Preferential Amplification of CD8 Effector-T Cells after Transcutaneous Application of an Inactivated Influenza Vaccine: A Randomized Phase I Trial

Background: Current conventional vaccination approaches do not induce potent CD8 T-cell responses for fighting mostly variable viral diseases such as influenza, avian influenza viruses or HIV. Following our recent study on vaccine penetration by targeting of vaccine to human hair follicular ducts surrounded by Langerhans cells, we tested in the first randomized Phase-Ia trial based on hair follicle penetration (namely transcutaneous route) the induction of virus-specific CD8 T cell responses. Methods and Findings: We chose the inactivated influenza vaccine – a conventional licensed tetanus/influenza (TETAGRIP®) vaccine – to compare the safety and immunogenicity of transcutaneous (TC) versus IM immunization in two randomized controlled, multi-center Phase I trials including 24 healthy-volunteers and 12 HIV-infected patients. Vaccination was performed by application of inactivated influenza vaccine according to a standard protocol allowing the opening of the hair duct for the TC route or needle-injection for the IM route. We demonstrated that the safety of the two routes was similar. We showed the superiority of TC application, but not the IM route, to induce a significant increase in influenza-specific CD8 cytokine-producing cells in healthy-volunteers and in HIV-infected patients. However, these routes did not differ significantly for the induction of influenza-specific CD4 responses, and neutralizing antibodies were induced only by the IM route. The CD8 cell response is thus the major immune response observed after TC vaccination. Conclusions: This Phase Ia clinical trial (Manon05) testing an anti-influenza vaccine demonstrated that vaccines designed for antibody induction by the IM route, generate vaccine-specific CD8 T cells when administered transcutaneously. These results underline the necessity of adapting vaccination strategies to control complex infectious diseases when CD8 cellular responses are crucial. Our work opens up a key area for the development of preventive and therapeutic vaccines for diseases in which CD8 cells play a crucial role

Peptide-Based Vaccination for Antibody Responses Against HIV

HIV-1 is responsible for a global pandemic of 35 million people and continues to spread at a rate of >2 million new infections/year. It is widely acknowledged that a protective vaccine would be the most effective means to reduce HIV-1 spread and ultimately eliminate the pandemic, whereas a therapeutic vaccine might help to mitigate the clinical course of the disease and to contribute to virus eradication strategies. However, despite more than 30 years of research, we do not have a vaccine capable of protecting against HIV-1 infection or impacting on disease progression. This, in part, denotes the challenge of identifying immunogens and vaccine modalities with a reduced risk of failure in late stage development. However, progress has been made in epitope identification for the induction of broadly neutralizing antibodies. Thus, peptide-based vaccination has become one of the challenges of this decade. While some researchers reconstitute envelope protein conformation and stabilization to conserve the epitope targeted by neutralizing antibodies, others have developed strategies based on peptide-carrier vaccines with a similar goal. Here, we will review the major peptide-carrier based approaches in the vaccine field and their application and recent development in the HIV-1 field

Engineered CCR5 superagonist chemokine as adjuvant in anti-tumor DNA vaccination

Chemokine receptors are promising targets for enhancing T-cell immunity and anti-cancer therapy. CCL5 is a potential adjuvant for DNA vaccination. We postulated that CCR5 superagonists could be even more effective. A CCR5 superagonist derived from natural CCL5 by directed in vitro evolution, namely 1P7, is used as a DNA vaccine adjuvant and expressed as fused chemokine-Ig (1P7-Ig). We show that OVA+1P7-Ig DNA co-inoculation induced higher frequencies of OVA-specific CD8 lymphocytes than OVA+CCL5-Ig or controls and gave an even better protection against tumor growth in a CCR5-dependant manner. Our results indicate that CCR5-superagonists may provide potent adjuvants for vaccines

Differential TCR Signaling Regulates Apoptosis and Immunopathology during Antigen Responses In Vivo

AbstractClonal selection theories postulate that lymphocyte fate is regulated by antigen receptor specificity. However, lymphocyte apoptosis is induced through non-antigen-specific receptors such as Fas (CD95/APO-1) or TNFR. We define a selective TCR that controls apoptosis by Fas or TNFR stimulation. Variant ligands can deliver this “competence to die” signal without the full TCR signals necessary for cytokine synthesis. These partial agonists regulate T cell deletion in vivo even when Fas or TNF is provided by T cells of unrelated specificity, but they do not cause the liver necrosis that is associated with T cell elimination by the full agonist. Thus, selective signaling ligands regulate T cell deletion and immune damage in vivo and may be important for peripheral T cell tolerance

Coadministration of seasonal influenza and COVID-19 vaccines: A systematic review of clinical studies

International audienceThe lifting of non-pharmaceutical measures preventing transmission of SARS-CoV-2 (and other viruses, including influenza viruses) raises concerns about healthcare resources and fears of an increased number of cases of influenza and COVID-19. For the 2021-2022 influenza season, the WHO and >20 European countries promoted coadministration of influenza and COVID-19 vaccines. Recently, the French Health Authority recommended coupling the COVID-19 vaccination with the 2022-2023 influenza vaccination campaign for healthcare professionals and people at risk of severe COVID-19. The present systematic review examines published data on the safety, immunogenicity, efficacy/effectiveness, and acceptability/acceptance of coadministration of influenza and COVID-19 vaccines. No safety concerns or immune interferences were found whatever the vaccines or the age of vaccinated subjects (65- or 65+). No efficacy/effectiveness data were available. The results should reassure vaccinees and vaccinators in case of coadministration and increase vaccine coverage. Healthcare systems promoting coupled campaigns must provide the necessary means for successful coadministration

Nucleocapsid-specific and PD-L1+CXCR3+ CD8 polyfunctional T-cell abundances are associated with survival of critical SARS-CoV2-infected patients

International audienceRationale. The importance of the adaptative T cell response in the control and resolution of viral infection has been well-established. However, the nature of T cell-mediated viral control mechanisms in life-threatening stages of COVID-19 has yet to be determined.Objective. The aim of the present study was to determine the function and phenotype of T cell populations associated with survival or death of COVID-19 patients under intensive care as a result of phenotypic and functional profiling by mass cytometry.Findings. Increased frequencies of circulating, polyfunctional, CD4+CXCR5+HLA-DR+ stem cell memory T cells (TSCM) and decreased proportions of Granzyme-B and Perforin-expressing effector memory T cells (TEM) were detected in recovered and deceased patients, respectively. The higher abundance of polyfunctional CD8+PD-L1+CXCR3+ T effector cells, CXCR5+HLA-DR+ TSCM, as well as anti-nucleocapsid (NC) cytokine-producing T cells permitted to differentiate between recovered and deceased patients. The results from a principal component analysis showed an imbalance in the T cell compartment allowed for the separation of recovered and deceased patients. The paucity of circulating CD8+PD-L1+CXCR3+ Teff-cells and NC-specific CD8+ T-cells accurately forecasts fatal disease outcome.Conclusion. This study provides insight into the nature of the T cell populations involved in the control of COVID-19 and therefor might impact T cell-based vaccine designs for this infectious disease