Vaccines
Abstract
SARS-CoV-2 mRNA vaccination generates protective B cell responses targeting the SARS-CoV-2 spike glycoprotein. Whereas anti-spike memory B cell responses are long-lasting, the anti-spike humoral antibody response progressively wanes, making booster vaccinations necessary for maintaining protective immunity. Here we investigated qualitatively the plasmablast responses by measuring from single cells within hours of sampling the affinity of their secreted antibody for the SARS-CoV-2 spike receptor binding domain in cohorts of BNT162b2-vaccinated naive and COVID-19-recovered individuals. Using a unique droplet microfluidic and imaging approach, we analyzed >4,000 single IgG-secreting cells revealing high inter-individual variability in affinity for RBD with variations over 4 logs. High-affinity plasmablasts were induced by BNT162b2 vaccination against Hu-1 and Omicron RBD but disappeared quickly thereafter, whereas low-affinity plasmablasts represented >65% of the plasmablast response at all timepoints. Our droplet-based method thus proves efficient at fast and qualitative immune monitoring and should be helpful for optimization of vaccination protocols.
Authors
Matteo Broketa, Aurélien Sokal, Michael Mor, Pablo Canales-Herrerias, Angga Perima, Annalisa Meola, Ignacio Fernández, Bruno Iannascoli, Guilhem Chenon, Alexis Vandenberghe, Laetitia Languille, Marc Michel, Bertrand Godeau, Sebastien Gallien, Giovanna Melica, Marija Backovic, Felix A. Rey, Jean Baudry, Natalia T. Freund, Matthieu Mahevas, Pierre Bruhns
Abstract
While the development of different vaccines slowed the dissemination of SARS-CoV-2, the occurrence of breakthrough infections has continued to fuel the COVID-19 pandemic. To at least secure partial protection in majority of the population through one dose of a COVID-19 vaccine, delayed administration of boosters has been implemented in many countries. However, waning immunity and emergence of new variants of SARS-CoV-2 suggest that such measures may induce breakthrough infections due to intermittent lapses in protection. Optimizing vaccine dosing schedules to ensure prolonged continuity in protection could thus help control the pandemic. We developed a mechanistic model of immune response to vaccines as an in-silico tool for dosing schedule optimization. The model was calibrated with clinical datasets of acquired immunity to COVID-19 mRNA vaccines in healthy and immunocompromised subjects and showed robust validation by accurately predicting neutralizing antibody kinetics in response to multiple doses of COVID-19 mRNA vaccines. Importantly, by estimating population vulnerability to breakthrough infections, we predicted tailored vaccination dosing schedules to minimize breakthrough infections, especially for immunocompromised subjects. We identified that the optimal vaccination schedules vary from CDC-recommended dosing, suggesting that the model is a valuable tool to optimize vaccine efficacy outcomes during future outbreaks.
Authors
Prashant Dogra, Carmine Schiavone, Zhihui Wang, Javier Ruiz-Ramírez, Sergio Caserta, Daniela I. Staquicini, Christopher Markosian, Jin Wang, H. Dirk Sostman, Renata Pasqualini, Wadih Arap, Vittorio Cristini
Abstract
BACKGROUND. The Omicron BA.5 subvariant of SARS-CoV-2 markedly escapes neutralizing antibodies induced by vaccination due to mutations in the Spike (S) protein. Solid organ transplant recipients (SOTRs) suffer high COVID-19 morbidity and demonstrate poor Omicron strain recognition after COVID-19 vaccination. T cell responses may provide a crucial second line of defense. Therefore, it is critical to understand which vaccine regimens induce robust, conserved T cell responses. METHODS. We evaluated anti-S IgG titers, subvariant pseudo-neutralization, and S-specific CD4+ and CD8+ T cell responses from SOTRs in a national, prospective observational trial (n=75). Participants were selected if they received 3 doses of mRNA (homologous boosting) or two doses of mRNA followed by Ad26.COV2.S (heterologous boosting). RESULTS. Homologous boosting with three mRNA doses induced the highest anti-S IgG titers. However, antibodies induced by both vaccine regimens demonstrated significantly lower pseudo-neutralization against BA.5 compared to the ancestral strain. In contrast, vaccine-induced S-specific T cells maintained cross-reactivity against BA.5 compared to ancestral recognition. Homologous boosting induced higher frequencies of activated polyfunctional CD4+ T cell responses, with polyfunctional IL-21+ peripheral T follicular helper cells increased in mRNA-1273 compared to BNT¬¬162b2. IL-21+ cells robustly correlated with antibody titers. Heterologous boosting with Ad26.COV2.S did not increase CD8+ responses compared to homologous boosting. CONCLUSIONS. These data demonstrate that boosting with the ancestral strain can induce cross-reactive T cell responses against emerging variants of concern in SOTRs, but alterative vaccine strategies are required to induce robust CD8+ T cell responses. TRIAL REGISTRATION. IRB00248540 FUNDING. U01AI138897, U54CA260492, Emory COVID-19 research repository
Authors
Elizabeth A. Thompson, Wabathi Ngecu, Laila Stoddart, T. Scott Johnston, Amy Chang, Katherine Cascino, Jennifer L. Alejo, Aura T. Abedon, Hady Samaha, Nadine Rouphael, Aaron A.R. Tobian, Dorry L. Segev, William A. Werbel, Andrew H. Karaba, Joel N. Blankson, Andrea L. Cox
Abstract
As the COVID-19 pandemic continues, long-term immunity against SARS-CoV-2 will be globally important. Official weekly cases have not dropped below 2 million since September of 2020, and continued emergence of novel variants have created a moving target for our immune systems and public health alike. The temporal aspects of COVID-19 immunity, particularly from repeated vaccination and infection, are less well understood than short-term vaccine efficacy. In this study, we explore the impact of combined vaccination and infection, also known as hybrid immunity, and the timing thereof on the quality and quantity of antibodies elicited in a cohort of 96 health care workers. We find robust neutralizing antibody responses among those with hybrid immunity against all variants, including Omicron BA.2, and significantly improved neutralizing titers with longer vaccine-infection intervals up to 400 days. These results indicate that anti-SARS-CoV-2 antibody responses undergo continual maturation following primary exposure by either vaccination or infection for at least 400 days after last antigen exposure. We show that neutralizing antibody responses improved upon secondary boosting with greater potency seen after extended intervals. Our findings may also extend to booster vaccine doses, a critical consideration in future vaccine campaign strategies.
Authors
Timothy A. Bates, Hans C. Leier, Savannah K. McBride, Devin Schoen, Zoe L. Lyski, David D. Xthona Lee, William B. Messer, Marcel E. Curlin, Fikadu G. Tafesse
Abstract
Modifications to vaccine delivery that increase serum antibody longevity are of great interest for maximizing efficacy. We have previously shown that a delayed fractional (DFx) dosing schedule (0-1-6 month) — using AS01B-adjuvanted RH5.1 malaria antigen — substantially improves serum IgG durability as compared with monthly dosing (0-1-2 month; NCT02927145). However, the underlying mechanism and whether there are wider immunological changes with DFx dosing were unclear. Here, PfRH5-specific Ig and B cell responses were analyzed in depth through standardized ELISAs, flow cytometry, systems serology, and single-cell RNA-Seq (scRNA-Seq). Data indicate that DFx dosing increases the magnitude and durability of circulating PfRH5-specific B cells and serum IgG1. At the peak antibody magnitude, DFx dosing was distinguished by a systems serology feature set comprising increased FcRn binding, IgG avidity, and proportion of G2B and G2S2F IgG Fc glycans, alongside decreased IgG3, antibody-dependent complement deposition, and proportion of G1S1F IgG Fc glycan. Concomitantly, scRNA-Seq data show a higher CDR3 percentage of mutation from germline and decreased plasma cell gene expression in circulating PfRH5-specific B cells. Our data, therefore, reveal a profound impact of DFx dosing on the humoral response and suggest plausible mechanisms that could enhance antibody longevity, including improved FcRn binding by serum Ig and a potential shift in the underlying cellular response from circulating short-lived plasma cells to nonperipheral long-lived plasma cells.
Authors
Carolyn M. Nielsen, Jordan R. Barrett, Christine Davis, Jonathan K. Fallon, Cyndi Goh, Ashlin R. Michell, Catherine Griffin, Andrew Kwok, Carolin Loos, Samuel Darko, Farida Laboune, Mehmet Tekman, Ababacar Diouf, Kazutoyo Miura, Joseph R. Francica, Amy Ransier, Carole A. Long, Sarah E. Silk, Ruth O. Payne, Angela M. Minassian, Douglas A. Lauffenburger, Robert A. Seder, Daniel C. Douek, Galit Alter, Simon J. Draper
Abstract
BACKGROUND. To minimize COVID-19 pandemic burden and spread, 3-dose vaccination campaigns commenced worldwide. Since patients who are pregnant are at increased risk for severe disease, they were recently included in that policy, despite the lack of available evidence regarding the impact of a third boosting dose during pregnancy, underscoring the urgent need for relevant data. We aimed to characterize the effect of the third boosting dose of mRNA Pfizer BNT162b2 vaccine in pregnancy.METHODS. We performed a prospective cohort study of anti–SARS-CoV-2 antibody titers (n = 213) upon delivery in maternal and cord blood of naive fully vaccinated parturients who received a third dose (n = 86) as compared with 2-dose recipients (n = 127).RESULTS. We found a robust surge in maternal and cord blood levels of anti–SARS-CoV-2 titers at the time of delivery, when comparing pregnancies in which the mother received a third boosting dose with 2-dose recipients. The effect of the third boosting dose remained significant when controlling for the trimester of last exposure, suggesting additive immunity extends beyond that obtained after the second dose. Milder side effects were reported following the third dose, as compared with the second vaccine dose, among the fully vaccinated group.CONCLUSION. The third boosting dose of mRNA Pfizer BNT162b2 vaccine augmented maternal and neonatal immunity with mild side effects. These data provide evidence to bolster clinical and public health guidance, reassure patients, and increase vaccine uptake among patients who are pregnant.FUNDING. Israel Science Foundation KillCorona grant 3777/19; Research grant from the “Ofek” Program of the Hadassah Medical Center.
Authors
Adva Cahen-Peretz, Lilah Tsaitlin-Mor, Hadas Allouche Kam, Racheli Frenkel, Maor Kabessa, Sarah M. Cohen, Michal Lipschuetz, Esther Oiknine-Djian, Sapir Lianski, Debra Goldman-Wohl, Asnat Walfisch, Michal Kovo, Michal Neeman, Dana G. Wolf, Simcha Yagel, Ofer Beharier
Abstract
Consecutive mRNA vaccinations against SARS-CoV-2 reinforced both innate and adaptive immune responses. However, it remains unclear whether the enhanced innate immune responses are mediated by epigenetic regulation and, if so, whether these effects persist. Using mass cytometry, RNA-seq, and ATAC-seq, we show that BNT162b2 mRNA vaccination upregulated antiviral and IFN-stimulated gene expression in monocytes with greater effects after the second vaccination than those after the first vaccination. Transcription factor-binding motif analysis also revealed enriched IFN regulatory factors and PU.1 motifs in accessible chromatin regions. Importantly, although consecutive BNT162b2 mRNA vaccinations boosted innate immune responses and caused epigenetic changes in isolated monocytes, we showed that these effects occur only transiently and disappear 4 weeks after the second vaccination. Furthermore, single-cell RNA sequencing analysis revealed that a similar gene signature was impaired in the monocytes of unvaccinated COVID-19 patients with acute respiratory distress syndrome. These results reinforce the importance of the innate immune response in the determination of COVID-19 severity but indicate that, unlike adaptive immunity, innate immunity is not unexpectedly sustained even after consecutive vaccination. This study, which focuses on innate immmune memory, may provide novel insights into the vaccine development against infectious diseases.
Authors
Yuta Yamaguchi, Yasuhiro Kato, Ryuya Edahiro, Jonas N. Søndergaard, Teruaki Murakami, Saori Amiya, Shinichiro Nameki, Yuko Yoshimine, Takayoshi Morita, Yusuke Takeshima, Shuhei Sakakibara, Yoko Naito, Daisuke Motooka, Yu-Chen Liu, Yuya Shirai, Yasutaka Okita, Jun Fujimoto, Haruhiko Hirata, Yoshito Takeda, James B. Wing, Daisuke Okuzaki, Yukinori Okada, Atsushi Kumanogoh
Abstract
Since the introduction of new generation pertussis vaccines, resurgence of pertussis is observed in many developed countries. Former whole-cell pertussis vaccines (wP) are able to protect against disease and transmission but have been replaced in several industrialized countries because of their reactogenicity and adverse effects. Current acellular pertussis vaccines (aP), made of purified proteins of Bordetella pertussis, are efficient at preventing disease but fail to induce long-term protection from infection. While the systemic and mucosal T cell immunity induced by the two types of vaccines has been well described, much less is known concerning B cell responses. Taking advantage of an inducible AID fate-mapping mouse model, we compared effector and memory B cells induced by the two classes of vaccines and showed that a stronger and broader memory B cell and plasma cell response is achieved by a wP prime. We also observed that homologous or heterologous vaccine combinations that include at least one wP administration, even as a booster dose, are sufficient to induce this broad effector response, thus highlighting its dominant imprint on the B cell profile. Finally, we describe the settlement of memory B cell populations in the lung following subcutaneous wP prime vaccination.
Authors
Viviana Valeri, Akhésa Sochon, Clara Cousu, Pascal Chappert, Damiana Lecoeuche, Pascal Blanc, Jean-Claude Weill, Claude-Agnès Reynaud
Abstract
Lentiviral vector-based dendritic cell vaccines induce protective T cell responses against viral infection and cancer in animal models. In this study, we tested whether preventative and therapeutic vaccination could be achieved by direct injection of antigen expressing lentiviral vector, obviating the need for ex vivo transduction of dendritic cells. Injected lentiviral vector preferentially transduced splenic dendritic cells and resulted in long-term expression. Injection of a lentiviral vector encoding an MHC class I restricted T cell epitope of LCMV and CD40L induced an antigen-specific cytolytic CD8+ T lymphocyte response that protected the mice from infection. The injection of chronically infected mice with a lentiviral vector encoding LCMV MHC class I and II T cell epitopes and a soluble PD-1 microbody rapidly cleared the virus. Vaccination by direct injection of lentiviral vector was more effective in SAMHD1 knock-out mice, suggesting that lentiviral vectors containing Vpx, a lentiviral protein that increases the efficiency of dendritic cell transduction by inducing the degradation of SAMHD1, would be an effective strategy for the treatment of chronic disease in humans.
Authors
Takuya Tada, Thomas D. Norton, Rebecca Leibowitz, Nathaniel R. Landau
Abstract
The immune factors associated with impaired SARS-CoV-2 vaccine response in the elderly are mostly unknown. We studied >60 and <60 years old people vaccinated with SARS-CoV-2 BNT162b2 mRNA before and after the first and second dose. Aging was associated with a lower anti-RBD IgG levels and a decreased magnitude and polyfunctionality of SARS-CoV-2 specific T cell response. The dramatic decrease in thymic function in aged people with >60 years of age, which fueled alteration in T cell homeostasis, and lower CD161+ T cell levels were associated with decreased T cell response two months after vaccination. Additionally, a deficient dendritic cell (DC) homing, activation and Toll like receptor (TLR)-mediated function, along with a proinflammatory functional profile in monocytes, were observed in the >60 years old group, which was also related to lower specific T cell response after vaccination. These findings might be relevant for the improvement of the current vaccination strategies and for the development of new vaccine prototypes.
Authors
Joana Vitallé, Alberto Pérez-Gómez, Francisco José Ostos, Carmen Gasca-Capote, Maria Reyes Jiménez-Leon, Sara Bachiller, Inmaculada Rivas-Jeremías, Maria del Mar Silva-Sánchez, Anabel M. Ruiz-Mateos, María Ángeles Martín-Sánchez, Luis Fernando López-Cortes, Mohammed Rafii El Idrissi Benhnia, Ezequiel Ruiz-Mateos
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