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According to recent regulatory guidance, clinical trial objectives should be translated into estimands, i.e., precise descriptions of that what is to be estimated. Hence, estimands are to be formulated for influenza vaccine immunogenicity (IVI) trials, notably for one of the most popular immunogenicity trials, the non-inferiority trial. In this paper an estimand for this trial design is proposed. An estimand should state how intercurrent events are handled. Intercurrent events are events that occur after the start of the trial and that affect the endpoint's measurement or interpretation or prevent its observation. In IVI trials the intercurrent events of interest are immunological intercurrent events (IIEs). Major IIEs are identified, i.e., protocol deviations occurring during the trial that affect immunogenicity endpoints, and the consequences for the trial data collection are discussed. In the statistical analysis endpoint values that are missing or excluded from the analysis due to IIEs are to be substituted by plausible values, by means of multiple imputing. Replacing values are based on predictors of the endpoint. A distinction is made between mandatory and non-mandatory predictors. Mandatory predictors are predictors necessary to prevent biased prediction. Non-mandatory predictors are predictors that limit the additional variance due to the imputing. The four steps of the multiple imputing are explained, and available software is listed. [ABSTRACT FROM AUTHOR]

• HIV+ individuals are an important subpopulation in areas at risk of an Ebola outbreak. • The Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine regimen induced antibodies that persisted 4·5 years. • Ad26.ZEBOV booster dose is safe and highly immunogenic in previously immunized HIV+ adults. • Ad26.ZEBOV boosters can be deployed safely to HIV+ adults with well-controlled infection. People living with HIV constitute an important part of the population in regions at risk of Ebola virus disease outbreaks. The two-dose Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine regimen induces strong immune responses in HIV-positive (HIV+) adults but the durability of this response is unknown. It is also unclear whether this regimen can establish immune memory to enable an anamnestic response upon re-exposure to antigen. This paper describes an open-label, phase 2 trial, conducted in Kenya and Uganda, of Ad26.ZEBOV booster vaccination in HIV+ participants who had previously received the Ad26.ZEBOV, MVA-BN-Filo primary regimen. HIV+ adults with well-controlled infection and on highly active antiretroviral therapy were enrolled, vaccinated with booster, and followed for 28 days. The primary objectives were to assess Ad26.ZEBOV booster safety and antibody responses against the Ebola virus glycoprotein using the Filovirus Animal Non-Clinical Group ELISA. The Ad26.ZEBOV booster was well-tolerated in HIV+ adults with mostly mild to moderate symptoms. No major safety concerns or serious adverse events were reported. Four and a half years after the primary regimen, 24/26 (92 %) participants were still classified as responders, with a pre-booster antibody geometric mean concentration (GMC) of 726 ELISA units (EU)/mL (95 %CI 447–1179). Seven days after the booster, the GMC increased 54-fold to 38,965 EU/mL (95 %CI 23532–64522). Twenty-one days after the booster, the GMC increased 176-fold to 127,959 EU/mL (95 %CI 93872–174422). The responder rate at both post-booster time points was 100 %. The Ad26.ZEBOV booster is safe and highly immunogenic in HIV+ adults with well-controlled infection. The Ad26.ZEBOV, MVA-BN-Filo regimen can generate long-term immune memory persisting for at least 4·5 years, resulting in a robust anamnestic response. Trial Registration: Pan African Clinical Trial Registry (PACTR202102747294430). Clinicaltrials.gov (NCT05064956). [ABSTRACT FROM AUTHOR]

• Heterologous mRNA boost following GLS-5310 DNA vaccination was well tolerated. • Neutralizing antibody responses were enhanced 110 fold to GMT of 1244.8. • Binding antibody responses were enhanced 1,187-fold to GMT of 405,920. • Boosted antibody responses similar to other vaccine combinations. • Boosted T cell responses were many-fold higher than other vaccine combinations. Heterologous boost regimens are being increasingly considered against SARS-CoV-2. We report results for the 32 of 45 participants in the Phase 1 CoV2-001 clinical trial (Kim et al., Int J Iinfect Dis 2023, 128:112–120) who elected to receive an EUA-approved SARS-CoV-2 mRNA vaccine 6 to 8 months following a two-dose primary vaccination with the GLS-5310 bi-cistronic DNA vaccine given intradermally and followed by application of suction using the GeneDerm device. Receipt of EUA-approved mRNA vaccines after GLS-5310 vaccination was well-tolerated, with no reported adverse events. Immune responses were enhanced such that binding antibody titers, neutralizing antibody titers, and T-cell responses increased 1,187-fold, 110-fold, and 2.9-fold, respectively. This paper is the first description of the immune responses following heterologous vaccination with a DNA primary series and mRNA boost. [ABSTRACT FROM AUTHOR]

• Ormutivimab is the third recombinant human anti-rabies monoclonal antibody marketed in the world. In China, it is the first. • The study reported in this paper is the first phase IIb clinical study carried out in China. It further evaluates the activity, safety and immunogenicity of Ormutivimab combined with rabies vaccine, and recommends a reasonable dosage for phase III confirmatory clinical study. • In this study, the activity and safety of Ormutivimab combined with rabies vaccine were compared with that of commercial HRIG combined with vaccine and vaccinated alone. • In this study, the effects of different doses of Ormutivimab on active immunization of rabies vaccine were evaluated and compared with that of commercially available HRIG. • This study evaluated the dose correlation of Ormutivimab immunogenicity (anti-antibody) and the effect of anti-antibody on the activity. This study was a randomized, double-blind, parallel-controlled trail to evaluate the rabies virus neutralizing activity（RVNA）, safety and immunogenicity of Ormutivimab + rabies vaccine in Chinese healthy adults. Subjects were randomly and equally assigned to 4 groups (20 IU/kg Omtv + vaccine, 40 IU/kg Omtv + vaccine, 20 IU/kg HRIG + vaccine, and placebo + vaccine). Subjects received vaccine as the WHO Essen regime combined with Omutivimab、HRIG or placebo on Day 0. The study lasted for 43 days. A total of 240 subjects were simultaneously assigned to both FAS and SS. Fifty subjects with baseline RVNA > 0.05 IU/ml (detection limit) were excluded, 190 were included into mITT. All the subjects from 40 IU/kg Omtv + vaccine group had a protection level of RNVA (≥0.5 IU/ml, WHO) on Day 14, and those in 20 IU/kg Omtv + vaccine group and placebo + vaccine group converted positive 100 % on Day 28. In contrast to 20 IU/kg HRIG + vaccine and placebo + vaccine, Ormutivimab + vaccine provided a higher RVNA during Days 0 to 7. And RVNA in 40 IU/kg Omtv + vaccine and 20 IU/kg Omtv + vaccine groups were always higher than 20 IU/kg HRIG + vaccine group during the whole study. Although anti-Omtv antibody were detected in some subjects, it did not influence the RVNA. The incidence of adverse reactions was significantly lower in 20 IU/kg Omtv + vaccine group (17.2 %) than in 40 IU/kg Omtv + vaccine (36.7 %) and 20 IU/kg HRIG + vaccine groups (40.3 %). Compared with HRIG + vaccine and placebo + vaccine, Omtv + vaccine provided higher RNVA for earlier immune protection. The interference of Ormutivimab on the long-term immune protection induced by rabies vaccine is weaker than HRIG. At the same dose, the adverse reactions of Omtv + vaccine group were less than HRIG + vaccine group. Registration: ClinicalTrials.gov #NCT02559921. [ABSTRACT FROM AUTHOR]

• OMVs from Bordetella bronchiseptica elicit immune responses in macrophages. • Host Defense Peptides modulate the immune responses differently for sOMV and hOMVs. • Signaling via human TLRs hTLR2, hTLR4, hTLR5 and hTLR9 is stimulated by OMVs. • hTLR2- and hTLR4-mediated signaling can be downregulated by LL-37 and K9CATH. • Uptake of OMVs plays a minimal role in eliciting an immune response in macrophages. Antibiotic resistance is increasing and one strategy to prevent resistance development is the use of bacterial vaccines. For Gram-negative bacteria, natural outer membrane vesicles (OMVs) could be used for vaccine development. These vesicular structures are naturally produced by all Gram-negative bacteria and contain several antigens in their native environment. However, despite that the presence of lipopolysaccharide (LPS) may aid as intrinsic adjuvant, there is a risk that it may also cause undesired immune responses. Therefore, molecules to dampen LPS-induced toll-like receptor (TLR) 4 activation may be needed. Here host defense peptides (HDPs), like cathelicidins, can play an important role. They have been shown to interact with LPS and thereby neutralize LPS-induced TLR4 activation. However, there is currently no knowledge about neutralization in an OMV-based setting. Therefore, in this paper the immune modulating capacity of HDPs was investigated after macrophage stimulation with either spontaneous or heat-induced B. bronchiseptica OMVs. This revealed that the cathelicidins LL-37, CATH-2, PMAP-36 and K9CATH were able to modulate immune responses. Interestingly, immune modulation by these cathelicidins was different for spontaneous compared to heat-induced OMVs. Interaction studies revealed that the mode of binding of cathelicidins to OMVs slightly differed between OMV classes. Furthermore, TLR screening revealed that TLR2, 4, 5 and 9 were involved in stimulation of macrophages by OMVs, with TLR4-mediated activation being the most important pathway. Uptake of OMVs did not play a major role in macrophage activation. Taken together, this study shows how OMVs can activate macrophages and how cathelicidins may modulate these immune responses. [ABSTRACT FROM AUTHOR]

Vaccines against bovine babesiosis must, ideally, induce a humoral immune response characterized by neutralizing antibodies against conserved epitopes and a cellular Th1 immune response. In Babesia bovis , proteins such as AMA-1, MSA-2c, and RAP-1 have been characterized and antibodies against these proteins have shown a neutralizing effect, demonstrating the implication of B and T-cell epitopes in the immune response. There is evidence of the existence of B and T-cell epitopes in these proteins, however, it remains to be defined, the presence of conserved peptides in strains from around the world containing B and T-cell epitopes, and their role in the generation of a long-lasting immunity. The aim in this paper was to identify peptides of Babesia bovis AMA-1, MSA-2c, and RAP-1 that elicit a neutralizing and long-lasting Th1 immune response. Peptides containing B-cell epitopes of AMA-1, MSA-2c and RAP-1, were identified. The immune response generated by each peptide was characterized in cattle. All peptides tested induced antibodies that recognized intraerythrocytic parasites, however, only 5 peptides generated neutralizing antibodies in vitro : P2AMA-1 (6.28%), P3MSA-2c (10.27%), P4MSA-2c (10.42%), P1RAP-1 (32.45%), and P4RAP-1 (36.98%). When these neutralizing antibodies were evaluated as a pool, the inhibition percentage of invasion increased to 52.37%. When the T cellular response was evaluated, two peptides: P3MSA2c and P2AMA1 induced a higher percentage (>70%) of activated CD4 +/CD45RO+ T cells than unstimulated cells. Additionally, both peptides induced the production of gamma interferon (IFN−) in PBMCs from vaccinated cattle after one year proving the implication of a long-lasting Th1 immune response. In conclusion, we identified conserved peptides containing B and T-cell epitopes in antigens of B. bovis that elicit a Th1 immune response and showed evidence that peptides from the same protein elicit different immune responses, which has implication for vaccine development in bovine babesiosis. [ABSTRACT FROM AUTHOR]

• RSV neutralization assays are complex biological assays used for measurement of functional antibody responses. • A broad variety of RSV neutralization assay formats are currently in use. • Use of the 1st International Standard for Antiserum to RSV is necessary to harmonize neutralization assay output across formats. • This paper outlines good practices for key assay components and data analysis to promote the quality and consistency of RSV neutralization assay results. Respiratory syncytial virus (RSV) is a leading cause of respiratory illness among children and infants worldwide, yet no licensed vaccine exists to reduce the risk of disease. At least 16 RSV vaccine candidates are currently in clinical development and many are designed to induce robust virus neutralizing immune responses. RSV neutralizing antibody (nAb)-mediated interventions such as intravenous immunoglobulin (IVIG) and palivizumab provide passive protection against serious lower respiratory tract disease due to RSV, validating nAbs as a correlate of protection. To identify correlates of protection for vaccine candidates that have demonstrated their protective efficacy, an investigator can use assays designed to measure nAb responses. However, there is no standard method of measurement; individual laboratories have developed their own methods to measure the ability of nAbs to reduce the infectivity of a defined virus dose in a variety of cell lines, leading to establishment of the broad variety of RSV neutralization assay formats currently in use. Standardizing the RSV neutralization assay is an essential step toward better assessment of nAb responses to vaccine candidates. Use of a common reference standard by all makes comparing the immunogenicity of different vaccine candidates feasible. In the context of vaccine development, the WHO 1st International Standard for Antiserum to RSV (RSV IS) has been shown to be suitable for harmonizing results across laboratories and assay formats used to measure nAb titers to RSV/A and RSV/B in human sera. This review describes the broad variety of RSV virus neutralization assay formats currently in use and the importance of the RSV IS for harmonization of results across formats and across laboratories. It also outlines good practices for key assay components and data analysis to promote the quality and consistency of measuring RSV nAb titers in serum specimens. [ABSTRACT FROM AUTHOR]

Reverse Cumulative Distribution Curves (RCDCs) have proven to be a useful tool in summarizing immune response profiles in vaccine studies since their introduction by Reed, Meade, and Steinhoff (RMS) (1995). They are able to display virtually all of the treatment data and characterize summary statistics such as means or even their confidence intervals (CIs) that might be obscure. RMS mentioned their similarity to survival curves often used to summarize time-to-event data which are usually not normally distributed. The RCDCs, while intuitively pleasing and useful, contain important properties which allow for more powerful statistical applications. In this paper, we will suggest several widely used rank-based tests to compare the curves in the context of vaccine studies. These rank-based tests allow for comparisons between treatments, for stratified analyses, weighted analyses, and other modifications that make them the alternative of parametric analyses without the normality assumptions. Clinical trial identification: NCT01712984 and NCT01230957. [ABSTRACT FROM AUTHOR]

In conjugate, inactivated, recombinant, and toxoid vaccines, adjuvants are extensively and essentially used for enhanced and long-lasting protective immune responses. Depending on the type of diseases and immune responses required, adjuvants with different design strategies are developed. With aluminum salt-based adjuvants as the most used ones in commercial vaccines, other limited adjuvants, e.g. , AS01, AS03, AS04, CpG ODN, and MF59, are used in FDA-approved vaccines for human use. In this paper, we review the uses of different adjuvants in vaccines including the ones used in FDA-approved vaccines and vaccines under clinical investigations. We discuss how adjuvants with different formulations could affect the magnitude and quality of adaptive immune response for optimized protection against specific pathogens. We emphasize the molecular mechanisms of various adjuvants, with the aim to establish structure-activity relationships (SARs) for designing more effective and safer adjuvants for both preventative and therapeutic vaccines. [ABSTRACT FROM AUTHOR]

In our previous study, ten candidate proteins have been identified with immunogenicity and protection against Vibrio anguillarum in flounder ( Paralichthys olivaceus ). Among them, FlaC is the important outer protein in the flagellum with immunogenicity; VAA, OmpK and OmpR are protection proteins against V. anguillarum . In this paper, FlaC supplemented with VAA, OmpK or OmpR as bivalent subunit vaccine candidates, and their immune response of flounder and protective effects were evaluated, respectively. Recombinant(r) proteins of FlaC were mixed with rVAA, rOmpK and rOmpR, respectively, rVAA + rFlaC (AF), rOmpK + rFlaC (KF) and rOmpR + rFlaC (RF); formalin-killed cells (FKC) or PBS were injected to flounder, respectively. After immunization, the percentages of CD3 + T lymphocytes and surface membrane immunoglobulin-positive (sIg + ) B lymphocytes in peripheral blood lymphocytes (PBLs), total antibodies (TA), specific antibodies against V. anguillarum (VA), specific antibodies against bivalent recombinant proteins (PA), the expression of immune-related genes and relative percent survivals (RPS) were measured, respectively. The results showed that three bivalent vaccines candidates and FKC could induce the proliferation of sIg + B lymphocytes and CD3 + T lymphocytes in PBLs. The TA, VA and PA induced in bivalent vaccines candidates and FKC groups were significantly higher than that of the control group. CD3, IgM, CD4-1, CD4-2, CD8α and CD8β genes were up-regulated. After challenge with V. anguillarum , RPS in AF, KF, RF and FKC groups exhibited 62.6 ± 2.33%, 78.95 ± 3.01%, 75.45 ± 0.97%, and 56.71 ± 2.15% respectively. The results revealed that three bivalent vaccines candidates and FKC could induce the immune response in flounder, and have good protection against V. anguillarum , and KF can be an efficient bivalent subunit vaccine candidate. [ABSTRACT FROM AUTHOR]

Haemophilus parasuis ( H. parasuis ) is the etiological agent of swine Glässer’s disease, which leads to significant economic loss in swine industry over the world. Subunit vaccine based on outer membrane protein is one of the promising choices to protect pigs against H. parasuis infection despite low immunity efficiency. In this paper, outer membrane protein 16 (Omp16) of H. parasuis encapsulated by alginate-chitosan microspheres as antigen carriers was explored for the first time in a mouse model. Our results showed that the microspheres with Omp16 induced significant higher H. parasuis -specific antibodies, and higher titers of IL-2, IL-4, and IFN-γ than those by Omp16-FIA in treated mice ( p < 0.05). Moreover, H. parasuis load in the tissues from liver, spleen, and lung of mice immunized with microspheres containing Omp16 was significantly decreased ( p < 0.05) than that in the same counterpart tissues of control groups. In addition, 80% mice treated with Omp16 and 70% mice with Omp16-FIA were survived after challenged with H. parasuis virulent strain LY02 (serovar 5). Therefore, Omp16-based microsphere vaccine induces both humoral and cellular immune responses and provides promising protection against H. parasuis infection in mice. [ABSTRACT FROM AUTHOR]

Background The evaluation of durable immune responses is important in HIV vaccine research and development. The efficiency of such evaluation could be increased by incorporating predictors of the responses in the statistical analysis. In this paper, we investigated whether and how baseline demographic variables and immune responses measured two weeks after vaccination predicted durable immune responses measured six months later. Methods We included data from seven preventive HIV vaccine regimens evaluated in three clinical trials: a Phase 1 study of four DNA, NYVAC and/or AIDSVAX vaccine regimens (HVTN096), a Phase 2 study of two DNA and/or MVA vaccine regimens (HVTN205), and a Phase 3 study of a single ALVAC/AIDSVAX regimen (RV144). Regularized random forests and linear regression models were used to identify and evaluate predictors of the positivity and magnitude of durable immune responses. Results We analyzed 201 vaccine recipients with data from 10 to 127 immune response biomarkers, and 3–5 demographic variables. The best prediction of participants’ durable response positivity based on two-week responses rendered up to close-to-perfect accuracy; the best prediction of participants’ durable response magnitude rendered correlation coefficients between the observed and predicted responses ranging up to 0.91. Though prediction performances differed among biomarkers, durable immune responses were best predicted by the two-week response level of the same biomarker. Adding demographic information and two-week response levels of different biomarkers provided little or no improvement in the predictions. Conclusions For some biomarkers and for the vaccines we studied, two-week post-vaccination responses can well predict durable responses six months later. Therefore, if immune response durability is only assessed in a sub-sample of vaccine recipients, statistical analyses of durable responses will have increased efficiency by incorporating two-week response data. Further research is needed to generalize the findings to other vaccine regimens and biomarkers. Clinicaltrials.gov identifiers: NCT01799954 , NCT00820846 , NCT00223080 . [ABSTRACT FROM AUTHOR]

Background In the elderly, traditional influenza inactivated vaccines are often only modestly immunogenic, owing to immunosenescence. Given that adjuvantation is a means of enhancing the immune response, the trivalent inactivated vaccine adjuvanted with MF59 (MF59-TIV) was specifically designed to overcome this problem. Considering that, for ethical reasons, the absolute effectiveness of an influenza vaccine in the elderly cannot be demonstrated in placebo-controlled studies, the present study aimed to assess the effectiveness of MF59-TIV in preventing influenza-related outcomes in the elderly. Methods We conducted a systematic review of observational studies aimed at evaluating the effectiveness of MF59-TIV against influenza-related outcomes. Results of single studies were pooled whenever possible. Results Of the 1993 papers screened, 11 (6 case-control, 3 cohort and 2 prospective case-control) studies were identified. Hospitalization due to pneumonia/influenza and laboratory-confirmed influenza were reported in more than one study, while other outcomes (influenza-like illness, cardio- and cerebrovascular accidents) were investigated only by one study each. Pooled analysis of four case-control studies showed an adjusted MF59-TIV effectiveness of 51% (95% CI: 39–61%) against hospitalizations for pneumonia/influenza among community-dwelling seniors. Pooled results of the adjusted vaccine effectiveness against laboratory-confirmed influenza were also high (60.1%), although the 95% CI passed through zero (−1.3 to 84.3%). Other single community-based studies showed very high effectiveness of MF59-TIV in preventing hospitalizations for acute coronary [87% (95% CI: 35–97%)] and cerebrovascular [93% (95% CI: 52–99%)] events. MF59-TIV proved highly effective [94% (95% CI: 47–100%] in reducing influenza-like illness among institutionalized elderly. Furthermore, MF59-TIV displayed greater efficacy than non-adjuvanted vaccines in preventing hospitalizations due to pneumonia/influenza [adjusted risk ratio 0.75 (95% CI: 0.57–0.98)] and laboratory-confirmed influenza [adjusted odds ratio 0.37 (0.14–0.96)]. Conclusions Our results suggest that MF59-TIV is effective in reducing several influenza-related outcomes among the elderly, especially hospitalizations due to influenza-related complications. [ABSTRACT FROM AUTHOR]

Abstract: This paper offers an overview of important veterinary viral diseases of mammals stemming from aberrant immune response. Diseases reviewed comprise those due to lentiviruses of equine infectious anaemia, visna/maedi and caprine arthritis encephalitis and feline immunodeficiency. Diseases caused by viruses of feline infectious peritonitis, feline leukaemia, canine distemper and aquatic counterparts, Aleutian disease and malignant catarrhal fever. We also consider prospects of immunoprophylaxis for the diseases and briefly other control measures. It should be realised that the outlook for effective vaccines for many of the diseases is remote. This paper describes the current status of vaccine research and the difficulties encountered during their development. [Copyright &y& Elsevier]

Recombinant subunit vaccines in general are poor immunogens likely due to the small size of peptides and proteins, combined with the lack or reduced presentation of repetitive motifs and missing complementary signal(s) for optimal triggering of the immune response. Therefore, recombinant subunit vaccines require enhancement by vaccine delivery vehicles in order to attain adequate protective immunity. Particle-based delivery platforms, including particulate antigens and particulate adjuvants, are promising delivery vehicles for modifying the way in which immunogens are presented to both the innate and adaptive immune systems. These particle delivery platforms can also co-deliver non-specific immunostimodulators as additional adjuvants. This paper reviews efforts and advances of the Particle-based delivery platforms in development of vaccines against malaria, a disease that claims over 600,000 lives per year, most of them are children under 5 years of age in sub-Sahara Africa. [ABSTRACT FROM AUTHOR]

Highlights: [•] This paper provides a novel and original strategy to develop subunit vaccines for sublingual delivery. [•] Sublingual administration of subunit influenza Ags adjuvanted with LTK63 elicited comparable antibody titers to intramuscular immunization. [•] The sublingual delivery elicited Ag-specific mucosal IgA with neutralizing activity, contributing to anti-influenza defenses. [•] The mucosal route in combination with LTK63 elicited an Ag-specific Th17 response that might play a role in protection against influenza. [•] Sublingual delivery of an adjuvanted subunit influenza vaccine could be an effective alternative to conventional intramuscular vaccines. [ABSTRACT FROM AUTHOR]

Highlights: [•] Asd-based balanced-lethal system for DNA vaccine was evaluated in this paper. [•] The C501(pVGS/2SS-asd) vaccine could induce systemic and mucosal immune responses. [•] The C501 (pVGS/2SS-asd) vaccine is safe and stable for clinical use in large animals. [•] The risk of gene integration into the host cellular genome was negligible. [Copyright &y& Elsevier]

Abstract: The bursa of Fabricius is critical for the normal development of the B lymphocytes responsible for antibody production. However, the mechanism of the bursal-derived bioactive factor on B cell development is little reported. In this paper, chicks were immunized with BPP-II and AIV vaccine or AIV antigen, and antibody and IL-4 production were detected. The results showed that BPP-II played strongly inducing roles on the humoral immune responses. To investigate the gene expression at transcriptional level, avian pre-B lymphocyte DT40 cells were treated with BPP-II, and were analyzed with the gene microarray. The results proved that BPP-II treatment regulated 11 pathways, in which homologous recombination is a vital mechanism which is involved in antibody Ig gene conversion and diversification during B cell development. These results suggested Bursal-derived biological active factor BPP-II might be involved in the antibody production processes and B cell development, which is vital to the humoral central immune organ, the bursa of Fabricius. [Copyright &y& Elsevier]

Abstract: Japanese encephalitis is an infectious disease caused by the Japanese encephalitis virus, which is widespread throughout Asia. The worldwide incidence is 50,000 cases per year. There is no specific treatment available, but inactivated mouse brain-derived vaccine was used from the 1950s to prevent infection. However, quality control of mouse brain-derived vaccines is difficult, and therefore a new freeze-dried, cell culture-derived Japanese encephalitis vaccine (inactivated) (JEBIK V; development code: BK-VJE) was developed. In this paper, we report an analysis of neutralizing antibody titers in vaccinated subjects enrolled in clinical study of BK-VJE at various doses, and study of BK-VJE with the mouse brain-derived vaccine as a control. The results show that BK-VJE has superior immunogenicity compared to mouse brain-derived vaccine. [Copyright &y& Elsevier]

Abstract: Influenza infection is associated with many complications, which can lead to hospitalizations and death. This is particularly true for the older adults who are not able to mount as good an immune response as younger adults due to their declining immune function. As such, different strategies are being evaluated to increase immunogenicity in the older adults, including use of adjuvanted vaccines and different delivery techniques, which can enhance immunogenicity as well as potentially be dose-sparing. The objective of this paper was to conduct a systematic review of studies that evaluated the efficacy (in terms of immunogenicity) and safety of intradermal (ID) influenza vaccines compared with traditional methods of administration in the general population and the older adults. Thirteen randomized, controlled, open-label trials were included in this systematic review. Seven trials were conducted in young adults 18–60 years of age, 4 trials were studied in older subjects >60 years, and 2 trials included both young and older adults, of which one did separate analyses for both groups and one did a separate analysis for the older adult population only. We found 7 studies out of 8 for the 18–60-year olds and 4 out of 6 studies in the over 60-year olds showed comparable efficacy between ID and intramuscular (IM) administration. Two out of 6 studies in the over 60-year olds showed superiority of ID administration over IM. Rates of adverse events occurring in the first 3 days were comparable between ID and IM administration of influenza vaccines; however, when assessing adverse events occurring in the first 7 days, rates of local adverse events were consistently higher in the ID group, specifically erythema, swelling, induration, and pruritis. In conclusion, our review shows comparable efficacy between ID and IM administration of influenza vaccine in both the younger and older adults. [Copyright &y& Elsevier]

Abstract: Dengue has recently been defined by the World Health Organization as a major international public health concern. Although several vaccine candidates are in various stages of development, there is no licensed vaccine available to assist in controlling the further spread of this mosquito borne disease. The need for a reliable animal model for dengue disease increases the risk to vaccine developers as they move their vaccine candidates into large-scale phase III testing. In this paper we describe the cellular immune responses observed in a human challenge model for dengue infection; a model that has the potential to provide efficacy data for potential vaccine candidates in a controlled setting. Serum levels of sIL-2Rα and sTNF-RII were increased in volunteers who developed illness. Supernatants from in vitro stimulated PBMC were tested for cytokines associated with a TH1 or TH2 T-cell response (IL-2, TNF-α, IFN-γ, IL-4, IL-10, IL-5) and only IFN-γ was associated with protection against fever and/or viremia. Interestingly, IFN-γ levels drop to 0pg/mL for volunteers who develop illness after challenge suggesting that some mechanism of immunosuppression may play a role in dengue illness. The human challenge model provides an opportunity to test potential vaccine candidates for efficacy prior to large-scale phase III testing, and hints at a possible mechanism for immune suppression by dengue. [Copyright &y& Elsevier]

Abstract: Safe and efficient vaccination is important for rabies prevention in domestic animals. Replicative vectors expressing the rabies virus glycoprotein, derived from canine adenovirus have been reported to be promising vaccines in various animal models. In this paper we compare the potential of a replicative and a non-replicative vector, both based on canine adenovirus type 2 and expressing the rabies glycoprotein. Upon inoculation in sheep, immune responses against the rabies virus protein elicited by recombinant vectors were monitored. All immunised sheep produced a rapid and potent neutralizing antibody response against rabies virus after a single inoculation of either replicative or non-replicative recombinant canine adenovirus type 2. In addition, the non-replicative vector expressing the rabies glycoprotein stimulated antigen-specific CD4+ and CD8+ lymphocyte proliferation as well as IFN-γ production. These results suggest that vectors derived from canine adenovirus 2 could be considered for the development of promising vaccines in the ruminant species. [ABSTRACT FROM AUTHOR]

Abstract: In the present work, the capacity of new pro-GSH molecules to increase the intra-macrophage thiol content in vitro and in vivo as well as to shift the immune response to Th1 in ovalbumin (Ova)-sensitized mice were examined. The molecules were the N-butanoyl GSH derivative, GSH-C4, and a pro-drug of N-acetylcysteine (NAC) and beta-mercaptoethylamine (MEA), I-152. In vitro, 2h-incubation with both molecules was found to increase intra-macrophage thiol content; in vivo, Ova-sensitized mice pre-treated by intraperitoneal administration of the pro-GSH molecules showed an increase in plasma anti-Ova IgG2a and IgG2b, characterizing Th1 immune response, and a decrease in IgG1, typical of the Th2 response. Such findings were connected to a shift to a Th1 response also involving splenocyte IFN-γ production as revealed by ELISPOT assay and higher levels of IL-12 in circulation. Although immune responses are in vivo mediated both by dendritic cells and macrophages, the data reported in this paper corroborate the suggestion that the pro-GSH molecules, increasing the intra-cellular thiol pool, modulate the Th1/Th2 balance favouring Th1-type responses and may be employed as Th1-directing adjuvants in new vaccination protocols and as immunomodulators in those diseases where Th1 response patterns are compromised in favour of Th2. [ABSTRACT FROM AUTHOR]

Abstract: Dendritic cells (DCs) are bone marrow-derived professional antigen presenting cells. Due to their role as potent inducers of immune responses, these cells are widely used as adjuvant in experimental clinical settings for cancer immune therapy. We have developed a DC-based vaccine using autologous blood monocytes loaded with allogeneic tumor cell lysate rich in cancer/testis antigens. This vaccine has at present been tested for activity in three phase II clinical trials including two cohorts of patients with advanced colorectal cancer (CRC) and one cohort of patients with advanced non-small-cell-lung-cancer (NSCLC). In the present paper we retrospectively compare the maturation profile based on surface marker expression on DCs generated from the three patient cohorts and between cancer patient cohorts and a cohort of healthy donors. Vaccines were generated under cGMP conditions and phenotypic profiles of DC were analyzed by flow cytometry and the obtained data were used as a basis to set guideline values for our quality control of GMP produced DC vaccines. Each vaccine batch was analyzed for the expression of the surface maturation and differentiation molecules CD14, CD1a, CD83, CD86, MHC class II and CCR7, and the optimal expression pattern is considered as CD14low, CD1a, CD83high, CD86high, MHC class IIhigh and CCR7high. In accordance with data from other studies including other types of cancer patients, especially breast cancer patients, we found that the maturation status of the DC batches depends on cancer type and correlates with clinical status of cancer patients included. [Copyright &y& Elsevier]

Abstract: Seoul virus (SEOV), a member of hantavirus genus, is one of the causative agents of hemorrhagic fever with renal syndrome (HFRS) and afflicts tens of thousands of people annually. In this paper, we evaluate the immune response induced by a replication-competent recombinant canine adenovirus type 2 expressing the Gn protein of SEOV (rCAV-2-Gn) in BALB/c mice. Sera from immunized mice contained neutralizing antibodies that could specifically recognize SEOV and neutralize its infectivity in vitro. Moreover, the recombinant virus induced complete protection against a lethal challenge with the highly virulent SEOV strain CC-2. Protective level neutralizing antibodies were maintained for at least 20 weeks. The efficacy of the recombinant was similar to that induced by a currently available inactivated HFRS vaccine. This recombinant virus is therefore a potential alternative to the inactivated vaccine. [Copyright &y& Elsevier]

Abstract: The molecular methods used in DNA vaccination and gene therapy resemble in many ways the methods applied in genetic modification of organisms. In some regulatory regimes, this creates an overlap between ‘gene medication’ and genetic modification. In Norway, an animal injected with plasmid DNA, in the form of DNA vaccine or gene therapy, currently is viewed as being genetically modified for as long as the added DNA is present in the animal. However, regulating a DNA-vaccinated animal as genetically modified creates both regulatory and practical challenges. It is also counter-intuitive to many biologists. Since immune responses can be elicited also to alter traits, the borderline between vaccination and the modification of properties is no longer distinct. In this paper, we discuss the background for the Norwegian interpretation and ways in which the regulatory challenge can be handled. [Copyright &y& Elsevier]

Abstract: Toxoplasma gondii and Neospora caninum are important causes of reproductive loss in ruminant species worldwide. Both parasites cause disease during pregnancy that may result in foetal death or birth of live congenitally infected offspring. T. gondii is also an important human pathogen with the main risk groups including pregnant women and immuno-compromised individuals, although clinical disease has also been observed in outbreaks among immuno-competent people. While the two parasites are closely related there are distinct differences between the two in their interactions with different host species and subsequent clinical outcome. This paper discusses the respective host–parasite relationships in ovine toxoplasmosis and bovine neosporosis and how the immune response may be host-protective, parasite-protective or contribute to disease pathogenesis, and how this knowledge may help in the development of more effective and targeted vaccination strategies. [Copyright &y& Elsevier]

Abstract: Emergence of Shigella vaccine is in great need in developing countries. In this paper we have shown that 34kDa Shigella flexneri 2a outer membrane protein has a role in eliciting immune responses. When injected parentarally this protein gives significant protection against challenge with virulent Shigella flexneri 2a. Macrophages activated with the 34kDa protein resulted in the dose dependent production of nitric oxide, the highly reactive free radical responsible for killing of invading bacterial pathogen. Also, treatment of murine peritoneal macrophages with the 34kDa protein showed dose dependent increase in the production of tumor necrosis factor-α and interleukin-12. However, there was no dose dependent increase in interleukin-10 production. These data indicated that the 34kDa outer membrane protein has the ability to modulate the protective immune response against the invading bacterial pathogen, mainly through TH1 mediated pathway. So, the 34kDa outer mebrane protein can be one of the major components for developing subunit vaccine against shigellosis. [Copyright &y& Elsevier]

Abstract: HIV-1 specific cellular immune responses play a significant part in controlling HIV-1 viral replication and are an important component of an HIV-1 vaccine induced immune response. We reported earlier that recombinant DNA vaccine delivered intramuscularly, and recombinant Listeria monocytogenes, delivered orally induced CD8+ and CD4+ T cell immune responses in rhesus macaques and that this vaccine protocol showed partial protection against an SIV239 challenge. In this paper, we have analyzed the SIV antigen-specific immune responses at the time of challenge and during the subsequent infection course. We find that the immune status of the animals, as measured by the frequency of antigen-specific IFN-gamma secreting peripheral blood mononuclear cells, at the time of challenge correlates more strongly with viral loads at set point than peak viral loads. The correlation between the immune response and viral load was strongest early, as viral set-point was just being established and disintegrates overtime. This study demonstrates the cellular immune response to SIV at the time of challenge of a nonhuman primate is able to impact on viral set-point following SIV239 challenge. Further, this study demonstrates that as virus replicates the T cell immune response to SIV antigens induced by the vaccine is modulated by antigen encountered by immune cells during viral replication. [Copyright &y& Elsevier]

The proliferation of influenza viruses causes costly, recurrent, annual epidemics. Current vaccines, mainly administered parenterally, have been shown to be suboptimal in terms of efficacy, particularly where local IgA responses are concerned. Recent investigations of virosomes as delivery systems for viral HA and NA antigens have demonstrated an improved immune response. This paper investigates the efficacy of a novel virosome-based intranasal influenza vaccine by its ability to reduce disease symptoms and its effect on viral shedding in nasal secretions of immunised ferrets. The use of ferrets in the study of influenza vaccines is based on the good comparability between ferret and human response to the disease. Intranasal, as opposed to parenteral, administration of a trivalent virosome-based subunit vaccine adjuvanted with HLT provides an almost total prevention of virus shedding combined with a high level of immunological protection against homologous virus challenge. The ease of application of an intranasal vaccine may have positive repercussions in the adoption of influenza vaccinations, particularly in ‘at-risk’ groups. [Copyright &y& Elsevier]

This paper describes the effects on the development of an immune response by changing the route of administration of a new vaccine adjuvant, starch microparticles with human serum albumin (HSA) as a model antigen. The model vaccine was administered to mice by oral, subcutaneous and intramuscular routes in various combinations and both the local secretory immunoglobulin antibody (s-IgA) and systemic humoral and cellular (delayed-type hypersensitivity assay (DTH)) responses were followed. The only immunisation regimens inducing a significant s-IgA response were those incorporating oral booster doses. Oral and subcutaneous immunisations had similar effects on the Th1/Th2 balance, as indicated by the IgG subclass ratios and cytokine analyses. However, significant differences between oral and intramuscular immunisations were seen in the IgG subclass ratios. The Th2 influence was stronger after oral primary immunisation than after intramuscular primary immunisation, while oral boosters elicited a comparatively stronger Th1 response than intramuscular boosters. This result was also supported by the DTH analyses. Subcutaneous immunisation induced a stronger Th2 response than intramuscular immunisation, as indicated by subclass ratio and the IgE response. In conclusion, our results show that the profile of an immune response depends on the route of administration, which should be considered when developing new vaccines or new routes of administration. [Copyright &y& Elsevier]

This paper focuses on the development of candidate DNA vaccine encoding antigenic epitopes of type O foot-and-mouth disease virus (FMDV). A series of plasmids encoding different combinations of B cell epitopes and a T cell epitope were constructed and characterized by inoculating BALB/c mice. The specific antibodies were only detectable in the mice inoculated with plasmids encoding the T cell epitope and B cell epitopes from sites 5 and 1, within which site 5 includes residues 135–167 of VP1 and site 1 includes 141–160 region (G–H loop) and carboxyl terminus of VP1. Stronger cellular immune responses were also observed in these mice using T cell proliferation assay. [Copyright &y& Elsevier]

Abstract: In the study reported by Gorse et al. a unique, educational opportunity was lost. The vaccine and biodefense communities almost experienced the rare chance in a Phase I study to scientifically compare head-to-head an early-stage, investigational recombinant anthrax vaccine (rPA102) with the safe, effective and already FDA-licensed anthrax vaccine, AVA (BioThrax®). The authors take a stab at making safety and immunogenicity comparisons between the candidate vaccine and AVA (BioThrax®) but the study design and analytical approach makes this inappropriate. Inaccurate and poorly substantiated editorial comments in the paper''s introduction compound these methodological problems. The reader is presented with a series of false and misleading statements about AVA (BioThrax®). Out-of-date sources are relied upon and these references are offered to the reader as the best evidence available when more current papers with up-to-date information and data exist. Additionally, the conclusions in several original contributions are misrepresented in this paper by Gorse et al. Issues with protocol and bias notwithstanding, the single most compelling observation from this trial could be that the response of those subjects in this study population (n =19) who received AVA on the altered schedule and route of two doses of AVA (BioThrax®) delivered intramuscularly (IM) in just 4 weeks mounted a robust immune response. Given the more than 30 year history of the safe and effective use of AVA (BioThrax®) as well as the more current data on AVA (BioThrax®) a strong case can be made for continued funding to investigate the feasibility of adding another route of delivery (IM) and optimizing the schedule for this already FDA-licensed vaccine. [Copyright &y& Elsevier]