Human Adenovirus Type 26 Infection Mediated by αvß3 Integrin Is Caveolin-1-Dependent.

Human adenovirus type 26 (HAdV26) has been recognized as a promising platform for vaccine vector development, and very recently vaccine against COVID-19 based on HAdV26 was authorized for emergency use. Nevertheless, basic biology of this virus, namely, pathway which HAdV26 uses to enter the cell, is still insufficiently known. We have shown here that HAdV26 infection of human epithelial cells expressing low amount of αvß3 integrin involves clathrin and is caveolin-1-independent, while HAdV26 infection of cells with high amount of αvß3 integrin does not involve clathrin but is caveolin-1-dependent. Thus, this study demonstrates that caveolin-1 is limiting factor in αvß3 integrin-mediated HAdV26 infection. Regardless of αvß3 integrin expression, HAdV26 infection involves dynamin-2. Our data provide for the first-time description of HAdV26 cell entry pathway, hence increase our knowledge of HAdV26 infection. Knowing that functionality of adenovirus vector is influenced by its cell entry pathway and intracellular trafficking, our results will contribute to better understanding of HAdV26 immunogenicity and antigen presentation when used as vaccine vector. IMPORTANCE In order to fulfill its role as a vector, adenovirus needs to successfully deliver its DNA genome to the host nucleus, a process highly influenced by adenovirus intracellular translocation. Thus, cell entry pathway and intracellular trafficking determine functionality of human adenovirus-based vectors. Endocytosis of HAdV26, currently extensively studied as a vaccine vector, has not been described so far. We present here that HAdV26 infection of human epithelial cells with high expression of αvß3 integrin, one of the putative HAdV26 receptors, is caveolin-1- and partially dynamin-2-dependent. Since caveolin containing domains provide a unique environment for specific signaling events and participate in inflammatory signaling one can imagine that directing HAdV26 cell entry toward caveolin-1-mediate pathway might play role in immunogenicity of this virus. Therefore, our results contribute to better understanding of HAdV26 infection pathway, hence, can be helpful in explaining induction of immune response and antigen presentation by HAdV26-based vaccine vector.

Severe Acute Hepatitis: An Emerging Grave Illness in Children

Acute hepatitis of unknown origin in children has been recently described in the literature, and a case definition has also been proposed for this condition. The exact etiology is unknown and exclusion of infectious, metabolic, autoimmune and toxin mediated injuries is essential. Management for this condition is supportive, but some may require liver transplantation. Infection prevention and control practices are important as the etiology remains unidentified.Copyright © 2023, Indian Academy of Pediatrics.

An Old Acquaintance: Could Adenoviruses Be Our Next Pandemic Threat?

Human adenoviruses (HAdV) are one of the most important pathogens detected in acute respiratory diseases in pediatrics and immunocompromised patients. In 1953, Wallace Rowe described it for the first time in oropharyngeal lymphatic tissue. To date, more than 110 types of HAdV have been described, with different cellular tropisms. They can cause respiratory and gastrointestinal symptoms, even urinary tract inflammation, although most infections are asymptomatic. However, there is a population at risk that can develop serious and even lethal conditions. These viruses have a double-stranded DNA genome, 25-48 kbp, 90 nm in diameter, without a mantle, are stable in the environment, and resistant to fat-soluble detergents. Currently the diagnosis is made with lateral flow immunochromatography or molecular biology through a polymerase chain reaction. This review aimed to highlight the HAdV variability and the pandemic potential that a HAdV3 and 7 recombinant could have considering the aggressive outbreaks produced in health facilities. Herein, we described the characteristics of HAdV, from the infection to treatment, vaccine development, and the evaluation of the social determinants of health associated with HAdV, suggesting the necessary measures for future sanitary control to prevent disasters such as the SARS-CoV-2 pandemic, with an emphasis on the use of recombinant AdV vaccines to control other potential pandemics.

Multiple detection of 13 kinds of viruses in 500 children with acute respiratory tract infection in Hami of Xinjiang province

OBJECTIVE: To investigate and analyze multiple detection of 13 kinds of viruses in 500 children with acute respiratory tract infection in Hami of Xinjiang. METHODS: A total of 500 children with acute respiratory tract infection treated in the hospital between Jan 2018 and Jan 2021 were enrolled. Thirteen kinds of respiratory infection viruses including human respiratory syncytial virus(RSV), human rhinovirus(hRV), respiratory adenovirus(AdV), influenza A and B viruses(Inf A, Inf B), parainfluenza virus(PIV 1/2/3), human enterovirus(hEV), human metapneumovirus(hMPV), human coronavirus(hCoV 229E/OC43) and human Boca virus(hBoV) were detected by multiple reverse transcription polymerase chain reaction(RT-PCR) amplification and capillary electrophoresis. And the results were compared with those by direct sequencing method. RESULTS: Of the 500 samples, 379 samples were positive(75.80%), and the top three detection rates were RSV(19.40%), hRV(16.00%) and Inf B(12.60%). The differences in positive rates of the respiratory virus among <1 year group, 1-3 years group and >3 years group were significant(84.97%, 77.47%, 65.45%)(P<0.05). The detection rate of RSV was the highest in <1 year group, and the detection rates of Inf A and Inf B were the highest in >3 years group. The differences in positive rates of respiratory viruses among the spring group, summer group, autumn group and winter group were significant(74.05%, 63.73%, 77.24%, 84.03%)(P<0.05). The detection rates of RSV, PIV 3, and hMPV were the highest in the winter group, and detection rate of AdV was the highest in spring group. CONCLUSION: RSV is the main infection virus in children with acute respiratory infection in Hami of Xinjiang. The distribution of respiratory viruses is related to age and onset season in children.

Surveillance of respiratory viruses infections in sentinel hospitals of Guangming district, Shenzhen, between 2018 and 2021

OBJECTIVE: To investigate the prevalence of respiratory tract viruses infections in sentinel hospitals of Guangming District, Shenzhen, from 2018 to 2021. METHODS: A total of 1 183 influenza-like patients who were treated in University of Chinese Academy of Sciences Shenzhen Hospital(Guangming District) from Jan 2018 to Dec 2021 were recruited as the research subjects. The respiratory viruses that were isolated from throat swab specimens were detected by real-time fluorescent quantitative PCR, and the prevalence of the infections was observed. RESULTS: Among the throat swab specimens that were collected from the 1 183 influenza-like patients, 45.48%(538/1183) were tested positive for respiratory viruses. Among the 538 positive samples, 533 were single infection, and 5 were mixed infection;the patients with influenza virus infection accounted for 77.51%(417 cases), higher than the patients with infections of other viruses [adenovirus infection(6.51%), respiratory syncytial virus infection(1.30%), human metapneumovirus infection(1.67%), rhinovirus infection(6.88%), coronavirus infection(1.86%), parainfluenza virus infection(3.16%), boca virus infection(0.19%), P<0.05]. The incidence of respiratory viruses infections was higher in winter than in spring, summer and autumn(P<0.05), the proportion of the influenza virus was higher than that of other viruses in winter(P<0.05). The population aged between 26 and 40 years old was dominant among the patients with influenza virus infection, and the infection rate of the age group was higher than that of other age groups(P<0.05). The population aged between 26 and 40 years old was dominant among the patients with coronavirus infection, while the population aged less than 15 years old was dominant among the patients with infections of other respiratory viruses;the patients aged less than 15 years accounted for 59.46%(22 cases) among the patients with rhinovirus infection;the patients aged less than 5 years old accounted for 42.86%(15 cases) among the patients with adenovirus infection. There was no significant difference in the proportion of the patients with respiratory viruses infection between genders. CONCLUSION: The influenza virus is dominant among the viruses causing the respiratory tract infection, which is prevalent in winter. The incidence of respiratory tract infections is relatively high among the patients aged between 26 and 40 years old but is not associated with the gender.

Liver Transaminases in Pediatric Adenovirus Infection-A Five-Year Study in Two Major Reference Centers from Romania.

Human adenovirus causes infections with a very heterogeneous clinical picture, and children are often the most frequently affected group. Interest in adenovirus has increased with the 2022 outbreak of severe acute hepatitis of unknown etiology as human adenovirus was considered as one of the possible etiological agents. We conducted a retrospective study over a 5-year period in two major tertiary hospitals in the Romanian capital with the aim to characterize the clinical picture and the dynamics of liver function tests in children with confirmed adenovirus infection. The study included 1416 children with a median age of 1.1 years (IQR: 0.3, 2.3 years). Digestive symptoms were predominant in 95.2% of children, mainly diarrhea (90.5%) and vomiting (50.5%), and 38.0% had respiratory symptoms. Increased transaminases were identified in 21.5% of patients. Age over 1 year, lethargy, vomiting and dehydration significantly increased the odds of liver cytolysis independent of other risk factors such as chronic conditions or co-infections. Aspartate aminotransferase (AST) was more commonly increased compared to alanine aminotransferase (ALT). Only six children had transaminase increases above 500 U/L, three of which had co-infections with rotavirus, Epstein-Barr virus (EBV), or respiratory syncytial virus (RSV). Liver function tests should be part of routine monitoring for pediatric patients with adenovirus infection. The current study fills a gap in current knowledge related to the frequency and the extent of liver involvement in human adenovirus infection among pediatric patients.

Phylogenetic characterization of rhinovirus and adenovirus in hospitalized children aged ≤ 18 years with severe acute respiratory infection in Iran.

Background and Objectives: Human rhinoviruses (HRVs) and human adenoviruses (HAdVs) are among the most prevalent viruses in hospitalized patients with severe acute respiratory infection (SARI). This study aimed to evaluate the molecular characterization of HRV and HAdV in hospitalized patients with SARI, who aged ≤ 18 years in Tehran, Iran. Materials and Methods: To detect these two viruses, a conventional nested RT-PCR (Reverse transcription-polymerase chain reaction) assay was performed on 264 throat swabs collected from December 2018 to March 2019. The epidemiological data were analyzed and phylogenetic trees were constructed. Results: Of 264 cases with SARI, 36 (13.6%) and 28 (10.6%) were positive for HAdV and HRV respectively. Of 21 HRV sequenced samples, HRV-A (42.9%), HRV-B (9.5%) and HRV-C (47.6%) and of 36 HAdV sequenced samples, HAdV-C6 (38.9%), HAdV-B7 (22.2%), HAdV-B3 (11.1%), HAdV-B16 (5.6%), HAdV-C5 (13.9%), HAdV-C57 (5.6%), HAdV-E4 (2.8%); were detected in children with SARI. Some viral genotypes appeared to cause more severe disease, which may lead to hospitalization. Conclusion: Large-scale studies are recommended to investigate the epidemiology and molecular characterizations through surveillance networks to provide useful information on etiology, seasonality, and demographic associations in patients with SARI.

Detection of human adenovirus F41 in wastewater and its relationship to clinical cases of acute hepatitis of unknown aetiology

As of 8 July 2022, the World Health Organization (WHO) have reported 1010 probable cases of acute hepatitis of unknown aetiology in children worldwide, including approximately 250 cases in the United Kingdom (UK). Clinical presentations have often been severe, with liver transplantation a frequent clinical outcome. Human adenovirus F41 (HAdV-F41) has been detected in most children with acute hepatitis, but its role in the pathogenesis of this infection has yet to be established. Wastewater-based epidemiology (WBE) has become a well-established tool for monitoring the community spread of SARS-CoV-2, as well as other pathogens and chemicals. In this study, we adopted a WBE approach to monitoring levels of HAdV-F40/41 in wastewater before and during an acute hepatitis outbreak in Northern Ireland. We report increasing detection of HAdV-F40/41 in wastewater, concomitant with increasing numbers of clinical cases. Amplicon whole genome sequencing further classified the wastewater-derived HAdV as belonging to the F41 genotype which in turn was homologous to clinically derived sequences. We propose that WBE has the potential to inform community surveillance of HAdV-F41 and can further contribute to the ongoing global discussion supporting HAdV-F41 involvement in acute hepatitis cases. © 2022 The Authors

The burden of viral infections in pediatric intensive care unit between endemic and pandemic coronavirus infections: A tertiary care center experience

Objectives: To measure the prevalence of viral infections, length of stay (LOS), and outcome in children admitted to the pediatric intensive care unit (PICU) during the period preceding the COVID-19 pandemic in a MERS-CoV endemic country. Methods: A retrospective chart review of children 0–14 years old admitted to PICU with a viral infection. Results: Of 1736 patients, 164 patients (9.45%) had a positive viral infection. The annual prevalence trended downward over a three-year period, from 11.7% to 7.3%. The median PICU LOS was 11.6 days. Viral infections were responsible for 1904.4 (21.94%) PICU patient-days. Mechanical ventilation was used in 91.5% of patients, including noninvasive and invasive modes. Comorbidities were significantly associated with intubation (P-value = 0.025). Patients infected with multiple viruses had median pediatric index of mortality 2 (PIM 2) scores of 4, as compared to 1 for patients with single virus infections (p < 0.001), and a median PICU LOS of 12 days, compared to 4 in the single-virus group (p < 0.001). Overall, mortality associated with viral infections in PICU was 7 (4.3%). Patients with viral infections having multiple organ failure were significantly more likely to die in the PICU (p = 0.001). Conclusion: Viral infections are responsible for one-fifth of PICU patient-days, with a high demand for mechanical ventilation. Patients with multiple viral infections had longer LOS, and higher PIM 2 scores. The downward trend in the yearly rate of PICU admissions for viral infections between the end of the MERS-CoV outbreak and the start of the COVID-19 pandemic may suggest viral interference that warrants further investigations. © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases

Alterations in bile acids as metabolic signatures in the patients with human adenovirus type 7 infection.

Objectives: The changes in metabolism by human adenovirus (HAdV) infection was unclear. The potential mechanism of HAdV-7 causing acute respiratory tract infection was explored. Methods: Totally 35 patients with HAdV-7 infection, 32 asymptomatic cases with HAdV-7 and 14 healthy controls were enrolled from an outbreak of HAdV-7 in the army. The serum samples were analyzed by untargeted and targeted metabolomics. The effects of differential metabolites were verified on HAdV-7 replication in an A549 cell line. Results: The untargeted metabolomics analysis revealed more significant changes in the classes of sphingolipids, polyketides, glycerolipids, fatty acyls, and carboxylic acids and their derivatives in the patients with HAdV-7 than in healthy controls. Two key metabolic pathways of secondary and primary bile acid biosynthesis were noted from pathway enrichment analysis. Targeted metabolomics analysis showed that the levels of unconjugated bile acids in the patients were significantly lower, while the levels of glyco- and tauro- conjugated bile acids in patients and asymptomatic cases were higher than those in the healthy controls. The profiles of cytokines and peripheral lymphocyte subsets obviously varied at different levels of bile acids, with significant differences after HAdV-7 infection. A cell verification test demonstrated that the replication of HAdV-7 significantly reduced when GCDCA and TCA were added. Conclusion: Bile acids inhibited HAdV-7 replication in vitro. Alterations in bile acids was metabolic signatures of HAdV-7 infected subjects, and our results suggested bile acids might play protective roles against HAdV-7 infection.

The changed endemic pattern of human adenovirus from species B to C among pediatric patients under the pressure of non-pharmaceutical interventions against COVID-19 in Beijing, China.

BACKGROUND: Under the pressure of non-pharmaceutical interventions (NPIs) targeting severe acute respiratory syndrome coronavirus 2, the prevalence of human adenovirus (HAdV) was monitored before and after NPIs launched on Jan 24, 2020 in pediatric patients in Beijing, China. METHODS: Respiratory samples collected from children hospitalized with acute respiratory infections from Jan 2015 to Dec 2021 were screened by direct immunofluorescence test or capillary electrophoresis-based multiplex PCR assay. The hexon, penton base, and fiber genes were amplified from HAdV positive specimens, then sequenced. For HAdV typing, phylogenetic trees were built by MEGA X. Then clinical data of HAdV positive cases were collected. All data were evaluated using SPSS Statistics 22.0 software. RESULTS: A total of 16,097 children were enrolled and 466 (2.89%, 466/16,097) were HAdV-positive. The positive rates of HAdV varied, ranging from 4.39% (151/3,438) in 2018 to1.25% (26/2,081) in 2021, dropped from 3.19% (428/13,408) to 1.41% (38/2,689) from before to after NPIs launched (P < 0.001). There were 350 cases typed into nine types of species B, C, or E and 34 recorded as undetermined. Among them, HAdV-B3 (51.56%, 198/384) was the most prevalent types from 2015 to 2017, and HAdV-B7 (29.17%, 112/384) co-circulated with HAdV-B3 from 2018 to 2019. After NPIs launched, HAdV-B3 and B7 decreased sharply with HAdV-B7 undetected in 2021, while HAdV-C1 became the dominant one and the undetermined were more. CONCLUSIONS: The endemic pattern of HAdV changed in Beijing because of the NPIs launched for COVID-19. Especially, the dominant types changed from HAdV-B to HAdV-C.

Characterization of adenovirus interactions with PF4 using a novel ELISA-qPCR technology

The COVID vaccines Janssen and AstraZeneca, based respectively on adenovirus (AdV) serotypes AdV26 and ChAdOx1, have been associated with rare cases of vaccine-induced thrombotic thrombocytopenia (VITT). It was recently demonstrated that the AdVs of the vaccines can bind to the blood protein platelet factor 4 (PF4), an interaction very likely to be involved in VITT. Since there are hundreds of known AdV serotypes, we hypothesized that certain serotypes have a lower affinity for PF4. We therefore aimed to screen a library comprising dozens of serotypes from different AdV species. For this purpose, we established the ELISA-qPCR technology. Like in standard ELISA, AdV viral particles are allowed to specifically interact with PF4 proteins coated on a plate. However, the revelation is not performed by antibody staining, but by qPCR after the genomes of bound AdVs are released through alkaline heat lysis. This technology enables fast, accurate and unbiased assessment of virus molecular interactions. Unlike most tested serotypes, the species D AdV37, AdV69 and AdV70 did not bind to PF4. Even though the ELISA-qPCR technique is not sensitive enough to detect potential low-affinity interactions, these serotypes may avoid or decrease the risk of VITT and represent safer candidates for vaccine or gene therapy vector development. In order to gain deeper insights into the mechanism of virion binding to PF4, we tested how AdV5 affinity for PF4 was affected by genetic removal or PEGylation of different hypervariable regions (HVR) of the hexon protein of the capsid.

Investigating sialic acid usage in species D human adenoviruses

Human adenoviruses are phylogenetically divided across seven species, A-G, causing transient mild illnesses, except in immunocompromised individuals. Their double stranded DNA genome is amenable to genetic manipulations, enabling development of highly engineered virotherapies. Species D adenoviruses have naturally low seroprevalence rates, an important trait in avoiding neutralising anti-vector immunity. We previously demonstrated that HAdV-D26, the platform of the Janssen SARS-CoV2 vaccine, uses sialic acid as a primary cell entry receptor. Here, we structurally and biologically investigated sialic acid usage across species D. We solved multiple structures of species D adenovirus fiber knob proteins alone and in complex with sialic acid, identifying a conserved binding pocket common with known sialic acid binders HAdV-D26 and 37. Using fiber-knob pseudotyped viruses, we demonstrate significantly reduced transduction in cells treated with neuraminidase to remove sialic acid residues in HAdV-D26 and 53, with HAdV-D15, 24 and 29 also demonstrating non-significant reductions. IC50 data also showed highlighted binding to CAR, although at a significantly lower affinity compared to the CAR-binding HAdV-C5. Improved understanding of the usage of sialic acid as a receptor will enable better exploitation of the species D adenoviruses as therapeutic vectors. Our findings raise the possibility of a conserved sialic acid binding pocket within species D adenoviruses resulting in varying affinity levels. Further evaluation of specific glycan binding patterns used by these viruses, as observed between HAdV-D37 and GD1a glycan, will better inform the design of appropriate antivirals to contain adenovirus outbreaks as well as the engineering of targeted vectors for translational applications.

Virus-cell interactions of the ChAdOx1 viral vector give insights into vaccine-induced immune thrombotic thrombocytopenia

The ChAdOx1 nCoV-19 vaccine (AZD1222/Vaxzervia) adapted from the chimpanzee adenovirus Y25 (ChAd-Y25) has been critical in combatting the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic. However, as part of the largest vaccination campaign in history, a potentially lifethreatening clotting disorder, thrombosis with thrombocytopenia, resembling heparin-induced thrombocytopenia (HIT), has been observed in a minority of AZD1222 patients following the first but not the second dose. Vaccine-induced immune thrombotic thrombocytopenia (VITT) is characterised by development of thromboses at uncommon sites such as the cerebral venous sinuses and the splanchnic veins, with concomitant thrombocytopaenia. Therefore, to determine how ChAdOx1 may contribute to this novel disorder, it is critical to investigate the vector-host interactions of ChAdOx1. Structural and in vitro analysis of the fiber knob responsible for the primary virus-cell interaction suggests that coxsackie and adenovirus receptor (CAR) is the primary ChAdOx1 receptor. However, ChAdOx1 infection of CAR(-) human vascular endothelial cells has been demonstrated in vitro, suggesting ChAdOx1 may be using additional receptors. Dual tropism has been demonstrated in other human adenoviruses, with HAdV-D26 and HAdV-D37 both using sialic acid and CAR for transduction. Furthermore, coagulation factor X (FX), a factor demonstrated to bind to the hexon and facilitate human adenovirus type 5 (HAdV-C5) transduction via a CARindependent pathway does not increase ChAdOx1 infection, with amino acid alignment between the hexon proteins suggesting ChAdOx1 is unable to bind FX. Taken together, these findings suggest ChAdOx1 uses additional as yet unknown mechanisms for transduction, which may further contribute to the pathogenesis of VITT.

Human Adenovirus and Influenza A Virus Exacerbate SARS-CoV-2 Infection in Animal Models.

In this study, we investigated the features of the infectious process by simulating co-infection with SARS-CoV-2 and human adenovirus type 5 (HAdV-5) or influenza A virus (IAV) in vitro and in vivo. The determination of infectious activity of viruses and digital PCR demonstrated that during simultaneous and sequential HAdV-5 followed by SARS-CoV-2 infection in vitro and in vivo, the HAdV-5 infection does not interfere with replication of SARS-CoV-2. The hamsters co-infected and mono-infected with SARS-CoV-2 exhibited nearly identical viral titers and viral loads of SARS-CoV-2 in the lungs. The hamsters and ferrets co-infected by SARS-CoV-2- and IAV demonstrated more pronounced clinical manifestations than mono-infected animals. Additionally, the lung histological data illustrate that HAdV-5 or IAV and SARS-CoV-2 co-infection induces more severe pathological changes in the lungs than mono-infection. The expression of several genes specific to interferon and cytokine signaling pathways in the lungs of co-infected hamsters was more upregulated compared to single infected with SARS-CoV-2 animals. Thus, co-infection with HAdV-5 or IAV and SARS-CoV-2 leads to more severe pulmonary disease in animals.

Detection of human adenovirus among Iranian pediatric hospitalized patients suspected of COVID-19: epidemiology and comparison of clinical features.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children typically results in similar symptoms with other viral respiratory agents including human adenoviruses (HAdVs). Mixed HAdV and SARS-CoV-2 infection (co-infection) in children might result in enhanced or reduced disease severity compared with single infections. The present study aims to investigate the rate of SARS-CoV2 and HAdV infection and also their coinfection and compare the two infections regarding their laboratory and clinical characteristics at hospital admission. A total of 360 combined oropharyngeal and nasopharyngeal swab samples from hospitalized children were examined by real-time PCR for the existence of the SARS-CoV-2 and HAdVs. The symptoms, the clinical characteristics and laboratory findings were retrieved and compared in SARS-CoV-2 and HAdVs positive cases. Of the total 360 suspected COVID-19 hospitalized children, 45 (12.5%) and 19 (5.3%) specimens were PCR-positive for SARS-CoV-2 and HAdV respectively. SARS-CoV-2 and HAdV co-infection was detected in 4 cases (1.1%). Regarding symptoms at hospital admission, fever in SARS-CoV-2 positive group was significantly higher than that in HAdV positive group [34 (85%) vs. 7 (46.7%), p = 0.012]. However, percentages of cases with sore throat, headache, fatigue, lymphadenopathy and conjunctivitis in HAdV positive group were significantly higher than those in SARS-CoV-2 positive group. SARS-CoV-2 and HAdV co-infected children showed mild respiratory symptoms. The present study revealed that SARS-CoV-2 positive children often appear to have a milder clinical course than children with respiratory HAdV infection and children co-infected with SARSCoV-2 and HAdV had less-severe disease on presentation.

Analysis of the Prevalence of Binding and Neutralizing Antibodies against 39 Human Adenovirus Types in Student Cohorts Reveals Low-Prevalence Types and a Decline in Binding Antibody Levels during the SARS-CoV-2 Pandemic.

Human adenoviruses (HAdVs) are important tools for vector development for applications such as immunization, oncolytic therapy, or gene therapy. However, their potential is limited by preexisting immunity against HAdV; therefore, it is important for future vector design to identify HAdV types of low seroprevalence. To provide such data, we performed an analysis of both binding and neutralizing antibodies in sera from three student cohorts. Among these young adults, we found the highest levels of binding antibodies against HAdV-C1, -D33, -A31, -B35, -C5, -D26, -E4, and -B7. The highest levels of neutralizing antibodies were detected against HAdV-C2, -B3, -C1, -F41, -G52, -C5, -A31, -E4, and -C6. While binding and neutralizing antibody levels were not different in males and females or in samples collected before and after the cold season, we found significantly lower levels of binding antibodies in sera collected 20 months after the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, indicating a waning of HAdV-specific antibody responses on that time scale. Our data indicate that mainly HAdV types of species A, B, and D show low seroprevalence with regard to both binding and neutralizing antibodies and may represent good candidates for further characterization and future development as novel vector systems. IMPORTANCE Vectors based on human adenoviruses (HAdVs) are important for the development of novel immunizations, oncolytic therapies, and gene therapies. The use of HAdV-based vaccines against Ebola virus, the rapid adaptation of the vector technology for vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and their very good efficacy have shown the great potential of HAdV-based vaccines. Preexisting immunity against HAdV-based vectors can limit their efficacy significantly; therefore, it is highly desirable to identify HAdV types with low seroprevalence. The identification of new suitable HAdV types for vector development will broaden the repertoire and contribute to future epidemic preparedness.

Molecular typing and epidemiology profiles of human adenovirus infection among children with severe acute respiratory infection in Huzhou, China.

Human adenoviruses (HAdVs) are prevalent worldwide and are a common cause of respiratory tract infection in people of all ages. However, little is known about HAdV infection among children with severe acute respiratory infection (SARI). The present study retrospectively analysed the molecular typing and epidemiological characteristics of HAdV-positive samples from children with SARI from January 2017 to December 2021 in Huzhou. The results showed that 89 (8·27%) of 1078 SARI paediatric patients were positive for HAdVs. Children <5 years of age accounted for 87·64% of the positive cases. The peak seasons for HAdV infection were the first quarter and the fourth quarter. In addition, HAdV-B and HAdV-C were circulating among paediatric patients with SARI, of which the B3 genotype (n = 30, 51·72%) was the most prevalent and was detected every year, indicating that B3 is the main epidemic strain in the Huzhou area, followed by C1 (n = 9, 15·52%), C2 (n = 7, 12·07%) and B7 (n = 5, 8·62%). These findings provide a benchmark for future epidemiology and prevention strategies for HAdVs.

Complement activation by SARS-CoV- 2 vaccines and the effect of anti-vector antibodies

Novel vaccine platforms against SARS-CoV- 2 are in large-scale use, but interactions of complement with the 3 major vaccines have been little studied. In this work, we studied whether ChAdOx1 (AstraZeneca), mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) vaccines activate the human complement system. Complement C3 activation by the vaccine preparations was determined by Western blotting (WB) and the terminal complement complex (TCC) levels by ELISA in sera from individuals with different vaccination status or disease history. Antibody (IgG) titers against ChAdOx1 vector and the human adenovirus 2 hexon (hAdV2) protein were measured by EIA, and IgGs from high-and low-titre sera were purified by MelonGel filtration ChAdOx1 strongly activated C3 and TCC in a dose-dependent manner. Activation was inhibited by Mg-EGTA indicating classical pathway activation. Sera containing antibodies to hAdV2 or with vaccination-induced antibodies against ChAdOx1 enhanced complement activation in a dose-dependent manner. mRNA-1273 activated C3, but to a lesser extent. Activation occurred via the AP but did not lead to TCC formation. No C3 activation or TCC formation by BNT162b2 was detected. The three studied vaccines differed in their ability to activate complement. ChAdOx1 induced a robust complement activation, which correlated with the amount of anti-vector antibodies in the individual sera. Surprisingly, the two lipid nanoparticle mRNA vaccines (mRNA-1273 and BNT162b2) differed in their ability to activate complement. In addition to the role of complement as an endogenous adjuvant in vaccination, complement activation by vaccines may be involved in potential side effects or in determining variations in vaccine efficacy.

Human adenovirus (HAdV) infection in children with acute respiratory tract infections in Guangzhou, China, 2010-2021: a molecular epidemiology study.

BACKGROUND: Human adenovirus (HAdV) infection can cause a variety of diseases. It is a major pathogen of pediatric acute respiratory tract infections (ARIs) and can be life-threatening in younger children. We described the epidemiology and subtypes shifting of HAdV among children with ARI in Guangzhou, China. METHODS: We conducted a retrospective study of 161,079 children diagnosed with acute respiratory illness at the Guangzhou Women and Children's Medical Center between 2010 and 2021. HAdV specimens were detected by real-time PCR and the hexon gene was used for phylogenetic analysis. RESULTS: Before the COVID-19 outbreak in Guangzhou, the annual frequency of adenovirus infection detected during this period ranged from 3.92% to 13.58%, with an epidemic peak every four to five years. HAdV demonstrated a clear seasonal distribution, with the lowest positivity in March and peaking during summer (July or August) every year. A significant increase in HAdV cases was recorded for 2018 and 2019, which coincided with a shift in the dominant HAdV subtype from HAdV-3 to HAdV-7. The latter was associated with a more severe disease compared to HAdV-3. The average mortality proportion for children infected with HAdV from 2016 to 2019 was 0.38% but increased to 20% in severe cases. After COVID-19 emerged, HAdV cases dropped to 2.68%, suggesting that non-pharmaceutical interventions probably reduced the transmission of HAdV in the community. CONCLUSION: Our study provides the foundation for the understanding of the epidemiology of HAdV and its associated risks in children in Southern China.