Vaccines
Abstract
Dengue is widespread in tropical and subtropical regions globally and imposes a considerable disease burden. Annually, dengue virus (DENV) causes up to 400 million infections, of which approximately 25% present with clinical manifestations ranging from mild to fatal. Despite its significance as a growing public health concern, developing effective DENV vaccines has been challenging. One reason is the lack of comprehensive understanding of the influence exerted by prior DENV infections and immune responses with cross-reactive properties. To investigate this, we collected samples from a pediatric cohort study in dengue-endemic Managua, Nicaragua. We characterized T cell responses in 71 healthy children who had previously experienced 1 or more natural DENV infections and who, within 1 year after sample collection, had a subsequent DENV infection that was either symptomatic or inapparent. Our study investigated the effect of preexisting DENV-specific T cell responses on clinical outcomes of subsequent DENV infection. We assessed DENV-specific T cell responses using an activation-induced marker assay. Children with only 1 prior DENV infection displayed heterogeneous DENV-specific CD4+ and CD8+ T cell frequencies. In contrast, children with 2 or more prior DENV infections showed significantly higher DENV-specific CD4+ and CD8+ T cell frequencies associated with inapparent rather than symptomatic outcomes in subsequent infection. These findings demonstrate the protective role of DENV-specific T cells against symptomatic DENV infection and advance efforts to identify protective immune correlates against dengue.
Authors
Rosa Isela Gálvez, Amparo Martínez-Pérez, E. Alexandar Escarrega, Tulika Singh, José Victor Zambrana, Ángel Balmaseda, Eva Harris, Daniela Weiskopf
Abstract
BACKGROUND. The immunogenicity of current influenza vaccines need improvement. Inactivated influenza and COVID-19 mRNA vaccines can be co-administered but randomized controlled trial data is lacking on whether the two vaccines are more immunogenic if given in the same or opposite arms. Murine studies suggest mRNA vaccines can adjuvant influenza vaccines when co-formulated and delivered together. METHODS. We randomly assigned 56 adults to receive the Afluria quadrivalent inactivated influenza and Moderna monovalent SARS-CoV-2 XBB.1.5 mRNA vaccines, either in opposite arms or both in the same arm at the same site. The primary endpoint was the difference in median combined serum haemagglutination inhibition titre to the H1, H3 and B-Vic vaccine influenza strains after vaccination. RESULTS. We found no significant difference in haemagglutination inhibition antibody levels between the groups (p = 0.30), with the same arm group having a 1.26-fold higher titre than the opposite arm group. There was no difference in analyses of antibodies to individual influenza strains, nor in nasal or saliva antibody levels. While both binding and neutralising antibody titres against SARS-CoV-2 were not significantly different between groups post-vaccination, there was a higher fold-change in BA.5 and ancestral strain neutralising antibodies in the opposite arm group. CONCLUSION. Influenza vaccination is equivalently immunogenic if given in same or opposite arms as the SARS-CoV-2 vaccine, but it may be preferable to administer the SARS-CoV-2 vaccine at a different site to influenza vaccines. TRIAL REGISTRATION. Australian New Zealand Clinical Trials Registry ACTRN12624000445572. FUNDING. Australian National Health and Medical Research Council and Medical Research Future Fund.
Authors
Wen Shi Lee, Kevin J. Selva, Jennifer Audsley, Helen E. Kent, Arnold Reynaldi, Timothy E. Schlub, Deborah Cromer, David S. Khoury, Heidi Peck, Malet Aban, Mai Ngoc Vu, Ming Z. M. Zheng, Amy W. Chung, Marios Koutsakos, Hyon-Xhi Tan, Adam K. Wheatley, Jennifer A. Juno, Steven Rockman, Miles P. Davenport, Ian Barr, Stephen J. Kent
Abstract
BACKGROUND Despite the currently prevailing, milder Omicron variant of COVID-19, older adults remain at elevated risk of hospital admission, critical illness, and death. Loss of efficacy of the immune system, including reduced strength, quality, and durability of antibody responses, may render generalized recommendations on booster vaccinations inadequate. There is a lack of data on the efficacy of antibody levels in older adults and on the utility of vaccination status versus antibody levels as a correlate of protection. It is further unclear whether antibody levels may be used to guide the timing of booster vaccinations in older adults.METHODS We conducted a prospective multicenter cohort study comprising hospitalized patients with COVID-19. Anti–SARS-CoV-2 spike antibodies were measured on hospital admission. The primary endpoint was in-hospital mortality. Patients were stratified by age, antibody levels, and vaccination status. Multiple logistic regression and Cox regression analyses were conducted.RESULTS In total, 785 older patients (≥60 years of age [a]) and 367 controls (<60a) were included. After adjusting for confounders, risk of mortality, ICU admission, endotracheal intubation, and oxygen administration was 4.9, 2.6, 6.5, and 2.3 times higher, respectively, if antibody levels were < 1,200 BAU/mL (aOR, 4.92 [95%CI, 2.59–9.34], P < 0.0001; aOR, 2.64 [95%CI, 1.52–4.62], P = 0.0006; aOR, 6.50 [95%CI, 1.48–28.47], P = 0.013; aOR, 2.34 [95%CI, 1.60–3.343], P < 0.0001). Older adults infected with the Omicron variant were approximately 6 times more likely to die if antibody levels were < 1,200 BAU/mL (aOR, 6.3 [95% CI, 2.43–16.40], P = 0.0002).CONCLUSION Antibody levels were a stronger predictor of in-hospital mortality than vaccination status. Monitoring antibody levels may constitute a better and more direct approach for safeguarding older adults from adverse COVID-19 outcomes.
Authors
Sylvia Mink, Christoph H. Saely, Andreas Leiherer, Patrick Reimann, Matthias Frick, Janne Cadamuro, Wolfgang Hitzl, Heinz Drexel, Peter Fraunberger
Abstract
BACKGROUND The mechanism(s) responsible for the efficacy of WHO-recommended malaria vaccine RTS,S/AS01 are not completely understood. We previously identified RTS,S vaccine–induced Plasmodium falciparum circumsporozoite protein–specific (PfCSP-specific) antibody measures associated with protection from controlled human malaria infection (CHMI). Here, we tested the protection-predicting capability of these measures in independent CHMI studies.METHODS Vaccine-induced total serum antibody (immunoglobulins, Igs) and subclass antibody (IgG1 and IgG3) responses were measured by biolayer interferometry and the binding antibody multiplex assay, respectively. Immune responses were compared between protected and nonprotected vaccinees using univariate and multivariate logistic regression.RESULTS Blinded prediction analysis showed that 5 antibody binding measures, including magnitude-avidity composite of serum Ig specific for PfCSP, major NANP repeats and N-terminal junction, and PfCSP- and NANP-specific IgG1 subclass magnitude, had good prediction accuracy (area under the receiver operating characteristic curves [ROC AUC] > 0.7) in at least 1 trial. Furthermore, univariate analysis showed a significant association between these antibody measures and protection (odds ratios 2.6–3.1). Multivariate modeling of combined data from 3 RTS,S CHMI trials identified the combination of IgG1 NANP binding magnitude plus serum NANP and N-junction Ig binding magnitude-avidity composite as the best predictor of protection (95% confidence interval for ROC AUC 0.693–0.834).CONCLUSION These results reinforce our previous findings and provide a tool for predicting protection in future trials.TRIAL REGISTRATION ClinicalTrials.gov NCT03162614, NCT03824236, NCT01366534, and NCT01857869.FUNDING This study was supported by Bill & Melinda Gates Foundation’s Global Health-Discovery Collaboratory grants (INV-008612 and INV-043419) to GDT.
Authors
Rachel L. Spreng, Kelly E. Seaton, Lin Lin, Sir’Tauria Hilliard, Gillian Q. Horn, Milite Abraha, Aaron W. Deal, Kan Li, Alexander J. Carnacchi, Elizabeth Feeney, Siam Shabbir, Lu Zhang, Valerie Bekker, Sarah V. Mudrak, Sheetij Dutta, Laina D. Mercer, Scott Gregory, C. Richter King, Ulrike Wille-Reece, Erik Jongert, Neville K. Kisalu, Georgia D. Tomaras, S. Moses Dennison
Abstract
BACKGROUND The level of nasal spike-specific secretory IgA (sIgA) is inversely correlated with the risk of SARS-CoV-2 Omicron infection. This study aimed to evaluate the safety and immunogenicity of intranasal vaccination using Ad5-S-Omicron (NB2155), a replication-incompetent human type 5 adenovirus carrying Omicron BA.1 spike.METHODS An open-label, single-center, investigator-initiated trial was carried out on 128 health care workers who had never been infected with SARS-CoV-2 and had previously received 2 or 3 injections of inactivated whole-virus vaccines, with the last dose given 3–19 months previously (median 387 days, IQR 333–404 days). Participants received 2 intranasal sprays of NB2155 at 28-day intervals between November 30 and December 30, 2022. Safety was evaluated by solicited adverse events and laboratory tests. The elevation of nasal mucosal spike-specific sIgA and serum neutralizing activities were assessed. All participants were monitored for infection by antigen tests, disease symptoms, and the elevation of nucleocapsid-specific sIgA in the nasal passage.RESULTS The vaccine-related solicited adverse events were mild. Nasal spike-specific sIgA against 10 strains had a mean geometric mean fold increase of 4.5 after the first dose, but it increased much higher to 51.5 after the second dose. Serum neutralizing titers also increased modestly to 128.1 (95% CI 74.4–220.4) against authentic BA.1 and 76.9 (95% CI 45.4–130.2) against BA.5 at 14 days after the second dose. Due to the lifting of the zero-COVID policy in China on December 7, 2022, 57.3% of participants were infected with BA.5 between days 15 and 28 after the first dose, whereas no participants reported having any symptomatic infections between day 3 and day 90 after the second dose. The elevation of nasal nucleocapsid-specific sIgA on days 0, 14, 42, and 118 after the first dose was assessed to verify that these 2-dose participants had no asymptomatic infections.CONCLUSION A 2-dose intranasal vaccination regimen using NB2155 was safe, was well tolerated, and could dramatically induce broad-spectrum spike-specific sIgA in the nasal passage. Preliminary data suggested that the intranasal vaccination may establish an effective mucosal immune barrier against infection and warranted further clinical studies.TRIAL REGISTRATION Chinese Clinical Trial Registry (ChiCTR2300070346).FUNDING Natural Science Foundation of China, Guangzhou Laboratory, The First Affiliated Hospital of Guangzhou Medical University.
Authors
Baoqing Sun, Qian Wang, Peiyan Zheng, Xuefeng Niu, Ying Feng, Weijie Guan, Si Chen, Jin Li, Tingting Cui, Yijun Deng, Zhangkai J. Cheng, Yongmei Li, Xinke Zhou, Yi Fang, Wei Wang, Zhongfang Wang, Ling Chen, Nanshan Zhong
Abstract
In patients who progress from acute hepatitis B virus (HBV) infection to a chronic HBV (CHB) infection, CD8+ T cells fail to eliminate the virus and become impaired. A functional cure of CHB likely requires new and highly functional CD8+ T cell responses different from those induced by the infection. Here we report preclinical immunogenicity and efficacy of an HBV therapeutic vaccine that includes herpes simplex virus (HSV) glycoprotein D (gD), a checkpoint modifier of early T cell activation, that enhances, broadens, and prolongs CD8+ T cell responses. We developed a therapeutic HBV vaccine based on a chimpanzee adenovirus serotype 6 (AdC6) vector, called AdC6-gDHBV2, that targets conserved and highly immunogenic regions of the viral polymerase (pol) and core antigens fused into HSV gD. The vaccine was tested with, and without gD, in mice for immunogenicity and in an adeno-associated virus (AAV)8-1.3HBV vector model for antiviral efficacy. The vaccine encoding the HBV antigens within gD stimulates potent and broad CD8+ T cell responses. In a surrogate model of HBV infection, a single intramuscular (i.m.) injection of AdC6-gDHBV2 achieved significant and sustained declines of circulating HBV DNA copies (cps) and HBV surface antigen (HBsAg); both inversely correlated with HBV specific CD8+ T cell frequencies in spleens and livers. AdC6-gDHBV2 is the first therapeutic vaccine to show significant reductions in levels of HBV genome copies and HBsAg when used alone, even when vaccination was delayed for months from infection.
Authors
Mohadeseh Hasanpourghadi, Mikhail Novikov, Robert Ambrose, Arezki Chekaoui, Dakota Newman, Zhiquan Xiang, Andrew D. Luber, Sue L. Currie, XiangYang Zhou, Hildegund C. Ertl
Abstract
BACKGROUND. Immune processes are influenced by circadian rhythms. We evaluate the association between varicella vaccine administration time-of-day and vaccine effectiveness. METHODS. A national cohort, children < 6 years were enrolled between January 2002 to December 2023. We compared children vaccinated during morning (7:00–10:59), late-morning to afternoon (11:00–15:59), or evening hours (16:00–19:59). A Cox proportional-hazards regression model was used to adjust for ethnicity, sex, and comorbidities. The first varicella infection occurring at least 14 days after vaccination, or a second dose administration were treated as a terminal event. RESULTS. 4,501 (1.8%), of 251,141 vaccinated children, experienced breakthrough infections. Infection rates differed based on vaccination time, with the lowest rates associated with late-morning to afternoon (11:00–15:59), HR 0.88, 95% CI 0.82–0.95, P < 0.001, and the highest rates with evening vaccination (16:00–19:59), HR 1.41, 95% CI 1.32–1.52, P < 0.001. Vaccination timing remained significant after adjustment for ethnicity, sex, and comorbidities. The association between immunization time and infection risk followed a sinusoidal pattern, consistent with a diurnal rhythm in vaccine effectiveness. CONCLUSIONS. We report a significant association between the time of varicella vaccination and its clinical effectiveness. Similar association was observed with the COVID-19 vaccine, providing proof of concept consistent with a diurnal rhythm in vaccine effectiveness.
Authors
Dana Danino, Yoav Kalron, Jeffrey Haspel, Guy Hazan
Abstract
The skin at the site of HSV-2 reactivation is enriched for HSV-2–specific T cells. To evaluate whether an immunotherapeutic vaccine could elicit skin-based memory T cells, we studied skin biopsies and HSV-2–reactive CD4+ T cells from PBMCs by T cell receptor (TCR) β chain (TRB) sequencing before and after vaccination with a replication-incompetent whole-virus HSV-2 vaccine candidate (HSV529). The representation of HSV-2–reactive CD4+ TRB sequences from PBMCs in the skin TRB repertoire increased after the first vaccine dose. We found sustained expansion after vaccination of unique, skin-based T cell clonotypes that were not detected in HSV-2–reactive CD4+ T cells isolated from PBMCs. In one participant, a switch in immunodominance occurred with the emergence of a TCR αβ pair after vaccination that was not detected in blood. This TCRαβ was shown to be HSV-2 reactive by expression of a synthetic TCR in a Jurkat-based NR4A1 reporter system. The skin in areas of HSV-2 reactivation possessed an oligoclonal TRB repertoire that was distinct from the circulation. Defining the influence of therapeutic vaccination on the HSV-2–specific TRB repertoire requires tissue-based evaluation.
Authors
Emily S. Ford, Alvason Z. Li, Kerry J. Laing, Lichun Dong, Kurt Diem, Lichen Jing, Koshlan Mayer-Blackwell, Krithi Basu, Mariliis Ott, Jim Tartaglia, Sanjay Gurunathan, Jack L. Reid, Matyas Ecsedi, Aude G. Chapuis, Meei-Li Huang, Amalia S. Magaret, Christine Johnston, Jia Zhu, David M. Koelle, Lawrence Corey
Abstract
Staphylococcus aureus is a major human pathogen. An effective anti–S. aureus vaccine remains elusive as the correlates of protection are ill-defined. Targeting specific T cell populations is an important strategy for improving anti–S. aureus vaccine efficacy. Potential bottlenecks that remain are S. aureus–induced immunosuppression and the impact this might have on vaccine-induced immunity. S. aureus induces IL-10, which impedes effector T cell responses, facilitating persistence during both colonization and infection. Thus, it was hypothesized that transient targeting of IL-10 might represent an innovative way to improve vaccine efficacy. In this study, IL-10 expression was elevated in the nares of persistent carriers of S. aureus, and this was associated with reduced systemic S. aureus–specific Th1 responses. This suggests that systemic responses are remodeled because of commensal exposure to S. aureus, which negatively implicates vaccine function. To provide proof of concept that targeting immunosuppressive responses during immunization may be a useful approach to improve vaccine efficacy, we immunized mice with T cell–activating vaccines in combination with IL-10–neutralizing antibodies. Blocking IL-10 during vaccination enhanced effector T cell responses and improved bacterial clearance during subsequent systemic and subcutaneous infection. Taken together, these results reveal a potentially novel strategy for improving anti–S. aureus vaccine efficacy.
Authors
Alanna M. Kelly, Karen N. McCarthy, Tracey J. Claxton, Simon R. Carlile, Eoin C. O’Brien, Emilio G. Vozza, Kingston H.G. Mills, Rachel M. McLoughlin
Abstract
Identifying immune correlates of protection is a major challenge in AIDS vaccine development. Anti-Envelope antibodies have been considered critical for protection against SIV/HIV (SHIV) acquisition. Here, we evaluated the efficacy of an SHIV vaccine against SIVmac251 challenge, where the role of antibody was excluded, as there was no cross-reactivity between SIV and SHIV envelope antibodies. After 8 low-dose intrarectal challenges with SIVmac251, 12 SHIV-vaccinated animals demonstrated efficacy, compared with 6 naive controls, suggesting protection was achieved in the absence of anti-envelope antibodies. Interestingly, CD8+ T cells (and some NK cells) were not essential for preventing viral acquisition, as none of the CD8-depleted macaques were infected by SIVmac251 challenges. Initial investigation of protective innate immunity revealed that protected animals had elevated pathways related to platelet aggregation/activation and reduced pathways related to interferon and responses to virus. Moreover, higher expression of platelet factor 4 on circulating platelet-leukocyte aggregates was associated with reduced viral acquisition. Our data highlighted the importance of innate immunity, identified mechanisms, and may provide opportunities for novel HIV vaccines or therapeutic strategy development.
Authors
Yongjun Sui, Thomas J. Meyer, Christine M. Fennessey, Brandon F. Keele, Kimia Dadkhah, Chi Ma, Celia C. LaBranche, Matthew W. Breed, Josh A. Kramer, Jianping Li, Savannah E. Howe, Guido Ferrari, LaTonya D. Williams, Maggie Cam, Michael C. Kelly, Xiaoying Shen, Georgia D. Tomaras, David Montefiori, Tim F. Greten, Christopher J. Miller, Jay A. Berzofsky
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