Control of SARS-CoV-2 infection after Spike DNA or Spike DNA+Proteinco-immunization in rhesus macaques

The speed of development, versatility and efficacy of mRNA-based vaccines have been amply demonstrated in the case of SARS-CoV-2. DNA vaccines represent an important alternative since they induce both humoral and cellular immune responses in animal models and in human trials. We tested the immunogenicity and protective efficacy of DNA-based vaccine regimens expressing different prefusion-stabilized SARS-CoV-2 Spike antigens upon intramuscular injection followed by electroporation in rhesus macaques. Different Spike DNA vaccine regimens induced antibodies that potently neutralized SARS-CoV-2 in vitro and elicited robust T cell responses. The DNA-only vaccine regimens were compared to a regimen that included co- immunization of Spike DNA and protein in the same anatomical site, the latter of which showed significant higher antibody responses. All vaccine regimens led to control of SARS-CoV-2 intranasal/intratracheal challenge and absence of virus dissemination to the lower respiratory tract. Vaccine-induced binding and neutralizing antibody titers and antibody-dependent cellular phagocytosis inversely correlated with transient virus levels in the nasal mucosa. Importantly, the Spike DNA+Protein co-immunization regimen induced the highest binding and neutralizing antibodies and showed the strongest control against SARS-CoV-2 challenge in rhesus macaques. Author summaryAnti-Spike neutralizing antibodies provide strong protection against SARS-CoV-2 infection in animal models, and correlate with protection in humans, supporting the notion that induction of strong humoral immunity is key to protection. We show induction of robust antibody and T cell responses by different Spike DNA-based vaccine regimens able to effectively mediate protection and to control SARS-CoV-2 infection in the rhesus macaque model. This study provides the opportunity to compare vaccines able to induce different humoral and cellular immune responses in an effort to develop durable immunity against the SARS-CoV-2. A vaccine regimen comprising simultaneous co-immunization of DNA and Protein at the same anatomical site showed best neutralizing abilities and was more effective than DNA alone in inducing protective immune responses and controlling SARS-CoV-2 infection. Thus, an expansion of the DNA vaccine regimen to include co-immunization with Spike protein may be of advantage also for SARS-CoV-2.

Molecular epidemiology of SARS-CoV-2 in Greece reveals low rates of onward virus transmission after lifting of travel restrictions based on risk assessment during summer 2020

Molecular epidemiology has provided an additive value to traditional public health tools by identifying SARS-CoV-2 clusters, or providing evidence that clusters based on virus sequences and contact tracing are highly concordant. Our aim was to infer the levels of virus importation and to estimate the impact of public health measures related to travel restrictions to local transmission in Greece. Our phylogenetic and phylogeographic analyses included 389 SARS-CoV-2 sequences collected during the first 7 months of the pandemic in Greece and a random collection in 5 replicates of 3,000 sequences sampled globally, as well as the best hits to our dataset identified by BLAST. Phylogenetic analyses revealed the presence of 70 genetically distinct viruses identified as independent introductions into Greece. The proportion of imported strains was 41%, 11.5%, and 8.8% during the three periods of sampling, namely, March (no travel restrictions), April to June (strict travel restrictions), and July to September (lifting of travel restrictions based on a thorough risk assessment), respectively. These findings reveal low levels of onward transmission from imported cases during summer and underscore the importance of targeted public health measures that can increase the safety of international travel during a pandemic.

Emerging drugs for the treatment of Waldenström macroglobulinemia.

INTRODUCTION: Waldenström's Macroglobulinemia (WM) is an indolent lymphoma with uniquely distinct and heterogenous clinical and genomic profiles. Clonal lymphoplasmacytic cells secrete monoclonal IgM. More than 90% of patients harbor a mutation in MYD88 gene, leading to the constitutive activation of downstream pathways, involving BTK-mediated signaling. The use of BTK inhibitors has changed the treatment landscape of WM and has paved the way for new approaches to therapy. AREAS COVERED: WM is an orphan disease and ibrutinib is the only FDA/EMA approved agent. Currently established agent combinations will be reviewed with a focus on emerging therapeutic options. These include second generation inhibitors, agents that target other molecules in the BCR signaling pathway, CXCR4 inhibitors, proteasome inhibitors and anti-CD38 antibodies. The current research goal is to establish a combination that can induce deep and durable responses with minimal associated toxicity. In addition, agents that can overcome ibrutinib resistance or act in a synergistic manner with BTKi are under investigation. EXPERT OPINION: The optimal therapeutic approach for WM patients is not currently established. The question of whether a combinatory (or synergistic) regimen to overcome resistance and allow for fixed- duration treatment will allow for deep/durable responses is being addressed in ongoing clinical trials.

Cisplatin-based chemotherapy for advanced seminoma: report of 52 cases treated in two institutions.

INTRODUCTION: We evaluated an intensified therapeutic strategy in order to optimize treatment outcomes while maintaining acceptable toxicity in patients with advanced seminoma. PATIENTS AND METHODS: Fifty-two patients with advanced pure seminoma were retrospectively evaluated. Patients with low-risk advanced seminoma, according to the International Germ Cell Cancer Collaborative Group Consensus Classification criteria, had received four cycles of the BEP regimen either in the 5-day or the alternative 3-day schedule, while patients with intermediate-risk advanced seminoma had received four cycles of the IBEP regimen. RESULTS: Forty-two patients (80.7%) had testicular seminoma while ten patients (19.3%) presented with primary extragonadal (mediastinal or retroperitoneal) tumor. Forty-seven (90.8%) patients belonged to the low-risk group and five patients (9.2%) to the intermediate-risk group. Treatment-related toxicity was moderate, with febrile neutropenia being the most prevalent (13.5%). Twenty patients (38.5%) achieved a complete response to chemotherapy. Twenty-three from the remaining 32 patients had residual masses more than 3 cm and were submitted to surgery (2 patients), FDG-PET scan (8 patients) or surveillance (13 patients). After 69 months of follow-up there were three recurrences that were successfully treated with high-dose or salvage chemotherapy. No death by any cause was recorded. CONCLUSIONS: Intensified cisplatin-based chemotherapy for patients with advanced seminoma does not confer evidence of superiority over radiotherapy alone or the standard BEP regimen. Patients with low-volume abdominal disease (clinical stage IIA and IIB) can be cured by four cycles of BEP instead of radiotherapy at the cost of a substantial increase in chemotherapy exposure and the resulting toxicity.