Effectiveness of Casirivimab and Imdevimab Antibody Combination in Immunocompromised Hospitalized Patients With Coronavirus Disease 2019: A Post Hoc Analysis in a Phase 1/2/3 Double-Blind Trial.

Background: Individuals who are immunocompromised (IC) are at high risk for severe coronavirus disease 2019 (COVID-19). Methods: Post hoc analyses of a double-blind trial conducted prior to Omicron (June 2020-April 2021), in hospitalized patients with COVID-19 assessed viral load, clinical outcomes, and safety of casirivimab plus imdevimab (CAS + IMD) versus placebo in IC versus overall study patients. Results: Ninety-nine of 1940 (5.1%) patients were IC. IC versus overall patients were more frequently seronegative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies (68.7% vs 41.2%) and had higher median baseline viral loads (7.21 vs 6.32 log10 copies/mL). On placebo, IC versus overall patients had slower viral load declines. CAS + IMD reduced viral load in IC and overall patients; least-squares mean difference versus placebo in time-weighted average change from baseline viral load at day 7 was -0.69 (95% confidence interval [CI], -1.25 to -.14) log10 copies/mL for IC patients and -0.31 (95% CI, -.42 to -.20) log10 copies/mL for overall patients. For IC patients, the cumulative incidence of death or mechanical ventilation at day 29 was lower with CAS + IMD (11.0%) versus placebo (17.2%), consistent with overall patients (15.7% CAS + IMD vs 18.3% placebo). IC and overall patients receiving CAS + IMD exhibited similar rates of treatment-emergent adverse events (30.4% and 26.6%, respectively), grade ≥2 hypersensitivity or infusion-related reactions (1.4% and 2.5%), and deaths (8.7% and 12.2%). Conclusions: IC patients were more likely to exhibit high viral loads and be seronegative at baseline. For susceptible SARS-CoV-2 variants, CAS + IMD reduced viral load and resulted in fewer death or mechanical ventilation events in IC and overall study patients. There were no new safety findings among IC patients. Clinical Trials Registration. NCT04426695.

Compassionate Use of REGEN-COV® in Patients With Coronavirus Disease 2019 (COVID-19) and Immunodeficiency-Associated Antibody Disorders.

BACKGROUND: Patients with immunodeficiency-associated antibody disorders are at a higher risk of prolonged/persistent COVID-19 infection, having no viable treatment options. METHODS: A retrospective analysis of patients with primary and/or secondary immunodeficiency-associated antibody disorders who received casirivimab and imdevimab (REGEN-COV®) under emergency compassionate use. Objective were to describe safety and response to REGEN-COV, focusing on the subset of patients who had COVID-19 duration ≥21 days before treatment. RESULTS: Quantitative (change in oxygenation status and/or viral load) and/or qualitative (physician-reported clinical status) outcomes data are reported from 64 patients. Improvement in ≥1 outcome was observed in 90.6% of the overall patient group. Thirty-seven of these had COVID-19 duration ≥21 days before treatment; median time from diagnosis to REGEN-COV treatment was 60.5 days. Of the 29 patients with COVID-19 duration ≥21 days before treatment and available outcome data, 96.6% showed improvement in ≥1 outcome. In the 14 patients with post-treatment reverse transcription-polymerase chain reaction (RT-PCR) results available, 11 (78.6%) reported a negative RT-PCR following treatment, with 5 (45.5%) and 8 (72.7%) patients reporting a negative RT-PCR within 5 days and 21 days of treatment, respectively. Ten of 85 patients (11.8%) experienced serious adverse events; only one was an infusion-related reaction, possibly related to REGEN-COV. Two deaths were reported; neither were attributed to REGEN-COV. CONCLUSIONS: In this retrospective analysis of immunodeficient patients granted REGEN-COV under emergency compassionate use, REGEN-COV treatment was associated with rapid viral clearance and clinical improvement in patients with longstanding COVID-19. Adverse events were consistent with COVID-19 and its associated complications, and due to patients' concurrent medical conditions.

Safety, immunogenicity, and efficacy of a Clostridioides difficile toxoid vaccine candidate: a phase 3 multicentre, observer-blind, randomised, controlled trial.

BACKGROUND: In the absence of a licensed vaccine, Clostridioides (formerly Clostridium) difficile infection represents a substantial health burden. The aim of this study was to evaluate the efficacy, immunogenicity, and safety of a toxoid vaccine candidate. METHODS: We did a phase 3 multicentre, observer-blind, randomised, controlled trial at 326 hospitals, clinics, and clinical research centres in 27 countries in the USA, Canada, Latin America, Europe, and the Asia-Pacific region. We included adults aged 50 years or older who were considered to be at an increased risk of C difficile infection because they had previously had two hospital stays (each ≥24 h in duration) and had received systemic antibiotics in the previous 12 months (risk stratum 1), or because they were anticipating being admitted to hospital for 72 h or more for elective surgery within 60 days of enrolment (risk stratum 2). Eligible participants were stratified by geographical region and the two risk strata, and randomly assigned (2:1), with a fixed block size of three, to receive either a C difficile toxoid vaccine candidate, containing toxoids A and B (C difficile vaccine candidate group), or a placebo vaccine (placebo group). Participants, investigators, and personnel responsible for collecting safety data and analysing blood and stool samples were masked to group assignment. Personnel responsible for study product preparation and administration were not masked to group assignment. One dose (0·5 mL) of C difficile vaccine candidate or placebo vaccine was administered intramuscularly on days 0, 7, and 30. The primary outcome was the efficacy of the vaccine in preventing symptomatic C difficile infection, defined as having three or more loose stools in a period of 24 h or less, loose stools for 24 h or more, and a PCR-positive test for C difficile toxin B in a loose stool sample, within 3 years after the final vaccine dose. The primary outcome was measured in the modified intention-to-treat population (ie, all participants who received at least one injection of the assigned vaccine). The safety of the vaccine was assessed in the safety analysis set (ie, all participants who had received at least one injection, analysed according to the product received). This study is registered with WHO/ICTRP, number U111-1127-7162, and ClinicalTrials.gov, number NCT01887912, and has been terminated. FINDINGS: Between July 30, 2013, and Nov 17, 2017, we enrolled and randomly assigned 9302 participants to the C difficile vaccine candidate group (n=6201) or to the placebo group (n=3101). 6173 (99·5%) participants in the C difficile vaccine candidate group and 3085 (99·5%) participants in the placebo group received at least one dose of the vaccine. The study was terminated after the first planned interim analysis because of futility. In the C difficile vaccine candidate group, 34 C difficile infections were reported over 11 697·2 person-years at risk (0·29 infections per 100 person-years [95% CI 0·20-0·41]) compared with 16 C difficile infections over 5789·4 person-years at risk in the placebo group (0·28 infections per 100 person-years [0·16-0·45]), indicating a vaccine efficacy of -5·2% (95% CI -104·1 to 43·5). In the C difficile vaccine candidate group, 2847 (46·6%) of 6113 participants reported an adverse event within 30 days of injection compared with 1282 (41·9%) of 3057 participants in the placebo group. The proportion of participants who had an adverse event leading to study discontinuation was 4·8% in both groups (296 participants in the C difficile vaccine candidate group and 146 participants in the placebo group). 1662 (27·2%) participants in the C difficile vaccine candidate group reported at least one serious adverse event compared with 851 (27·8%) participants in the placebo group. INTERPRETATION: In adults at risk for C difficile infection, a bivalent C difficile toxoid vaccine did not prevent C difficile infection. Since the C difficile vaccine candidate met the criteria for futility, the study was terminated and clinical development of this vaccine candidate was stopped. FUNDING: Sanofi Pasteur.

Correction to: Proteomic identification and characterization of hepatic glyoxalase 1 dysregulation in non-alcoholic fatty liver disease.

[This corrects the article DOI: 10.1186/s12953-018-0131-y.].

Proteomic identification and characterization of hepatic glyoxalase 1 dysregulation in non-alcoholic fatty liver disease.

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. However, its molecular pathogenesis is incompletely characterized and clinical biomarkers remain scarce. The aims of these experiments were to identify and characterize liver protein alterations in an animal model of early, diet-related, liver injury and to assess novel candidate biomarkers in NAFLD patients. Methods: Liver membrane and cytosolic protein fractions from high fat fed apolipoprotein E knockout (ApoE-/-) animals were analyzed by quantitative proteomics, utilizing isobaric tags for relative and absolute quantitation (iTRAQ) combined with nano-liquid chromatography and tandem mass spectrometry (nLC-MS/MS). Differential protein expression was confirmed independently by immunoblotting and immunohistochemistry in both murine tissue and biopsies from paediatric NAFLD patients. Candidate biomarkers were analyzed by enzyme-linked immunosorbent assay in serum from adult NAFLD patients. Results: Through proteomic profiling, we identified decreased expression of hepatic glyoxalase 1 (GLO1) in a murine model. GLO1 protein expression was also found altered in tissue biopsies from paediatric NAFLD patients. In vitro experiments demonstrated that, in response to lipid loading in hepatocytes, GLO1 is first hyperacetylated then ubiquitinated and degraded, leading to an increase in reactive methylglyoxal. In a cohort of 59 biopsy-confirmed adult NAFLD patients, increased serum levels of the primary methylglyoxal-derived advanced glycation endproduct, hydroimidazolone (MG-H1) were significantly correlated with body mass index (r = 0.520, p < 0.0001). Conclusion: Collectively these results demonstrate the dysregulation of GLO1 in NAFLD and implicate the acetylation-ubquitination degradation pathway as the functional mechanism. Further investigation of the role of GLO1 in the molecular pathogenesis of NAFLD is warranted.

Design and evaluation of the immunogenicity and efficacy of a biomimetic particulate formulation of viral antigens.

Subunit viral vaccines are typically not as efficient as live attenuated or inactivated vaccines at inducing protective immune responses. This paper describes an alternative 'biomimetic' technology; whereby viral antigens were formulated around a polymeric shell in a rationally arranged fashion with a surface glycoprotein coated on to the surface and non-structural antigen and adjuvant encapsulated. We evaluated this model using BVDV E2 and NS3 proteins formulated in poly-(D, L-lactic-co-glycolic acid) (PLGA) nanoparticles adjuvanted with polyinosinic:polycytidylic acid (poly(I:C) as an adjuvant (Vaccine-NP). This Vaccine-NP was compared to ovalbumin and poly(I:C) formulated in a similar manner (Control-NP) and a commercial adjuvanted inactivated BVDV vaccine (IAV), all inoculated subcutaneously and boosted prior to BVDV-1 challenge. Significant virus-neutralizing activity, and E2 and NS3 specific antibodies were observed in both Vaccine-NP and IAV groups following the booster immunisation. IFN-γ responses were observed in ex vivo PBMC stimulated with E2 and NS3 proteins in both vaccinated groups. We observed that the protection afforded by the particulate vaccine was comparable to the licenced IAV formulation. In conclusion, the biomimetic particulates showed a promising immunogenicity and efficacy profile that may be improved by virtue of being a customisable mode of delivery.

Prevention and control of meningococcal outbreaks: The emerging role of serogroup B meningococcal vaccines.

Recently an investigational meningococcal B vaccine has been used in two college outbreaks in the US. This is the first time that a meningococcal B vaccine has been used for outbreak control in the US. However, strain specific vaccines for meningococcal B outbreaks have been developed in Norway, Cuba and to control a large prolonged outbreak in New Zealand. Although meningococcal disease is mostly endemic and baseline rates in the US have fallen over the past decade, outbreaks are not uncommon in the US and globally. In an outbreak, disease risk can rise 1000 fold or more and such outbreaks can last a decade or longer causing significant morbidity and mortality. Here we review the evolution of several serogroup B outbreaks, and, when applicable, the development and impact of meningococcal B vaccines to control these outbreaks. Prior to the availability of "broad spectrum" meningococcal B vaccines, vaccines developed to control meningococcal B outbreaks were strain specific. With the development of two newly licensed meningococcal B vaccines - a four component meningococcal B vaccine (Bexsero, Novartis) and the two component fHBP vaccine (Trumenba, Pfizer) that target a broad array of meningococcal B strains, there is now the potential to prevent outbreaks and as well as to shorten the delay between identification of an outbreak and availability of a vaccine.

Surveillance for Neisseria meningitidis Disease Activity and Transmission Using Information Technology.

BACKGROUND: While formal reporting, surveillance, and response structures remain essential to protecting public health, a new generation of freely accessible, online, and real-time informatics tools for disease tracking are expanding the ability to raise earlier public awareness of emerging disease threats. The rationale for this study is to test the hypothesis that the HealthMap informatics tools can complement epidemiological data captured by traditional surveillance monitoring systems for meningitis due to Neisseria meningitides (N. meningitides) by highlighting severe transmissible disease activity and outbreaks in the United States. METHODS: Annual analyses of N. meningitides disease alerts captured by HealthMap were compared to epidemiological data captured by the Centers for Disease Control's Active Bacterial Core surveillance (ABCs) for N. meningitides. Morbidity and mortality case reports were measured annually from 2010 to 2013 (HealthMap) and 2005 to 2012 (ABCs). FINDINGS: HealthMap N. meningitides monitoring captured 80-90% of alerts as diagnosed N. meningitides, 5-20% of alerts as suspected cases, and 5-10% of alerts as related news articles. HealthMap disease alert activity for emerging disease threats related to N. meningitides were in agreement with patterns identified historically using traditional surveillance systems. HealthMap's strength lies in its ability to provide a cumulative "snapshot" of weak signals that allows for rapid dissemination of knowledge and earlier public awareness of potential outbreak status while formal testing and confirmation for specific serotypes is ongoing by public health authorities. CONCLUSIONS: The underreporting of disease cases in internet-based data streaming makes inadequate any comparison to epidemiological trends illustrated by the more comprehensive ABCs network published by the Centers for Disease Control. However, the expected delays in compiling confirmatory reports by traditional surveillance systems (at the time of writing, ABCs data for 2013 is listed as being provisional) emphasize the helpfulness of real-time internet-based data streaming to quickly fill gaps including the visualization of modes of disease transmission in outbreaks for better resource and action planning. HealthMap can also contribute as an internet-based monitoring system to provide real-time channel for patients to report intervention-related failures.

Connexin40 regulates platelet function.

The presence of multiple connexins was recently demonstrated in platelets, with notable expression of Cx37. Studies with Cx37-deficient mice and connexin inhibitors established roles for hemichannels and gap junctions in platelet function. It was uncertain, however, whether Cx37 functions alone or in collaboration with other family members through heteromeric interactions in regulation of platelet function. Here we report the presence and functions of an additional platelet connexin, Cx40. Inhibition of Cx40 in human platelets or its deletion in mice reduces platelet aggregation, fibrinogen binding, granule secretion and clot retraction. The effects of the Cx37 inhibitor (37,43)Gap27 on Cx40(-/-) mouse platelets and of the Cx40 inhibitor (40)Gap27 on Cx37(-/-) mouse platelets revealed that each connexin is able to function independently. Inhibition or deletion of Cx40 reduces haemostatic responses in mice, indicating the physiological importance of this protein in platelets. We conclude that multiple connexins are involved in regulating platelet function, thereby contributing to haemostasis and thrombosis.

Perspectives on vaccine development for the elderly.

Modern society is characterized by a steady increase in the aged population. Increasing numbers of elderly people are exposed to infectious diseases in addition to suffering from chronic non-communicable illnesses. Key differences exist between immune responses elicited against infectious agents in the elderly and in the youngest population. Responses in the aged are characterized by a physiological state of impaired immunity. Such state has forced scientist and vaccine manufacturers to re-think the way vaccines are designed and tested in the elderly. Multiple strategies have been used to overcome the consequences of immunosenescence including the use of higher antigen dose, adjuvanted vaccines, and alternative routes of immunization. However, the lack of understanding of the immune regulatory mechanisms underlying immunosenescence in the elderly represents one of the main hurdles in the pathway to produce effective vaccines for seniors. This article reviews in a succinct form the current state of the art on the development of vaccines for the elderly and critically assesses the past and current literature on this topic, while also proposing new avenues for future studies.

Protective efficacy induced by recombinant Clostridium difficile toxin fragments.

Clostridium difficile is a spore-forming bacterium that can reside in animals and humans. C. difficile infection causes a variety of clinical symptoms, ranging from diarrhea to fulminant colitis. Disease is mediated by TcdA and TcdB, two large enterotoxins released by C. difficile during colonization of the gut. In this study, we evaluated the ability of recombinant toxin fragments to induce neutralizing antibodies in mice. The protective efficacies of the most promising candidates were then evaluated in a hamster model of disease. While limited protection was observed with some combinations, coadministration of a cell binding domain fragment of TcdA (TcdA-B1) and the glucosyltransferase moiety of TcdB (TcdB-GT) induced systemic IgGs which neutralized both toxins and protected vaccinated animals from death following challenge with two strains of C. difficile. Further characterization revealed that despite high concentrations of toxin in the gut lumens of vaccinated animals during the acute phase of the disease, pathological damage was minimized. Assessment of gut contents revealed the presence of TcdA and TcdB antibodies, suggesting that systemic vaccination with this pair of recombinant polypeptides can limit the disease caused by toxin production during C. difficile infection.

A novel transport mechanism for MOMP in Chlamydophila pneumoniae and its putative role in immune-therapy.

Major outer membrane proteins (MOMPs) of Gram negative bacteria are one of the most intensively studied membrane proteins. MOMPs are essential for maintaining the structural integrity of bacterial outer membranes and in adaptation of parasites to their hosts. There is evidence to suggest a role for purified MOMP from Chlamydophila pneumoniae and corresponding MOMP-derived peptides in immune-modulation, leading to a reduced atherosclerotic phenotype in apoE(-/-) mice via a characteristic dampening of MHC class II activity. The work reported herein tests this hypothesis by employing a combination of homology modelling and docking to examine the detailed molecular interactions that may be responsible. A three-dimensional homology model of the C. pneumoniae MOMP was constructed based on the 14 transmembrane ß-barrel crystal structure of the fatty acid transporter from Escherichia coli, which provides a plausible transport mechanism for MOMP. Ligand docking experiments were used to provide details of the possible molecular interactions driving the binding of MOMP-derived peptides to MHC class II alleles known to be strongly associated with inflammation. The docking experiments were corroborated by predictions from conventional immuno-informatic algorithms. This work supports further the use of MOMP in C. pneumoniae as a possible vaccine target and the role of MOMP-derived peptides as vaccine candidates for immune-therapy in chronic inflammation that can result in cardiovascular events.

Immune responses elicited by apoB-100-derived peptides in mice.

Peptides derived from apolipoprotein B (apoB)-100 have been previously used in vaccine preparations to treat atherosclerosis. Such vaccines have been shown to reduce atherosclerotic plaque development by 50 % in experimental animals, and this effect is associated with induction of T helper (Th)2 immune responses. In this study we immunised apolipoprotein E-deficient (apoE(-/-)) mice with apoB-100-derived peptides P2, P45 and P210. Animals received BSA-conjugated peptides or peptide-loaded bone marrow-derived dendritic cells (DCs). We used enzyme-linked immunosorbent assays to assess the synthesis of anti-peptide-specific IgG1 and IgG2a as well as the levels of interleukin (IL-)10 and interferon gamma (IFN-γ) in plasma of immunised animals. We also measured the effect of immunisation on the number of spleen-derived CD4(+) and CD8(+) regulatory T cells (Tregs) in these animals. Peptide and peptide-loaded DC immunisation significantly increased the levels of peptide-specific immunoglobulins and the number of Tregs in apoE(-/-) mice. This was accompanied by a significant increase in the secretion of IL-10 with no effect on IFN-γ levels. The results also show that the peptides can modulate the homing properties of DCs. Altogether, this study provides novel evidence for the immune mechanisms excerpted by apoB-100-derived peptides and their effect on Tregs and DCs relevant to their use in vaccine preparations.

Vaccines and antibiotic resistance.

Vaccines and antibiotics have significantly contributed to improve health and also to increase the longevity of human beings. The fast-acting effect of antibiotics makes them indispensable to treat infected patients. Likewise, when the causative agent of the infection is unknown and in cases of superinfections with different species of bacteria, antibiotics appear to be the only therapeutic option. On the contrary, vaccines are usually not efficacious in people already infected and their action is generally limited to a much narrowed range of pathogens. However, vaccines have contributed to the eradication of some of the most deadly infectious agents worldwide, can generate immunity to infections lasting for several years or life-long, and are able to induce herd immunity. Nonetheless, infectious diseases are still among the leading causes of morbidity and mortality worldwide. This is mainly owing to the emergence of bacterial resistance to antibiotics and the lack of efficacious medications to treat several other infectious diseases. Development of new vaccines appears to be a promising solution to these issues. Indeed, with the advent of new discovery approaches and adjuvants, today is possible to make vaccines virtually against every pathogen. In addition, while vaccine-resistant bacteria have never been reported, accumulating literature is providing evidence that vaccination can reduce the raise of antibiotic resistant strains by decreasing their use.

Gap junctions and connexin hemichannels underpin hemostasis and thrombosis.

BACKGROUND: Connexins are a widespread family of membrane proteins that assemble into hexameric hemichannels, also known as connexons. Connexons regulate membrane permeability in individual cells or couple between adjacent cells to form gap junctions and thereby provide a pathway for regulated intercellular communication. We have examined the role of connexins in platelets, blood cells that circulate in isolation but on tissue injury adhere to each other and the vessel wall to prevent blood loss and to facilitate wound repair. METHODS AND RESULTS: We report the presence of connexins in platelets, notably connexin37, and that the formation of gap junctions within platelet thrombi is required for the control of clot retraction. Inhibition of connexin function modulated a range of platelet functional responses before platelet-platelet contact and reduced laser-induced thrombosis in vivo in mice. Deletion of the Cx37 gene (Gja4) in transgenic mice reduced platelet aggregation, fibrinogen binding, granule secretion, and clot retraction, indicating an important role for connexin37 hemichannels and gap junctions in platelet thrombus function. CONCLUSIONS: Together, these data demonstrate that platelet gap junctions and hemichannels underpin the control of hemostasis and thrombosis and represent potential therapeutic targets.

Progress in understanding adjuvant immunotoxicity mechanisms

Over the last twenty years research has provided an important insight into the mechanisms responsible for the immunotoxicity of both local and systemic adverse reactions following the use of immunostimulating drugs and adjuvants. In this article we provide an update of the present knowledge relating to the various parameters and reactants of the immune system at the cellular as well as molecular level that are believed to play a key role in reactogenicity. We discuss evidence obtained from observations in vitro, in vivo in animal models and from clinical applications, including adjuvants used in large scale vaccination today. The data discussed are mainly taken from animal models following hyperstimulation of the immune system; either by the use of very powerful adjuvants, like Freunds that are too toxic for use in practical vaccination, by deliberate high dose application of adjuvants or by the in vivo application of cytokines. Although such hyperstimulating regimens are unlikely to find their way into practical vaccination of humans, this information is of great value as it may facilitate the understanding of the toxicity mechanisms, aid the design of standardised models for the assessment of adjuvant safety and the possible application of new adjuvants in vaccines for humans(AU)

Influenza vaccination promotes stable atherosclerotic plaques in apoE knockout mice.

OBJECTIVE: Current evidence suggests a relationship between seasonal Influenza viral infection and cardiovascular disease (CVD). Experimental animals inoculated with Influenza A virus have shown to develop thrombotic complications similar to those seen in humans. Conversely, several epidemiological studies and clinical trials have suggested that Influenza vaccination may have a protective effect on CVD. However, the potential mechanisms behind this protective effect remain unstudied. We aimed to study the effect of Influenza vaccination on atherosclerotic plaque development in apoE(-/-) mice. METHODS AND RESULTS: The effect of immunization with increasing doses of Influenza vaccine (0.38, 1.8, 9 and 45 µg/0.5 mL Vaxigrip®, Sanofi-Aventis) on atherogenesis was compared with that of animals immunized with Pneumo23® (pneumococcus vaccine, Sanofi-Aventis) and control group inoculated with phosphate buffered saline (PBS). Animals vaccinated with 45 µg/0.5 mL Vaxigrip®, (the same dose used to immunize humans adults against Influenza) developed smaller atherosclerotic lesions with lower lipid content but richer in smooth muscle cells and collagen when compared with control animals. Concomitantly, they showed lower levels of interferon gamma (IFNγ), interleukin (IL)-2 and tumor necrosis factor alpha (TNFα) but higher levels of IL-4. Furthermore, we found increased levels of anti-Influenza immunoglobulin (Ig) G1 or anti-Pneumo23® IgM specific antibodies in a time and dose dependent fashion in animals immunized with these vaccines. CONCLUSIONS: These results indicate that vaccination against Influenza may protect against the development of CVD by promoting smaller and stable atherosclerotic plaques and by inducing atheroprotective immune responses.

Progress in understanding adjuvant immunotoxicity mechanisms.

Over the last twenty years research has provided an important insight into the mechanisms responsible for the immunotoxicity of both local and systemic adverse reactions following the use of immunostimulating drugs and adjuvants. In this article we provide an update of the present knowledge relating to the various parameters and reactants of the immune system at the cellular as well as molecular level that are believed to play a key role in reactogenicity. We discuss evidence obtained from observations in vitro, in vivo in animal models and from clinical applications, including adjuvants used in large scale vaccination today. The data discussed are mainly taken from animal models following hyperstimulation of the immune system; either by the use of very powerful adjuvants, like Freund's that are too toxic for use in practical vaccination, by deliberate high dose application of adjuvants or by the in vivo application of cytokines. Although such hyperstimulating regimens are unlikely to find their way into practical vaccination of humans, this information is of great value as it may facilitate the understanding of the toxicity mechanisms, aid the design of standardised models for the assessment of adjuvant safety and the possible application of new adjuvants in vaccines for humans.