Human Antibodies for Viral Infections.

Antibodies have been used to prevent or treat viral infections since the nineteenth century, but the full potential to use passive immunization for infectious diseases has yet to be realized. The advent of efficient methods for isolating broad and potently neutralizing human monoclonal antibodies is enabling us to develop antibodies with unprecedented activities. The discovery of IgG Fc region modifications that extend antibody half-life in humans to three months or more suggests that antibodies could become the principal tool with which we manage future viral epidemics. Antibodies for members of most virus families that cause severe disease in humans have been isolated, and many of them are in clinical development, an area that has accelerated during the effort to prevent or treat COVID-19 (coronavirus disease 2019). Broad and potently neutralizing antibodies are also important research reagents for identification of protective epitopes that can be engineered into active vaccines through structure-based reverse vaccinology.

Dual neutralization of influenza virus hemagglutinin and neuraminidase by a bispecific antibody leads to improved antiviral activity.

Targeting multiple viral proteins is pivotal for sustained suppression of highly mutable viruses. In recent years, broadly neutralizing antibodies that target the influenza virus hemagglutinin and neuraminidase glycoproteins have been developed, and antibody monotherapy has been tested in preclinical and clinical studies to treat or prevent influenza virus infection. However, the impact of dual neutralization of the hemagglutinin and neuraminidase on the course of infection, as well as its therapeutic potential, has not been thoroughly tested. For this purpose, we generated a bispecific antibody that neutralizes both the hemagglutinin and the neuraminidase of influenza viruses. We demonstrated that this bispecific antibody has a dual-antiviral activity as it blocks infection and prevents the release of progeny viruses from the infected cells. We show that dual neutralization of the hemagglutinin and the neuraminidase by a bispecific antibody is advantageous over monoclonal antibody combination as it resulted an improved neutralization capacity and augmented the antibody effector functions. Notably, the bispecific antibody showed enhanced antiviral activity in influenza virus-infected mice, reduced mice mortality, and limited the virus mutation profile upon antibody administration. Thus, dual neutralization of the hemagglutinin and neuraminidase could be effective in controlling influenza virus infection.

Recombinant neutralizing secretory IgA antibodies for preventing mucosal acquisition and transmission of SARS-CoV-2.

Passive delivery of antibodies to mucosal sites may be a valuable adjunct to COVID-19 vaccination to prevent infection, treat viral carriage, or block transmission. Neutralizing monoclonal IgG antibodies are already approved for systemic delivery, and several clinical trials have been reported for delivery to mucosal sites where SARS-CoV-2 resides and replicates in early infection. However, secretory IgA may be preferred because the polymeric complex is adapted for the harsh, unstable external mucosal environment. Here, we investigated the feasibility of producing neutralizing monoclonal IgA antibodies against SARS-CoV-2. We engineered two class-switched mAbs that express well as monomeric and secretory IgA (SIgA) variants with high antigen-binding affinities and increased stability in mucosal secretions compared to their IgG counterparts. SIgAs had stronger virus neutralization activities than IgG mAbs and were protective against SARS-CoV-2 infection in an in vivo murine model. Furthermore, SIgA1 can be aerosolized for topical delivery using a mesh nebulizer. Our findings provide a persuasive case for developing recombinant SIgAs for mucosal application as a new tool in the fight against COVID-19.

Targeting tau only extracellularly is likely to be less efficacious than targeting it both intra- and extracellularly.

Aggregation of the tau protein is thought to be responsible for the neurodegeneration and subsequent functional impairments in diseases that are collectively named tauopathies. Alzheimer's disease is the most common tauopathy, but the group consists of over 20 different diseases, many of which have tau pathology as their primary feature. The development of tau therapies has mainly focused on preventing the formation of and/or clearing these aggregates. Of these, immunotherapies that aim to either elicit endogenous tau antibodies or deliver exogenous ones are the most common approach in clinical trials. While their mechanism of action can involve several pathways, both extra- and intracellular, pharmaceutical companies have primarily focused on antibody-mediated clearance of extracellular tau. As we have pointed out over the years, this is rather surprising because it is well known that most of pathological tau protein is found intracellularly. It has been repeatedly shown by several groups over the past decades that antibodies can enter neurons and that their cellular uptake can be enhanced by various means, particularly by altering their charge. Here, we will briefly describe the potential extra- and intracellular mechanisms involved in antibody-mediated clearance of tau pathology, discuss these in the context of recent failures of some of the tau antibody trials, and finally provide a brief overview of how the intracellular efficacy of tau antibodies can potentially be further improved by certain modifications that aim to enhance tau clearance via specific intracellular degradation pathways.

Reducing huntingtin by immunotherapy delays disease progression in a mouse model of Huntington disease.

In Huntington disease (HD), the mutant huntingtin (mtHTT) protein is the principal cause of pathological changes that initiate primarily along the cortico-striatal axis. mtHTT is ubiquitously expressed and there is, accordingly, growing recognition that HD is a systemic disorder with functional interplay between the brain and the periphery. We have developed a monoclonal antibody, C6-17, targeting an exposed region of HTT near the aa586 Caspase 6 cleavage site. As recently published, mAB C6-17 can block cell-to-cell propagation of mtHTT in vitro. In order to reduce the burden of the mutant protein in vivo, we queried whether extracellular mtHTT could be therapeutically targeted in YAC128 HD mice. In a series of proof of concept experiments, we found that systemic mAB C6-17 treatment resulted in the distribution of the mAB C6-17 to peripheral and CNS tissues and led to the reduction of HTT protein levels. Compared to CTRL mAB or vehicle treated mice, the mAB C6-17 treated YAC128 animals showed improved body weight and motor behaviors, a delayed progression in motor deficits and reduced striatal EM48 immunoreactivity. These results provide the first proof of concept for the feasibility and therapeutic efficacy of an antibody-based anti-HTT passive immunization approach and suggest this modality as a potential new HD treatment strategy.

Prophylactic antibodies inhibit spike-specific T and B cell responses after COVID-19 vaccination.

Active and passive immunization is used in high-risk patients to prevent severe courses of COVID-19, but the impact of prophylactic neutralizing antibodies on the immune reaction to the mRNA vaccines has remained enigmatic. Here we show that CD4 T and B cell responses to Spikevax booster immunization are suppressed by the therapeutic antibodies Casirivimab and Imdevimab. B cell and T cell responses were significantly induced in controls but not in antibody-treated patients. The data indicates that humoral immunity, i. e. high levels of antibodies, negatively impacts reactive immunity, resulting in blunted cellular responses upon boosting. This argues for temporal separation of vaccination efforts; with active vaccination preferably applied before prophylactic therapeutic antibody treatment.

Development of fentanyl-specific monoclonal antibody (mAb) to antagonize the pharmacological effects of fentanyl.

Fentanyl, a critical component of opioid analgesics, poses a severe threat to public health, exacerbating the drug problem due to its potential fatality. Herein, we present two novel haptens designed with different attachment sites conjugated to keyhole limpet hemocyanin (KLH), aiming to develop an efficacious vaccine against fentanyl. KLH-Fent-1 demonstrated superior performance over KLH-Fent-2 in antibody titer, blood-brain distribution, and antinociceptive tests. Consequently, we immunized mice with KLH-Fent-1 to generate fentanyl-specific monoclonal antibodies (mAbs) using the hybridoma technique to compensate for the defects of active immunization in the treatment of opioid overdose and addiction. The mAb produced by hybridoma 9D5 exhibited the ability to recognize fentanyl and its analogs with a binding affinity of 10-10 M. Subsequently, we developed a human IgG1 chimeric mAb to improve the degree of humanization. Pre-treatment with murine and chimeric mAb significantly reduced the analgesic effect of fentanyl and altered its blood-brain biodistribution in vivo. Furthermore, in a mouse model of fentanyl-induced respiratory depression, the chimeric mAb effectively reversed respiratory depression promptly and maintained a certain level during the week. The development of high-affinity chimeric mAb gives support to combat the challenges of fentanyl misuse and its detrimental consequences. In conclusion, mAb passive immunization represents a viable strategy for addressing fentanyl addiction and overdose.

Passive immunoprophylaxis with Ccombodies against Vibrio parahaemolyticus in Pacific white shrimp (Penaeus vannamei).

The Vibrio parahaemolyticus strain causing acute hepatopancreatic necrosis disease (AHPND) in shrimp secretes toxins A and B (PirAVp/PirBVp). These toxins have been implicated in pathogenesis and are targets for developing anti-AHPND therapeutics or prophylactics that include passive immunization. We have previously reported that Ccombodies (recombinant hagfish variable lymphocyte receptor B antibodies; VLRB) targeting PirBVp conferred protection against V. parahaemolyticus in shrimp when administered as a feed supplement. In this study, we screened a phage-displayed library of engineered VLRBs for PirAVp-targeting Ccombodies that were mass-produced in a bacterial expression system. We then introduced these Ccombodies into the diet of Pacific white shrimp (Penaeus vannamei) over a seven-day period. Subsequently, the shrimp were exposed to a challenge with V. parahaemolyticus. Mortality rates were then observed and recorded over the following seven days. Administering shrimp feed supplemented with Ccombodies at a high dose (100 mg per 100 g feed) reduced mortality in recipient animals (2.96-5.19 %) statistically similar to mock-challenged control (1.48 %), but significantly different from the Ccombody-deficient control (74.81 %). This suggests that the Ccombodies provided strong protection against the bacterium. Feeding shrimp with a median dose (10 mg/100 g feed) gave statistically comparable low mortality (5.93-6.67 %) as the high dose. Reducing the Ccombody dose to 1 mg/100 g feed showed variable effects. Ccombody A2 showed mortality (11.85 %) significantly lower than that of the Ccombody-deficient group (74.81 %), suggesting that it can effectively protect against the bacterial challenge at a low dose. Our results demonstrate the ability of the phage-displayed VLRB library to generate antigen-specific Ccombodies rapidly and simply, with the expression of high protein levels in bacteria. The protective effect provided by these Ccombodies aligns with our earlier results, strongly supporting the use of VLRB antibodies as a substitute for IgY in passive immunoprophylaxis against AHPND in shrimp.

Safety and Immunogenicity of an Investigational Respiratory Syncytial Virus Vaccine (RSVPreF3) in Mothers and Their Infants: A Phase 2 Randomized Trial.

BACKGROUND: In a phase 1/2 study, a maternal respiratory syncytial virus vaccine candidate (RSVPreF3) demonstrated an acceptable safety profile and efficiently increased RSV-specific humoral immune responses in non-pregnant women. METHODS: In this phase 2 observer-blind, placebo-controlled, randomized clinical trial (NCT04126213), the safety of RSVPreF3 (60 or 120 µg), administered during late second or third trimester, was evaluated in 213 18- to 40-year-old healthy pregnant women through 6 months postdelivery and their offspring through infancy; immunogenicity was evaluated through day 43 postdelivery and day 181 postbirth, respectively. RESULTS: RSVPreF3 was well tolerated. No pregnancy-related or neonatal adverse events of special interest were considered vaccine/placebo related. In the 60 and 120 µg RSVPreF3 groups: (1) neutralizing antibody (nAb) titers in mothers increased 12.7- and 14.9-fold against RSV-A and 10.6- and 13.2-fold against RSV-B, respectively, 1 month postvaccination and remained 8.9-10.0-fold over prevaccination at day 43 postdelivery; (2) nAb titers were consistently higher compared to placebo recipients; (3) placental transfer ratios for anti-RSVPreF3 antibodies at birth were 1.62 and 1.90, respectively, and (4) nAb levels in infants were highest at birth and declined through day 181 postbirth. CONCLUSIONS: RSVPreF3 maternal vaccination had an acceptable safety risk profile and induced robust RSV-specific immune responses with successful antibody transfer to their newborns. CLINICAL TRIALS REGISTRATION: NCT04126213.

WHAT IS THE CONTEXT?: Infants, especially those less than 6 months of age, are at increased risk of lung infection caused by respiratory syncytial virus (RSV). However, this risk could be reduced with maternal vaccination against RSV during pregnancy. A previous clinical trial found that a vaccine candidate (named RSVPreF3) was well tolerated when given to non-pregnant women. WHAT IS NEW?: In pregnant women, RSVPreF3 was also well tolerated. Occurrence of unsolicited adverse events was similar between vaccine and placebo recipients. None of the serious adverse events or events of interest for pregnant women or newborns were considered related to the study intervention. One month after vaccination, mothers who received RSVPreF3 had 11­15 times higher levels of antibodies against RSV than before vaccination. These antibody levels remained similar until 43 days after delivery. In the infants born to mothers vaccinated during pregnancy with RSVPreF3, antibody levels were highest at birth, when levels were higher than in their mothers, and declined through day 181 postbirth. WHAT IS THE IMPACT?: RSVPreF3 had an acceptable safety risk profile in pregnant women and their babies. This vaccine induced potent immune responses against RSV, with maternal antibodies transferred to infants of the vaccinated mothers.

Guidance on the Use of Convalescent Plasma to Treat Immunocompromised Patients With Coronavirus Disease 2019.

Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) is a safe and effective treatment for COVID-19 in immunocompromised (IC) patients. IC patients have a higher risk of persistent infection, severe disease, and death from COVID-19. Despite the continued clinical use of CCP to treat IC patients, the optimal dose, frequency/schedule, and duration of CCP treatment has yet to be determined, and related best practices guidelines are lacking. A group of individuals with expertise spanning infectious diseases, virology and transfusion medicine was assembled to render an expert opinion statement pertaining to the use of CCP for IC patients. For optimal effect, CCP should be recently and locally collected to match circulating variant. CCP should be considered for the treatment of IC patients with acute and protracted COVID-19; dosage depends on clinical setting (acute vs protracted COVID-19). CCP containing high-titer severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies, retains activity against circulating SARS-CoV-2 variants, which have otherwise rendered monoclonal antibodies ineffective.

Passive Immunization with a Single Monoclonal Neutralizing Antibody Protects against Cutaneous and Mucosal Mouse Papillomavirus Infections.

We have established a mouse papillomavirus (MmuPV1) model that induces both cutaneous and mucosal infections and cancers. In the current study, we use this model to test our hypothesis that passive immunization using a single neutralizing monoclonal antibody can protect both cutaneous and mucosal sites at different time points after viral inoculation. We conducted a series of experiments involving the administration of either a neutralizing monoclonal antibody, MPV.A4, or control monoclonal antibodies to both outbred and inbred athymic mice. Three clinically relevant mucosal sites (lower genital tract for females and anus and tongue for both males and females) and two cutaneous sites (muzzle and tail) were tested. At the termination of the experiments, all tested tissues were harvested for virological analyses. Significantly lower levels of viral signals were detected in the MPV.A4-treated female mice up to 6 h post-viral inoculation compared to those in the isotype control. Interestingly, males displayed partial protection when they received MPV.A4 at the time of viral inoculation, even though they were completely protected when receiving MPV.A4 at 24 h before viral inoculation. We detected MPV.A4 in the blood starting at 1 h and up to 8 weeks postadministration in some mice. Parallel to these in vivo studies, we conducted in vitro neutralization using a mouse keratinocyte cell line and observed complete neutralization up to 8 h post-viral inoculation. Thus, passive immunization with a monoclonal neutralizing antibody can protect against papillomavirus infection at both cutaneous and mucosal sites and is time dependent. IMPORTANCE This is the first study testing a single monoclonal neutralizing antibody (MPV.A4) by passive immunization against papillomavirus infections at both cutaneous and mucosal sites in the same host in the mouse papillomavirus model. We demonstrated that MPV.A4 administered before viral inoculation can protect both male and female athymic mice against MmuPV1 infections at cutaneous and mucosal sites. MPV.A4 also offers partial protection at 6 h post-viral inoculation in female mice. MPV.A4 can be detected in the blood from 1 h to 8 weeks after intraperitoneal (i.p.) injection. Interestingly, males were only partially protected when they received MPV.A4 at the time of viral inoculation. The failed protection in males was due to the absence of neutralizing MPV.A4 at the infected sites. Our findings suggest passive immunization with a single monoclonal neutralizing antibody can protect against diverse papillomavirus infections in a time-dependent manner in mice.

Polyvalent passive vaccine candidates from egg yolk antibodies (IgY) of important outer membrane proteins (PF1380 and ExbB) of Pseudomonas fluorescens in fish.

Polyvalent antibodies can resist multiple bacterial species, and immunoglobulin Y (IgY) antibody can be economically prepared in large quantities from egg yolk; further, IgY polyvalent antibodies have application value in aquaculture. The outer membrane proteins (OMPs) PF1380 and ExbB of Pseudomonas fluorescens were expressed and purified, and the corresponding IgY antibodies were prepared. PF1380, ExbB, and the corresponding IgY antibodies could activate the innate immune responses of chicken and Carassius auratus. The passive immunization to C. auratus showed that the IgY antibodies of PF1380 and ExbB had an immune protection rate, down-regulated the expression of antioxidant-related factors (MDA, SOD, GSH-Px, and CAT) to reduce the antioxidant reaction, down-regulated the expression of inflammation-related genes (IL-6, IL-8, TNF-α, and IL-1ß) to reduce the inflammatory reaction, maintained the integrity of visceral tissue structure, and reduced apoptosis and damage of tissue cells in relation to P. fluorescens and Aeromonas hydrophila infections. Thus, the IgY antibodies of PF1380 and ExbB could be considered as passive polyvalent vaccine candidates in aquaculture.

Characterization of an Anti-Ebola Virus Hyperimmune Globulin Derived From Convalescent Plasma.

BACKGROUND: Convalescent plasma has been used to treat many viral diseases including Ebola. The manufacture of a purified anti-Ebola virus (EBOV) intravenous immunoglobulin (IVIG) from pooled convalescent plasma is described in this paper. METHODS: An enzyme-linked immunosorbent assay (ELISA) targeting an EBOV surface glycoprotein antigen was used to determine the immunoglobulin titer of pooled plasma and purified anti-EBOV IVIG. Anti-EBOV IVIG was also tested in neutralization assays using a vesicular stomatitis virus pseudovirion expressing EBOV glycoprotein on its surface and with live EBOV. Finally, the efficacy of the anti-EBOV IVIG was assessed in a mouse model of EBOV infection. RESULTS: In the ELISA, the anti-EBOV IVIG was shown to have a 7-fold increase in immunoglobulin G (IgG) titer over pooled convalescent plasma. In both the pseudovirion and live virus assays, the anti-EBOV IVIG showed approximately 5- to 6-fold increased potency over pooled plasma. Anti-EBOV IVIG also significantly improved survivability in mice infected with the virus when administered concurrently or 2 days after infection. CONCLUSIONS: These data support this purified anti-EBOV IVIG merits additional investigation and clinical trials for treatment and postexposure prophylaxis of Ebola virus disease. The experience gained can be applied to manufacture hyperimmune globulins against other emerging viruses.

[The burden of COVID-19 in a heterogeneous population of immunocompromised patients - realities of the postpandemic].

On July 3, 2023, an interdisciplinary Council of Experts "The burden of COVID-19 in a heterogeneous population of immunocompromised patients - post-pandemic realities" was held in Moscow with leading experts in pulmonology, rheumatology, hematology, oncology, nephrology, allergology-immunology, transplantation, and infectious diseases. The aim of the meeting was to discuss the current clinical and epidemiologic situation related to COVID-19, the relevance of disease prevention strategies for high-risk patients. The experts addressed the following issues: 1) the disease burden of COVID-19 in 2023 for patients with immunodeficiency in different therapeutic areas; 2) the place of passive immunization with monoclonal antibodies as a method of COVID-19 prophylaxis among immunocompromised patients; 3) prerequisites for the inclusion of passive immunization of immunocompromised patients into routine clinical practice.

[Efficacy and safety of patients immunization with chronic obstructive pulmonary disease with monoclonal antibodies].

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by a high level of morbidity and mortality and is associated with significant social and economic damage to the health system and society. COPD and COVID-19 have many potentially negative relationships that can lead to worse outcomes of COVID-19, including impaired lung function, old age and the presence of concomitant diseases Aim. To assess efficacy and safety of the drug Tixagevimab + Cilgavimab for the pre-contact prevention of COVID-19 infection in patients with COPD. MATERIAL AND METHODS: A total of 324 male patients were included in the study, who were treated or monitored at the Regional Clinic Hospital №3 and the Regional Pulmonological Center of Chelyabinsk in April-May 2022. The main endpoints of observation, for 3 and 6 months, to assess the effectiveness were the dynamics of shortness of breath according to The Modified Medical Research Council Dyspnea Scale - mMRC, the The forced expiratory volume in 1 second, the number of exacerbations, emergency calls, hospitalizations, polymerase chain reaction for SARS-CoV-2. Local and general reactions after immunization were evaluated. The drug Evusheld (150 mg Tixsagevimab +150 mg Cilgavimab, AstraZeneca) was used for immunization. RESULTS AND CONCLUSION: The effectiveness of pre-contact prevention of COVID-19 was 88.8%. The administration of the drug does not provoke an exacerbation of the underlying disease. The main clinical and functional indicators have positive dynamics by the 6th month of follow-up. The drug is well tolerated and has no significant both early and late complications.

High-Dose Convalescent Plasma for Treatment of Severe COVID-19.

To assess whether high-dose coronavirus disease (COVID-19) convalescent plasma (CCP) transfusion may benefit patients with severe COVID-19, we conducted a multicenter randomized trial in Brazil. Patients with severe COVID-19 who were within 10 days of initial symptom onset were eligible. Patients in the CCP group received 3 daily doses of CCP (600 mL/d) in addition to standard treatment; control patients received standard treatment only. Primary outcomes were death rates at days 30 and 60 of study randomization. Secondary outcomes were ventilator-free days and hospital-free days. We enrolled 107 patients: 36 CCP and 71 control. At day 30, death rates were 22% for CCP and 25% for the control group; at day 60, rates were 31% for CCP and 35% for control. Needs for invasive mechanical ventilation and durations of hospital stay were similar between groups. We conclude that high-dose CCP transfused within 10 days of symptom onset provided no benefit for patients with severe COVID-19.

Effect of monoclonal antibody therapy on the endogenous SARS-CoV-2 antibody response.

Monoclonal antibody treatment of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been widely implemented. Effects of treatment on the endogenous primary humoral response to the virus are unknown. A retrospective cohort study performed at a Veterans Health Administration medical center compared serologic responses of treated and untreated COVID-19 patients at high risk for severe outcomes. Three anti-viral spike protein IgG monoclonal treatments were used during the study period, 1) bamlanivimab, 2) casirivimab with imdevimab, and 3) bamlanivimab with etesevimab. Data were analyzed at acute (0-9 days), seroconversion (10-19 days), and maximum antibody (20-39 days) stages. SARS-Cov-2 infection induced a dynamic primary humoral response with anti-spike IgM and anti-nucleocapsid IgG seroconversion occurring after 9 days with maximum serologic indices achieved by 20-39 days. All monoclonal antibody treatments suppressed the endogenous anti-spike IgM response by 85-90% with minor effect on the anti-nucleocapsid response. Thus, passive immunization therapy may cause immunologic interference.

Broadly Neutralizing Antibodies for HIV Prevention.

In the last decade, over a dozen potent broadly neutralizing antibodies (bnAbs) to several HIV envelope protein epitopes have been identified, and their in vitro neutralization profiles have been defined. Many have demonstrated prevention efficacy in preclinical trials and favorable safety and pharmacokinetic profiles in early human clinical trials. The first human prevention efficacy trials using 10 sequential, every-two-month administrations of a single anti-HIV bnAb are anticipated to conclude in 2020. Combinations of complementary bnAbs and multi-specific bnAbs exhibit improved breadth and potency over most individual antibodies and are entering advanced clinical development. Genetic engineering of the Fc regions has markedly improved bnAb half-life, increased mucosal tissue concentrations of antibodies (especially in the genital tract), and enhanced immunomodulatory and Fc effector functionality, all of which improve antibodies' preventative and therapeutic potential. Human-derived monoclonal antibodies are likely to enter the realm of primary care prevention and therapy for viral infections in the near future.

Promising targets for immunotherapeutic approaches against Acinetobacter baumannii.

Acinetobacter baumannii is an opportunistic pathogen associated with the occurrence of outbreaks in hospital settings, especially in Intensive Care Units (ICUs). Pneumonia, septicemias, urinary tract infections, and recurrent infections associated with the use of hospital devices are some of the most frequent complications. Due to the increase of A. baumannii strains resistant to multiple antimicrobials, associated with their high capacity to form biofilms on biotic and abiotic surfaces, the therapeutic strategies routinely applied have become increasingly restricted and ineffective, resulting in high mortality rates. Many studies have focused on the development of new therapeutic approaches, mainly non-antibiotic-based. Polyclonal (pAb) and monoclonal (mAb) antibodies are increasingly cited in the literature as alternative strategies to the use of antimicrobial drugs and are evaluated for the prevention and treatment of these infections. In this context, this review aimed to synthesize the main strategies based on the use of antibodies that are being evaluated for the control of A. baumannii infections. Here, we describe the main A. baumannii antigenic targets used in studies to assess their potential to induce the formation of antibodies and their possible application in immunotherapy strategies.

In vitro and in vivo efficacies of Dectin-1-Fc(IgG)(s) fusion proteins against invasive fungal infections.

Fungal infections have increased in the last years, particularly associated to an increment in the number of immunocompromised individuals and the emergence of known or new resistant species, despite the difficulties in the often time-consuming diagnosis. The controversial efficacy of the currently available strategies for their clinical management, apart from their high toxicity and severe side effects, has renewed the interest in the research and development of new broad antifungal alternatives. These encompass vaccines and passive immunization strategies with monoclonal antibodies (mAbs), recognizing ubiquitous fungal targets, such as fungal cell wall ß-1,3-glucan polysaccharides, which could be used in early therapeutic intervention without the need for the diagnosis at species level. As additional alternatives, based on the Dectin-1 great affinity to ß-1,3-glucan, our group developed broad antibody-like Dectin1-Fc(IgG)(s) from distinct subclasses (IgG2a and IgG2b) and compared their antifungal in vitro and passive immunizations in vivo performances. Dectin1-Fc(IgG2a) and Dectin1-Fc(IgG2b) demonstrated high affinity to laminarin and the fungal cell wall by ELISA, flow cytometry, and microscopy. Both Dectin-1-Fc(IgG)(s) inhibited Histoplasma capsulatum and Cryptococcus neoformans growth in a dose-dependent fashion. For Candida albicans, such inhibitory effect was observed with concentrations as low as 0.098 and 0.049 µg/ml, respectively, which correlated with the impairment of the kinetics and lengths of germ tubes in comparison to controls. Previous opsonization with Dectin-1-Fc(IgG)(s) enhanced considerably the macrophage antifungal effector functions, increasing the fungi macrophages interactions and significantly reducing the intraphagosome fungal survival, as lower CFUs were observed. The administration of both Dectin1-Fc(IgG)(s) reduced the fungal burden and mortality in murine histoplasmosis and candidiasis models, in accordance with previous evaluations in aspergillosis model. These results altogether strongly suggested that therapeutic interventions with Dectin-1-Fc(IgG)(s) fusion proteins could directly impact the innate immunity and disease outcome in favor of the host, by direct neutralization, opsonization, phagocytosis, and fungal elimination, providing interesting information on the potential of these new strategies for the control of invasive fungal infections. LAY SUMMARY: Mycoses have increased worldwide, and new efficient therapeutics are needed. Passive immunizations targeting universally the fungal cell would allow early interventions without the species-level diagnosis. Lectins with affinity to carbohydrates could be used to engineer 'antibody-like' strategies.