Last data update: Apr 22, 2024. (Total: 46599 publications since 2009)
Records 1-21 (of 21 Records) |
Query Trace: Rajam G [original query] |
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Maternal Tdap vaccination during pregnancy: Impact on infant anti-pertussis antibody concentrations by maternal pertussis priming series
Havers FP , Skoff TH , Rench MA , Epperson M , Rajam G , Schiffer J , Hariri S , Swaim LS , Baker CJ , Mary Healy C . Clin Infect Dis 2022 76 (3) e1087-e1093 BACKGROUND: Acellular pertussis (aP) vaccines replaced whole cell pertussis (wP) vaccines for the U.S. childhood primary series in 1997. As women primed with aP vaccines enter childbearing age, protection of infants through Tdap (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis) vaccination during pregnancy may be impacted. METHODS: Term infants born to women vaccinated with Tdap during pregnancy were included. Geometric mean concentrations (GMC) of pertussis-specific IgG antibodies (IU/mL) in cord blood of infants born to women born after 1997 (aP-primed) were compared with those born to women born before 1992 (wP-primed). RESULTS: 253 and 506 infants born to aP- and wP-primed women, respectively, were included. Compared with wP-primed women, aP-primed women were younger, more likely to be Hispanic or non-Hispanic Black, and had lower birthweight infants (p < 0.01 for all). Antibodies against pertussis toxin (PT) and filamentous hemagglutinin (FHA) were lower among infants born to aP-primed versus wP-primed women (PT: 17.3 vs. 36.4, GMC ratio 0.475 (95% Confidence Interval [CI], 0.408-0.552); FHA: 104.6 vs. 121.4, GMC ratio 0.861 (95% CI, 0.776-0.958)). No differences were observed for anti-fimbriae or anti-pertactin antibodies. CONCLUSIONS: Transplacental anti-pertussis antibody concentrations in infants of women vaccinated with Tdap during pregnancy differed by type of childhood vaccine the woman received. Notably, anti-PT antibody levels, considered most important in preventing severe infant disease, were lower in infants born to aP- vs. wP-primed women. Maternal Tdap vaccination may confer less protection against pertussis in young infants born to aP-primed than those born to wP-primed women. |
Diagnosis of Streptococcus pneumoniae infection using circulating antibody secreting cells
Kyu S , Ramonell RP , Kuruvilla M , Kraft CS , Wang YF , Falsey AR , Walsh EE , Daiss JL , Paulos S , Rajam G , Wu H , Velusamy S , Lee FE . PLoS One 2021 16 (11) e0259644 BACKGROUND: Streptococcus pneumoniae infections cause morbidity and mortality worldwide. A rapid, simple diagnostic method could reduce the time needed to introduce definitive therapy potentially improving patient outcomes. METHODS: We introduce two new methods for diagnosing S. pneumoniae infections by measuring the presence of newly activated, pathogen-specific, circulating Antibody Secreting Cells (ASC). First, ASC were detected by ELISpot assays that measure cells secreting antibodies specific for signature antigens. Second, the antibodies secreted by isolated ASC were collected in vitro in a novel matrix, MENSA (media enriched with newly synthesized antibodies) and antibodies against S. pneumoniae antigens were measured using Luminex immunoassays. Each assay was evaluated using blood from S. pneumoniae and non-S. pneumoniae-infected adult patients. RESULTS: We enrolled 23 patients with culture-confirmed S. pneumoniae infections and 24 controls consisting of 12 non-S. pneumoniae infections, 10 healthy donors and two colonized with S. pneumoniae. By ELISpot assays, twenty-one of 23 infected patients were positive, and all 24 controls were negative. Using MENSA samples, four of five S. pneumoniae-infected patients were positive by Luminex immunoassays while all five non-S. pneumoniae-infected patients were negative. CONCLUSION: Specific antibodies produced by activated ASC may provide a simple diagnostic for ongoing S. pneumoniae infections. This method has the potential to diagnose acute bacterial infections. |
Effect of maternal Tdap on infant antibody response to a primary vaccination series with whole cell pertussis vaccine in So Paulo, Brazil
Vaz-de-Lima LRA , Sato APS , Pawloski LC , Fernandes EG , Rajam G , Sato HK , Patel D , Li H , de Castilho EA , Tondella ML , Schiffer J . Vaccine: X 2021 7 100087 Background: Maternal Tetanus, diphtheria, and acellular pertussis (Tdap) vaccination provides antibody transfer to newborn infants and may affect their antibody response to the primary vaccination series. This study aimed to assess the effect of Tdap vaccination during pregnancy on infant antibody response to the whole cell pertussis (DTwP) primary series. Methods: Plasma from 318 pregnant women (243 Tdap-vaccinated and 75 unvaccinated) and their infants (cord blood) was collected at delivery; infant blood was again collected at 2 and 7 months, before and after their primary DTwP series. Anti-pertussis toxin (PT), pertactin (PRN), filamentous hemagglutinin (FHA), fimbriae 2/3 (FIM) and adenylate cyclase toxin (ACT) IgG antibodies were quantified by a microsphere-based multiplex antibody capture assay and anti-PT neutralizing antibodies by the Real Time Cell analysis system. Results: Infant geometric mean concentrations (GMCs) of IgG anti-Tdap antigens were significantly higher (p < 0.001) among the Tdap-vaccinated (PT: 57.22 IU/mL; PRN: 464.86 IU/mL; FHA: 424.0 IU/mL), versus the unvaccinated group (4 IU/mL, 15.43 IU/mL, 31.99 IU/mL, respectively) at delivery. Anti-FIM and ACT GMCs were similar between the two groups. At 2 months of age, anti-PT, PRN, and FHA GMCs remained higher (p < 0.001) in the Tdap-vaccinated group (12.64 IU/mL; 108.76 IU/mL; 87.41 IU/mL, respectively) than the unvaccinated group (1.02 IU/mL; 4.46 IU/mL; 6.89 IU/mL). However, at 7 months, after receiving the third DTwP dose, the anti-PT GMC was higher (p = 0.016) in the unvaccinated group (7.91 IU/mL) compared to the vaccinated group (2.27 IU/mL), but without differences for anti-PRN, FHA, FIM and ACT GMCs. Conclusion: Elevated antibody levels suggest that maternal Tdap vaccination might protect infants until 2 months of age. Reduced anti-PT levels at 7 months indicate potential blunting of immune response in infants. Surveillance would help determine if blunting alters vaccine immunity and impacts pertussis prevention in infants. © 2021 The Authors |
Kinetics of maternal pertussis-specific antibodies in infants of mothers vaccinated with tetanus, diphtheria and acellular pertussis (Tdap) during pregnancy
Healy CM , Rench MA , Swaim LS , Timmins A , Vyas A , Sangi-Haghpeykar H , Ng N , Rajam G , Havers F , Schiffer J , Baker CJ . Vaccine 2020 38 (37) 5955-5961 BACKGROUND: Kinetics of Tdap-induced maternally-derived antibodies in infants are poorly understood. Pre-Tdap era data suggest that maternal pertussis antibodies in infants have a half-life of approximately 5-6 weeks. METHODS: 34 mother-infant pairs had blood collected before maternal Tdap vaccination, 4 weeks later, at delivery (maternal and cord), and at infant ages 3 and 6 weeks from June 2014-March 2015. Immunoglobulin G (IgG) to pertussis toxin (PT), filamentous hemagglutinin (FHA), fimbrial proteins (FIM) and pertactin (PRN) was quantified by multiplex luminex assay (IU/ml). Geometric mean concentrations (GMCs) with 95% confidence intervals (C.I.) and half-life of pertussis antibodies were calculated. RESULTS: Tdap was administered to 34 women (mean age 31.1 years) at mean gestation 30.7 weeks (28-32.7). Mean neonatal gestation was 39.1 weeks (36-41.1) and mean birthweight was 3379 g (2580-4584). Four weeks post-Tdap vaccination, maternal pertussis-specific IgG GMCs increased ≥4-fold in 59%, 41%, 29% and 44% of women for PT, FHA, FIM and PRN, respectively, and then waned. The transplacental transport ratio of pertussis antibodies was 1.35 for PT, 1.41 for FHA, 1.31 for FIM and 1.36 for PRN. Between birth and age 6 weeks, infant serum GMC for PT-specific IgG decreased from 55.1 IU/mL (38.6-78.6) to 21.1 IU/ml (14.7-30.2), and the proportion of infants with PT levels ≥10 IU/ml fell from 97% to 67%. Half-life of pertussis-specific IgG in infants in days was 29.4 (95% CI 27.3-31.7) for PT, 29.8 (95% CI 27.7-32.2) for FHA, 31.2 (95% CI 28.9-33.7) for PRN, and 35.8 (95% CI 30.1-44.3) for FIM. CONCLUSION: The half-life of pertussis-specific antibodies in infants induced by maternal Tdap vaccination (29-36 days) is shorter than previously reported. Understanding how the durability of passively-acquired antibodies impacts infant susceptibility to pertussis and response to primary vaccination is critical to refine prevention strategies. |
Late effects of total body irradiation on hematopoietic recovery and immune function in rhesus macaques
Hale LP , Rajam G , Carlone GM , Jiang C , Owzar K , Dugan G , Caudell D , Chao N , Cline JM , Register TC , Sempowski GD . PLoS One 2019 14 (2) e0210663 While exposure to radiation can be lifesaving in certain settings, it can also potentially result in long-lasting adverse effects, particularly to hematopoietic and immune cells. This study investigated hematopoietic recovery and immune function in rhesus macaques Cross-sectionally (at a single time point) 2 to 5 years after exposure to a single large dose (6.5 to 8.4 Gray) of total body radiation (TBI) derived from linear accelerator-derived photons (2 MeV, 80 cGy/minute) or Cobalt 60-derived gamma irradiation (60 cGy/min). Hematopoietic recovery was assessed through measurement of complete blood counts, lymphocyte subpopulation analysis, and thymus function assessment. Capacity to mount specific antibody responses against rabies, Streptococcus pneumoniae, and tetanus antigens was determined 2 years after TBI. Irradiated macaques showed increased white blood cells, decreased platelets, and decreased frequencies of peripheral blood T cells. Effects of prior radiation on production and export of new T cells by the thymus was dependent on age at the time of analysis, with evidence of interaction with radiation dose for CD8+ T cells. Irradiated and control animals mounted similar mean antibody responses to proteins from tetanus and rabies and to 10 of 11 serotype-specific pneumococcal polysaccharides. However, irradiated animals uniformly failed to make antibodies against polysaccharides from serotype 5 pneumococci, in contrast to the robust responses of non-irradiated controls. Trends toward decreased serum levels of anti-tetanus IgM and slower peak antibody responses to rabies were also observed. Taken together, these data show that dose-related changes in peripheral blood cells and immune responses to both novel and recall antigens can be detected 2 to 5 years after exposure to whole body radiation. Longer term follow-up data on this cohort and independent validation will be helpful to determine whether these changes persist or whether additional changes become evident with increasing time since radiation, particularly as animals begin to develop aging-related changes in immune function. |
Streptococcus infantis, Streptococcus mitis , and Streptococcus oralis Strains With Highly Similar cps5 Loci and Antigenic Relatedness to Serotype 5 Pneumococci.
Pimenta F , Gertz RE Jr , Park SH , Kim E , Moura I , Milucky J , Rouphael N , Farley MM , Harrison LH , Bennett NM , Bigogo G , Feikin DR , Breiman R , Lessa FC , Whitney CG , Rajam G , Schiffer J , da Gloria Carvalho M , Beall B . Front Microbiol 2018 9 3199 Streptococcus pneumoniae is a highly impactful bacterial pathogen on a global scale. The principal pneumococcal virulence factor and target of effective vaccines is its polysaccharide capsule, of which there are many structurally distinct forms. Here, we describe four distinct strains of three Mitis group commensal species (Streptococcus infantis, Streptococcus mitis, and Streptococcus oralis) recovered from upper respiratory tract specimens from adults in Kenya and the United States that were PCR-positive for the pneumococcal serotype 5 specific gene, wzy5. For each of the four strains, the 15 genes comprising the capsular polysaccharide biosynthetic gene cluster (cps5) shared the same order found in serotype 5 pneumococci, and each of the serotype 5-specific genes from the serotype 5 pneumococcal reference strain shared 76-99% sequence identity with the non-pneumococcal counterparts. Double-diffusion experiments demonstrated specific reactivity of the non-pneumococcal strains with pneumococcal serotype 5 typing sera. Antiserum raised against S. mitis strain KE67013 specifically reacted with serotype 5 pneumococci for a positive Quellung reaction and stimulated serotype 5 specific opsonophagocytic killing of pneumococci. Four additional commensal strains, identified using PCR serotyping assays on pharyngeal specimens, revealed loci highly homologous to those of pneumococci of serotypes 12F, 15A, 18C, and 33F. These data, in particular the species and strain diversity shown for serotype 5, highlight the existence of a broad non-pneumococcal species reservoir in the upper respiratory tract for the expression of capsular polysaccharides that are structurally related or identical to those corresponding to epidemiologically significant serotypes. Very little is known about the genetic and antigenic capsular diversity among the vast array of commensal streptococcal strains that represent multiple diverse species. The discovery of serotype 5 strains within three different commensal species suggests that extensive capsular serologic overlap exists between pneumococci and other members of the diverse Mitis group. These findings may have implications for our current understanding of naturally acquired immunity to S. pneumoniae and pneumococcal serotype distributions in different global regions. Further characterization of commensal strains carrying homologs of serotype-specific genes previously thought to be specific for pneumococci of known serotypes may shed light on the evolution of these important loci. |
Genetic Meningococcal Antigen Typing System (gMATS): A genotyping tool that predicts 4CMenB strain coverage worldwide.
Muzzi A , Brozzi A , Serino L , Bodini M , Abad R , Caugant D , Comanducci M , Lemos AP , Gorla MC , Krizova P , Mikula C , Mulhall R , Nissen M , Nohynek H , Simoes MJ , Skoczynska A , Stefanelli P , Taha MK , Toropainen M , Tzanakaki G , Vadivelu-Pechai K , Watson P , Vazquez JA , Rajam G , Rappuoli R , Borrow R , Medini D . Vaccine 2019 37 (7) 991-1000 BACKGROUND: The Meningococcal Antigen Typing System (MATS) was developed to identify meningococcus group B strains with a high likelihood of being covered by the 4CMenB vaccine, but is limited by the requirement for viable isolates from culture-confirmed cases. We examined if antigen genotyping could complement MATS in predicting strain coverage by the 4CMenB vaccine. METHODS: From a panel of 3912 MATS-typed invasive meningococcal disease isolates collected in England and Wales in 2007-2008, 2014-2015 and 2015-2016, and in 16 other countries in 2000-2015, 3481 isolates were also characterized by antigen genotyping. Individual associations between antigen genotypes and MATS coverage for each 4CMenB component were used to define a genetic MATS (gMATS). gMATS estimates were compared with England and Wales human complement serum bactericidal assay (hSBA) data and vaccine effectiveness (VE) data from England. RESULTS: Overall, 81% of the strain panel had genetically predictable MATS coverage, with 92% accuracy and highly concordant results across national panels (Lin's accuracy coefficient, 0.98; root-mean-square deviation, 6%). England and Wales strain coverage estimates were 72-73% by genotyping (66-73% by MATS), underestimating hSBA values after four vaccine doses (88%) and VE after two doses (83%). The gMATS predicted strain coverage in other countries was 58-88%. CONCLUSIONS: gMATS can replace MATS in predicting 4CMenB strain coverage in four out of five cases, without requiring a cultivable isolate, and is open to further improvement. Both methods underestimated VE in England. Strain coverage predictions in other countries matched or exceeded England and Wales estimates. |
Streptococcus mitis Expressing Pneumococcal Serotype 1 Capsule.
Lessa FC , Milucky J , Rouphael NG , Bennett NM , Talbot HK , Harrison LH , Farley MM , Walston J , Pimenta F , Gertz RE , Rajam G , Carvalho MDG , Beall B , Whitney CG . Sci Rep 2018 8 (1) 17959 Streptococcus pneumoniae's polysaccharide capsule is an important virulence factor; vaccine-induced immunity to specific capsular polysaccharide effectively prevents disease. Serotype 1 S. pneumoniae is rarely found in healthy persons, but is highly invasive and a common cause of meningitis outbreaks and invasive disease outside of the United States. Here we show that genes for polysaccharide capsule similar to those expressed by pneumococci were commonly detected by polymerase chain reaction among upper respiratory tract samples from older US adults not carrying pneumococci. Serotype 1-specific genes were predominantly detected. In five oropharyngeal samples tested, serotype 1 gene belonging to S. mitis expressed capsules immunologically indistinct from pneumococcal capsules. Whole genome sequencing revealed three distinct S. mitis clones, each representing a cps1 operon highly similar to the pneumococcal cps1 reference operon. These findings raise important questions about the contribution of commensal streptococci to natural immunity against pneumococci, a leading cause of mortality worldwide. |
Development and validation of a robust multiplex serological assay to quantify antibodies specific to pertussis antigens
Rajam G , Carlone G , Kim E , Choi J , Paulos S , Park S , Jeyachandran A , Gorantla Y , Wong E , Sabnis A , Browning P , Desai R , Quinn CP , Schiffer J . Biologicals 2018 57 9-20 Despite wide spread vaccination, the public health burden of pertussis remains substantial. Current acellular pertussis vaccines comprise upto five Bordetella pertussis (Bp) antigens. Performing an ELISA to quantify antibody for each antigen is laborious and challenging to apply to pediatric samples where serum volume may be limited. We developed a microsphere based multiplex antibody capture assay (MMACA) to quantify antibodies to five pertussis antigens; pertussis toxin, pertactin, filamentous hemagglutinin and fimbrial antigens 2/3, and adenylate cyclase toxin in a single reaction (5-plex) with a calibrated reference standard, QC reagents and SAS((R)) based data analysis program. The goodness of fit (R(2)) of the standard curves for five analytes was >/=0.99, LLOQ 0.04-0.15 IU or AU/mL, accuracy 1.9%-23.8% (%E), dilutional linearity slopes 0.93-1.02 and regression coefficients r(2)=0.91-0.99. MMACA had acceptable precision within a median CV of 16.0%-22.8%. Critical reagents, antigen conjugated microsphere and reporter antibody exhibited acceptable (<12.3%) lot-lot variation. MMACA can be completed in <3h, requires low serum volume (5muL/multiplex assay) and has fast data turnaround time (<1min). MMACA has been successfully developed and validated as a sensitive, specific, robust and rugged method suitable for simultaneous quantification of anti-Bp antibodies in serum, plasma and DBS. |
Impact of maternally derived pertussis antibody titers on infant whole-cell pertussis vaccine response in a low income setting
Ibrahim R , Ali SA , Kazi AM , Rizvi A , Guterman LB , Bednarczyk RA , Kim E , Park S , Paulos S , Jeyachandran A , Patel D , Gorantla Y , Wong E , Rajam G , Schiffer J , Omer SB . Vaccine 2018 36 (46) 7048-7053 BACKGROUND: Maternal vaccines against pertussis are not yet recommended in the developing world. Besides unclear burden estimates, another concern is that transplacental transfer of maternal pertussis antibodies could result in attenuation of the immune response to whole cell pertussis (DTwP) primary vaccination series in infants. This study was taken up to determine whether higher levels of maternal pertussis antibodies attenuate immune response of infants to DTwP vaccination series given at 6-10-14weeks of age. METHODOLOGY: A total of 261 pregnant women and their infants from four low-income settlements in Karachi, Pakistan were enrolled in this study. The study endpoints were infant antibody titers for Pertussis toxin (PTx), Filamentous hemagglutinin antigen (FHA), Pertactin (PRN) and Fimbriae type 2/3 (FIM) - from birth through 18weeks of age. Cord blood or pre-vaccine pertussis antibody titers indicate the concentration of maternal antibodies transferred to infants. Linear regression models were used to determine the association between higher maternal antibody titers and infant immune response to DTwP vaccine. Geometric Mean Ratio (GMR) was calculated as the ratio of infant antibody titers at specified time points against the maternal antibody titers at the time of delivery. RESULTS: At eighteen weeks of age, the adjusted beta regression coefficient for PTx was 0.06 (95% CI: -0.49-0.61), FHA 0.02 (95% CI: -0.26 -0.29), PRN 0.02 (95%CI -0.38- 0.43), and FIM 0.17 (95%CI: -0.21-0.54). Among infants who received at least two doses of DTwP vaccine, higher maternal antibody titers did not have any attenuating effect on infant post-immunization antibody titers against all four pertussis antigens. CONCLUSION: Maternal pertussis antibodies did not attenuate infant's immune response to pertussis antigens in DTwP primary vaccine given at 6-10-14weeks of age. |
Meningococcal Antigen Typing System (MATS)-based Neisseria meningitidis serogroup B coverage prediction for the MenB-4C vaccine in the United States
Rajam G , Stella M , Kim E , Paulos S , Boccadifuoco G , Serino L , Carlone G , Medini D . mSphere 2017 2 (6) Neisseria meningitidis is the most common cause of bacterial meningitis in children and young adults worldwide. A 4-component vaccine against N. meningitidis serogroup B (MenB) disease (MenB-4C [Bexsero]; GSK) combining factor H binding protein (fHBP), neisserial heparin binding protein (NHBA), neisserial adhesin A (NadA), and PorA-containing outer membrane vesicles was recently approved for use in the United States and other countries worldwide. Because the public health impact of MenB-4C in the United States is unclear, we used the meningococcal antigen typing system (MATS) to assess the strain coverage in a panel of strains representative of serogroup B (NmB) disease in the United States. MATS data correlate with killing in the human complement serum bactericidal assay (hSBA) and predict the susceptibility of NmB strains to killing in the hSBA, the accepted correlate of protection for MenB-4C vaccine. A panel of 442 NmB United States clinical isolates (collected in 2000 to 2008) whose data were down weighted with respect to the Oregon outbreak was selected from the Active Bacterial Core Surveillance (ABCs; CDC, Atlanta, GA) laboratory. MATS results examined to determine strain coverage were linked to multilocus sequence typing and antigen sequence data. MATS predicted that 91% (95% confidence interval [CI95], 72% to 96%) of the NmB strains causing disease in the United States would be covered by the MenB-4C vaccine, with the estimated coverage ranging from 88% to 97% by year with no detectable temporal trend. More than half of the covered strains could be targeted by two or more antigens. NHBA conferred coverage to 83% (CI95, 45% to 93%) of the strains, followed by factor H-binding protein (fHbp), which conferred coverage to 53% (CI95, 46% to 57%); PorA, which conferred coverage to 5.9%; and NadA, which conferred coverage to 2.5% (CI95, 1.1% to 5.2%). Two major clonal complexes (CC32 and CC41/44) had 99% strain coverage. The most frequent MATS phenotypes (39%) were fHbp and NHBA double positives. MATS predicts over 90% MenB-4C strain coverage in the United States, and the prediction is stable in time and consistent among bacterial genotypes. IMPORTANCE The meningococcal antigen typing system (MATS) is an enzyme-linked immunosorbent assay (ELISA)-based system that assesses the levels of expression and immune reactivity of the three recombinant MenB-4C antigens and, in conjunction with PorA variable 2 (VR2) sequencing, provides an estimate of the susceptibility of NmB isolates to killing by MenB-4C-induced antibodies. MATS assays or similar antigen phenotype analyses assume importance under conditions in which analyses of vaccine coverage predictions are not feasible with existing strategies, including large efficacy trials or functional antibody screening of an exhaustive strain panel. MATS screening of a panel of NmB U.S. isolates (n = 442) predicts high MenB-4C vaccine coverage in the United States. |
Augmented passive immunotherapy with P4 peptide improves phagocyte activity in severe sepsis
Morton B , Mitsi E , Pennington SH , Reine J , Wright AD , Parker R , Welters ID , Blakey JD , Rajam G , Ades EW , Ferreira DM , Wang D , Kadioglu A , Gordon SB . Shock 2016 46 (6) 635-641 INTRODUCTION: Antimicrobial resistance threatens to undermine treatment for severe infection; new therapeutic strategies are urgently needed. Pre-clinical work shows that augmented passive immunotherapy with P4 peptide increases phagocytic activity and shows promise as a novel therapeutic strategy. Our aim was to determine ex vivo P4 activity in a target population of patients admitted to critical care with severe infection. METHODS: We prospectively recruited UK critical care unit patients with severe sepsis and observed clinical course (≥3 months post discharge). Blood samples were taken in early (≤ 48hrs post-diagnosis, n = 54), latent (seven days post-diagnosis, n = 39) and convalescent (3-6 months post-diagnosis, n = 18) phases of disease. The primary outcome measure was killing of opsonised S.pneumoniae by neutrophils with and without P4 peptide stimulation. We also used a flow cytometric whole blood phagocytosis assay to determine phagocyte association and oxidation of intraphagosomal reporter beads. RESULTS: P4 peptide increased neutrophil killing of opsonised pneumococci by 8.6% (C.I. 6.35 - 10.76, p < 0.001) in all phases of sepsis, independent of infection source and microbiological status. This represented a 54.9% increase in bacterial killing compared to unstimulated neutrophils (15.6%) in early phase samples. Similarly, P4 peptide treatment significantly increased neutrophil and monocyte intraphagosomal reporter bead association and oxidation, independent of infection source. CONCLUSIONS: We have extended pre-clinical work to demonstrate that P4 peptide significantly increases phagocytosis and bacterial killing in samples from a target patient population with severe sepsis. This study supports the rationale for augmented passive immunotherapy as a therapeutic strategy in severe sepsis. |
Immune Responses in U.S. Military Personnel Who Received Meningococcal Conjugate Vaccine (MenACWY) Concomitantly with Other Vaccines Were Higher than in Personnel Who Received MenACWY Alone
Broderick MP , Romero-Steiner S , Rajam G , Johnson SE , Milton A , Kim E , Choi LJ , Radin JM , Schmidt DS , Carlone GM , Messonnier N , Faix DJ . Clin Vaccine Immunol 2016 23 (8) 672-80 Immunological responses to vaccination can differ depending on whether the vaccine is given alone or with other vaccines. This study was a retrospective evaluation of the immunogenicity of a tetravalent meningococcal conjugate vaccine (MenACWY) administered alone (n = 41) or concomitantly with other vaccines (n = 279) to United States military personnel (mean age = 21.6 years) entering the military between 2006 and 2008. Concomitant vaccines included tetanus/diphtheria (Td), inactivated polio vaccine (IPV), hepatitis vaccines, various influenza vaccines, among others; two vaccine groups excluded Tdap and IPV. Immune responses were evaluated in baseline and post-vaccination sera for Neisseria meningitidis serogroups C and Y 1-12 months (mean = 4.96) following vaccination. Functional antibodies were measured by using a serum bactericidal antibody assay with rabbit complement (rSBA) and by measurement of serogroup-specific immunoglobulin G (IgG) antibodies. The percentage of vaccinees reaching threshold levels (IgG ≥2 mug/mL; rSBA titer ≥8) corresponding to an immunologic response was higher post-vaccination than at baseline (p < 0.001). Administration of MenACWY along with other vaccines was associated with higher geometric means of IgG concentrations and rSBA titers than those measured 4.60 months after a single dose of MenACWY. In addition, higher percentages of vaccinees reached the immunological threshold (odds ratios [ORs] range = 1.5 to 21.7) and more of them seroconverted (ORs range = 1.8 to 4.8) when MenACWY was administered with any other vaccine than when administered alone. Additional prospective randomized clinical trials are needed to confirm the observed differences among groups in the immune response to MenACWY when given concomitantly with other vaccines to United States military personnel. |
Molecular signatures of antibody responses derived from a systems biology study of five human vaccines.
Li S , Rouphael N , Duraisingham S , Romero-Steiner S , Presnell S , Davis C , Schmidt DS , Johnson SE , Milton A , Rajam G , Kasturi S , Carlone GM , Quinn C , Chaussabel D , Palucka AK , Mulligan MJ , Ahmed R , Stephens DS , Nakaya HI , Pulendran B . Nat Immunol 2013 15 (2) 195-204 Many vaccines induce protective immunity via antibodies. Systems biology approaches have been used to determine signatures that can be used to predict vaccine-induced immunity in humans, but whether there is a 'universal signature' that can be used to predict antibody responses to any vaccine is unknown. Here we did systems analyses of immune responses to the polysaccharide and conjugate vaccines against meningococcus in healthy adults, in the broader context of published studies of vaccines against yellow fever virus and influenza virus. To achieve this, we did a large-scale network integration of publicly available human blood transcriptomes and systems-scale databases in specific biological contexts and deduced a set of transcription modules in blood. Those modules revealed distinct transcriptional signatures of antibody responses to different classes of vaccines, which provided key insights into primary viral, protein recall and anti-polysaccharide responses. Our results elucidate the early transcriptional programs that orchestrate vaccine immunity in humans and demonstrate the power of integrative network modeling. |
Interlaboratory standardization of the sandwich enzyme-linked immunosorbent assay designed for MATS, a rapid, reproducible method for estimating the strain coverage of investigational vaccines
Plikaytis BD , Stella M , Boccadifuoco G , Detora LM , Agnusdei M , Santini L , Brunelli B , Orlandi L , Simmini I , Giuliani M , Ledroit M , Hong E , Taha MK , Ellie K , Rajam G , Carlone GM , Claus H , Vogel U , Borrow R , Findlow J , Gilchrist S , Stefanelli P , Fazio C , Carannante A , Oksnes J , Fritzsonn E , Klem AM , Caugant DA , Abad R , Vazquez JA , Rappuoli R , Pizza M , Donnelly JJ , Medini D . Clin Vaccine Immunol 2012 19 (10) 1609-17 The meningococcal antigen typing system (MATS) sandwich enzyme-linked immunosorbent assay (ELISA) was designed to measure the immunologic cross-reactivity and quantity of antigens in target strains of a pathogen. It was first used to measure the factor H-binding protein (fHbp), neisserial adhesin A (NadA), and neisserial heparin-binding antigen (NHBA) content of serogroup B meningococcal (MenB) isolates relative to a reference strain, or "relative potency" (RP). With the PorA genotype, the RPs were then used to assess strain coverage by 4CMenB, a multicomponent MenB vaccine. In preliminary studies, MATS accurately predicted killing in the serum bactericidal assay using human complement, an accepted correlate of protection for meningococcal vaccines. A study across seven laboratories assessed the reproducibility of RPs for fHbp, NadA, and NHBA and established qualification parameters for new laboratories. RPs were determined in replicate for 17 MenB reference strains at laboratories A to G. The reproducibility of RPs among laboratories and against consensus values across laboratories was evaluated using a mixed-model analysis of variance. Interlaboratory agreement was very good; the Pearson correlation coefficients, coefficients of accuracy, and concordance correlation coefficients exceeded 99%. The summary measures of reproducibility, expressed as between-laboratory coefficients of variation, were 7.85% (fHbp), 16.51% (NadA), and 12.60% (NHBA). The overall within-laboratory measures of variation adjusted for strain and laboratory were 19.8% (fHbp), 28.8% (NHBA), and 38.3% (NadA). The MATS ELISA was successfully transferred to six laboratories, and a further laboratory was successfully qualified. |
P4-mediated antibody therapy in an acute model of invasive pneumococcal disease
Bangert M , Bricio-Moreno L , Gore S , Rajam G , Ades EW , Gordon SB , Kadioglu A . J Infect Dis 2012 205 (9) 1399-407 New treatments against severe bacterial infections are needed because the response to antibiotic treatment is slow in acute settings and is becoming less effective owing to the emergence of antibiotic-resistant pathogens. P4-mediated antibody therapy offers a unique treatment strategy that combines exogenous immunoglobulin with the immunoactivating peptide P4. In an acute model of pneumococcal disease, mice were infected with Streptococcus pneumoniae and treated intravenously or intranasally with P4 and intravenous immunoglobulin (IVIG). Survival of P4-IVIG-treated mice increased from 0% to 60% among those that received intravenous treatment and from 0% to 100% among those that received intranasal treatment. Importantly, intranasal administration of P4 at an early stage of infection prevented the onset of bacteremia and sepsis. Increased survival was associated with reduced bacterial burden in affected tissues and with recruitment and activation of professional phagocytes, as manifested by increased expression of Fc-gamma receptors. In vitro studies involving P4-stimulated alveolar, peritoneal, and J774.2 murine macrophages showed an increased ability of these immune cells to phagocytose pneumococci independent of capsule. The use of adjunct antibody therapies to treat infectious diseases shows promise. |
Immunotherapy with a combination of intravenous immune globulin and p4 peptide rescues mice from postinfluenza pneumococcal pneumonia
Weeks JN , Boyd KL , Rajam G , Ades EW , McCullers JA . Antimicrob Agents Chemother 2011 55 (5) 2276-81 Alternate therapies are needed for treatment of secondary bacterial pneumonia following influenza. The immunomodulatory peptide P4 has shown promise in mouse models of primary pneumococcal infection. Mice infected with influenza virus then challenged with Streptococcus pneumoniae were treated with a combination of P4 peptide and intravenous immune globulin. Survival was improved from 20% to 80% in treated mice relative to controls. Clinical cure correlated with increased clearance of bacteria and decreased lung consolidation. Greater trafficking of professional phagocytic cells to the site of pneumococcal infection coupled with enhanced opsonophagocytosis as manifest by decreased surface display of Fcgamma receptors on neutrophils and macrophages were associated with P4 peptide treatment. This suggests that the mechanism of action for improved clearance of bacteria engendered by P4 is through improved uptake by phagocytes mediated by IgG Fc - Fcgamma receptor interactions following antibody mediated opsonophagocytosis of bacteria. Antibody-based therapies, when coupled with immune modulators such as P4 peptide, may be an effective tool together with antibiotics in our armamentarium against severe pneumonia. |
P4 peptide therapy rescues aged mice from fatal pneumococcal sepsis
Rajam G , Bangert M , Hammons GM , Melnick N , Carlone GM , Sampson JS , Ades EW . Clin Vaccine Immunol 2010 17 (11) 1823-4 Many studies suggest that with aging, immune capabilities gradually diminish, leading to a decrease in antibody production, cytokines, and various effector cells (1-4). In this study, we examined the effects of an immune-enhancing peptide on aged mice. P4, a 28-amino-acid cationic peptide derived from pneumococcal surface adhesin A (PsaA), is a eukaryotic cellular activator (10). Previously, we demonstrated that the cellular activation properties of P4 can be utilized to rescue severely ill young mice from fatal pneumococcal infection in the presence of pathogen-specific antibodies and active complement (8, 12). While P4 therapy was used to rescue young Swiss Webster mice (6 to 10 weeks old), we questioned its effectiveness in aged mice (11 and 15 months old). | Intranasal inoculation of mice with Streptococcus pneumoniae WU2 (serotype 3) and P4 therapy were done using protocols previously described, with minor modifications (12). Eleven-month-old BALB/c (n = 20) and 15-month-old Swiss Webster mice (n = 20) were infected intranasally with S. pneumoniae WU2 (∼2.1 × 107 cells/mouse). Mice were monitored and visually scored twice daily for moribund characteristics as previously described (12). At 48 h postchallenge, 80% (16/20) were moribund. Moribund mice were divided into a control (n = 8) and a treatment group (n = 8). Two doses of P4 therapy with pathogen-specific antibody (intravenous immunoglobulin [IVIG]; Gamunex, Telecris, NC) and P4 were administered intravenously (postinfection) in the treatment group. Treated and untreated animals were monitored for 166 h, and the data computed for significant differences among various groups using a t test for paired samples for the means (MS Excel 2007). |
An augmented passive immune therapy to treat fulminant bacterial infections
Rajam G , Sampson J , Carlone GM , Ades EW . Recent Pat Antiinfect Drug Discov 2010 5 (2) 157-67 In the early 1900s, passive immunization/antibody therapy was used to treat a variety of human ailments such as hypoimmunoglobulinemia, cancer and infectious disease. The advent of antibiotic therapy had relegated this type of therapy obsolete for treatment of infectious diseases. Emergence of multi-drug resistant pathogens along with novel monoclonal antibody production techniques has rekindled the interest in passive immunization (PI). An increase in the number of monoclonal antibody patent applications in the recent past suggests a renewed commercial interest in PI. Despite these developments, antibody therapy for infectious diseases has limitations including the need for large or frequent dosages. P4, a 28-amino acid peptide is a multi-lineage cellular activator. P4, along with infectious disease (i.e. Pathogen) specific immunoglobulin, has been shown in vitro and in vivo in mice to potentiate innate immunity. This review will discuss the progress made in passive antibody therapy, the challenges still to be surmounted, and the potential expanded role of an immune-potentiating peptide (bio-molecule) in the quest to utilize and revitalize passive immunization. |
Concomitant administration of recombinant PsaA and PCV7 reduces Streptococcus pneumoniae serotype 19A colonization in a murine model
Whaley MJ , Sampson JS , Johnson SE , Rajam G , Stinson-Parks A , Holder P , Mauro E , Romero-Steiner S , Carlone GM , Ades EW . Vaccine 2010 28 (18) 3071-5 A murine colonization model was used to determine the effect of co-administering 7-valent polysaccharide-protein conjugate vaccine and pneumococcal surface adhesin A. Mice were challenged intranasally with either PCV7 serotypes, 4 or 14, or a non-PCV7 serotype, 19A. Post-challenge samples were evaluated for IgG antibody levels, opsonophagocytic activity, and nasopharyngeal colonization. No interference was observed between immune responses from the concomitant and individual immunizations. Concomitant immunizations reduced carriage for tested serotypes; largest reduction was observed for 19A. From these mouse studies, co-administering pneumococcal antigens appear to expand coverage and reduce colonization against a non-PCV7 serotype without inhibiting immunogenicity to other serotypes. |
Revaccination with a 23-valent pneumococcal polysaccharide vaccine induces elevated and persistent functional antibody responses in adults aged 65 > or = years
Manoff SB , Liss C , Caulfield MJ , Marchese RD , Silber J , Boslego J , Romero-Steiner S , Rajam G , Glass NE , Whitney CG , Carlone GM . J Infect Dis 2010 201 (4) 525-33 BACKGROUND: Older adults are at high risk of developing invasive pneumococcal disease, but the optimal timing and number of vaccine doses needed to prevent disease among this group are unknown. We compared revaccination with 23-valent pneumococcal polysaccharide vaccine (PN23) with primary vaccination for eliciting initial and persistent functional antibody responses. METHODS: Subjects aged > or = 65 years were enrolled. Functional (opsonic) and total immunoglobulin (Ig) G antibody levels were measured following either PN23 primary vaccination (n = 60) or revaccination 3-5 years after receiving a first PN23 vaccination (n = 60). Antibody against vaccine serotypes 4, 14, and 23F was measured at prevaccination (day 0), 30 days after vaccination, and 5 years after vaccination. RESULTS: By day 30, both primary vaccination and revaccination induced significant increases in opsonic and IgG antibody levels. Day 30 levels following revaccination were slightly lower but not significantly different than those after primary vaccination. Year 5 levels were similar in both groups and remained significantly higher than prevaccination levels for primary vaccination subjects. There was good agreement between postvaccination opsonic and IgG antibody levels. CONCLUSIONS: Revaccination of older adults with PN23 was comparable to primary vaccination for inducing elevated and persistent functional and IgG antibody responses. |
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