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1.
NPJ Vaccines ; 6(1): 158, 2021 Dec 21.
Article in English | MEDLINE | ID: covidwho-1585847

ABSTRACT

Emulsion adjuvants such as MF59 and AS03 have been used for more than two decades as key components of licensed vaccines, with over 100 million doses administered to diverse populations in more than 30 countries. Substantial clinical experience of effectiveness and a well-established safety profile, along with the ease of manufacturing have established emulsion adjuvants as one of the leading platforms for the development of pandemic vaccines. Emulsion adjuvants allow for antigen dose sparing, more rapid immune responses, and enhanced quality and quantity of adaptive immune responses. The mechanisms of enhancement of immune responses are well defined and typically characterized by the creation of an "immunocompetent environment" at the site of injection, followed by the induction of strong and long-lasting germinal center responses in the draining lymph nodes. As a result, emulsion adjuvants induce distinct immunological responses, with a mixed Th1/Th2 T cell response, long-lived plasma cells, an expanded repertoire of memory B cells, and high titers of cross-neutralizing polyfunctional antibodies against viral variants. Because of these various properties, emulsion adjuvants were included in pandemic influenza vaccines deployed during the 2009 H1N1 influenza pandemic, are still included in seasonal influenza vaccines, and are currently at the forefront of the development of vaccines against emerging SARS-CoV-2 pandemic variants. Here, we comprehensively review emulsion adjuvants, discuss their mechanism of action, and highlight their profile as a benchmark for the development of additional vaccine adjuvants and as a valuable tool to allow further investigations of the general principles of human immunity.

2.
J Control Release ; 342: 388-399, 2022 02.
Article in English | MEDLINE | ID: covidwho-1562303

ABSTRACT

The efficacy of RNA-based vaccines has been recently demonstrated, leading to the use of mRNA-based COVID-19 vaccines. The application of self-amplifying mRNA within these formulations may offer further enhancement to these vaccines, as self-amplifying mRNA replicons enable longer expression kinetics and more potent immune responses compared to non-amplifying mRNAs. To investigate the impact of administration route on RNA-vaccine potency, we investigated the immunogenicity of a self-amplifying mRNA encoding the rabies virus glycoprotein encapsulated in different nanoparticle platforms (solid lipid nanoparticles (SLNs), polymeric nanoparticles (PNPs) and lipid nanoparticles (LNPs)). These were administered via three different routes: intramuscular, intradermal and intranasal. Our studies in a mouse model show that the immunogenicity of our 4 different saRNA vaccine formulations after intramuscular or intradermal administration was initially comparable; however, ionizable LNPs gave higher long-term IgG responses. The clearance of all 4 of the nanoparticle formulations from the intramuscular or intradermal administration site was similar. In contrast, immune responses generated after intranasal was low and coupled with rapid clearance for the administration site, irrespective of the formulation. These results demonstrate that both the administration route and delivery system format dictate self-amplifying RNA vaccine efficacy.


Subject(s)
COVID-19 , Nanoparticles , Animals , COVID-19 Vaccines , Humans , Liposomes , Mice , RNA, Messenger , SARS-CoV-2 , Vaccine Potency , Vaccines, Synthetic
3.
Cell ; 184(21): 5432-5447.e16, 2021 10 14.
Article in English | MEDLINE | ID: covidwho-1454060

ABSTRACT

Understanding vaccine-elicited protection against SARS-CoV-2 variants and other sarbecoviruses is key for guiding public health policies. We show that a clinical stage multivalent SARS-CoV-2 spike receptor-binding domain nanoparticle (RBD-NP) vaccine protects mice from SARS-CoV-2 challenge after a single immunization, indicating a potential dose-sparing strategy. We benchmarked serum neutralizing activity elicited by RBD-NPs in non-human primates against a lead prefusion-stabilized SARS-CoV-2 spike (HexaPro) using a panel of circulating mutants. Polyclonal antibodies elicited by both vaccines are similarly resilient to many RBD residue substitutions tested, although mutations at and surrounding position 484 have negative consequences for neutralization. Mosaic and cocktail nanoparticle immunogens displaying multiple sarbecovirus RBDs elicit broad neutralizing activity in mice and protect mice against SARS-CoV challenge even in the absence of SARS-CoV RBD in the vaccine. This study provides proof of principle that multivalent sarbecovirus RBD-NPs induce heterotypic protection and motivates advancing such broadly protective sarbecovirus vaccines to the clinic.

4.
Mol Pharm ; 18(8): 2867-2888, 2021 08 02.
Article in English | MEDLINE | ID: covidwho-1310776

ABSTRACT

Despite the many advances that have occurred in the field of vaccine adjuvants, there are still unmet needs that may enable the development of vaccines suitable for more challenging pathogens (e.g., HIV and tuberculosis) and for cancer vaccines. Liposomes have already been shown to be highly effective as adjuvant/delivery systems due to their versatility and likely will find further uses in this space. The broad potential of lipid-based delivery systems is highlighted by the recent approval of COVID-19 vaccines comprising lipid nanoparticles with encapsulated mRNA. This review provides an overview of the different approaches that can be evaluated for the design of lipid-based vaccine adjuvant/delivery systems for protein, carbohydrate, and nucleic acid-based antigens and how these strategies might be combined to develop multicomponent vaccines.


Subject(s)
Adjuvants, Immunologic/administration & dosage , Antigens/administration & dosage , Drug Delivery Systems , Lipids/chemistry , Nanoparticles/chemistry , Vaccines/administration & dosage , COVID-19 Vaccines/administration & dosage , Humans , Liposomes , SARS-CoV-2/immunology , Vaccines/chemistry
5.
Nature ; 594(7862): 253-258, 2021 06.
Article in English | MEDLINE | ID: covidwho-1192479

ABSTRACT

The development of a portfolio of COVID-19 vaccines to vaccinate the global population remains an urgent public health imperative1. Here we demonstrate the capacity of a subunit vaccine, comprising the SARS-CoV-2 spike protein receptor-binding domain displayed on an I53-50 protein nanoparticle scaffold (hereafter designated RBD-NP), to stimulate robust and durable neutralizing-antibody responses and protection against SARS-CoV-2 in rhesus macaques. We evaluated five adjuvants including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an α-tocopherol-containing oil-in-water emulsion; AS37, a Toll-like receptor 7 (TLR7) agonist adsorbed to alum; CpG1018-alum, a TLR9 agonist formulated in alum; and alum. RBD-NP immunization with AS03, CpG1018-alum, AS37 or alum induced substantial neutralizing-antibody and CD4 T cell responses, and conferred protection against SARS-CoV-2 infection in the pharynges, nares and bronchoalveolar lavage. The neutralizing-antibody response to live virus was maintained up to 180 days after vaccination with RBD-NP in AS03 (RBD-NP-AS03), and correlated with protection from infection. RBD-NP immunization cross-neutralized the B.1.1.7 SARS-CoV-2 variant efficiently but showed a reduced response against the B.1.351 variant. RBD-NP-AS03 produced a 4.5-fold reduction in neutralization of B.1.351 whereas the group immunized with RBD-NP-AS37 produced a 16-fold reduction in neutralization of B.1.351, suggesting differences in the breadth of the neutralizing-antibody response induced by these adjuvants. Furthermore, RBD-NP-AS03 was as immunogenic as a prefusion-stabilized spike immunogen (HexaPro) with AS03 adjuvant. These data highlight the efficacy of the adjuvanted RBD-NP vaccine in promoting protective immunity against SARS-CoV-2 and have led to phase I/II clinical trials of this vaccine (NCT04742738 and NCT04750343).


Subject(s)
Adjuvants, Immunologic , Antibodies, Neutralizing/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , SARS-CoV-2/immunology , Vaccines, Subunit/immunology , Alum Compounds , Animals , Antibodies, Viral/immunology , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , COVID-19/virology , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Disease Models, Animal , Immunity, Cellular , Immunity, Humoral , Macaca mulatta/immunology , Male , Oligodeoxyribonucleotides , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Squalene
6.
Nat Rev Drug Discov ; 20(6): 454-475, 2021 06.
Article in English | MEDLINE | ID: covidwho-1171144

ABSTRACT

Adjuvants are vaccine components that enhance the magnitude, breadth and durability of the immune response. Following its introduction in the 1920s, alum remained the only adjuvant licensed for human use for the next 70 years. Since the 1990s, a further five adjuvants have been included in licensed vaccines, but the molecular mechanisms by which these adjuvants work remain only partially understood. However, a revolution in our understanding of the activation of the innate immune system through pattern recognition receptors (PRRs) is improving the mechanistic understanding of adjuvants, and recent conceptual advances highlight the notion that tissue damage, different forms of cell death, and metabolic and nutrient sensors can all modulate the innate immune system to activate adaptive immunity. Furthermore, recent advances in the use of systems biology to probe the molecular networks driving immune response to vaccines ('systems vaccinology') are revealing mechanistic insights and providing a new paradigm for the vaccine discovery and development process. Here, we review the 'known knowns' and 'known unknowns' of adjuvants, discuss these emerging concepts and highlight how our expanding knowledge about innate immunity and systems vaccinology are revitalizing the science and development of novel adjuvants for use in vaccines against COVID-19 and future pandemics.


Subject(s)
Adjuvants, Immunologic/pharmacology , COVID-19 Vaccines/pharmacology , COVID-19 , Immunity, Innate/drug effects , COVID-19/immunology , COVID-19/prevention & control , Drug Development , Humans , SARS-CoV-2 , Vaccinology/methods , Vaccinology/trends
7.
Pharmaceutics ; 13(2)2021 Feb 09.
Article in English | MEDLINE | ID: covidwho-1081806

ABSTRACT

Recent approval of mRNA vaccines to combat COVID-19 have highlighted the potential of this platform. Lipid nanoparticles (LNP) is the delivery vehicle of choice for mRNA as they prevent its enzymatic degradation by encapsulation. We have recently shown that surface exposition of mannose, incorporated in LNPs as stable cholesterol-amine conjugate, enhances the potency of self-amplifying RNA (SAM) replicon vaccines through augmented uptake by antigen presenting cells (APCs). Here, we generated a new set of LNPs whose surface was modified with mannans of different length (from mono to tetrasaccharide), in order to study the effect on antibody response of model SAM replicon encoding for the respiratory syncytial virus fusion F protein. Furthermore, the impact of the mannosylated liposomal delivery through intradermal as well as intramuscular routes was investigated. The vaccine priming response showed to improve consistently with increase in the chain length of mannoses; however, the booster dose response plateaued above the length of disaccharide. An increase in levels of IgG1 and IgG2a was observed for mannnosylated lipid nanoparticles (MLNPs) as compared to LNPs. This work confirms the potential of mannosylated SAM LNPs for both intramuscular and intradermal delivery, and highlights a disaccharide length as sufficient to ensure improved immunogenicity compared to the un-glycosylated delivery system.

8.
Semin Immunol ; 50: 101426, 2020 08.
Article in English | MEDLINE | ID: covidwho-951436

ABSTRACT

In the last decade there have been some significant advances in vaccine adjuvants, particularly in relation to their inclusion in licensed products. This was proceeded by several decades in which such advances were very scarce, or entirely absent, but several novel adjuvants have now been included in licensed products, including in the US. These advances have relied upon several key technological insights that have emerged in this time period, which have finally allowed an in depth understanding of how adjuvants work. These advances include developments in systems biology approaches which allow the hypotheses first advanced in pre-clinical studies to be critically evaluated in human studies. This review highlights these recent advances, both in relation to the adjuvants themselves, but also the technologies that have enabled their successes. Moreover, we critically appraise what will come next, both in terms of new adjuvant molecules, and the technologies needed to allow them to succeed. We confidently predict that additional adjuvants will emerge in the coming years that will reach approval in licensed products, but that the components might differ significantly from those which are currently used. Gradually, the natural products that were originally used to build adjuvants, since they were readily available at the time of initial development, will come to be replaced by synthetic or biosynthetic materials, with more appealing attributes, including more reliable and robust supply, along with reduced heterogeneity. The recent advance in vaccine adjuvants is timely, given the need to create novel vaccines to deal with the COVID-19 pandemic. Although, we must ensure that the rigorous safety evaluations that allowed the current adjuvants to advance are not 'short-changed' in the push for new vaccines to meet the global challenge as quickly as possible, we must not jeopardize what we have achieved, by pushing less established technologies too quickly, if the data does not fully support it.


Subject(s)
Adjuvants, Immunologic/therapeutic use , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Alum Compounds/pharmacology , COVID-19/immunology , COVID-19 Vaccines/therapeutic use , Humans , SARS-CoV-2/immunology , Systems Biology , Vaccinology/methods
9.
NPJ Vaccines ; 5: 88, 2020.
Article in English | MEDLINE | ID: covidwho-904724

ABSTRACT

Vaccines represent the most successful medical intervention in history, with billions of lives saved. Although multiple doses of the same vaccine are typically required to reach an adequate level of protection, it would be advantageous to develop vaccines that induce protective immunity with fewer doses, ideally just one. Single-dose vaccines would be ideal to maximize vaccination coverage, help stakeholders to greatly reduce the costs associated with vaccination, and improve patient convenience. Here we describe past attempts to develop potent single dose vaccines and explore the reasons they failed. Then, we review key immunological mechanisms of the vaccine-specific immune responses, and how innovative technologies and approaches are guiding the preclinical and clinical development of potent single-dose vaccines. By modulating the spatio-temporal delivery of the vaccine components, by providing the appropriate stimuli to the innate immunity, and by designing better antigens, the new technologies and approaches leverage our current knowledge of the immune system and may synergize to enable the rational design of next-generation vaccination strategies. This review provides a rational perspective on the possible development of future single-dose vaccines.

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