After decades of slow progress, the last years have seen a rapid acceleration of the development of adjuvanted vaccines which have lately been approved for human use. These adjuvants consist of ...different components, e.g. aluminium salts, emulsions such as MF59 and AS03, Toll-like receptor (TLR) agonists (CpG ormonophosphoryl lipid A (MPL) adsorbed on aluminium salts as in AS04) or combination of immunopotentiators (QS-21 and MPL in AS01). Despite their distinctive features, most of these adjuvants share some key characteristics. For example, they induce early activation (although at different levels) of innate immunity which then translates into higher antibody and cellular responses to the vaccine antigens. In addition, most of these adjuvants (e.g. MF59, AS03, AS04) clearly induce a wider breadth of adaptive responses able to confer protection against, for example, heterovariants of the influenza viruses (MF59, AS03) or against human papillomavirus strains not contained in the vaccine (AS04). Finally, the use of some of these adjuvants has contributed to significantly enhance the immune response and the efficacy and effectiveness of vaccines in the elderly who experience a waning of the immune responsiveness to infection and vaccination, as shown for MF59- or AS03-adjuvanted influenza vaccines and AS01-adjuvanted herpes zoster vaccine. These results, together with the track record of acceptable safety profiles of the adjuvanted vaccines, pave the way for the development of novel vaccines at the extremes of age and against infections with a high toll of morbidity and mortality. Here, we review the mechanisms associated with the performance of those adjuvanted vaccines in animal models and in humans through recent advances in systems vaccinology and biomarker discovery. We also provide some perspectives on remaining knowledge gaps but also on opportunities that could accelerate the development of new vaccines.
Abstract
Emerging SARS-CoV-2 variants raise questions about escape from previous immunity. As the population immunity to SARS-CoV-2 has become more complex due to prior infections with different ...variants, vaccinations or the combination of both, understanding the antigenic relationship between variants is needed. Here, we have assessed neutralizing capacity of 120 blood specimens from convalescent individuals infected with ancestral SARS-CoV-2, Alpha, Beta, Gamma or Delta, double vaccinated individuals and patients after breakthrough infections with Delta or Omicron-BA.1. Neutralization against seven authentic SARS-CoV-2 isolates (B.1, Alpha, Beta, Gamma, Delta, Zeta and Omicron-BA.1) determined by plaque-reduction neutralization assay allowed us to map the antigenic relationship of SARS-CoV-2 variants. Highest neutralization titers were observed against the homologous variant. Antigenic cartography identified Zeta and Omicron-BA.1 as separate antigenic clusters. Substantial immune escape in vaccinated individuals was detected for Omicron-BA.1 but not Zeta. Combined infection/vaccination derived immunity results in less Omicron-BA.1 immune escape. Last, breakthrough infections with Omicron-BA.1 lead to broadly neutralizing sera.
The total mass of a galaxy cluster is one of its most fundamental properties. Together with the redshift, the mass links observation and theory, allowing us to use the cluster population to test ...models of structure formation and to constrain cosmological parameters. Building on the rich heritage from X-ray surveys, new results from Sunyaev-Zeldovich and optical surveys have stimulated a resurgence of interest in cluster cosmology. These studies have generally found fewer clusters than predicted by the baseline
Planck
Λ
CDM model, prompting a renewed effort on the part of the community to obtain a definitive measure of the true cluster mass scale. Here we review recent progress on this front. Our theoretical understanding continues to advance, with numerical simulations being the cornerstone of this effort. On the observational side, new, sophisticated techniques are being deployed in individual mass measurements and to account for selection biases in cluster surveys. We summarise the state of the art in cluster mass estimation methods and the systematic uncertainties and biases inherent in each approach, which are now well identified and understood, and explore how current uncertainties propagate into the cosmological parameter analysis. We discuss the prospects for improvements to the measurement of the mass scale using upcoming multi-wavelength data, and the future use of the cluster population as a cosmological probe.
Introduction: Adjuvants are used to improve vaccine immunogenicity and efficacy by enhancing antigen presentation to antigen-specific immune cells with the aim to confer long-term protection against ...targeted pathogens. Adjuvants have been used in vaccines for more than 90 years. Combinations of immunostimulatory molecules, such as in the Adjuvant System AS01, have opened the way to the development of new or improved vaccines.
Areas covered: AS01 is a liposome-based vaccine adjuvant system containing two immunostimulants: 3-O-desacyl-4ʹ-monophosphoryl lipid A (MPL) and the saponin QS-21. Here we describe studies investigating the mode of action of AS01, and consider the role of AS01 in enhancing specific immune responses to the antigen for selected candidate vaccines targeting malaria and herpes zoster. The effects of AS01 are rapid and transient, being localized to the injected muscle and draining lymph node. AS01 is efficient at promoting CD4
+
T cell-mediated immune responses and is an appropriate candidate adjuvant for inclusion in vaccines targeting viruses or intracellular pathogens.
Expert commentary: AS01 activity to enhance adaptive responses depends on synergistic activities of QS-21 and MPL. AS01 adjuvantation shows good prospects for use in new vaccines targeted to populations with challenging immune statuses and against diseases caused by complex pathogens.
Reactogenicity represents the physical manifestation of the inflammatory response to vaccination, and can include injection-site pain, redness, swelling or induration at the injection site, as well ...as systemic symptoms, such as fever, myalgia, or headache. The experience of symptoms following vaccination can lead to needle fear, long-term negative attitudes and non-compliant behaviours, which undermine the public health impact of vaccination. This review presents current knowledge on the potential causes of reactogenicity, and how host characteristics, vaccine administration and composition factors can influence the development and perception of reactogenicity. The intent is to provide an overview of reactogenicity after vaccination to help the vaccine community, including healthcare professionals, in maintaining confidence in vaccines by promoting vaccination, setting expectations for vaccinees about what might occur after vaccination and reducing anxiety by managing the vaccination setting.
SARS-CoV-2 infection in children is less severe than it is in adults. We perform a longitudinal analysis of the early innate responses in children and adults with mild infection within household ...clusters. Children display fewer symptoms than adults do, despite similar initial viral load, and mount a robust anti-viral immune signature typical of the SARS-CoV-2 infection and characterized by early interferon gene responses; increases in cytokines, such as CXCL10 and GM-CSF; and changes in blood cell numbers. When compared with adults, the antiviral response resolves faster (within a week of symptoms), monocytes and dendritic cells are more transiently activated, and genes associated with B cell activation appear earlier in children. Nonetheless, these differences do not have major effects on the quality of SARS-CoV-2-specific antibody responses. Our findings reveal that better early control of inflammation as observed in children may be key for rapidly controlling infection and limiting the disease course.
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•Innate response against SARS-CoV-2 is robust in children despite limited symptoms•Resolution of inflammation and onset of B cell response occur faster in children•Antibody response is not compromised by the shorter antiviral inflammatory response
SARS-CoV-2 infection in children is less severe than it is in adults. Vono et al. find that children mount a potent, but more transient, antiviral innate response with a more rapid onset of B cell response. A more efficient early control of inflammation may be key to limiting disease severity.
Adjuvant System AS01 is a liposome-based vaccine adjuvant containing 3-O-desacyl-4'-monophosphoryl lipid A and the saponin QS-21. AS01 has been selected for the clinical development of several ...candidate vaccines including the RTS,S malaria vaccine and the subunit glycoprotein E varicella zoster vaccine (both currently in phase III). Given the known immunostimulatory properties of MPL and QS-21, the objective of this study was to describe the early immune response parameters after immunization with an AS01-adjuvanted vaccine and to identify relationships with the vaccine-specific adaptive immune response. Cytokine production and innate immune cell recruitment occurred rapidly and transiently at the muscle injection site and draining lymph node postinjection, consistent with the rapid drainage of the vaccine components to the draining lymph node. The induction of Ag-specific Ab and T cell responses was dependent on the Ag being injected at the same time or within 24 h after AS01, suggesting that the early events occurring postinjection were required for these elevated adaptive responses. In the draining lymph node, after 24 h, the numbers of activated and Ag-loaded monocytes and MHCII(high) dendritic cells were higher after the injection of the AS01-adjuvanted vaccine than after Ag alone. However, only MHCII(high) dendritic cells appeared efficient at and necessary for direct Ag presentation to T cells. These data suggest that the ability of AS01 to improve adaptive immune responses, as has been demonstrated in clinical trials, is linked to a transient stimulation of the innate immune system leading to the generation of high number of efficient Ag-presenting dendritic cells.
This is a Brighton Collaboration Case Definition of the term “Vaccine Associated Enhanced Disease” to be utilized in the evaluation of adverse events following immunization. The Case Definition was ...developed by a group of experts convened by the Coalition for Epidemic Preparedness Innovations (CEPI) in the context of active development of vaccines for SARS-CoV-2 vaccines and other emerging pathogens. The case definition format of the Brighton Collaboration was followed to develop a consensus definition and defined levels of certainty, after an exhaustive review of the literature and expert consultation. The document underwent peer review by the Brighton Collaboration Network and by selected Expert Reviewers prior to submission.
Recent Sunyaev–Zeldovich (SZ) surveys (ACT, Planck, SPT) have provided new cluster catalogs, very significantly expanding the coverage of the mass–redshift plane, while XMM‐Newton surveys are pushing ...cluster detection to lower masses, up to z ∼ 1 and beyond. Cosmological analysis of the new cluster samples, particularly that of the largest Planck sample, found fewer clusters than predicted by the base Planck ΛCDM model derived from cosmic microwave (CMB) anisotropies. This could imply a need for extension of the model and/or a revision of cluster physics. In parallel, Chandra and XMM‐Newton follow‐up programs on these new SZ‐discovered clusters have improved our knowledge of evolution, as well as providing new information on survey selection. These results challenge our understanding of fundamental issues such as (a) what the true mass of clusters is, with implications for the baryon depletion at cluster scales and cluster dynamical evolution, and (b) what the true underlying population is, that we are only partly detecting at various wavelengths. Potential new observations to address these issues with XMM‐Newton in conjunction with other observatories are discussed.
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