Subsequent Booster Research Articles

Early DNA vaccination of puppies against canine distemper in the presence of maternally derived immunity

Canine distemper (CD) is a disease in carnivores caused by CD virus (CDV), a member of the morbillivirus genus. It still is a threat to the carnivore and ferret population. The currently used modified attenuated live vaccines have several drawbacks of which lack of appropriate protection from severe infection is the most outstanding one. In addition, puppies up to the age of 6–8 weeks cannot be immunized efficiently due to the presence of maternal antibodies. In this study, a DNA prime modified live vaccine boost strategy was investigated in puppies in order to determine if vaccinated neonatal dogs induce a neutralizing immune response which is supposed to protect animals from a CDV challenge. Furthermore, a single DNA vaccination of puppies, 14 days after birth and in the presence of high titers of CDV neutralizing maternal antibodies, induced a clear and significant priming effect observed as early as 3 days after the subsequent booster with a conventional CDV vaccine. It was shown that the priming effect develops faster and to higher titers in puppies preimmunized with DNA 14 days after birth than in those vaccinated 28 days after birth. Our results demonstrate that despite the presence of maternal antibodies puppies can be vaccinated using the CDV DNA vaccine, and that this vaccination has a clear priming effect leading to a solid immune response after a booster with a conventional CDV vaccine.

Pre-exposure rabies vaccination: strategies and cost-minimization study

An alternative strategy for pre-exposure rabies vaccination to the institutional recommendations of the World Health Organization and the Centers for Disease Control and Prevention is proposed based on recent long-term follow-up of post-vaccinal seroconversion rates. The alternative strategy uses the same primary series (i.e. vaccination in the deltoid area on D0, D7, and D28), but is completed by a scheduled booster vaccination at D365. The frequency of recommended subsequent booster injections depends on the serological test results obtained by a RFFIT on D379 and 3 years later. The objective of this study was to compare the efficiency of the two pre-exposure strategies. A cost-minimization analysis was carried out to compare the two rabies pre-exposure vaccination and serological test strategies based on the data from two published studies on the long-term evolution of the immunity achieved using the different recommendations. For a theoretically equivalent immunogenicity, the cost of the alternative strategy ranged from 1.7 to 5.2 times lower than that of the institutional recommendations. A sensitivity analysis confirmed the robustness of the results. The alternative strategy should be validated externally under field conditions. This approach would compare its real efficiency to the institutional recommendations.

The role of T-cell-mediated mechanisms in virus infections of the nervous system.

T lymphocytes play a decisive role in the course and clinical outcome of viral CNS infection. Summarizing the information presented in this review, the following sequence of events might occur during acute virus infection: After invasion of the host and a few initial rounds of replication, the virus reaches the CNS in most cases by hematogeneous spread. After passage through the BBB, CNS cells are infected and replication of virus in brain cells causes activation of the surrounding microglia population. Moreover, local production of IFN-alpha/beta induces expression of MHC antigens on CNS cells, and microglial cells start to phagocytose cellular debris, which accumulates as a result of virus-induced cytopathogenic effects. Upon phagocytosis, microglia becomes more activated; they up-regulate MHC molecules, acquire antigen presentation capabilities and secrete chemokines. This will initiate up-regulation of adhesion molecules on adjacent endothelial cells of the BBB. Transmigration of activated T lymphocytes through the BBB is followed by interaction with APC, presenting the appropriate peptides in the context of MHC antigens. It appears that CD8+ T lymphocytes are amongst the first mononuclear cells to arrive at the infected tissue. Without a doubt, their induction and attraction is deeply influenced by natural killer cells, which, after virus infection, secrete IFN-gamma, a cytokine that stimulates CD8+ T cells and diverts the immune response to a TH1-type CD4+ T cell-dominated response. Following the CD8+ T lymphocytes, tissue-penetrating, TH1 CD4+ T cells contact local APC. This results in a tremendous up-regulation of MHC molecules and secretion of more chemotactic and toxic substances. Consequently an increasing number of inflammatory cells, including macrophages/microglia and finally antibody-secreting plasma cells, are attracted to the site of virus infection. All trapped cells are mainly terminally differentiated cells that are going to enter apoptosis during or shortly after exerting their effector functions. The clinical consequences and the influence of the effector phase on the further course of the infection depends on the balance and fine-tuning of the contributing lymphoid cell populations. Generally, any delay in the recruitment of effector lymphocytes to the tissue or an unbalanced combination of lymphocyte subsets allows the virus to spread in the CNS, which in turn will cause severe immune-mediated tissue effects as well as disease. If either too late or partially deficient, the immune system response may contribute to a lethal outcome or cause autosensitization to brain-specific antigens by epitope spreading to the antigen-presenting system in peripheral lymphoid tissue. This could form the basis for subsequent booster reactions of autosensitized CD4+ T cells--a process that finally will end in an inflammatory autoimmune reaction, which in humans we call multiple sclerosis. In contrast, a rapid and specific local response in the brain tissue will result in efficient limitation of viral spread and thereby a subclinical immune system-mediated termination of the infection. After clearance of virus-infected cells, downsizing of the local response probably occurs via self-elimination of the contributing T cell populations and/or by so far unidentified signal pathways. However, much of this is highly speculative, and more data have to be collected to make decisive conclusions regarding this matter. Several strategies have been developed by viruses to escape T cell-mediated eradication, including interference with the MHC class I presentation pathway of the host cell or "hiding" in cells which lack MHC class I expression. This may result in life-long persistence of the virus in the brain, a state which probably is actively controlled by T lymphocytes. Under severe immunosuppression, however, reactivation of viral replication can occur, which is a lethal threat to the host.

Induction of Genital Immunity by DNA Priming and Intranasal Booster Immunization with a Replication-Defective Adenoviral Recombinant

Mice immunized through different routes such as i.m., intradermally, or intratracheally with a DNA vaccine to rabies virus developed high titers of serum Ab but only borderline levels of mucosal Abs determined from vaginal secretions. DNA vaccines given by either route enhanced vaginal IgA and IgG2a secretion upon a subsequent intranasal booster immunization with an E1-deleted adenoviral recombinant expressing the same Ag of rabies virus. DNA vaccine priming reduced the Ab response to the adenoviral Ags and counterbalanced the impaired B cell response to the rabies virus Ag expressed by the adenoviral recombinant in mice preimmune to adenovirus. The vaginal B cell response could further be enhanced by using the Th2-type cytokines IL-4 or IL-5 as genetic adjuvants concomitantly with the DNA vaccine before intranasal booster immunization with the recombinant vaccine.

The effect of reconstitution of an Haemophilus influenzae type b-tetanus toxoid conjugate (PRP-T) vaccine on the immune responses to a diphtheria–tetanus-whole cell pertussis (DTwP) vaccine: a five-year follow-up

Controversial results have been obtained from previous studies on the combined administration of Haemophilus influenzae type b-tetanus toxoid conjugate (PRP-T) and diphtheria–tetanus-whole-cell pertussis (DTwP) combination vaccines, with regard to possible reciprocal interference between the constituent antigens. To document the priming effect and possible long-term immunogenic interference of PRP-T and DTwP combination vaccines, a randomized, double-blind, controlled study was conducted in Belgium. A total of 168 healthy infants received, at 3, 4 and 5 months of age, DTwP vaccine mixed just prior to injection either with PRP-T vaccine (group A, DTwP//PRP-T, N=85) or with placebo (group B, DTwP//Placebo, N=83). At the age of 14 months, children of both groups were randomized to receive either a dose of DTwP//PRP-T vaccine (subgroups A1 and B1) or a dose of Hib polysaccharide (PRP) vaccine (subgroups A2 and B2). Those children in subgroups A1 and B1 had an additional serum sample taken at the age of 5 years (at the time of a DT booster). The immune response to Hib polysaccharide at the age of 4, 5 and 6 months confirmed the excellent immunogenicity profile of PRP-T in infants. In addition, the vigorous anamnestic response (i.e. a 20-fold increase of GMT) to a booster dose of the plain capsular polysaccharide (PRP) reflected the efficient Hib-priming induced by the combined DTwP//PRP-T vaccine. Reconstitution of PRP-T with DTwP did not affect the immune response to diphtheria toxoid or pertussis agglutinins. Nevertheless, at almost any time point during the five-year follow-up, the tetanus antitoxin GMT values were significantly lower in the DTwP//PRP-T group (A and A1) than in the DTwP//Placebo group (B and B1). Despite the suppressive effect on GMT values, intergroup differences in rates of seroprotection were never significant, except after doses 2 and 3 for which there were lower percentages of children in group A with antitoxin titers >0.05 IU/mL and >1.0 IU/mL. In the group primed with the combined DTwP//PRP-T vaccine, (1) a DT booster dose at the age of 5 years provoked a 150-fold increase in tetanus antitoxin GMT, (2) a high tetanus antitoxin GMT value was attained (GMT=19.3 IU/mL) and (3) all children in this group had tetanus antitoxin titers >1.0 IU/mL, so it may be concluded that all these children will still be protected against tetanus until at least the age of the next recommended booster dose (i.e. the age of 15 years). No differences in the occurrence of adverse events were observed between the groups who received the DTwP//PRP-T vaccine or the DTwP//Placebo vaccine, both vaccines being associated with events customarily attributable to DTwP (data not shown). Our results indicate (1) that the combination vaccine, DTwP//PRP-T, represents a safe and effective alternative for the existing uncombined vaccines and (2) that the long-term effect of interference between the components of future combination vaccines should be studied with subsequent booster doses, followed by the evaluation of persistence of antibodies over several years.

Malaria vaccines: are seven antigens better than one?

Multicomponent vaccines containing a combination of antigens against Plasmodium falciparum derived from different stages of the parasite offer an immediate solution to the issue of which parasite stage to target and may circumvent the problems of antigenic variability. NYVAC-Pf7 an attenuated vaccine with seven P. falciparum genes inserted into its genome met the goal of inducing immune responses to multiple developmental stages of the parasite in studies in rhesus monkeys. However a phase I/IIa trial in human volunteers of low- and high-dose NYVAC-Pf7 and placebo produced disappointing results. 34 of the 35 volunteers who received NYVAC-Pf7 developed malaria after exposure to mosquitos infected with the P. falciparum 3D7 clone. On the other hand vaccination clearly primed individuals for increased antibody responses to the blood-stage antigens MSP-1 and AMA1 after the malaria challenge. Use of NYVAC-Pf7 to prime for subsequent booster immunizations with recombinant antigens has been suggested to increase the immune response. Before such a strategy is implemented the advantages of targeting multiple antigens and parasite stages require further study. For example it is possible that the best use of a multi-antigen vaccine may be the provision of antigenic variants of a single antigen.

Persistence of serum and salivary antibody responses after oral immunization with a bacterial protein antigen genetically linked to the A2/B subunits of cholera toxin.

Primary oral immunization of mice with a bacterial protein antigen genetically coupled to the A2 and B subunits of cholera toxin induced specific secretory immunoglobulin A and serum immunoglobulin G antibodies that persisted at substantial levels for at least 11 months. A subsequent single booster immunization did not further enhance the antibody responses. Long-term antibody persistence may be especially important in infections caused by common pathogens for which continuous immunity would be advantageous.

Rabies ribonucleocapsid as an oral immunogen and immunological enhancer.

The administration of rabies ribonucleocapsid (RNP) by oral as well as parenteral routes was found to prime specific T cells and elicit N-protein-specific antibodies. per os and intramuscular immunization led to the production of antibodies of the IgA and IgG isotypes, respectively. Mice primed orally with RNP produced significantly enhanced amounts of virus-neutralizing antibody, compared with non-immune controls, upon subsequent parenteral booster immunization with inactivated rabies virus. Thus oral immunization with rabies RNP primed cells capable of mediating a secondary systemic response to rabies virus. The results of experiments in which peptide and protein antigens were administered either physically coupled to or mixed with RNP indicate that RNP has an inherent capacity to enhance immune responses.

Immunological approach to inhibit formation of anti-antibodies to allo- and xenogeneic anti-T cell immunoglobulin.

Inhibitory anti-antibodies induced in patients by xenogeneic or even by humanized anti-T cell antibodies remain an unresolved problem. Mice also produce anti-antibodies following injection of xeno- or allogeneic anti-T cell antibodies. Here we report a principle based on sequentially applied anti-T cell antibodies generated in different species, which results in suppressed anti-antibody formation and prolonged immunosuppression. Thus, a single priming injection in mice of mouse (MmT1 or MmT5 differing by idiotype only) or of rat (RmT1) anti-mouse Thy-1 monoclonal antibodies (mAb) or of rat anti-mouse L3T4 + Ly-2 (RmCD4 + CD8) mAb suppressed anti-antibody formation against subsequent booster injections of one of the above antibodies, provided that they differed in species origin from the priming antibody. Correspondingly, a sixfold and longer prolongation of 50% survival of fully mismatched skin grafts was observed. Less or no anti-antibody suppression and little prolongation of graft survival was obtained if the 'first' and the 'second' (and following) antibody injections were of the same species, differing by iso- or idiotype only. Finally, the suppressive principle did not manifest itself at all if the initial antibody injection included both the first and second antibody. These findings are discussed with reference to earlier studies on hapten/carrier effects as well as on immunosuppression attributed to 'non-depleting' rat anti-CD4/CD8 T cell antibodies.

Hepatitis B vaccination and booster in predialysis patients: A 4-year analysis

Patients undergoing chronic haemodialysis are at increased risk for infection with hepatitis B virus (HBV), but response to currently available vaccines is suboptimal. We undertook a 4-year prospective study of the efficacy of hepatitis B vaccine in patients with renal insufficiency, who were not yet dialysis-dependent. A booster dose of Recombivax HB was given at 3 or 4 years to those whose antibody levels fell below a predetermined point. Progression to dialysis was associated with poorer initial response to vaccination compared with those remaining dialysis-independent, but response to booster immunization was favourable in both groups. It is concluded that immunization of predialysis patients and subsequent booster vaccine results in a more favourable antibody response than has been seen historically in haemodialysis patients. Local endemicity and cost of vaccine should be considered when determining the best strategy for HBV immunization of patients with chronic renal failure.

Clinical and immunologic studies of rapid venom immunotherapy in Hymenoptera-sensitive patients

A 2- to 5-hour regimen of rapid venom immunotherapy (RVIT) was administered to 33 patients with anaphylactic sensitivity to Hymenoptera venom in a hospital setting in which full emergency resuscitation equipment was available. The RVIT was administered as 10 increasing doses of each treatment venom every 10 to 15 minutes to achieve a final dose on day 1 of 58.55 μg per venom. Patients returned for booster venom injections of 60 μg on day 3, 70 μg on day 7, 80 μg on day 21, and 100 μg on day 35 after RVIT. Serial antigen-induced leukocyte histamine release studies were performed on day 1 in 10 patients before and after RVIT, as well as 3 1 2 months after initiation of RVIT. Of 33 patients, 32 achieved a cumulative venom dose on day 1 of at least 50 μg, and the entire group received a mean dose of 95.46 μg. Local reactions during RVIT occurred in 18 (55%) patients. Four patients (12%) experienced mild systemic reactions during or after completion of RVIT. Subsequent booster venom doses administered to 29 patients were well tolerated. A decrease in venom-induced leukocyte-histamine release from baseline was detected in three (30%) patients immediately after RVIT and in seven (70%) patients months after achieving maintenance doses. Cutaneous sensitivity decreased by at least one log 10 concentration in eight (32%) of 25 patients. Twenty-two natural re-sting events occurred in 12 (50%) of 24 patients surveyed after successful completion of RVIT, of whom seven identified the insect as one for which they had been treated. No systemic reactions were reported. Results of this study indicate that RVIT is a safe, alternative method of venom administration for patients who are at immediate risk for re-sting anaphylactic episodes.

Priming immune response to cholera toxin induced by synthetic peptides.

A systematic study has been conducted of the priming effect in the immunization against cholera toxin (CT). We demonstrate that a priming phenomenon can be achieved by synthetic peptides of the CT B subunit, leading (after a subsequent booster with a subimmunizing dose of the intact toxin) to an efficient anti-CT neutralizing antibody response. This effect is obtained even upon a single administration of a peptide conjugate and even by peptides that as such are not able to induce CT cross-reactive antibodies whatsoever. This effect is specific and dose dependent. A macromolecular carrier as well as an adjuvant are essential for the induction of anti-toxin response. In this respect, a totally synthetic priming agent, CTP3-poly(DL-alanyl)--poly(L-lysine), was adequate for an effective priming response. The specificity of the antibodies formed after the booster was mainly towards the whole CT molecule and only a small fraction of them were specific towards the peptide used for priming. The ability of synthetic peptides to prime the immune system towards a secondary stimulus with whole organism or native protein might be of general practical value, especially in endemic areas where the population is probably constantly exposed to a low level of a particular infectious agent. This exposure, which has no influence on the unprimed immune system, could serve as a booster in the case of individuals primed with an appropriate peptide, leading to a secondary immune response.

Suppression of antibody response to transfusions in rats by preconditioning with antibody-coated cells.

In a Lewis-BN rat model, the antibody response to transfused blood cells from strongly histoincompatible donors was suppressed by preincubation of blood with specific antidonor antiserum or broadly reactive heterologous antilymphocyte serum (ALS). Suppression was achieved even when excess antiserum was removed by washing prior to injection. The suppressive effect was dose-dependent. Broadly reactive ALS was even more effective than specific antidonor antiserum in inhibiting the primary antibody response. Lewis animals pretreated three times with ALS-coated BN blood showed no secondary antibody response against subsequent BN-blood booster injections. Our experiments may be relevant for the prevention of undesired sensitization to donor-specific transfusions prior to related donor kidney transplantation.

Levels of human and rat hypothalamic growth hormone-releasing factor as determined by specific radioimmunoassay systems.

Polyclonal antibodies to synthetic human pancreatic growth hormone-releasing factor [hpGRF(1-44)NH2] and rat hypothalamic growth hormone-releasing factor [rhGRF(1-43)OH] were produced in rabbits by injecting these weak immunogens, coupled to thyroglobulin and emulsified with complete Freund's adjuvant in the presence of activated charcoal, directly into the spleen. A subsequent booster injection by the conventional intramuscular route resulted in high-titer antibodies, which at a 1:20,000 dilution were used to develop highly sensitive and specific radioimmunoassays for these peptides. By using antibodies with an apparent Ka of 3.3 X 10(-12) (human) and 7.7 X 10(-11) (rat), the sensitivity of these assays in both human and rat was found to be less than 1 fmol. The antibody to hpGRF(1-44)NH2 is directed against the COOH-terminal region of the molecule, as shown by its crossreactivity with various hpGRF analogues: 140% with hpGRF(30-44)NH2; 1%-2% with hpGRF(1-37)OH, hpGRF(1-40)OH, and hpGRF(1-40)NH2; and none with hpGRF(1-29)NH2. Serial dilutions of human and rat hypothalamic extracts demonstrated parallelism with the corresponding species-specific standard and 125I-labeled tracer. There was no crossreactivity with other neuropeptides, gastrointestinal peptides, or hypothalamic extracts of other species. The hypothalamic content in fmol/mg (wet weight) of tissue was 3.6 +/- 0.2 for the human and 11.1 +/- 5.5 for the rat. Age-related changes in hypothalamic GRF content were present in rats, with a gradual increase from 2 to 16 weeks and a correlation between increasing body weight and GRF content. These radioimmunoassays will serve as important tools for understanding the regulation of growth hormone secretion in both human and rat.

Reversal of Neutropenia With Intravenous Gammaglobulin in Autoimmune Neutropenia of Infancy

AbstractIntravenous gammaglobulin (IVIgG) was used to treat autoimmune neutropenia of infancy in two males with repeated infections. The neutrophil count increased significantly in both patients with the initial IVIgG therapy; 1 patient went into remission. The neutrophil count in the other remained above baseline for 3 wk, and a subsequent booster infusion also caused the neutrophil count to increase. The patients have remained clinically well since their treatment began. Serial studies of antineutrophil antibody and serum lysozyme, performed to elucidate the mechanism of action, suggested decreased neutrophil destruction, perhaps by Fc receptor blockade, as well as decreased synthesis of antineutrophil antibody. Neutrophil function was not impaired after the neutrophil count increased. Many patients with immune neutropenia have a benign course, but those who have significant infections could be treated, acutely or prophylactically, with intravenous gammaglobulin.

Reversal of neutropenia with intravenous gammaglobulin in autoimmune neutropenia of infancy

Intravenous gammaglobulin (IVIgG) was used to treat autoimmune neutropenia of infancy in two males with repeated infections. The neutrophil count increased significantly in both patients with the initial IVIgG therapy; 1 patient went into remission. The neutrophil count in the other remained above baseline for 3 wk, and a subsequent booster infusion also caused the neutrophil count to increase. The patients have remained clinically well since their treatment began. Serial studies of antineutrophil antibody and serum lysozyme, performed to elucidate the mechanism of action, suggested decreased neutrophil destruction, perhaps by Fc receptor blockade, as well as decreased synthesis of antineutrophil antibody. Neutrophil function was not impaired after the neutrophil count increased. Many patients with immune neutropenia have a benign course, but those who have significant infections could be treated, acutely or prophylactically, with intravenous gammaglobulin.

Genetic Control of the Immune Response to Mammalian Myoglobins in Mice

Abstract The antibody response to the major chromatographic component IV of sperm whale myoglobin (MbIV) has been found to be under H-2-linked Ir gene control in several series of congenic resistant strains of mice on the C57BL/10, A, and DBA/2 backgrounds by using an assay which measures molar concentration of antibody independent of affinity. The H-2d and H-2s mice were high responders, whereas the H-2k, H-2b, and H-2q mice were low responders. High responsiveness was dominant in the (H-2d × H-2b)F1 cross. The genetic control was mapped to within the I (or S, G) regions by the low response of A.TL mice. The presence of two (or more) genes within this region controlling the response was indicated by the intermediate response of the B10.A, A/J, and B10.A(5R) strains, indicating at least one gene to the right of H-2K but left of I-C, tentatively called Ir-Mb-1, and at least one other to the right of I-E but left of H-2D (presumably in I-C), tentatively called Ir-Mb-2. The former of these was further mapped to the I-A subregion by the high responsiveness of the D2.GD mice (which are d in K and I-A and b elsewhere), virtually identical to that of the DBA/2 (H-2d) mice with which these are congenic. This last observation suggests that either Ir-Mb-1 can confer full responsiveness by itself, or that coupled complementation is active. In contrast, Ir-Mb-2 alone confers only intermediate responsiveness. Whether these genes control the response to different determinants on the myoglobin molecule remains the subject of further study. In addition, for a given H-2 haplotype, the response of A background mice was about 5-fold higher than that of B10 background mice. Thus, non-H-2-linked genes also control the level of response. All of the above levels of control, both H-2 and non-H-2 linked, appeared to operate both after a single immunization in complete Freund's and after two subsequent booster immunizations.

Clinical and Serological Responses to Plague Vaccine U.S.P.

Abstract : Twenty-nine volunteers were administered a basic inoculation and two booster doses of plague vaccine. Reactogenicity was determined following each dose of vaccine, and sera for serological tests were collected at selected intervals over a period of 390 days. The vaccine was found to be of low reactogenicity. Thirty days after the initial dose of vaccine, 86 per cent of the subjects produced detectable HA antibodies. Subsequent booster doses of vaccine stimulated increased production of HA antibody, which persisted longer with each successive dose. Individuals developing an HA antibody titer of 1:128 or greater had MPI values of 10 or less. CF antibody in low titer developed following the first and second booster doses of vaccine in 19 per cent and 17 per cent.

Synchronous Transfer of Beam from the NAL Fast Cycling Booster Synchrotron to the NAL Main Ring System

Beam from successive cycles of the 15-Hz booster synchrotron is stacked end to end in the main synchrotron with constant magnetic field. Beam already injected into the main ring is held in stationary rf buckets, and the rest field is determined by the circulating beam. To capture beam from subsequent booster cycles into the empty buckets in the main ring, the phase and frequency of the rf beam bunches in the booster are locked to the main ring rf system before beam is transferred. The magnetic fields in the booster and the main ring are regulated separately and tuned for the correct orbit radii and particle momentum. The azimuth of the beam circulating in the main ring is monitored by counting main ring rf cycles, and the beam transfer system is timed to inject beam from successive booster cycles in the correct sequence around the main-ring circumference.

γ-Globulin and Antibody Formation In Vitro

Summary The effect of whole body irradiation, administered on days 8 or 21 after a primary intravenous injection of BGG, on the ability to respond to a subsequent booster injection given at various intervals was studied in rabbits. It was found that late irradiation was followed by a permanent partial inhibition of the booster response, whereas early irradiation resulted in inhibition followed by a rapid recovery during the following week. This recovery was correlated with the destruction and reappearance of secondary nodules in the white pulp of the spleen. The cellular aspects of the various parameters of the irradiation effects are discussed.