Whole sporozoite vaccines engender sterilizing immunity against malaria in animal models and importantly, in humans. Gene editing allows for the removal of specific parasite genes, enabling generation of genetically attenuated parasite (GAP) strains for vaccination. Using rodent malaria parasites, we have previously shown that late liver stage-arresting replication-competent (LARC) GAPs confer superior protection when compared to early liver stage-arresting replication-deficient (EARD) GAPs and radiation-attenuated sporozoites. However, generating a LARC GAP in the human malaria parasite Plasmodium falciparum (Pf) has been challenging. Here we report the generation and characterization of an unprecedented Pf LARC GAP generated by targeted gene deletion of the Mei2 gene; Pf mei2–. Robust exoerythrocytic schizogony with extensive cell growth and DNA replication was observed for Pf mei2- liver stages in human liver-chimeric mice. However, Pf mei2– liver stages failed to complete development and did not form infectious exo-erythrocytic merozoites, thereby preventing their transition to asexual blood stage infection. Therefore, Pf mei2– is a replication-competent, attenuated human malaria parasite strain with potentially increased potency, useful for vaccination to protect against Pf malaria infection.
Debashree Goswami, William Betz, Navin K. Locham, Chaitra Parthiban, Carolyn Brager, Carola Schäfer, Nelly Camargo, Thao Nguyen, Spencer Y. Kennedy, Sean C. Murphy, Ashley M. Vaughan, Stefan H.I. Kappe
Background: HVTN 098, a randomized, double-blind, placebo-controlled trial, evaluated the safety, tolerability and immunogenicity of PENNVAX®-GP HIV DNA vaccine, administered with or without plasmid IL-12 (pIL-12), via intradermal (ID) or intramuscular (IM) electroporation (EP) in healthy, HIV-uninfected adults. The study tested whether PENNVAX®-GP delivered via ID/EP at 1/5th the dose could elicit equivalent immune responses to delivery via IM/EP, and if inclusion of pIL-12 provided additional benefit. Methods: Participants received DNA encoding HIV-1 env/gag/pol in three groups: 1.6mg ID (ID no IL-12 group, n=20), 1.6mg ID + 0.4mg pIL-12 (ID+IL-12 group, n=30), 8mg IM + 1mg pIL-12 (IM+IL-12 group, n=30) or placebo (n=9) via EP at 0, 1, 3 and 6 months. Results of cellular and humoral immunogencity assessments are reported. Results: Following vaccination, the frequency of responders (response rate) to any HIV protein based on CD4+ T-cells expressing IFN-γ and/or IL-2 was 96% for both the ID+IL-12 and IM+IL-12 groups; CD8+ T-cell response rates were 64% and 44%, respectively. For ID delivery, the inclusion of pIL-12 increased CD4+ T-cell response rate from 56% to 96%. The frequency of responders was similar (>90%) for IgG binding Ab to gp140 consensus Env across all groups, but the magnitude was higher in the ID+IL-12 group compared to the IM+IL-12 group. Conclusion: PENNVAX®-GP DNA induced robust cellular and humoral immune responses, demonstrating that immunogenicity of DNA vaccines can be enhanced by EP route and inclusion of pIL-12. ID/EP was dose-sparing, inducing equivalent, or in some aspects superior, immune responses compared to IM/EP. Trial registration: ClinicalTrials.gov NCT02431767 Funding: This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID, https://www.niaid.nih.gov/) U.S. Public Health Service Grants UM1 AI068618 [LC: HIV 75 Vaccine Trials Network], UM1 AI068614 [LOC: HIV Vaccine Trials Network], UM1 AI068635 76 [SDMC: HIV Vaccine Trials Network], , U01 AI069418-ˇ08 [Emory-ˇCDC Clinical Trials Unit], UM AI069511 [University of Rochester HIV/AIDS Clinical Trials Unit], UM1 AI069439 77 [Vanderbilt Clinical Trial Unit], UM1 AI069481 [Seattle-ˇLausanne Clinical Trials Unit] and HVDDT Contract HHSN2722008000063C (Inovio Pharmaceuticals). This work was also supported, in part, by IPCAVD award U19 AI09646-ˇ03 (DBW) and NIH award P01 AI120756 (GDT). The opinions expressed in this article are those of the authors and do not necessarily represent the official views of the NIAID or the National Institutes of Health (NIH).
Stephen DeRosa, Srilatha Edupuganti, Yunda Huang, Xue Han, Marnie Elizaga, Edith Swann, Laura Polakowski, Spyros A. Kalams, Michael C. Keefer, Janine Maenza, Yiwen Lu, Megan C. Wise, Jian Yan, Matthew P. Morrow, Amir S. Khan, Jean Boyer, Laurent M. Humeau, Scott White, Michael N. Pensiero, Niranjan Y. Sardesai, Mark Bagarazzi, David B. Weiner, Guido Ferrari, Georgia Tomaras, David Montefiori, Lawrence Corey, M. Juliana McElrath
Protein-based, self-assembling nanoparticles elicit superior immunity compared with soluble protein vaccines, but the immune mechanisms underpinning this effect remain poorly defined. Here, we investigated the immunogenicity of a prototypic ferritin-based nanoparticle displaying influenza hemagglutinin (HA) in mice and macaques. Vaccination of mice with HA-ferritin nanoparticles elicited higher serum antibody titers and greater protection against experimental influenza challenge compared with soluble HA protein. Germinal centers in the draining lymph nodes were expanded and persistent following HA-ferritin vaccination, with greater deposition of antigen that colocalized with follicular dendritic cells. Our findings suggest that a highly ordered and repetitive antigen array may directly drive germinal centers through a B cell–intrinsic mechanism that does not rely on ferritin-specific T follicular helper cells. In contrast to mice, enhanced immunogenicity of HA-ferritin was not observed in pigtail macaques, where antibody titers and lymph node immunity were comparable to soluble vaccination. An improved understanding of factors that drive nanoparticle vaccine immunogenicity in small and large animal models will facilitate the clinical development of nanoparticle vaccines for broad and durable protection against diverse pathogens.
Hannah G. Kelly, Hyon-Xhi Tan, Jennifer A. Juno, Robyn Esterbauer, Yi Ju, Wenbo Jiang, Verena C. Wimmer, Brigette C. Duckworth, Joanna R. Groom, Frank Caruso, Masaru Kanekiyo, Stephen J. Kent, Adam K. Wheatley
Success of DC vaccines relies on the quality of antigen presentation, costimulation, lymph node migration, and the release of IL-12, in case of Th1 priming. Here, we provide evidence for interaction between the injected vaccine DCs with endogenous lymph node–resident DCs for Th1 induction. While migration of the injected DCs was essential for antigen delivery to the lymph node, the injected DCs contributed only partially to Th0 priming and were unable to instruct Th1 generation. Instead, we provide evidence that the lymph node–resident XCR1+ DCs are activated by the injected DCs to present the cognate antigen and release IL-12 for Th1 polarization. The timing of interactions in the draining lymph nodes appeared step-wise as (a) injected DCs with cognate T cells, (b) injected DCs with bystander DCs, and (c) bystander DCs with T cells. The transcriptome of the bystander DCs showed a downregulation of Treg- and Th2/Th9-inducing genes and self-antigen presentation, as well as upregulation of MHC class II and genes required for Th1 instruction. Together, these data show that injected mature lymph node migratory DCs direct T cell priming and bystander DC activation, but not Th1 polarization, which is mediated by endogenous IL-12p70+XCR1+ resident bystander DCs. Our results are of importance for clinical DC-based vaccinations against tumors where endogenous DCs may be functionally impaired by chemotherapy.
DiyaaElDin Ashour, Panagiota Arampatzi, Vladimir Pavlovic, Konrad U. Förstner, Tsuneyasu Kaisho, Andreas Beilhack, Florian Erhard, Manfred B. Lutz
BACKGROUND Obesity has been associated with attenuated vaccine responses and an increased risk of contracting pneumococcal pneumonia, but no study to our knowledge has assessed the impact of obesity and genetics on 23-valent pneumococcal vaccine (PPSV23) efficacy. We assessed the relationship of obesity (primary analysis) and stimulator of interferon genes (STING1) genotype (secondary analysis) on PPSV23 efficacy.METHODS Nonobese (BMI 22–25 kg/m2) and obese participants (BMI ≥30 kg/m2) were given a single dose of PPSV23. Blood was drawn immediately prior to and 4–6 weeks after vaccination. Serum samples were used to assess PPSV23-specific antibodies. STING1 genotypes were identified using PCR on DNA extracted from peripheral blood samples.RESULTS Forty-six participants were categorized as nonobese (n = 23; 56.5% women; mean BMI 23.3 kg/m2) or obese (n = 23; 65.2% women; mean BMI 36.3 kg/m2). Obese participants had an elevated fold change in vaccine-specific responses compared with nonobese participants (P < 0.0001). The WT STING1 group (R232/R232) had a significantly higher PPSV23 response than individuals with a single copy of HAQ-STING1 regardless of BMI (P = 0.0025). When WT was assessed alone, obese participants had a higher fold serotype-specific response compared with nonobese participants (P < 0.0001), but no difference was observed between obese and nonobese individuals with 1 HAQ allele (P = 0.693).CONCLUSIONS These observations demonstrate a positive association between obesity and PPSV23 efficacy specifically in participants with the WT STING1 genotype.TRIAL REGISTRATION ClinicalTrials.gov NCT02471014.FUNDING This research was supported by the NIH and the University of Florida MD-PhD Training Program.
Mathew Sebastian, Chu J. Hsiao, Hunter S. Futch, Robert S. Eisinger, Leanne Dumeny, Seema Patel, Mesfin Gobena, Divya S. Katikaneni, Joel Cohen, Anne-Marie Carpenter, Lisa Spiryda, Coy D. Heldermon, Lei Jin, Mark L. Brantly
Broadly neutralizing Abs targeting the HA stem can provide broad protection against different influenza subtypes, raising the question of how best to elicit such Abs. We have previously demonstrated that vaccination with pandemic live-attenuated influenza vaccine (pLAIV) establishes immune memory for HA head-specific Abs. Here, we determine the extent to which matched versus mismatched LAIV-inactivated subunit vaccine (IIV) prime-boost vaccination elicits stem-specific memory B cells and Abs. We vaccinated African green monkeys with H5N1 pLAIV-pIIV or H5N1 pLAIV followed by seasonal IIV (sIIV) or with H5N1 pLAIV alone and measured Abs and HA-specific B cell responses. While we observed an increase in stem-specific memory B cells, head-specific memory B cell responses were substantially higher than stem-specific responses and were dominant even following boost with mismatched IIV. Neutralizing Abs against heterologous influenza viruses were undetectable. Head-specific B cells from draining lymph nodes exhibited germinal center markers, while stem-specific B cells found in the spleen and peripheral blood did not. Thus, although mismatched prime-boost generated a pool of stem-specific memory B cells, head-specific B cells and serum Abs substantially dominated the immune response. These findings have implications for including full-length native HA in prime-boost strategies intended to induce stem-specific Abs for universal influenza vaccination.
Sinthujan Jegaskanda, Sarah F. Andrews, Adam K. Wheatley, Jonathan W. Yewdell, Adrian B. McDermott, Kanta Subbarao
Immune activation is associated with increased risk of tuberculosis (TB) disease in infants. We performed a case control analysis to identify drivers of immune activation and disease risk. Among 49 infants who developed TB disease over the first two years of life, and 129 matched controls who remained healthy, we found the cytomegalovirus (CMV) stimulated IFNγ response at age 4-6 months to be associated with CD8+ T cell activation (Spearmans rho, P = 6 x 10-8). A CMV specific IFNγ response was also associated with increased risk of developing TB disease (Conditional Logistic Regression, P = 0.043, OR 2.2, 95% CI 1.02-4.83), and shorter time to TB diagnosis (Log Rank Mantel-Cox P = 0.037). CMV positive infants who developed TB disease had lower expression of natural killer cell associated gene signatures and a lower frequency of CD3−CD4−CD8− lymphocytes. We identified transcriptional signatures predictive of risk of TB disease among CMV ELISpot positive (AUROC 0.98, accuracy 92.57%) and negative (AUROC 0.9, accuracy 79.3%) infants; the CMV negative signature validated in an independent infant study (AUROC 0.71, accuracy 63.9%). Understanding and controlling the microbial drivers of T cell activation, such as CMV, could guide new strategies for prevention of TB disease in infants.
Julius Müller, Rachel Tanner, Magali Matsumiya, Margaret A. Snowden, Bernard Landry, Iman Satti, Stephanie A. Harris, Matthew K. O'Shea, Lisa Stockdale, Leanne Marsay, Agnieszka Chomka, Rachel Harrington-Kandt, Zita-Rose Manjaly Thomas, Elena Stylianou, Vivek Naranbhai, Stanley Kimbung Mbandi, Mark Hatherill, Gregory Hussey, Hassan Mahomed, Michele Tameris, J. Bruce McClain, Willem A. Hanekom, Thomas G. Evans, Thomas J. Scriba, Helen McShane, Helen A. Fletcher
The adoptive cell transfer (ACT) of T cells targeting mutated neoantigens can cause objective responses in varieties of metastatic cancers, but the development of new T cell–based treatments relies on accurate animal models. To investigate the therapeutic effect of targeting a neoantigen with ACT, we used T cells from pmel-1 T cell receptor–transgenic mice, known to recognize a WT peptide, gp100, and a mutated version of the peptide that has higher avidity. We gene-engineered B16 cells to express the WT or mutated gp100 epitopes and found that pmel-1–specific T cells targeting a neoantigen tumor target augmented recognition as measured by IFN-γ production. Neoantigen expression by B16 also enhanced the capacity of pmel-1 T cells to trigger the complete and durable regression of large, established, vascularized tumor and required less lymphodepleting conditioning. Targeting neoantigen uncovered the possibility of using enforced expression of the IL-2Rα chain (CD25) in mutation-reactive CD8+ T cells to improve their antitumor functionality. These data reveal that targeting of “mutated-self” neoantigens may lead to improved efficacy and reduced toxicities of T cell–based cellular immunotherapies for patients with cancer.
Ken-ichi Hanada, Zhiya Yu, Gabrielle R. Chappell, Adam S. Park, Nicholas P. Restifo
Induction of a potent CD4 and CD8 T-cell response against tumor-specific and tumor-associated antigen is critical for eliminating tumor cells. Recent vaccination strategies have been hampered by an inefficacious and low amplitude immune response. Here we describe a self-adjuvanted chimeric protein vaccine platform to address these challenges, characterized by a multidomain construction incorporating (i) a cell penetrating peptide (CPP) allowing internalization of several multiantigenic Major Histocompatibility Complex (MHC)-restricted peptides within (ii) the multiantigenic domain (Mad) and (iii) a TLR2/4 agonist domain (TLRag). Functionality of the resulting chimeric protein is based on the combined effect of the above-mentioned three different domains for simultaneous activation of antigen presenting cells and antigen cross-presentation, leading to an efficacious multiantigenic and multiallelic cellular immune response. Helper and cytotoxic T-cell responses were observed against model-, neo- and self-antigens, and were highly potent in several murine tumor models. The safety and the immunogenicity of a human vaccine candidate designed for colorectal cancer treatment was demonstrated in a non-human primate model. This newly engineered therapeutic vaccine approach is promising for the treatment of poorly infiltrated tumors that do not respond to currently marketed immunotherapies.
Elodie Belnoue, Jean-François Mayol, Susanna Carboni, Wilma Di Berardino Besson, Eloise Dupuychaffray, Annika Nelde, Stefan Stevanovic, Marie-Laure Santiago-Raber, Paul R. Walker, Madiha Derouazi
Pathogen recognition receptor (PRR) agonists are currently being developed and tested as adjuvants in various formulations to optimize the immunogenicity and efficacy of vaccines. Using an original in vitro approach to prime naive precursors from unfractionated human peripheral blood mononuclear cells, we assessed the influence of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), a ligand for the stimulator of interferon genes (STING), on the induction of antigen-specific CD8+ T cells. We found that 2′3′-cGAMP and 3′3′-cGAMP were especially potent adjuvants in this system, driving the expansion and maturation of functionally replete antigen-specific CD8+ T cells via the induction of type I IFNs. The biological relevance of these findings was confirmed in vivo using two mouse models, in which 2′3′-cGAMP–adjuvanted vaccination elicited protective antitumor or antiviral CD8+ T cell responses. These results identify particular isoforms of cGAMP as effective adjuvants that may find utility in the development of novel immunotherapies and vaccines.
Alice Gutjahr, Laura Papagno, Francesco Nicoli, Tomohiro Kanuma, Nozomi Kuse, Mariela Pires Cabral-Piccin, Nicolas Rochereau, Emma Gostick, Thierry Lioux, Eric Perouzel, David A. Price, Masafumi Takiguchi, Bernard Verrier, Takuya Yamamoto, Stéphane Paul, Victor Appay
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