Clinical And Vaccine Immunology[JOURNAL]
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200 papers
Australian Aboriginal Children with Otitis Media Have Reduced Antibody Titers to Specific Nontypeable Haemophilus influenzae Vaccine Antigens.
Thornton RB, Kirkham LS, Corscadden KJ … +8 more , Wiertsema SP, Fuery A, Jones BJ, Coates HL, Vijayasekaran S, Zhang G, Keil A, Richmond PC
Clin Vaccine Immunol · 2017 Apr · PMID 28151410 · Full text
Indigenous populations experience high rates of otitis media (OM), with increased chronicity and severity, compared to those experienced by their nonindigenous counterparts. Data on immune responses to otopathogenic bact...
Indigenous populations experience high rates of otitis media (OM), with increased chronicity and severity, compared to those experienced by their nonindigenous counterparts. Data on immune responses to otopathogenic bacteria in these high-risk populations are lacking. Nontypeable (NTHi) is the predominant otopathogen in Australia. No vaccines are currently licensed to target NTHi; however, protein D (PD) from NTHi is included as a carrier protein in the 10-valent pneumococcal polysaccharide conjugate vaccine (PHiD10-CV), and other promising protein vaccine candidates exist, including outer membrane protein 4 (P4) and protein 6 (P6). We measured the levels of serum and salivary IgA and IgG against PD, P4, and P6 in Aboriginal and non-Aboriginal children with chronic OM who were undergoing surgery and compared the levels with those in healthy non-Aboriginal children (controls). We found that Aboriginal cases had lower serum IgG titers to all NTHi proteins assessed, particularly PD. In contrast, serum IgA and salivary IgA and IgG titers to each of these 3 proteins were equivalent to or higher than those in both non-Aboriginal cases and healthy controls. While serum antibody levels increased with age in healthy controls, no changes in titers were observed with age in non-Aboriginal cases, and a trend toward decreasing titers with age was observed in Aboriginal cases. This suggests that decreased serum IgG responses to NTHi outer membrane proteins may contribute to the development of chronic and severe OM in Australian Aboriginal children and other indigenous populations. These data are important for understanding the potential benefits of PHiD10-CV implementation and the development of NTHi protein-based vaccines for indigenous populations.
Cytokine Profiles in Malawian Children Presenting with Uncomplicated Malaria, Severe Malarial Anemia, and Cerebral Malaria.
Mandala WL, Msefula CL, Gondwe EN … +3 more , Drayson MT, Molyneux ME, MacLennan CA
Clin Vaccine Immunol · 2017 Apr · PMID 28122790 · Full text
Proinflammatory cytokines are involved in clearance of , and very high levels of these cytokines have been implicated in the pathogenesis of severe malaria. In order to determine how cytokines vary with disease severity...
Proinflammatory cytokines are involved in clearance of , and very high levels of these cytokines have been implicated in the pathogenesis of severe malaria. In order to determine how cytokines vary with disease severity and syndrome, we enrolled Malawian children presenting with cerebral malaria (CM), severe malarial anemia (SMA), and uncomplicated malaria (UCM) and healthy controls. We analyzed serum cytokine concentrations in acute infection and in convalescence. With the exception of interleukin 5 (IL-5), cytokine concentrations were highest in acute CM, followed by SMA, and were only mildly elevated in UCM. Cytokine concentrations had fallen to control levels when remeasured at 1 month of convalescence in all three clinical malaria groups. Ratios of IL-10 to tumor necrosis factor alpha (TNF-α) and of IL-10 to IL-6 followed a similar pattern. Children presenting with acute CM had significantly higher concentrations of TNF-α ( < 0.001), interferon gamma (IFN-γ) ( = 0.0019), IL-2 ( = 0.0004), IL-6 ( < 0.001), IL-8 ( < 0.001), and IL-10 ( < 0.001) in sera than healthy controls. Patients with acute CM had significantly higher concentrations of IL-6 ( < 0.001) and IL-10 ( = 0.0003) than those presenting with acute SMA. Our findings are consistent with the concept that high levels of proinflammatory cytokines, despite high levels of the anti-inflammatory cytokine IL-10, could contribute to the pathogenesis of CM.
The Predominant CD4 Th1 Cytokine Elicited to Chlamydia trachomatis Infection in Women Is Tumor Necrosis Factor Alpha and Not Interferon Gamma.
Jordan SJ, Gupta K, Ogendi BMO … +6 more , Bakshi RK, Kapil R, Press CG, Sabbaj S, Lee JY, Geisler WM
Clin Vaccine Immunol · 2017 Apr · PMID 28100498 · Full text
infection is the most prevalent bacterial sexually transmitted infection and can cause significant reproductive morbidity in women. There is insufficient knowledge of -specific immune responses in humans, which could be...
infection is the most prevalent bacterial sexually transmitted infection and can cause significant reproductive morbidity in women. There is insufficient knowledge of -specific immune responses in humans, which could be important in guiding vaccine development efforts. In contrast, murine models have clearly demonstrated the essential role of T helper type 1 (Th1) cells, especially interferon gamma (IFN-γ)-producing CD4 T cells, in protective immunity to chlamydia. To determine the frequency and magnitude of Th1 cytokine responses elicited to infection in humans, we stimulated peripheral blood mononuclear cells from 90 chlamydia-infected women with elementary bodies, Pgp3, and major outer membrane protein and measured IFN-γ-, tumor necrosis factor alpha (TNF-α)-, and interleukin-2 (IL-2)-producing CD4 and CD8 T-cell responses using intracellular cytokine staining. The majority of chlamydia-infected women elicited CD4 TNF-α responses, with frequency and magnitude varying significantly depending on the antigen used. CD4 IFN-γ and IL-2 responses occurred infrequently, as did production of any of the three cytokines by CD8 T cells. About one-third of TNF-α-producing CD4 T cells coproduced IFN-γ or IL-2. In summary, the predominant Th1 cytokine response elicited to infection in women was a CD4 TNF-α response, not CD4 IFN-γ, and a subset of the CD4 TNF-α-positive cells produced a second Th1 cytokine.
Avian and Human Seasonal Influenza Hemagglutinin Proteins Elicit CD4 T Cell Responses That Are Comparable in Epitope Abundance and Diversity.
DiPiazza A, Richards K, Poulton N … +1 more , Sant AJ
Clin Vaccine Immunol · 2017 Mar · PMID 28100497 · Full text
Avian influenza viruses remain a significant concern due to their pandemic potential. Vaccine trials have suggested that humans respond poorly to avian influenza vaccines relative to seasonal vaccines. It is important to...
Avian influenza viruses remain a significant concern due to their pandemic potential. Vaccine trials have suggested that humans respond poorly to avian influenza vaccines relative to seasonal vaccines. It is important to understand, first, if there is a general deficiency in the ability of avian hemagglutinin (HA) proteins to generate immune responses and, if so, what underlies this defect. This question is of particular interest because it has been suggested that in humans, the poor immunogenicity of H7 vaccines may be due to a paucity of CD4 T cell epitopes. Because of the generally high levels of cross-reactive CD4 T cells in humans, it is not possible to compare the inherent immunogenicities of avian and seasonal HA proteins in an unbiased manner. Here, we empirically examine the epitope diversity and abundance of CD4 T cells elicited by seasonal and avian HA proteins. HLA-DR1 and HLA-DR4 transgenic mice were vaccinated with purified HA proteins, and CD4 T cells to specific epitopes were identified and quantified. These studies revealed that the diversity and abundance of CD4 T cells specific for HA do not segregate on the basis of whether the HA was derived from human seasonal or avian influenza viruses. Therefore, we conclude that failure in responses to avian vaccines in humans is likely due to a lack of cross-reactive CD4 T cell memory perhaps coupled with competition with or suppression of naive, HA-specific CD4 T cells by memory CD4 T cells specific for more highly conserved proteins.
Preexisting Immunity, Not Frailty Phenotype, Predicts Influenza Postvaccination Titers among Older Veterans.
Van Epps P, Tumpey T, Pearce MB … +8 more , Golding H, Higgins P, Hornick T, Burant C, Wilson BM, Banks R, Gravenstein S, Canaday DH
Clin Vaccine Immunol · 2017 Mar · PMID 28100496 · Full text
Both preexisting immunity to influenza and age have been shown to be correlates of influenza vaccine responses. Frailty, an indicator of functional impairment in older adults, was also shown in one study to predict lower...
Both preexisting immunity to influenza and age have been shown to be correlates of influenza vaccine responses. Frailty, an indicator of functional impairment in older adults, was also shown in one study to predict lower influenza vaccine responses among nonveterans. In the current study, we aimed to determine the associations between frailty, preexisting immunity, and immune responses to influenza vaccine among older veterans. We studied 117 subjects (age range, 62 to 95 years [median age, 81 years]), divided into three cohorts based on the Fried frailty test, i.e., nonfrail (NF) ( = 23 [median age, 68 years]), prefrail ( = 50 [median age, 80 years]), and frail ( = 44 [median age, 82 years]), during the 2010-2011 and 2011-2012 influenza seasons. Subjects received the seasonal trivalent inactivated influenza vaccine, and baseline and postvaccination samples were obtained. Anti-influenza humoral immunity, as measured by hemagglutination inhibition (HI) and microneutralization assays, was measured for influenza B, A(H1N1)pdm09, and A(H3N2) viruses. Postvaccination titers were not different between frail and NF subjects overall in this older subset of veterans. However, preexisting HI titers were strongly correlated with postvaccination titers among all functional status groups. When microneutralization titers were compared, the association between preexisting immunity and vaccine responses varied by frailty status, with the strongest correlation being observed for the NF group. In conclusion, preexisting immunity rather than frailty appeared to predict postvaccination titers in this older veteran cohort.
Using Data from Macaques To Predict Gamma Interferon Responses after Mycobacterium bovis BCG Vaccination in Humans: a Proof-of-Concept Study of Immunostimulation/Immunodynamic Modeling Methods.
Rhodes SJ, Sarfas C, Knight GM … +7 more , White A, Pathan AA, McShane H, Evans TG, Fletcher H, Sharpe S, White RG
Clin Vaccine Immunol · 2017 Mar · PMID 28077441 · Full text
Macaques play a central role in the development of human tuberculosis (TB) vaccines. Immune and challenge responses differ across macaque and human subpopulations. We used novel immunostimulation/immunodynamic modeling m...
Macaques play a central role in the development of human tuberculosis (TB) vaccines. Immune and challenge responses differ across macaque and human subpopulations. We used novel immunostimulation/immunodynamic modeling methods in a proof-of-concept study to determine which macaque subpopulations best predicted immune responses in different human subpopulations. Data on gamma interferon (IFN-γ)-secreting CD4 T cells over time after recent BCG vaccination were available for 55 humans and 81 macaques. Human population covariates were baseline BCG vaccination status, time since BCG vaccination, gender, and the monocyte/lymphocyte cell count ratio. The macaque population covariate was the colony of origin. A two-compartment mathematical model describing the dynamics of the IFN-γ T cell response after BCG vaccination was calibrated to these data using nonlinear mixed-effects methods. The model was calibrated to macaque and human data separately. The association between subpopulations and the BCG immune response in each species was assessed. The macaque subpopulations that best predicted immune responses in different human subpopulations were identified using Bayesian information criteria. We found that the macaque colony and the human baseline BCG status were significantly ( < 0.05) associated with the BCG-induced immune response. For humans who were BCG naïve at baseline, Indonesian cynomolgus macaques and Indian rhesus macaques best predicted the immune response. For humans who had already been BCG vaccinated at baseline, Mauritian cynomolgus macaques best predicted the immune response. This work suggests that the immune responses of different human populations may be best modeled by different macaque colonies, and it demonstrates the potential utility of immunostimulation/immunodynamic modeling to accelerate TB vaccine development.
Monophosphoryl Lipid A Enhances Efficacy of a Francisella tularensis LVS-Catanionic Nanoparticle Subunit Vaccine against F. tularensis Schu S4 Challenge by Augmenting both Humoral and Cellular Immunity.
Richard K, Mann BJ, Qin A … +3 more , Barry EM, Ernst RK, Vogel SN
Clin Vaccine Immunol · 2017 Mar · PMID 28077440 · Full text
, a bacterial biothreat agent, has no approved vaccine in the United States. Previously, we showed that incorporating lysates from partially attenuated LVS or fully virulent Schu S4 strains into catanionic surfactant v...
, a bacterial biothreat agent, has no approved vaccine in the United States. Previously, we showed that incorporating lysates from partially attenuated LVS or fully virulent Schu S4 strains into catanionic surfactant vesicle (V) nanoparticles (LVS-V and Schu S4-V, respectively) protected fully against LVS intraperitoneal (i.p.) challenge in mice. However, we achieved only partial protection against Schu S4 intranasal (i.n.) challenge, even when employing heterologous prime-boost immunization strategies. We now extend these findings to show that both LVS-V and Schu S4-V immunization (i.p./i.p.) elicited similarly high titers of anti- IgG and that the titers could be further increased by adding monophosphoryl lipid A (MPL), a nontoxic Toll-like receptor 4 (TLR4) adjuvant that is included in several U.S. FDA-approved vaccines. LVS-V+MPL immune sera also detected more antigens than LVS-V immune sera and, after passive transfer to naive mice, significantly delayed the time to death against Schu S4 subcutaneous (s.c.) but not i.n. challenge. Active immunization with LVS-V+MPL (i.p./i.p.) also increased the frequency of gamma interferon (IFN-γ)-secreting activated helper T cells, IFN-γ production, and the ability of splenocytes to control intramacrophage LVS replication Active LVS-V+MPL immunization via heterologous routes (i.p./i.n.) significantly elevated IgA and IgG levels in bronchoalveolar lavage fluid and significantly enhanced protection against i.n. Schu S4 challenge (to ∼60%). These data represent a significant step in the development of a subunit vaccine against the highly virulent type A strains.
Otitis-Prone Children Produce Functional Antibodies to Pneumolysin and Pneumococcal Polysaccharides.
Kirkham LS, Wiertsema SP, Corscadden KJ … +5 more , Mateus T, Mullaney GL, Zhang G, Richmond PC, Thornton RB
Clin Vaccine Immunol · 2017 Mar · PMID 28031178 · Full text
The pneumococcus is a major otitis media (OM) pathogen, but data are conflicting regarding whether otitis-prone children have impaired humoral immunity to pneumococcal antigens. We and others have shown that otitis-prone...
The pneumococcus is a major otitis media (OM) pathogen, but data are conflicting regarding whether otitis-prone children have impaired humoral immunity to pneumococcal antigens. We and others have shown that otitis-prone and healthy children have similar antibody titers to pneumococcal proteins and polysaccharides (vaccine and nonvaccine types); however, the quality of antibodies from otitis-prone children has not been investigated. Antibody function, rather than titer, is considered to be a better correlate of protection from pneumococcal disease. Therefore, we compared the capacities of antibodies from otitis-prone (cases) and healthy (controls) children to neutralize pneumolysin, the pneumococcal toxin currently in development as a vaccine antigen, and to opsonize pneumococcal vaccine and nonvaccine serotypes. A pneumolysin neutralization assay was conducted on cholesterol-depleted complement-inactivated sera from 165 cases and 61 controls. A multiplex opsonophagocytosis assay (MOPA) was conducted on sera from 20 cases and 20 controls. Neutralizing and opsonizing titers were calculated with antigen-specific IgG titers to determine antibody potency for pneumolysin, pneumococcal conjugate vaccine (PCV) polysaccharides, and non-PCV polysaccharides. There was no significant difference in antibody potencies between cases and controls for the antigens tested. Antipneumolysin neutralizing titers increased with the number of episodes of acute OM, but antibody potency did not. Pneumolysin antibody potency was lower in children colonized with pneumococci than in noncarriers, and this was significant for the otitis-prone group ( < 0.05). The production of functional antipneumococcal antibodies in otitis-prone children demonstrates that they respond to the current PCV and are likely to respond to pneumolysin-based vaccines as effectively as healthy children.
Challenges in Interpretation of Diagnostic Test Results in a Mumps Outbreak in a Highly Vaccinated Population.
Trotz-Williams LA, Mercer NJ, Paphitis K … +5 more , Walters JM, Wallace D, Kristjanson E, Gubbay J, Mazzulli T
Clin Vaccine Immunol · 2017 Feb · PMID 28003216 · Full text
In spite of a greatly reduced incidence rate due to vaccination, mumps outbreaks continue to occur in several areas of the world, sometimes in vaccinated populations. This article describes an outbreak in a highly vaccin...
In spite of a greatly reduced incidence rate due to vaccination, mumps outbreaks continue to occur in several areas of the world, sometimes in vaccinated populations. This article describes an outbreak in a highly vaccinated population in southwestern Ontario, Canada, and the challenges encountered in interpreting the results of diagnostic tests used in the outbreak. During the outbreak, patients were interviewed and classified according to the outbreak case definition, and specimens were collected for diagnostic testing according to Ontario guidelines. Twenty-seven individuals were classified as confirmed cases (n = 19) or suspect cases (n = 8) according to the case definition, only 9 of which were laboratory-confirmed cases: 7 confirmed by reverse transcriptase PCR (RT-PCR) and 2 by IgM serology. All 19 confirmed cases represented patients who were associated with secondary schools in the local area and had been vaccinated against mumps with one (n = 2) or two (n = 17) doses of the measles-mumps-rubella (MMR) vaccine. This is the first published report of an outbreak of mumps in Ontario in which all confirmed cases had been vaccinated against the disease. It highlights the limitations of and difficulties in interpreting current mumps diagnostic tests when used in vaccinated individuals.
Serological Analysis of Tuberculosis in Goats by Use of the Enferplex Caprine TB Multiplex Test.
O'Brien A, Whelan C, Clarke JB … +3 more , Hayton A, Watt NJ, Harkiss GD
Clin Vaccine Immunol · 2017 Feb · PMID 27974399 · Full text
Tuberculosis in goats is usually diagnosed clinically, at postmortem, or by a positive skin test. However, none of these approaches detects all infected animals. Serology offers an additional tool to identify infected an...
Tuberculosis in goats is usually diagnosed clinically, at postmortem, or by a positive skin test. However, none of these approaches detects all infected animals. Serology offers an additional tool to identify infected animals missed by current tests. We describe the use of the Enferplex Caprine TB serology test to aid the management of a large dairy goat herd undergoing a tuberculosis breakdown. Initial skin and serology testing showed that IgG antibodies were present in both serum and milk from 100% of skin test-positive animals and in serum and milk from 77.8 and 95.4% of skin test-negative animals, respectively. A good correlation was observed between serum and milk antibody levels. The herd had been vaccinated against Mycobacterium avium subsp. paratuberculosis, but no direct serological cross-reactions were found. Subsequent skin testing revealed 13.7% positive animals, 64.9% of which were antibody positive, while 42.1% of skin test-negative animals were seropositive. Antibody responses remained high 1 month later (57.1% positive), and the herd was slaughtered. Postmortem analysis of 20 skin test-negative goats revealed visible lesions in 6 animals, all of which had antibodies to six Mycobacterium bovis antigens. The results provide indirect evidence that serology testing with serum or milk could be a useful tool in the diagnosis and management of tuberculosis in goats.
Safety and Immunogenicity of the Recombinant Mycobacterium bovis BCG Vaccine VPM1002 in HIV-Unexposed Newborn Infants in South Africa.
Loxton AG, Knaul JK, Grode L … +10 more , Gutschmidt A, Meller C, Eisele B, Johnstone H, van der Spuy G, Maertzdorf J, Kaufmann SHE, Hesseling AC, Walzl G, Cotton MF
Clin Vaccine Immunol · 2017 Feb · PMID 27974398 · Full text
Tuberculosis is a global threat to which infants are especially vulnerable. Effective vaccines are required to protect infants from this devastating disease. VPM1002, a novel recombinant Mycobacterium bovis bacillus Calm...
Tuberculosis is a global threat to which infants are especially vulnerable. Effective vaccines are required to protect infants from this devastating disease. VPM1002, a novel recombinant Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine previously shown to be safe and immunogenic in adults, was evaluated for safety in its intended target population, namely, newborn infants in a region with high prevalence of tuberculosis. A total of 48 newborns were vaccinated intradermally with VPM1002 (n = 36) or BCG Danish strain (n = 12) in a phase II open-labeled, randomized trial with a 6-month follow-up period. Clinical and laboratory measures of safety were evaluated during this time. In addition, vaccine-induced immune responses to mycobacteria were analyzed in whole-blood stimulation and proliferation assays. The safety parameters and immunogenicity were comparable in the two groups. Both vaccines induced interleukin-17 (IL-17) responses; however, VPM1002 vaccination led to an increase of CD8 IL-17 T cells at the week 16 and month 6 time points. The incidence of abscess formation was lower for VPM1002 than for BCG. We conclude that VPM1002 is a safe, well-tolerated, and immunogenic vaccine in newborn infants, confirming results from previous trials in adults. These results strongly support further evaluation of the safety and efficacy of this vaccination in larger studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01479972.).
Assignment of Opsonic Values to Pneumococcal Reference Serum 007sp for Use in Opsonophagocytic Assays for 13 Serotypes.
Burton RL, Antonello J, Cooper D … +9 more , Goldblatt D, Kim KH, Plikaytis BD, Roalfe L, Wauters D, Williams F, Xie GL, Nahm MH, Akkoyunlu M
Clin Vaccine Immunol · 2017 Feb · PMID 27974397 · Full text
Opsonophagocytic assays (OPAs) are routinely used for assessing the immunogenicity of pneumococcal vaccines, with OPA data often being utilized for licensure of new vaccine formulations. However, no reference serum for p...
Opsonophagocytic assays (OPAs) are routinely used for assessing the immunogenicity of pneumococcal vaccines, with OPA data often being utilized for licensure of new vaccine formulations. However, no reference serum for pneumococcal OPAs is available, making evaluation of data among different laboratories difficult. This international collaboration was initiated to (i) assign consensus opsonic indexes (OIs) to FDA pneumococcal reference serum lot 007sp (here referred to as 007sp) and a panel of serum samples used for calibration of the OPA and (ii) determine if the normalization of the OPA results obtained with test samples to those obtained with 007sp decreases the variability in OPA results among laboratories. To meet these goals, six participating laboratories tested a panel of serum samples in five runs for 13 serotypes. For each serum sample, consensus OIs were obtained using a mixed-effects analysis of variance model. For the calibration serum samples, normalized consensus values were also determined on the basis of the results obtained with 007sp. For each serotype, the overall reduction in interlaboratory variability was calculated by comparing the coefficients of variation of the unadjusted and the normalized values. Normalization of the results substantially reduced the interlaboratory variability, ranging from a 15% reduction in variability for serotype 9V to a 64% reduction for serotype 7F. Normalization also increased the proportion of data within 2-fold of the consensus value from approximately 70% (average for all serotypes) to >90%. On the basis of the data obtained in this study, pneumococcal reference standard lot 007sp will likely be a useful reagent for the normalization of pneumococcal OPA results from different laboratories. The data also support the use of the 16 FDA serum samples used for calibration of the OPA as part of the initial evaluation of new assays or periodic assessment of established assays.
Functional and Antigen-Specific Serum Antibody Levels as Correlates of Protection against Shigellosis in a Controlled Human Challenge Study.
Shimanovich AA, Buskirk AD, Heine SJ … +4 more , Blackwelder WC, Wahid R, Kotloff KL, Pasetti MF
Clin Vaccine Immunol · 2017 Feb · PMID 27927680 · Full text
Shigella is an important cause of diarrheal disease in young children living in developing countries. No approved vaccines are available, and the development of vaccine candidates has been hindered by the lack of firm im...
Shigella is an important cause of diarrheal disease in young children living in developing countries. No approved vaccines are available, and the development of vaccine candidates has been hindered by the lack of firm immunological correlates of protection, among other reasons. To address this gap in knowledge, we established quantitative assays to measure Shigella-specific serum bactericidal antibody (SBA) and opsonophagocytic killing antibody (OPKA) activities and investigated their potential association with protection against disease in humans. SBA, OPKA, and Ipa-, VirG (IscA)-, and Shigella flexneri 2a lipopolysaccharide-specific serum IgG titers were determined in adult volunteers who received Shigella vaccine candidate EcSf2a-2 and in unvaccinated controls, all of whom were challenged with virulent Shigella flexneri 2a. Prechallenge antibody titers were compared with disease severity after challenge. SBA and OPKA, as well as IpaB- and VirG-specific IgG, significantly correlated with reduced illness. SBA and OPKA assays were also used to evaluate the immunogenicity of leading live attenuated vaccine candidates Shigella CVD 1204 and CVD 1208S in humans. A single oral immunization with CVD 1204 or CVD 1208S resulted in SBA seroconversion rates of 71% and 47% and OPKA seroconversion rates of 57% and 35%, respectively. Higher functional antibody responses were induced by CVD 1204, which is consistent with its lower attenuation. This is the first demonstration of SBA, OPKA, and IpaB- and VirG-specific IgG levels as potential serological correlates of protection against shigellosis in humans. These results warrant further studies to establish their capacity to predict protective immunity and vaccine efficacy.
Kinetics of Meningococcal Serogroup C-Specific Functional Antibody Levels Up to 15 Years after a Single Immunization with a Meningococcal Serogroup C Conjugate Vaccine during Adolescence.
Stoof SP, van Ravenhorst MB, van Rooijen DM … +6 more , de Voer RM, van der Klis FRM, Boland GJ, Sanders EAM, Berbers GAM, Teunis PF
Clin Vaccine Immunol · 2017 Feb · PMID 27881489 · Full text
Adolescent vaccination is now considered the key factor for offering direct protection against meningococcal disease but also for reducing carriage and transmission and, in this way, establishing herd protection. This st...
Adolescent vaccination is now considered the key factor for offering direct protection against meningococcal disease but also for reducing carriage and transmission and, in this way, establishing herd protection. This study estimated age-dependent patterns in functional meningococcal serogroup C (MenC) antibody kinetics after primary MenC conjugate (MenCC) vaccination in adolescents. Serum samples (n = 1,676) were drawn from 2006 to 2011 from individuals aged 9 to 18 years at the time of primary MenCC vaccination in 2002. Functional antibody levels were measured with a serum bactericidal antibody assay (SBA) using rabbit complement. SBA titers gradually declined with time. Up to 9 years after primary vaccination, SBA titers were estimated to be higher in individuals who were aged 13 to 18 years at priming than in those who were aged 9 to 10 years at priming. Based on a linear mixed model, the higher functional antibody levels with age seem to be due to the achievement of higher peak levels upon vaccination rather than to lower rates of decline. It is estimated that 35 to 50% of individuals who received a single primary MenCC vaccination at an age of 9 to 18 years in 2002 will still have sufficient protective antibody levels 15 years later. Using a linear mixed model based on cohort data for a single dated serum sample per person, we were able to estimate the level of protection against MenC up to 15 years after a single vaccination. The current study shows that analysis of antibody kinetics can be done using cross-sectional serology data and is therefore relevant for future serosurveillance studies.
An Opsonic Phagocytosis Assay for Plasmodium falciparum Sporozoites.
Steel RW, Sack BK, Tsuji M … +5 more , Navarro MJ, Betz W, Fishbaugher ME, Flannery EL, Kappe SH
Clin Vaccine Immunol · 2017 Feb · PMID 27881488 · Full text
Plasmodium falciparum malaria remains the deadliest parasitic disease worldwide. Vaccines targeting the preerythrocytic sporozoite and liver stages have the potential to entirely prevent blood-stage infection and disease...
Plasmodium falciparum malaria remains the deadliest parasitic disease worldwide. Vaccines targeting the preerythrocytic sporozoite and liver stages have the potential to entirely prevent blood-stage infection and disease, as well as onward transmission. Sporozoite surface and secreted proteins are leading candidates for inclusion in a preerythrocytic stage-specific, antibody-based vaccine. Preclinical functional assays to identify humoral correlates of protection in vitro and to validate novel sporozoite protein targets for inclusion in multisubunit vaccines currently do not consider the interaction of sporozoite-targeting antibodies with other components of the immune system. Here, we describe the development of a simple flow cytometric assay to quantitatively assess the ability of antibodies directed against P. falciparum sporozoites to facilitate their phagocytosis. We demonstrate that this sporozoite opsonic phagocytosis assay (SOPA) is compatible with both monoclonal antibodies and human immune serum and can be performed using cryopreserved P. falciparum sporozoites. This simple, accessible assay will aid with the assessment of antibody responses to vaccination with Plasmodium antigens and their interaction with phagocytic cells of the immune system.
Calibration and Evaluation of Quantitative Antibody Titers for Measles Virus by Using the BioPlex 2200.
Hatchette TF, Scholz H, Bolotin S … +4 more , Crowcroft NS, Jackson C, McLachlan E, Severini A
Clin Vaccine Immunol · 2017 Jan · PMID 27852634 · Full text
The BioPlex 2200 (Bio-Rad Laboratories, Hercules, CA) is a rapid, automated platform, which can screen large numbers of specimens for antibodies to measles, mumps, rubella, and varicella. Although approved for producing...
The BioPlex 2200 (Bio-Rad Laboratories, Hercules, CA) is a rapid, automated platform, which can screen large numbers of specimens for antibodies to measles, mumps, rubella, and varicella. Although approved for producing qualitative results, in this study we validated the test (off-label) to allow reporting of quantitative results. To do this, we used the third anti-measles World Health Organization standard to generate a calibration curve that allowed relative fluorescence intensity to be translated into quantitative antibody titer (antibody units [AU]/ml). The results from the BioPlex 2200 and the reference plaque reduction neutralization test (PRNT) exhibited a reasonable correlation following an exponential function, but correlation was poor in low-titer samples. Using a receiver operating characteristics analysis, an equivocal zone for the BioPlex 2200 was established between ≥0.13 and <1.10 AU/ml to achieve 100% specificity (95% confidence interval [CI] = 83.2 to 100%) and 100% sensitivity (95% CI = 93.5 to 100%) versus PRNT. By determining an equivocal range requiring confirmation by PRNT, we can avoid underestimating the levels of immunity through false-negative results and optimize methods for seroepidemiological studies.
Trained Immunity and Susceptibility to HIV.
Derrick SC
Clin Vaccine Immunol · 2017 Jan · PMID 27847369 · Full text
In this issue of Clinical and Vaccine Immunology, K. Jensen et al. (Clin Vaccine Immunol 24:e00360-16, 2017, https://doi.org/10.1128/CVI.00360-16) describe a dual-purpose attenuated Mycobacterium tuberculosis-simian immu...
In this issue of Clinical and Vaccine Immunology, K. Jensen et al. (Clin Vaccine Immunol 24:e00360-16, 2017, https://doi.org/10.1128/CVI.00360-16) describe a dual-purpose attenuated Mycobacterium tuberculosis-simian immunodeficiency virus vaccine (AMTB-SIV). Interestingly, immunized infant macaques required fewer oral exposures to SIV to become infected relative to nonimmunized animals. The authors hypothesized that augmented susceptibility to SIV was due to activation of CD4 T cells through trained immunity. This commentary explores the possible relationship between trained immunity, enhanced CD4 T cell responses, and increased susceptibility to human immunodeficiency virus (HIV).
The Live Attenuated Cholera Vaccine CVD 103-HgR Primes Responses to the Toxin-Coregulated Pilus Antigen TcpA in Subjects Challenged with Wild-Type Vibrio cholerae.
Mayo-Smith LM, Simon JK, Chen WH … +9 more , Haney D, Lock M, Lyon CE, Calderwood SB, Kirkpatrick BD, Cohen M, Levine MM, Gurwith M, Harris JB
Clin Vaccine Immunol · 2017 Jan · PMID 27847368 · Full text
One potential advantage of live attenuated bacterial vaccines is the ability to stimulate responses to antigens which are only expressed during the course of infection. To determine whether the live attenuated cholera va...
One potential advantage of live attenuated bacterial vaccines is the ability to stimulate responses to antigens which are only expressed during the course of infection. To determine whether the live attenuated cholera vaccine CVD 103-HgR (Vaxchora) results in antibody responses to the in vivo-induced toxin-coregulated pilus antigen TcpA, we measured IgA and IgG responses to Vibrio cholerae O1 El Tor TcpA in a subset of participants in a recently reported experimental challenge study. Participants were challenged with V. cholerae O1 El Tor Inaba N16961 either 10 days or 90 days after receiving the vaccine or a placebo. Neither vaccination nor experimental infection with V. cholerae alone resulted in a robust TcpA IgG or IgA response, but each did elicit a strong response to cholera toxin. However, compared to placebo recipients, vaccinees had a marked increase in IgG TcpA antibodies following the 90-day challenge, suggesting that vaccination with CVD 103-HgR resulted in priming for a subsequent response to TcpA. No such difference between vaccine and placebo recipients was observed for volunteers challenged 10 days after vaccination, indicating that this was insufficient time for vaccine-induced priming of the TcpA response. The priming of the response to TcpA and potentially other antigens expressed in vivo by attenuated V. cholerae may have relevance to the maintenance of immunity in areas where cholera is endemic.
Serum Bactericidal Antibody Responses of Adults Immunized with the MenB-4C Vaccine against Genetically Diverse Serogroup B Meningococci.
Giuntini S, Lujan E, Gibani MM … +4 more , Dold C, Rollier CS, Pollard AJ, Granoff DM
Clin Vaccine Immunol · 2017 Jan · PMID 27847367 · Full text
MenB-4C is a meningococcal vaccine for the prevention of serogroup B disease. The vaccine contains factor H binding protein (FHbp) and three other antigens that can elicit serum bactericidal antibodies (SBA). For vaccine...
MenB-4C is a meningococcal vaccine for the prevention of serogroup B disease. The vaccine contains factor H binding protein (FHbp) and three other antigens that can elicit serum bactericidal antibodies (SBA). For vaccine licensure, efficacy was inferred from the SBA responses against three antigen-specific indicator strains. The relation between those results and broad protection against circulating genetically diverse strains is not known. Twenty adults were immunized with two doses of MenB-4C given 1 to 2 months apart. SBA activity against 3 reference strains and 15 serogroup B test strains (6 from college outbreaks) was measured. Compared to the preimmunization titers, 70%, 95%, and 95% of subjects had ≥4-fold increases in the titers of anti-PorA P1.4, anti-NadA, and anti-FHbp antibodies against the reference strains, respectively. In contrast, only 25 to 45% of the subjects had ≥4-fold increases in responses to 10 of the 15 test strains, including 8 that expressed one to three of the antigens in the vaccine. At 1 month, the majority of subjects with <4-fold titer increases had serum titers of ≥1:4, which are considered sufficient for protection. However, the titers against four strains declined to <1:4 by 4 to 6 months in one-third to greater than 50% of the subjects tested. Clinically relevant isolates are often more resistant to SBA than the indicator strains used to measure antigen-specific SBA. A working model is that the percentage of subjects with titers of ≥1:4 at 1 month postimmunization correlates with short-term protection against that strain, whereas the percentage of subjects with ≥4-fold titer increases represents a more robust response. (The protocol used at the Oxford Vaccine Group has been registered at ClinicalTrials.gov under registration no. NCT02398396.).
Comparisons of the Humoral and Cellular Immune Responses Induced by Live Attenuated Influenza Vaccine and Inactivated Influenza Vaccine in Adults.
Hoft DF, Lottenbach KR, Blazevic A … +7 more , Turan A, Blevins TP, Pacatte TP, Yu Y, Mitchell MC, Hoft SG, Belshe RB
Clin Vaccine Immunol · 2017 Jan · PMID 27847366 · Full text
Both live attenuated influenza vaccines (LAIV) and inactivated influenza vaccines (IIV) induce protective immunity against influenza. There is evidence that LAIV induces superior protection in children, whereas IIV may i...
Both live attenuated influenza vaccines (LAIV) and inactivated influenza vaccines (IIV) induce protective immunity against influenza. There is evidence that LAIV induces superior protection in children, whereas IIV may induce superior protection in adults. The immune mechanisms responsible for these differences have not been identified. We previously compared LAIV and IIV in young children of 6 to 36 months of age, and we demonstrated that while both induced similar hemagglutination inhibition (HAI) antibody responses, only LAIV induced significant increases in T cell responses. In the present study, 37 healthy adult subjects of 18 to 49 years of age were randomized to receive seasonal influenza vaccination with LAIV or IIV. Influenza virus-specific HAI, T cell, and secretory IgA (sIgA) responses were studied pre- and postvaccination. In contrast to the responses seen in young children, LAIV induced only minimal increases in serum HAI responses in adults, which were significantly lower than the responses induced by IIV. Both LAIV and IIV similarly induced only transient T cell responses to replication-competent whole virus in adults. In contrast, influenza virus-specific sIgA responses were induced more strongly by LAIV than by IIV. Our previous studies suggest that LAIV may be more protective than IIV in young children not previously exposed to influenza virus or influenza vaccines due to increased vaccine-induced T cell and/or sIgA responses. Our current work suggests that in adults with extensive and partially cross-reactive preexisting influenza immunity, LAIV boosting of sIgA responses to hemagglutinin (HA) and non-HA antigenic targets expressed by circulating influenza virus strains may be an important additional mechanism of vaccine-induced immunity.
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