Respiratory viruses are a common cause of morbidity and mortality around the world. Viruses like influenza, RSV, and most recently SARS‐CoV‐2 can rapidly spread through a population, causing acute ...infection and, in vulnerable populations, severe or chronic disease. Developing effective treatment and prevention strategies often becomes a race against ever‐evolving viruses that develop resistance, leaving therapy efficacy either short‐lived or relevant for specific viral strains. On June 29 to July 2, 2022, researchers met for the Keystone symposium “Respiratory Viruses: New Frontiers.” Researchers presented new insights into viral biology and virus–host interactions to understand the mechanisms of disease and identify novel treatment and prevention approaches that are effective, durable, and broad.
Respiratory viruses are a common cause of morbidity and mortality around the world. Viruses like influenza, RSV, and most recently SARS‐CoV‐2 can rapidly spread through a population, causing acute infection and, in vulnerable populations, severe or chronic disease. On June 29 to July 2, 2022, researchers met for the Keystone symposium “Respiratory Viruses: New Frontiers”. The meeting was held jointly with the symposium “Viral Immunity: Basic Mechanisms and Therapeutic Applications.” Researchers presented new insights into viral biology and virus‐host interactions to understand the mechanisms of disease and identify novel treatment and prevention approaches that are effective, durable, and broad.
Summary
Antiretroviral therapy (ART) for the treatment of human immunodeficiency virus (HIV) infection represents a major breakthrough in the treatment of HIV/acquired immune‐deficiency syndrome. ...However, it remains unclear how ART influences virus‐specific immune responses and understanding this is important for developing novel cure and eradication interventions for HIV‐1. In the present study, we evaluate how ART impacts T‐cell and antibody responses in simian immunodeficiency virus (SIV) ‐infected rhesus macaques. We evaluated CD4 and CD8 T‐cell responses by multiparameter flow cytometry, viral loads by quantitative RT‐PCR by a two‐step process using SIV‐specific primers and antibody neutralization function by luciferase‐based TZM‐bl assays. We demonstrate that macaques treated with ART exhibit phenotypic and qualitative effects on T‐cell and antibody responses. Macaques on ART exhibited low numbers of virus‐specific T‐cell responses, and these responses appeared to be partially biased towards central memory subsets. More importantly, there were significantly reduced neutralizing antibody responses in macaques treated with ART. Collectively, these data improve the understanding of how virus‐specific immune responses are generated during ART, and suggest the potential importance of therapeutic vaccines to maintain adaptive immunity during treated infection.
SIV‐specific immune responses are affected by ART.
CD4+ T follicular helper (TFH) cells are central for generation of long‐term B‐cell immunity. A defining phenotypic attribute of TFH cells is the expression of the chemokine R CXCR5, and TFH cells ...are typically identified by co‐expression of CXCR5 together with other markers such as PD‐1, ICOS, and Bcl‐6. Herein, we report high‐level expression of the nutrient transporter folate R 4 (FR4) on TFH cells in acute viral infection. Distinct from the expression profile of conventional TFH markers, FR4 was highly expressed by naive CD4+ T cells, was downregulated after activation and subsequently re‐expressed on TFH cells. Furthermore, FR4 expression was maintained, albeit at lower levels, on memory TFH cells. Comparative gene expression profiling of FR4hi versus FR4lo Ag‐specific CD4+ effector T cells revealed a molecular signature consistent with TFH and TH1 subsets, respectively. Interestingly, genes involved in the purine metabolic pathway, including the ecto‐enzyme CD73, were enriched in TFH cells compared with TH1 cells, and phenotypic analysis confirmed expression of CD73 on TFH cells. As there is now considerable interest in developing vaccines that would induce optimal TFH cell responses, the identification of two novel cell surface markers should be useful in characterization and identification of TFH cells following vaccination and infection.
The outbreak of 2019 coronavirus disease (COVID‐19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has resulted in a global pandemic. Despite intensive research, the current ...treatment options show limited curative efficacies. Here the authors report a strategy incorporating neutralizing antibodies conjugated to the surface of a photothermal nanoparticle (NP) to capture and inactivate SARS‐CoV‐2. The NP is comprised of a semiconducting polymer core and a biocompatible polyethylene glycol surface decorated with high‐affinity neutralizing antibodies. The multifunctional NP efficiently captures SARS‐CoV‐2 pseudovirions and completely blocks viral infection to host cells in vitro through the surface neutralizing antibodies. In addition to virus capture and blocking function, the NP also possesses photothermal function to generate heat following irradiation for inactivation of virus. Importantly, the NPs described herein significantly outperform neutralizing antibodies at treating authentic SARS‐CoV‐2 infection in vivo. This multifunctional NP provides a flexible platform that can be readily adapted to other SARS‐CoV‐2 antibodies and extended to novel therapeutic proteins, thus it is expected to provide a broad range of protection against original SARS‐CoV‐2 and its variants.
A multifunctional neutralizing antibody‐conjugated nanoparticle is developed to capture and inactivate SARS‐CoV‐2. It efficiently captures SARS‐CoV‐2 pseudovirions and completely blocks viral infection of host cells in vitro through the surface neutralizing antibodies. In addition, its photothermal function inactivates viruses upon light irradiation. More importantly, it treats authentic SARS‐CoV‐2 infection in vivo outperforming neutralizing antibodies.
Summary
The primary function of the immune system is to protect the host from infectious microorganisms and cancers. However, a major component of the immune response involves the direct elimination ...of cells in the body and the induction of systemic inflammation, which may result in life‐threatening immunopathology. Therefore, the immune system has developed complex mechanisms to regulate itself with a specialized subset of CD4 T lymphocytes (referred to as regulatory T cells) and immune checkpoint pathways, such as the programmed cell death protein 1 pathway. These immune regulatory mechanisms can be exploited by pathogens and tumours to establish persistence in the host, warranting a deeper understanding of how to fine‐tune immune responses during these chronic diseases. Here, I discuss various features of immune regulatory pathways and what important aspects must be considered in the next generation of therapies to reverse immune exhaustion, understanding that this process is a natural mechanism to prevent the host from destroying itself.
T regulatory (Treg) cells and programmed cell death protein 1 (PD‐1) play a critical role in modulating CD8 T‐cell exhaustion. In this review, Penaloza‐MacMaster discusses how Treg cells and PD‐1 modulate CD8 T‐cell responses during antigen persistence versus antigen clearance, and how the careful manipulation of these immunoregulatory pathways can be promising for the treatment of chronic infections and cancers.
SARS-CoV-2 infection causes respiratory insufficiency and neurological manifestations, including loss of smell and psychiatric disorders, and can be fatal. Most vaccines are based on the spike ...antigen alone, and although they have shown efficacy at preventing severe disease and death, they do not always confer sterilizing immunity. Here, we interrogate whether SARS-CoV-2 vaccines could be improved by incorporating nucleocapsid as an antigen. We show that, after 72 h of challenge, a spike-based vaccine confers acute protection in the lung, but not in the brain. However, combining a spike-based vaccine with a nucleocapsid-based vaccine confers acute protection in both the lung and brain. These findings suggest that nucleocapsid-specific immunity can improve the distal control of SARS-CoV-2, warranting the inclusion of nucleocapsid in next-generation COVID-19 vaccines.
Display omitted
•SARS-CoV-2 vaccines do not prevent breakthrough infection in K18-ACE2 mice•A spike vaccine confers better protection than a nucleocapsid vaccine•A spike vaccine confers acute protection in lung, but not in brain•Combining spike and nucleocapsid vaccines improves distal protection in brain
Most SARS-CoV-2 vaccines are based on the spike antigen alone, and it is unknown whether including other viral antigens improves protection. Dangi et al. show that combining a spike vaccine with a nucleocapsid vaccine improves the control of a SARS-CoV-2 infection, warranting the inclusion of nucleocapsid in next-generation SARS-CoV-2 vaccines.
Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines have shown efficacy against SARS-CoV-2, it is unknown if coronavirus vaccines can also protect against other ...coronaviruses that may infect humans in the future. Here, we show that coronavirus vaccines elicited cross-protective immune responses against heterologous coronaviruses. In particular, we show that a severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) vaccine developed in 2004 and known to protect against SARS-CoV-1 conferred robust heterologous protection against SARS-CoV-2 in mice. Similarly, prior coronavirus infections conferred heterologous protection against distinct coronaviruses. Cross-reactive immunity was also reported in patients with coronavirus disease 2019 (COVID-19) and in individuals who received SARS-CoV-2 vaccines, and transfer of plasma from these individuals into mice improved protection against coronavirus challenges. These findings provide the first demonstration to our knowledge that coronavirus vaccines (and prior coronavirus infections) can confer broad protection against heterologous coronaviruses and establish a rationale for universal coronavirus vaccines.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein is the main antigen in all approved COVID-19 vaccines and is also the only target for monoclonal antibody (mAb) ...therapies. Immune responses to other viral antigens are generated after SARS-CoV-2 infection, but their contribution to the antiviral response remains unclear. Here, we interrogated whether nucleocapsid-specific antibodies can improve protection against SARS-CoV-2. We first immunized mice with a nucleocapsid-based vaccine and then transferred sera from these mice into naive mice, followed by challenge with SARS-CoV-2. We show that mice that received nucleocapsid-specific sera or a nucleocapsid-specific mAb exhibited enhanced control of SARS-CoV-2. Nucleocapsid-specific antibodies elicited NK-mediated, antibody-dependent cellular cytotoxicity (ADCC) against infected cells. To our knowledge, these findings provide the first demonstration in the coronavirus literature that antibody responses specific to the nucleocapsid protein can improve viral clearance, providing a rationale for the clinical evaluation of nucleocapsid-based mAb therapies to treat COVID-19.
The unprecedented challenges of developing effective vaccines against intracellular pathogens such as HIV, malaria, and tuberculosis have resulted in more rational approaches to vaccine development. ...Apart from the recent advances in the design and selection of improved epitopes and adjuvants, there are also ongoing efforts to optimize delivery platforms. Viral vectors are the best-characterized delivery tools because of their intrinsic adjuvant capability, unique cellular tropism, and ability to trigger robust adaptive immune responses. However, a known limitation of viral vectors is preexisting immunity, and ongoing efforts are aimed at developing novel vector platforms with lower seroprevalence. It is also becoming increasingly clear that different vectors, even those derived from phylogenetically similar viruses, can elicit substantially distinct immune responses, in terms of quantity, quality, and location, which can ultimately affect immune protection. This review provides a summary of the status of viral vector development for HIV vaccines, with a particular focus on novel viral vectors and the types of adaptive immune responses that they induce.
Summary
T regulatory (Treg) cells are critical for preventing autoimmunity and suppressing immune responses during cancer and chronic infection. However, the role of Treg cells in the generation of ...vaccine‐induced immune memory remains ill‐defined. Using the mouse model of lymphocytic choriomeningitis virus (LCMV) infection, we demonstrate that transient absence of Treg cells during effector to memory CD8 T‐cell transition results in a permanent impairment in the maintenance, function and recall capacity of CD8 T cells. Memory CD8 T cells in mice that were transiently depleted of Treg cells exhibited defective up‐regulation of memory markers with a significant decrease in polyfunctionality. However, Treg‐depleted mice showed no significant change in CD4 T‐cell responses, and antibody levels relative to control. Altogether, this study evaluates the role of Treg cells in the formation of immune memory and demonstrates an important role for Treg cells in promoting memory CD8 T‐cell differentiation and vaccine‐induced immune protection against intracellular pathogens.
T regulatory (Treg) cells play a critical role in the regulation of self‐tolerance and immune exhaustion. However, their role in the context of acutely controlled infection or vaccination remains ill‐defined. In this paper, the Penaloza‐MacMaster laboratory demonstrates the effects of transient Treg depletion on various arms of the adaptive immune response, including CD8 T cells, and antibodies.
PDF
