Clusters of SARS-CoV-2 Lineage B.1.1.7 Infection after Vaccination with Adenovirus-Vectored and Inactivated Vaccines.

A SARS-CoV-2 B.1.1.7 variant of concern (VOC) has been associated with increased transmissibility, hospitalization, and mortality. This study aimed to explore the factors associated with B.1.1.7 VOC infection in the context of vaccination. On March 2021, we detected SARS-CoV-2 RNA in nasopharyngeal samples from 14 of 22 individuals vaccinated with a single-dose of ChAdOx1 (outbreak A, n = 26), and 22 of 42 of individuals with two doses of the CoronaVac vaccine (outbreak B, n = 52) for breakthrough infection rates for ChAdOx1 of 63.6% and 52.4% for CoronaVac. The outbreaks were caused by two independent clusters of the B.1.1.7 VOC. The serum of PCR-positive symptomatic SARS-CoV-2-infected individuals had ~1.8-3.4-fold more neutralizing capacity against B.1.1.7 compared to the serum of asymptomatic individuals. These data based on exploratory analysis suggest that the B.1.1.7 variant can infect individuals partially immunized with a single dose of an adenovirus-vectored vaccine or fully immunized with two doses of an inactivated vaccine, although the vaccines were able to reduce the risk of severe disease and death caused by this VOC, even in the elderly.

The Viral Polymerase Inhibitor 7-Deaza-2'-C-Methyladenosine Is a Potent Inhibitor of In Vitro Zika Virus Replication and Delays Disease Progression in a Robust Mouse Infection Model.

Zika virus (ZIKV) is an emerging flavivirus typically causing a dengue-like febrile illness, but neurological complications, such as microcephaly in newborns, have potentially been linked to this viral infection. We established a panel of in vitro assays to allow the identification of ZIKV inhibitors and demonstrate that the viral polymerase inhibitor 7-deaza-2'-C-methyladenosine (7DMA) efficiently inhibits replication. Infection of AG129 (IFN-α/ß and IFN-γ receptor knock-out) mice with ZIKV resulted in acute neutrophilic encephalitis with viral antigens accumulating in neurons of the brain and spinal cord. Additionally, high levels of viral RNA were detected in the spleen, liver and kidney, and levels of IFN-γ and IL-18 were systematically increased in serum of ZIKV-infected mice. Interestingly, the virus was also detected in testicles of infected mice. In line with its in vitro anti-ZIKV activity, 7DMA reduced viremia and delayed virus-induced morbidity and mortality in infected mice, which also validates this small animal model to assess the in vivo efficacy of novel ZIKV inhibitors. Since AG129 mice can generate an antibody response, and have been used in dengue vaccine studies, the model can also be used to assess the efficacy of ZIKV vaccines. .

Dengue virus requires the CC-chemokine receptor CCR5 for replication and infection development.

Dengue is a mosquito-borne disease that affects millions of people worldwide yearly. Currently, there is no vaccine or specific treatment available. Further investigation on dengue pathogenesis is required to better understand the disease and to identify potential therapeutic targets. The chemokine system has been implicated in dengue pathogenesis, although the specific role of chemokines and their receptors remains elusive. Here we describe the role of the CC-chemokine receptor CCR5 in Dengue virus (DENV-2) infection. In vitro experiments showed that CCR5 is a host factor required for DENV-2 replication in human and mouse macrophages. DENV-2 infection induces the expression of CCR5 ligands. Incubation with an antagonist prevents CCR5 activation and reduces DENV-2 positive-stranded (+) RNA inside macrophages. Using an immunocompetent mouse model of DENV-2 infection we found that CCR5(-/-) mice were resistant to lethal infection, presenting at least 100-fold reduction of viral load in target organs and significant reduction in disease severity. This phenotype was reproduced in wild-type mice treated with CCR5-blocking compounds. Therefore, CCR5 is a host factor required for DENV-2 replication and disease development. Targeting CCR5 might represent a therapeutic strategy for dengue fever. These data bring new insights on the association between viral infections and the chemokine receptor CCR5.

IL-22 modulates IL-17A production and controls inflammation and tissue damage in experimental dengue infection.

Dengue virus (DENV), a mosquito-borne flavivirus, is a public health problem in many tropical countries. IL-22 and IL-17A are key cytokines in several infectious and inflammatory diseases. We have assessed the contribution of IL-22 and IL-17A in the pathogenesis of experimental dengue infection using a mouse-adapted DENV serotype 2 strain (P23085) that causes a disease that resembles severe dengue in humans. We show that IL-22 and IL-17A are produced upon DENV-2 infection in immune-competent mice. Infected IL-22(-/-) mice had increased lethality, neutrophil accumulation and pro-inflammatory cytokines in tissues, notably IL-17A. Viral load was increased in spleen and liver of infected IL-22(-/-) mice. There was also more severe liver injury, as seen by increased transaminases levels and tissue histopathology. γδ T cells and NK cells are sources of IL-17A and IL-22, respectively, in liver and spleen. We also show that DENV-infected HepG2 cells treated with rhIL-22 had reduced cell death and decreased IL-6 production. IL-17RA(-/-) mice were protected upon infection and IL-17A-neutralizing-Ab-treatment partially reversed the phenotype observed in IL-22(-/-) -infected mice. We suggest that disrupting the balance between IL-22 and IL-17A levels may represent an important strategy to reduce inflammation and tissue injury associated with severe dengue infection.