Comparative Safety of Vaccine Adjuvants: A Summary of Current Evidence and Future Needs.
ABSTRACT: 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.
Project description:PURPOSE OF REVIEW:The gradual replacement of inactivated whole cell and live attenuated vaccines with subunit vaccines has generally reduced reactogenicity but in many cases also immunogenicity. Although only used when necessary, adjuvants can be key to vaccine dose/antigen-sparing, broadening immune responses to variable antigens, and enhancing immunogenicity in vulnerable populations with distinct immunity. Licensed vaccines contain an increasing variety of adjuvants, with a growing pipeline of adjuvanted vaccines under development. RECENT FINDINGS:Most adjuvants, including Alum, Toll-like receptor agonists and oil-in-water emulsions, activate innate immunity thereby altering the quantity and quality of an adaptive immune response. Adjuvants activate leukocytes, and induce mediators (e.g., cytokines, chemokines, and prostaglandin-E2) some of which are biomarkers for reactogenicity, that is, induction of local/systemic side effects. Although there have been safety concerns regarding a hypothetical risk of adjuvants inducing auto-immunity, such associations have not been established. As immune responses vary by population (e.g., age and sex), adjuvant research now incorporates principles of precision medicine. Innovations in adjuvant research include use of human in vitro models, immuno-engineering, novel delivery systems, and systems biology to identify biomarkers of safety and adjuvanticity. SUMMARY:Adjuvants enhance vaccine immunogenicity and can be associated with reactogenicity. Novel multidisciplinary approaches hold promise to accelerate and de-risk targeted adjuvant discovery and development. VIDEO ABSTRACT: http://links.lww.com/MOP/A53.
Project description:BACKGROUND:Avian H7N9 influenza viruses possess a potential pandemic threat to public health worldwide, and have caused severe infection and high mortality in humans. A series of clinical trials of H7N9 vaccines have been completed. Meta-analyses need to be performed to assess the immunogenicity and safety of H7N9 vaccines. METHODS:Database research with defined selection criteria was conducted in PubMed, Cochrane Central Register of Controlled Trials, the World Health Organization's International Clinical Trials Registry Platform, ClinicalTrials.gov, etc. Data from randomized clinical trials regarding the immunogenicity and safety of H7N9 vaccines were collected and meta-analyzed. RESULTS:For non-adjuvanted H7N9 vaccines, high dose formulations induced limited immunogenicity and increased the risk of local and systemic adverse events, simultaneously. For adjuvanted H7N9 vaccines, on the one hand, ISCOMATRIX, MF59, AS03 and aluminium adjuvants applied in H7N9 vaccines could improve immune responses effectively, and non-aluminium adjuvants had superior performance in saving vaccine dose; on the other hand, aluminium adjuvant had the advantages of safety amongst these adjuvants applied in H7N9 vaccines. CONCLUSION:H7N9 influenza vaccines with adjuvant might represent the optimal available option in an influenza pandemic, at present.
Project description:In recent years, heterologous prime-boost vaccines have been demonstrated to be an effective strategy for generating protective immunity, consisting of both humoral and cell-mediated immune responses against a variety of pathogens including HIV-1. Previous reports of preclinical and clinical studies have shown the enhanced immunogenicity of viral vector or DNA vaccination followed by heterologous protein boost, compared to using either prime or boost components alone. With such approaches, the selection of an adjuvant for inclusion in the protein boost component is expected to impact the immunogenicity and safety of a vaccine. In this study, we examined in a mouse model the serum cytokine and chemokine profiles for several candidate adjuvants: QS-21, Al(OH)3, monophosphoryl lipid A (MPLA) and ISCOMATRIX™ adjuvant, in the context of a previously tested pentavalent HIV-1 Env DNA prime-protein boost formulation, DP6-001. Our data revealed that the candidate adjuvants in the context of the DP6-001 formulation are characterized by unique serum cytokine and chemokine profiles. Such information will provide valuable guidance in the selection of an adjuvant for future AIDS vaccine development, with the ultimate goal of enhancing immunogenicity while minimizing reactogenicity associated with the use of an adjuvant. More significantly, results reported here will add to the knowledge on how to include an adjuvant in the context of a heterologous prime-protein boost vaccination strategy in general.
Project description:A central goal in vaccinology is the induction of high and sustained Ab responses. Protein-in-adjuvant formulations are commonly used to achieve such responses. However, their clinical development can be limited by the reactogenicity of some of the most potent preclinical adjuvants and the cost and complexity of licensing new adjuvants for human use. Also, few adjuvants induce strong cellular immunity, which is important for protection against many diseases, such as malaria. We compared classical adjuvants such as aluminum hydroxide to new preclinical adjuvants and adjuvants in clinical development, such as Abisco 100, CoVaccine HT, Montanide ISA720, and stable emulsion-glucopyranosyl lipid A, for their ability to induce high and sustained Ab responses and T cell responses. These adjuvants induced a broad range of Ab responses when used in a three-shot protein-in-adjuvant regimen using the model Ag OVA and leading blood-stage malaria vaccine candidate Ags. Surprisingly, this range of Ab immunogenicity was greatly reduced when a protein-in-adjuvant vaccine was used to boost Ab responses primed by a human adenovirus serotype 5 vaccine recombinant for the same Ag. This human adenovirus serotype 5-protein regimen also induced a more cytophilic Ab response and demonstrated improved efficacy of merozoite surface protein-1 protein vaccines against a Plasmodium yoelii blood-stage challenge. This indicates that the differential immunogenicity of protein vaccine adjuvants may be largely overcome by prior immunization with recombinant adenovirus, especially for adjuvants that are traditionally considered poorly immunogenic in the context of subunit vaccination and may circumvent the need for more potent chemical adjuvants.
Project description:Novel vaccine strategies include the so-called subunit vaccines, which encompass only the part of the pathogen to which immune recognition results in protection. The high purity of these vaccines make adverse events less likely, but it also makes the vaccines less immunogenic and therefore potentially less effective. Vaccine adjuvants that increase and modulate the immunogenicity of the vaccine are therefore added to solve this problem. Besides aluminum salts, which have been used in vaccines for 90 years, a number of novel vaccine adjuvants have been included in licensed vaccines over the last 30 years. Increasing insight into immunological mechanisms and how to manipulate them has replaced empirical with rational design of adjuvants, leading to vaccine adjuvants with increased and customized immunogenicity profiles without compromising vaccine safety.
Project description:Vaccine adjuvants help to enhance the immunogenicity of weak antigens. The adjuvant effect of certain substances was noted long ago (the 40s of the last century), and since then a large number of adjuvants belonging to different groups of chemicals have been studied. This review presents research data on the nonspecific action of substances originated from marine organisms, their derivatives and complexes, united by the name 'adjuvants'. There are covered the mechanisms of their action, safety, as well as the practical use of adjuvants derived from marine hydrobionts in medical immunology and veterinary medicine to create modern vaccines that should be non-toxic and efficient. The present review is intended to briefly describe some important achievements in the use of marine resources to solve this important problem.
Project description:The current paradigm that subunit vaccines require adjuvants to optimally activate innate immunity implies that increased vaccine reactogenicity will invariably be linked to improved immunogenicity. Countering this paradigm, nanoparticulate vaccines have been reported to act as delivery systems for vaccine antigens and induce immunity without the need for exogenous adjuvants or local inflammation; however, the mechanisms underlying the immunogenicity of nanoparticle vaccines are incompletely identified. Here, we show that antigens displayed on self-assembling nanofiber scaffolds and delivered intranasally are presented by CD103+ and CD11b+ lung dendritic cells that up-regulate CD80 and migrate into the draining lymph node (LN). This was accompanied by a nearly exclusive priming and accumulation of antigen-specific TH17 cells occurring independently in both LN and lung. Thus, self-assembling peptide nanofiber vaccines may represent a novel, needle- and adjuvant-free means of eliciting protective immunity against fungal and bacterial infections at skin and mucosal barrier surfaces.
Project description:<h4>Background</h4>Fully efficient vaccines against malaria pre-erythrocytic stage are still lacking. The objective of this dose/adjuvant-finding study was to evaluate the safety, reactogenicity and immunogenicity of a vaccine candidate based on a peptide spanning the C-terminal region of Plasmodium falciparum circumsporozoite protein (PfCS102) in malaria naive adults.<h4>Methodology and principal findings</h4>Thirty-six healthy malaria-naive adults were randomly distributed into three dose blocks (10, 30 and 100 microg) and vaccinated with PfCS102 in combination with either Montanide ISA 720 or GSK proprietary Adjuvant System AS02A at days 0, 60, and 180. Primary end-point (safety and reactogenicity) was based on the frequency of adverse events (AE) and of abnormal biological safety tests; secondary-end point (immunogenicity) on P. falciparum specific cell-mediated immunity and antibody response before and after immunization. The two adjuvant formulations were well tolerated and their safety profile was good. Most AEs were local and, when systemic, involved mainly fatigue and headache. Half the volunteers in AS02A groups experienced severe AEs (mainly erythema). After the third injection, 34 of 35 volunteers developed anti-PfCS102 and anti-sporozoite antibodies, and 28 of 35 demonstrated T-cell proliferative responses and IFN-gamma production. Five of 22 HLA-A2 and HLA-A3 volunteers displayed PfCS102 specific IFN-gamma secreting CD8(+) T cell responses. Responses were only marginally boosted after the 3(rd) vaccination and remained stable for 6 months. For both adjuvants, the dose of 10 microg was less immunogenic in comparison to 30 and 100 microg that induced similar responses. AS02A formulations with 30 microg or 100 microg PfCS102 induced about 10-folds higher antibody and IFN-gamma responses than Montanide formulations.<h4>Conclusions/significance</h4>PfCS102 peptide was safe and highly immunogenic, allowing the design of more advanced trials to test its potential for protection. Two or three immunizations with a dose of 30 microg formulated with AS02A appeared the most appropriate choice for such studies.<h4>Trial registration</h4>Swissmedic.ch 2002 DR 1227.
Project description:Enterovirus 71 (EV71) is a major causative agent of hand-foot-and-mouth disease (HFMD) frequently occurring in children. HFMD induced by EV71 can cause serious health problems and has been reported worldwide, particularly in the Asia-Pacific region. In this study, we assessed the immunogenicity of a formalin-inactivated HFMD vaccine using an EV71 strain (FI-EV71 C4a) isolated from a Korean patient. The vaccine candidate was evaluated in mice to determine the vaccination doses and vaccine schedules. BALB/c mice were intramuscularly administered 5, 10, or 20 ?g FI-EV71 vaccine, followed by a booster 2 weeks later. EV71-specific antibodies and neutralizing antibodies were induced and maintained until the end of the experimental period in all vaccinated groups. To determine the effectiveness of adjuvant for the EV71 vaccine, three adjuvants, i.e., aluminium hydroxide gel, monophosphoryl lipid A, and polyinosinic-polycytidylic acid, were administered separately with the FI-EV71 vaccine to mice via the intramuscular route. Mice administered the FI-EV71 vaccine formulated with all three adjuvants induced a significantly increased antibody response compared with that of the single adjuvant groups. The vaccinated group with triple adjuvants exhibited more rapid induction of EV71-specific and neutralizing antibodies than the other groups. These results suggested that the role of adjuvant in inactivated vaccine was important for eliciting effective immune responses against EV71. In conclusion, our results showed that FI-EV71 was a potential candidate vaccine for prevention of EV71 infection.
Project description:This phase 2/3, randomized, placebo-controlled, observer-blinded study assessed the immunogenicity, reactogenicity, and safety of an inactivated, split-virion H5N1 influenza vaccine (A/Indonesia/5/2005) in children aged 6 months through 17 years.Children received 2 influenza vaccine doses 21 days apart, each containing 1.9 µg of hemagglutinin and AS03B adjuvant (5.93 mg of ?-tocopherol). The randomization ratio was 8:3 for vaccine to placebo, with equal allocation between 3 age strata (6-35 months, 3-8 years, and 9-17 years). Immunogenicity against the vaccine strain was assessed 21 days after the first and second vaccine doses for all vaccinees, at day 182 for half, and at day 385 for the remaining half. Reactogenicity after each dose and safety up to 1 year after vaccination were evaluated.Within each age stratum, the lower limit of the 98.3% confidence interval for the day 42 seroprotection rate was ?70%, thus fulfilling the US and European licensure criteria. The immune responses elicited by vaccine persisted well above baseline levels for 1 year. The vaccine was more reactogenic than placebo, but no major safety concerns were identified.AS03B-adjuvanted H5N1 influenza vaccine was immunogenic and showed an acceptable safety profile in all age groups studied. Clinical Trials Registration: NCT01310413.