Note: This article was originally published with an incorrect version of the Acknowledgments, which appeared on p. 218 of the print version. The correct version of the Acknowledgments appeared on pp. ...1-2. The corrected article is available below.
A vaccine against coronavirus disease 2019 (COVID-19) is urgently needed.
To evaluate the safety and immunogenicity of an investigational inactivated whole-virus COVID-19 vaccine in China.
In the ...phase 1 trial, 96 participants were assigned to 1 of the 3 dose groups (2.5, 5, and 10 μg/dose) and an aluminum hydroxide (alum) adjuvant-only group (n = 24 in each group), and received 3 intramuscular injections at days 0, 28, and 56. In the phase 2 trial, 224 adults were randomized to 5 μg/dose in 2 schedule groups (injections on days 0 and 14 n = 84 vs alum only n = 28, and days 0 and 21 n = 84 vs alum only n = 28).
Interim analysis of ongoing randomized, double-blind, placebo-controlled, phase 1 and 2 clinical trials to assess an inactivated COVID-19 vaccine. The trials were conducted in Henan Province, China, among 96 (phase 1) and 224 (phase 2) healthy adults aged between 18 and 59 years. Study enrollment began on April 12, 2020. The interim analysis was conducted on June 16, 2020, and updated on July 27, 2020.
The primary safety outcome was the combined adverse reactions 7 days after each injection, and the primary immunogenicity outcome was neutralizing antibody response 14 days after the whole-course vaccination, which was measured by a 50% plaque reduction neutralization test against live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Among 320 patients who were randomized (mean age, 42.8 years; 200 women 62.5%), all completed the trial up to 28 days after the whole-course vaccination. The 7-day adverse reactions occurred in 3 (12.5%), 5 (20.8%), 4 (16.7%), and 6 (25.0%) patients in the alum only, low-dose, medium-dose, and high-dose groups, respectively, in the phase 1 trial; and in 5 (6.0%) and 4 (14.3%) patients who received injections on days 0 and 14 for vaccine and alum only, and 16 (19.0%) and 5 (17.9%) patients who received injections on days 0 and 21 for vaccine and alum only, respectively, in the phase 2 trial. The most common adverse reaction was injection site pain, followed by fever, which were mild and self-limiting; no serious adverse reactions were noted. The geometric mean titers of neutralizing antibodies in the low-, medium-, and high-dose groups at day 14 after 3 injections were 316 (95% CI, 218-457), 206 (95% CI, 123-343), and 297 (95% CI, 208-424), respectively, in the phase 1 trial, and were 121 (95% CI, 95-154) and 247 (95% CI, 176-345) at day 14 after 2 injections in participants receiving vaccine on days 0 and 14 and on days 0 and 21, respectively, in the phase 2 trial. There were no detectable antibody responses in all alum-only groups.
In this interim report of the phase 1 and phase 2 trials of an inactivated COVID-19 vaccine, patients had a low rate of adverse reactions and demonstrated immunogenicity; the study is ongoing. Efficacy and longer-term adverse event assessment will require phase 3 trials.
Chinese Clinical Trial Registry Identifier: ChiCTR2000031809.
Aluminum salts, although they have been used as adjuvants in many vaccine formulations since 1926, exclusively induce a Th2-biased immune response, thereby limiting their use against intracellular ...pathogens like
.
Herein, we synthesized amorphous and crystalline forms of aluminum hydroxide nanoparticles (AH nps) of 150-200 nm size range. Using
protective antigen domain 4 (D4) as a model antigen, we demonstrated that both amorphous and crystalline forms of AH nps displayed enhanced antigen D4 uptake by THP1 cells as compared to commercial adjuvant aluminum hydroxide gel (AH gel). In a mouse model, both amorphous and crystalline AH nps triggered an enhanced D4-specific Th2- and Th1-type immune response and conferred superior protection against anthrax spore challenge as compared to AH gel. Physicochemical characterization of crystalline and amorphous AH nps revealed stronger antigen D4 binding and release than AH gel.
These results demonstrate that size and crystallinity of AH nps play important roles in mediating enhanced antigen presenting cells (APCs) activation and potentiating a strong antigen-specific immune response, and are critical parameters for the rational design of alum-based Th1-type adjuvant to induce a more balanced antigen-specific immune response.
This study introduces a new strategy for periodic stacking of positively charged NiAl layered double hydroxides (LDHs) nanosheets with negatively charged monolayers of graphene (G) by systematically ...optimizing several parameters in a controlled co-feeding fashion and resultant heterostacked NiAl LDH/G LBL nanocomposites have been practically applied in sensitive detection of dopamine released from live cells as early Parkinson's disease (PD) diagnostic tool. PD is the second most chronic neurodegenerative disorder with gradual progressive loss of movement and muscle control causing substantial disability and threatening the life seriously. Unfortunately majority of dopaminergic neurons present in substantia nigra of PD patients are destroyed before it is being clinically diagnosed, so early stages PD diagnosis is essential. Because of direct neighboring of extremely conductive graphene to semiconductive LDHs layers, enhanced intercalation capability of LDHs, and huge surface area with numerous active sites, good synergy effect is harvested in heteroassembled NiAl LDH/G LBL material, which in turn shows admirable electrocatalytic ability in DA detection. The interference induced by UA and AA is effectively eliminated especially after the modifying the electrode with Nafion. The outstanding electrochemical sensing performance of NiAl LDH/G LBL modified electrode has been achieved in terms of broad linear range and lowest real detection limit of 2 nM (S/N = 3) towards DA oxidation. Benefitting from superior efficiency, biosensor has been successfully used for real-time in-vitro tracking of DA efflux from live human nerve cell after being stimulated. We believe that our biosensing platform of structurally integrated well-ordered LBL heteroassembly by inserting graphene directly to the interlayer galleries of LDHs material will open up new avenue in diseases determination window.
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•Optimized co-feeding methodology has been used for the fabrication of NiAl LDH/G LBL nanocomposites.•Graphene nanosheets as π-electron-rich substrate modulate electronic structure of NiAl LDHs.•NiAl LDH/G electrode exhibits excellent electrochemical performance for the sensitive detection of DA.•Real-time monitoring of DA secretions from live human nerve cells.
In the past few decades, hundreds of materials have been tried as adjuvant; however, only aluminum-based adjuvants continue to be used widely in the world. Aluminum hydroxide, aluminum phosphate and ...alum constitute the main forms of aluminum used as adjuvants. Among these, aluminum hydroxide is the most commonly used chemical as adjuvant. In spite of its wide spread use, surprisingly, the mechanism of how aluminum hydroxide-based adjuvants exert their beneficial effects is still not fully understood. Current explanations for the mode of action of aluminum hydroxide-based adjuvants include, among others, the repository effect, pro-phagocytic effect, and activation of the pro-inflammatory NLRP3 pathway. These collectively galvanize innate as well as acquired immune responses and activate the complement system. Factors that have a profound influence on responses evoked by aluminum hydroxide-based adjuvant applications include adsorption rate, strength of the adsorption, size and uniformity of aluminum hydroxide particles, dosage of adjuvant, and the nature of antigens. Although vaccines containing aluminum hydroxide-based adjuvants are beneficial, sometimes they cause adverse reactions. Further, these vaccines cannot be stored frozen. Until recently, aluminum hydroxide-based adjuvants were known to preferentially prime Th2-type immune responses. However, results of more recent studies show that depending on the vaccination route, aluminum hydroxide-based adjuvants can enhance both Th1 as well as Th2 cellular responses. Advances in systems biology have opened up new avenues for studying mechanisms of aluminum hydroxide-based adjuvants. These will assist in scaling new frontiers in aluminum hydroxide-based adjuvant research that include improvement of formulations, use of nanoparticles of aluminum hydroxide and development of composite adjuvants.
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No United States Food and Drug Administration-licensed vaccines protective against Ebola virus (EBOV) infections are currently available. EBOV vaccine candidates currently in ...development, as well as most currently licensed vaccines in general, require transport and storage under a continuous cold chain in order to prevent potential decreases in product efficacy. Cold chain requirements are particularly difficult to maintain in developing countries. To improve thermostability and reduce costly cold chain requirements, a subunit protein vaccine against EBOV was formulated as a glassy solid using lyophilization. Formulations of the key antigen, Ebola glycoprotein (EBOV-GP), adjuvanted with microparticulate aluminum hydroxide were prepared in liquid and lyophilized forms, and the vaccines were incubated at 40 °C for 12 weeks. Aggregation and degradation of EBOV-GP were observed in liquid formulations during the 12-week incubation period, whereas changes were minimal in lyophilized formulations. Antibody responses against EBOV-GP following three intramuscular immunizations in BALB/c mice were used to determine vaccine immunogenicity. EBOV-GP formulations were equally immunogenic in liquid and lyophilized forms. After lyophilization and reconstitution, adjuvanted vaccine formulations produced anti-EBOV-GP IgG antibody responses in mice similar to those generated against corresponding adjuvanted liquid vaccine formulations. More importantly, antibody responses in mice injected with reconstituted lyophilized vaccine formulations that had been incubated at 40 °C for 12 weeks prior to injection indicated that vaccine immunogenicity was fully retained after high-temperature storage, showing promise for future vaccine development efforts.
Aluminum salts have been used as vaccine adjuvants for >50 years, and they are currently present in at least 146 licensed vaccines worldwide. In this study we examined whether adsorption of Army ...Liposome Formulation (ALF) to an aluminum salt that already has an antigen adsorbed to it might result in improved immune potency of the aluminum-adsorbed antigen. ALF is composed of a family of anionic liposome-based adjuvants, in which the liposomes contain synthetic phospholipids having dimyristoyl fatty acyl groups, cholesterol and monophosphoryl lipid A (MPLA). For certain candidate vaccines, ALF has been added to aluminum hydroxide (AH) gel as a second adjuvant to form ALFA. Here we show that different methods of preparation of ALF changed the physical structures of both ALF and ALFA. Liposomes containing the saponin QS21 (ALFQ) have also been mixed with AH to form ALFQA as an effective combination. In this study, we first adsorbed one of two different antigens to AH, either tetanus toxoid conjugated to 34 copies of a hapten (MorHap), which has been used in a candidate heroin vaccine, or gp140 protein derived from the envelope protein of HIV-1. We then co-adsorbed ALF or ALFQ to the AH to form ALFA or ALFQA. In each case, the immune potency of the antigen adsorbed to AH was greatly increased by co-adsorbing either ALF or ALFQ to the AH. Based on IgG subtype and cytokine analysis by ELISPOT, ALFA induced predominately a Th2-type response and ALFQ and ALFQA each induced more balanced Th1/Th2 responses.
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Shigella remains in the top four pathogens responsible for moderate to severe diarrhoea in children below 5 years of age. The shigella O-specific polysaccharide (O-SP) is a promising vaccine target. ...We developed a conjugate vaccine prototype incorporating a unique well defined synthetic oligosaccharide hapten, chemically designed for optimal antigenic, conformational, structural, and functional mimicry of the O-SP from Shigella flexneri 2a (SF2a). We aimed to assess the safety, tolerability, and immunogenicity of this original synthetic oligosaccharide-based vaccine candidate, SF2a-TT15, conceived to drive the antibody response towards the key protective determinants of the native lipopolysaccharide antigen, in a first-in-human phase 1 study.
We did a first-in-human, dose-escalating, single-blind, observer-masked, randomised, placebo-controlled study at the Clinical Research Center of Tel Aviv Sourasky Medical Center (Israel). Participants were healthy adults aged 18–45 years with low titres of serum SF2a-specific IgG antibodies. 64 eligible participants were assigned to one of two cohorts. 32 participants in each of the two cohorts were randomly assigned via computer-generated algorithm in a stepwise manner to receive the 2 μg (cohort 1) and 10 μg oligosaccharide dose (cohort 2) of the SF2a-TT15 vaccine candidate non-adjuvanted or adjuvanted with aluminium hydroxide (alum) or matching placebos. The vaccine was administered as three single intramuscular injections into the arm, 28 days apart. The primary outcome was the incidence and severity of adverse events, which were assessed in the intention-to-treat safety population analysis including all participants who were randomly assigned and received at least one vaccine or placebo injection. The immunogenicity endpoints were secondary outcomes and were analysed in all participants who were randomly assigned, received all of the assigned injections before the time of the immunogenicity assessment, and provided blood samples for immunological follow-up (per-protocol immunogenicity analysis). The study is registered with ClinicalStudies.gov, NCT02797236 and is completed.
Of 203 volunteers initially screened, 64 participants were enrolled between Sept 20, 2016, and Sept 26, 2017. In each of the two cohorts, 12 participants received the adjuvanted vaccine, 12 received the non-adjuvanted vaccine and eight received the matching placebo (four each). The SF2a-TT15 glycoconjugate was well tolerated at both doses. No serious or severe adverse events occurred. Overall, seven (88%) of eight to 12 (100%) of 12 in each group of volunteers had one adverse event or more after receiving the study agents with the majority of adverse events, 300 (98%) of 307, considered mild in intensity. Of the seven adverse events defined as moderate in severity, one (nausea) was suspected to be related to the vaccine candidate. At all post-immunisation days and for both oligosaccharide doses, whether adjuvanted or not, SF2a-TT15 induced significantly higher serum IgG anti-SF2a lipopolysaccharide geometric mean titres (GMTs) as compared with baseline or with the corresponding GMTs in placebo recipients (p<0·01). After one injection, the non-adjuvanted 10 μg oligosaccharide dose induced a 27-times increase in IgG GMT (5080 vs 189) and the non-adjuvanted 2 μg oligosaccharide dose induced a five-times increase (1411 vs 283), compared with baseline. Alum enhanced the specific IgG response at 2 μg oligosaccharide dose after the third injection (GMTs 3200 vs 1176, p=0.045).
SF2a-TT15 was safe and well tolerated and induced high titres of anti-SF2a LPS IgG antibodies. These results support further evaluation of this original synthetic oligosaccharide-protein conjugate vaccine candidate for safety, immunogenicity, and protective efficacy in target populations.
The European Union Seventh Framework Programme.
Abstract Aluminium (Al) oxyhydroxide (Alhydrogel® ), the main adjuvant licensed for human and animal vaccines, consists of primary nanoparticles that spontaneously agglomerate. Concerns about its ...safety emerged following recognition of its unexpectedly long-lasting biopersistence within immune cells in some individuals, and reports of chronic fatigue syndrome, cognitive dysfunction, myalgia, dysautonomia and autoimmune/inflammatory features temporally linked to multiple Al-containing vaccine administrations. Mouse experiments have documented its capture and slow transportation by monocyte-lineage cells from the injected muscle to lymphoid organs and eventually the brain. The present study aimed at evaluating mouse brain function and Al concentration 180 days after injection of various doses of Alhydrogel® (200, 400 and 800 μg Al/kg of body weight) in the tibialis anterior muscle in adult female CD1 mice. Cognitive and motor performances were assessed by 8 validated tests, microglial activation by Iba-1 immunohistochemistry, and Al level by graphite furnace atomic absorption spectroscopy. An unusual neuro-toxicological pattern limited to a low dose of Alhydrogel® was observed. Neurobehavioural changes, including decreased activity levels and altered anxiety-like behaviour, were observed compared to controls in animals exposed to 200 μg Al/kg but not at 400 and 800 μg Al/kg. Consistently, microglial number appeared increased in the ventral forebrain of the 200 μg Al/kg group. Cerebral Al levels were selectively increased in animals exposed to the lowest dose, while muscle granulomas had almost completely disappeared at 6 months in these animals. We conclude that Alhydrogel® injected at low dose in mouse muscle may selectively induce long-term Al cerebral accumulation and neurotoxic effects. To explain this unexpected result, an avenue that could be explored in the future relates to the adjuvant size since the injected suspensions corresponding to the lowest dose, but not to the highest doses, exclusively contained small agglomerates in the bacteria-size range known to favour capture and, presumably, transportation by monocyte-lineage cells. In any event, the view that Alhydrogel® neurotoxicity obeys “the dose makes the poison” rule of classical chemical toxicity appears overly simplistic.
Anode‐free batteriesgreatly promote overall energy density, but they require an extremely high Coulombic efficiency (CE, >99.7%) to function normally. It becomes very challenging in aqueous ...batteries, because of water‐related parasitic reactions and dendrite growth on Zn anodes. Herein, aluminum hydroxide fluoride coated on Cu foils (Cu@AOF) is used to realize the anode‐free aqueous batteries. AOF exhibits a high adsorption affinity to H2O and a low diffusion energy barrier for Zn adatoms, promoting the desolvation process and surface migration. Meanwhile, the strong interaction between AOF and Zn2+ enables it to regulate the Zn2+ flux and benefit lateral growth. Then, the anode‐free full cells of Cu@AOF||Zn0.5VO2 exhibit a record‐high cycle life of 2000 cycles at 1 A g−1 with an ultra‐high average CE of 99.95%. More impressively, the full cell shows a long cycle life of 400 cycles with a high CE of 99.94% at −20 °C. This work provides sheds light on the rational engineering of the electrode interfaces to obtain excellent performance at low temperatures.
In this work, aluminum hydroxide fluoride coated on Cu foils (Cu@AOF) is used to realize anode‐free aqueous batteries. AOF promotes the desolvation process and the surface migration of Zn2+. Therefore, the anode‐free full cells of Cu@AOF||Zn0.5VO2 exhibit a record‐high cycle life of 2000 cycles at 25 °C and a long cycle life of 400 cycles at −20 °C.
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