are associated with protection against severe malaria in children. Vaccination of mice with SEA-1A from (PbSEA-1A) decreases parasitemia and prolongs survival following ANKA challenge. To enhance the immunogenicity of PfSEA-1A, we identified five linear B-cell epitopes using peptide microarrays probed with antisera from nonhuman primates vaccinated with recombinant PfSEA-1A (rPfSEA-1A). We evaluated the relationship between epitope-specific antibody levels and protection from parasitemia in a longitudinal treatment-reinfection cohort in western Kenya. Antibodies to three epitopes were associated with 16 to 17% decreased parasitemia over an 18-week high transmission season. We are currently designing immunogens to enhance antibody responses to these three epitopes.
van der Most RG, Clément F, Willekens J
… +4 more, Dewé W, Walravens K, Vaughn DW, Leroux-Roels G
Clin Vaccine Immunol
· 2017 Jun · PMID 28446441
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We investigated the role of AS03 (here AS03), an α-tocopherol oil-in-water emulsion-based adjuvant system, on the long-term persistence of humoral and cell-mediated immune responses to A(H1N1)pdm09 influenza vaccines. In...We investigated the role of AS03 (here AS03), an α-tocopherol oil-in-water emulsion-based adjuvant system, on the long-term persistence of humoral and cell-mediated immune responses to A(H1N1)pdm09 influenza vaccines. In two studies, a total of 261 healthy adults (≤60 years old) were randomized to receive two doses of AS03-adjuvanted vaccine containing 3.75 μg of hemagglutinin (HA) or nonadjuvanted vaccine containing 15 μg of hemagglutinin (in study A) or 3.75 μg of hemagglutinin (in study B) 21 days apart. Hemagglutination inhibition (HI) antibody, memory B-cell, and CD4/CD8 T-cell responses were characterized up to 1 year following dose 1. We also assessed the effects of age and seasonal influenza vaccination history. AS03-adjuvanted (3.75 μg HA) vaccine and nonadjuvanted vaccine at 15 μg but not at 3.75 μg HA elicited HI antibody responses persisting at levels that continued to meet European licensure criteria through month 12. At month 12, the geometric mean titer for AS03-adjuvanted vaccine was similar to that for nonadjuvanted (15-μg) vaccine in study A (1:86 and 1:88, respectively) and higher than that for nonadjuvanted (3.75-μg) vaccine in study B (1:77 and 1:35, respectively). A(H1N1)pdm09-specific CD4 T-cell and B-cell responses were stronger in AS03-adjuvanted groups and persisted only in these groups for 12 months at levels exceeding prevaccination frequencies. Advancing age and a seasonal vaccination history tended to reduce HI antibody and memory B-cell responses and, albeit less consistently, CD4 T-cell responses. Thus, AS03 seemed to enhance the persistence of humoral and cell-mediated responses to A(H1N1)pdm09 vaccine, allowing for antigen sparing and mitigating potential negative effects of age and previous seasonal vaccination. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00968539 and NCT00989287.).
Clin Vaccine Immunol
· 2017 Jun · PMID 28424198
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Immunity to pneumococcal infections is impaired in older people, and current vaccines are poorly protective against pneumococcal disease in this population. Naturally acquired immunity to pneumococcal capsular polysaccha...Immunity to pneumococcal infections is impaired in older people, and current vaccines are poorly protective against pneumococcal disease in this population. Naturally acquired immunity to pneumococcal capsular polysaccharides develops during childhood and is robust in young adults but deteriorates with advanced age. In particular, antibody levels and function are reduced in older people. Pneumococcal vaccines are recommended for people >65 years old. However, the benefits of polysaccharide and protein-conjugated vaccines in this population are small, because of both serotype replacement and incomplete protection against vaccine serotype pneumococcal disease. In this review, we overview the immune mechanisms by which naturally acquired and vaccine-induced pneumococcal capsular polysaccharide immunity declines with age, including altered colonization dynamics, reduced opsonic activity of antibodies (particularly IgM), and impaired mucosal immunity.