Explore the vast range of titles available.

Gardasil® (Merck) and Cervarix® (GlaxoSmithKline) both provide protection against infection with Human Papillomavirus 16 (HPV16) and Human Papillomavirus 18 (HPV18), that account for around 70% of cervical cancers. Both vaccines have been shown to induce high levels of neutralizing antibodies and are known to protect against progression beyond cervical intraepithelial neoplasia grade 2 (CIN2+), although Cervarix® has been linked to enhanced protection from progression. However, beyond the transmission-blocking activity of neutralizing antibodies against HPV, no clear correlate of protection has been defined that may explain persistent control and clearance elicited by HPV vaccines. Beyond blocking, antibodies contribute to antiviral activity via the recruitment of the cytotoxic and opsonophagocytic power of the immune system. Thus, here, we used systems serology to comprehensively profile Gardasil®- and Cervarix®- induced antibody subclass, isotype, Fc-receptor binding, and Fc-effector functions against the HPV16 and HPV18 major capsid protein (L1). Overall, both vaccines induced robust functional humoral immune responses against both HPV16 and HPV18. However, Cervarix® elicited higher IgG3 and antibody-dependent complement activating responses, and an overall more coordinated response between HPV16 and 18 compared to Gardasil®, potentially related to the distinct adjuvants delivered with the vaccines. Thus, these data point to robust Fc-effector functions induced by both Gardasil® and Cervarix®, albeit with enhanced coordination observed with Cervarix®, potentially underlying immunological correlates of post-infection control of HPV.

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coupled with a lack of therapeutics, has paralyzed the globe. Although significant effort has been invested in identifying antibodies that block infection, the ability of antibodies to target infected cells through Fc interactions may be vital to eliminate the virus. To explore the role of Fc activity in SARS-CoV-2 immunity, the functional potential of a cross–SARS-reactive antibody, CR3022, was assessed. CR3022 was able to broadly drive antibody effector functions, providing critical immune clearance at entry and upon egress. Using selectively engineered Fc variants, no protection was observed after administration of WT IgG1 in mice or hamsters. Conversely, the functionally enhanced Fc variant resulted in increased pathology in both the mouse and hamster models, causing weight loss in mice and enhanced viral replication and weight loss in the more susceptible hamster model, highlighting the pathological functions of Fc-enhancing mutations. These data point to the critical need for strategic Fc engineering for the treatment of SARS-CoV-2 infection.

The dissemination of HIV from an initial site of infection is facilitated by motile HIV-infected CD4(+) T-cells. However, the impact of infected target cell migration on antigen recognition by HIV-specific CD8(+) T-cells is unclear. Using a 3D in vitro model of tissue, we visualized dynamic interactions between HIV-infected or peptide-pulsed CD4(+) T-cells and HIV-specific CD8(+) T-cells. CTLs engaged motile HIV-infected targets, but ∼ 50% of targets broke contact and escaped. In contrast, immobilized target cells were readily killed, indicating target motility directly inhibits CD8(+) T-cell function. Strong calcium signals occurred in CTLs killing a motile target but calcium signaling was weak or absent in CTLs which permitted target escape. Neutralization of adhesion receptors LFA-1 and CD58 inhibited CD8(+) T-cell function within the 3D matrix, demonstrating that efficient motile target lysis as dependent on adhesive engagement of targets. Antigen sensitivity (a convolution of antigen density, TCR avidity and CD8 coreceptor binding) is also critical for target recognition. We modulated this parameter (known as functional avidity but referred to here as \"avidity\" for the sake of simplicity) by exploiting common HIV escape mutations and measured their impact on CTL function at the single-cell level. Targets pulsed with low avidity mutant antigens frequently escaped while CTLs killed targets bearing high avidity antigen with near-perfect efficiency. CTLs engaged, arrested, and killed an initial target bearing high avidity antigen within minutes, but serial killing was surprisingly rare. CD8 cells remained committed to their initial dead target for hours, accumulating TCR signals that sustained secretion of soluble antiviral factors. These data indicate that high-avidity CD8(+) T-cells execute an antiviral program in the precise location where antigen has been sensed: CTL effector functions are spatiotemporally coordinated with an early lytic phase followed by a sustained stationary secretory phase to control local viral infection.

The dissemination of HIV from an initial site of infection is facilitated by motile HIV-infected CD4.sup.+ T-cells. However, the impact of infected target cell migration on antigen recognition by HIV-specific CD8.sup.+ T-cells is unclear. Using a 3D in vitro model of tissue, we visualized dynamic interactions between HIV-infected or peptide-pulsed CD4.sup.+ T-cells and HIV-specific CD8.sup.+ T-cells. CTLs engaged motile HIV-infected targets, but ~50% of targets broke contact and escaped. In contrast, immobilized target cells were readily killed, indicating target motility directly inhibits CD8.sup.+ T-cell function. Strong calcium signals occurred in CTLs killing a motile target but calcium signaling was weak or absent in CTLs which permitted target escape. Neutralization of adhesion receptors LFA-1 and CD58 inhibited CD8.sup.+ T-cell function within the 3D matrix, demonstrating that efficient motile target lysis as dependent on adhesive engagement of targets. Antigen sensitivity (a convolution of antigen density, TCR avidity and CD8 coreceptor binding) is also critical for target recognition. We modulated this parameter (known as functional avidity but referred to here as \"avidity\" for the sake of simplicity) by exploiting common HIV escape mutations and measured their impact on CTL function at the single-cell level. Targets pulsed with low avidity mutant antigens frequently escaped while CTLs killed targets bearing high avidity antigen with near-perfect efficiency. CTLs engaged, arrested, and killed an initial target bearing high avidity antigen within minutes, but serial killing was surprisingly rare. CD8 cells remained committed to their initial dead target for hours, accumulating TCR signals that sustained secretion of soluble antiviral factors. These data indicate that high-avidity CD8.sup.+ T-cells execute an antiviral program in the precise location where antigen has been sensed: CTL effector functions are spatiotemporally coordinated with an early lytic phase followed by a sustained stationary secretory phase to control local viral infection.

We describe a physics-based learning model for predicting the immunogenicity of Cytotoxic T Lymphocyte (CTL) epitopes derived from diverse pathogens, given a Human Leukocyte Antigen (HLA) genotype. The model was trained and tested on experimental data on the relative immunodominance of CTL epitopes in Human Immunodeficiency Virus infection. The method is more accurate than publicly available models. Our model predicts that only a fraction of SARS-CoV-2 epitopes that have been predicted to bind to HLA molecules is immunogenic. The immunogenic CTL epitopes across all SARS-CoV-2 proteins are predicted to provide broad population coverage, but the immunogenic epitopes in the SARS-CoV-2 spike protein alone are unlikely to do so. Our model predicts that several immunogenic SARS-CoV-2 CTL epitopes are identical to those contained in low-pathogenicity coronaviruses circulating in the population. Thus, we suggest that some level of CTL immunity against COVID-19 may be present in some individuals prior to SARS-CoV-2 infection.