T Cell Memory in Infection, Cancer, and Autoimmunity

Long-term immunological memory represents a unique performance of the adaptive immunity selected during evolution to support long-term survival of species in vertebrates, through protection against dangerous “invaders”, namely, infectious agents or unwanted (e.g., tumor) cells. The balance between the development of T cell memory and various mechanisms of immunoregulation (namely, T cell effector exhaustion and regulatory T cell suppression) dictates the fate in providing protection or not in different conditions, such as (acute or chronic) infection, vaccination, cancer, and autoimmunity. Here, these different environments are taken in consideration to outline the up-to-date cellular and molecular features regulating the development or damping of immunological memory and to delineate therapeutic strategies capable to improve or control it, in order to address pathological contexts, such as infection, tumor, and autoimmunity.

Long-lasting cellular immunity to SARS-CoV-2 following infection or vaccination and implications for booster strategies

Immunization against SARS-CoV-2, the causative agent of coronavirus disease-19 (COVID-19) occurs via natural infection or vaccination. However, it is currently unknown how long infection- or vaccination-induced immunological memory will last. We performed a longitudinal evaluation of immunological memory to SARS-CoV-2 following mRNA vaccination in naïve and COVID-19 recovered individuals. We found that cellular immunity is still detectable 8 months after vaccination, while antibody levels decline significantly especially in naïve subjects. We also found that a booster injection is more efficacious in reactivating immunological memory to spike protein in naïve than in previously SARS-CoV-2 infected subjects. Finally, we observed a similar kinetics of decay of humoral and cellular immunity to SARS-CoV-2 up to one year following natural infection in a cohort of unvaccinated individuals. Short-term persistence of humoral immunity may account for reinfections and breakthrough infections, although long-lived memory B and CD4+ T cells may protect from severe disease. A booster dose restores optimal anti-spike immunity in naïve subjects, while the need for vaccinated COVID-19 recovered subjects has yet to be defined.

mRNA COVID-19 Vaccines and Long-Lived Plasma Cells: A Complicated Relationship

mRNA COVID-19 vaccines have hegemonized the world market, and their administration to the population promises to stop the pandemic. However, the waning of the humoral immune response, which does not seem to last so many months after the completion of the vaccination program, has led us to study the molecular immunological mechanisms of waning immunity in the case of mRNA COVID-19 vaccines. We consulted the published scientific literature and from the few articles we found, we were convinced that there is an immunological memory problem after vaccination. Although mRNA vaccines have been demonstrated to induce antigen-specific memory B cells (MBCs) in the human population, there is no evidence that these vaccines induce the production of long-lived plasma cells (LLPCs), in a SARS-CoV-2 virus naïve population. This obstacle, in our point of view, is caused by the presence, in almost all subjects, of a cellular T and B cross-reactive memory produced during past exposures to the common cold coronaviruses. Due to this interference, it is difficult for a vaccination with the Spike protein alone, without adjuvants capable of prolonging the late phase of the generation of the immunological memory, to be able to determine the production of protective LLPCs. This would explain the possibility of previously and completely vaccinated subjects to become infected, already 4–6 months after the completion of the vaccination cycle.

Immune Memory in Aging: a Wide Perspective Covering Microbiota, Brain, Metabolism, and Epigenetics

Non-specific innate and antigen-specific adaptive immunological memories are vital evolutionary adaptations that confer long-lasting protection against a wide range of pathogens. Adaptive memory is established by memory T and B lymphocytes following the recognition of an antigen. On the other hand, innate immune memory, also called trained immunity, is imprinted in innate cells such as macrophages and natural killer cells through epigenetic and metabolic reprogramming. However, these mechanisms of memory generation and maintenance are compromised as organisms age. Almost all immune cell types, both mature cells and their progenitors, go through age-related changes concerning numbers and functions. The aging immune system renders the elderly highly susceptible to infections and incapable of mounting a proper immune response upon vaccinations. Besides the increased infectious burden, older individuals also have heightened risks of metabolic and neurodegenerative diseases, which have an immunological component. This review discusses how immune function, particularly the establishment and maintenance of innate and adaptive immunological memory, regulates and is regulated by epigenetics, metabolic processes, gut microbiota, and the central nervous system throughout life, with a focus on old age. We explain in-depth how epigenetics and cellular metabolism impact immune cell function and contribute or resist the aging process. Microbiota is intimately linked with the immune system of the human host, and therefore, plays an important role in immunological memory during both homeostasis and aging. The brain, which is not an immune-isolated organ despite former opinion, interacts with the peripheral immune cells, and the aging of both systems influences the health of each other. With all these in mind, we aimed to present a comprehensive view of the aging immune system and its consequences, especially in terms of immunological memory. The review also details the mechanisms of promising anti-aging interventions and highlights a few, namely, caloric restriction, physical exercise, metformin, and resveratrol, that impact multiple facets of the aging process, including the regulation of innate and adaptive immune memory. We propose that understanding aging as a complex phenomenon, with the immune system at the center role interacting with all the other tissues and systems, would allow for more effective anti-aging strategies.

751 Neo-X-Prime bispecific antibodies targeting CD40 and tumor antigens promote cross-presentation of tumor exosome-derived neoantigen and induce superior anti-tumor responses compared to CD40 mAb

BackgroundAlligator's Neo-X-Prime platform aims to enable antigen presenting cells to efficiently enhance priming of tumor neoantigen-specific T cells with the goal of overcoming PD-1 resistance in certain tumor types. We hypothesize that binding of a CD40 x TAA bispecific antibody (bsAb) to CD40 on dendritic cells (DCs) and a tumor-associated antigen (TAA) on tumor exosomes or tumor debris leads to (i) activation of the DC, (ii) uptake of the tumor material, (iii) cross-presentation of tumor-derived neoantigen (present in exosomes or debris) and, iv) priming of tumor neoantigen-specific T cells, resulting in an increased quantity and/or quality of the tumor-targeting T cell pool.MethodsFunctionality was evaluated in vitro using CD40 reporter cells and monocyte-derived DCs, co-cultured with cells expressing TAA. Further, co-localization of TAA-expressing cellular debris with a CD40-expressing human B cell line in the presence of bsAbs was assessed using live cell imaging. In vivo, anti-tumor efficacy and immunological memory were assessed in human CD40 transgenic (hCD40tg) mice bearing MB49 bladder carcinoma tumors transfected with human TAA or controls. T cells isolated from OVA-specific TCR-transgenic mice were used to evaluate the effect of Neo-X-Prime bsAbs on antigen-specific T cell expansion in the presence of hCD40tg DCs and exosomes from MB49 tumors transfected with both human TAA and OVA using flow cytometry.ResultsUsing CEA as a highly expressed TAA, we have developed lead Neo-X-Prime CD40-CEA bsAbs engineered to achieve an optimal profile. Further, using Neo-X-Prime concept molecules targeting EpCAM, we have demonstrated the ability to mediate co-localization of tumor debris and CD40 expressing antigen presenting cells that is dependent on the receptor density of the TAA. We have further shown that addition of Neo-X-Prime bsAbs to a co-culture of murine DCs, T cells and tumor-derived exosomes induces increased expansion of model neoantigen-specific T cells. In vivo, Neo-X-Prime bsAbs display a potent, TAA-dependent anti-tumor effect that is superior to CD40 mAbs. Cured mice develop a broad immunological memory that is not dependent on expression of the TAA. The tumor-localizing property of Neo-X-Prime bsAbs also shows potential for improved safety compared to CD40 monospecific antibodies.ConclusionsNeo-X-Prime bsAbs have the potential to tumor-selectively target CD40-expressing antigen-presenting cells to mediate an expansion of the tumor-specific T cell repertoire, resulting in increased T cell infiltration and potent anti-tumor effects.Ethics ApprovalAll experiments were performed after approval from the Malmö/Lund Animal Ethics Committee.

The prevalence of adaptive immunity to COVID-19 and reinfection after recovery – a comprehensive systematic review and meta-analysis of 12 011 447 individuals

Research purpose: The research aims to estimate the prevalence of detectable SARS-CoV-2 antibodies, T and B memory cells after recovery, to determine the prevalence of SARS-CoV-2 reinfection, and to investigate the protective efficacy of infection with SARS-CoV-2 against reinfection. Methodology: Several online databases were searched for studies conducted between 1 January 2020 to 1 April 2021. Studies which compared COVID-19 infection between individuals with and without prior infection were included and assessed for quality and risk of bias. Pooled estimates of the prevalence of humoral and cellular immunity parameters and reinfection were obtained in a meta-analysis using bias adjusted synthesis methods. Findings: At ≥ 6 months after recovery, the prevalence of SARS-CoV-2 specific immunological memory remained high; IgG – 90.4% (95%CI 72.2-99.9, I2=89.0%, p<0.01, 5 studies), and CD4+ - 91.7% (95%CI 78.2 – 97.1, one study). The pooled prevalence of reinfection was 0.2% (95%CI 0.0 – 0.7, I2 = 98.8, 9 studies). Individuals previously infected with SARS-CoV-2 had an 81% reduction in odds of a reinfection (OR 0.19, 95% CI 0.1 - 0.3, I2 = 90.5%, 5 studies). Research value: This review of 12 million individuals presents evidence that most individuals who recover from COVID-19 develop immunological memory to SARS-CoV-2, thus, reinfection after recovery was rare.

The prevalence of adaptive immunity to COVID-19 and reinfection after recovery – a comprehensive systematic review and meta-analysis of 12 011 447 individuals

ObjectivesThis study aims to estimate the prevalence and longevity of detectable SARS-CoV-2 specific antibodies as well as memory T and B cells after recovery. In addition, the prevalence of COVID-19 reinfection, and the preventive efficacy of previous infection with SARS-CoV-2 were investigated.Methods and analysesA synthesis of existing research was conducted. The Cochrane Library for COVID-19 resources, the China Academic Journals Full Text Database, PubMed, and Scopus as well as preprint servers were searched for studies conducted between 1 January 2020 to 1 April 2021. We included studies with the relevant outcomes of interest. All included studies were assessed for methodological quality and pooled estimates of relevant outcomes were obtained in a meta-analysis using a bias adjusted synthesis method. Proportions were synthesized with the Freeman-Tukey double arcsine transformation and binary outcomes using the odds ratio (OR). Heterogeneity between included studies was assessed using the I2 and Cochran’s Q statistics and publication bias was assessed using Doi plots.ResultsFifty-four studies, from 18 countries, with a total of 12 011 447 individuals, followed up to 8 months after recovery, were included. At 6-8 months after recovery, the prevalence of detectable SARS-CoV-2 specific immunological memory remained high; IgG – 90.4% (95%CI 72.2-99.9, I2=89.0%, 5 studies), CD4+ - 91.7% (95%CI 78.2 – 97.1, one study), and memory B cells 80.6% (95%CI 65.0-90.2, one study) and the pooled prevalence of reinfection was 0.2% (95%CI 0.0 – 0.7, I2 = 98.8, 9 studies). Individuals who recovered from COVID-19 had an 81% reduction in odds of a reinfection (OR 0.19, 95% CI 0.1 - 0.3, I2 = 90.5%, 5 studies).ConclusionAround 90% of people previously infected with SARS-CoV-2 had evidence of immunological memory to SARS-CoV-2, which was sustained for at least 6-8 months after recovery, and had a low risk of reinfection.RegistrationPROSPERO: CRD42020201234