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Human immune response to a secondary immunization by the oral route was studied by enumerating specific antibody-secreting cells (ASC) in the peripheral blood, believed to reflect the local immune response in the mucosa. The volunteers had been immunized 1-2 years earlier with live Salmonella typhi Ty21a given orally as three doses of vaccine in enteric-coated capsules (3 x E); their ASC and serum antibody responses have been published. In the present study 17 of the same volunteers received one booster dose of the same vaccine (B-E). Specific ASC appeared in the blood of all volunteers after vaccination, peaked on day 5 and faded away thereafter so that on day 9 specific ASC were detected in only seven subjects. The ASC responses to the single booster dose were significantly higher than those to one dose in primary immunization and at least as high as those of the same volunteers to three doses in primary immunization. Serum antibody responses were not seen in any of the vaccinees after secondary immunization, whereas after primary immunization 60% of these subjects responded. This study shows the presence of immunologic memory also in respect of the human ASC response, and confirms the separate nature of ASC and serum response.
Healthy varicella zoster virus (VZV) immune subjects > 55 years old, were immunized with 4,000 PFU of Oka strain VZV live vaccine or a similar amount of heat-inactivated vaccine. A subset of each group was also immunized with tetanus toxoid (TT) 3 months before receiving the VZV vaccine. The live and inactivated VZV vaccine groups had similar ages, sex distribution, and previous immunity to VZV. The live and inactivated VZV vaccines elicited similar increases in the frequency in blood of VZV-specific T cells, in vitro interferon-gamma production, and serum antibody levels both 3 and 12 months after immunization. Individuals with the highest responder cell frequency (RCF) at entry had the highest postimmunization RCF following either vaccine. There was no correlation at entry between the RCF to TT or RCF to VZV. There was a weak (P = 0.05) correlation in the incremental response to TT and VZV among individuals who responded to both vaccines. Entry variables that did not correlate with the response included percent of T cells or the CD45R0 (memory) T cell subset in blood, serum antibody levels, or amount of interferon-gamma production. The results indicate that the inactivated vaccine is safe for VZV-immune subjects and boosts their antibody and T-cell responses as effectively as the live vaccine for at least 1 year following immunization.
The secondary immune response is one of the most important features of immune systems. During the secondary immune response, the immune system can eliminate the antigen, which has been encountered by the individual during the primary invasion, more rapidly and efficiently. Both T and B memory cells contribute to the secondary response. In this paper, we only concentrate on the functions of memory B cells. We explore a model describing the memory contributed by the specific long-lived clone which is maintained by continued stimulation with a small amount of antigens sequestered on the surfaces of the follicular dendritic cells (FDC). The behavior of the secondary response provided by the model can be compared with experimental observations. The model shows that memory B cells indeed play an important role in the secondary response. It is found that a single memory cell in a long-lived clone may not be long-lived. In the present note, the influences of relevant parameters on the secondary response are also explored.
Primary infection to Histoplasma capsulatum often results in a self-limited upper respiratory infection in humans; however, in immunocompromised hosts, disseminated infection can occur through reactivation of a previous infection. Since disseminated histoplasmosis has emerged as a difficult clinical entity to treat in individuals infected with HIV, it was of interest to study the mechanisms involved in maintaining an effective memory immune response. It has been previously shown in a murine model of disseminated histoplasmosis that IL-12, IFN-gamma, and TNF-alpha were important factors in mediating primary protection. To study whether these and other factors were involved in maintaining a protective immune response following secondary infection, normal C57BL/6 mice were first infected with a sublethal dose of H. capsulatum (1 x 10(5)) and then reinfected 3 wk later with a lethal dose of H. capsulatum (6 x 10(5)). Under these conditions, all mice developed an effective immune response with sterilizing immunity. Moreover, normal C57BL/6 mice treated with neutralizing Abs against either IL-12, TNF-alpha, or IFN-gamma, depleted of neutrophils or treated with aminoguanidine at the time of reinfection, maintained an effective immune response. The ability of animals to survive a secondary infection in the absence of IFN-gamma was verified by showing that IFN-gamma(-/-) mice previously immunized with H. capsulatum and treated with amphotericin B at the time of primary infection had prolonged survival following reinfection with a normally lethal dose. It was further shown that enhancement of TNF-alpha production in IFN-gamma(-/-) mice was the major mechanism by which these mice were effective in controlling secondary infection.
Normal adult outbred rabbits were immunized intravenously (iv) with sheep erythrocytes (SRBC). At varying times thereafter, the different lymphoid organs were investigated for spontaneous and culture-induced antibody secreting cells by the aqueous hemolytic plaque-forming cell (PFC) technique. During the phase of active antibody formation (Days 3 to 30), immediate PFC, indicative of spontaneous antibody synthesis and secretion, were detected principally in the spleen. In the early postimmune memory period (Days 30 to 90), memory cells capable of generating PFC following secondary immunization in in vitro culture with SRBC were detected only in the spleen. However, by 4 months postimmunization, memory cells were detected in the thymus and popliteal lymph node (PLN) as well as in the spleen. The number of memory cells in the thymus and PLN was significantly higher by 6 months postprimary iv immunization and was even further elevated by 9 months postprimary iv immunization. Following in vivo secondary immunization by the iv injection of SRBC 2 or 6 months postprimary immunization, immediate PFC were detected in large numbers in the spleen, the bone marrow, and the blood, marginally in the PLN and not at all in the thymus. Similar results were obtained at 9 months following primary immunization with SRBC with the exception that large numbers of immediate PFC were detected in the PLN following secondary iv immunization. Following culture of these lymphoid cells for 5 days in vitro with SRBC, the thymus and PLN cells, as well as the spleen cells, generated large numbers of PFC. Since immediate PFC were never detected among the freshly isolated thymus cells whereas thymic cell cultures 6 and 9 months postprimary iv immunization invariably generated large numbers of PFC following secondary immunization in vitro, the thymus memory cells would appear to be inaccessible to particulate antigen injected intravenously; they can only be detected following activation by the antigen in culture. The PFC generated by thymus memory cells (and spleen and PLN) were totally inhibited by the inclusion of sheep anti-rabbit IgG into the PFC assay. This finding demonstrates unequivocally that the plaques induced by thymus cells, just as the plaques induced by spleen and PLN cells, are antibody mediated and not false plaques. Therefore, the thymic PFC cells must be antibody-secreting B-memory cells since T cells do not synthesize or secrete immunoglobulins.
The effects of the cannabinoids delta 9-tetrahydrocannabinol (THC), cannabinol and cannabidiol on the primary humoral immune response, the secondary humoral immune response and the memory aspect of humoral immunity in response to sheep red blood cell (SRBC) immunization was investigated. Mice treated with THC (10 and 15 mg/kg) during the primary immunization period exhibited a suppression of the primary humoral immune response. Mice treated with THC during the secondary immunization period showed no measurable suppression of the secondary humoral immune response to the immunizing antigen. The memory aspect of humoral immunity was assessed when treatment with cannabinoids was carried out during the primary immunization period and the ability of mice to undergo a secondary immune response was evaluated; suppression of the secondary humoral immune response was evident with THC treatment (10 and 15 mg/kg). Cannabinol and cannabidiol (10 and 25 mg/kg) treated mice showed no impairment in the ability to undergo primary or secondary immune responses with any treatment protocol. In vivo investigations of the effects of cannabinoids on the thymus were also carried out. Thymus weight and thymus cell number were depressed in mice undergoing a primary humoral immune response when treated with THC (10 and 15 mg/kg) during this period. THC treatment, however, did not alter these parameters in mice not challenged with antigen. In both challenged and unchallenged animals, cannabinol and cannabidiol did not measurably alter the thymus.
The objective was to study the effect of natural pure honey on the antibody production against thymus-dependent antigen [sheep red blood cells (SRBCs)] and thymus-independent antigen (Escherichia coli) in mice. Forty-two mice (mean weight 28.33 +/- 3.44 g) were divided into two groups: group A (21 mice) fed regular diet and group B (21 mice) fed regular diet plus 0.8 g/kg of body weight/day of honey administered in four equally divided doses. Each animal was injected intraperitoneally with 0.1 mL of 5% SRBCs and 0.1 mL of killed E. coli. The same dose of both antigens was given after 17 days. At days 7 and 16 after primary immunization and at day 4 after secondary immunization, blood samples were collected from seven mice at each time interval from group A and group B to estimate antibody titer using the hemoaggulination test. At day 7 after primary immunization, the mean antibody titer against SRBCs was 9.14 +/- 3.02 in group A and 13.7 +/- 3.9 in group B (P < .05), while the mean antibody titer against E. coli was 14.8 +/- 8.5 in group A and 14.8 +/- 9.35 in group B. At day 16, the mean antibody titer against SRBCs was 13.71 +/- 3.9 in group A and 20 +/- 9.8 in group B, while the mean antibody titer against E. coli was 14.69 +/- 935 in group A and 26.67 +/- 8.26 in group B (P < .05). Four days after secondary immunization, the mean antibody titer against SRBCs was 13.33 +/- 4.62 in group A and 16 +/- 8.7 in group B, while the mean antibody titer against E. coli was 42.67 +/- 18.4 in group A and 69.33 +/- 31.4 in group B. It might be concluded that oral honey stimulates antibody production during primary and secondary immune responses against thymus-dependent and thymus-independent antigens.
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Primary and secondary immunizations with live, attenuated yellow fever virus vaccine (17D strain) were performed in order to study the course of appearance of virus-neutralizing antibodies and immunoglobulin M (IgM) and IgG antibodies directed against the virus and the interferon-dependent enzyme 2',5'-oligoadenylate synthetase (2',5'AS) activity, determined in homogenates of peripheral B and T lymphocytes. From cellular ATP, this enzyme generates 2',5'-oligoadenylates which mediate degradation of viral mRNA by stimulation of a latent RNase. By day 4 after the first immunization, the earliest and highest 2',5'AS activity was present in the T-lymphocyte fraction. By day 7, the enzyme activity was highest in the B-lymphocyte fraction. Virus-neutralizing antibodies appeared on day 7, and IgM antibodies were present on day 12. After the second immunization, performed 2 years +/- 2 months later, the only significant increase in 2',5'AS activity was observed in the T-lymphocyte fraction. Virus-neutralizing antibodies were present from day 1, whereas no IgM antibodies were detected. By day 12, 80% of the vaccines were IgG positive. In the primary and secondary (memory) immune responses, 2',5'AS activity is expressed in the T-lymphocyte fraction prior to the appearance of antibodies directed against the virus and may serve as an early and sensitive marker of an ongoing virus infection which is otherwise difficult to detect. No change in conventional laboratory analysis parameters, such as in differential blood cell counts or total IgA, IgG, and IgM, disclosed the immune activity in either the primary or the secondary immunization.
After secondary immunizations of rhesus(D)-negative male volunteers with Rh(D)-positive red cells, changes were found in the in vitro transformation and antibody-dependent cell-mediated cytotoxicity (ADCC) capacities of the volunteers' lymphocytes. Responders, who produced anti-D, showed marked depressions of ADCC which were not found in non-responders. Responders and non-responders in general showed similar changes in lymphocyte transformation. The relationships between altered lymphocyte functions following immunization, immunoregulatory activity and responsiveness to the Rh(D) antigen are discussed.
The localization of antigen (chicken serum albumin) and specific antibodies in sections from the spleens of rabbits after primary and secondary immunization was studied by means of histoautoradiography. After primary immunization, both antigen and antibodies were demonstrated in the lymphoid follicles consistently between 3 and 42 days after injection. Antigen was detected in addition in the marginal zone on the 5th day, and antibody-forming cells in the marginal zone and periarteriolar lymphocyte sheaths between 3 and 9 days after immunization. After secondary immunization, follicular antigen trapping was detected as early as 2 hours after injection, reaching a peak in the follicles and marginal zone on the 3rd day after immunization. At later periods of time the presence of antigen in the follicles was less prominent than that of specific antibodies. The numbers of antibody-forming cells were 10-100-fold higher in the secondary than in the primary response. The findings are discussed in relation to the role of antigen-antibody complex in the lymphoid follicles in the development of the capacity to produce the secondary type of immune response.
The benefit of re-immunization with pneumococcal polysaccharide vaccine is an important question in clinical practice. In an experimental model, BALB/c and CBA/J mice were re-immunized s.c. with a 23-valent pneumococcal polysaccharide vaccine at various time intervals after a first immunization with the same vaccine. The antibody response after the secondary immunization showed similar kinetics as after primary immunization, and was mainly an IgM antibody response. Re-immunization at 28 days or earlier induced a decrease in the serum antibody levels to the vaccine. Reimmunization at 120 days or later induced higher antibody levels than after the first immunization. Significant increases in antibody levels to serotypes 1, 4, 7F and 19F out of six serotypes tested were observed. In CBA/J mice, but not in BALB/c mice, the dose used for primary immunization appeared to influence the magnitude of the antibody response to secondary immunization. Our results indicate that the time interval between primary and secondary immunization is an important determinant with regard to the magnitude of the antibody response to re-immunization with pneumococcal polysaccharide vaccine.
Serological evidence indicates that measles virus (MV) could circulate in seropositive, fully protected populations. Among individuals fully protected against disease, those prone to asymptomatic secondary immune response are the most likely to support subclinical MV transmission. The serological characteristics of protected subjects who developed secondary immune response after reexposure to measles have been described recently [Huiss et al. (1997): Clinical and Experimental Immunology 109:416-420]. On the basis of these data, a threshold of susceptibility was defined to estimate frequencies of secondary immune response competence in different populations. Among measles, late convalescent adults (n = 277) and vaccinated high school children (n = 368), 3.2-3.9% and 22.2-33.2%, respectively, were considered susceptible to secondary immune response. A second vaccination did not seem to lower this incidence. Even when estimates of symptomatic secondary immune response (e.g., secondary vaccine failure) were taken into account, susceptibility to subclinical secondary immune response was still 5-8 times higher after vaccination than after natural infection. Although viral transmission between protected individuals has never been directly demonstrated, the data describe a population in which protected but infectious persons could potentially be of epidemiological importance.
The production of anti-tetanus toxoid antibody and rheumatoid factor (RF) by individual peripheral blood mononuclear cells (PBMC) was studied at various times after booster immunization of healthy volunteers with tetanus toxoid (TT). TT-specific antibody-secreting cells and RF-secreting cells were assayed by the enzyme-linked immunospot (ELISPOT) assay. Cells obtained 5-9 days after immunization were found to spontaneously secrete TT-specific antibodies. This response was specific for the immunogen, was abrogated by cycloheximide and accounted for most of the immunoglobulins produced. TT-specific antibody-secreting cells were found concomitantly with cells secreting RF, mainly of the IgM isotype. Elevated levels of circulating immune complexes (CIC) containing IgG and C3 were observed shortly before the appearance of both TT-specific antibody-secreting cells and IgM RF-secreting cells. Thus, after booster immunization with TT, two major subpopulations of immunoglobulin-secreting cells appear concomitantly in the peripheral circulation: a population of cells secreting TT-specific antibody and a population of cells secreting IgM RF. It is suggested that RF production in man represents a physiological event which might be triggered by IgG-containing immune complexes formed during a secondary immune response.
In the present experiments, the secondary immune response against antigens is studied after priming with liposome associated antigens and booster injections with the antigen alone, in order to study the effect of liposomes on the generation of immunological memory against the associated antigens. Liposomes show adjuvant activity with respect to both the primary and secondary immune response against associated human serum albumin (HSA). When the injected dose of liposome associated HSA was too low to elicit a primary immune response, generation of immunological memory against the antigen could not be detected. Horse radish peroxidase (HRP) associated with liposomes did not elicit a primary immune response, but immunological memory against the antigen was established.
Stimulatory effects of several types of adjuvants on secondary antibody response to inactivated Newcastle disease virus (iNDV) were examined in chickens. For this purpose, animals were primed with iNDV without adjuvant resulting in a low but significant antibody response, boosted with iNDV plus adjuvant 3 weeks later, and analysed for specific antibody titres in serum 3 weeks after the booster. Water-in-mineral oil emulsion (W/O) caused significant increase in antibody titres measured in an indirect enzyme-linked immunosorbent (ELISA), haemagglutination inhibition (HI), and virus neutralisation (VN) assay. The adjuvants tested included three oil-in-water emulsions (i.e. mineral oil-in-water, sulpholipo(SL)-Ficoll400/squalane-in-water and sulpholipo-cyclodextrin/squalane-in-water), three negatively-charged polymers with high molecular weight (i.e. polyacrylate, polystyrenesulphonate and sulpho(S)-Ficoll400) and two surface-active agents (i.e. dimethyldioctadecylammonium bromide (DDA) and Quil A). These adjuvants enhanced significantly the secondary immune response but none reached the titre obtained with W/O. Combinations of adjuvants with distinct physicochemical properties, i.e. polyacrylate and DDA revealed only slight, beneficial effects. We concluded that the various types of adjuvants tested can stimulate secondary immune responses in primed animals but that W/O is superior.
The kinetics of the reactive cell clones after primary and secondary immunization with SRBC1) modified by cyclophosphamide and a newly synthesized cyclophosphamide analogue 036.5122 (Asta), have been studied. After primary immunization, both substances caused a severe and dose dependent depletion of 19 S PFC2). The 7 S PFC in the late primary response were only slightly inhibited by cyclophosphamide in low dose ranges, indicating, that sensitization could not be prevented by this substance. In contrast, 0.36.5122 was fully able to suppress 7 S PFC. Thus, treatment with 0.36.5122 after primary immunization can fully prevent the expression of the specific response. Experiments dealing with inhibition of a secondary immune response revealed that both test substances were able to strongly suppress the 19 S as well as the 7 S PFC. In general, 036.5122 demonstrates a higher suppressive potency, and the timing of its application for optimal suppression is less delicate than that of cyclophosphamide. 036.5122 was equally well inhibitory, whether given directly before or after antigenic challenge. The hypothesis is discussed, whether the immunosuppressive effect of 036.5122 given before antigenic challenge in the secondary immune response is due to cytotoxic damage of antigen reactive clones stimulated by persisting antigen.