Abstract
Coronavirus disease 2019 (COVID-19) vaccine trials provide valuable insight into the safety and efficacy of vaccines, with individually randomized, placebo-controlled trials being the gold ...standard in trial design. However, a myriad of variables must be considered as clinical trial data are interpreted and used to guide policy decisions. These variables include factors such as the characteristics of the study population and circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains, the force of infection, the definition and ascertainment of endpoints, the timing of vaccine efficacy assessment, and the potential for performance bias. In this Viewpoints article, we discuss critical variables to consider when comparing efficacy measurements across current and future COVID-19 vaccine trials.
COVID-19 vaccine trials provide valuable insight into the safety and efficacy of vaccines. Simple comparison of trial efficacy estimates, however, is problematic. When comparing efficacy results from COVID-19 vaccine trials, factors related to trial context and design must be considered.
Alveolar macrophages represent a first-line innate host defense mechanism for clearing inhaled Aspergillus fumigatus from the lungs, yet contradictory data exist as to which alveolar macrophage ...recognition receptor is critical for innate immunity to A. fumigatus. Acknowledging that the A. fumigatus cell wall contains a high beta-1,3-glucan content, we questioned whether the beta-glucan receptor dectin-1 played a role in this recognition process. Monoclonal antibody, soluble receptor, and competitive carbohydrate blockage indicated that the alveolar macrophage inflammatory response, specifically the production of tumor necrosis factor-alpha (TNF-alpha), interleukin-1alpha (IL-1alpha), IL-1beta, IL-6, CXCL2/macrophage inflammatory protein-2 (MIP-2), CCL3/macrophage inflammatory protein-1alpha (MIP-1alpha), granulocyte-colony stimulating factor (G-CSF), and granulocyte monocyte-CSF (GM-CSF), to live A. fumigatus was dependent on recognition via the beta-glucan receptor dectin-1. The inflammatory response was triggered at the highest level by A. fumigatus swollen conidia and early germlings and correlated to the levels of surface-exposed beta glucans, indicating that dectin-1 preferentially recognizes specific morphological forms of A. fumigatus. Intratracheal administration of A. fumigatus conidia to mice in the presence of a soluble dectin-Fc fusion protein reduced both lung proinflammatory cytokine/chemokine levels and cellular recruitment while modestly increasing the A. fumigatus fungal burden, illustrating the importance of beta-glucan-initiated dectin-1 signaling in defense against this pathogen. Collectively, these data show that dectin-1 is centrally required for the generation of alveolar macrophage proinflammatory responses to A. fumigatus and to our knowledge provides the first in vivo evidence for the role of dectin-1 in fungal innate defense.
Immune reconstitution inflammatory syndrome (IRIS) is an exaggerated immune response to a variety of pathogens in response to antiretroviral therapy-mediated recovery of the immune system in ...HIV-infected patients. Although IRIS can occur in many organs, pulmonary IRIS, associated with opportunistic infections such as Mycobacterium tuberculosis and Pneumocystis jirovecii, is particularly associated with high morbidity and mortality. The pathology of IRIS is associated with a variety of innate and adaptive immune factors, including CD4
T-cells, CD8
T-cells, γδ T-cells, natural killer cells, macrophages, the complement system and surfactant proteins, Toll-like receptors and pro-inflammatory cytokines and chemokines. Although there are numerous reports about the immune factors involved in IRIS, the mechanisms involved in the development of pulmonary IRIS are poorly understood. Here, we propose that studies using gene-deficient murine and nonhuman primate models will help to identify the specific molecular targets associated with the development of IRIS. An improved understanding of the mechanisms involved in the pathology of pulmonary IRIS will help to identify potential biomarkers and therapeutic targets in this syndrome.
pneumonia is a life-threatening opportunistic fungal infection observed in individuals with severe immunodeficiencies, such as AIDS. Molecules with the ability to bind β-glucan and signal at Fcγ ...receptors enhance defense against
f. sp.
, though it is unclear whether antibodies reactive with fungal cell wall carbohydrates are induced during
infection. We observed that systemic and lung mucosal immunoglobulins cross-reactive with β-glucan and chitosan/chitin are generated after
infection, with increased quantities within the lung mucosal fluid after challenge. While IgG responses against
protein antigens are markedly CD4
T cell dependent, CD4
T cell depletion did not impact quantities of IgG cross-reactive with β-glucan or chitosan/chitin in the serum or mucosa after challenge. Notably, lung mucosal quantities of IgA cross-reactive with β-glucan or chitosan/chitin are decreased in the setting of CD4
T cell deficiency, occurring in the setting of concurrent reduced quantities of active transforming growth factor β, while mucosal IgM is significantly increased in the setting of CD4
T cell deficiency. Interleukin-21 receptor deficiency does not lead to reduction in mucosal IgA reactive with fungal carbohydrate antigens after
challenge. These studies demonstrate differential CD4
T cell-dependent regulation of mucosal antibody responses against β-glucan and chitosan/chitin after
challenge, suggesting that different B cell subsets may be responsible for the generation of these antibody responses, and suggest a potential immune response against fungi that may be operative in the setting of CD4
T cell-related immunodeficiency.
Using adjuvants to drive features of T cell responses to vaccine antigens is an important technological challenge in the design of new and improved vaccines against infections. Properties such as T ...helper cell function, T cell memory, and CD8+ T cell cytotoxicity may play critical roles in optimal and long-lived immunity through vaccination. Directly manipulating specific immune activation or antigen delivery pathways with adjuvants may selectively augment desired T cell responses in vaccination and may improve the effectiveness and durability of vaccine responses in humans. In this review we outline recently studied adjuvants in their potential for antigen presenting cell and T cell programming during vaccination, with an emphasis on what has been observed in studies in humans as available.
Host defense against opportunistic fungi requires coordination between innate and adaptive immunity for resolution of infection. Antibodies generated in mice vaccinated with the fungus Pneumocystis ...prevent growth of Pneumocystis organisms within the lungs, but the mechanisms whereby antibodies enhance antifungal host defense are poorly defined. Nearly all species of fungi contain the conserved carbohydrates β-glucan and chitin within their cell walls, which may be targets of innate and adaptive immunity. In this study, we show that natural IgM antibodies targeting these fungal cell wall carbohydrates are conserved across many species, including fish and mammals. Natural antibodies bind fungal organisms and enhance host defense against Pneumocystis in early stages of infection. IgM antibodies influence recognition of fungal antigen by dendritic cells, increasing their migration to draining pulmonary lymph nodes. IgM antibodies are required for adaptive T helper type 2 (Th2) and Th17 cell differentiation and guide B cell isotype class-switch recombination during host defense against Pneumocystis. These experiments suggest a novel role for the IgM isotype in shaping the earliest steps in recognition and clearance of this fungus. We outline a mechanism whereby serum IgM, containing ancient specificities against conserved fungal antigens, bridges innate and adaptive immunity against fungal organisms.
Dengue human infection models (DHIMs) are important tools to down-select dengue vaccine candidates and establish tetravalent efficacy before advanced clinical field trials. We aimed to provide data ...for the safety and immunogenicity of DHIM and evaluate dengue vaccine efficacy.
We performed an open-label, phase 1 trial at the University of Maryland (Baltimore, MD, USA). Eligible participants were healthy individuals aged 18–50 years who either previously received a tetravalent dengue purified inactivated vaccine prime followed by a live-attenuated vaccine boost (ie, the vaccinee group), or were unvaccinated flavivirus-naive participants (ie, the control group). Participants in the vaccinee group with detectable pre-challenge dengue virus-1 neutralising antibody titres and flavivirus-naive participants in the control group were inoculated with dengue virus-1 strain 45AZ5 in the deltoid region, 27–65 months following booster dosing. These participants were followed-up from days 4–16 following dengue virus-1 live virus human challenge, with daily real-time quantitative PCR specific to dengue virus-1 RNA detection, and dengue virus-1 solicited local and systemic adverse events were recorded. The primary outcomes were safety (ie, solicited local and systemic adverse events) and vaccine efficacy (ie, dengue virus-1 RNAaemia) following dengue challenge. This study is registered with ClinicalTrials.gov, number NCT04786457.
In January 2021, ten eligible participants were enrolled; of whom, six (60%) were in the vaccinee group and four (40%) were in the control group. Daily quantitative PCR detected dengue virus-1 RNA in nine (90%) of ten participants (five 83% of six in the vaccinee group and all four 100% in the control group). The mean onset of RNAaemia occurred on day 5 (SD 1·0) in the vaccinee group versus day 8 (1·5) in the control group (95% CI 1·1–4·9; p=0·007), with a trend towards reduced RNAaemia duration in the vaccinee group compared with the control group (8·2 days vs 10·5 days; 95% CI –0·08 to 4·68; p=0·056). Mild-to-moderate symptoms (nine 90% of ten), leukopenia (eight 89% of nine), and elevated aminotransferases (seven 78% of nine) were commonly observed. Severe adverse events were detected only in the vaccinee group (fever ≥38·9°C in three 50% of six, headache in one 17%, and transient grade 4 aspartate aminotransferase elevation in one 17%). No deaths were reported.
Participants who had tetravalent dengue purified inactivated vaccine prime and live-attenuated vaccine boost were unprotected against dengue virus-1 infection and further showed increased clinical, immunological, and transcriptomic evidence for inflammation potentially mediated by pre-existing infection-enhancing antibodies. This study highlights the impact of small cohort, human challenge models studying dengue pathogenesis and downstream vaccine development.
Military Infectious Disease Research Program and Medical Technology Enterprise Consortium and Advanced Technology International.
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