Active Immunization Strategies Research Articles

Anticipating HIV viral escape - resistance to active and passive immunization.

Active and passive immunization strategies are challenged by the extraordinary diversity of HIV, and the need for high titers of neutralizing antibodies to confer protective immunity. This review summarises recent studies and the barrier that these interventions will need to overcome to prevent viral resistance. Studies from the antibody mediated prevention trial identified a measure of protective titers, finding that higher titers than anticipated will be needed to prevent infection. This benchmark has advanced our ability to predict combinations of broadly neutralizing antibodies (bNAbs) that will provide optimal coverage. To limit escape, these combinations should ensure that the majority of viruses are bound by a minimum of two antibodies. The characterization of currently circulating viruses has revealed increased resistance to some bNAbs over time, highlighting the need for continued surveillance, especially in under-studied populations and subtypes. Active vaccination will face similar challenges in combating diversity, although despite successes in germline targeting, this approach is not yet able to elicit bNAbs. Cumulatively these studies highlight the need to target multiple antibody epitopes for maximum coverage, but also to restrict escape pathways. Successful immunization strategies should anticipate viral escape and devise strategies to counteract this.

Exploring the Role of Antiviral Nasal Sprays in the Control of Emerging Respiratory Infections in the Community.

The COVID-19 pandemic has demonstrated that there is an unmet need for the development of novel prophylactic antiviral treatments to control the outbreak of emerging respiratory virus infections. Passive antibody-based immunisation approaches such as intranasal antibody prophylaxis have the potential to provide immediately accessible universal protection as they act directly at the most common route of viral entry, the upper respiratory tract. The need for such products is very apparent for SARS-CoV-2 at present, given the relatively low effectiveness of vaccines to prevent infection and block virus onward transmission. We explore the benefits and challenges ofthe use of antibody-based nasal sprays prior and post exposure to the virus. The classic susceptible-exposed-infectious-removed (SEIR) mathematical model was extended to describe the potential population-level impact of intranasal antibody prophylaxis on controlling the spread of an emerging respiratory infection in the community. Intranasal administration ofmonoclonal antibodies provides only a short-term protection to the mucosal surface. Consequently, sustained intranasal antibody prophylaxis of a substantial proportion of the population would be needed to contain infections. Post-exposure prophylaxis against the development of severe disease would be essential for the overallreduction in hospital admissions. Antibody-based nasal sprays could provide protection against infection to individuals that are likely to be exposed to the virus. Large-scale administration for a long period of time would be challenging. Intranasal antibody prophylaxis alone cannot prevent community-wide transmission of the virus. It could be used along with other protective measures, such as non-pharmaceutical interventions, to bridge the time required to develop and produce effective vaccines, and complement active immunisation strategies.

Characterization of SARS-CoV-2 Escape Mutants to a Pair of Neutralizing Antibodies Targeting the RBD and the NTD.

Mutations in the spike protein of SARS-CoV-2 can lead to evasion from neutralizing antibodies and affect the efficacy of passive and active immunization strategies. Immunization of mice harboring an entire set of human immunoglobulin variable region gene segments allowed to identify nine neutralizing monoclonal antibodies, which either belong to a cluster of clonally related RBD or NTD binding antibodies. To better understand the genetic barrier to emergence of SARS-CoV-2 variants resistant to these antibodies, escape mutants were selected in cell culture to one antibody from each cluster and a combination of the two antibodies. Three independently derived escape mutants to the RBD antibody harbored mutations in the RBD at the position T478 or S477. These mutations impaired the binding of the RBD antibodies to the spike protein and conferred resistance in a pseudotype neutralization assay. Although the binding of the NTD cluster antibodies were not affected by the RBD mutations, the RBD mutations also reduced the neutralization efficacy of the NTD cluster antibodies. The mutations found in the escape variants to the NTD antibody conferred resistance to the NTD, but not to the RBD cluster antibodies. A variant resistant to both antibodies was more difficult to select and only emerged after longer passages and higher inoculation volumes. VOC carrying the same mutations as the ones identified in the escape variants were also resistant to neutralization. This study further underlines the rapid emergence of escape mutants to neutralizing monoclonal antibodies in cell culture and indicates the need for thorough investigation of escape mutations to select the most potent combination of monoclonal antibodies for clinical use.

Identification of Epitopes on Rhinovirus 89 Capsid Proteins Capable of Inducing Neutralizing Antibodies.

Rhinoviruses (RVs) are major causes of the common cold, but they can also trigger exacerbations of asthma. More than 160 different RV strains exist and can be classified into three genetic species (RV-A, RV-B and RV-C) which bind to different receptors on human cells including intracellular adhesion molecule 1 (ICAM-1), the low-density lipoprotein receptor (LDLR) or the cadherin-related family member 3 (CDHR3). Epitopes located in the RV capsid have mainly been determined for RV2, a minor-group RV-A strain binding to LDLR, and for RV14, a major-group RV-B strain binding to ICAM-1. In order to study epitopes involved in the neutralization of RV89, an ICAM-1-binding RV-A strain which is highly different from RV2 and RV14 in terms of receptor specificity and sequence, respectively, we analyzed the specificity and epitopes of a highly neutralizing antiserum using recombinantly produced RV89 capsid proteins (VP1, VP2, VP3 and VP4), recombinant fragments and synthetic overlapping peptides thereof. We found that the antiserum which neutralized in vitro RV89 infection up to a dilution of 1:24,000 reacted with the capsid proteins VP1 and VP2 but not with VP3 and VP4. The neutralizing antibodies recognized recombinant fragments comprising approximately 100 amino acids of the N- and C-terminus of VP1 and the middle part of VP2, in particular, three peptides which, according to molecular modeling based on the three-dimensional structure of RV16, were surface-exposed on the viral capsid. Two recombinant fusion proteins containing the identified peptides fused to hepatitis B (HBV)-derived preS as a carrier protein induced upon immunization of rabbits antibodies capable of neutralizing in vitro RV89 infections. Interestingly, the virus-neutralizing epitopes determined for RV89 corresponded to those determined for minor-group RV2 binding to LDL and major-group RV14 belonging to the RV-B species, which are highly different from RV89. Our results indicate that highly different RV strains, even when reacting with different receptors, seem to engage similar parts of their capsid in the infection process. These results may be important for the design of active and passive immunization strategies for RV.

The protective effect of flagellin a and b as candidate vaccine against Pseudomonas aeruginosa respiratory infections

Background: Multi drug resistance (MDR) P. aeruginosa consider the main cause of morbidity in hospitalize patients suffering from chronic airway infections such as chronic pulmonary disease, pneumonia and cystic fibrosis (CF). Also, the rapidly development of antibiotic resistance to the last generations of a broad spectrum antibiotic were detected for many P. aeruginosa isolates. Accordingly the vaccines have the potential to prevent and treatment such infections. Aim: The present study aimed to investigate active immunization strategies using flagellin in order to provide complete protection against MDR P. aeruginosa clinical isolates in the acute fatal respiratory infection in animal model. Methods: Flagellin a and flagellin b purified partially from P. aeruginosa as mentioned in previous study. After that the animals were immunized intranasally after sedative the animal by applying 10 μl of flagellin a (4.8 μg), or flagellin b (4.8 μgl) on each nostril for 100 mg weight of rat at weekly intervals. After week from the 6th dose, the animal were exposed to 2*107 CFU of P. aeruginosa intranasally directly into each nostril.

Electron-Beam Inactivation of Human Rotavirus (HRV) for the Production of Neutralizing Egg Yolk Antibodies

Electron beam (eBeam) inactivation of pathogens is a commercially proven technology in multiple industries. While commonly used in a variety of decontamination processes, this technology can be considered relatively new to the pharmaceutical industry. Rotavirus is the leading cause of severe gastroenteritis among infants, children, and at-risk adults. Infections are more severe in developing countries where access to health care, clean food, and water is limited. Passive immunization using orally administered egg yolk antibodies (chicken IgY) is proven for prophylaxis and therapy of viral diarrhea, owing to the stability of avian IgY in the harsh gut environment. Since preservation of viral antigenicity is critical for successful antibody production, the aim of this study was to demonstrate the effective use of electron beam irradiation as a method of pathogen inactivation to produce rotavirus-specific neutralizing egg yolk antibodies. White leghorn hens were immunized with the eBeam-inactivated viruses every 2 weeks until serum antibody titers peaked. The relative antigenicity of eBeam-inactivated Wa G1P[8] human rotavirus (HRV) was compared to live virus, thermally, and chemically inactivated virus preparations. Using a sandwich ELISA (with antibodies against recombinant VP8 for capture and detection of HRV), the live virus was as expected, most immunoreactive. The eBeam-inactivated HRV’s antigenicity was better preserved when compared to thermally and chemically inactivated viruses. Additionally, both egg yolk antibodies and serum-derived IgY were effective at neutralizing HRV in vitro. Electron beam inactivation is a suitable method for the inactivation of HRV and other enteric viruses for use in both passive and active immunization strategies.

Lack of Induction of RBD-Specific Neutralizing Antibodies despite Repeated Heterologous SARS-CoV-2 Vaccination Leading to Seroconversion and Establishment of T Cell-Specific Memory in a Patient in Remission of Multiple Myeloma.

Background: Prophylactic vaccination against infectious diseases may induce a state of long-term protection in the otherwise healthy host. However, the situation is less predictable in immunocompromised patients and may require adjustment of vaccination schedules and/or basic therapy. Methods: A patient in full remission of multiple myeloma since the last three years and on long-term maintenance therapy with pomalidomide, a drug inhibiting angiogenesis and myeloma cell growth, was vaccinated twice with Comirnaty followed by two vaccinations with Vaxzevria. Seroconversion and SARS-CoV-2-specific cellular responses were monitored. Results: No signs of seroconversion or T cellular memory were observed after the first “full immunization” with Comirnaty. Consequently, long-term-maintenance therapy with Pomalidomide was stopped and two additional shots of Vaxzevria were administered after which the patient seroconverted with Spike(S)-protein specific antibody levels reaching 49 BAU/mL, mild S-peptide pool-specific T cell proliferation, effector cytokine production (IL-2, IL-13), and T cellular activation with increased numbers of CD3+CD4+CD25+ T cells as compared to vaccinated and non-vaccinated control subjects. However, despite suspension of immunosuppression and administration of in total four consecutive heterologous SARS-CoV-2 vaccine shots, the patient did not develop neutralizing RBD-specific antibodies. Conclusions: Despite immunomonitoring-based adjustment of vaccination and/or therapy schedules vaccination success, with clear correlates of protection, the development of RBD-specific antibodies could not be achieved in the immunocompromised patient with current SARS-CoV-2 vaccines. Thus, our report emphasizes the need for improved active and passive immunization strategies for SARS-CoV-2 infections.

Staphylococcus aureus, ESKAPE Bacteria Challenging Current Health Care and Community Settings: a Literature Review.

Staphylococcus aureus is a gram-positive coccus forming grape like clusters performing both aerobic and anaerobic respiration. Most strains of S. aureus ferment mannitol and they form characteristic golden yellow colonies. They produce catalase, coagulase, and extracellular cell clumping factor. Some strains can also produce capsules. It is a major commensal bacterium and a human pathogen that causes a wide range of clinical infections including abscesses of various organs, pneumonia, osteomyelitis, endocarditis, arthritis, and sepsis. S. aureus is the key organism for food poisoning and it is the third most important cause of food borne disorders in the world. We reviewed all the relevant literature available on PubMed, Web of Science, and Google Scholar. We selected different scientific studies and reports published in English language which addressed prevalence, pathogenesis, burden and laboratory diagnosis methods of S. aureus to compile the current review. Staphylococcus aureus has an outstanding ability to acquire resistance to most classes of antimicrobial agents. This successful and adaptable resistance has made treatment and control of staphylococcal infections increasingly difficult. Expression of virulence factors of S. aureus is controlled by bacterial cell density and many environmental factors such as pH, oxygen, and carbon dioxide. There are different mechanisms that microorganisms use to prevent attack by antimicrobial agents. These include limiting uptake of the drug, modification of the drug target, inactivation of the drug, and active efflux of the drug. Specimens collected for diagnosis of S. aureus infection depend on the type of infection. The samples for diagnosis are pus, sputum, blood, feces, vomit and the remains of suspected food, and nasal swab for the detection of carriers. Gram stain, culture, biochemical tests, serological tests and molecular techniques are the common laboratory diagnosis methods. Multidrug resistant S. aureus strains are emerging and current antibiotics are not efficacious against such strains. Both active and passive immunization strategies have thus far failed to show efficacy in humans. Therefore, infection preventive measures, and further research is required to develop vaccines and antibiotics to target this pathogen.

Vaccination against β-Amyloid as a Strategy for the Prevention of Alzheimer's Disease.

Simple SummaryImmunization against β-amyloid has been explored as a vaccination strategy for Alzheimer’s disease for over 20 years. No vaccine has been licensed so far, and immunotherapy has come under considerable criticism following the negative results of several phase III clinical trials. In this narrative review, we illustrate the working hypothesis behind immunization against β-amyloid as a vaccination strategy for Alzheimer’s disease, and the outcome of the active immunization strategies that have been tested in humans. On the basis of the lessons learned from preclinical and clinical research, we discuss roadblocks and current perspectives in this challenging enterprise in translational immunology.Vaccination relies on the phenomenon of immunity, a long-term change in the immunological response to subsequent encounters with the same pathogen that occurs after the recovery from some infectious diseases. However, vaccination is a strategy that can, in principle, be applied also to non-infectious diseases, such as cancer or neurodegenerative diseases, if an adaptive immune response can prevent the onset of the disease or modify its course. Immunization against β-amyloid has been explored as a vaccination strategy for Alzheimer’s disease for over 20 years. No vaccine has been licensed so far, and immunotherapy has come under considerable criticism following the negative results of several phase III clinical trials. In this narrative review, we illustrate the working hypothesis behind immunization against β-amyloid as a vaccination strategy for Alzheimer’s disease, and the outcome of the active immunization strategies that have been tested in humans. On the basis of the lessons learned from preclinical and clinical research, we discuss roadblocks and current perspectives in this challenging enterprise in translational immunology.

Tryptic Shaving of Staphylococcus aureus Unveils Immunodominant Epitopes on the Bacterial Cell Surface.

The opportunistic pathogen Staphylococcus aureus has become a major threat for human health and well-being by developing resistance to antibiotics and by fast evolution into new lineages that rapidly spread within the healthy human population. This calls for development of active or passive immunization strategies to prevent or treat acute phase infections. Since no such anti-staphylococcal immunization approaches are available for clinical implementation, the present studies were aimed at identifying new leads for their development. For this purpose, we profiled the cell-surface-exposed staphylococcal proteome under infection-mimicking conditions by combining two approaches for "bacterial shaving" with immobilized or soluble trypsin and subsequent mass spectrometry analysis of liberated peptides. In parallel, non-covalently cell-wall-bound proteins extracted with potassium thiocyanate and the exoproteome fraction were analyzed by gel-free proteomics. All data are available through ProteomeXchange accession PXD000156. To pinpoint immunodominant bacterial-surface-exposed epitopes, we screened selected cell-wall-attached proteins of S. aureus for binding of immunoglobulin G from patients who have been challenged by different types of S. aureus due to chronic wound colonization. The combined results of these analyses highlight particular cell-surface-exposed S. aureus proteins with highly immunogenic exposed epitopes as potential targets for development of protective anti-staphylococcal immunization strategies.

Treating Parkinson's Disease with Antibodies: Previous Studies and Future Directions.

Parkinson’s disease is a neurodegenerative disorder mainly characterized by the degeneration of dopaminergic neurons in the substantia nigra. Degenerating neurons contain abnormal aggregates called Lewy bodies, that are predominantly composed of the misfolded and/or mutated alpha-synuclein protein. Post-translational modifications, cellular stress, inflammation and gene mutations are thought to trigger its pathological misfolding and aggregation. With alpha-synuclein pathology being strongly associated with dopaminergic neuronal toxicity, strategies aimed to reduce its burden are expected to be beneficial in slowing disease progression. Moreover, multiple sources of evidence suggest a cell-to-cell transmission of pathological alpha-synuclein in a prion-like manner. Therefore, antibodies targeting extra- or intracellular alpha-synuclein could be efficient in limiting the aggregation and transmission. Several active and passive immunization strategies have been explored to target alpha-synuclein. Here, we summarize immunotherapeutic approaches that were tested in pre-clinical or clinical studies in the last two decades in an attempt to treat Parkinson’s disease.

Anti-outer Membrane Vesicle Antibodies Increase Antibiotic Sensitivity of Pan-Drug-Resistant Acinetobacter baumannii.

Acinetobacter baumannii often causes serious nosocomial infections. Because of its serious drug resistance problems, complex drug resistance mechanism, and rapid adaptation to antibiotics, it often shows pan-drug resistance and high fatality rates, which represent great challenges for clinical treatment. Therefore, identifying new ways to overcome antibiotic resistance is particularly important. In this study, mice immunized with A. baumannii outer membrane vesicles (AbOMVs) produced high IgG levels for a long time, and this antiserum significantly increased the small molecule intracellular aggregation rate and concentrations. In vitro experiments demonstrated that the combined used of anti-AbOMV serum and quinolone antibiotics significantly increased the sensitivity of the bacteria to these antibiotics. Mouse sepsis model experiments demonstrated that delivery of these antibodies using both active and passive immunization strategies significantly improved the susceptibility to quinolone antibiotics, improved the survival rate of mice infected with A. baumannii, and reduced the bacterial load in the organs. In a pneumonia model, the combination of serum anti-AbOMVs and levofloxacin improved levofloxacin sensitivity, which significantly reduced the bacterial loads in the lung and spleen compared with those of the antibiotic or antibody alone. This combination also significantly reduced lung inflammatory cell infiltration and inflammatory cytokine aggregation. In this study, the main protein targets that bound to these antibodies were identified. Structural modeling showed that seven of the proteins were porins. Therefore, we speculated that the anti-AbOMV antibodies mainly improved the intracellular aggregation of antibiotics by affecting porins, thus improving susceptibility to quinolone antibiotics. This study provides a method to improve susceptibility to existing antibiotics and a novel idea for the prevention and treatment of pan-drug-resistant A. baumannii.

Targeting Clostridium difficile Surface Components to Develop Immunotherapeutic Strategies Against Clostridium difficile Infection.

New therapies are needed to prevent and treat Clostridium difficile infection and to limit the rise in antibiotic resistance. Besides toxins, several surface components have been characterized as colonization factors and have been shown as immunogenic. This review will focus on passive and active immunization strategies targeting C. difficile surface components to combat C. difficile. Concerning passive immunization, the first strategies used antisera raised against the entire bacterium to prevent infection in the hamster model. Then, surface components such as the flagellin and the S-layer proteins were used for immunization and the passive transfer of antibodies was protective in animal models. Passive immunotherapy with polyvalent immunoglobulins was used in humans and bovine immunoglobulin concentrates were evaluated in clinical trials. Concerning active immunization, vaccine assays targeting surface components were tested mainly in animal models, mouse models of colonization and hamster models of infection. Bacterial extracts, spore proteins and surface components of vegetative cells such as cell wall proteins, flagellar proteins, and polysaccharides were used as vaccine targets. Vaccine assays were performed by parenteral and mucosal routes of immunization. Both gave promising results and pave the way to development of new vaccines.

A natural human monoclonal antibody targeting Staphylococcus Protein A protects against Staphylococcus aureus bacteremia.

Staphylococcus aureus can cause devastating and life-threatening infections. With the increase in multidrug resistant strains, novel therapies are needed. Limited success with active and passive immunization strategies have been attributed to S. aureus immune evasion. Here, we report on a monoclonal antibody, 514G3, that circumvents a key S. aureus evasion mechanism by targeting the cell wall moiety Protein A (SpA). SpA tightly binds most subclasses of immunoglobulins via their Fc region, neutralizing effector function. The organism can thus shield itself with a protective coat of serum antibodies and render humoral immunity ineffective. The present antibody reactivity was derived from an individual with natural anti-SpA antibody titers. The monoclonal antibody is of an IgG3 subclass, which differs critically from other immunoglobulin subclasses since its Fc is not bound by SpA. Moreover, it targets a unique epitope on SpA that allows it to bind in the presence of serum antibodies. Consequently, the antibody opsonizes S. aureus and maintains effector function to enable natural immune mediated clearance. The data presented here provide evidence that 514G3 antibody is able to successfully rescue mice from S. aureus mediated bacteremia.

Immunization Strategies Against Clostridium difficile.

C. difficile infection (CDI) is an important healthcare- but also community-associated disease. CDI is considered a public health threat and an economic burden. A major problem is the high rate of recurrences. Besides classical antibiotic treatments, new therapeutic strategies are needed to prevent infection, to treat patients and prevent recurrences. If fecal transplantation has been recommended to treat recurrences, another key approach is to restore immunity against C. difficile and its virulence factors. Here, after a summary concerning the virulence factors, the host immune response against C. difficile and its role in the outcome of disease, we review the different approaches of passive immunotherapies and vaccines developed against CDI. Passive immunization strategies are designed in function of the target antigen, the antibody-based product and its administration route. Similarly, for active immunization strategies, vaccine antigens can target toxins or surface proteins and immunization can be performed by parenteral or mucosal routes. For passive immunization and vaccination as well, we first present immunization assays performed in animal models and second in humans and associated clinical trials. The different studies are presented according to the mode of administration either parenteral or mucosal and the target antigens, either toxins or colonization factors.

Vaccine against arteriosclerosis: an update.

Substantial data from experimental and clinical investigation support the role of immune-mediated mechanisms in atherogenesis, with immune systems responding to many endogenous and exogenous antigens that play either proatherogenic or atheroprotective roles. An active immunization strategy against many of these antigens could potentially alter the natural history of atherosclerosis. This review mainly focuses on the important studies on the search for antigens that have been tested in vaccine formulations to reduce atherosclerosis in preclinical models. It will also address the opportunities and challenges associated with potential clinical application of this novel therapeutic paradigm.

Cancer anti-angiogenesis vaccines: Is the tumor vasculature antigenically unique?

Angiogenesis is essential for the growth and metastasis of solid tumors. The tumor endothelium exists in a state of chronic activation and proliferation, fueled by the tumor milieu where angiogenic mediators are aberrantly over-expressed. Uncontrolled tumor growth, immune evasion, and therapeutic resistance are all driven by the dysregulated and constitutive angiogenesis occurring in the vasculature. Accordingly, great efforts have been dedicated toward identifying molecular signatures of this pathological angiogenesis in order to devise selective tumor endothelium targeting therapies while minimizing potential autoimmunity against physiologically normal endothelium. Vaccination with angiogenic antigens to generate cellular and/or humoral immunity against the tumor endothelium has proven to be a promising strategy for inhibiting or normalizing tumor angiogenesis and reducing cancer growth. Here we review tumor endothelium vaccines developed to date including active immunization strategies using specific tumor endothelium-associated antigens and whole endothelial cell-based vaccines designed to elicit immune responses against diverse target antigens. Among the novel therapeutic options, we describe a placenta-derived endothelial cell vaccine, ValloVax™, a polyvalent vaccine that is antigenically similar to proliferating tumor endothelium and is supported by pre-clinical studies to be safe and efficacious against several tumor types.

Bovine herpesvirus 4-based vector delivering a hybrid rat/human HER-2 oncoantigen efficiently protects mice from autochthonous Her-2+ mammary cancer

ABSTRACTThe epidermal growth factor receptor 2 (HER-2) oncogene is a major target for the immunotherapy of breast cancer. Following up to the therapeutic success achieved with Her-2-targeting monoclonal antibodies, immune-prophylactic approaches directed against Her-2 have also been investigated taking into account, and trying to overcome, Her-2 self-tolerance. Perhaps due to safety (and efficacy) concerns, the least explored anti-Her-2 active immunization strategy so far has been the one relying on viral-vectored vaccine formulations. Taking advantage of the favorable properties of bovine herpesvirus 4 (BoHV-4) in terms of safety and ease of manipulation as well as its previously documented ability to transduce and confer immunogenicity to heterologous antigens, we tested the ability of different recombinant HER-2-BoHV-4 immunogens to 8break tolerance and elicit a protective, anti-mammary tumor antibody response in HER-2 transgenic BALB-neuT mice. All the tested constructs expressed the HER-2 transgenes at high levels and elicited significant cellular immune responses in BALB/c mice upon administration via either DNA vaccination or viral infection. In BALB-neuT mice, instead, only the viral construct expressing the membrane-bound chimeric form of Her-2 protein (BoHV-4-RHuT-gD) elicited a humoral immune response that was more intense and earlier-appearing than that induced by DNA vaccination. In keeping with this observation, two administrations of BoHV-4-RHuT-gD effectively protected BALB-neuT mice from tumor formation, with 50% of vaccinated animals tumor-free after 30 weeks from immunization compared to 100% of animals exhibiting at least one palpable tumor in the case of animals vaccinated with the other BoHV-4-HER-2 constructs.

Mouse Models of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder characterized by synovitis that leads to cartilage and bone erosion by invading fibrovascular tissue. Mouse models of RA recapitulate many features of the human disease. Despite the availability of medicines that are highly effective in many patient populations, autoimmune diseases (including RA) remain an area of active biomedical research, and consequently mouse models of RA are still extensively used for mechanistic studies and validation of therapeutic targets. This review aims to integrate morphologic features with model biology and cover the key characteristics of the most commonly used induced and spontaneous mouse models of RA. Induced models emphasized in this review include collagen-induced arthritis and antibody-induced arthritis. Collagen-induced arthritis is an example of an active immunization strategy, whereas antibody- induced arthritis models, such as collagen antibody-induced arthritis and K/BxN antibody transfer arthritis, represent examples of passive immunization strategies. The coverage of spontaneous models in this review is focused on the TNFΔ (ARE) mouse, in which arthritis results from overexpression of TNF-α, a master proinflammatory cytokine that drives disease in many patients.

Antibodies for prevention of mother-to-child transmission of HIV-1.

Although antiretroviral (ARV) prophylaxis can reduce mother-to-child transmission (MTCT) of HIV-1 to less than 2%, one-quarter of a million infants continue to be infected with HIV-1 annually. ARV prophylaxis alone will fail to eliminate infant HIV-1 infection because of issues of maternal adherence, toxicities, ARV-resistant virus strains, and acute maternal infection. Effective maternal and/or infant immunization will likely be required to achieve the goal of an HIV-free generation. This article describes recent studies of antibody responses that protect against vertical HIV-1 transmission. Studies have shown that maternal neutralization breadth is not a critical factor in MTCT, yet the ability of maternal plasma to neutralize autologous virus variants may be important in infant protection. There is also new evidence that infants mount robust and durable antibody responses to HIV-1 envelope following vaccination and can develop broad neutralization during infection. Finally, passive immunization of infants with highly potent and broad neutralizing antibodies may be an effective strategy to protect infants against infection with postnatally transmitted variants. Defining the characteristics of maternal and infant antibody responses that protect against MTCT will inform development of effective passive and active immunization strategies that will likely be required to eliminate pediatric HIV-1.