Brianna Johnson

All Publications

• Role of affinity in plasma cell development in the germinal center light zone. The Journal of experimental medicine ElTanbouly, M. A., Ramos, V., MacLean, A. J., Chen, S. T., Loewe, M., Steinbach, S., Ben Tanfous, T., Johnson, B., Cipolla, M., Gazumyan, A., Oliveira, T. Y., Nussenzweig, M. C. 2024; 221 (1)

  Abstract

  Protective immune responses to many pathogens depend on the development of high-affinity antibody-producing plasma cells (PC) in germinal centers (GCs). Transgenic models suggest that there is a stringent affinity-based barrier to PC development. Whether a similar high-affinity barrier regulates PC development under physiologic circumstances and the nature of the PC fate decision has not been defined precisely. Here, we use a fate-mapping approach to examine the relationship between GC B cells selected to undergo additional rounds of affinity maturation, GC pre-PC, and PC. The data show that initial PC selection overlaps with GC B cell selection, but that the PC compartment accumulates a less diverse and higher affinity collection of antibodies over time. Thus, whereas the GC continues to diversify over time, affinity-based pre-PC selection sieves the GC to enable the accumulation of a more restricted group of high-affinity antibody-secreting PC.

  View details for DOI 10.1084/jem.20231838

  View details for PubMedID 37938344

• Memory B cell development elicited by mRNA booster vaccinations in the elderly JOURNAL OF EXPERIMENTAL MEDICINE Wang, Z., Muecksch, F., Raspe, R., Johannsen, F., Turroja, M., Canis, M., ElTanbouly, M. A., Santos, G., Johnson, B., Baharani, V. A., Patejak, R., Yao, K., Chirco, B. J., Millard, K. G., Shimeliovich, I., Gazumyan, A., Oliveira, T. Y., Bieniasz, P. D., Hatziioannou, T., Caskey, M., Nussenzweig, M. C. 2023; 220 (9)

  Abstract

  Despite mRNA vaccination, elderly individuals remain especially vulnerable to severe consequences of SARS-CoV-2 infection. Here, we compare the memory B cell responses in a cohort of elderly and younger individuals who received mRNA booster vaccinations. Plasma neutralizing potency and breadth were similar between the two groups. By contrast, the absolute number of SARS-CoV-2-specific memory B cells was lower in the elderly. Antibody sequencing revealed that the SARS-CoV-2-specific elderly memory compartments were more clonal and less diverse. Notably, memory antibodies from the elderly preferentially targeted the ACE2-binding site on the RBD, while those from younger individuals targeted less accessible but more conserved epitopes. Nevertheless, individual memory antibodies elicited by booster vaccines in the elderly and younger individuals showed similar levels of neutralizing activity and breadth against SARS-CoV-2 variants. Thus, the relatively diminished protective effects of vaccination against serious disease in the elderly are associated with a smaller number of antigen-specific memory B cells that express altered antibody repertoires.

  View details for DOI 10.1084/jem.20230668

  View details for Web of Science ID 001018413400001

  View details for PubMedID 37368240

  View details for PubMedCentralID PMC10300432

• Antibody feedback regulates immune memory after SARS-CoV-2 mRNA vaccination NATURE Schaefer-Babajew, D., Wang, Z., Muecksch, F., Cho, A., Loewe, M., Cipolla, M., Raspe, R., Johnson, B., Canis, M., DaSilva, J., Ramos, V., Turroja, M., Millard, K. G., Schmidt, F., Witte, L., Dizon, J., Shimeliovich, I., Yao, K., Oliveira, T. Y., Gazumyan, A., Gaebler, C., Bieniasz, P. D., Hatziioannou, T., Caskey, M., Nussenzweig, M. C. 2023; 613 (7945): 735-+

  Abstract

  Feedback inhibition of humoral immunity by antibodies was first documented in 19091. Subsequent studies showed that, depending on the context, antibodies can enhance or inhibit immune responses2,3. However, little is known about how pre-existing antibodies influence the development of memory B cells. Here we examined the memory B cell response in individuals who received two high-affinity anti-SARS-CoV-2 monoclonal antibodies and subsequently two doses of an mRNA vaccine4-8. We found that the recipients of the monoclonal antibodies produced antigen-binding and neutralizing titres that were only fractionally lower compared than in control individuals. However, the memory B cells of the individuals who received the monoclonal antibodies differed from those of control individuals in that they predominantly expressed low-affinity IgM antibodies that carried small numbers of somatic mutations and showed altered receptor binding domain (RBD) target specificity, consistent with epitope masking. Moreover, only 1 out of 77 anti-RBD memory antibodies tested neutralized the virus. The mechanism underlying these findings was examined in experiments in mice that showed that germinal centres formed in the presence of the same antibodies were dominated by low-affinity B cells. Our results indicate that pre-existing high-affinity antibodies bias germinal centre and memory B cell selection through two distinct mechanisms: (1) by lowering the activation threshold for B cells, thereby permitting abundant lower-affinity clones to participate in the immune response; and (2) through direct masking of their cognate epitopes. This may in part explain the shifting target profile of memory antibodies elicited by booster vaccinations9.

  View details for DOI 10.1038/s41586-022-05609-w

  View details for Web of Science ID 001057523600019

  View details for PubMedID 36473496

  View details for PubMedCentralID PMC9876794

• Memory B cell responses to Omicron subvariants after SARS-CoV-2 mRNA breakthrough infection in humans JOURNAL OF EXPERIMENTAL MEDICINE Wang, Z., Zhou, P., Muecksch, F., Cho, A., Ben Tanfous, T., Canis, M., Witte, L., Johnson, B., Raspe, R., Schmidt, F., Bednarski, E., Da Silva, J., Ramos, V., Zong, S., Turroja, M., Millard, K. G., Yao, K., Shimeliovich, I., Dizon, J., Kaczynska, A., Jankovic, M., Gazumyan, A., Oliveira, T. Y., Caskey, M., Gaebler, C., Bieniasz, P. D., Hatziioannou, T., Nussenzweig, M. C. 2022; 219 (12)

  Abstract

  Individuals who receive a third mRNA vaccine dose show enhanced protection against severe COVID-19, but little is known about the impact of breakthrough infections on memory responses. Here, we examine the memory antibodies that develop after a third or fourth antigenic exposure by Delta or Omicron BA.1 infection, respectively. A third exposure to antigen by Delta breakthrough increases the number of memory B cells that produce antibodies with comparable potency and breadth to a third mRNA vaccine dose. A fourth antigenic exposure with Omicron BA.1 infection increased variant-specific plasma antibody and memory B cell responses. However, the fourth exposure did not increase the overall frequency of memory B cells or their general potency or breadth compared to a third mRNA vaccine dose. In conclusion, a third antigenic exposure by Delta infection elicits strain-specific memory responses and increases in the overall potency and breadth of the memory B cells. In contrast, the effects of a fourth antigenic exposure with Omicron BA.1 are limited to increased strain-specific memory with little effect on the potency or breadth of memory B cell antibodies. The results suggest that the effect of strain-specific boosting on memory B cell compartment may be limited.

  View details for DOI 10.1084/jem.20221006

  View details for Web of Science ID 000862383600001

  View details for PubMedID 36149398

  View details for PubMedCentralID PMC9513381

• Humoral immunity to SARS-CoV-2 elicited by combination COVID-19 vaccination regimens JOURNAL OF EXPERIMENTAL MEDICINE Wang, Z., Muecksch, F., Muenn, F., Cho, A., Zong, S., Raspe, R., Ramos, V., Johnson, B., Ben Tanfous, T., DaSilva, J., Bednarski, E., Guzman-Cardozo, C., Turroja, M., Millard, K. G., Tober-Lau, P., Hillus, D., Yao, K., Shimeliovich, I., Dizon, J., Kaczynska, A., Jankovic, M., Gazumyan, A., Oliveira, T. Y., Caskey, M., Bieniasz, P. D., Hatziioannou, T., Kurth, F., Sander, L., Nussenzweig, M. C., Gaebler, C. 2022; 219 (10)

  Abstract

  The SARS-CoV-2 pandemic prompted a global vaccination effort and the development of numerous COVID-19 vaccines at an unprecedented scale and pace. As a result, current COVID-19 vaccination regimens comprise diverse vaccine modalities, immunogen combinations, and dosing intervals. Here, we compare vaccine-specific antibody and memory B cell responses following two-dose mRNA, single-dose Ad26.COV.2S, and two-dose ChAdOx1, or combination ChAdOx1/mRNA vaccination. Plasma-neutralizing activity, as well as the magnitude, clonal composition, and antibody maturation of the RBD-specific memory B cell compartments, showed substantial differences between the vaccination regimens. While individual monoclonal antibodies derived from memory B cells exhibited similar binding affinities and neutralizing potency against Wuhan-Hu-1 SARS-CoV-2, there were significant differences in epitope specificity and neutralizing breadth against viral variants of concern. Although the ChAdOx1 vaccine was inferior to mRNA and Ad26.COV.2S in several respects, biochemical and structural analyses revealed enrichment in a subgroup of memory B cell neutralizing antibodies with distinct RBD-binding properties resulting in remarkable potency and breadth.

  View details for DOI 10.1084/jem.20220826

  View details for Web of Science ID 000860491900001

  View details for PubMedID 36006380

  View details for PubMedCentralID PMC9418484

• Antibody evolution to SARS-CoV-2 after single-dose Ad26.COV2.S vaccine in humans JOURNAL OF EXPERIMENTAL MEDICINE Cho, A., Muecksch, F., Wang, Z., Ben Tanfous, T., DaSilva, J., Raspe, R., Johnson, B., Bednarski, E., Ramos, V., Schaefer-Babajew, D., Shimeliovich, I., Dizon, J. P., Yao, K., Schmidt, F., Millard, K. G., Turroja, M., Jankovic, M., Oliveira, T. Y., Gazumyan, A., Gaebler, C., Caskey, M., Hatziioannou, T., Bieniasz, P. D., Nussenzweig, M. C. 2022; 219 (8)

  Abstract

  The single-dose Ad.26.COV.2 (Janssen) vaccine elicits lower levels of neutralizing antibodies and shows more limited efficacy in protection against infection than either of the two available mRNA vaccines. In addition, Ad.26.COV.2 has been less effective in protection against severe disease during the Omicron surge. Here, we examined the memory B cell response to single-dose Ad.26.COV.2 vaccination. Compared with mRNA vaccines, Ad.26.COV.2 recipients had significantly lower numbers of RBD-specific memory B cells 1.5 or 6 mo after vaccination. Despite the lower numbers, the overall quality of the memory B cell responses appears to be similar, such that memory antibodies elicited by both vaccine types show comparable neutralizing potency against SARS-CoV-2 Wuhan-Hu-1, Delta, and Omicron BA.1 variants. The data help explain why boosting Ad.26.COV.2 vaccine recipients with mRNA vaccines is effective and why the Ad26.COV2.S vaccine can maintain some protective efficacy against severe disease during the Omicron surge.

  View details for DOI 10.1084/jem.20220732

  View details for Web of Science ID 000860798300001

  View details for PubMedID 35776090

  View details for PubMedCentralID PMC9253517

• Increased memory B cell potency and breadth after a SARS-CoV-2 mRNA boost NATURE Muecksch, F., Wang, Z., Cho, A., Gaebler, C., Ben Tanfous, T., DaSilva, J., Bednarski, E., Ramos, V., Zong, S., Johnson, B., Raspe, R., Schaefer-Babajew, D., Shimeliovich, I., Daga, M., Yao, K., Schmidt, F., Millard, K. G., Turroja, M., Jankovic, M., Oliveira, T. Y., Gazumyan, A., Caskey, M., Hatziioannou, T., Bieniasz, P. D., Nussenzweig, M. C. 2022; 607 (7917): 128-+

  Abstract

  The Omicron variant of SARS-CoV-2 infected many vaccinated and convalescent individuals1-3. Despite the reduced protection from infection, individuals who received three doses of an mRNA vaccine were highly protected from more serious consequences of infection4. Here we examine the memory B cell repertoire in a longitudinal cohort of individuals receiving three mRNA vaccine doses5,6. We find that the third dose is accompanied by an increase in, and evolution of, receptor-binding domain (RBD)-specific memory B cells. The increase is due to expansion of memory B cell clones that were present after the second dose as well as the emergence of new clones. The antibodies encoded by these cells showed significantly increased potency and breadth when compared with antibodies obtained after the second dose. Notably, the increase in potency was especially evident among newly developing clones of memory cells, which differed from persisting clones in targeting more conserved regions of the RBD. Overall, more than 50% of the analysed neutralizing antibodies in the memory compartment after the third mRNA vaccine dose neutralized the Omicron variant. Thus, individuals receiving three doses of an mRNA vaccine have a diverse memory B cell repertoire that can respond rapidly and produce antibodies capable of clearing even diversified variants such as Omicron. These data help to explain why a third dose of a vaccine that was not specifically designed to protect against variants is effective against variant-induced serious disease.

  View details for DOI 10.1038/s41586-022-04778-y

  View details for Web of Science ID 000804521800001

  View details for PubMedID 35447027

  View details for PubMedCentralID PMC9259484

• <i>Vibrio cholerae</i>'s mysterious Seventh Pandemic island (VSP-II) encodes novel Zur-regulated zinc starvation genes involved in chemotaxis and cell congregation PLOS GENETICS Murphy, S. G., Johnson, B. A., Ledoux, C. M., Doerr, T. 2021; 17 (6): e1009624

  Abstract

  Vibrio cholerae is the causative agent of cholera, a notorious diarrheal disease that is typically transmitted via contaminated drinking water. The current pandemic agent, the El Tor biotype, has undergone several genetic changes that include horizontal acquisition of two genomic islands (VSP-I and VSP-II). VSP presence strongly correlates with pandemicity; however, the contribution of these islands to V. cholerae's life cycle, particularly the 26-kb VSP-II, remains poorly understood. VSP-II-encoded genes are not expressed under standard laboratory conditions, suggesting that their induction requires an unknown signal from the host or environment. One signal that bacteria encounter under both host and environmental conditions is metal limitation. While studying V. cholerae's zinc-starvation response in vitro, we noticed that a mutant constitutively expressing zinc starvation genes (Δzur) congregates at the bottom of a culture tube when grown in a nutrient-poor medium. Using transposon mutagenesis, we found that flagellar motility, chemotaxis, and VSP-II encoded genes were required for congregation. The VSP-II genes encode an AraC-like transcriptional activator (VerA) and a methyl-accepting chemotaxis protein (AerB). Using RNA-seq and lacZ transcriptional reporters, we show that VerA is a novel Zur target and an activator of the nearby AerB chemoreceptor. AerB interfaces with the chemotaxis system to drive oxygen-dependent congregation and energy taxis. Importantly, this work suggests a functional link between VSP-II, zinc-starved environments, and energy taxis, yielding insights into the role of VSP-II in a metal-limited host or aquatic reservoir.

  View details for DOI 10.1371/journal.pgen.1009624

  View details for Web of Science ID 000671676300002

  View details for PubMedID 34153031

  View details for PubMedCentralID PMC8248653