BACKGROUND. Long-term prognosis of WHO grade II low-grade glioma (LGG) is poor secondary to risk of recurrence and malignant transformation into high-grade glioma. Given the relatively intact immune system of patients with LGG and the slow tumor growth rate, vaccines are an attractive treatment strategy. METHODS. We conducted a pilot study to evaluate the safety and immunological effects of vaccination with GBM6-AD, lysate of an allogeneic glioblastoma stem cell line, with poly-ICLC in patients with LGG. Patients were randomized to receive the vaccines before surgery (Arm 1) or not (Arm 2) and all patients received adjuvant vaccine. Co-primary outcomes were to evaluate the safety and immune response in the tumor. RESULTS. A total of 17 eligible patients were enrolled – nine into Arm 1 and eight into Arm 2. This regimen was well-tolerated with no regimen-limiting toxicity. Neoadjuvant vaccination induced upregulation of type-1 cytokines and chemokines, and increased activated CD8+ T-cells in peripheral blood. Single-cell RNA/TCR-sequencing detected CD8+ T-cell clones that expanded with effector phenotype and migrated into tumor microenvironment (TME) in response to neoadjuvant vaccination. Mass cytometric analyses detected increased tissue resident-like CD8+ T-cells with effector memory phenotype in TME following the neoadjuvant vaccination. CONCLUSION. The current regimen induces effector CD8+ T-cell response in peripheral blood and enables vaccine-reactive CD8+ T-cells to migrate into TME. Further refinements of the regimen may have to be integrated into future strategies. TRIAL REGISTRATION. ClinicalTrials.gov NCT02549833. FUNDING. NIH (1R35NS105068, 1R21CA233856), Dabbiere Foundation, Parker Institute for Cancer Immunotherapy, and Daiichi Sankyo Foundation of Life Science.
Hirokazu Ogino, Jennie W. Taylor, Takahide Nejo, David Gibson, Payal B. Watchmaker, Kaori Okada, Atsuro Saijo, Meghan R. Tedesco, Anny Shai, Cynthia M. Wong, Jane E. Rabbitt, Michael R. Olin, Christopher L. Moertel, Yasuhiko Nishioka, Andres M. Salazar, Annette M. Molinaro, Joanna J. Phillips, Nicholas A. Butowski, Jennifer L. Clarke, Nancy Ann Oberheim Bush, Shawn L. Hervey-Jumper, Philip Theodosopoulos, Susan M. Chang, Mitchel S. Berger, Hideho Okada
Although Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccines have shown efficacy against SARS-CoV-2, it is unknown if coronavirus vaccines can also protect against other coronaviruses that may infect humans in the future. Here, we show that coronavirus vaccines elicit cross-protective immune responses against heterologous coronaviruses. In particular, we show that a Severe Acute Respiratory Syndrome Coronavirus 1 (SARS-CoV-1) vaccine developed in 2004 and known to protect against SARS-CoV-1, confers robust heterologous protection against SARS-CoV-2 in mice. Similarly, prior coronavirus infections conferred heterologous protection against distinct coronaviruses. Cross-reactive immunity was also reported in Coronavirus Disease 2019 (COVID-19) patients and humans who received SARS-CoV-2 vaccines, and transfer of plasma from these individuals into mice improved protection against coronavirus challenges. These findings provide the first demonstration that coronavirus vaccines (and prior coronavirus infections) can confer broad protection against heterologous coronaviruses, providing a rationale for universal coronavirus vaccines.
Tanushree Dangi, Nicole Palacio, Sarah Sanchez, Mincheol Park, Jake Class, Lavanya Visvabharathy, Thomas Ciucci, Igor J. Koralnik, Justin M. Richner, Pablo Penaloza-MacMaster
Nucleoside-modified mRNA vaccines have gained global attention because of COVID-19. We evaluated a similar vaccine approach for preventing a chronic latent genital infection rather than an acute respiratory infection. We used animal models to compare an HSV-2 trivalent nucleoside-modified mRNA vaccine with the same antigens prepared as proteins with an emphasis on antigen-specific memory B cell responses and immune correlates of protection. In guinea pigs, serum neutralizing antibody titers were higher at one month and declined far less by eight months in mRNA- than protein-immunized animals. Both vaccines protected against death and genital lesions when infected one month after immunization; however, protection was more durable in the mRNA than protein group when infected after eight months, an interval representing >15% of the animal’s lifespan. Serum and vaginal neutralizing antibody titers correlated with protection against infection as measured by genital lesions and vaginal virus titers two days post infection. In mice, the mRNA vaccine generated more antigen-specific memory B cells than the protein vaccine at early times post immunization that persisted for up to one year. High neutralizing titers and robust B cell immune memory likely explain the more durable protection by the HSV-2 mRNA vaccine.
Sita Awasthi, James J. Knox, Angela Desmond, Mohamad-Gabriel Alameh, Brian T. Gaudette, John M. Lubinski, Alexis Naughton, Lauren M. Hook, Kevin P. Egan, Ying K. Tam, Norbert Pardi, David Allman, Eline T. Luning Prak, Michael P. Cancro, Drew Weissman, Gary H. Cohen, Harvey M. Friedman
The mRNA-1273 vaccine is effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and was granted emergency use authorization by the Food and Drug Administration . Clinical studies, however, cannot provide the controlled response to infection and complex immunological insight that are only possible with preclinical studies. Hamsters are the only model that reliably exhibit severe SARS-CoV-2 disease similar to hospitalized patients, making them pertinent for vaccine evaluation. We demonstrate that prime or prime-boost administration of mRNA-1273 in hamsters elicited robust neutralizing antibodies, ameliorated weight loss, suppressed SARS-CoV-2 replication in the airways, and better protected against disease at the highest prime-boost dose. Unlike in mice and non-human primates, low level virus replication in mRNA-1273 vaccinated hamsters coincided with an anamnestic response. Single-cell RNA sequencing of lung tissue permitted high resolution analysis which is not possible in vaccinated humans. mRNA-1273 prevented inflammatory cell infiltration and the reduction of lymphocyte proportions, but enabled antiviral responses conducive to lung homeostasis. Surprisingly, infection triggered transcriptome programs in some types of immune cells from vaccinated hamsters that were shared, albeit attenuated, with mock-vaccinated hamsters. Our results support the use of mRNA-1273 in a two-dose schedule and provide insight into the potential responses within the lungs of vaccinated humans who are exposed to SARS-CoV-2.
Michelle Meyer, Yuan Wang, Darin Edwards, Gregory R. Smith, Aliza B. Rubenstein, Palaniappan Ramanathan, Chad E. Mire, Colette Pietzsch, Xi Chen, Yongchao Ge, Wan Sze Cheng, Carole Henry, Angela Woods, LingZhi Ma, Guillaume B.E. Stewart-Jones, Kevin W. Bock, Mahnaz Minai, Bianca M. Nagata, Sivakumar Periasamy, Pei-Yong Shi, Barney S. Graham, Ian N. Moore, Irene Ramos, Olga G. Troyanskaya, Elena Zaslavsky, Andrea Carfi, Stuart C. Sealfon, Alexander Bukreyev
Therapeutic vaccines that augment T cell responses to tumor antigens have been limited by poor potency in clinical trials. In contrast, the transfer of T cells modified with foreign transgenes frequently induces potent endogenous T cell responses to epitopes in the transgene product, and these responses are undesirable, because they lead to rejection of the transferred T cells. We sought to harness gene-modified T cells as a vaccine platform and developed cancer vaccines composed of autologous T cells modified with tumor antigens and additional adjuvant signals (Tvax). T cells expressing model antigens and a broad range of tumor neoantigens induced robust and durable T cell responses through cross-presentation of antigens by host DCs. Providing Tvax with signals such as CD80, CD137L, IFN-β, IL-12, GM-CSF, and FLT3L enhanced T cell priming. Coexpression of IL-12 and GM-CSF induced the strongest CD4+ and CD8+ T cell responses through complimentary effects on the recruitment and activation of DCs, mediated by autocrine IL-12 receptor signaling in the Tvax. Therapeutic vaccination with Tvax and adjuvants showed antitumor activity in subcutaneous and metastatic preclinical mouse models. Human T cells modified with neoantigens readily activated specific T cells derived from patients, providing a path for clinical translation of this therapeutic platform in cancer.
Joshua R. Veatch, Naina Singhi, Shivani Srivastava, Julia L. Szeto, Brenda Jesernig, Sylvia M. Stull, Matthew Fitzgibbon, Megha Sarvothama, Sushma Yechan-Gunja, Scott E. James, Stanley R. Riddell
Natural killer (NK) cell suppression of T cells is a key determinant of viral pathogenesis and vaccine efficacy. This process involves perforin-dependent elimination of activated CD4 T cells during the first three days of infection. Although this mechanism requires cell-cell contact, NK cells and T cells typically reside in different compartments of lymphoid tissues at steady state. Here, we showed that NK-cell suppression of T cells is associated with transient accumulation of NK cells within T cell-rich sites of the spleen during lymphocytic choriomeningitis virus infection. The chemokine receptor CXCR3 was required for this relocation and suppression of antiviral T cells. Accordingly, NK-cell migration was mediated by type I interferon (IFN)-dependent promotion of CXCR3 ligand expression. In contrast, adenoviral vectors that weakly induced type I IFN and did not stimulate NK-cell inhibition of T cells also did not promote measurable redistribution of NK cells to T-cell zones. Exogenous IFN rescued NK-cell migration during adenoviral vector immunization. Thus, type I IFN and CXCR3 were critical for properly positioning NK cells to constrain antiviral T-cell responses. Development of strategies to curtail migration of NK cells between lymphoid compartments may enhance vaccine-elicited immune responses.
Ayad Ali, Laura M. Canaday, H. Alex Feldman, Hilal Cevik, Michael T. Moran, Sanjeeth Rajaram, Nora Lakes, Jasmine A. Tuazon, Harsha Seelamneni, Durga Krishnamurthy, Eryn Blass, Dan H. Barouch, Stephen N. Waggoner
Seasonal influenza vaccination elicits a diminished adaptive immune response in the elderly, and the mechanisms of immunosenescence are not fully understood. Using Ig-Seq, we found a marked increase with age in the prevalence of cross-reactive (CR) serum antibodies that recognize both the H1N1 (vaccine-H1) and H3N2 (vaccine-H3) components of an egg-produced split influenza vaccine. CR antibodies accounted for 73% ± 18% of the serum vaccine responses in a cohort of elderly donors, 65% ± 15% in late middle-aged donors, and only 13% ± 5% in persons under 35 years of age. The antibody response to non-HA antigens was boosted by vaccination. Recombinant expression of 19 vaccine-H1+H3 CR serum monoclonal antibodies (s-mAbs) revealed that they predominantly bound to non-HA influenza proteins. A sizable fraction of vaccine-H1+H3 CR s-mAbs recognized with high affinity the sulfated glycans, in particular sulfated type 2 N-acetyllactosamine (Galβ1-4GalNAcβ), which is found on egg-produced proteins and thus unlikely to contribute to protection against influenza infection in humans. Antibodies against sulfated glycans in egg-produced vaccine had been identified in animals but were not previously characterized in humans. Collectively, our results provide a quantitative basis for how repeated exposure to split influenza vaccine correlates with unintended focusing of serum antibody responses to non-HA antigens that may result in suboptimal immunity against influenza.
Jiwon Jung, Sophia T. Mundle, Irina V. Ustyugova, Andrew P. Horton, Daniel R. Boutz, Svetlana Pougatcheva, Ponraj Prabakaran, Jonathan R. McDaniel, Gregory R. King, Daechan Park, Maria D. Person, Congxi Ye, Bing Tan, Yuri Tanno, Jin Eyun Kim, Nicholas C. Curtis, Joshua DiNapoli, Simon Delagrave, Ted M. Ross, Gregory C. Ippolito, Harry Kleanthous, Jiwon Lee, George Georgiou
The four serotypes of dengue virus (DENV1-4) are mosquito-borne flaviviruses that infect humans. Live attenuated tetravalent DENV vaccines are at different phases of clinical testing. DENV vaccine developers have relied on neutralizing antibodies (NAbs) as a correlate of protection. A leading tetravalent vaccine (Dengvaxia) stimulated NAbs to the 4 DENV serotypes, yet overall vaccine efficacy was low in children who were DENV seronegative at baseline before vaccination. We compared the properties of 1) NAbs induced by wild type DENV1 or 3 infections, which are strongly correlated with protection from repeat infections, and 2) NAbs induced by Dengvaxia in individuals who subsequently experienced DENV1 or DENV3 breakthrough infections. Wild type infections induced NAbs that recognized epitopes unique (type-specific) to each serotype, whereas the vaccine stimulated qualitatively different NAbs that recognized epitopes conserved (cross-reactive) between serotypes. Our results indicate that among children who were DENV seronegative at baseline, unbalanced replication of the DENV type 4 vaccine component in the tetravalent vaccine stimulates Abs capable of cross neutralizing DENV1 and 3 in vitro but not protect in vivo. In DENV seronegative individuals who are vaccinated, we propose that type specific NAbs are a better correlate of protection than total levels of NAbs.
Sandra Henein, Cameron Adams, Matthew Bonaparte, Janice M. Moser, Alina Munteanu, Ralph Baric, Aravinda M. Desilva
BACKGROUND. Currently used COVID-19 vaccines require two doses to achieve optimal vaccination, and there is no indication as to whether individuals who have been exposed to SARS-CoV-2 should be vaccinated, or should receive one or two vaccine doses. METHODS. Here, we tested the antibody response developed after administration of the Pfizer/BioNTech vaccine in 124 healthcare professionals of which 57 had a previous history of SARS-CoV-2 exposure (SARS-CoV-2-Exp), with or without symptoms. RESULTS. Post-vaccine antibodies in SARS-CoV-2 exposed individuals increased exponentially within 5-18 days after the first dose compared to naïve subjects (P < 0.0001). In a multivariate Linear Regression (LR) model we showed that the antibody response depended on the IgG pre-vaccine titer and on the exposure to SARS-CoV-2. In symptomatic SARS-CoV-2 exposed individuals, IgG reached a plateau after the second dose, and those that voluntarily refrained from receiving the second dose (n = 7) retained their antibody response. Gastrointestinal symptoms, muscle pain and fever significantly positively correlated with increased IgG responses. By contrast, all a/paucisymptomatic and unexposed individuals showed an important increase after the second dose. CONCLUSION. Thus, one vaccine dose is sufficient in symptomatic SARS-CoV-2 exposed subjects to reach a high titer of antibodies suggesting no need for a second dose, particularly in light of current vaccine shortage. TRIAL REGISTRATION. ClincalTrials.gov NCT04387929 FUNDING. This work was partially supported by a philantropic donation by Dolce & Gabbana and by the Italian Ministry of Health (Ricerca corrente).
Riccardo Levi, Elena Azzolini, Chiara Pozzi, Leonardo Ubaldi, Michele Lagioia, Alberto Mantovani, Maria Rescigno
A(H3N2) Influenza vaccine effectiveness (VE) were low during 2016-2019 seasons and varied by age. We analyzed neutralizing antibody responses to egg- and cell-propagated vaccine and circulating viruses following vaccination in 375 individuals (aged 7 months to 82 years) across all vaccine eligible age groups in 3 influenza seasons. Antibody responses to cell- compared to egg-propagated vaccine viruses were significantly reduced due to egg-adapted changes T160K, D225G, and L194P in the vaccine hemagglutinins. Vaccine egg-adaptation had differential impact on antibody responses across different age groups. Immunologically naive children immunized with egg-adapted vaccines mostly mounted antibodies targeting egg-adapted epitopes, whereas those previously primed with infection produced broader responses even when vaccinated with egg-based vaccines. In elderly, repeated boost of vaccine egg-adapted epitopes significantly reduced antibody responses to the wild type cell-grown viruses. Analysis with reverse genetics viruses suggested that the response to each egg-adapted substitution varied by age. Antibody responses did not differ in male versus female vaccinees. Here, the combination of age-specific responses to vaccine egg-adapted substitutions, diverse host immune priming histories and virus antigenic drift impacted antibody responses following vaccination and may have led to the low and variable VE against A(H3N2) viruses across different age groups.
Feng Liu, F. Liaini Gross, Stacie N. Jefferson, Crystal Holiday, Yaohui Bai, Li Wang, Bin Zhou, Min Z. Levine
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