Research projects
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Why is protection following HBV vaccination so variable?
We seek to understand why some people respond to HBV vaccines strongly whereas others respond weakly or not at all.
Vaccines rank among humanity’s greatest health advances. By preventing morbidity and mortality, countless lives have been saved. However, we still lack vaccines against many of the pathogens causing the greatest morbidity and mortality, and the vaccines we do use are not always protective, sometimes despite multiple doses. Responses to vaccines are not routinely measured, leaving people unknowingly susceptible to disease.
Although we’ve used vaccines for centuries, major questions remain. What predicts durability of the response? How does the T and B cell change over time with boosters? Using the hepatitis B vaccine as a model, we are performing a prospective clinical trial to understand why some people respond strongly and others poorly by focusing on the longitudinal phenotypes, transcriptional profiles, and antigen-receptor repertoire of antigen-specific T follicular helper CD4 cells and B cells.
How does inflammation impact T and B cells?
Inflammation present at the time memory T and B cells form can leave a lasting imprint.
Inflammation is a normal part of how the immune system responds to germs and is needed for proper development of T and B cells and resolution of infection. However, too much inflammation can be harmful. Big-picture consequences of excessive inflammation have been studied for decades, but whether T and B cells are affected by excessive inflammation at the single-cell scale is not known.
In our studies, we observed a lasting imprint of acute inflammation of COVID-19 on the transcriptional and epigenetic state of immune cells that affected how these cells responded to booster vaccination and/or breakthrough infection. Treatments such as convalescent plasma for viral infections may also alter inflammation during acute infection and shape later responses. Understanding whether, and how, immune cells are impacted by inflammation will be necessary for the development of optimal next-generation vaccine strategies.
How do T-B cell interactions in the tumor and in the sentinel lymph node predict outcomes?
Inflammation present at the time memory T and B cells form can leave a lasting imprint.
The heart of the immune response involves cellular interactions and cues that must be delivered at the precise time and in the right micro-environment. Understanding how and when these interactions matter will help us understand disease and might offer opportunities to affect biology in a targeted way. Our goal is to understand the cellular microenvironment, and in particular how cells are organized into “neighborhoods” and what effect this has on cell function, using cellular phenotypes with spatial information.
We are studying tumor and sentinel lymph node tissue taken at the time of diagnosis with Stage II melanoma and interrogating these samples with high-parameter immunofluorescence methods. By focusing on T-B cell interactions particularly in the tertiary lymphoid structures, we can learn what cellular interactions are most important to be able to predict outcomes.
Prior published work
PD-1 directed immunotherapy alters Tfh and humoral immune responses to seasonal influenza vaccine
Nat Immunol. 2022 Aug;23(8):1183-1192.
Problem: Anti-PD1 immunotherapy mediates anti-tumor effect through CD8 T cells, but what happens to Tfh, which express high levels of PD-1? What happens to the germinal center reaction in the context of anti-PD1 therapy?
Approach: Adults with melanoma or genitourinary cancer, who were receiving maintenance anti-PD1, were enrolled for longitudinal blood draws around the time of seasonal influenza vaccination.
Findings:
- Much higher circulating Tfh induction in the context of anti-PD1 therapy, also higher plasmablast and serum CXCL13 responses
- Anti-PD1 participants had greater fold-change increase in neutralizing antibodies
- Immune-related adverse events, independent of the vaccine, were associated with Tfh responsiveness to influenza vaccination during anti-PD1
Activated Tfh were assessed in the circulation before and one week after influenza vaccination in adults with melanoma who were receiving anti-PD1 immunotherapy.
Robust immune responses are observed after one dose of BNT162b2 mRNA vaccine dose in SARS-CoV-2-experienced individuals
Sci Transl Med. 2022 Feb 9;14(631):eabi8961
Problem: Some individuals who received mRNA vaccination had already recovered from COVID-19. How do immune responses to mRNA vaccination differ if one already has immunity generated by viral infection?
Approach: Adults who were receiving two-dose primary mRNA vaccination against COVID-19 were longitudinally profiled for B and T cell responses.
Findings:
- People with prior SARS-CoV-2 had dramatic increases in antibody titer after just one dose of mRNA vaccination
- The second dose of mRNA vaccine induced minimal further antibody responses in people who had had prior SARS-CoV-2 immunity
- RBD-specific T cell responses in people who lacked prior SARS-CoV-2 immunity were detectable by Activation-Induced Markers following
Antibody titers were assessed after primary two-dose mRNA vaccination at baseline, one week after first immunization (Post 1st dose), on the day of second immunization (Pre 2nd dose), one week after second immunization (Post 2nd dose), or One month after second immunization. Orange, adults with no prior SARS-CoV-2 immunity. Purple, adults who had previously recovered from SARS-CoV-2.
Vaccine-induced ICOS+CD38+ circulating Tfh are sensitive biosensors of age-related changes in inflammatory pathways.
Cell Rep Med. 2021 May 7;2(5):100262.
Problem: Aging is associated with poor vaccine responses. How do Tfh responses from the elderly compare with Tfh responses from young adults?
Approach: Adults either ages 18-40 or >65 who were receiving seasonal influenza vaccine. PBMC at baseline and 1 week after flu vaccine were sorted for ICOS+CD38+ cTfh, ICOS-CD38- cTfh, and naive CD4 subsets and bulk mRNAseq performed.
Findings:
- Activated Tfh responses do not differ at a quantitative level with aging
- mRNAseq reveals upregulation of TNF-NFkB and other inflammatory signaling pathways in Tfh from the elderly
- The activated cTfh transcriptional profile is a more faithful biosensor of age-related transcriptional changes than other CD4 T cell subsets.
Normalized enrichment scores were compared between cohorts before and 7 days after influenza vaccination. Although pathway enrichment was similar across CD4 subsets, the magnitude of enrichment score change was greatest in the ICOS+CD38+ cTfh.