A new vaccination regimen using adenovirus-vectored vaccine confers effective protection against African swine fever virus in swine.

African swine fever (ASF) is an acute and highly contagious lethal infectious disease in swine that severely threatens the global pig industry. At present, a safe and efficacious vaccine is urgently required to prevent and control the disease. In this study, we evaluated the safety and immunogenicity of replication-incompetent type-2 adenoviruses carrying African swine fever virus (ASFV) antigens, namely CP204L (p30), E183L (p54), EP402R (CD2v), B646L (p72), and B602L (p72 chaperone). A vaccine cocktail delivered by simultaneous intramuscular (IM) and intranasal (IN) administration robustly elicited both systemic and mucosal immune responses against AFSV in mice and swine and provided highly effective protection against the circulating ASFV strain in farmed pigs. This multi-antigen cocktail vaccine was well tolerated in the vaccinated animals. No significant interference among antigens was observed. The combined IM and IN vaccination using this adenovirus-vectored antigen cocktail vaccine warrants further evaluation for providing safe and effective protection against ASFV infection and transmission.

Intranasal booster using an Omicron vaccine confers broad mucosal and systemic immunity against SARS-CoV-2 variants.

The highly contagious SARS-CoV-2 Omicron subvariants severely attenuated the effectiveness of currently licensed SARS-CoV-2 vaccines based on ancestral strains administered via intramuscular injection. In this study, we generated a recombinant, replication-incompetent human adenovirus type 5, Ad5-S-Omicron, that expresses Omicron BA.1 spike. Intranasal, but not intramuscular vaccination, elicited spike-specific respiratory mucosal IgA and residential T cell immune responses, in addition to systemic neutralizing antibodies and T cell immune responses against most Omicron subvariants. We tested intranasal Ad5-S-Omicron as a heterologous booster in mice that previously received intramuscular injection of inactivated ancestral vaccine. In addition to inducing serum broadly neutralizing antibodies, there was a significant induction of respiratory mucosal IgA and neutralizing activities against Omicron subvariants BA.1, BA.2, BA.5, BA.2.75, BF.7 as well as pre-Omicron strains Wildtype, Beta, and Delta. Serum and mucosal neutralizing activities against recently emerged XBB, BQ.1, and BQ.1.1 could also be detected but were much lower. Nasal lavage fluids from intranasal vaccination contained multimeric IgA that can bind to at least 10 spike proteins, including Omicron subvariants and pre-Omicron strains, and possessed broadly neutralizing activities. Intranasal vaccination using Ad5-S-Omicron or instillation of intranasal vaccinee's nasal lavage fluids in mouse nostrils protected mice against Omicron challenge. Taken together, intranasal Ad5-S-Omicron booster on the basis of ancestral vaccines can establish effective mucosal and systemic immunity against Omicron subvariants and multiple SARS-CoV-2 variants. This candidate vaccine warrants further development as a safe, effective, and user-friendly infection and transmission-blocking vaccine.

An adenovirus-vectored COVID-19 vaccine confers protection from SARS-COV-2 challenge in rhesus macaques.

The rapid spread of coronavirus SARS-CoV-2 greatly threatens global public health but no prophylactic vaccine is available. Here, we report the generation of a replication-incompetent recombinant serotype 5 adenovirus, Ad5-S-nb2, carrying a codon-optimized gene encoding Spike protein (S). In mice and rhesus macaques, intramuscular injection with Ad5-S-nb2 elicits systemic S-specific antibody and cell-mediated immune (CMI) responses. Intranasal inoculation elicits both systemic and pulmonary antibody responses but weaker CMI response. At 30 days after a single vaccination with Ad5-S-nb2 either intramuscularly or intranasally, macaques are protected against SARS-CoV-2 challenge. A subsequent challenge reveals that macaques vaccinated with a 10-fold lower vaccine dosage (1 × 1010 viral particles) are also protected, demonstrating the effectiveness of Ad5-S-nb2 and the possibility of offering more vaccine dosages within a shorter timeframe. Thus, Ad5-S-nb2 is a promising candidate vaccine and warrants further clinical evaluation.

Human Desmoglein-2 and Human CD46 Mediate Human Adenovirus Type 55 Infection, but Human Desmoglein-2 Plays the Major Roles.

Human adenovirus type 55 (HAdV55) represents an emerging respiratory pathogen and causes severe pneumonia with high fatality in humans. The cellular receptors, which are essential for understanding the infection and pathogenesis of HAdV55, remain unclear. In this study, we found that HAdV55 binding and infection were sharply reduced by disrupting the interaction of viral fiber protein with human desmoglein-2 (hDSG2) but only slightly reduced by disrupting the interaction of viral fiber protein with human CD46 (hCD46). Loss-of-function studies using soluble receptors, blocking antibodies, RNA interference, and gene knockout demonstrated that hDSG2 predominantly mediated HAdV55 infection. Nonpermissive rodent cells became susceptible to HAdV55 infection when hDSG2 or hCD46 was expressed, but hDSG2 mediated more efficient HAd55 infection than hCD46. We generated two transgenic mouse lines that constitutively express either hDSG2 or hCD46. Although nontransgenic mice were resistant to HAdV55 infection, infection with HAdV55 was significantly increased in hDSG2+/+ mice but was much less increased in hCD46+/+ mice. Our findings demonstrate that both hDSG2 and hCD46 are able to mediate HAdV55 infection but hDSG2 plays the major roles. The hDSG2 transgenic mouse can be used as a rodent model for evaluation of HAdV55 vaccine and therapeutics.IMPORTANCE Human adenovirus type 55 (HAdV55) has recently emerged as a highly virulent respiratory pathogen and has been linked to severe and even fatal pneumonia in immunocompetent adults. However, the cellular receptors mediating the entry of HAdV55 into host cells remain unclear, which hinders the establishment of HAdV55-infected animal models and the development of antiviral approaches. In this study, we demonstrated that human desmoglein-2 (hDSG2) plays the major roles during HAdV55 infection. Human CD46 (hCD46) could also mediate the infection of HAdV55, but the efficiency was much lower than for hDSG2. We generated two transgenic mouse lines that express either hDSG2 or hCD46, both of which enabled HAd55 infection in otherwise nontransgenic mice. hDSG2 transgenic mice enabled more efficient HAdV55 infection than hCD46 transgenic mice. Our study adds to our understanding of HAdV55 infection and provides an animal model for evaluating HAdV55 vaccines and therapeutics.

Dibutyltin depressed immune functions via NF-κB, and JAK/STAT signaling pathways in zebrafish (Danio rerio).

Dibutyltin (DBT) is the degradation products of TBT, which is generally considered higher toxicity than TBT in the immune system. In order to learn more about the mechanisms of immune-toxic of DBT, we exposed zebrafish (Danio rerio) to 0, 1, 10 and 100 ng/L DBT for 8 weeks. At the end of the experiment, we determined the immune parameters and immune-related genes. The results showed that with an increase in TBT dose, lysozyme activities and IgM, C3, C4 content in intestine, skin and spleen were all significantly inhibited by the DBT exposure. Fish exposed to 10 ng/L and 100 ng/L showed significantly lower lysozyme activities and IgM, C3, C4 content than those of the control group. Zebrafish exposed to 10 ng/L and 100 ng/L DBT, the mRNA transcript levels of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), interferon γ2 (INFγ2), nuclear factor-κB p65 (NF-kB p65), inhibitor protein-κBα (IκBα), IκB kinases ß (IKKß), Janus family of protein tyrosine kinases (JAKs) and the signal transducers and activators of transcription proteins (STATs) all increased with the DBT levels in the intestine and spleen. Those parameters showed significantly higher values in 10 ng/L and 100 ng/L than those of fish in the control group. However, no significant difference was found in IκB kinases α (IKKα) and IκB kinase γ (IKKγ) mRNA levels in the intestine and spleen. These data imply that DBT might be via suppression on IKKß/IkBa/NF-kBp65 and JAK/STAT signaling pathways to regulate the immunity of zebrafish.

Effects of Lactobacillus delbrueckii on immune response, disease resistance against Aeromonas hydrophila, antioxidant capability and growth performance of Cyprinus carpio Huanghe var.

The aim of the present study was to investigate effects of dietary Lactobacillus delbrueckii (L. delbrueckii) on immune response, disease resistance against Aeromonas hydrophila (A. hydrophila), antioxidant capability and growth performance of Cyprinus carpio Huanghe var. 450 fish (mean weight of 1.05 ± 0.03 g) were randomly distributed into five groups that fed diets containing different levels of L. delbrueckii (0, 1 × 105, 1 × 106, 1 × 107 and 1 × 108 CFU g-1) for 8 weeks. The results showed that intestinal immune parameters such as lysozyme, acid phosphatase, and myeloperoxidase activities, immunoglobulin M content, and the survival rate were improved in fish fed with 1 × 106 and 1 × 107 CFU g-1L. delbrueckii. In addition, 1 × 107 CFU g-1L. delbrueckii supplementation down-regulated mRNA levels of TNF-α, IL-8, IL-1ß and NF-κBp65, and up-regulated IL-10 and TGF-ß mRNA levels in the intestine. The survival rate was significantly (P < 0.05) higher (68.33%) in fish fed 1 × 106 CFU g-1L. delbrueckii than the control diet-fed group (40%) after challenge by A. hydrophila. Fish fed with diet containing 1 × 106 CFU g-1L. delbrueckii showed higher antioxidant enzyme activities such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and total antioxidant capacity (T-AOC) and lower MDA concentrations than those of the control group (P < 0.05). The relative gene expression (SOD, CAT, GPX) showed the same trend with their activities. In addition, the growth performance was significantly improved in fish fed with the diet containing 1 × 106 and 1 × 107 CFU g-1L. delbrueckii (P < 0.05). These results demonstrated that dietary optimal levels of L. delbrueckii enhanced immunity, disease resistance against A. hydrophila antioxidant capability and growth performance in Cyprinus carpio Huanghe var.