Vaccines
Abstract
The presence of B cells is essential for the formation of CD8 T cell memory after infection and vaccination. In this study, we investigated whether B cells influence the programming of naïve CD8 T cells prior to their involvement in an immune response. RNA sequencing indicated that B cells are necessary for sustaining the FOXO1-controlled transcriptional program, which is critical for their homeostasis. Without an appropriate B cell repertoire, mouse naïve CD8 T cells exhibit a terminal, effector-skewed phenotype, which significantly impacts their response to vaccination. A similar effector-skewed phenotype with reduced FOXO1 expression was observed in naïve CD8 T cells from human patients undergoing B cell-depleting therapies. Furthermore, we show that patients without B cells have a defect in generating long-lived CD8 T cell memory following COVID vaccination. In summary, we demonstrate that B cells promote the quiescence of naïve CD8 T cells, poising them to become memory cells upon vaccination.
Authors
Cameron Manes, Miguel Guerrero Moreno, Jennifer Cimons, Marc A. D'Antonio, Tonya M. Brunetti, Michael G. Harbell, Sean Selva, Christopher Mizenko, Tyler L. Borko, Erika L. Lasda, Jay R. Hesselberth, Elena W.Y. Hsieh, Michael R. Verneris, Amanda L. Piquet, Laurent Gapin, Ross M. Kedl, Jared Klarquist
Abstract
BACKGROUND. The neonatal immune system is uniquely poised to generate broadly neutralizing antibodies (bnAbs) and thus infants are ideal for evaluating HIV vaccine candidates. We present the design and safety of a new-in-infants glucopyranosyl lipid A (GLA)-stable emulsion (SE) adjuvant admixed with a first-in-infant CH505 transmitter-founder (CH505TF) gp120 immunogen designed to induce precursors for bnAbs against HIV. METHODS. HVTN 135 is a phase I randomized, placebo-controlled trial of CH505TF+GLA-SE or placebo. Healthy infants aged ≤ 5 days, born to mothers living with HIV but HIV nucleic acid negative at birth were randomized to five doses of CH505TF + GLA-SE or placebo at birth and 8, 16, 32, and 54 weeks. RESULTS. 38 infants (median age = 4 days; interquartile range 4, 4.75 days) were enrolled November 2020 to January 2022. Among 28 (10) infants assigned to receive CH505TF + GLA-SE (placebo), most (32/38) completed the 5-dose immunization series and follow-up (35/38). Solicited local and systemic reactions were more frequent in vaccine (8, 28.6% local; 16, 57.1% systemic) vs. placebo recipients (1, 10% local, P = 0.25; 4, 40.0% systemic, P = 0.38). All events were Grade 1 except two Grade 2 events (pain, lethargy). Serious vaccine-related adverse events were not recorded. CONCLUSIONS. This study illustrates the feasibility of conducting trials of new-in-infants adjuvanted HIV vaccines in HIV-exposed infants receiving standard infant vaccinations. The safety profile of the CH505TF + GLA-SE vaccine was reassuring. TRIAL REGISTRATION. ClinicalTrials.gov NCT04607408. FUNDING. The trial was funded through National Institute of Allergy and Infectious Disease of the National Institutes of Health under grants UM1 AI068614 (HVTN Leadership and Operations Center), UM1 AI068635 (HVTN Statistical and Data Management Center), and UM1 AI068618 (HVTN Laboratory Center).
Authors
Avy Violari, Kennedy Otwombe, William Hahn, Shiyu Chen, Deirdre Josipovic, Vuyelwa Baba, Asimenia Angelidou, Kinga K. Smolen, Ofer Levy, Nonhlanhla N. Mkhize, Amanda S. Woodward Davis, Troy M. Martin, Barton F. Haynes, Wilton B. Williams, Zachary K. Sagawa, James G. Kublin, Laura Polakowski, Margaret Brewinski Isaacs, Catherine Yen, Georgia Tomaras, Lawrence Corey, Holly Janes, Glenda E. Gray
Abstract
BACKGROUND. Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC), but the existence of NPC protective antibody against EBV-associated antigens remains inconclusive. METHODS. NPC cases and matched controls were identified from prospective cohorts comprising 75,481 participants in southern China. ELISA and conditional logistic regression were applied to assess effects of gp42-IgG on NPC. The expression of HLA-II, the gp42 receptor, in nasopharyngeal atypical dysplasia and its impact on EBV infecting epithelial cells were evaluated. FINDINGS. gp42-IgG titers were significantly lower in NPC cases compared to controls across various follow-up years before NPC diagnosis (P<0.05). Individuals in the highest quartile of gp42-IgG titers had a 71% NPC risk reduction comparing to those in the lowest quartile (odds ratios [OR]Q4vsQ1=0.29, 95% confidence intervals [CIs]=0·15 to 0·55, P<0.001). Each unit antibody titer increase was associated with 34% lower risk of NPC (OR=0.66, 95% CI=0.54 to 0.81, Ptrend <0.001). Their protective effect was observed in cases diagnosed ≥5 years, 1-5 years and <1 year after blood collection (P<0.05). HLA-II expression was detected in 13 of 27 nasopharyngeal atypical dysplasia and its overexpression substantially promoted epithelial-cell-origin EBV infection. CONCLUSION. Elevated EBV gp42-IgG titers can reduce NPC risk, indicating gp42 as a potential EBV prophylactic vaccine design target. TRIAL REGISTRATION. NCT00941538, NCT02501980, ChiCTR2000028776, ChiCTR2100041628. FUNDING. Noncommunicable Chronic Diseases-National Science and Technology Major Project, National Natural Science Foundation of China, Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program, Central Financial Transfer Payment Projects of the Chinese Government, Cancer Research Grant of Zhongshan City.
Authors
Xiang-Wei Kong, Guo-Long Bu, Hua Chen, Yu-Hua Huang, Zhiwei Liu, Yin-Feng Kang, Yan-Cheng Li, Xia Yu, Biao-Hua Wu, Zi-Qian Li, Xin-Chun Chen, Shang-Hang Xie, Dong-Feng Lin, Tong Li, Shu-Mei Yan, Run-Kun Han, Nan Huang, Qian-Yu Wang, Yan Li, Ao Zhang, Qian Zhong, Xiao-Ming Huang, Weimin Ye, Ming-Fang Ji, Yong-Lin Cai, Su-Mei Cao, Mu-Sheng Zeng
Abstract
Vaccine adjuvants are thought to work by stimulating innate immunity in the draining lymph node (LN), although this has not been proven in humans. To bridge data obtained in animals to humans, we have developed an in situ human LN explant model to investigate how adjuvants initiate immunity. Slices of explanted LNs were exposed to vaccine adjuvants and revealed responses that were not detectable in LN cell suspensions. We used this model to compare the liposome-based AS01 with its components MPL and QS-21, and TLR ligands. Liposomes were predominantly taken up by subcapsular sinus-lining macrophages, monocytes and dendritic cells. AS01 induced dendritic cell maturation and a strong pro-inflammatory cytokine response in intact LN slices but not in dissociated cell cultures, in contrast to R848. This suggests the onset of the immune response to AS01 requires a coordinated activation of LN cells in time and space. Consistent with the robust immune response observed in older adults with AS01-adjuvanted vaccines, the AS01 response in human LNs was independent of age, unlike R848. This human LN explant model is a valuable tool for studying the mechanism of action of adjuvants in humans and for screening new formulations to streamline vaccine development.
Authors
Vicki V. Stylianou, Kirstie M. Bertram, Van Anh Vo, Elizabeth B. Dunn, Heeva Baharlou, Darcii J. Terre, James Elhindi, Elisabeth Elder, James French, Farid Meybodi, Stéphane T. Temmerman, Arnaud M. Didierlaurent, Margherita Coccia, Kerrie J. Sandgren, Anthony L. Cunningham
Abstract
BACKGROUND. There is uncertainty around the timing of booster vaccination against COVID-19 in highly vaccinated populations during the present endemic phase of COVID-19. Studies focused on primary vaccination have previously suggested improved immunity after delaying immunisation. METHODS. We conducted a randomised controlled trial (Nov 2022 – Aug 2023) and assigned 52 fully vaccinated adults to an immediate or a 3-month delayed bivalent Spikevax mRNA booster vaccine. Follow-up visits were completed for 48 participants (n = 24 per arm), with saliva and plasma samples collected following each visit. RESULTS. The rise in neutralising antibody responses to ancestral and Omicron strains were almost identical between the immediate and delayed vaccination arms. Analyses of plasma and salivary antibody responses (IgG, IgA), plasma antibody-dependent phagocytic activity, and the decay kinetics of antibody responses were similar between the 2 arms. Symptomatic and asymptomatic SARS-CoV-2 infection occurred in 49% (21/49) participants over the median 11.5 months of follow up and were also similar between the 2 arms. CONCLUSIONS. Our data suggests no benefit from delaying COVID-19 mRNA booster vaccination in pre-immune populations during the present endemic phase of COVID-19 TRIAL REGISTRATION. Australian New Zealand Clinical Trials Registry number 12622000411741. FUNDING. National Health and Medical Research Council, Australia, Program Grant App1149990 and Medical Research Future Fund App2005544.
Authors
Wen Shi Lee, Jennifer Audsley, Mai-Chi Trieu, Arnold Reynaldi, L. Carissa Aurelia, Palak H. Mehta, Joanne Patterson, Helen E. Kent, Julie Nguyen, Thakshila Amarasena, Robyn Esterbauer, Ebene R. Haycroft, Pradhipa Ramanathan, Miles P. Davenport, Timothy E. Schlub, Joseph Sasadeusz, Adam K. Wheatley, Amy W. Chung, Jennifer A. Juno, Kevin J. Selva, Stephen J. Kent
Abstract
Viral vectors are being used for the treatment of cancer. Yet their efficacy varies among tumors and their use poses challenges in immunosuppressed patients, underscoring the need for alternatives. We report striking antitumoral effects by a nonlytic viral vector based on attenuated lymphocytic choriomeningitis virus (r3LCMV). We show in multiple tumor models that injection of tumor-bearing mice with this vector results in improved tumor control and survival. Importantly, r3LCMV improved tumor control in immunodeficient Rag1–/– mice and MyD88–/– mice, suggesting that multiple pathways contributed to the antitumoral effects. The antitumoral effects of r3LCMV were also observed when this vector was administered several weeks before tumor challenges, suggesting the induction of trained immunity. Single cell RNA-Seq analyses, antibody blockade experiments, and KO models revealed a critical role for host-intrinsic IFN-I in the antitumoral efficacy of r3LCMV vectors. Collectively, these data demonstrate potent antitumoral effects by r3LCMV vectors and unveil multiple mechanisms underlying their antitumoral efficacy.
Authors
Young Rock Chung, Bakare Awakoaiye, Tanushree Dangi, Nahid Irani, Slim Fourati, Pablo Penaloza-MacMaster
Abstract
BACKGROUND. Malaria transmission blocking vaccines aim to interrupt the transmission of malaria from one person to another. METHODS. The candidates, R0.6C and ProC6C, share the Plasmodium falciparum sexual stage antigen, Pfs48/45 “6C” domain. R0.6C utilizes the Glutamate Rich Protein (GLURP) as a carrier and ProC6C includes a second domain (Pfs230-Pro) and a short 36 amino acids CSP sequence. Healthy adults (n = 125) from a malaria endemic area of Burkina Faso were immunized with three intramuscular injections, four weeks apart, of 30 μg or 100 μg R0.6C or ProC6C each adsorbed to Alhydrogel adjuvant (AlOH) alone or in combination with Matrix-M (15 μg or 50 μg, respectively). The allocation was random and double blind for this Phase 1 trial. RESULTS. The vaccines were safe and well tolerated with no vaccine-related serious adverse events. A total of seven adverse events, mild to moderate in intensity and considered possibly related to the study vaccines were recorded. Vaccine-specific antibodies were highest in volunteers immunized with 100 μg ProC6C-AlOH with Matrix-M, and 13/20 (65%) subjects in the group showed greater than 80% transmission reducing activity (TRA) when evaluated in the standard membrane feeding assay at 15 mg/mL IgG. In contrast, R0.6C induced sporadic TRA. CONCLUSIONS. All formulations were safe and well tolerated in a malaria endemic area of Africa in healthy adults. The ProC6C-AlOH/Matrix-M vaccine elicited the highest levels of functional antibodies, meriting further investigation. TRIAL REGISTRATION. Pactr.org PACTR202201848463189. FUNDING. The study was funded by the European Union and Developing Countries Clinical Trials Partnership (Grant number RIA2018SV-2311).
Authors
B. Alfred Tiono, Jordan L. Plieskatt, Alphonse Ouedraogo, Ben Idriss Soulama, Kazutoyo Miura, Edith C. Bougouma, Mohammad Naghizadeh, Aissata Barry, Jean Baptiste B. Yaro, Sem Ezinmegnon, Noelie B. Henry, Ebenezer Ofori, Bright Adu, Susheel K. Singh, Augustin Konkobo, Karin Lövgren Bengtsson, Amidou Diarra, Cecilia Carnrot, Jenny M. Reimer, Amidou Z. Ouedraogo, Moussa Tienta, Carole A. Long, Issa N. Nebie, Issaka Sagara, Sodiomon B. Sirima, Michael Theisen
Abstract
BACKGROUND. Sanaria PfSPZ Vaccine, composed of attenuated Plasmodium falciparum (Pf) sporozoites (SPZ), protects against malaria. We conducted this clinical trial to assess the safety and efficacy of PfSPZ Vaccine in HIV positive (HIV+) individuals since the HIV infection status of participants in mass vaccination programs may be unknown. METHODS. This randomized, double blind, placebo-controlled trial enrolled 18-45-year-old HIV negative (HIV-) and well-controlled HIV+ Tanzanians (HIV viral load < 40 copies/mL, CD4 counts > 500 cells/µL). Participants received 5 doses of PfSPZ Vaccine or normal saline over 28 days followed by controlled human malaria infection (CHMI) 3 weeks later. RESULTS. There were no solicited adverse events in the 9 HIV- and 12 HIV+ participants. After CHMI, 6/6 normal saline (NS) controls, 1/5 HIV- vaccinees and 4/4 HIV+ vaccinees were Pf positive by qPCR. Post-immunization, anti-PfCSP (isotype and IgG subclass) and anti-PfSPZ antibodies, anti-PfSPZ CD4 T cell responses and Vδ2+ γδ CD3+ T cells were non-significantly higher in HIV- than HIV+ vaccinees. Sera from HIV- vaccinees had significantly higher inhibition of PfSPZ invasion of hepatocytes in vitro, and antibody-dependent complement deposition (ADCD) and Fcγ3B binding by anti-PfCSP and ADCD by anti-PfCelTOS antibodies. CONCLUSIONS. PfSPZ Vaccine was safe and well tolerated in HIV+ vaccinees, but not protective. Vaccine efficacy was 80% in HIV- vaccinees (P = 0.012), whose sera had significantly higher inhibition of PfSPZ invasion of hepatocytes and enrichment of multi-functional PfCSP antibodies. A more potent PfSPZ vaccine or regimen is needed to protect those living with HIV against Pf infection in Africa.
Authors
Said Jongo, L.W. Preston Church, Florence Milando, Munira Qassim, Tobias Schindler, Mohammed Rashid, Anneth Tumbo, Gloria Nyaulingo, Bakari M. Bakari, Thabit Athuman Mbaga, Latipha Mohamed, Kamaka Kassimu, Beatus S. Simon, Maxmillian Mpina, Irfan Zaidi, Patrick E. Duffy, Phillip A. Swanson II, Robert Seder, Jonathan D. Herman, Maanasa Mendu, Yonatan Zur, Galit Alter, Natasha KC, Pouria Riyahi, Yonas Abebe, Tooba Murshedkar, Eric R. James, Peter F. Billingsley, B. Kim Lee Sim, Thomas L. Richie, Claudia Daubenberger, Salim Abdulla, Stephen L. Hoffman
Abstract
Intranasal vaccines are anticipated to be powerful tools for combating many infectious diseases, including SARS-CoV-2, because they induce not only systemic immunity but also mucosal immunity at the site of initial infection. However, they are generally inefficient in inducing an antigen-specific immune response without adjuvants. Here, we developed an adjuvant-free intranasal vaccine platform that utilizes the preexisting immunity induced by previous infection or vaccination to enhance vaccine effectiveness. We made RBD-HA, a fusion of the receptor-binding domain (RBD) of spike derived from SARS-CoV-2 as a vaccine target with HA derived from influenza A virus (IAV) as a carrier protein. Intranasal immunization of previously IAV-infected mice with RBD-HA without an adjuvant elicited robust production of RBD-specific systemic IgG and mucosal IgA by utilizing both HA-specific preexisting IgG and CD4+ T cells. Consequently, the mice were efficiently protected from SARS-CoV-2 infection. Additionally, we demonstrated the high versatility of this intranasal vaccine platform by assessing various vaccine antigens and preexisting immunity associated with a variety of infectious diseases. The results of this study suggest the promising potential of this intranasal vaccine platform to address problems associated with intranasal vaccines.
Authors
Atsushi Kawai, Nagisa Tokunoh, Eigo Kawahara, Shigeyuki Tamiya, Shinya Okamura, Chikako Ono, Jessica Anindita, Hiroki Tanaka, Hidetaka Akita, Sho Yamasaki, Jun Kunisawa, Toru Okamoto, Yoshiharu Matsuura, Toshiro Hirai, Yasuo Yoshioka
Abstract
Even with the prolific clinical use of next-generation cancer therapeutics, many tumors remain unresponsive or become refractory to therapy, creating a medical need. In cancer, DCs are indispensable to T cell activation, so there is a restriction on cytotoxic T cell immunity if DCs are not present in sufficient numbers in the tumor and draining lymph nodes to uptake and present relevant cancer antigens. To address this bottleneck, we developed a Flt3L-based therapeutic named Alb-Flt3L that demonstrated superior pharmacokinetic properties compared to Flt3L, including significantly longer half-life, accumulation in tumor and lymph node, and cross-presenting DCs expansion following a single injection. We demonstrated that Alb-Flt3L, in combination with standard-of-care chemotherapy and radiation therapy, serves as an in situ vaccination strategy capable of engendering polyclonal tumor neoantigen-specific immunity spontaneously. In addition, Alb-Flt3L-mediated tumor control synergized with immune checkpoint blockade delivered as anti-PD-L1. The mechanism of action of Alb-Flt3L treatment revealed a dependency on Batf3, type-I-interferons, and plasmacytoid DCs. Finally, the ability of Alb-Flt3L to expand human DC was explored in humanized mice. We observed significant expansion of human cross-presenting DC subsets, supporting the notion that Alb-Flt3L could be used clinically to modulate human DC populations in future cancer therapeutic regimens.
Authors
Brandon Lam, Yu Jui Kung, John Lin, Ssu-Hsueh Tseng, Hsin-Fang Tu, Claire Huang, Brandon Lee, Esteban Velarde, Ya Chea Tsai, Rafael Villasmil, Sung Taek Park, Deyin Xing, Chien-Fu Hung, T.-C. Wu
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