Vaccines
Abstract
Tissue-resident lymphocytes provide organ-adapted protection against invading pathogens. Whereas their biology has been examined in great detail in various infection models, their generation and functionality in response to vaccination has not been comprehensively analyzed in humans. We therefore studied SARS-CoV2 mRNA-vaccine-specific T cells in surgery specimens of kidney, liver, lung, bone marrow and spleen in comparison to paired blood samples from largely virus-naïve individuals. As opposed to lymphoid tissues, non-lymphoid organs harbored significantly elevated frequencies of Spike-specific CD4+ T cells compared to blood showing hallmarks of tissue residency and an expanded memory pool. Organ-derived CD4+ T cells further exhibited increased polyfunctionality over those detected in blood. Single-cell RNA sequencing together with T cell receptor repertoire analysis indicated that the clonotype rather than organ origin is a major determinant of transcriptomic state in vaccine-specific CD4+ T cells. In summary, our data demonstrate that SARS-CoV2 vaccination entails acquisition of tissue memory and residency features in organs distant from the inoculation site, thereby contributing to our understanding of how local tissue protection might be accomplished.
Authors
Vanessa Proß, Arne Sattler, Söeren Lukassen, Laura Tóth, Linda Marie Laura Thole, Janine Siegle, Carolin Stahl, An He, Georg Damm, Daniel Seehofer, Christina Götz, Christian Bayerl, Pia Jäger, Alexander Macke, Stephan Eggeling, Bernadette Kirzinger, Thomas Mayr, Hermann Herbst, Katharina Beyer, Dominik Laue, Jan Krönke, Jan Braune, Friederike Rosseck, Beatrice Kittner, Frank Friedersdorff, Mandy Hubatsch, Sarah Weinberger, Nils Lachmann, Veit Maria Hofmann, Eva Schrezenmeier, Carolin Ludwig, Hubert Schrezenmeier, Katharina Jechow, Christian Conrad, Katja Kotsch
Abstract
Herpes zoster (HZ) is a substantial problem for people with decreased cell-mediated immunity, including older adults. The first vaccine approved for HZ prevention, the zoster vaccine live (ZVL), which provided limited and short-lived protection, has been supplanted by the superior recombinant zoster vaccine (RZV), which provides robust and durable protection. To understand the mechanisms underlying the differential immunologic characteristics of the two vaccines, we used T cell receptor beta sequencing and peptide-MHC class II tetramer staining to analyze gE-specific CD4+ T cell clonotypes in RZV and ZVL recipients. Compared to ZVL, RZV expanded more gE-specific CD4+ clonotypes with greater breadth and higher frequency of public clonotypes. RZV recruited a higher proportion of clonotypes from the naïve than from memory cells, while ZVL recruited equally from memory and naïve compartments. Compared to memory-, naïve-derived clonotypes were more likely to last ≥ 5 years post-immunization. Moreover, the frequency of tetramer+ persistent clones correlated with the frequency of tetramer+ naïve CD4+ T cells pre-vaccination. We conclude that the ability of RZV to recruit naive CD4+ T cells into the response may contribute to the durability of its effect. The abundance, breadth, and the frequency of public clonotypes may further add to its protective effect.
Authors
Kerry J. Laing, Emily S. Ford, Michael J. Johnson, Myron J. Levin, David M. Koelle, Adriana Weinberg
Abstract
Authors
Christoph Strumann, Otavio T. Ranzani, Jeanne Moor, Reinhard Berner, Nicole Toepfner, Cho-Ming Chao, Matthias B. Moor
Abstract
Therapeutic benefit to immune checkpoint blockade (ICB) is currently limited to the subset of cancers thought to possess a sufficient tumor mutational burden (TMB) to allow for the spontaneous recognition of neoantigens (NeoAg) by autologous T cells. We explored whether the response to ICB of an aggressive low-TMB squamous cell tumor could be improved through combination immunotherapy using functionally defined NeoAg as targets for endogenous CD4+ and CD8+ T cells. We found that, whereas vaccination with CD4+ or CD8+ NeoAg alone did not offer prophylactic or therapeutic immunity, vaccines containing NeoAg recognized by both subsets overcame ICB resistance and led to the eradication of large established tumors that contained a subset of PD-L1+ tumor-initiating cancer stem cells (tCSC), provided the relevant epitopes were physically linked. Therapeutic CD4+/CD8+ T cell NeoAg vaccination produced a modified tumor microenvironment (TME) with increased numbers of NeoAg-specific CD8+ T cells existing in progenitor and intermediate exhausted states enabled by combination ICB-mediated intermolecular epitope spreading. We believe that the concepts explored herein should be exploited for the development of more potent personalized cancer vaccines that can expand the range of tumors treatable with ICB.
Authors
Joseph S. Dolina, Joey Lee, Spencer E. Brightman, Sara McArdle, Samantha M. Hall, Rukman R. Thota, Karla S. Zavala, Manasa Lanka, Ashmitaa Logandha Ramamoorthy Premlal, Jason A. Greenbaum, Ezra E. W. Cohen, Bjoern Peters, Stephen P. Schoenberger
Abstract
Authors
Natalie E. Stevens, Feargal J. Ryan, Nicole L. Messina, Stephen J. Blake, Todd S. Norton, Susie Germano, Jane James, Georgina L. Eden, Yee C. Tee, Miriam A. Lynn, Rochelle Botten, Simone E. Barry, Nigel Curtis, David J. Lynn
Abstract
Typhoid fever is caused by the Gram-negative bacterium Salmonella enterica serovar Typhi and poses a substantial public health burden worldwide. Vaccines have been developed based on the surface Vi-capsular polysaccharide of S. Typhi, this includes a plain-polysaccharide-based vaccine, ViPS, and a glycoconjugate vaccine, ViTCV. Previous studies have provided partial insight into the protective mechanisms of these Vi-derived vaccines. To understand immune responses to these vaccines and their vaccine-induced immunological protection, bulk RNA-sequencing (RNA-Seq) data were generated from blood samples obtained from adult human volunteers enrolled in a vaccine trial, who were then challenged with S. Typhi in a controlled human infection model (CHIM). Transcriptomic responses revealed strong differential molecular signatures between the two vaccines mostly driven by the upregulation in humoral immune signatures, including selective usage of immunoglobulin heavy chain variable region (IGHV) genes and more polarised clonal expansions. We describe several molecular correlates of protection against S. Typhi infection including clusters of B cell receptor (BCR) clonotypes associated with protection, with known binders of Vi-polysaccharide among these. Taken together, we report a series of contemporary analyses that reveal the transcriptomic signatures after vaccination and infectious challenge, while identifying molecular correlates of protection that may inform future vaccine design and assessment.
Authors
Henderson Zhu, Irina Chelysheva, Deborah L. Cross, Luke Blackwell, Celina Jin, Malick M. Gibani, Elizabeth Jones, Jennifer Hill, Johannes Trück, Dominic F. Kelly, Christoph Blohmke, Andrew J. Pollard, Daniel O'Connor
Abstract
Heterogeneity in human immune responses is difficult to model in standard laboratory mice. To understand how host variation affects BCG-induced immunity against Mycobacterium tuberculosis, we studied 24 unique Collaborative Cross (CC) mouse strains, which differ primarily in the genes and alleles they inherit from founder strains. The CC strains were vaccinated with or without BCG, and then challenged with aerosolized M. tuberculosis. As BCG protects only half of the CC strains tested, we conclude that host genetics has a major influence on BCG-induced immunity against M. tuberculosis infection, making it an important barrier to vaccine-mediated protection. Importantly, BCG efficacy is dissociable from inherent susceptibility to TB. T cell immunity was extensively characterized to identify components associated with protection that were stimulated by BCG and recalled after Mtb infection. Although considerable diversity is observed, BCG has little impact on the composition of T cells in the lung after infection. Instead, variability is largely shaped by host genetics. BCG-elicited protection against TB correlated with changes in immune function. Thus, CC mice can be used to define correlates of protection and to identify vaccine strategies that protect a larger fraction of genetically diverse individuals instead of optimizing protection for a single genotype.
Authors
Rocky Lai, Diana N. Gong, Travis Williams, Abiola F. Ogunsola, Kelly Cavallo, Cecilia S. Lindestam Arlehamn, Sarah Acolatse, Gillian Beamer, Martin T. Ferris, Christopher M. Sassetti, Douglas A. Lauffenburger, Samuel M. Behar
Abstract
BACKGOUND. Basic immune processes exhibit circadian rhythms, but it is unclear if rhythms exist in clinical endpoints like vaccine protection. Here, we examined associations between Coronavirus Infectious Disease 2019 (COVID-19) vaccination timing and effectiveness. METHODS. We retrospectively analyzed a large Israeli cohort with timestamped COVID-19 vaccinations (n=1,515,754 patients over 12 years-old, 99.2% receiving BNT162b2). Endpoints included COVID-19 breakthrough infection, COVID-19 associated emergency department (ED) visits, and hospitalizations. Our main comparison was between patients vaccinated during morning (8:00-11:59), afternoon (12:00-15:59), or evening hours (16:00-19:59). We employed Cox regression to adjust for differences in age, sex, and co-morbidities. RESULTS. Breakthrough infections differed based on vaccination time, with lowest rates associated with late morning to early afternoon, and highest rates with evening vaccination. Vaccination timing remained significant after adjustment for patient age, sex, and co-morbidities. Results were consistent in patients who received the basic two-dose series and who received booster doses. The relationship between COVID-19 immunization time and breakthrough infections was sinusoidal, consistent with a biological rhythm that modifies vaccine effectiveness by 8.6-25%. The benefits of daytime vaccination were concentrated in younger (<20 years old) and older patients (>50 years old). COVID-19 related hospitalizations varied significantly with the timing of the second booster dose, an intervention reserved for older and immunosuppressed patients (HR=0.64 morning vs. evening, 0.43-0.97 95% CI, p=0.038). CONCLUSION. We report a significant association between the time of COVID-19 vaccination and its effectiveness. This has implications for mass vaccination programs. FUNDING. National Institutes of Health.
Authors
Guy Hazan, Or A. Duek, Hillel Alapi, Huram Mok, Alexander T. Ganninger, Elaine M. Ostendorf, Carrie Gierasch, Gabriel Chodick, David Greenberg, Jeffrey A. Haspel
Abstract
BACKGROUND. Maintaining durable immunity to vaccination represents a major challenge, but whether booster mRNA vaccination improves durability is unknown. METHODS. We measured antibody responses in 55 healthy adults who received a booster dose of Pfizer-BioNTech or Moderna vaccine against SARS-CoV-2 and calculated the half-life of antibody titers. We also measured memory B and T cell responses in a subset of 28 participants. In 13 volunteers who received a second booster, we measured serum antibody titers, and memory B and T cell responses. RESULTS. The booster (3rd immunization) dose at 6 - 10 months increased the half-life of serum neutralizing antibody (nAb) titers to 76 days from 56 - 66 days after the primary two-dose vaccination. A second booster dose (4th immunization) a year after the primary vaccination increased the half-life further to 88 days. However, despite this modestly improved durability in nAb responses against the ancestral (WA.1) strain, there was a loss in neutralization capacity against Omicron subvariants BA.2.75.2, BQ.1.1, and XBB.1.5 (48, 71, and 66-fold drop in titers respectively, relative to the WA.1 strain). While only 45 – 65% of participants demonstrated a detectable nAb titer against the newer variants after the booster (3rd dose), the response declined to below the detection limit in almost all individuals by 6 months. In contrast, booster vaccination induced antigen-specific memory B and T cells that persisted for at least 6 months. CONCLUSION. The durability of serum antibody responses improves only marginally following booster immunizations with the Pfizer-BioNTech or Moderna mRNA vaccines.
Authors
Prabhu S Arunachalam, Lilin Lai, Hady Samaha, Yupeng Feng, Mengyun Hu, Harold Sai-yin Hui, Bushra Wali, Madison L. Ellis, Meredith E. Davis-Gardner, Christopher M. Huerta, Kareem Bechnak, Sarah Bechnak, Matthew Lee, Matthew B. Litvack, Cecilia Losada, Alba Grifoni, Alessandro Sette, Veronika I. Zarnitsyna, Nadine Rouphael, Mehul S. Suthar, Bali Pulendran
Abstract
BACKGROUND Mosaic and consensus HIV-1 immunogens provide two distinct approaches to elicit greater breadth of coverage against globally circulating HIV-1 and have shown improved immunologic breadth in nonhuman primate models.METHODS This double-blind randomized trial enrolled 105 healthy HIV-uninfected adults who received 3 doses of either a trivalent global mosaic, a group M consensus (CON-S), or a natural clade B (Nat-B) gp160 env DNA vaccine followed by 2 doses of a heterologous modified vaccinia Ankara–vectored HIV-1 vaccine or placebo. We performed prespecified blinded immunogenicity analyses at day 70 and day 238 after the first immunization. T cell responses to vaccine antigens and 5 heterologous Env variants were fully mapped.RESULTS Env-specific CD4+ T cell responses were induced in 71% of the mosaic vaccine recipients versus 48% of the CON-S recipients and 48% of the natural Env recipients. The mean number of T cell epitopes recognized was 2.5 (95% CI, 1.2–4.2) for mosaic recipients, 1.6 (95% CI, 0.82–2.6) for CON-S recipients, and 1.1 (95% CI, 0.62–1.71) for Nat-B recipients. Mean breadth was significantly greater in the mosaic group than in the Nat-B group using overall (P = 0.014), prime-matched (P = 0.002), heterologous (P = 0.046), and boost-matched (P = 0.009) measures. Overall T cell breadth was largely due to Env-specific CD4+ T cell responses.CONCLUSION Priming with a mosaic antigen significantly increased the number of epitopes recognized by Env-specific T cells and enabled more, albeit still limited, cross-recognition of heterologous variants. Mosaic and consensus immunogens are promising approaches to address global diversity of HIV-1.TRIAL REGISTRATION ClinicalTrials.gov NCT02296541.FUNDING US NIH grants UM1 AI068614, UM1 AI068635, UM1 AI068618, UM1 AI069412, UL1 RR025758, P30 AI064518, UM1 AI100645, and UM1 AI144371, and Bill & Melinda Gates Foundation grant OPP52282.
Authors
Kristen W. Cohen, Andrew Fiore-Gartland, Stephen R. Walsh, Karina Yusim, Nicole Frahm, Marnie L. Elizaga, Janine Maenza, Hyman Scott, Kenneth H. Mayer, Paul A. Goepfert, Srilatha Edupuganti, Giuseppe Pantaleo, Julia Hutter, Daryl E. Morris, Stephen C. De Rosa, Daniel E. Geraghty, Merlin L. Robb, Nelson L. Michael, Will Fischer, Elena E. Giorgi, Harman Malhi, Michael N. Pensiero, Guido Ferrari, Georgia D. Tomaras, David C. Montefiori, Peter B. Gilbert, M. Juliana McElrath, Barton F. Haynes, Bette T. Korber, Lindsey R. Baden, the NIAID HVTN 106 Study Group
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Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)