Combination of dexamethasone and dexmedetomidine as adjuvants of transversus abdominis plane block for postoperative analgesia in gastric cancer patients: A double-blinded randomized controlled trial.

STUDY OBJECTIVE: We conducted this double-blinded randomized controlled trial to examine whether the combination of dexamethasone and dexmedetomidine as adjuvants of transversus abdominis plane (TAP) block could improve analgesia efficacy and duration for gastric cancer patients. DESIGN: Randomized controlled trial. SETTING: The preoperative area, operating room, postanesthesia recovery room and bed ward. PATIENTS: A total of 312 adult patients (104 per group) with gastric cancer were included. INTERVENTIONS: Patients received bilateral subcostal TAP block with three different anesthetics (60 ml 0.25% ropivacaine added with 10 mg dexamethasone and 1 µg·kg-1 dexmedetomidine [A] or 10 mg dexamethasone [B] or 1 µg·kg-1 dexmedetomidine [C]). MEASUREMENTS: The primary outcome was the incidence of moderate-to-severe pain 24 h on movement. Secondary outcomes included incidence of moderate-to-severe pain, pain score, opioids use, recovery quality and adverse events. MAIN RESULTS: The incidence of moderate-to-severe pain on movement 24 h postoperatively of group A was significantly lower than group B (45.19% vs 63.46%; RR 0.71; 95% CI, 0.55 to 0.92) and group C (45.19% vs 73.08%, RR 0.62; 95% CI, 0.49 to 0.79). The median moving pain scores decreased significantly at 24 h (3.00 [3.00,5.00] vs 4.00 [3.00,6.00] vs 4.00 [3.00,5.00]; P < 0.001). There were significant differences in the opioids consumption within the first 24 h (27.5 [17.0,37.2] vs 30.0 [20.0,42.0] vs 32.0 [25.0,44.0] mg; P = 0.01) and the duration to first rescue analgesia (65.5 ± 26.7 vs 45.9 ± 34.5 vs 49.2 ± 27.2 h; P = 0.04). CONCLUSIONS: The combination with dexamethasone and dexmedetomidine as adjuvants for TAP block reduced the incidence of moderate-to-severe pain and pain score both on movement and at rest at 24 h with prolonged duration to first rescue analgesia after gastric cancer surgery. TRIAL REGISTRATION NUMBER: ChiCTR2000037981.

Next-Generation Vaccine Development with Nanomaterials: Recent Advances, Possibilities, and Challenges.

Nanomaterials are becoming important tools for vaccine development owing to their tunable and adaptable nature. Unique properties of nanomaterials afford opportunities to modulate trafficking through various tissues, complement or augment adjuvant activities, and specify antigen valency and display. This versatility has enabled recent work designing nanomaterial vaccines for a broad range of diseases, including cancer, inflammatory diseases, and various infectious diseases. Recent successes of nanoparticle vaccines during the coronavirus disease 2019 (COVID-19) pandemic have fueled enthusiasm further. In this review, the most recent developments in nanovaccines for infectious disease, cancer, inflammatory diseases, allergic diseases, and nanoadjuvants are summarized. Additionally, challenges and opportunities for clinical translation of this unique class of materials are discussed.

CD38 and extracellular NAD+ regulate the development and maintenance of Hp vaccine-induced CD4+ TRM in the gastric epithelium.

Tissue-resident memory T cells (TRM) can be induced by infection and vaccination, and play a key role in maintaining long-term protective immunity against mucosal pathogens. Our studies explored the key factors and mechanisms affecting the differentiation, maturation, and stable residence of gastric epithelial CD4+ TRM induced by Helicobacter pylori (Hp) vaccine and optimized Hp vaccination to promote the generation and residence of TRM.CD38 regulated mitochondrial activity and enhanced TGF-ß signal transduction to promote the differentiation and residence of gastric epithelial CD4+ TRM by mediating the expression of CD105. Extracellular nucleotides influenced the long-term maintenance of TRM in gastric epithelium by P2RX7. Vitamin D3 and Gram-positive enhancer matrix particles (GEMs)as immune adjuvants combined with Hp vaccination promoted the production of CD69+CD103+CD4+ TRM.

Current Progress in the Science of Novel Adjuvant Nano-Vaccine-Induced Protective Immune Responses.

Vaccinations are vital as they protect us from various illness-causing agents. Despite all the advancements in vaccine-related research, developing improved and safer vaccines against devastating infectious diseases including Ebola, tuberculosis and acquired immune deficiency syndrome (AIDS) remains a significant challenge. In addition, some of the current human vaccines can cause adverse reactions in some individuals, which limits their use for massive vaccination program. Therefore, it is necessary to design optimal vaccine candidates that can elicit appropriate immune responses but do not induce side effects. Subunit vaccines are relatively safe for the vaccination of humans, but they are unable to trigger an optimal protective immune response without an adjuvant. Although different types of adjuvants have been used for the formulation of vaccines to fight pathogens that have high antigenic diversity, due to the toxicity and safety issues associated with human-specific adjuvants, there are only a few adjuvants that have been approved for the formulation of human vaccines. Recently, nanoparticles (NPs) have gain specific attention and are commonly used as adjuvants for vaccine development as well as for drug delivery due to their excellent immune modulation properties. This review will focus on the current state of adjuvants in vaccine development, the mechanisms of human-compatible adjuvants and future research directions. We hope this review will provide valuable information to discovery novel adjuvants and drug delivery systems for developing novel vaccines and treatments.

Flagellin conjugated Per a 10 and its T cell peptides attenuate airway inflammation and restore cellular function.

Adjuvants were used to modulate response towards relevant immune cells. The present study aims to investigate FlaA-conjugated Per a 10 and T cell peptides in amelioration of allergic airway disease in mice. Mice given Per a 10 showed allergic features with higher cellular infiltration, IgE, Th-2 cytokines and alarmins. Fusion protein treatment reduced lung inflammation (p < 0.0001) and cellular infiltrates (p < 0.001) with higher IgG2a/IgE indicating resolution of disease. Immunotherapy with FPT1 and FPT3 reduces IL-4, IL-5 and IL-13 levels (p < 0.0001) with a fourfold increase in IFN-γ secretion in BALF. FPT1- and FPT3-treated mice have increased IL-10 and TGF-ß levels (p < 0.001) with CD4+Foxp3+ T cells (p < 0.01) indicating Treg response. There was enhanced expression of claudin-1 (1.7-fold) and occludin (fourfold) in lungs of FPT1- and FPT3-treated mice with reduced TSLP (p < 0.01) and IL-33 (p < 0.0001) secretion in BALF indicating recovery of epithelial function. Peptide-conjugated FlaA proteins showed protective immunity in mice and have potential for immunotherapy with restoration of cellular function.

Upregulation of iNOS/NO in Cancer Cells That Survive a Photodynamic Challenge: Role of No in Accelerated Cell Migration and Invasion.

Anti-tumor photodynamic therapy (PDT) is a unique modality that employs a photosensitizer (PS), PS-exciting light, and O2 to generate cytotoxic oxidants. For various reasons, not all malignant cells in any given tumor will succumb to a PDT challenge. Previous studies by the authors revealed that nitric oxide (NO) from inducible NO synthase (iNOS/NOS2) plays a key role in tumor cell resistance and also stimulation of migratory/invasive aggressiveness of surviving cells. iNOS was the only NOS isoform implicated in these effects. Significantly, NO from stress-upregulated iNOS was much more important in this regard than NO from preexisting enzymes. Greater NO-dependent resistance, migration, and invasion was observed with at least three different cancer cell lines, and this was attenuated by iNOS activity inhibitors, NO scavengers, or an iNOS transcriptional inhibitor. NO diffusing from PDT-targeted cells also stimulated migration/invasion potency of non-targeted bystander cells. Unless counteracted by appropriate measures, all these effects could seriously compromise clinical PDT efficacy. Here, we will review specific examples of these negative side effects of PDT and how they might be suppressed by adjuvants such as NO scavengers or inhibitors of iNOS activity or expression.

Influence of adjuvant type and route of administration on the immunogenicity of Leishmania-derived tick-borne encephalitis virus-like particles - A recombinant vaccine candidate.

Tick-borne encephalitis virus (TBEV) is a tick-borne flavivirus that induces severe central nervous system disorders. It has recently raised concerns due to an expanding geographical range and increasing infection rates. Existing vaccines, though effective, face low coverage rates in numerous TBEV endemic regions. Our previous work demonstrated the immunogenicity and full protection afforded by a TBEV vaccine based on virus-like particles (VLPs) produced in Leishmania tarentolae cells in immunization studies in a mouse model. In the present study, we explored the impact of adjuvants (AddaS03™, Alhydrogel®+MPLA) and administration routes (subcutaneous, intramuscular) on the immune response. Adjuvanted groups exhibited significantly enhanced antibody responses, higher avidity, and more balanced Th1/Th2 response. IFN-γ responses depended on the adjuvant type, while antibody levels were influenced by both adjuvant and administration routes. The combination of Leishmania-derived TBEV VLPs with Alhydrogel® and MPLA via intramuscular administration emerged as a highly promising prophylactic vaccine candidate, eliciting a robust, balanced immune response with substantial neutralization potential.

Biomimetic Multilayered Lipid Nanovesicles for Potent Protein Vaccination.

Lipid vesicles are widely used for drug and gene delivery, but their structural instability reduces in vivo efficacy and requires specialized handling. To address these limitations, strategies like lipid cross-linking and polymer-lipid conjugation are suggested to enhance stability and biological efficacy. However, the in vivo metabolism of these altered lipids remains unclear, necessitating further studies. A new stabilization technique without chemical modification is urgently needed. Here, a bio-mimetic approach for fabricating robust multilamellar lipid vesicles to enhance in vivo delivery and stabilization of protein antigens is presented. This method leverages 1-O-acylceramide, a natural skin lipid, to facilitate the self-assembly of lipid nanovesicles. Incorporating 1-O-acylceramide, anchoring lipid bilayers akin to its role in the stratum corneum, provides excellent stability under environmental stresses, including freeze-thaw cycles. Encapsulating ovalbumin as a model antigen and the adjuvant monophosphoryl lipid A demonstrates the vesicle's potential as a nanovaccine platform. In vitro studies show enhanced immune responses with both unilamellar and multilamellar vesicles, but in vivo analyses highlight the superior efficiency of multilamellar vesicles in inducing higher antibody and cytokine levels. This work suggests ceramide-induced multilamellar lipid vesicles as an effective nanovaccine platform for enhanced antigen delivery and stability.

Selenium nanoparticles enhance mucosal immunity against Mycobacterium bovis infection.

Selenium nanoparticles (SeNPs) enhance the immune response as adjuvants, increasing the efficacy of viral vaccines, including those for COVID-19. However, the efficiency of mucosal SeNPs in boosting vaccine-induced protective immunity against tuberculosis remains unclear. Therefore, this study aims to investigate whether the combination of SeNPs with the AH antigen (Ag85A-HspX) can boost respiratory mucosal immunity and thereby enhance the protective effects against tuberculosis. We synthesized SeNPs and assessed their impact on the immune response and protection against Mycobacterium bovis (M. bovis) as a mucosal adjuvant in mice, administered intranasally at a dose of 20 µg. SeNPs outperformed polyinosinic-polycytidylic acid (Poly IC) in stimulating the maturation of bone marrow-derived dendritic cells (BMDCs), which enhanced antigen presentation. SeNPs significantly activated and proliferated tissue-resident memory T cells (TRMs) and effector CD4+ T cells in the lungs. The vaccines elicited specific antibody responses in the respiratory tract and stimulated systemic Th1 and Th17 immune responses. Immunization with AH and SeNPs led to higher levels of mucosal secretory IgA in bronchoalveolar lavage fluid (BALF) and secretory IL-17 in splenocytes. Moreover, SeNPs immunized mice showed reduced M. bovis infection loads and inflammatory lesions in the lungs post-challenge. Notably, immunization with AH and SeNPs significantly reduced bacterial load in the lungs, achieving the lowest levels compared to all other tested groups. This study calls for pre-clinical investigation of AHB-SeNPs as an anti-bovine tuberculosis vaccine and for exploring its human vaccine potential, which is anticipated to aid in the development of innovative vaccines or adjuvants.

Effect of an increased dose of intrathecal fentanyl on cesarean delivery anesthesia at a Texas level IV maternal care center.

Background: We hypothesized that increasing our intrathecal fentanyl dose for cesarean delivery from 10 µg to 15 µg would result in fewer patients receiving a rescue analgesia intervention. Methods: Patients who had a cesarean delivery from February 15, 2021 to February 14, 2023 and received a single injection spinal or combined spinal-epidural anesthetic for cesarean delivery were eligible for inclusion. We defined a rescue analgesia intervention as administration of local anesthetic through an epidural catheter, administration of systemic anesthetic adjuvant medication, or conversion to general anesthesia. Results: A total of 520 and 556 patients received 10 µg and 15 µg of intrathecal fentanyl for cesarean delivery, respectively, of which 154 (29.6%) and 122 (21.9%) patients required rescue analgesia interventions, respectively (P = 0.004). The odds ratio for receiving a rescue analgesia intervention was 0.668 (95% confidence interval 0.507 to 0.880; P = 0.004) for patients who received 15 µg of intrathecal fentanyl compared to 10 µg. Conclusion: Following implementation of an increased dose of intrathecal fentanyl, patients who received 15 µg of intrathecal fentanyl for cesarean delivery were approximately 33% less likely to require a rescue analgesia intervention during cesarean delivery compared to patients who received 10 µg.

The Impact of Pain on Mobility in Patients with Cancer.

OBJECTIVES: Provide an overview of how pain impacts mobility in patients with cancer. METHODS: A literature search was conducted in PubMed and on Google Scholar using search terms, cancer pain with mobility, acute and chronic pain syndromes, enhanced recovery after surgery, nursing care, and rehabilitation. Peer-reviewed research studies, review articles, and pain guidelines and position papers were reviewed to provide an overview on cancer pain, its impact on mobility, and the nurse's role in managing pain and optimizing mobility and functional outcomes. RESULTS: Firty-two references were included in this overview. This body of literature is replete with studies on the management of pain; however, the tie between pain and mobility has not been well described aside from the breakthrough pain literature. This manuscript weaves these two important concepts together to better inform nurses and other clinicians regarding the importance of managing pain to even begin mobilizing patients, especially following surgery and for other painful conditions. CONCLUSIONS: Oncology nurses play an integral role in assessing and managing cancer pain. It is important for nurses to recognize how their pain management interventions lead to improved mobility and functioning in patients with cancer. IMPLICATIONS FOR NURSING PRACTICE: Nurses comprise the largest workforce around the globe and are well-equipped to assess and manage cancer pain in all cancer care settings. As leaders within the healthcare team, making recommendations to better control pain and communicating with other team members regarding the pain plan is essential in improving mobility in patients with cancer.

Screening structure and predicting toxicity of pesticide adjuvants using molecular dynamics simulation and machine learning for minimizing environmental impacts.

Surfactants as synergistic agents are necessary to improve the stability and utilization of pesticides, while their use is often accompanied by unexpected release into the environment. However, there are no efficient strategies available for screening low-toxicity surfactants, and traditional toxicity studies rely on extensive experimentation which are not predictive. Herein, a commonly used agricultural adjuvant Triton X (TX) series was selected to study the function of amphipathic structure to their toxicity in zebrafish. Molecular dynamics (MD) simulations, transcriptomics, metabolomics and machine learning (ML) were used to study the toxic effects and predict the toxicity of various TX. The results showed that TX with a relatively short hydrophilic chain was highly toxic to zebrafish with LC50 of 1.526 mg/L. However, TX with a longer hydrophilic chain was more likely to damage the heart, liver and gonads of zebrafish through the arachidonic acid metabolic network, suggesting that the effect of surfactants on membrane permeability is the key to determine toxic results. Moreover, biomarkers were screened through machine learning, and other hydrophilic chain lengths were predicted to affect zebrafish heart health potentially. Our study provides an advanced adjuvants screening method to improve the bioavailability of pesticides while reducing environmental impacts.

A Comprehensive Review of Our Understanding and Challenges of Viral Vaccines against Swine Pathogens.

Pig farming has become a strategically significant and economically important industry across the globe. It is also a potentially vulnerable sector due to challenges posed by transboundary diseases in which viral infections are at the forefront. Among the porcine viral diseases, African swine fever, classical swine fever, foot and mouth disease, porcine reproductive and respiratory syndrome, pseudorabies, swine influenza, and transmissible gastroenteritis are some of the diseases that cause substantial economic losses in the pig industry. It is a well-established fact that vaccination is undoubtedly the most effective strategy to control viral infections in animals. From the period of Jenner and Pasteur to the recent new-generation technology era, the development of vaccines has contributed significantly to reducing the burden of viral infections on animals and humans. Inactivated and modified live viral vaccines provide partial protection against key pathogens. However, there is a need to improve these vaccines to address emerging infections more comprehensively and ensure their safety. The recent reports on new-generation vaccines against swine viruses like DNA, viral-vector-based replicon, chimeric, peptide, plant-made, virus-like particle, and nanoparticle-based vaccines are very encouraging. The current review gathers comprehensive information on the available vaccines and the future perspectives on porcine viral vaccines.

Intravenous versus perineural dexamethasone to prolong analgesia after interscalene brachial plexus block: a systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: The efficacy of perineural vs intravenous dexamethasone as a local anaesthetic adjunct to increase duration of analgesia could be particular to specific peripheral nerve blocks because of differences in systemic absorption depending on the injection site. Given this uncertainty, we performed a systematic review with meta-analysis and trial sequential analysis comparing dexamethasone administered perineurally or intravenously combined with local anaesthetic for interscalene brachial plexus block. METHODS: Following a search of various electronic databases, we included 11 trials (1145 patients). The primary outcome was the duration of analgesia defined as the time between peripheral nerve block or onset of sensory blockade and the time to first analgesic request or initial report of pain. RESULTS: The primary outcome, duration of analgesia, was greater in the perineural dexamethasone group, with a mean difference (95% confidence interval) of 122 (62-183) min, I2=73%, P<0.0001. Trial sequential analysis indicated that firm evidence had been reached. The quality of evidence was downgraded to low, mainly because of moderate inconsistency and serious publication bias. No significant differences were present for any of the secondary outcomes, except for onset time of sensory and motor blockade and resting pain score at 12 h, but the magnitude of differences was not clinically relevant. CONCLUSIONS: There is low-quality evidence that perineural administration of dexamethasone as a local anaesthetic adjunct increases duration of analgesia by an average of 2 h compared with intravenous injection for interscalene brachial plexus block. Given the limited clinical relevance of this difference, the off-label use of perineural administration, and the risk of drug crystallisation, we recommend intravenous dexamethasone administration. SYSTEMATIC REVIEW PROTOCOL: PROSPERO (CRD42023466147).

Polyamine-Mediated Sensitization of Klebsiella pneumoniae to Macrolides through a Dual Mode of Action.

Chemicals bacteria encounter at the infection site could shape their stress and antibiotic responses; such effects are typically undetected under standard lab conditions. Polyamines are small molecules typically overproduced by the host during infection and have been shown to alter bacterial stress responses. We sought to determine the effect of polyamines on the antibiotic response of Klebsiella pneumoniae, a Gram-negative priority pathogen. Interestingly, putrescine and other natural polyamines sensitized K. pneumoniae to azithromycin, a macrolide protein translation inhibitor typically used for Gram-positive bacteria. This synergy was further potentiated in the physiological buffer, bicarbonate. Chemical genomic screens suggested a dual mechanism, whereby putrescine acts at the membrane and ribosome levels. Putrescine permeabilized the outer membrane of K. pneumoniae (NPN and ß-lactamase assays) and the inner membrane (Escherichia coli ß-galactosidase assays). Chemically and genetically perturbing membranes led to a loss of putrescine-azithromycin synergy. Putrescine also inhibited protein synthesis in an E. coli-derived cell-free protein expression assay simultaneously monitoring transcription and translation. Profiling the putrescine-azithromycin synergy against a combinatorial array of antibiotics targeting various ribosomal sites suggested that putrescine acts as tetracyclines targeting the 30S ribosomal acceptor site. Next, exploiting the natural polyamine-azithromycin synergy, we screened a polyamine analogue library for azithromycin adjuvants, discovering four azithromycin synergists with activity starting from the low micromolar range and mechanisms similar to putrescine. This work sheds light on the bacterial antibiotic responses under conditions more reflective of those at the infection site and provides a new strategy to extend the macrolide spectrum to drug-resistant K. pneumoniae.

Vaccination with nanoparticles displaying gH/gL from Epstein-Barr virus elicits limited cross-protection against rhesus lymphocryptovirus.

Epstein-Barr virus (EBV) is associated with infectious mononucleosis, cancer, and multiple sclerosis. A vaccine that prevents infection and/or EBV-associated morbidity is an unmet need. The viral gH/gL glycoprotein complex is essential for infectivity, making it an attractive vaccine target. Here, we evaluate the immunogenicity of a gH/gL nanoparticle vaccine adjuvanted with the Sigma Adjuvant System (SAS) or a saponin/monophosphoryl lipid A nanoparticle (SMNP) in rhesus macaques. Formulation with SMNP elicits higher titers of neutralizing antibodies and more vaccine-specific CD4+ T cells. All but one animal in the SMNP group were infected after oral challenge with the EBV ortholog rhesus lymphocryptovirus (rhLCV). Their immune plasma had a 10- to 100-fold lower reactivity against rhLCV gH/gL compared to EBV gH/gL. Anti-EBV neutralizing monoclonal antibodies showed reduced binding to rhLCV gH/gL, demonstrating that EBV gH/gL neutralizing epitopes are poorly conserved on rhLCV gH/gL. Prevention of rhLCV infection despite antigenic disparity supports clinical development of gH/gL nanoparticle vaccines against EBV.

Can glucose facilitate fear exposure? Randomized, placebo-controlled trials on the effects of glucose administration on fear extinction processes.

Previous studies showed that glucose has beneficial effects on memory function and can enhance contextual fear learning. To derive potential therapeutic interventions, further research is needed regarding the effects of glucose on fear extinction. In two experimental studies with healthy participants (Study 1: N = 68, 39 females; Study 2: N = 89, 67 females), we investigated the effects of glucose on fear extinction learning and its consolidation. Participants completed a differential fear conditioning paradigm consisting of acquisition, extinction, and return of fear tests: reinstatement, and extinction recall. US-expectancy ratings, skin conductance response (SCR), and fear potentiated startle (FPS) were collected. Participants were pseudorandomized and double-blinded to one of two groups: They received either a drink containing glucose or saccharine 20 min before (Study 1) or immediately after extinction (Study 2). The glucose group showed a significantly stronger decrease in differential FPS during extinction (Study 1) and extinction recall (Study 2). Additionally, the glucose group showed a significantly lower contextual anxiety at test of reinstatement (Study 2). Our findings provide first evidence that glucose supports the process of fear extinction, and in particular the consolidation of fear extinction memory, and thus has potential as a beneficial adjuvant to extinction-based treatments. Registered through the German Clinical Trials Registry (https://www.bfarm.de/EN/BfArM/Tasks/German-Clinical-Trials-Register/_node.html; Study 1: DRKS00010550; Study 2: DRKS00018933).

A reactogenic "placebo" and the ethics of informed consent in Gardasil HPV vaccine clinical trials: A case study from Denmark.

BACKGROUND: Medical ethics guidelines require of clinical trial investigators and sponsors to inform prospective trial participants of all known and potential risks associated with investigational medical products, and to obtain their free informed consent. These guidelines also require that clinical research be so designed as to minimize harms and maximize benefits. OBJECTIVE: To examine Merck's scientific rationale for using a reactogenic aluminum-containing "placebo" in Gardasil HPV vaccine pre-licensure clinical trials. METHODS: We examined the informed consent form and the recruitment brochure for the FUTURE II Gardasil vaccine trial conducted in Denmark; and we interviewed several FUTURE II trial participants and their treating physicians. We also reviewed regulatory documentation related to Gardasil vaccine approval process and the guidelines on evaluation of adjuvants used in human vaccines. RESULTS: It was found that the vaccine manufacturer Merck made several inaccurate statements to trial participants that compromised their right to informed consent. First, even though the study protocol listed safety testing as one of the study's primary objectives, the recruitment brochure emphasized that FUTURE II was not a safety study, and that the vaccine had already been proven safe. Second, the advertising material for the trial and the informed consent forms stated that the placebo was saline or an inactive substance, when, in fact, it contained Merck's proprietary highly reactogenic aluminum adjuvant which does not appear to have been properly evaluated for safety. Several trial participants experienced chronic disabling symptoms, including some randomized to the adjuvant "placebo" group. CONCLUSION: In our view, the administration of a reactive placebo in Gardasil clinical trials was without any possible benefit, needlessly exposed study subjects to risks, and was therefore a violation of medical ethics. The routine use of aluminum adjuvants as "placebos" in vaccine clinical trials is inappropriate as it hinders the discovery of vaccine-related safety signals.

Hypothetical adhesin CAM87009.1 formulated in alum or biogenic silver nanoparticles protects mice from lethal infection by multidrug-resistant Acinetobacter baumannii.

Due to its antimicrobial resistance characteristics, the World Health Organization (WHO) classifies A. baumannii as one of the critical priority pathogens for the development of new therapeutic strategies. Vaccination has been approached as an interesting strategy to overcome the lack of effective antimicrobials and the long time required to develop and approve new drugs. In this study, we aimed to evaluate as a vaccine the hypothetical adhesin protein CAM87009.1 in its recombinant format (rCAM87009.1) associated with aluminum hydroxide (Alhydrogel®) or biogenic silver nanoparticles (bio-AgNP) as adjuvant components against lethal infection by A. baumannii MDR strain. Both vaccine formulations were administered in three doses intramuscularly in BALB/c murine models and the vaccinated animals were tested in a challenge assay with A. baumannii MDR strain (DL100). rCAM87009.1 protein associated with both adjuvants was able to protect 100 % of animals challenged with the lethal strain during the challenge period. After the euthanasia of the animals, no A. baumannii colonies were detected in the lungs of animals vaccinated with the rCAM87009.1 protein in both formulations. Since the first immunization, high IgG antibody titers were observed (1:819,200), with results being statistically similar in both vaccine formulations evaluated. rCAM87009.1 associated with both adjuvants was capable of inducing at least one class of isotypes associated with the processes of neutralization (IgG2b and IgA for bio-AgNP and Alhydrogel®, respectively), opsonization (IgG1 in both vaccines) and complement activation (IgM and IgG3 for bio-AgNP and Alhydrogel®, respectively). Furthermore, reduced tissue damage was observed in animals vaccinated with rCAM87009.1 + bio-AgNP when compared to animals vaccinated with Alhydrogel®. Our results indicate that the rCAM87009.1 protein associated with both bio-AgNP and Alhydrogel® are combinations capable of promoting immunity against infections caused by A. baumannii MDR. Additionally, we demonstrate the potential of silver nanoparticles as alternative adjuvant molecules to the use of aluminum salts.