A common strategy to make vaccines more powerful is to deliver them along with an adjuvant—a compound that stimulates the immune system to produce a stronger response.
Researchers from MIT, the La Jolla Institute for Immunology, and other institutions have now designed a new nanoparticle adjuvant that may be more potent than others now in use.
“We started looking at this particular formulation and found that it was incredibly potent, better than almost anything else we had tried,” says Darrell Irvine, the Underwood-Prescott Professor with appointments in MIT’s departments of Biological Engineering and Materials Science and Engineering; an associate director of MIT’s Koch Institute for Integrative Cancer Research; and a member of the Ragon Institute of MGH, MIT, and Harvard.
The researchers now hope to incorporate the adjuvant into an HIV vaccine that is currently being tested in clinical trials, in hopes of improving its performance.
Irvine and Shane Crotty, a professor at the Center for Infectious Disease and Vaccine Research at the La Jolla Institute for Immunology, are the senior authors of the study, which appears today in Science Immunology. The lead authors of the paper are Murillo Silva, a former MIT postdoc, and Yu Kato, a staff scientist at the La Jolla Institute.
More powerful vaccines
Although the idea of using adjuvants to boost vaccine effectiveness has been around for decades, there are only a handful of FDA-approved vaccine adjuvants. One is aluminum hydroxide, an aluminum salt that induces inflammation, and another is an oil and water emulsion that is used in flu vaccines. A few years ago, the FDA approved an adjuvant based on saponin, a compound derived from the bark of the Chilean soapbark tree.
Saponin formulated in liposomes is now used as an adjuvant in the shingles vaccine, and saponins are also being used in a cage-like nanoparticle called an immunostimulatory complex (ISCOM) in a COVID-19 vaccine that is currently in clinical trials.
Researchers have shown that saponins promote inflammatory immune responses and stimulate antibody production, but how they do that is unclear. In the new study, the MIT and La Jolla team wanted to figure out how the adjuvant exerts its effects, and to see if they could make it more potent.
They designed a new type of adjuvant that is similar to the ISCOM adjuvant but also incorporates a molecule called MPLA, which is a toll-like receptor agonist. When these molecules bind to toll-like receptors on immune cells, they promote inflammation.
The researchers call their new adjuvant SMNP (saponin/MPLA nanoparticles).
“We expected that this could be interesting because saponin and toll-like receptor agonists are both adjuvants that have been studied separately and shown to be very effective,” Irvine says.
The researchers tested the adjuvant by injecting it into mice along with a few different antigens, or fragments of viral proteins. These included two HIV antigens, as well as diphtheria and influenza antigens. They compared the adjuvant to several other approved adjuvants and found that the new saponin-based nanoparticle elicited a stronger antibody response than any of the others.
One of the HIV antigens that they used is an HIV envelope protein nanoparticle, which presents many copies of the gp120 antigen that is present on the HIV viral surface. This antigen recently completed initial testing in phase 1 clinical trials. Irvine and Crotty are part of the Consortium for HIV/AIDS Vaccine Development at the Scripps Research Institute, which ran that trial.
The researchers now hope to develop a way to manufacture the new adjuvant at large scale so it can be tested along with an HIV envelope trimer in another clinical trial beginning next year. Clinical trials that combine envelope trimers with the traditional vaccine adjuvant aluminum hydroxide are also underway.
“Aluminum hydroxide is safe but not particularly potent, so we hope that (the new adjuvant) would be an interesting alternative to elicit neutralizing antibody responses in people,” Irvine says.
When vaccines are injected into the arm, they travel through lymph vessels to the lymph nodes, where they encounter and activate B cells. The research team found that the new adjuvant speeds up the flow of lymph to the nodes, helping the antigen to get there before it starts to break down. It does this in part by stimulating immune cells called mast cells, which previously were not known to be involved in vaccine responses.
“Getting to the lymph nodes quickly is useful because once you inject the antigen, it starts slowly breaking down. The sooner a B cell can see that antigen, the more likely it’s fully intact, so that B cells are targeting the structure as it will be present on the native virus,” Irvine says.
Additionally, once the vaccine reaches the lymph nodes, the adjuvant causes a layer of cells called macrophages, which act as a barrier, to die off quickly, making it easier for the antigen to get into the nodes.
Another way that the adjuvant helps boost immune responses is by activating inflammatory cytokines that drive a stronger response. The TLR agonist that the researchers included in the adjuvant is believed to amplify that cytokine response, but the exact mechanism for that is not known yet.
This kind of adjuvant could also be useful for any other kind of subunit vaccine, which consists of fragments of viral proteins or other molecules. In addition to their work on HIV vaccines, the researchers are also working on a potential COVID-19 vaccine, along with J. Christopher Love’s lab at the Koch Institute. The new adjuvant also appears to help stimulate T cell activity, which could make it useful as a component of cancer vaccines, which aim to stimulate the body’s own T cells to attack tumors.
Adjuvants are substances that enhance antigen-specific immune responses by triggering and modulating both the innate and adaptive (acquired) immunity2. They also allow the dose of expensive antigens to be limited, reduce booster immunizations, generate more rapid and durable immune responses, and increase the effectiveness of vaccines in poor responders.
Despite their key role, few sufficiently potent adjuvants with acceptable toxicity for human use are available in licensed vaccines. For more than 70 years, alum (a mixture of diverse aluminium salts) has been the only approved adjuvant in humans and is still one of the most popular in human vaccines.
In late 2009, Adjuvant System 04 (AS04), a proprietary combination of alum and the Toll-like receptor 4 (TLR4) ligand monophosphoryl lipid A (MPLA), was approved for the vaccine against human papillomavirus (HPV), Cervarix. However, aluminium adjuvants have relatively low potency and elicit primarily an antibody-mediated T helper 2 (TH2)-type immune response (Box 1), with weak stimulation of cell-mediated immunity.
Alum has been shown to act mainly as a delivery system that traps the antigen at the injection site by forming macromolecular aggregates, facilitating its slow release and uptake by antigen-presenting cells3. Nonetheless, the precise mechanism by which aluminium-containing adjuvants enhance the immune response remains poorly understood4.
Apart from aluminium salts, the only other licensed adjuvants in human vaccines are oil-in-water emulsions containing squalene (MF59, AS03), in vitro-assembled influenza-virus-like particles (virosomes), and, most recently, the liposome-based Adjuvant System AS01 (ref.5).
However, emulsion adjuvants have raised significant concerns owing to their adverse side effects6,7, and their molecular mechanisms of action are not fully defined8. AS01, a liposomal formulation containing MPLA and the saponin natural product QS-21, has only been recently approved for GSK’s malaria (Mosquirix) and shingles (Shingrix) vaccines, benefiting from a synergistic effect of both adjuvants in the early interferon-γ (IFNγ) response that enhanced vaccine immunogenicity9,10.
Therefore, there is still a pressing need for novel, potent and less toxic adjuvants and new formulations for use in subunit vaccines. Classical adjuvant searches focused on improving the strength of the immune response by increasing antibody and/or cytokine production.
Current efforts towards enhancing vaccine efficacy centre on the rational development of adjuvants that can elicit optimal, antigen-specific immune responses (responses associated with T helper 1 (TH1) cells or T helper 2 (TH2) cells, see Box 1), including tailored antibody isotype profiles and CD8+ T cell responses11.
To identify such adjuvants and select optimal adjuvant–antigen combinations with defined immunological profiles and low toxicity, elucidating their precise pharmacological pathways and molecular mechanisms of action is essential. This mechanistic understanding will, in turn, enable the rational development of future vaccines against various human diseases.
Carbohydrates represent the most widespread class of biomolecules in nature. They play crucial roles in the immune system function and the stimulation of the immune response12 that can be exploited by the chemistry community13. Carbohydrates possess many beneficial properties that make them promising adjuvant candidates, namely, high biocompatibility and tolerability and a strong safety profile14.
A variety of natural carbohydrate structures, particularly MPLA and QS-21, have been clinically evaluated as adjuvants and are part of licensed Adjuvant Systems (AS) in human vaccines against HPV (AS04), herpes zoster and malaria (AS01). However, carbohydrate-based immunopotentiators obtained from natural sources are usually difficult to obtain in sufficient quantity, purity and homogeneity.
Moreover, although the mechanisms of action of carbohydrate-based adjuvants have been extensively investigated, the molecular bases underlying the adjuvant activity of some of these compounds have not yet been fully elucidated. This is partly owing to the lack of tools to better explore its immune-potentiating effects. This, in turn, has hampered the rational design and development of optimized adjuvants and adjuvant combinations.
Furthermore, the complexity and sensitivity of the diverse functionalities of the natural product structure limit the chemical derivatization of the parent compound, leaving limited opportunities for generation of synthetic analogues and structure–activity studies.
By contrast, synthetic organic chemistry, including total synthesis and semi-synthetic strategies, offers a more attractive approach to molecularly defined, improved versions of carbohydrate-containing immunostimulants and chemical probes for mechanistic investigation, enabling structural modification of the corresponding natural products with a high level of chemical control.
Saponins are plant-derived natural products with a range of biological activities that consist of a lipophilic triterpenoid core flanked by one or more oligosaccharide chains (Fig. 1a). While the adjuvant activity of saponins has been widely investigated, including the recently identified Quillaja brasiliensis saponins15, the triterpene glycosides extracted from the bark of the Chilean tree Quillaja saponaria (i.e. QS) have been the primary focus for saponin-based adjuvant research since more than 30 years ago16.
Purification by reverse-phase high-performance liquid chromatography (HPLC) of a heterogeneous, adjuvant-active, semi-purified bark extract (i.e. Quil-A) containing more than 20 water-soluble Q. saponaria saponins led to the identification of several QS saponin fractions that elicited humoral and cell-mediated responses, including QS-21, QS-18, QS-17 and QS-7 (ref.17) (Fig. 1a).
The main saponin component, QS-18, was found to be highly toxic in mice but saponins QS-7 and QS-21 showed less toxicity. As QS-7 was less abundant, QS-21 was selected and has become the most widely studied saponin adjuvant for the past 25 years18.
QS-21 is not a single compound but a mixture of two isomeric saponins, QS-21-apiose (65% abundance) and QS-21-xylose (35% abundance), that share a glycosylated pseudo-dimeric acyl chain and a branched trisaccharide at the C3 position of the quillaic acid triterpene core, and differ in the terminal sugar of the linear tetrasaccharide that is linked to the C28 carboxyl group of the triterpene19 (Fig. 1a).
QS-21 has been the preferred adjuvant in numerous vaccine clinical trials against a variety of cancers18 and infectious diseases20, and vaccine formulations containing QS-21 as an adjuvant have been recently licensed for human use5. QS-21 stimulates both antibody-based and cell-mediated immune responses, eliciting a TH1-biased immune response21 with production of high titres of antibodies (IgG2a and IgG2b, in addition to IgG1), as well as antigen-specific cytotoxic T lymphocytes. However, except its recent approval as part of the AS01 system in GSK’s malaria (Mosquirix)22 and shingles (Shingrix)23 vaccines, the inherent liabilities of QS-21, including scarcity, heterogeneity, hydrolytic instability and dose-limiting toxicity, have limited its clinical advancement as a stand-alone adjuvant.
reference link : https://www.nature.com/articles/s41570-020-00244-3
More information: Murillo Silva et al, A particulate saponin/TLR agonist vaccine adjuvant alters lymph flow and modulates adaptive immunity, Science Immunology (2021). DOI: 10.1126/sciimmunol.abf1152. www.science.org/doi/10.1126/sciimmunol.abf1152