key: cord-280979-0vaarrji
authors: Gauttier, V.; Morello, A.; Girault, I.; Mary, C.; Belarif, L.; Desselle, A.; Wilhelm, E.; Bourquard, T.; Pengam, S.; Teppaz, G.; Thepenier, V.; Biteau, K.; De Barbeyrac, E.; Kiepferlé, D.; Vasseur, B.; Le Flem, FX.; Debieuvre, D.; Costantini, D.; Poirier, N.
title: Tissue-resident memory CD8 T-cell responses elicited by a single injection of a multi-target COVID-19 vaccine
date: 2020-08-14
journal: bioRxiv
DOI: 10.1101/2020.08.14.240093
sha: 
doc_id: 280979
cord_uid: 0vaarrji

The COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) which enters the body principally through the nasal and larynx mucosa and progress to the lungs through the respiratory tract. SARS-CoV-2 replicates efficiently in respiratory epithelial cells motivating the development of alternative and rapidly scalable vaccine inducing mucosal protective and long-lasting immunity. We have previously developed an immunologically optimized multi-neoepitopes-based peptide vaccine platform which has already demonstrated tolerance and efficacy in hundreds of lung cancer patients. Here, we present a multi-target CD8 T cell peptide COVID-19 vaccine design targeting several structural (S, M, N) and non-structural (NSPs) SARS-CoV-2 proteins with selected epitopes in conserved regions of the SARS-CoV-2 genome. We observed that a single subcutaneous injection of a serie of epitopes induces a robust immunogenicity in-vivo as measured by IFNγ ELIspot. Upon tetramer characterization we found that this serie of epitopes induces a strong proportion of virus-specific CD8 T cells expressing CD103, CD44, CXCR3 and CD49a, the specific phenotype of tissue-resident memory T lymphocytes (Trm). Finally, we observed broad cellular responses, as characterized by IFNγ production, upon restimulation with structural and non-structural protein-derived epitopes using blood T cells isolated from convalescent asymptomatic, moderate and severe COVID-19 patients. These data provide insights for further development of a second generation of COVID-19 vaccine focused on inducing lasting Th1-biased memory CD8 T cell sentinels protection using immunodominant epitopes naturally observed after SARS-CoV-2 infection resolution. Statement of Significance Humoral and cellular adaptive immunity are different and complementary immune defenses engaged by the body to clear viral infection. While neutralizing antibodies have the capacity to block virus binding to its entry receptor expressed on human cells, memory T lymphocytes have the capacity to eliminate infected cells and are required for viral clearance. However, viruses evolve quickly, and their antigens are prone to mutations to avoid recognition by the antibodies (phenomenon named ‘antigenic drift’). This limitation of the antibody-mediated immunity could be addressed by the T-cell mediated immunity, which is able to recognize conserved viral peptides from any viral proteins presented by virus-infected cells. Thus, by targeting several proteins and conserved regions on the genome of a virus, T-cell epitope-based vaccines are less subjected to mutations and may work effectively on different strains of the virus. We designed a multi-target T cell-based vaccine containing epitope regions optimized for CD8+ T cell stimulation that would drive long-lasting cellular immunity with high specificity, avoiding undesired effects such as antibody-dependent enhancement (ADE) and antibody-induced macrophages hyperinflammation that could be observed in subjects with severe COVID-19. Our in-vivo results showed that a single injection of selected CD8 T cell epitopes induces memory viral-specific T-cell responses with a phenotype of tissue-resident memory T cells (Trm). Trm has attracted a growing interest for developing vaccination strategies since they act as immune sentinels in barrier tissue such as the respiratory tract and the lung. Because of their localization in tissues, they are able to immediately recognize infected cells and, because of their memory phenotypes, they rapidly respond to viral infection by orchestrating local protective immune responses to eliminate pathogens. Lastly, such multiepitope-based vaccination platform uses robust and well-validated synthetic peptide production technologies that can be rapidly manufactured in a distributed manner.

The COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) which enters the body principally through the nasal and larynx mucosa and progress to the lungs through the respiratory tract. SARS-CoV-2 replicates efficiently in respiratory epithelial cells motivating the development of alternative and rapidly scalable vaccine inducing mucosal protective and long-lasting immunity. We have previously developed an immunologically optimized multi-neoepitopes-based peptide vaccine platform which has already demonstrated tolerance and efficacy in hundreds of lung cancer patients. Here, we present a multi-target CD8 T cell peptide COVID-19 vaccine design targeting several structural (S, M, N) and non-structural (NSPs) SARS-CoV-2 proteins with selected epitopes in conserved regions of the SARS-CoV-2 genome. We observed that a single subcutaneous injection of a serie of epitopes induces a robust immunogenicity in-vivo as measured by IFNγ ELIspot. Upon tetramer characterization we found that this serie of epitopes induces a strong proportion of virus-specific CD8 T cells expressing CD103, CD44, CXCR3 and CD49a, the specific phenotype of tissue-resident memory T lymphocytes (Trm). Finally, we observed broad cellular responses, as characterized by IFNγ production, upon restimulation with structural and nonstructural protein-derived epitopes using blood T cells isolated from convalescent asymptomatic, moderate and severe COVID-19 patients. These data provide insights for further development of a second generation of COVID-19 vaccine focused on inducing lasting Th1biased memory CD8 T cell sentinels protection using immunodominant epitopes naturally observed after SARS-CoV-2 infection resolution.

COVID-19, the infectious disease caused by the zoonotic coronavirus SARS-CoV-2, is a global pandemic which has infected more than 16 immune responses against this type of respiratory viruses but that antibody responses are shortterm [1] [2] [3] [4] [5] in contrast to the cellular immunity which is still observed 11 and 17 years after the infection 6, 7 .

Current and previous CoVs vaccine strategies have been almost exclusively focused on eliciting a humoral immune response, particularly anti-Spike neutralizing IgG antibody. However, the generation of non-neutralizing antibody responses 8 , insufficient antibody titers 9 , Th2-biased immune response or glycosylation changes in the IgG Fc tail 10 may be associated with vaccine failure, and in the worst case scenario may enhance disease upon viral exposure, either through the induction of enhanced pulmonary macrophage-mediated hyper-inflammation 11 , or Fc receptor-mediated antibody-dependent enhancement (ADE) 12 . Th1-biasing immunization using CD8 T cells optimized peptide vaccination may offer an important alternative and complementary approach with a history of safe administration, may be developed and updated rapidly, and should avoid safety pitfalls in the pursuit of a COVID-19 vaccine 8, 13, 14 .

The discovery of memory T lymphocytes resident in diverse tissues, in particular mucosal and barrier tissues, has highlighted the importance of site-specific responses and continuous surveillance mediated by a specific tissue-resident memory T cell population (Trm) [15] [16] [17] . A couple of studies demonstrated that after induction Trm migrate and reside in the lung, skin, and gut long after infection resolution and provide localized protective immunity and immunosurveillance in tissues [18] [19] [20] [21] . Trm represents an attractive target population and a growing interest for developing vaccine strategies since they act as immune sentinels in mucosal and barrier tissue and rapidly respond to infection by orchestrating local protective immune responses to eliminate pathogens 22 . Previous CD8 T cell-based vaccines against SARS-CoV-1 23 and influenza A 24 viruses showed lasting virus-specific memory CD8 T cells induction in the spleen, lung and bronchoalveolar fluids (BALs) and protection of mice from lethal SARS-CoV-1 or influenza challenges. Expression of chemokine receptors, such as CXCR3, is critical for CD8+ Trm to populate the airways after vaccination and protection against influenza A viruses 25 . More recently, a Trm-inducing HIV vaccine durably prevented mucosal infection in non-human primates even with lower neutralizing antibody titers 26 .

Altogether, these data emphasize the interest of tissue-resident memory viral-specific CD8 T cell generation upon vaccination for optimal protection against airways viruses.

Stimulation of a proper immune response that leads to protection is highly dependent on presentation of epitopes to circulating T-cells via the HLA complex. MEMOPI ® is a robust vaccine platform based on selection and immunogenicity optimization of HLA-restricted peptides (neo-epitope) technologies 27, 28 and formulation 29 for multi-epitopes and targets combination with a pan-DR helper epitope (PADRE) providing help for memory CD8 T cell generation 30 . A combination of multi-target antitumor neo-epitopes, Tedopi ® , based on this platform already demonstrated good safety profile and efficacy in clinical Phase 2 trial 31 and 6 more recently successfully validated in the first step of a Phase 3 clinical testing in lung cancer paients 32 . While induction of mucosal immunity using parenteral administration of conventional virus vaccine technologies was challenging, we observed that subcutaneous injection of our neo-epitopes multi-target cancer vaccine promotes Th1-biased antigen-specific memory CD8 T cell responses in the lung and BALs of vaccinated mice in the absence of tumor.

Based on this original preclinical observation and the significant survival increase measured during clinical trials in lung cancer patients correlating with epitope responses, we generated and screened individually a large number of immuno-dominant SARS-CoV-2 epitopes, and their neo-epitopes generated using artificial intelligence (AI) algorithms, covering all sequenced circulating SARS-CoV-2 strains and derived from 11 structural (including Spike) and non-structural proteins with significant homology with previous SARS-CoV-1 virus.

Previous research in SARS-CoV-1 suggests that the structural Spike (S) protein is one of the main antigenic component responsible for inducing the host immune responses 33 ORF1a/b non-structural proteins (nsp3, nsp4, nsp6, nsp12, nsp13, nsp14, nsp16) (Figure 1 and Table 1 ). Based on our knowledge of key fixed-anchor positions to enhance HLA binding and increase their immunogenicity potential, we designed 400 mutated sequences for each individual peptide resulting in 22 000 total analyzed sequences of the 55 selected epitopes. We first screened these potential peptides using in-silico bioinformatic analyses (e.g. IEDB Immune epitope database, netMHCpan EL 4.0 algorithm) and a first series of the most optimized mutant for each epitope was selected (neo-epitopes A). In parallel, 22000 in silico HLA-A*0201peptide docking models were generated using computational tools and analyzed using newly Europe, then spread worldwide and became the most prevalent form 62, 63 . We eliminated T cell epitopes with recurrent mutation and homoplasic site in order to cover all circulating SARS-CoV-2 strains and anticipate future evolution of the virus in hotspot mutation regions.

134 WT and mutated peptides (neoepitopes A and B) were produced using synthetic peptide synthesis (Proteogenix, France). HLA-A2 binding property characterization at 37°C, using UV peptide exchange assay on HLA-A*0201 monomer, showed that the majority of selected WT epitopes binds to HLA-A2 with good efficacy (Figure 2A ) as compared to our MEMOPI ® internal positive neoepitope control (mutated peptide with increased HLA-A*0201 binding and in-vivo immunogenicity). HLA-A2 binding was increased with several neoepitopes A and/or B, particularly when the corresponding WT peptide showed weak (< 15%: Figure 3A) . Similarly, broad immunogenicity response was observed by HLA-A*0201-tetramer flow cytometry analyses to a higher number of epitopes since 44 out of 60 (73%) evaluated peptides, derived from 10 out of the 11 selected proteins, exhibited significant frequency (0.1-1%) of viral-specific CD8 T cells ( Figure 3B ). Phenotypic characterization of Tetramer+ cells showed that 17 out of 44 (39%) positive peptides elicited viral-specific CD8 T cells with mainly a Trm phenotype: co-expressing the memory marker CD44, the CD103 αE integrin, the Th1-biased CXCR3 chemokine receptor and to a lesser extent the CD49a α1 integrin (Figure 4) . Altogether, these data showed that optimized peptide vaccination against selected SARS-CoV-2 epitopes elicits robust and broad Th1-biased immunogenicity against several structural (S, M, N) and non-structural proteins in HLA-A2 expressing mice and that several peptides induce viral-specific memory CD8 T cells displaying all characteristics of T lymphocyte sentinels in barrier tissues.

In order to identify and select naturally SARS-CoV-2 CD8 T cell immunodominant epitopes, peripheral blood mononuclear cells (PBMC) from asymptomatic and moderate or severe COVID-19 patients with a previously confirmed (at least one month before sampling) and Altogether, when we compared convalescent SARS-CoV-2 individuals to unexposed healthy donors, we identified 25 significantly different CD8 T cell immunodominant epitopes against 3 structural proteins (S, M, N), 1 accessory factor (ORF3a) and 7 non-structural proteins (nsp3, nsp4, nsp6, nsp12, nsp13, nsp14, nsp16). 16 of these epitopes are of particular interest for vaccination since they were able to elicit also in-vivo immunogenicity (Elispot response) against all 11 structural and non-structural SARS-CoV-2 proteins after a single peptide injection. Finally, we selected a combination of 12 CD8 T cells epitopes based on manufacturing facilities, HLA-I coverage, previous CoVs homology and SARS-CoV-2 proteins diversity considerations ( Table 2) . These 12 epitopes covered the 11 selected proteins, 1 epitope/protein excepting Spike for which 2 epitopes (including 1 RBD epitope) have been selected. Bioinformatic analyses illustrate these 12 epitopes are not restricted only to the HLA-A*0201 allele, hence are predict (netMHCpan score < 1) to bind efficiently to different HLA-I (A, B, C) alleles with high genetic coverage in all geographical region of the world. Despite HLA polymorphism and different worldwide HLA-I distribution, the combination of these 12 T cell epitopes should induce at least 1 to 4 positive peptide responses in all individuals globally and achieve the 60-70% 'herd immunity' threshold 66 with at least 4 to 5 positive peptide responses in each geographical region ( Table 3 ).

Here we report a differentiated SARS-COV-2 vaccine design based on memory T-cell induction technology. Using sequence design through reverse vaccinology selection approach based on previous CoVs knowledge on immunodominant epitopes and computational immunology optimization, we developed a combination of 12 CD8 T cell synthetic peptides originating from 11 SARS-CoV-2 structural and non-structural proteins capable to cover HLA polymorphism with high coverage globally and to induce immunogenicity to different proteins independently of HLA alleles expression. These epitopes are naturally immunogenic after SARS-COV-2 infection in recovered individuals and, for most of them, elicit a specialized sub-population of viral-specific memory CD8 T cells with a tissue-resident phenotype hence capable to migrate, stay attached and patrolling in airways barrier tissues. vaccine-induced T cell entry to the lung mucosal compartments [75] [76] [77] [78] [79] . Here we showed that, as previously observed with our MEMOPI ® -based neoepitope cancer vaccine approach, several peptides induced viral-specific CD8 T cells expressing the E (CD103) and α1 (CD49a) integrins and the CD44 memory marker, altogether characteristic of Trm. These cells express also the CXCR3 marker of chemoattraction, which is also a surrogate marker of Th1 CD8 T cells since CXCR3 is transactivate directly by the Th1 master gene T-bet 79 

Animal housing and procedures have been conducted according to the guidelines of the French Agriculture Ministry and were approved by the regional ethical committee (APAFIS 25256. 

T-cell WT and mutated peptides binding property on HLA-A2 has been evaluated using the Flex-T HLA-A*02:01 monomer ultraviolet (UV) exchange assay according to the manufacturer recommendation (Biolegend, San Diego, USA). HLA-A*02:01 monomer (200 µg/ml) were exposed to a 366-nm UV lamp in the presence or absence of 400 µM of peptide. After UVexposure, HLA-peptide complexes were incubated at 37°C for 30 min to promote unfolding of peptide-free HLA molecule. HLA-peptide complexes stability was detected by ELISA with β2microglobulin coated antibodies and incubation of 3 ng/ml of complexes for 1h at room temperature under shaking condition. Avidin-HRP were used to reveal stable biotinylated HLA-peptide complexes and absorbance was monitored at 450 nm. Data are expressed as percentage of binding relative to an MEMOPI ® internal positive control neoepitope.

A visualization tool was used to determine T-cell and B-cell epitope location in SARS-CoV-2 genomes according to single nucleotide polymorphism (SNPs) and homoplasic site (https://macman123.shinyapps.io/ugi-scov2-alignment-screen/) 85 

All subjects were enrolled in the COVEPIT- were not considered as an exclusion criterion.

PBMC were isolated after a Ficoll density-gradient centrifugation and a red blood cell lysis.

HLA-A2 phenotyping was performed by flow cytometry (clone BB7.2, BD Bioscience). Exvivo stimulation protocol was adapted from a previously described protocol 86 

Continuous variables were expressed as the mean ± SEM, unless otherwise indicated, and raw data were compared with nonparametric tests: Mann-Whitney for 2 groups or Kruskall-Wallis with Dunn's comparison when the number of groups was > 2. P values of <0.05 were considered statistically significant. All statistical analyses were performed on GraphPad Software (GraphPad Software, San Diego, CA).

This work was supported by funding from Nantes Metropole as part of the Metropolitan Fund to Support Health Innovations Linked to the COVID-19 Health Crisis. We thank clinicians and patients involved in the COVEPIT-1 trial as well as the eXYSTAT company for biometric expertise and data management for the COVEPIT-1 trial. Figure 1 : T-cell epitopes location in SARS-CoV-2 genome SARS-CoV-2 genome annotation by the Krogran lab 52 and schematic representation of T-cell epitopes location in each encoded proteins. n=4 structural proteins; n=16 non-structural proteins (NSPs); n=9 accessory factors.

HLA-A2 binding characterization of WT and mutated T-cell epitopes (A) WT and mutated peptides were incubated with HLA-A*02:01 monomer, exposed to UV for peptide exchange and then HLA-peptide complexes stability at 37°C was measured by ELISA. Data are mean +/-SEM (n=4) expressed as percentage of binding relative to an internal MEMOPI ® positive control neoepitope. (B) WT and mutated peptides (25µM) binding to TAPdeficient human cell line (T2) expressing HLA-A2. Data are expressed as percentage of binding relative to an internal MEMOPI ® positive control neoepitope. X mark indicates that the peptide was not tested in the assay. Figure 4A ). Medium and High response threshold were defined based on 2-fold or 3-fold increase respectively compared to the background frequency measured in the non-vaccinated mice control group. Controls+ are MEMOPI ® peptides with previously validated immunogenicity. Data are mean +/-SD of pooled female (n=3) and pooled male (n=3) vaccinated mice. Medium level: Two-fold background.

High level: Three-fold background IFNγ secretion responses for 48 hours after one week of restimulation of human PBMC from unexposed HLA-A2+ healthy donors (n=5), asymptomatic confirmed COVID-19 HLA-A2+ individuals (n=4) and moderate or severe COVID-19 HLA-A2+ convalescent patients (n=7) with each of the isolated peptides and HLA-A2+ antigen-presenting cells. Data were normalized to negative control peptides. Data are expressed as mean +/-min to max. *p<0.05 Table 1 : T-cell WT epitopes HLA-I alleles numbers and regional HLA-I coverage were determined using IEDB public database and netMHCpan score < 1. 

Duration of Antibody Responses after Severe Acute Respiratory Syndrome

Lack of Peripheral Memory B Cell Responses in Recovered Patients with Severe Acute Respiratory Syndrome: A Six-Year Follow-Up Study

A systematic review of antibody mediated immunity to coronaviruses: antibody kinetics, correlates of protection, and association of antibody responses with severity of disease

Longitudinal evaluation and decline of antibody responses in SARS-CoV-2 infection

Rapid Decay of Anti-SARS-CoV-2 Antibodies in Persons with Mild Covid-19

Memory T cell responses targeting the SARS coronavirus persist up to 11 years post-infection

SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls

Rapid COVID-19 vaccine development

The potential danger of suboptimal antibody responses in COVID-19

Anti-SARS-CoV-2 IgG from severely ill COVID-19 patients promotes macrophage hyper-inflammatory responses

A double-inactivated severe acute respiratory syndrome coronavirus vaccine provides incomplete protection in mice and induces increased eosinophilic proinflammatory pulmonary response upon challenge

Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry

Avoiding pitfalls in the pursuit of a COVID-19 vaccine

T-cell-inducing vaccines -what's the future

Preferential localization of effector memory cells in nonlymphoid tissue

Visualizing the generation of memory CD4 T cells in the whole body

Location, location, location: Tissue resident memory T cells in mice and humans

Dendritic cellinduced memory T cell activation in nonlymphoid tissues

Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus

Dynamic T cell migration program provides resident memory within intestinal epithelium

Cutting edge: Tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection

Sensing and alarm function of resident memory CD8 + T cells

Provide Substantial Protection from Lethal Severe Acute Respiratory Syndrome Coronavirus Infection

The design and proof of concept for a CD8+ T cell-based vaccine inducing cross-subtype protection against influenza A virus

Lung airway-surveilling CXCR3(hi) memory CD8(+) T cells are critical for protection against influenza A virus

T cell-inducing vaccine durably prevents mucosal SHIV infection even with lower neutralizing antibody titers

Identification of new epitopes from four different tumor-associated antigens: recognition of naturally processed epitopes correlates with HLA-A*0201-binding affinity

Improved Immunogenicity of an Immunodominant Epitope of the Her-2/neu Protooncogene by Alterations of MHC Contact Residues

Formulation and characterization of a ten-peptide single-vial vaccine, EP-2101, designed to induce cytotoxic T-lymphocyte responses for cancer immunotherapy

Development of high potency universal DR-restricted helper epitopes by modification of high affinity DR-blocking peptides

Induction of immune responses and clinical efficacy in a phase II trial of IDM-2101, a 10-epitope cytotoxic T-lymphocyte vaccine, in metastatic non-small-cell lung cancer

The spike protein of SARS-CoV--a target for vaccine and therapeutic development

Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals

Robust T cell immunity in convalescent individuals with asymptomatic or mild

Single-cell transcriptomic analysis of SARS-CoV-2 reactive CD4 + T cells

Different pattern of pre-existing SARS-COV-2 specific T cell immunity in SARSrecovered and uninfected individuals

Overwhelming mutations or SNPs of SARS-CoV-2: A point of caution

Emergence of genomic diversity and recurrent mutations in SARS-CoV-2

SARS-CoV-2 Alignment Screen

Large scale genomic analysis of 3067 SARS-CoV-2 genomes reveals a clonal geo-distribution and a rich genetic variations of hotspots mutations

Polymorphism and Selection Pressure of SARS-CoV-2 Vaccine and Diagnostic Antigens: Implications for Immune Evasion and Serologic Diagnostic Performance

Preliminary Identification of Potential Vaccine Targets for the COVID-19 Coronavirus (SARS-CoV-2) Based on SARS-CoV Immunological Studies

Prioritization of SARS-CoV-2 epitopes using a pan-HLA and global population inference approach

A Sequence Homology and Bioinformatic Approach Can Predict Candidate Targets for Immune Responses to SARS-CoV-2

COVID-19 Vaccine Candidates: Prediction and Validation of 174 SARS-CoV-2

Development of epitope-based peptide vaccine against novel coronavirus 2019 (SARS-COV-2): Immunoinformatics approach

Personalized workflow to identify optimal Tcell epitopes for peptide-based vaccines against

In silico identification of vaccine targets for 2019-nCoV

SARS-CoV-2 (COVID-19) by the numbers

A structural analysis of M protein in coronavirus assembly and morphology

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

Gene of the month: the 2019-nCoV/SARS-CoV-2 novel coronavirus spike protein

Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus

Structural basis of receptor recognition by SARS-CoV-2

Structure of SARS Coronavirus Spike Receptor-Binding Domain Complexed with Receptor

Structural Analysis of Major Species Barriers between Humans and Palm Civets for

Severe Acute Respiratory Syndrome Coronavirus Infections

Recent Advances in the Vaccine Development Against Middle East Respiratory Syndrome-Coronavirus

Spike mutation pipeline reveals the emergence of a more transmissible form of SARS-CoV-2

Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus

Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans

SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19

Herd immunity thresholds for SARS-CoV-2 estimated from unfolding epidemics

Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial

Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind

An mRNA Vaccine against SARS-CoV-2 -Preliminary Report

Genomic diversity and hotspot mutations in 30,983 SARS-CoV-2 genomes: moving toward a universal vaccine for the "confined virus

Intranasal administration of RSV antigen-expressing MCMV elicits robust tissue-resident effector and effector memory CD8+ T cells in the lung

Lung-resident memory CD8 T cells (TRM) are indispensable for optimal crossprotection against pulmonary virus infection

Vaccine-generated lung tissue-resident memory T cells provide heterosubtypic protection to influenza infection

Expression of Chemokine Receptors by Lung T Cells from Normal and Asthmatic Subjects

A small-molecule compound targeting CCR5 and CXCR3 prevents airway hyperresponsiveness and inflammation

CXCR3 Signaling Is Required for Restricted Homing of Parenteral Tuberculosis Vaccine-Induced T Cells to Both the Lung Parenchyma and Airway

Lung Tissue Resident Memory T-Cells in the Immune Response to Mycobacterium tuberculosis

Lung Airway-Surveilling CXCR3hi Memory

CD8+ T Cells Are Critical for Protection against Influenza A Virus

TRM integrins CD103 and CD49a differentially support adherence and motility after resolution of influenza virus infection

CD49a Expression Defines Tissue-Resident CD8+ T Cells Poised for Cytotoxic Function in Human Skin

Potently neutralizing and protective human antibodies against SARS-CoV-2

Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine

Altered reactivity to measles virus

Atypical measles in children previously immunized with inactivated measles virus vaccines

No evidence for increased transmissibility from recurrent mutations in SARS-CoV-2

Spatially resolved analyses link genomic and immune diversity and reveal unfavorable neutrophil activation in melanoma