Use of highly pure antigens to improve vaccine safety has led to reduced vaccine immunogenicity and efficacy. This has led to the need to use adjuvants to improve vaccine immunogenicity. The ideal ...adjuvant should maximize vaccine immunogenicity without compromising tolerability or safety. Unfortunately, adjuvant research has lagged behind other vaccine areas such as antigen discovery, with the consequence that only a very limited number of adjuvants based on aluminium salts, monophosphoryl lipid A and oil emulsions are currently approved for human use. Recent strategic initiatives to support adjuvant development by the National Institutes of Health should translate into greater adjuvant choices in the future. Mechanistic studies have been valuable for better understanding of adjuvant action, but mechanisms of adjuvant toxicity are less well understood. The inflammatory or danger-signal model of adjuvant action implies that increased vaccine reactogenicity is the inevitable price for improved immunogenicity. Hence, adjuvant reactogenicity may be avoidable only if it is possible to separate inflammation from adjuvant action. The biggest remaining challenge in the adjuvant field is to decipher the potential relationship between adjuvants and rare vaccine adverse reactions, such as narcolepsy, macrophagic myofasciitis or Alzheimer's disease. While existing adjuvants based on aluminium salts have a strong safety record, there are ongoing needs for new adjuvants and more intensive research into adjuvants and their effects.
Recombinant protein vaccines represent a well-established, reliable and safe approach for pandemic vaccination. SpikoGen® is a recombinant spike protein trimer manufactured in insect cells and ...formulated with Advax-CpG55.2 adjuvant. In murine, hamster, ferret and non-human primate studies, SpikoGen® consistently provided protection against a range of SARS-CoV-2 variants. A pivotal Phase 3 placebo-controlled efficacy trial involving 16,876 participants confirmed the ability of SpikoGen® to prevent infection and severe disease caused by the virulent Delta strain. SpikoGen® subsequently received a marketing authorization from the Iranian FDA in early October 2021 for prevention of COVID-19 in adults. Following a successful pediatric study, its approval was extended to children 5 years and older. Eight million doses of SpikoGen® have been delivered, and a next-generation booster version is currently in development. This highlights the benefits of adjuvanted protein-based approaches which should not overlook when vaccine platforms are being selected for future pandemics.Recombinant protein vaccines represent a well-established, reliable and safe approach for pandemic vaccination. SpikoGen® is a recombinant spike protein trimer manufactured in insect cells and formulated with Advax-CpG55.2 adjuvant. In murine, hamster, ferret and non-human primate studies, SpikoGen® consistently provided protection against a range of SARS-CoV-2 variants. A pivotal Phase 3 placebo-controlled efficacy trial involving 16,876 participants confirmed the ability of SpikoGen® to prevent infection and severe disease caused by the virulent Delta strain. SpikoGen® subsequently received a marketing authorization from the Iranian FDA in early October 2021 for prevention of COVID-19 in adults. Following a successful pediatric study, its approval was extended to children 5 years and older. Eight million doses of SpikoGen® have been delivered, and a next-generation booster version is currently in development. This highlights the benefits of adjuvanted protein-based approaches which should not overlook when vaccine platforms are being selected for future pandemics.
In the two decades since their initial discovery, DNA vaccines technologies have come a long way. Unfortunately, when applied to human subjects inadequate immunogenicity is still the biggest ...challenge for practical DNA vaccine use. Many different strategies have been tested in preclinical models to address this problem, including novel plasmid vectors and codon optimization to enhance antigen expression, new gene transfection systems or electroporation to increase delivery efficiency, protein or live virus vector boosting regimens to maximise immune stimulation, and formulation of DNA vaccines with traditional or molecular adjuvants. Better understanding of the mechanisms of action of DNA vaccines has also enabled better use of the intrinsic host response to DNA to improve vaccine immunogenicity. This review summarizes recent advances in DNA vaccine technologies and related intracellular events and how these might impact on future directions of DNA vaccine development.
Abstract
The devastating impact of the COVID-19 pandemic caused by SARS–coronavirus 2 (SARS-CoV-2) has raised important questions about its origins and the mechanism of its transfer to humans. A ...further question was whether companion or commercial animals could act as SARS-CoV-2 vectors, with early data suggesting susceptibility is species specific. To better understand SARS-CoV-2 species susceptibility, we undertook an in silico structural homology modelling, protein–protein docking, and molecular dynamics simulation study of SARS-CoV-2 spike protein’s ability to bind angiotensin converting enzyme 2 (ACE2) from relevant species. Spike protein exhibited the highest binding to human (h)ACE2 of all the species tested, forming the highest number of hydrogen bonds with hACE2. Interestingly, pangolin ACE2 showed the next highest binding affinity despite having a relatively low sequence homology, whereas the affinity of monkey ACE2 was much lower despite its high sequence similarity to hACE2. These differences highlight the power of a structural versus a sequence-based approach to cross-species analyses. ACE2 species in the upper half of the predicted affinity range (monkey, hamster, dog, ferret, cat) have been shown to be permissive to SARS-CoV-2 infection, supporting a correlation between binding affinity and infection susceptibility. These findings show that the earliest known SARS-CoV-2 isolates were surprisingly well adapted to bind strongly to human ACE2, helping explain its efficient human to human respiratory transmission. This study highlights how in silico structural modelling methods can be used to rapidly generate information on novel viruses to help predict their behaviour and aid in countermeasure development.
•Polysaccharides have physical and chemical properties suitable for drug delivery systems.•Polysaccharides provide a range of drug stabilization, delivery and release mechanisms.•Polysaccharide drug ...delivery systems are biocompatible, biodegradable and non-toxic.•Particle-based drug delivery systems are easily constructed from polysaccharides.•Polysaccharide particles can deliver protein, oligonucleotide and small molecule drug forms.
This review investigates the significant role polysaccharide particles play in functional drug delivery. The importance of these systems is due to the wide variety of polysaccharides and their natural source meaning that they can provide biocompatible and biodegradable systems with a range of both biological and chemical functionality valuable for drug delivery. This functionality includes protection and presentation of working therapeutics through avoidance of the reticuloendothelial system, stabilization of biomacromolecules and increasing the bioavailability of incorporated small molecule drugs. Transport of the therapeutic is also key to the utility of polysaccharide particles, moving drugs from the site of administration through mucosal binding and transport and using chemistry, size and receptor mediated drug targeting to specific tissues. This review also scrutinizes the methods of synthesizing and constructing functional polysaccharide particle drug delivery systems that maintain and extend the functionality of the natural polysaccharides.
The problem with pure recombinant or synthetic antigens used in modern day vaccines is that they are generally far less immunogenic than older style live or killed whole organism vaccines. This has ...created a major need for improved and more powerful adjuvants for use in these vaccines. With few exceptions, alum remains the sole adjuvant approved for human use in the majority of countries worldwide. Although alum is able to induce a good antibody (Th2) response, it has little capacity to stimulate cellular (Th1) immune responses which are so important for protection against many pathogens. In addition, alum has the potential to cause severe local and systemic side-effects including sterile abscesses, eosinophilia and myofascitis, although fortunately most of the more serious side-effects are relatively rare. There is also community concern regarding the possible role of aluminium in neurodegenerative diseases such as Alzheimer's disease. Consequently, there is a major unmet need for safer and more effective adjuvants suitable for human use. In particular, there is demand for safe and non-toxic adjuvants able to stimulate cellular (Th1) immunity. Other needs in light of new vaccine technologies are adjuvants suitable for use with mucosally-delivered vaccines, DNA vaccines, cancer and autoimmunity vaccines. Each of these areas are highly specialized with their own unique needs in respect of suitable adjuvant technology. This paper reviews the state of the art in the adjuvant field, explores future directions of adjuvant development and finally examines some of the impediments and barriers to development and registration of new human adjuvants.
Blockchain technology provides a major advance for excipient supply chains, assisting in the delivery of unadulterated, source, process and transit verifiable excipients (or APIs and drug products), ...but does not alleviate the necessity for quality audits. The adoption of blockchain technology should make the process faster and make the transactional record more robust and reliable, however other rate-limiting steps of the excipient supply chain including transit and testing time will remain. In terms of pure speed, blockchain is suited to financial transactions where no physical goods change hands (such as financial instruments and derivatives, stocks, insurance, land-registry, taxation, medical records etc.) but this does not mean that it should be ignored in respect of the advantages it could offer in improving the excipient supply chain.
COVID-19 vaccines have played an important role in reducing the impact of the current pandemic. Previously, we developed NARUVAX-C19 vaccine based on a recombinant Wuhan spike protein extracellular ...domain expressed in insect cells and formulated with a squalene emulsion adjuvant (Sepivac SWE™). The current study assessed the immunogenicity, efficacy, and safety of NARUVAX-C19 vaccine in rhesus macaques and hamsters. Macaques immunized intramuscularly with two doses of NARUVAX-C19 vaccine showed no adverse effects and demonstrated cellular immunity as assessed by T cell IFN-γ responses against spike protein, in addition to inducing a humoral response. Serum from immunized animals neutralized the homologous wild-type SARS-CoV-2 virus as well as the Alpha and Delta variants. In hamsters, immunization with NARUVAX-C19 vaccine protected against a heterologous challenge with the Delta virus, as reflected by reduced lung and nasal viral loads and lung pathology in immunized animals. Nevertheless, some NARUVAX-C19 vaccinated animals were still shown to transmit infection to naïve sentinel animals. Overall, NARUVAX-C19 vaccine induced broadly cross-neutralizing antibody and T cell IFN-γ responses in rhesus macaques and provided heterologous protection of hamsters against infection by the Delta virus variant. This data supports the utility of squalene emulsion-based adjuvanted recombinant vaccine in protection against SARS-CoV-2 and supports their continued clinical development.
A malaria vaccine that elicits long-lasting protection and is suitable for use in endemic areas remains urgently needed. Here, we assessed the immunogenicity and prophylactic efficacy of a vaccine ...targeting a recently described epitope on the major surface antigen on Plasmodium falciparum sporozoites, circumsporozoite protein (CSP). Using a virus-like particle (VLP)-based vaccine platform technology, we developed a vaccine that targets the junctional region between the N-terminal and central repeat regions of CSP. This region is recognized by monoclonal antibodies, including mAb CIS43, that have been shown to potently prevent liver invasion in animal models. We show that CIS43 VLPs elicit high-titer and long-lived anti-CSP antibody responses in mice and is immunogenic in non-human primates. In mice, vaccine immunogenicity was enhanced by using mixed adjuvant formulations. Immunization with CIS43 VLPs conferred partial protection from malaria infection in a mouse model, and passive transfer of serum from immunized macaques also inhibited parasite liver invasion in the mouse infection model. Our findings demonstrate that a Qβ VLP-based vaccine targeting the CIS43 epitope combined with various adjuvants is highly immunogenic in mice and macaques, elicits long-lasting anti-CSP antibodies, and inhibits parasite infection in a mouse model. Thus, the CIS43 VLP vaccine is a promising pre-erythrocytic malaria vaccine candidate.
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