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.
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
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.
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
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.
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
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.
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
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.
Viviana Valeri, Akhésa Sochon, Clara Cousu, Pascal Chappert, Damiana Lecoeuche, Pascal Blanc, Jean-Claude Weill, Claude-Agnès Reynaud
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.
Takuya Tada, Thomas D. Norton, Rebecca Leibowitz, Nathaniel R. Landau
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.
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
Chikungunya virus (CHIKV) is a re-emerging mosquito-borne alphavirus responsible for numerous outbreaks. Chikungunya can cause debilitating acute and chronic disease. Thus, the development of a safe and effective CHIKV vaccine is an urgent global health priority.This study evaluated the effectiveness of the live-attenuated CHIKV vaccine VLA1553 against WT CHIKV infection by using passive transfer of sera from vaccinated volunteers to non-human primates (NHP) subsequently exposed to WT CHIKV and established a serological surrogate of protection. We demonstrated that human VLA1553 sera transferred to NHPs conferred complete protection from CHIKV viremia and fever after challenge with homologous WT CHIKV. In addition, serum transfer protected animals from other CHIKV associated clinical symptoms and from CHIKV persistence in tissue. Based on this passive transfer study, a 50% micro plaque reduction neutralization test titer of ≥150 was determined as a surrogate of protection which was supported by analysis of samples from a sero-epidemiological study.In conclusion, considering the unfeasibility of an efficacy trial due to the unpredictability and explosive, rapidly moving nature of chikungunya outbreaks, the definition of a surrogate of protection for VLA1553 is an important step towards vaccine licensure to reduce the medical burden caused by chikungunya.
Pierre Roques, Andrea Fritzer, Nathalie Dereuddre-Bosquet, Nina Wressnigg, Romana Hochreiter, Laetitia Bossevot, Quentin Pascal, Fabienne Guehenneux, Annegret Bitzer, Irena Corbic Ramljak, Roger Le Grand, Urban Lundberg, Andreas Meinke
In situ vaccination has demonstrated the feasibility of priming local immunity for systemic antitumor responses. Although direct intratumoral delivery of adjuvant is the mainstay, tumor-draining lymph nodes (TDLNs) also play essential roles in antitumor immunity. We report that directing an adjuvant to both tumors and TDLNs during in situ vaccination can induce robust antitumor responses. Conventional intratumoral dosing leads to tumor-limited delivery of agents; however, delivery to both tumors and TDLNs can be ensured through a micellar formation. The peritumoral delivery of micellar MEDI9197 (mcMEDI), a toll-like receptor 7/8 agonist, induced significantly stronger innate and adaptive immune responses than those on conventional dosing. Optimal dosing was crucial because excessive or insufficient accumulation of the adjuvant in the TDLNs compromised therapeutic efficacy. The combination of local mcMEDI therapy significantly improved the efficacy of systemic anti-programmed death receptor-1 therapy. These data suggest that rerouting adjuvants to tumors and TDLNs can augment the therapeutic efficacy of in situ vaccination.
Moonkyoung Jeong, Heegon Kim, Junyong Yoon, Dong-Hyun Kim, Ji-Ho Park
We have previously demonstrated that active immunization with the apolipoprotein B-100 (ApoB-100) peptide P210 reduces experimental atherosclerosis. To advance this immunization strategy to future clinical testing, we explored the possibility of delivering P210 as an antigen using nanoparticles, given this approach has now been used clinically. To that end, we first charactered the responses of T cells to P210 using PBMCs from human subjects with atherosclerotic cardiovascular disease (ASCVD). We then investigated the use of P210 in self-assembling peptide amphiphile micelles (P210-PAM) as a vaccine formulation to reduce atherosclerosis in ApoE-/- mice and its potential mechanisms of action. We also generated and characterized a humanized mouse model with chimeric HLA-A*02:01/Kb in ApoE-/- background to test the efficacy of P210-PAM immunization as a bridge for future clinical testing. P210 provoked T cell activation and memory response in PBMCs of human subjects with ASCVD. Dendritic cell uptake of P210-PAM and its co-staining with MHC-I molecules supported its use as a vaccine formulation. In ApoE-/- mice, immunization with P210-PAM dampened P210-specific CD4+ T cell proliferative response and CD8+ T cell cytolytic response, modulated macrophage phenotype, and significantly reduced aortic atherosclerosis. Potential clinical relevance of P210-PAM immunization was demonstrated by reduced atherosclerosis in the humanized ApoE-/- mouse model expressing chimeric HLA-A*02:01/Kb. Taken together, our data supports the experimental and translational use of P210-PAM as a potential vaccine candidate against human ASCVD.
Kuang-Yuh Chyu, Xiaoning Zhao, Jianchang Zhou, Paul C. Dimayuga, Nicole W.M. Lio, Bojan Cercek, Noah T. Trac, Eun Ji Chung, Prediman K. Shah
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