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Background Within-host models describe the dynamics of immune cells when encountering a pathogen, and how these dynamics can lead to an individual-specific immune response. This systematic review aims to summarize which within-host methodology has been used to study and quantify antibody kinetics after infection or vaccination. In particular, we focus on data-driven and theory-driven mechanistic models. Materials PubMed and Web of Science databases were used to identify eligible papers published until May 2022. Eligible publications included those studying mathematical models that measure antibody kinetics as the primary outcome (ranging from phenomenological to mechanistic models). Results We identified 78 eligible publications, of which 8 relied on an Ordinary Differential Equations (ODEs)-based modelling approach to describe antibody kinetics after vaccination, and 12 studies used such models in the context of humoral immunity induced by natural infection. Mechanistic modeling studies were summarized in terms of type of study, sample size, measurements collected, antibody half-life, compartments and parameters included, inferential or analytical method, and model selection. Conclusions Despite the importance of investigating antibody kinetics and underlying mechanisms of (waning of) the humoral immunity, few publications explicitly account for this in a mathematical model. In particular, most research focuses on phenomenological rather than mechanistic models. The limited information on the age groups or other risk factors that might impact antibody kinetics, as well as a lack of experimental or observational data remain important concerns regarding the interpretation of mathematical modeling results. We reviewed the similarities between the kinetics following vaccination and infection, emphasising that it may be worth translating some features from one setting to another. However, we also stress that some biological mechanisms need to be distinguished. We found that data-driven mechanistic models tend to be more simplistic, and theory-driven approaches lack representative data to validate model results.

This paper describes a field trial involving 13 calves raised on a farm known to be endemic for Trichophyton verrucosum infection. Seven calves were immunized by subcutaneous inoculations with a crude ribosomal fraction (CRF) of T. verrucosum suspended in aluminium hydroxide as adjuvant. Six animals were sham-immunized with buffer suspended in the adjuvant and served as controls. Two injections were given: one at the age of 2 weeks and a second 2 weeks later. CRF was prepared from T. verrucosum cultures grown in a vitamin-enriched liquid medium. The fungal mat was disrupted mechanically and CRF was separated from the cell-free extract by differential ultracentrifugation. The CRF was characterized biochemically (RNA and protein content) and physically (electron microscopy). The protection induced by vaccination was assessed through a clinical follow-up of the animals to determine the presence and duration of dermatophyte infection following their exposure to a T. verrucosum -contaminated environment. Vaccination with the CRF resulted in a statistically significant decrease in the period during which clinical signs of dermatophytosis were observed (from a mean of 9.5 weeks to 3.7 weeks). To assess the humoral response, serum samples were taken before each vaccination and 2 weeks after the second inoculation. For the cell-mediated immune (CMI) response assessment, whole-blood samples were taken 2 weeks after the second vaccination. The presence of anti- T. verrucosum antibodies in the sera was determined by ELISA and the CMI response was assessed in vitro by the lymphocyte stimulation test. The results indicate that both the cell-mediated and humoral components of the immune system were stimulated by vaccination. The overall results of the present research indicate that the T. verrucosum CRF shows potential as a basis for the development of a vaccine against bovine tricophytosis.

This paper reports on a novel immunoadjuvant activity of liposomes. An influenza subunit preparation, containing the isolated viral surface antigens, was incorporated in a liposomal formulation. Administration of this vaccine to mice via the intranasal (i.n.) route resulted in a stimulated serum IgG response relative to the response to i.n. immunization with the antigen alone. In addition, the liposomal vaccine induced a secretory IgA (sIgA) response in the mucosa of the lungs and nasal cavity. Both serum IgG and sIgA responses persisted up to at least 21 weeks postimmunization. Immune stimulation was observed with negatively charged liposomes consisting of phosphatidylcholine (PC), cholesterol and dicetylphosphate (DCP), but not with zwitterionic liposomes, consisting of PC and cholesterol alone. Remarkably, for stimulation of serum IgG responses and induction of an sIgAsbesponse, liposomes could be simply mixed with the antigen. Moreover, i.n. administration of empty liposomes up to 48 h prior to i.n. immunization with the subunit antigen also resulted in immune stimulation, indicating that the liposomes did not exert their adjuvant effect by acting as a carrier for the antigen. The liposomal vaccine conferred protection against infection. It is concluded that liposomes, administered i.n., provide a promising adjuvant system for stimulation of antibody responses in general, and mucosal sIgA responses in particular.

Using conalbumin as a model antigen, we demonstrate in this paper that liposomal antigen differently influences the activation of the immune system depending on the mode of association of the antigen with the liposomal vehicle whether it is by encapsulation or surface linkage. This conclusion is based on in vivo data showing that encapsulated antigen induces a short-lasting response dominated by IgG1 production while surface-linked antigen has a longer-lasting effect characterized by increased production of IgM, IgG2a, IgG3 as well as of IgG1. The in vivo data were complemented by in vitro proliferation studies carried out on spleen cells or macrophage-depleted spleen cells obtained from mice sensitized in vivo and rechallenged in vitro on day 4 following sensitization. Rechallenge was carried out in the absence or presence of anti-IL1. The data indicate that, in contrast to what is generally observed in vivo, liposomes alone potentiate spleen cell proliferative response in a dose-dependent manner. This liposomal effect totally obscures the antigen-specific proliferation that was expected with encapsulated antigen without masking that induced by surface-linked antigen. The mode of antigen association also influences anti-cytokine responsiveness as demonstrated by the insensitivity of the surface-linked antigen response to the presence of anti-IL1 and the significantly decreased response observed with encapsulated antigen under identical conditions. The response to both liposomal antigenic formulations was almost totally abolished in adherent cell-depleted cultures. The overall results therefore suggest that encapsulated and surface-linked antigens activated different immune pathways.

Enteric disease remains one of the greatest causes of mortality and morbidity in both human and veterinary species. There has been a remarkable lack of success in vaccination to control mucosal disease and it is therefore apparent that novel strategies are required to achieve effective mucosal immunity. Basic studies described in this paper have addressed problems associated with antigen handling and the induction of an immune response in the intestine, and the subsequent dissemination of effector cells and molecules to intestinal and extra-intestinal submucosal regions. Effective induction of IgA responses is dependent on T-cell help and requires cognate interactions between T cells and B cells within organized gut-associated lymphoid tissue (GALT). The delivery of an IgA antibody response to mucosal sites is also a T cell dependent but antigen driven process. The normal route by which antigen is taken up by GALT is via the epithelial surface but antigen presented in this way via villus epithelial cells generates predominantly a suppressor response. Strategies designed to overcome this effect include the use of powerful adjuvants (such as cholera toxin, muramyldipeptide and phorbol esters), the use of immunogenic carriers, or delivery via liposomes, microspheres or genetically engineered viral or bacterial vectors. Alternatively, the feasibility of accessing GALT via the serosal surface by administration of intraperitoneal antigen in oil emulsion has been explored and a vaccine formulation (Auspharm (patent pending)) has been developed which is suitable for IP delivery in commercial applications.

Recombinant cholera toxin B subunit (rCTB) produced by Bacillus brevis carrying pNU212-CTB has been previously found to be a potent mucosal adjuvant to aluminium-non-adsorbed tetanus toxoid (nTT) and diphtheria toxoid (nDT) co-administered intranasally, and the possibility of needle-free inoculation of these vaccines with rCTB has been suggested. In this paper we examined the potentiality of rCTB as a mucosal adjuvant to aluminium-non-adsorbed yeast-derived recombinant hepatitis B surface antigen (rHBs) being a particulate antigen when administered intranasally with rCTB. In-house ELISA showed that a mixture of rHBs (1 or 5 microg) and rCTB (10 microg) elevated not only systemic responses but also mucosal immune responses at the nasal cavity, the lung, the saliva, the small intestine and the vagina against rHBs, and these could be further increased with higher doses of antigen. With antibody isotypes of IgG, there were equally high levels of serum HBs-specific IgG1, IgG2a and IgG2b antibodies and induction of mixed Th1- and Th2-type responses was considered to occur in combination of rHBs and rCTB. Serum anti-HBs titres in almost all mice obtained from sandwich EIA using a commercial kit were higher than 1000 milli-international units ml(-1) (mIU ml(-1)). These results show that rCTB is also very effective as a mucosal adjuvant for a particulate antigen like rHBs, as well as soluble antigens like nTT and nDT reported previously, suggesting the possibility of intranasal immunization with rHBs plus rCTB in humans.

This paper describes attempts to map the location of host-protective epitopes of a recombinant vaccine antigen by assessing the ability of truncated regions of the antigen to elicit protective immune responses in sheep. Sheep were immunised with three truncated regions (EG95-1, EG95-2 and EG95-3) of the hydatid vaccine antigen, EG95. These regions overlapped each other and corresponded to amino acids 1-70 (EG95-1), 51-106 (EG95-2) and 89-153 (EG95-3) of the full length recombinant protein. Each region elicited antibody which reacted with the parent antigen, although these reactivities were a small proportion of the level of reactivity generated by immunisation with the full length antigen. Antisera raised against each of the truncated proteins reacted with the native parasite antigen. In vaccination and parasite challenge trials in sheep, none of the truncated regions elicited significant protection against challenge infection or antibody which was lethal to the parasite in vitro. Antibodies from sheep immunised with the combination of all three overlapping truncations elicited a comparatively low but significant level of lysis of the parasite in vitro. These antigens did not inhibit anti-EG95 antibody reactivity with EG95 nor did they inhibit in vitro oncosphere killing induced by anti-EG95 antibodies. These results indicate that the major part of the immune response induced by EG95 vaccination is directed against conformational epitopes and that the host-protective epitope(s) is/are conformational.

This paper is concerned with the use of passive immunity for the prevention and treatment of infections from a historic perspective, particularly in regard to the research of Paul Ehrlich on diphtheria and that of O.T. Avery on pneumonia. It is timely to reexamine this matter, particularly in regard to virus infections, in view of the difficulties in developing antiviral drugs. In addition, specific antibodies can serve as an alternative therapy for antibiotic resistant microbes. It is worth recalling in the history of vaccine development that success in passive immunity has been the key element in devising a successful strategy to develop a vaccine to produce humoral immunity.

DNA vaccines have a demonstrated ability to induce humoral and cellular immune responses in animal models and humans. The technology, although it dates back to the 1950's, has had an insurgence of interest within the past few years following concurrent research papers. The basic technology is being applied broadly to viral, bacterial and parasitic infections. It has also been demonstrated that genes delivered via plasmid expression vectors result in expression of functional proteins in the inoculated host. Further, injection of plasmids encoding cytokine, chemokine or co-stimulatory molecules, also referred to as immunomodulatory plasmids can lead to the further expansion of this technology to include directed immunology. We have been developing DNA technology specifically with a focus as a vaccine against HIV-1 infection. We report that such vaccines can stimulate immune responses in a variety of relevant animal systems including humoral and cellular responses as well as the production of beta-chemokines. We describe that the beta-chemokines can both modulate the immune response induced by DNA vaccines and be modulated by the DNA vaccines in the murine and chimpanzee models as well as in humans.

In a previous work we selected montanide ISA720 (M-ISA720) among different adjuvants for the vaccination with a V3 loop based multi-epitope polypeptide TAB9. In this paper we present the evaluation of the toxicity and immunogenicity of this formulation in non-human primates. TAB9 in M-ISA720 was highly immunogenic in macaques (Macaca fascicularis) inducing antibodies against TAB9 in all animals after one inoculation and a strong anamnestic response after booster injections. Furthermore 97% of the V3 peptides included were recognized by TAB9 sera. No differences between doses of 200 microg and 1 mg of TAB9 in M-ISA720 were observed after four immunizations. Neutralizing antibodies against five HIV-1 isolates were detected in most animals. Animals remain healthy throughout the study and did not show lesions at the inoculation site.

A variety of experimental models have shown that immunization using the glutathione S-transferase from Schistosoma mansoni (Sm28GST) can induce protective immunity against this parasite. This immunity has been related to the production of Th2 type antibodies against the antigen in both mice and humans. The work presented in this paper describes the development of a mucosal immunization protocol using liposomes which is designed to promote production of specific antibodies of isotypes related to a Th2 immune response. The liposomes were multilamellar and composed of various synthetic phospholipid mixtures. The liposome vector was used to convey the Sm28GST antigen to gut associated lymphoid tissue. The association of the Sm28GST antigen with liposomes containing different lipid mixtures was initially studied. The degree of interaction of the antigen was found to increase with the hydrocarbon chain length of the lipids used. It was demonstrated that the protein was present on both the inner and the outer membranes of the liposome vesicles. It was also shown that the major epitopes of Sm28GST were accessible to specific antibodies, confirming a conservation of its main antigenic features. Additionally, enzymatic activity of the proteinlliposomes complex was also demonstrated, indicating a conservation of the tertiary structure of the protein. An optimal Sm28GST/liposome complex was established and administered orally to mice. This treatment resulted in both a mucosal and systemic immune response to the antigen Sm28GST. This was demonstrated by the detection of specific IgA in gut washes and specific IgG1, IgG2b in sera. Immunization by Sm28GST/liposome complex followed by challenge with parasite showed that Sm28GST given orally in these conditions bore protective activity. This last result opens the possibility of mucosal vaccination against schistosomiasis.