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Model of heterologous immunity in the lung.Some of the memory T cells that are specific for one virus (lymphocytic choriomeningitis virus; LCMV) are crossreactively stimulated by antigens from a second heterologous virus (vaccinia virus; VV). This causes the release of interferon- (IFN-), which further activates antigen-presenting cells (APCs) and enhances their expression of MHC molecules. Together, these events antagonize viral replication and, at the same time, facilitate the development of immunopathological lesions, perhaps in part through the release of tumour-necrosis factor and other inflammatory cytokines. Lymphocyte function-associated antigen 1 (LFA1) is an adhesion molecule, the expression of which is upregulated on memory T cells. CD44 is a memory-cell phenotypic marker. TCR, T-cell receptor.
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Memory T cells that are specific for one virus can become activated during infection with an unrelated heterologous virus, and might have roles in protective immunity and immunopathology. The course of each infection is influenced by the T-cell memory pool that has been laid down by a host's history of previous infections, and with each successive...
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Context 1
... proliferation of subpopulations of LCMV-specific CD8 + T cells. Adoptive-transfer studies indicated that protection against either virus was mediated by a combination of CD4 + and CD8 + T cells from LCMV-immune mice 65,69 . Mechanistic studies indicated a strong role for IFN-γ in protection against vaccinia virus but not against Pichinde virus (FIG. 4). Vaccinia virus -which is very sensitive to IFN-γ -induced the in vivo production of IFN-γ by LCMV-specific CD8 + T cells by 3-4 days after infection, and heterologous immunity against vaccinia virus did not occur in mice that lacked IFN-γ responses 38,65 . Infection with Pichinde virus induced relatively low levels of IFN-γ in ...
Context 2
... to be immune-mediated and to occur in associ- ation with viral and intracellular bacterial infections. These experimental models indicate that potent T H 1 responses have an important role in immunopathology, as the lesions in both fat and lungs were dependent on the production of IFN-γ in the vaccinia-virus-infected LCMV-immune mice 65,69 (FIG. 4). These models indicate clearly that an individual's past history of infection might influence the immunopathology that develops on encounter with another infectious ...
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Simple Summary
Memory T cells from healthy individuals respond to stimulation with peptides derived from cancer-specific RAS mutations, thus suggesting that healthy individuals have been challenged with RAS mutations earlier in life.
Abstract
The RAS mutations are the most frequently occurring somatic mutations in humans, and several studies have...
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T cell memory in comparison with B cell memory is not well understood. This review focuses on CD8+ and CD4+ memory T cells. In this article we try to define memory cells and also present models of memory T cells formation. We would also like to delineate their differentiation into distinct subsets. Long-lived memory T cells consist in two main subs...
Whooping cough remains a problem despite vaccination and worldwide resurging of pertussis is evident. Since cellular immunity plays a role in long-term protection against pertussis, we studied pertussis-specific T-cell responses. We compared T-cell memory responses in children, who have been primed during infancy with either a whole-cell-pertussis...
The highly regulated secretion of effector cytokines by
CD4
1
T cells plays a critical role in immune protection
against pathogens such as cytomegalovirus. Here, we directly
compare the frequency and functional characteristics
of cytomegalovirus-specific CD4
1
memory/effector T cells
in normal and HIV
1
subjects using a novel, highly efficient
mult...
Changes in T cell trafficking accompany the naive to memory T cell antigen-driven differentiation, which remains an incompletely defined developmental step. Upon priming, each naive T cell encounters essential signals – i.e., antigen, co-stimuli and cytokines – in a secondary lymphoid organ; nevertheless, its daughter effector and memory T cells re...
Citations
... Similar to the concept of "trained immunity", "heterologous immunity" is an immune response that is induced against a prior vaccination or exposure/infection with one pathogen but also can boost or weaken protective immunity against another unrelated pathogen, as suggested in studies with humans and mouse models [67][68][69]. Thanks to the cross-reactivity of T cell receptors, heterologous immunity to VACV infection has been experimentally shown in a mouse model that had been earlier exposed to infections with lymphocytic choriomeningitis virus, murine cytomegalovirus, Pichinde virus, or influenza A virus [67][68][69]. More research is needed to study the role of heterologous immunity and trained immunity in MPXV infection and co-infection with other etiologies. ...
... Similar to the concept of "trained immunity", "heterologous immunity" is an immune response that is induced against a prior vaccination or exposure/infection with one pathogen but also can boost or weaken protective immunity against another unrelated pathogen, as suggested in studies with humans and mouse models [67][68][69]. Thanks to the cross-reactivity of T cell receptors, heterologous immunity to VACV infection has been experimentally shown in a mouse model that had been earlier exposed to infections with lymphocytic choriomeningitis virus, murine cytomegalovirus, Pichinde virus, or influenza A virus [67][68][69]. More research is needed to study the role of heterologous immunity and trained immunity in MPXV infection and co-infection with other etiologies. ...
Epidemiologic studies have established that mpox (formerly known as monkeypox) outbreaks worldwide in 2022–2023, due to Clade IIb mpox virus (MPXV), disproportionately affected gay, bisexual, and other men who have sex with men. More than 35% and 40% of the mpox cases suffer from co-infection with HIV and sexually transmitted infections (STIs) (e.g., Chlamydia trachomatis, Neisseria gonorrhoeae, Treponema pallidum, and herpes simplex virus), respectively. Bacterial superinfection can also occur. Co-infection of MPXV and other infectious agents may enhance disease severity, deteriorate outcomes, elongate the recovery process, and potentially contribute to the morbidity and mortality of the ensuing diseases. However, the interplays between MPXV and HIV, bacteria, other STI pathogens and host cells are poorly studied. There are many open questions regarding the impact of co-infections with HIV, STIs, or bacterial superinfections on the diagnosis and treatment of MPXV infections, including clinical and laboratory-confirmed mpox diagnosis, suboptimal treatment effectiveness, and induction of antiviral drug resistance. In this review article, we will discuss the progress and knowledge gaps in MPXV biology, antiviral therapy, pathogenesis of human MPXV and its co-infection with HIV, STIs, or bacterial superinfections, and the impact of the co-infections on the diagnosis and treatment of mpox disease. This review not only sheds light on the MPXV infection and co-infection of other etiologies but also calls for more research on MPXV life cycles and the molecular mechanisms of pathogenesis of co-infection of MPXV and other infectious agents, as well as research and development of a novel multiplex molecular testing panel for the detection of MPXV and other STI co-infections.
... Similar to the concept of "trained immunity", "heterologous immunity" is an immune response that is induced against a prior vaccination or exposure/infection with one pathogen but also can boost or weaken protective immunity against another unrelated pathogen, as suggested in studies with humans and mouse models [67][68][69]. Thanks to the cross-reactivity of T cell receptors, heterologous immunity to VACV infection has been experimentally shown in a mouse model that had been earlier exposed to infections with lymphocytic choriomeningitis virus, murine cytomegalovirus, Pichinde virus, or influenza A virus [67][68][69]. More research is needed to study the role of heterologous immunity and trained immunity in MPXV infection and co-infection with other etiologies. ...
... Similar to the concept of "trained immunity", "heterologous immunity" is an immune response that is induced against a prior vaccination or exposure/infection with one pathogen but also can boost or weaken protective immunity against another unrelated pathogen, as suggested in studies with humans and mouse models [67][68][69]. Thanks to the cross-reactivity of T cell receptors, heterologous immunity to VACV infection has been experimentally shown in a mouse model that had been earlier exposed to infections with lymphocytic choriomeningitis virus, murine cytomegalovirus, Pichinde virus, or influenza A virus [67][68][69]. More research is needed to study the role of heterologous immunity and trained immunity in MPXV infection and co-infection with other etiologies. ...
... The specificity of the TCRpMHC interaction is essential for the efficiency of cellular immunity against infectious pathogens and cancer cells, as well as for the safety of new game-changing T-cell-based immunotherapies (2). However, it is well established that the same TCR can recognize multiple pMHC complexes with varying affinities/avidities (3)(4)(5)(6), and such "promiscuity" has several biomedical implications, related to mechanisms of self-tolerance (1), heterologous immunity between pathogens (7,8), autoimmunity, transplant rejection (1,9), allergies (10), and off-target toxicity in Tcell based immunotherapies (11)(12)(13). Unfortunately, the complexity and diversity of the molecules involved in these interactions has slowed the development of both experimental and computational methods to detect, quantify, and predict these T-cell cross-reactivity events. ...
... This Research Topic highlights recent studies in this field, including further analysis of T-cell cross-reactivity in antiviral immunity, and new computational approaches to predict TCR specificity and off-target toxicity. TCR cross-reactivity is an intrinsic feature of T-cell biology, required to maximize immunity against an overwhelming diversity of antigenic peptide-targets (4,13,22,23). The benefits of crossreactivity for antiviral immunity are further evidenced by Petrova et al. ...
... Moreover, altered inflammatory cytokine levels in the microenvironment can also induce activation of memory CD8 T cells in the absence of cognate antigen, a process termed 'bystander activation'. Compared to the naive state, memory CD8 T cells have decreased activation signal requirements to the extent that they can become activated by cytokine(s) alone or peptide concentrations as low as 1/50th of that required for stimulation of naive T cells (Welsh and Selin, 2002;Youngblood et al., 2013). Indeed, both mouse and human studies have found that influenza virus infection induces activation and expansion of non-specific memory CD8 T cells (Sandalova et al., 2010;Sckisel et al., 2014). ...
Analysis of pre-existing immunity and its effects on acute infection often focus on memory responses associated with a prior infectious exposure. However, memory responses occur in the context of the overall immune state and leukocytes must interact with their microenvironment and other immune cells. Thus, it is important to also consider non-antigen-specific factors which shape the composite basal state and functional capacity of the immune system, termed here as I 0 (‘I naught’). In this review, we discuss the determinants of I 0 . Utilizing influenza virus as a model, we then consider the effect of I 0 on susceptibility to infection and disease severity. Lastly, we outline a mathematical framework and demonstrate how researchers can build and tailor models to specific needs. Understanding how diverse factors uniquely and collectively impact immune competence will provide valuable insights into mechanisms of immune variation, aid in screening for high-risk populations, and promote the development of broadly applicable prophylactic and therapeutic treatments.
... We propose that an inappropriate immune response to an infection triggers Long COVID and at least a subset of ME/CFS, resulting in chronically dysregulated immune responses with CD8 T-cell dysfunction. For instance, inappropriate immune responses to viruses can occur in the presence of heterologous immunity and activation of crossreactive CD8 T-cells (Welsh and Selin, 2002;Selin et al., 2011). Cross-reactive activation of memory influenza A (IAV)-specific memory CD8 T-cells in HLA-A2+ patients during acute EBV infections result in the highly dysregulated immune response and syndrome of acute infectious mononucleosis, wherein there is massive over-expansion of Fig. 10. ...
Background
Patients with post-acute sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection (PASC, i.e., Long COVID) have a symptom complex highly analogous to many features of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), suggesting they may share some aspects of pathogenesis in these similar disorders. ME/CFS is a complex disease affecting numerous organ systems and biological processes and is often preceded by an infection-like episode. It is postulated that the chronic manifestations of illness may result from an altered host response to infection or inability to resolve inflammation, as is being reported in Long COVID. The immunopathogenesis of both disorders is still poorly understood. Here, we show data that suggest Long COVID and ME/CFS may be due to an aberrant response to an immunological trigger-like infection, resulting in a dysregulated immune system with CD8 T-cell dysfunction reminiscent of some aspects of T-cell clonal exhaustion, a phenomenon associated with oxidative stress. As there is an urgent need for diagnostic tools and treatment strategies for these two related disabling disorders, here, in a retrospective case series, we have also identified a potential nebulized antioxidant/anti-pathogen treatment that has evidence of a good safety profile. This nebulized agent is comprised of five ingredients previously reported individually to relieve oxidative stress, attenuate NF-κB signaling, and/or to act directly to inhibit pathogens, including viruses. Administration of this treatment by nebulizer results in rapid access of small doses of well-studied antioxidants and agents with anti-pathogen potential to the lungs; components of this nebulized agent are also likely to be distributed systemically, with potential to enter the central nervous system.
Methods
and Findings: We conducted an analysis of CD8 T-cell function and severity of symptoms by self-report questionnaires in ME/CFS, Long COVID and healthy controls. We developed a CD8 T-cell functional assay, assessing CD8 T-cell dysfunction by intracellular cytokine staining (ICS) in a group of ME/CFS (n = 12) and Long COVID patients (n = 8), comparing to healthy controls (HC) with similar age and sex (n = 10). Magnet-enriched fresh CD8 T-cells in both patient groups had a significantly diminished capacity to produce both cytokines, IFNγ or TNFα, after PMA stimulation when compared to HC. The symptom severity questionnaire showed similar symptom profiles for the two disorders. Fortuitously, through a retrospective case series, we were able to examine the ICS and questionnaire data of 4 ME/CFS and 4 Long COVID patients in conjunction with their treatment (3–15 months). In parallel with the treatment pursued electively by participants in this retrospective case series, there was an increase in CD8 T-cell IFNγ and TNFα production and a decrease in overall self-reported symptom severity score by 54%. No serious treatment-associated side effects or laboratory anomalies were noted in these patients.
Conclusions
Here, in this small study, we present two observations that appear potentially fundamental to the pathogenesis and treatment of Long COVID and ME/CFS. The first is that both disorders appear to be characterized by dysfunctional CD8 T-cells with severe deficiencies in their abilities to produce IFNγ and TNFα. The second is that in a small retrospective Long COVID and ME/CFS case series, this immune dysfunction and patient health improved in parallel with treatment with an immunomodulatory, antioxidant pharmacological treatment with anticipated anti-pathogen activity. This work provides evidence of the potential utility of a biomarker, CD8 T-cell dysfunction, and suggests the potential for benefit from a new nebulized antioxidant/anti-pathogen treatment. These immune biomarker data may help build capacity for improved diagnosis and tracking of treatment outcomes during clinical trials for both Long COVID and ME/CFS while providing clues to new treatment avenues that suggest potential efficacy for both conditions.
... However, the proportion of HBV-speci c and non-HBV-speci c T cells within CD38 + HLA-DR + CD8 + T cells was not signi cantly higher compared to CD38 − HLA-DR − CD8 + T cells, aligning with one set of literature but differing from another (4,27). According to the literature, cross-reactive T cells might be caused by heterologous viruses (29). Nevertheless, it was worth noting that HBV epitopes did not display signi cant homology with the amino acid sequence of CMV or EBV viruses. ...
Background: Liver cirrhosis could lead to immune dysfunction. During the pathogenesis of liver cirrhosis, CD8⁺ T cells play a critical role. While CD38⁺HLA-DR⁺CD8⁺ T cells, also called bystander activation CD8⁺ T cells, had been shown to
be involved in host injury, its specific contribution to liver cirrhosis had remained not unclear. The aim of this study was to understand how these CD38⁺HLA-DR⁺CD8⁺ T cells exerted a pathogenic role in liver cirrhosis.
Methods: Flow cytometry was performed to detect the immunophenotype, antigen-specific T cells, cytokines secretion, and cytotoxicity related indicators of CD38⁺HLA-DR⁺CD8⁺ T cells. Transcriptome analysis was utilized to analyze the functional properties of these cells. The cytotoxicity of CD38⁺HLA-DR⁺CD8⁺ T cells was detected by cytotoxicity assay and antibody blocking assay.
Results: The percentage of CD38⁺HLA-DR⁺CD8⁺ T cells in patients with liver cirrhosis significantly increased and was correlated with liver injury. These CD8⁺ T cells contained largely non-HBV specific T cells. Transcriptome analysis revealed that these CD8⁺ T cells subsets exhibited innate-like functional characteristic. In addition, these cells mainly consisted of effector memory T cells and displayed high expression levels of cytotoxicity-related cytokines, especially granzyme B and perforin. Stimulation experiments with cytokines shown that IL-15 could promote the activation and proliferation of these CD8⁺ T cells. Lastly, blocking assays indicated that CD38⁺HLA-DR⁺CD8⁺ T cells had strong cytotoxic effects in a TCR-independent manner, mediated by NKG2D.
Conclusion: CD38⁺HLA-DR⁺CD8⁺ T cells were correlated with the liver injury in liver cirrhosis, and these cells exerted liver damaging effects through NKG2D in a TCR-independent manner.
... Almost all cells of the memory population expressed CD44, distinguishing them from CD44naïve cells that have not yet encountered antigen and represent a minority of peripheral CD8 T cells. As noted in the important work by Welsh and Selin, "no one is naïve" [74], so that memory cells of numerous antigen specificities make up the memory cell population. Trivially, most memory CD8 T cells are not specific for the virus under investigation but collectively reflect all preceding antigen encounters in the past life. ...
Cytomegaloviruses (CMVs) are host species-specific in their replication. It is a hallmark of all CMVs that productive primary infection is controlled by concerted innate and adaptive immune responses in the immunocompetent host. As a result, the infection usually passes without overt clinical symptoms and develops into latent infection, referred to as "latency". During latency, the virus is maintained in a non-replicative state from which it can reactivate to productive infection under conditions of waning immune surveillance. In contrast, infection of an immunocompromised host causes CMV disease with viral multiple-organ histopathology resulting in organ failure. Primary or reactivated CMV infection of hematopoietic cell transplan-tation (HCT) recipients in a "window of risk" between therapeutic hemato-ablative leukemia therapy and immune system reconstitution remains a clinical challenge. Studies in the mouse model of experimental HCT and infection with murine CMV (mCMV), followed by clinical trials in HCT patients with human CMV (hCMV) reactivation, have revealed a protective function of virus-specific CD8 T cells upon adoptive cell transfer (AT). Memory CD8 T cells derived from latently infected hosts are a favored source for immunotherapy by AT. Strikingly low numbers of these cells were found to prevent CMV disease, suggesting either an immediate effector function of few transferred cells or a clonal expansion generating high numbers of effector cells. In the murine model, the memory population consists of resting central memory T cells (TCM), as well as of conventional effector-memory T cells (cTEM) and inflationary effector-memory T cells (iTEM). iTEM increase in numbers over time in the latently infected host, a phenomenon known as 'memory inflation' (MI). They thus appeared to be a promising source for use in immunotherapy. However, we show here that iTEM contribute little to the control of infection after AT, which relies almost entirely on superior proliferative potential of TCM.
... Furthermore, in both acute and chronic conditions, the establishment of adaptive and innate immune memory modulates responses to subsequent challenges and has both beneficial and harmful effects (Netea et al. 2020;Divangahi et al. 2020). For example, cross-reactive memory T cells can have a protective effect but they can also lead to immunopathology (Welsh and Selin 2002). ...
Many microbes responsible for infectious diseases are known to run an asymptomatic course in a significant portion of the population. By highlighting the conceptual complexities of host-microbe interactions, this paper elucidates the fact that while many infections remain asymptomatic, this does not necessarily mean that such infections are of no concern for health. The paper builds on the so-called damage-response framework and considers several developments required to gain a more comprehensive perspective on infections and their relationship to diseases. Irrespective of their (short-term) clinical manifestation, infections leave an imprint with consequences for health. Finally, these considerations regarding host-microbe interactions must be incorporated into policy decisions and public understanding of health if we hope to handle future pandemics such as Covid-19 better.
... Epitopes presented in the context of MHC only make 2-3 contacts with the TCR during antigen recognition, meaning homology between viral and drugderived antigen may only relate to a small number of residues increasing the likelihood of cross-reactivity. Polyspecific T-cell receptors are capable of recognising multiple distinct peptides, including several derived from allogenic targets (Welsh and Selin, 2002). ...
... Self or drug derived peptides need to be present in proximity to virus specific TRMs, as with the case of EBV specific T-cell responses that are observed as cross reactive to allogenic targets limited to the skin and mucous membranes; where a peptide similar to EBV nuclear antigen 3a is preferentially presented on the surface of keratinocytes and endothelial cells (D'Orsogna et al., 2011). Heterologous immunity accounts for the durable reactivity that is observed in patients recovering from cutaneous hypersensitivity reactions, where ordinarily a waning of response would be expected following long-term cessation of treatment however persistent pathogen encounters maintains these populations of polyspecific TRMs (Welsh and Selin, 2002). ...
... The idea that "no one is naïve", a phrase used by Welsh et al., is an emerging concept in drug hypersensitivity. It describes a theory by which antigen specific T-cells may possess a polyspecific TCR capable of cross reacting to an antigen that has not previously been encountered based on memory of structurally similar antigens (Welsh and Selin, 2002). Correspondingly, there is renewed interest and Overview of the typical pathogenesis of cutaneous adverse drug reactions. ...
Cutaneous hypersensitivity reactions represent the most common manifestation of drug allergy seen in the clinic, with 25% of all adverse drug reactions appearing in the skin. The severity of cutaneous eruptions can vastly differ depending on the cellular mechanisms involved from a minor, self-resolving maculopapular rash to major, life-threatening pathologies such as the T-cell mediated bullous eruptions, i.e., Stevens Johnson syndrome/toxic epidermal necrolysis. It remains a significant question as to why these reactions are so frequently associated with the skin and what factors polarise these reactions towards more serious disease states. The barrier function which the skin performs means it is constantly subject to a barrage of danger signals, creating an environment that favors elicitation. Therefore, a critical question is what drives the expansion of cutaneous lymphocyte antigen positive, skin homing, T-cell sub-populations in draining lymph nodes. One answer could be the heterologous immunity hypothesis whereby tissue resident memory T-cells that express T-cell receptors (TCRs) for pathogen derived antigens cross-react with drug antigen. A significant amount of research has been conducted on skin immunity in the context of contact allergy and the role of tissue specific antigen presenting cells in presenting drug antigen to T-cells, but it is unclear how this relates to epitopes derived from circulation. Studies have shown that the skin is a metabolically active organ, capable of generating reactive drug metabolites. However, we know that drug antigens are displayed systemically so what factors permit tolerance in one part of the body, but reactivity in the skin. Most adverse drug reactions are mild, and skin eruptions tend to be visible to the patient, whereas minor organ injury such as transient transaminase elevation is often not apparent. Systemic hypersensitivity reactions tend to have early cutaneous manifestations, the progression of which is halted by early diagnosis and treatment. It is apparent that the preference for cutaneous involvement of drug hypersensitivity reactions is multi-faceted, therefore this review aims to abridge the findings from literature on the current state of the field and provide insight into the cellular and metabolic mechanisms which may contribute to severe cutaneous adverse reactions.
... Cross-reactive immunity occurs when preexisting memory T and B cells elicited by a particular antigen/infectious agent recognize and respond against different antigens/infections (21,22). The occurrence of cross-reactive immunity between unrelated pathogens, including between bacteria and viruses, is well documented (21,(23)(24)(25)(26) and it is facilitated by the polyspecificity of B and T cell receptors (27)(28)(29)(30) and also by the recognition on small portions within the antigens (epitopes) (31). ...
Bacteria are well known to provide heterologous immunity against viral infections through various mechanisms including the induction of innate trained immunity and adaptive cross-reactive immunity. Cross-reactive immunity from bacteria to viruses is responsible for long-term protection and yet its role has been downplayed due the difficulty of determining antigen-specific responses. Here, we carried out a systematic evaluation of the potential cross-reactive immunity from selected bacteria known to induce heterologous immunity against various viruses causing recurrent respiratory infections. The bacteria selected in this work were Bacillus Calmette Guerin and those included in the poly-bacterial preparation MV130: Streptococcus pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, Klebsiella pneumoniae, Branhamella catarrhalis and Haemophilus influenzae. The virus included influenza A and B viruses, human rhinovirus A, B and C, respiratory syncytial virus A and B and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Through BLAST searches, we first identified the shared peptidome space (identity ≥ 80%, in at least 8 residues) between bacteria and viruses, and subsequently predicted T and B cell epitopes within shared peptides. Interestingly, the potential epitope spaces shared between bacteria in MV130 and viruses are non-overlapping. Hence, combining diverse bacteria can enhance cross-reactive immunity. We next analyzed in detail the cross-reactive T and B cell epitopes between MV130 and influenza A virus. We found that MV130 contains numerous cross-reactive T cell epitopes with high population protection coverage and potentially neutralizing B cell epitopes recognizing hemagglutinin and matrix protein 2. These results contribute to explain the immune enhancing properties of MV130 observed in the clinic against respiratory viral infections.
