Heterologous chimpanzee adenovirus vector immunizations for SARS-CoV-2 spike and nucleocapsid protect hamsters against COVID-19.

Available COVID-19 vaccine only provide protection for a limited time due in part to the rapid emergence of viral variants with spike protein mutations, necessitating the generation of new vaccines to combat SARS-CoV-2. Two serologically distinct replication-defective chimpanzee-origin adenovirus (Ad) vectors (AdC) called AdC6 and AdC7 expressing early SARS-CoV-2 isolate spike (S) or nucleocapsid (N) proteins, the latter expressed as a fusion protein within herpes simplex virus glycoprotein D (gD), were tested individually or as a mixture in a hamster COVID-19 SARS-CoV-2 challenge model. The S protein expressing AdC (AdC-S) vectors induced antibodies including those with neutralizing activity that in part cross-reacted with viral variants. Hamsters vaccinated with the AdC-S vectors were protected against serious disease and showed accelerated recovery upon SARS-CoV-2 challenge. Protection was enhanced if AdC-S vectors were given together with the AdC vaccines that expressed the gD N fusion protein (AdC-gDN). In contrast hamsters that just received the AdC-gDN vaccines showed only marginal lessening of symptoms compared to control animals. These results indicate that immune response to the N protein that is less variable than the S protein may potentiate and prolong protection achieved by the currently used S protein based genetic COVID-19 vaccines.

Antiviral Activity of N1,N3-Disubstituted Uracil Derivatives against SARS-CoV-2 Variants of Concern.

Despite the widespread use of the COVID-19 vaccines, the search for effective antiviral drugs for the treatment of patients infected with SARS-CoV-2 is still relevant. Genetic variability leads to the continued circulation of new variants of concern (VOC). There is a significant decrease in the effectiveness of antibody-based therapy, which raises concerns about the development of new antiviral drugs with a high spectrum of activity against VOCs. We synthesized new analogs of uracil derivatives where uracil was substituted at the N1 and N3 positions. Antiviral activity was studied in Vero E6 cells against VOC, including currently widely circulating SARS-CoV-2 Omicron. All synthesized compounds of the panel showed a wide antiviral effect. In addition, we determined that these compounds inhibit the activity of recombinant SARS-CoV-2 RdRp. Our study suggests that these non-nucleoside uracil-based analogs may be of future use as a treatment for patients infected with circulating SARS-CoV-2 variants.

T cell responses to adenoviral vectors expressing the SARS-CoV-2 nucleoprotein.

SARS-CoV-2 vaccines aim to protect against COVID-19 through neutralizing antibodies against the viral spike protein. Mutations within the spike's receptor-binding domain may eventually reduce vaccine efficacy, necessitating periodic updates. Vaccine-induced immunity could be broadened by adding T cell-inducing antigens such as SARS-CoV-2's nucleoprotein (N). Here we describe two replication-defective chimpanzee adenovirus (AdC) vectors from different serotypes expressing SARS-CoV-2 N either in its wild-type form or fused into herpes simplex virus glycoprotein D (gD), an inhibitor of an early T cell checkpoint. The vaccines induce potent and sustained CD8+ T cell responses that are broadened upon inclusion of gD. Depending on the vaccine regimen booster immunizations increase magnitude and breadth of T cell responses. Epitopes that are recognized by the vaccine-induced T cells are highly conserved among global SARS-CoV-2 isolates indicating that addition of N to COVID-19 vaccines may lessen the risk of loss of vaccine-induced protection due to variants.

Uracil derivatives as non-nucleoside inhibitors of viral infections

Viral infections are one of the important factors that influence the development of mankind. In recent decades, there has been a steady increase in the number of infectious diseases of viral etiology. This is due to the peculiarities of demography and human behavior, uncontrolled urbanization in developing countries, intensification of international travel and trade, lack of effective sanitation, environmental pollution, lack of programs to combat vectors of various diseases, adaptation of viruses themselves to new conditions, the emergence of a large number of refugees, and the shortcomings of public health measures. Such a tense situation is seen as a new challenge not only to modern medicine, but also to humanity as a whole. One of the ways to overcome this problem is the search and development of new highly effective antiviral drugs to combat socially significant diseases. This chapter summarizes the literature data on the study of uracil derivatives, acting as non-nucleoside inhibitors against various RNA and DNA viruses.