Immunization with DNA vaccines in early life: Advantages and limitations as compared to conventional vaccines

Conclusion: DNA vaccines favorably compare to conventional vaccines in their unique capacity to induce, in murine models, adult-like antibody, Th1 and CTL responses at a time of yet significant immune immaturity. Immune responses to DNA vaccines are, however, significantly slower than the one induced by adjuvanted subunit or live vaccines. Although they persist for life in mice, preliminary data in non-human adult primates suggest that this could not be the case in higher mammals. The issue of potential tolerance induction will likely not emerge as a critical feature of human neonatal DNA immunization. However, DNA vaccines are unlikely to prove superior to conventional vaccines in their capacity to circumvent the inhibitory influence of maternal antibodies. Thus, the greater perspectives for neonatal DNA immunization could be found in models where the induction of Th1 and CTL responses are of utmost importance. These are essentially infections with intracellular agents responsible for severe/persistent infections upon early exposure and for which no current efficient and safe conventional vaccine exists. Evaluating neonatal DNA immunization strategies against RSV or herpes viruses, tuberculosis or Chlamydiae therefore emerge as sound prioritie

COMPARISON OF THE IMMUNE RESPONSIVENESS OF NZB AND NZB x NZW F1 HYBRID MICE WITH THAT OF OTHER STRAINS OF MICE

The immune responsiveness of (NZB x NZW) F1 hybrid mice (NZB/W) has been compared with that of three other strains of mice, A/J, BALB/c, and CBA/J. The antigens used included sheep red blood cells (SRBC), keyhole limpet hemocyanin (KLH), bovine serum albumin (BSA), and human γ-globulin (HGG). It was found that important strain differences existed in the amount of antibody produced, but the relative immune responsiveness depended very much upon the nature of antigen. By comparison with the other strains tested, NZB/W mice had a higher antibody production to some antigens (SRBC and BSA) but were low responders to others (KLH). Induction of unresponsiveness to HGG by treatment with ultracentrifuged HGG was studied in the strains cited above. NZB/W mice became tolerant after injection of HGG ultracentrifuged at 100,000 g for 2 hr. Similar experiments carried out with another preparation of HGG (centrifuged at 20,000 g for 30 min) failed to reveal any abnormal behavior of NZB/W mice as compared to BALB/c or A/J mice. These results do not support the concept that NZB/W mice possess a general immune hyperreactivity or a relative inability to be made tolerant to protein antigens. However, they do not rule out the possibility that these mice have a genetically determined hyperresponsiveness to some antigens, in particular to nuclear antigens

Complement-Mediated Opsonic Activity in Normal and Infected Human Cerebrospinal Fluid: Early Response During Bacterial Meningitis

A local defense mechanism in bacterial meningitis was evaluated in humans by measuring complement-mediated opsonic activity (CMOA) in normal and infected cerebrospinal fluid (CSF) with a complement-dependent phagocytic bactericidal assay. CMOA was absent in normal untreated CSF and remained undetectable in 20 samples of CSF from patients with viral meningitis and five samples from patients with acute meningococcemia. In contrast, 15 of 27 samples of CSF from patients with acute bacterial meningitis had a measurable CMOA, which was correlated with protein concentrations (P < 0.01) and C4 hemolytic activity (P < 0.001) in the CSF. A favorable outcome of bacterial meningitis was associated with the presence of CMOA in CSF (P < 0.005). Recovery was also correlated with higher levels of C4 (P < 0.01) and C3 (P < 0.05) in CSF and with lower concentrations of microorganisms in the sample of CSF collected at the time of admission (P < 0.01). Thus, CMOA, although absent in normal CSF, can appear in CSF during acute bacterial meningitis, particularly in patients who recover completel

Production of Specific Monoclonal Antibodies to Salmonella typhi Flagellin and Possible Application to Immunodiagnosis of Typhoid Fever

Four murine monoclonal antibodies (MAbs)to Salmonella typhi flagellin were produced. These MAbs did not react with eight other enterobacterial strains tested: Salmonella enteritidis, Salmonella typhimurium, Salmonella paratyphi A, Escherichia coli, Shigella flexneri, Shigella sonnei, Yersinia enterocolitica, and Campylobacter jejuni. Allfour MAbscross-reactedwith Salmonella muenchen flagellin indicating specificityfor d antigenic flagellar epitope. One MAb(C4) was selected to developa double antibody sandwich enzyme-linked immunosorbent assay (ELISA) to detect S. typhi flagellin in serum samples. By use of this assay S. typhi flagellar antigen was detected in 95.5% of serum samples from patients with positive hemoculture for S. typhi, in 93.6% of samples from patients with positive serodiagnosis of typhoid fever, in 26% of samples collected from patients who were initially hemoculture-positive for S. typhi and who had undergone 7-8 d of chemotherapy, in 8.5% of samples from healthy persons from an endemic area, and in no samples from healthy persons from a nonendemic area. The presence of high levelsof flagellin antibody titers did not interfere with the antigen detection. The detection of S. typhi flagellar antigen in patient serum may have practical value for rapid diagnosis of typhoid feve

Time-dependent multistate switching of topological antiferromagnetic order in Mn3_3Sn

The manipulation of antiferromagnetic order by means of spin-orbit torques opens unprecedented opportunities to exploit the dynamics of antiferromagnets in spintronic devices. In this work, we investigate the current-induced switching of the magnetic octupole vector in the Weyl antiferromagnet Mn$_3$Sn as a function of pulse shape, field, temperature, and time. We find that the switching behavior can be either bistable or tristable depending on the temporal structure of the current pulses. Time-resolved Hall effect measurements reveal that Mn$_3$Sn switching proceeds via a two-step demagnetization-remagnetization process caused by self-heating over a timescale of tens of ns followed by cooling in the presence of spin-orbit torques. Our results shed light on the switching dynamics of Mn$_3$Sn and prove the existence of extrinsic limits on its switching speed.Comment: Rectified wrong order of MS and Supplemen

Site-Specific DC Surface Signatures Influence CD4⁺ T Cell Co-stimulation and Lung-Homing

Dendritic cells (DCs) that drain the gut and skin are known to favor the establishment of T cell populations that home to the original site of DC-antigen (Ag) encounter by providing soluble "imprinting" signals to T cells in the lymph node (LN). To study the induction of lung T cell-trafficking, we used a protein-adjuvant murine intranasal and intramuscular immunization model to compare in vivo-activated Ag+ DCs in the lung and muscle-draining LNs. Higher frequencies of Ag+ CD11b+ DCs were observed in lung-draining mediastinal LNs (MedLN) compared to muscle-draining inguinal LNs (ILN). Ag+ CD11b+ MedLN DCs were qualitatively superior at priming CD4+ T cells, which then expressed CD49a and CXCR3, and preferentially trafficked into the lung parenchyma. CD11b+ DCs from the MedLN expressed higher levels of surface podoplanin, Trem4, GL7, and the known co-stimulatory molecules CD80, CD86, and CD24. Blockade of specific MedLN DC molecules or the use of sorted DC and T cell co-cultures demonstrated that DC surface phenotype influences the ability to prime T cells that then home to the lung. Thus, the density of dLN Ag+ DCs, and DC surface molecule signatures are factors that can influence the output and differentiation of lung-homing CD4+ T cells

Protective Immunity against Respiratory Syncytial Virus in Early Life after Murine Maternal or Neonatal Vaccination with the Recombinant G Fusion Protein BBG2Na

Maternal and neonatal immunization were evaluated for their capacity to induce protective immunity against respiratory syncytial virus (RSV) lower respiratory tract infections in early life. Murine models were studied by use of a novel recombinant vaccine candidate, designated BBG2Na, which was derived in part from the RSV (Long) G protein. Maternal immunization resulted in the passive transfer of high levels of RSV-A antibodies to the offspring, which protected them from RSV challenge for up to 14 weeks. Indeed, protection correlated with the detection of RSV antibodies in the serum. Neonatal immunization with BBG2Na induced significant antibody responses even in the first week of life. Most importantly, these neonatal responses were not inhibited by the presence of RSV maternal antibodies. Consequently, the combination of maternal and neonatal immunization with BBG2Na resulted in the continual presence of protective levels of antibodies in the offsprin

Prognostic Values of Tumor Necrosis Factor/Cachectin, Interleukin-l, Interferon-α, and Interferon-γ in the Serum of Patients with Septic Shock

Serum concentrations of immunoreactive tumor necrosis factor/cachectin (TNF), interleukin-1β (IL-1β), interferon-γ (IFNγ, and interferon-α (IFNα) were prospectively measured in 70 patients with septic shock to determine their evolution and prognostic values. In a univariate analysis, levels of TNF (P = .002) and IL-1β (P = .05) were associated with the patient's outcome, but not IFNα (P = .15) and IFNγ (P = .26). In contrast, in a stepwise logistic regression analysis, the severity of the underlying disease (P = .01), the age of the patient (P = .02), the documentation of infection (nonbacteremic infections vs. bacteremias, P = .03), the urine output (P = .04), and the arterial pH (P = .05) contributed more significantly to prediction of patient outcome than the serum levels of TNF (P = .07). After 10 days, the median concentration of TNF was undetectable <100 pg/ml) in the survivors, whereas it remained elevated (305 pg/ml, P = .002) in the nonsurvivors. Thus, in patients with septic shock due to various gram-negative bacteria, other parameters than the absolute serum concentration of immunoreactive TNF contributed significantly to the prediction of outcom

Protective Efficacy against Respiratory Syncytial Virus following Murine Neonatal Immunization with BBG2Na Vaccine: Influence of Adjuvants and Maternal Antibodies

Alum-adsorbed BBG2Na, a recombinant vaccine derived in part from the respiratory syncytial virus (RSV) subgroup A G protein, induced moderate antibody titers after 1 immunization in 1-week-old mice but conferred complete lung protection upon RSV challenge. The anti-BBG2Na IgG1-IgG2a neonatal isotype profile was suggestive of dominant Th2 responses compared with those in adults. Formulation of BBG2Na with a Th1-driving adjuvant efficiently shifted neonatal responses toward a more balanced and adultlike IgG1-IgG2a profile without compromising its protective efficacy. BBG2Na-induced protective immunity was maintained even after early life immunization in the presence of high titers of maternal antibodies. Under these conditions, the protective efficacy (86%-100%) reflected the high capacity of the nonglycosylated G2Na immunogen to escape inhibition by RSV-A—induced maternal antibodies. Thus, immunization with BBG2Na protected against viral challenge despite neonatal immunologic immaturity and the presence of maternal antibodies, two major obstacles to neonatal RSV vaccine developmen

Adult-Like Anti-Mycobacterial T Cell and In Vivo Dendritic Cell Responses Following Neonatal Immunization with Ag85B-ESAT-6 in the IC31® Adjuvant

BACKGROUND: With the exception of some live vaccines, e.g. BCG, subunit vaccines formulated with "classical" adjuvants do not induce similar responses in neonates as in adults. The usual neonatal profile is characterized by lower levels of TH1-associated biomarkers. This has hampered the development of new neonatal vaccines for diseases that require early protection. Tuberculosis is one of the major targets for neonatal immunization. In this study, we assessed the immunogenicity of a novel candidate vaccine comprising a mycobacterial fusion protein, Ag85B-ESAT-6, in a neonatal murine immunization model. METHODS/FINDINGS: The Ag85B-ESAT-6 fusion protein was formulated either with a classical alum based adjuvant or with the novel IC31 adjuvant. Following neonatal or adult immunization, 3 parameters were studied in vivo: (1) CD4(+) T cell responses, (2) vaccine targeting/activation of dendritic cells (DC) and (3) protection in a surrogate mycobacterial challenge model. Conversely to Alum, IC31 induced in both age groups strong Th1 and Th17 responses, characterized by multifunctional T cells expressing IL-2 and TNF-alpha with or without IFN-gamma. In the draining lymph nodes, a similarly small number of DC contained the adjuvant and/or the antigen following neonatal or adult immunization. Expression of CD40, CD80, CD86 and IL-12p40 production was focused on the minute adjuvant-bearing DC population. Again, DC targeting/activation was similar in adults and neonates. These DC/T cell responses resulted in an equivalent reduction of bacterial growth following infection with M. bovis BCG, whereas no protection was observed when Alum was used as adjuvant. CONCLUSION: Neonatal immunization with the IC31-adjuvanted Ag85B-ESAT-6 subunit vaccine elicited adult-like multifunctional protective anti-mycobacterial T cell responses through the induction of an adult pattern of in vivo DC activation