The Brighton Collaboration standardized template for collection of key information for benefit-risk assessment of viral vector vaccines.

Many of the vaccines under development for COVID-19 involve the use of viral vectors. The Brighton Collaboration Benefit-Risk Assessment of Vaccines by Technology (BRAVATO, formerly the Viral Vector Vaccine Safety Working Group, V3SWG) working group has prepared a standardized template to describe the key considerations for the benefit-risk assessment of viral vector vaccines. This will facilitate key stakeholders to anticipate potential safety issues and interpret or assess safety data. This would also help improve communication and public acceptance of licensed viral vector vaccines.

Long-lasting decrease in viremia in macaques chronically infected with simian immunodeficiency virus SIVmac251 after therapeutic DNA immunization.

Rhesus macaques chronically infected with highly pathogenic simian immunodeficiency virus (SIV) SIVmac251 were treated with antiretroviral drugs and vaccinated with combinations of DNA vectors expressing SIV antigens. Vaccination during therapy increased cellular immune responses. After the animals were released from therapy, the virus levels of 12 immunized animals were significantly lower (P = 0.001) compared to those of 11 animals treated with only antiretroviral drugs. Vaccinated animals showed a persistent increase in immune responses, thus indicating both a virological and an immunological benefit following DNA therapeutic vaccination. Several animals show a long-lasting decrease in viremia, suggesting that therapeutic vaccination may provide an additional benefit to antiretroviral therapy.

A novel and efficient approach to discriminate between pre- and post-transcription HIV inhibitors.

Established anti-human immunodeficiency virus (HIV) treatments are not always effective or well tolerated, highlighting the need for further refinement of antiviral drug design and development. Given the multitude of molecular targets with which the anti-HIV agents can interact, studies on the mechanism of action of newly discovered HIV inhibitors are quite elaborate. In this article, we describe the use of an efficient reporter system allowing rapid discrimination between a pre- or post-transcriptional mode of action of anti-HIV compounds based on infection by a replication competent HIV-1 molecular clone expressing the green fluorescent protein as part of the nef multiply spliced RNA. Using fluorescence microscopy and flow cytometry, this system enabled us to differentiate between compounds acting at a pre- or post-transciptional level of the virus life cycle. Antiviral activities were determined for four reference compounds as well as one putative novel HIV inhibitor. The results obtained were in agreement with the known characteristics of the reference compounds and revealed that the novel compound interfered with a target before or overlapping with HIV transcription. We showed that during a single replication cycle, compounds inhibiting a molecular target occurring before or coinciding with HIV transcription suppressed GFP expression, whereas compounds interfering at a later stage (such as protease inhibitors, which act after transcription) did not inhibit GFP expression. This GFP-based reporter system is adaptable for high-throughput screening.

A potent anti-HIV immunotoxin blocks spreading infection by primary HIV type 1 isolates in multiple cell types.

Although several immunotoxins that selectively kill HIV-1-infected cells have been described, their clinical utility is limited by low potency against spreading viral infection. We show here that changing the carboxyterminal sequence of an anti-HIV-1 envelope immunotoxin to the consensus endoplasmic reticulum retention sequence KDEL substantially improves its ability to block infection of peripheral blood mononuclear cells by primary HIV-1 isolates without increasing nonspecific toxicity. Polychromatic flow cytometry of peripheral blood mononuclear cells (PBMC) infected with an HIV-1-GFP reporter virus demonstrated that the improved immunotoxin is active against a variety of primary cell types including memory T cells, NK-T cells, and monocyte/macrophages. The subnanomolar potency of this agent suggests that it could be clinically useful either as an adjuvant to highly active antiretroviral therapy (HAART) in drug-resistant patients or to reduce the reservoir of latently infected cells that is implicated in HIV-1 persistence.