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Background: It is unclear whether human immunodeficiency virus (HIV) infection results in permanent loss of T-cell memory or if it affects preexisting antibodies to childhood vaccinations or infections., Methods: We conducted a matched cohort study involving 50 pairs of HIV-infected and HIV-uninfected women. Total memory T-cell responses were measured after anti-CD3 or vaccinia virus (VV) stimulation to measure T cells elicited after childhood smallpox vaccination. VV-specific antibodies were measured by means of enzyme-linked immunosorbent assay (ELISA)., Results: There was no difference between HIV-infected and HIV-uninfected study participants in terms of CD4+ T-cell responses after anti-CD3 stimulation (P = .19) although HIV-infected participants had significantly higher CD8+ T-cell responses (P = .03). In contrast, there was a significant loss in VV-specific CD4+ T-cell memory among HIV-infected participants (P = .04) whereas antiviral CD8+ T-cell memory remained intact (P > .99). VV-specific antibodies were maintained indefinitely among HIV-uninfected participants (half-life, infinity; 95% confidence interval, 309 years to infinity) but declined rapidly among HIV-infected participants (half-life; 39 years; 24-108 years; P = .001)., Conclusions: Despite antiretroviral therapy-associated improvement in CD4+ T-cell counts (nadir, <200/μL; >350/μL after antiretroviral therapy), antigen-specific CD4+ T-cell memory to vaccinations or infections that occurred before HIV infection did not recover after immune reconstitution, and a previously unrealized decline in preexisting antibody responses was observed., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Vaccines play a vital role in protecting our communities against infectious disease. Unfortunately, some vaccines provide only partial protection or in some cases vaccine-mediated immunity may wane rapidly, resulting in either increased susceptibility to that disease or a requirement for more booster vaccinations in order to maintain immunity above a protective level. The durability of antibody responses after infection or vaccination appears to be intrinsically determined by the structural biology of the antigen, with multivalent protein antigens often providing more long-lived immunity than monovalent antigens. This forms the basis for the Imprinted Lifespan model describing the differential survival of long-lived plasma cell populations. There are, however, exceptions to this rule with examples of highly attenuated live virus vaccines that are rapidly cleared and elicit only short-lived immunity despite the expression of multivalent surface epitopes. These exceptions have led to the concept that multivalency alone may not reliably determine the duration of protective humoral immune responses unless a minimum number of long-lived plasma cells are generated by reaching an appropriate antigenic threshold of B cell stimulation. Examples of long-term and in some cases, potentially lifelong antibody responses following immunization against human papilloma virus (HPV), Japanese encephalitis virus (JEV), Hepatitis B virus (HBV), and Hepatitis A virus (HAV) provide several lessons in understanding durable serological memory in human subjects. Moreover, studies involving influenza vaccination provide the unique opportunity to compare the durability of hemagglutinin (HA)-specific antibody titers mounted in response to antigenically repetitive whole virus (i.e., multivalent HA), or detergent-disrupted "split" virus, in comparison to the long-term immune responses induced by natural influenza infection. Here, we discuss the underlying mechanisms that may be associated with the induction of protective immunity by long-lived plasma cells and their importance in future vaccine design.

Pre-existing serum antibodies play an important role in vaccine-mediated protection against infection but the underlying mechanisms of immune memory are unclear. Clinical studies indicate that antigen-specific antibody responses can be maintained for many years, leading to theories that reactivation/differentiation of memory B cells into plasma cells is required to sustain long-term antibody production. Here, we present a decade-long study in which we demonstrate site-specific survival of bone marrow-derived plasma cells and durable antibody responses to multiple virus and vaccine antigens in rhesus macaques for years after sustained memory B cell depletion. Moreover, BrdU + cells with plasma cell morphology can be detected for 10 years after vaccination/BrdU administration, indicating that plasma cells may persist for a prolonged period of time in the absence of cell division. On the basis of these results, long-lived plasma cells represent a key cell population responsible for long-term antibody production and serological memory.

NF-κB-inducing kinase [(NIK), MAP3K14] is an essential kinase linking a subset of TNFR family members to the noncanonical NF-κB pathway. To assess the cell-intrinsic role of NIK in murine T cell function, we generated mixed bone marrow chimeras using bone marrow from NIK knockout (KO) and wild-type (WT) donor mice and infected the chimeras with lymphocytic choriomeningitis virus (LCMV). The chimeras possess an apparently normal immune system, including a mixture of NIK KO and WT T cells, and the virus was cleared normally. Comparison of the NIK KO and WT CD4 and CD8 T cell responses at 8 d post infection revealed modest but significant differences in the acute response. In both CD4 and CD8 compartments, relatively fewer activated (CD44(hi)) NIK KO T cells were present, but within the CD44(hi) population, a comparable percentage of the activated cells produced IFN-γ in response to ex vivo stimulation with antigenic LCMV peptides, although IL-7R expression was reduced in the NIK KO CD8 T cells. Assessment of the LCMV-specific memory at 65 d post infection revealed many more LCMV-specific WT memory T cells than NIK KO memory T cells in both the CD4 and the CD8 compartments, although the small number of surviving NIK KO memory T cells responded to secondary challenge with virus. These results demonstrate a cell-intrinsic requirement for NIK in the generation and/or maintenance of memory T cells in response to acute viral infection.

During infection, CD8(+) T cells not only respond to antigenic signals through their T cell receptor (TCR) but also incorporate inflammatory signals from cytokines produced in the local infected microenvironment. Transient TCR-mediated stimulation will result in programmed proliferation that continues despite removal of the antigenic stimulus, but it remains unclear whether brief exposure to specific cytokines will elicit similar effects. Here, we have demonstrated that brief stimulation of memory T cells with interleukin-12 (IL-12) and interleukin-18 (IL-18) results in tightly regulated programmed proliferation, in addition to acquisition of enhanced virus-specific cytokine production and cytolytic activity. CD8(+) T cells briefly exposed to IL-12 and IL-18 in vitro showed improved antiviral activity in vivo, as demonstrated by increased proliferation and reduced viremia. These results indicate that even transitory exposure to inflammatory cytokines can provide a selective advantage to infiltrating CD8(+) T cells by triggering a developmental program that is initiated prior to direct contact with virus-infected cells., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Once established, serum antibody responses against a specific pathogen may last a lifetime. We describe a cohort of four subjects who received smallpox vaccination, and a single subject who received multiple vaccinations, with antibody levels to unrelated antigens monitored for 1-3 years. These immunizations provided the opportunity to determine if infection/vaccination and the resulting toll-like receptor stimulation would alter antigen-specific serological memory to other antigens, including bacterial toxins (tetanus, diphtheria, and pertussis) and viruses (yellow fever virus, measles, mumps, rubella, Epstein-Barr virus, and varicella-zoster virus). Our results indicate that serum IgG levels are remarkably stable and infection or vaccination are unlikely to increase or decrease pre-existing antigen-specific antibody responses., (Copyright © 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Investigation of T-cell-mediated immunity following acute viral infection represents an area of research with broad implications for both fundamental immunology research as well as vaccine development. Here, we review techniques that are used to assess T-cell memory including limiting dilution analysis, enzyme-linked immunospot (ELISPOT) assays, intracellular cytokine staining (ICCS) and peptide-MHC Class I tetramer staining. The durability of T-cell memory is explored in the context of several acute viral infections including vaccinia virus (VV), measles virus (MV) and yellow fever virus (YFV). Following acute infection, different virus-specific T-cell subpopulations exhibit distinct cytokine profiles and these profiles change over the course of infection. Differential regulation of the cytotoxic proteins, granzyme A, granzyme B and perforin are also observed in virus-specific T cells following infection. As a result of this work, we have gained a broader understanding of the kinetics and magnitude of antiviral T-cell immunity as well as new insight into the patterns of immunodominance and differential regulation of cytokines and cytotoxicity-associated molecules. This information may eventually lead to the generation of more effective vaccines that elicit T-cell memory with the optimal combination of functional characteristics required for providing protective immunity against infectious disease.

CD40 ligand (CD40L) is an essential effector cytokine for macrophage activation, dendritic cell licensing, and T-cell-dependent antibody responses. Although CD40L is known to be made de novo following antigen recognition, several reports have described surface mobilization of preformed, intracellular CD40L in certain CD4(+) effector T cells. Here we show that rapid surface expression of preformed CD40L following antigen recognition is a general property of both effector and memory CD4(+) T cells, including in vitro and in vivo activated T-cell-receptor transgenic T cells, memory phenotype CD4(+) T cells from pathogen-free naive mice, and polyclonal virus-specific effector and memory T cells. Intracellular CD40L is stored in secretory lysosomes, and colocalizes more strongly with Fas ligand than with CTLA-4, two other molecules that are delivered to the cell surface following antigen recognition. Stimulated surface expression of preformed CD40L is found in memory CD4(+) T cells from CD40-deficient mice, indicating that it does not depend on CD40-induced internalization for delivery to the secretory compartment. We suggest that delivery of preformed CD40L to antigen-presenting cells (APCs) could enable antigen-specific activation of APCs in transient interactions that are too brief to permit de novo synthesis of CD40L.

Current methodology for quantitation of memory B cells (MBC) in clinical samples is limited and often does not allow for detection of multiple MBC specificities in a single assay. Here we describe two independent approaches to antigen-specific MBC quantitation. First, a sensitive flow cytometry (FC) assay was developed for simultaneous quantitation of two prototypical B cell antigens, tetanus and diphtheria. Second, an ELISA-based MBC limiting dilution assay (LDA) was developed that provides quantitative analysis of up to 8-12 different MBC frequencies from a single blood sample. Cross-validation studies indicated that MBC numbers measured by FC correlated significantly with the frequencies obtained by LDA (R(2)=0.92, p=0.0002). These two functionally distinct approaches will be useful for accurate quantitation of rare MBC populations specific for either simple antigens (e.g. tetanus and diphtheria) or complex antigens (e.g. vaccinia or other viruses), and is amenable for use in a variety of model systems.

The smallpox vaccine consists of live vaccinia virus and is generally considered the gold standard of vaccines, since it is the only one that has led to the complete eradication of an infectious disease from the human population. Renewed fears that smallpox might be deliberately released in an act of bioterrorism have led to resurgence in the study of immunity and immunological memory to vaccinia virus and other poxviruses. Here we review our current understanding of memory T-cell, memory B-cell, and antibody responses to vaccinia and related poxviruses, both in animal models and human subjects. Of particular interest are recent advances in understanding protective immunity to poxviruses, quantifying immunological memory to the smallpox vaccine in humans, and identifying major vaccinia-specific T-cell and B-cell epitopes. In addition, potential mechanisms for maintenance of immunological memory are discussed.

Immunological memory is defined by the ability of a host to remember a past encounter with a specific pathogen and to respond to it in an effective manner upon re-exposure. How long immunological memory can be maintained in the absence of re-infection continues to be a subject of great controversy. Recent studies on immunity following smallpox vaccination demonstrate that T-cell memory declines steadily with a half-life of 8-15 years, whereas antiviral antibody responses are maintained for up to 75 years without appreciable decline. By combining recent advances in quantitative immunology with historical accounts of protection against smallpox dating back to the time of Edward Jenner, we are gaining a better understanding of the duration and magnitude of immunological memory and how it relates to protective immunity.

As with most herpesviruses, CMVs encode viral genes that inhibit Ag presentation to CD8 T cells (VIPRs). VIPR function has been assumed to be essential for CMV to establish its characteristic lifetime infection of its host. We compared infection of C57BL/6 mice with wild-type murine CMV (MCMV) and a virus lacking each of MCMV's three known VIPRs: m4, m6, and m152. During acute infection, there was very little difference between the two viruses with respect to the kinetics of viral replication and clearance, or in the size and kinetics of the virus-specific CD8 T cell response. During chronic infection, a large, effector memory, virus-specific CD8 T cell population (CD8(low)CD62L(-)CD11c(+)NKG2A(+)) was maintained in both infections; the size and phenotype of the CD8 T cell response to both viruses was remarkably similar. The characteristic effector memory phenotype of the CD8 T cells suggested that both wild-type and Deltam4+m6+m152 virus continued to present Ag to CD8 T cells during the chronic phase of infection. During the chronic phase of infection, MCMV cannot be isolated from immunocompetent mice. However, upon immunosuppression, both Deltam4+m6+m152 and wild-type virus could be reactivated from mice infected for 6 wk. Thus, restoring the ability of CD8 T cells to detect MCMV had little apparent effect on the course of MCMV infection and on the CD8 T cell response to it. These results challenge the notion that VIPR function is necessary for CMV persistence in the host.

Although naturally occurring smallpox was eliminated through the efforts of the World Health Organization Global Eradication Program, it remains possible that smallpox could be intentionally released. Here we examine the magnitude and duration of antiviral immunity induced by one or more smallpox vaccinations. We found that more than 90% of volunteers vaccinated 25-75 years ago still maintain substantial humoral or cellular immunity (or both) against vaccinia, the virus used to vaccinate against smallpox. Antiviral antibody responses remained stable between 1-75 years after vaccination, whereas antiviral T-cell responses declined slowly, with a half-life of 8-15 years. If these levels of immunity are considered to be at least partially protective, then the morbidity and mortality associated with an intentional smallpox outbreak would be substantially reduced because of pre-existing immunity in a large number of previously vaccinated individuals.

The unprecedented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has called for substantial investigations into the capacity of the human immune system to protect against reinfection and keep pace with the evolution of SARS-CoV-2. We evaluated the magnitude and durability of the SARS-CoV-2-specific antibody responses against parental WA-1 SARS-CoV-2 receptor-binding domain (RBD) and a representative variant of concern (VoC) RBD using antibodies from 2 antibody compartments: long-lived plasma cell-derived plasma antibodies and antibodies encoded by SARS-CoV-2-specific memory B cells (MBCs). Thirty-five participants naturally infected with SARS-CoV-2 were evaluated; although only 25 of 35 participants had VoC RBD-reactive plasma antibodies, 34 of 35 (97%) participants had VoC RBD-reactive MBC-derived antibodies. Our finding that 97% of previously infected individuals have MBCs specific for variant RBDs provides reason for optimism regarding the capacity of vaccination, prior infection, and/or both, to elicit immunity with the capacity to limit disease severity and transmission of VoCs as they arise and circulate. [ABSTRACT FROM AUTHOR]

It is estimated that over 2.5 billion people are at risk for contracting dengue, a virus responsible for 50-390 million infections in addition to thousands of hospitalizations and deaths each year.There are no licensed vaccines available to combat this pathogen but substantial efforts are underway to develop live-attenuated, inactivated, and subunit vaccines that will protect against each of the four serotypes of dengue. Unfortunately, the results of a recent Phase IIb efficacy trial involving a tetravalent live-attenuated chimeric dengue virus vaccine have raised questions with regard to our current understanding of vaccine-mediated immunity to this important flavivirus. Here, we will briefly summarize these vaccination efforts and discuss the importance of informative in vivo models for determining vaccine efficacy and the need to establish a quantitative correlate of immunity in order to predict the duration of vaccine-induced antiviral protection. [ABSTRACT FROM AUTHOR]

Humoral immunity following vaccination or infection is mainly derived from two types of cells: memory B cells and plasma cells. Memory B cells do not actively secrete antibody but instead maintain their immunoglobulin in the membrane-bound form that serves as the antigen-specific B-cell receptor. In contrast, plasma cells are terminally differentiated cells that no longer express surface-bound immunoglobulin but continuously secrete antibody without requiring further antigenic stimulation. Pre-existing serum or mucosal antibody elicited by plasma cells (or other intermediate antibody-secreting cells) represents the first line of defense against reinfection and is critical for protection against many microbial diseases. However, the mechanisms involved with maintaining long-term antibody production are not fully understood. Here, we examine several models of long-term humoral immunity and present a new model, described as the ‘Imprinted Lifespan’ model of plasma cell longevity. The foundation of this model is that plasma cells are imprinted with a predetermined lifespan based on the magnitude of B-cell signaling that occurs during the induction of an antigen-specific humoral immune response. This represents a testable hypothesis and may explain why some antigen-specific antibody responses fade over time whereas others are maintained essentially for life. [ABSTRACT FROM AUTHOR]

Abstract: Vaccination is one of the most effective methods used for protecting the public against infectious disease. Vaccines can be segregated into two general categories: replicating vaccines (i.e., live, attenuated vaccines) and non-replicating vaccines (e.g., inactivated or subunit vaccines). It has been assumed that live attenuated vaccines are superior to non-replicating vaccines in terms of the quality of the antiviral immune response, the level of protective immunity, and the duration of protective immunity. Although this a prevalent viewpoint within the field, there are several exceptions to the rule. Here, we will explore the historical literature in which some of these conclusions have been based, including “Experiments of Nature” and describe examples of the efficacy of replicating vaccines compared to their non-replicating counterparts. By building a better understanding of how successful vaccines work, we hope to develop better “next-generation” vaccines as well as new vaccines against HIV—a pathogen of global importance for which no licensed vaccine currently exists. [Copyright &y& Elsevier]