mRNA vaccines are likely to become widely used for the prevention of infectious diseases in the future. Nevertheless, a notable gap exists in mechanistic data, particularly concerning the potential effects of sequential mRNA immunization or preexisting immunity on the early innate immune response triggered by vaccination. In this study, healthy adults, with or without documented prior SARS-CoV-2 infection, were vaccinated with the BNT162b2/Comirnaty mRNA vaccine. Prior infection conferred significantly stronger induction of proinflammatory and type I IFN–related gene signatures, serum cytokines, and monocyte expansion after the prime vaccination. The response to the second vaccination further increased the magnitude of the early innate response in both study groups. The third vaccination did not further increase vaccine-induced inflammation. In vitro stimulation of PBMCs with TLR ligands showed no difference in cytokine responses between groups, or before or after prime vaccination, indicating absence of a trained immunity effect. We observed that levels of preexisting antigen-specific CD4 T cells, antibody, and memory B cells correlated with elements of the early innate response to the first vaccination. Our data thereby indicate that preexisting memory formed by infection may augment the innate immune activation induced by mRNA vaccines.
Fredrika Hellgren, Anja Rosdahl, Rodrigo Arcoverde Cerveira, Klara Lenart, Sebastian Ols, Yong-Dae Gwon, Seta Kurt, Anna Maria Delis, Gustav Joas, Magnus Evander, Johan Normark, Clas Ahlm, Mattias N.E. Forsell, Sara Cajander, Karin Loré
A systems analysis was conducted to determine the potential molecular mechanisms underlying differential immunogenicity and protective efficacy results of a clinical trial of the radiation-attenuated whole sporozoite PfSPZ Vaccine in African infants. Innate immune activation and myeloid signatures at pre-vaccination baseline correlated with protection from Pf parasitemia in placebo controls. These same signatures were associated with susceptibility to parasitemia among infants who received the highest and most protective PfSPZ Vaccine dose. Machine learning identified spliceosome, proteosome, and resting dendritic cell signatures as pre-vaccination features predictive of protection after highest-dose PfSPZ vaccination, whereas baseline CSP-specific IgG predicted non-protection. Pre-vaccination innate inflammatory and myeloid signatures were associated with higher sporozoite-specific IgG Ab response but undetectable PfSPZ-specific CD8+ T-cell responses post-vaccination. Consistent with these human data, innate stimulation in vivo conferred protection against infection by sporozoite injection in malaria-naïve mice while diminishing the CD8+ T-cell response to radiation-attenuated sporozoites. These data suggest a dichotomous role of innate stimulation for malaria protection and induction of protective immunity of whole-sporozoite malaria vaccines. The uncoupling of vaccine-induced protective immunity achieved by Abs from more protective CD8+ T cell responses suggest that PfSPZ Vaccine efficacy in malaria-endemic settings may be constrained by opposing antigen presentation pathways.
Leetah Senkpeil, Jyoti Bhardwaj, Morgan R. Little, Prasida Holla, Aditi Upadhye, Elizabeth M. Fusco, Phillip A. Swanson II, Ryan E. Wiegand, Michael D. Macklin, Kevin Bi, Barbara J. Flynn, Ayako Yamamoto, Erik L. Gaskin, D. Noah Sather, Adrian L. Oblak, Edward Simpson, Hongyu Gao, W. Nicholas Haining, Kathleen B. Yates, Xiaowen Liu, Tooba Murshedkar, Thomas L. Richie, B. Kim Lee Sim, Kephas Otieno, Simon Kariuki, Xiaoling Xuei, Yunlong Liu, Rafael B. Polidoro, Stephen L. Hoffman, Martina Oneko, Laura C. Steinhardt, Nathan W. Schmidt, Robert A. Seder, Tuan M. Tran
Understanding the immune responses to SARS-CoV-2 vaccination is critical to optimizing vaccination strategies for individuals with autoimmune diseases, such as systemic lupus erythematosus (SLE). Here, we comprehensively analyzed innate and adaptive immune responses in 19 patients with SLE receiving a complete 2-dose Pfizer-BioNTech mRNA vaccine (BNT162b2) regimen compared with a control cohort of 56 healthy control (HC) volunteers. Patients with SLE exhibited impaired neutralizing antibody production and antigen-specific CD4+ and CD8+ T cell responses relative to HC. Interestingly, antibody responses were only altered in patients with SLE treated with immunosuppressive therapies, whereas impairment of antigen-specific CD4+ and CD8+ T cell numbers was independent of medication. Patients with SLE also displayed reduced levels of circulating CXC motif chemokine ligands, CXCL9, CXCL10, CXCL11, and IFN-γ after secondary vaccination as well as downregulation of gene expression pathways indicative of compromised innate immune responses. Single-cell RNA-Seq analysis reveals that patients with SLE showed reduced levels of a vaccine-inducible monocyte population characterized by overexpression of IFN-response transcription factors. Thus, although 2 doses of BNT162b2 induced relatively robust immune responses in patients with SLE, our data demonstrate impairment of both innate and adaptive immune responses relative to HC, highlighting a need for population-specific vaccination studies.
Kavita Y. Sarin, Hong Zheng, Yashaar Chaichian, Prabhu S. Arunachalam, Gayathri Swaminathan, Alec Eschholz, Fei Gao, Oliver F. Wirz, Brandon Lam, Emily Yang, Lori W. Lee, Allan Feng, Matthew A. Lewis, Janice Lin, Holden T. Maecker, Scott D. Boyd, Mark M. Davis, Kari C. Nadeau, Bali Pulendran, Purvesh Khatri, Paul J. Utz, Lisa C. Zaba
SARS-CoV-2 spike-based vaccines are used to control the COVID-19 pandemic. However, emerging variants became resistant to antibody neutralization and further mutations may lead to full resistance. We tested whether T cells alone could provide protection without antibodies. We designed a T cell-based vaccine in which SARS-CoV-2 spike sequences were rearranged and attached to ubiquitin. Immunization of mice with the vaccine induced no specific antibodies but strong specific T cell responses. We challenged mice with SARS-CoV-2 wild-type strain or an Omicron variant after the immunization and monitored survival or viral titers in the lungs. The mice were significantly protected against death and weight loss caused by SARS-CoV-2 wild-type strain, and the viral titers in the lungs of mice challenged with SARS-CoV-2 wild-type or the Omicron variant were significantly reduced. Importantly, depletion of CD4+ or CD8+ T cells led to significant loss of the protection. Our analyses of spike protein sequences of the variants indicated that fewer than 1/3 presented by dominant HLA alleles were mutated and that most of the mutated epitopes were in subunit 1 region. As subunit 2 region is conservative, the vaccines targeting spike protein are expected to protect against future variants due to the T cell responses.
Juan Shi, Jian Zheng, Xiujuan Zhang, Wanbo Tai, Ryan Compas, Jack C. Deno, Natalie Jachym, Abhishek K. Verma, Gang Wang, Xiaoqing Guan, Abby E. Odle, Yushun Wan, Fang Li, Stanley Perlman, Liang Qiao, Lanying Du
Functional avidity is supposed to critically shape the quality of immune responses, thereby impacting host protection against infectious agents including SARS-CoV2. Here we show that after human SARS-CoV2 vaccination, a large portion of high-avidity spike-specific CD4+ T cells lose CD3 expression after in vitro activation. The CD3- subset is enriched for cytokine positive cells, including elevated per-cell expression levels, and shows increased polyfunctionality. Assessment of key metabolic pathways by flow cytometry revealed that superior functionality is accompanied by a shift towards fatty acid-synthesis at the expense of their oxidation, whereas glucose transport and glycolysis were similarly regulated in SARS-CoV2-specific CD3- and CD3+ subsets. As opposed to their CD3+ counterparts, frequencies of vaccine-specific CD3- T cells positively correlate with both the size of the naïve CD4+ T cell pool and vaccine-specific IgG levels. Moreover, their frequencies negatively correlate with advancing age and are impaired in patients under immunosuppressive therapy. Typical recall-antigen-reactive T cells show a comparable segregation into functionally and metabolically distinct CD3+ and CD3- subsets, but are quantitatively maintained upon ageing, likely due to earlier recruitment in life. In summary, our data identify CD3- T helper cells as correlates of high quality immune responses that are impaired in at-risk populations.
Arne Sattler, Stefanie Gamradt, Vanessa Proß, Linda Marie Laura Thole, An He, Eva Vanessa Schrezenmeier, Katharina Jechow, Stefan M. Gold, Soeren Lukassen, Christian Conrad, Katja Kotsch
Nipah virus (NiV), a bat-borne paramyxovirus, results in neurological and respiratory diseases with high mortality in humans and animals. Developing vaccines is crucial against the diseases. Previous few studies focused on fusion (F) protein alone as the immunogen. Numerous NiV strains have been identified, including two representative strains from Malaysia (NiV-M) and Bangladesh (NiV-B), which differ significantly from the other. In this study, an F protein sequence with the potential to prevent different NiV strain infections was designed by bioinformatics analysis after an in-depth study of NiV sequences in GenBank. Then, a chimpanzee adenovirus vector vaccine and a DNA vaccine were developed. High levels of immune responses were detected by AdC68-F, pVAX1-F and a prime-boost strategy (pVAX1-F/AdC68-F) in mice. After high titers of humoral responses were induced, the hamsters were challenged by the lethal NiV-M and NiV-B strains, respectively. It was reassuring that the vaccinated hamsters did not show any clinical signs and survived 21 days after infection with either strain of NiV, and no virus was detected in different tissues either. These results indicated that vaccines provided complete protection against representative strains of NiV infection and had the potential to be developed as a broad-spectrum vaccine for human use.
Mingqing Lu, Yanfeng Yao, Hang Liu, Xuekai Zhang, Xuejie Li, Yuanhua Liu, Yun Peng, Tong Chen, Yun Sun, Ge Gao, Miaoyu Chen, Jiaxuan Zhao, XiaoYu Zhang, Chunhong Yin, Weiwei Guo, Peipei Yang, Xue Hu, Juhong Rao, Entao Li, Gary Wong, Zhiming Yuan, Sandra Chiu, Chao Shan, Jiaming Lan
SARS-CoV-2 is the third zoonotic coronavirus to cause a major outbreak in humans in recent years, and many more SARS-like coronaviruses with pandemic potential are circulating in several animal species. Vaccines inducing T cell immunity against broadly conserved viral antigens may protect against hospitalisation and death caused by outbreaks such viruses. We report the design and pre-clinical testing of two T-cell-based pan-sarbecovirus vaccines, based on conserved regions within viral proteins of sarbecovirus isolates of human and other carrier animals, like bats and pangolins. One vaccine (CoVAX_ORF1ab) encoded antigens derived from non-structural proteins, the other (CoVAX_MNS) antigens from structural proteins. Both multi-antigen DNA vaccines contained a large set of antigens shared across sarbecoviruses and were rich in predicted and experimentally validated human T cell epitopes. In mice, the multi-antigen vaccines generated both CD8 and CD4 T cell responses to shared epitopes. Upon encounter of full-length spike antigen, CoVAX_MNS-induced CD4 T cells were responsible for accelerated CD8 T cell and IgG antibody responses specific to the incoming spike, irrespective of its sarbecovirus origin. Finally, both vaccines elicited partial protection against a lethal SARS-CoV-2 challenge in human-ACE2-transgenic mice. These results support clinical testing of this universal sarbecovirus vaccine for pandemic preparedness.
Jeroen van Bergen, Marcel Camps, Iris N. Pardieck, Dominique Veerkamp, Wing Yan Leung, Anouk A. Leijs, Sebenzile K. Myeni, Marjolein Kikkert, Ramon Arens, Gerben C. Zondag, Ferry Ossendorp
Given the resurgence of pertussis, several countries have introduced maternal tetanus, diphtheria, and acellular pertussis (aP) vaccination during pregnancy to protect young infants against severe pertussis. Although protective against the disease, the effect of maternal aP vaccination on bacterial colonization of the offspring is unknown. Here, we used a mouse model to demonstrate that maternal aP immunization, either before or during pregnancy, protects pups from lung colonization by Bordetella pertussis. However, it substantially prolongs nasal carriage by inhibiting the recruitment of IL-17-producing resident memory T cells and ensuing neutrophil influx in the nasal tissue upon B. pertussis infection, especially of those with pro-inflammatory and cytotoxic properties. Prolonged nasal carriage after aP vaccination is due to IL-4 signaling, as it is abolished in IL-4Ra-/- mice. The effect of maternal aP vaccination can be transferred transplacentally to the offspring or by breastfeeding and is long-lasting, as it persists into adulthood. Maternal aP vaccination may thus potentially augment the B. pertussis reservoir.
Violaine Dubois, Jonathan Chatagnon, Manon Depessemier, Camille Locht
Antibodies capable of neutralising SARS-CoV-2 are well studied, but Fc receptor-dependent antibody activities that can also significantly impact the course of infection have not been studied in such depth. As most SARS-CoV-2 vaccines induce only anti-spike antibodies, here we investigated spike-specific antibody-dependent cellular cytotoxicity (ADCC). Vaccination produced antibodies that weakly induced ADCC, however, antibodies from individuals who were infected prior to vaccination (‘hybrid’ immunity) elicited strong anti-spike ADCC. Quantitative and qualitative aspects of humoral immunity contributed to this capability, with infection skewing IgG antibody production towards S2, vaccination skewing towards S1 and hybrid immunity evoking strong responses against both domains. Antibodies targeting both spike domains support strong antibody-dependent NK cell activation, with three regions of antibody reactivity outside the receptor-binding domain (RBD) corresponding with potent anti-spike ADCC. Consequently, ADCC induced by hybrid immunity with ancestral antigen was conserved against variants containing neutralisation escape mutations in the RBD. Induction of antibodies recognising a broad range of spike epitopes and eliciting strong and durable ADCC may partially explain why hybrid immunity provides superior protection against infection and disease than vaccination alone, and demonstrates that spike-only subunit vaccines would benefit from strategies that induce combined anti-S1 and S2 antibody responses.
Michael D. Grant, Kirsten Bentley, Ceri A. Fielding, Keeley M. Hatfield, Danielle P. Ings, Debbie Harnum, Eddie C.Y. Wang, Richard J. Stanton, Kayla A. Holder
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder that causes debilitating swelling and destruction of the joints. People with RA are treated with drugs that actively suppress one or more parts of their immune system, and these may alter their response to vaccination against SARS-CoV-2. In this study, we analyzed blood samples from a cohort of RA subjects after receiving a 2-dose mRNA COVID-19 vaccine regimen. Our data show that individuals on the CTLA4-Ig therapy abatacept have reduced levels of SARS-CoV-2-neutralizing antibodies after vaccination. At a cellular level, these subjects show reduced activation and class-switching of SARS-CoV-2-specific B cells, as well as reduced numbers and impaired helper cytokine production by SARS-CoV-2-specific CD4+ T cells. Individuals on methotrexate showed similar but less severe defects in vaccine response, whereas individuals on the B cell-depleting therapy rituximab had a near-total loss of antibody production after vaccination. These data define a specific cellular phenotype associated with impaired response to SARS-CoV-2 vaccination in RA subjects on different immune-modifying therapies, and help inform efforts to improve vaccination strategies in this vulnerable population.
Samuel D Klebanoff, Lauren B. Rodda, Chihiro Morishima, Mark H. Wener, Yevgeniy Yuzefpolskiy, Estelle Bettelli, Jane H. Buckner, Cate Speake, Marion Pepper, Daniel J. Campbell
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