Patent Application
20230181728
This disclosure pertains to a conjugate opioid vaccine combined with various adjuvants.
Fentanyl and derivatives are highly addictive synthetic opioids that are also associated with fatal outcomes. Fatal outcomes result from accidental overdose and unintentional drug exposure. The prevalence of opioid used disorder and overdose deaths secondary to synthetic opioids continues to be a significant problem worldwide.
Although there are presently approved treatments for opioid use disorder (OUD), the pernicious epidemic in the United States and abroad suggests novel treatments are urgently needed. Recent statistics for the United States indicate an alarming increase in overdose deaths (72,306) in 2017 with nearly 50,000 of those deaths involving opioids. Of those deaths related to opioids, nearly 30,000 were linked to synthetic opioids. The distressing increase in overdose deaths among individuals with OUD is in part due to increased availability and use of fentanyl (FEN), a potent synthetic opioid. FEN is a mu opioid receptor agonist indicated for the treatment of moderate to severe pain. FEN and FEN-analogs (e.g. carfentanil, sufentanil, alfentanil, lofentanil) are highly lipophilic and rapidly penetrate the CNS (central nervous system) which is often lethal. The standard medication to reverse FEN's effects is the mu antagonist naloxone. Because of FEN's potency however, reversing an overdose requires very high and quickly administered doses of naloxone. Further, replacement therapies for OUD have considerable abuse liability themselves and marginally decrease relapse. An alternative treatment strategy that could potentially avert overdose and prevent relapse in individuals with OUD is vaccination with an anti-FEN vaccine.
Vaccines against drug targets show promise since they can induce the production of drug-specific antibodies and neutralize its biochemical activity. These antibodies bind to the drug sequestering it in the periphery preventing CNS penetration associated with euphoria or potential death by way of respiratory depression. Vaccines against substances associated with use disorders have been under development for decades. For example, vaccines against nicotine and cocaine were tested in Phase III clinical trials, but with limited success. The failure of previous vaccines was primarily due to low proportions of vaccinated subjects attaining sufficient antibody levels needed to bind to the drug and prevent CNS entry. Further, studies showed a majority of subjects failed to maintain high enough antibody concentrations in the periphery over time. Another factor to overcome as identified in past studies is high inter-subject variability in vaccine response. To surmount these factors an anti-FEN vaccine must produce high and enduring immunogenicity to the point at which low responders will have sufficient concentrations of anti-FEN for clinical efficacy.
The present disclosure relates generally to an anti-opioid vaccine. When admixed with various adjuvants, the vaccine generates substantive anti-opioid antibodies that block the opioid's analgesic effects and lethality.
Generally, the adjuvanted conjugate opioid vaccine disclosed herein includes a protein carrier (CRM197) linked to a fentanyl (FEN) backbone, combined with selected adjuvants. Administration of embodiments of the vaccine admixed with adjuvants resulted in high and enduring anti-opioid antibody levels. This effect corresponded with increased antibody secreting cells in bone marrow. Compared to unvaccinated rats, rats that received the adjuvanted conjugate vaccine showed comprehensive blockade of fentanyl's analgesic effects and complete protection from the lethal effects of the drug. Overall, embodiments of the vaccine may address the pressing need for an efficacious treatment for opioid use disorder and associated adverse events.
The present disclosure relates to an anti-opioid vaccine. The vaccine is a conjugate and mixed with various adjuvants.
In preferred embodiments, the adjuvanted conjugate opioid vaccine described herein is a conjugate of a protein carrier and at least one opioid backbone component or hapten conjugated thereto. Ideally, the protein carrier should not produce an immune response. In additional preferred embodiments, the CRM197 protein carrier linked to a FEN backbone is the conjugate entity of the vaccine. CRM197 is a form of detoxified diphtheria toxin, which has a history of safety and efficacy in conjugate vaccines for adults and infants. Importantly CRM197 has demonstrated reduced adverse events with pre-existing immunity compared to other common carrier proteins (e.g., tetanus toxoid, diphtheria toxoid). FEN-CRM has about 12 FEN haptens linked to the CRM protein through surface lysine residues. A synthesis scheme for FEN-CRM illustrated is shown in
A unique component of the vaccine is the vaccine formulation itself whereby the conjugate, which may be FEN-CRM, is combined with adjuvants such as dmLT or LTA 1. The history and development of dmLT, or double mutant of heat-labile toxin (LT) from E. coli specifically, has been reviewed in detail. In short, dmLT was generated by introducing two mutations, R192G and L211A, into LT enterotoxin in order to divorce oral enterotoxicity from adjuvanticity. Notably, dmLT has been found safe by intramuscular, oral, sublingual, intradermal routes in humans. There has been extensive characterization of dmLT along with other documented improvement of parenteral and mucosal immunity to bacterial and viral antigens following oral, transcutaneous, sublingual, intradermal and intramuscular delivery with dmLT in animal models. dmLT promotes a mixed Th1/Th2/Th17 and IgA response similar to LT. This induction of Th17 cells is also a distinctive feature of dmLT, benefiting germinal center development which is key to generation of high titer antibodies.
dmLT cannot be used for respiratory delivery, as LT and older AB5 mutants elicited Bell's palsy when delivered intranasal (IN) during 1990s clinical trials, including a short-lived commercial influenza vaccine. This is a direct consequence of B-subunit neuronal ganglioside binding combined with the inflammatory response to the vaccine. For this reason, an LTA1 adjuvant was developed that lacks the B-subunit and contains only a portion of dmLT's (and LT's) Al domain. Mice treated with up to 30pg LTA1 exhibit no signs of the intranasal toxicity that was seen with enterotoxin treatment, including inflammation in the olfactory epithelium or alterations in nerve function through olfactory testing. Like dmLT, LTA1 also activates antigen presenting cells and improves immune responses to co-delivered antigens. LTA1 improves antibody and cellular vaccine response to bacterial antigens by intranasal or intradermal delivery. LTA1 also improves antibody responses to viral antigens, including studies with intranasal flu vaccination where both survival and weight loss after influenza challenge in mice was improved with LTA1 adjuvant inclusion. Importantly, the adjuvants dmLT and LTA1 have never been reported for efficacy in substance abuse vaccines prior to these studies.
Accordingly, preferred embodiments disclosed herein relate to an adjuvanted conjugate opioid vaccine comprising a protein carrier, at least one opioid backbone hapten conjugated to the protein carrier, and at least one adjuvant admixed with the protein-hapten conjugate. In preferred embodiments of the opioid vaccine, the protein carrier is CRM197 and the opioid backbone hapten is fentanyl, where the fentanyl hapten is covalently attached to CRM197 through a glutaryl linker. In additional preferred embodiments of the opioid vaccine, the protein carrier is conjugated to at least one fentanyl hapten and no more than twenty fentanyl haptens.
In additional preferred embodiments, the adjuvanted conjugate opioid vaccine comprises a protein-hapten conjugate having the following structure:
wherein P is a protein carrier, wherein P is preferably CRM197, wherein n is at least 1, and wherein n is preferably between 1 and 15.
In additional preferred embodiments of the adjuvanted conjugate opioid vaccine, the protein-hapten conjugate is admixed with one or more adjuvants. The adjuvants are preferably dmLT, LTA1, or combinations thereof. Other suitable adjuvants include alum (aluminum hydroxide, aluminum hydroxyphosphate sulfate), squalene based oil-in-water, MPLA-SM (TLR-4 agonist), flagellin derivatives (TLR-5 agonist) and saponin based adjuvants (TQL 1055, QS-21) among others.
The exemplary adjuvanted conjugate opioid vaccines described herein may occur in different geometric and enantiomeric forms, and both pure forms and mixtures of these separate isomers are included in the scope of this invention, as well as any physiologically functional or pharmacologically acceptable salt derivatives or prodrugs thereof. Production of these alternate forms would be well within the capabilities of one skilled in the art.
The current invention also pertains to methods of prevention or treatment of opioid use disorder, or otherwise minimizing or inhibiting the effects of opioids in a subject, including the step of administering an adjuvanted conjugate opioid vaccine in accordance with preferred embodiments disclosed herein. In preferred embodiments, the methods of prevention or treatment for opioid use disorder, or for minimizing or inhibiting the effects of opioids in a subject, include the step of administering a compound that is a conjugate of CRM197 and fentanyl haptens in accordance with preferred embodiments disclosed herein.
In another aspect of the present invention there is provided a pharmaceutical composition including a therapeutically effective amount of an adjuvanted conjugate opioid vaccine in accordance with preferred embodiments disclosed herein and a pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabilizer. A “therapeutically effective amount” is to be understood as an amount of an exemplary adjuvanted conjugate opioid vaccine that is sufficient to show inhibition of the effects of an opioid. The actual amount, rate and time-course of administration will depend on the opioid, the subject, the opioid dosage, and the nature and severity of the effects. Prescription of treatment is within the responsibility of general practitioners and other medical doctors. The pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabiliser should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration, which may be oral, sublingual, intranasal, or by injection, such as cutaneous, subcutaneous, or intravenous injection, or by dry powder inhaler.
Pharmaceutical compositions for oral administration may be in tablet, capsule, powder or liquid form. A tablet may comprise a solid carrier or an adjuvant. Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included. A capsule may comprise a solid carrier such as gelatin. For intravenous, cutaneous or subcutaneous injection, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has a suitable pH, isotonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as sodium chloride solution, Ringer's solution, or lactated Ringer's solution. Preservatives, stabilizers, buffers, antioxidants and/or other additives may be included as required.
In another aspect, there is provided the use in the manufacture of a medicament of a therapeutically effective amount of an adjuvanted conjugate opioid vaccine as defined above for administration to a subject.
The term “pharmacologically acceptable salt” used throughout the specification is to be taken as meaning any acid or base derived salt formed from hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic, isoethonic acids and the like, and potassium carbonate, sodium or potassium hydroxide, ammonia, triethylamine, triethanolamine and the like.
The term “prodrug” means a pharmacological substance that is administered in an inactive, or significantly less active, form. Once administered, the prodrug is metabolised in vivo into an active metabolite.
The term “therapeutically effective amount” means a nontoxic but sufficient amount of the drug to provide the desired therapeutic effect. The amount that is “effective” will vary from subject to subject, depending on the age and general condition of the individual, the particular concentration and composition being administered, and the like. Thus, it is not always possible to specify an exact effective amount. However, an appropriate effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. Furthermore, the effective amount is the concentration that is within a range sufficient to permit ready application of the formulation so as to deliver an amount of the drug that is within a therapeutically effective range.
Further aspects of the present invention will become apparent from the following description given by way of example only.
A general scheme for synthesis of a CRM-FEN conjugate according to preferred embodiments disclosed herein is shown in
To a solution of 4-piperidone monohydrate hydrochloride 1 (2.0 g, 14.75 mmol) was dissolved in acetonitrile (40 mL) was added K2CO3 (6.1 g, 44.14 mmol) and (2-bromoethyl)benzene 5 (2.46 g, 13.27 mmol) at ambient temperature. The resulting suspension was refluxed at 80° C. for 5 h. The reaction mixture was monitored by TLC (50% ethylacetate in hexane). Upon completion of the reaction, the reaction mixture was allowed to cool to room temperature and filtered through a small celite pad. The crude material was purified by flash column chromatography (0-30% ethyl acetate in hexane) to afford compound 2 (1.72 g, 57%) as off-white solid; mp 57-59° C. 1H NMR (500 MHz, CDCl3): δ 7.32-7.29 (m, 2H), 7.23-7.20 (m, 3H), 2.86-2.82 (m, 6H), 2.75-2.71(m, 2H), 2.49 (t, J=6.0 Hz, 4H); 13C NMR (125 MHz, CDCl3): δ 209.1, 139.9, 128.6, 128.4, 126.2, 59.3, 53.0, 41.2, 34.1.
To a solution of aniline (90 μL, 0.98 mmol) in dichloromethane (3 mL) was added acetic acid (56 μL, 0.98 mmol) drop wise at 0° C. Subsequently N-phenylethylpiperidin-4-one 2 (200 mg, 0.984 mmol, dissolved in 1 mL dichloromethane) was added drop wise, followed by addition of sodium triacetoxyborohydride (313 mg, 1.476 mmol) in 3 portions over a 12 minutes timeframe. The reaction mixture was stirred at ambient temperature for 16 h. After completion of the reaction, methanol (3 mL) was added and the reaction mixture was partitioned between dichloromethane and sat. NaHCO3. The organic phase was separated and washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed under reduced pressure providing the crude compound. This material was purified by flash column chromatography (0-50% ethylacetate in hexane) to obtain the desired compound 3 as a off-white solid (211 mg,76%). mp 96-98° C. 1H NMR (500 MHz, CDCl3): δ 7.31-7.28 (m, 2H), 7.22-7.15 (m, 5H), 6.68 (t, J=7.5 Hz, 1H), 6.60 (d, J=8.0 Hz, 2H), 3.52 (brs, 1H), 3.34-3.30 (m, 1H), 2.98-2.95 (m, 2H), 2.84-2.80 (m, 2H), 2.63-2.59 (m, 2H), 2.21 (t, J=10.9 Hz, 2H), 2.10-2.07 (m, 2H), 1.54-1.46 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 147.0, 140.3, 129.3, 128.7, 128.4, 126.0, 117.2, 113.2, 60.6, 52.4, 49.8, 33.8, 32.5.
To a solution of compound 3 (200 mg, 0.713 mmol) in anhydrous dichloromethane was added pyridine (112 mg, 1.415 mmol) and methyl 4-(chloroformyl)butyrate (129 mg, 0.783 mmol) at 0° C. The reaction mixture was stirred for 5-10 min at 0° C. The reaction mixture was allowed to warm to room temperature and then stir for 1.5 h. Reaction progress was monitored by TLC (5% methanol in dichloromethane). Upon completion, the reaction was quenched with sat. NaHCO3 solution. The organic layer was separated and the aqueous layer was washed with ethyl acetate (2×10 mL). The combined organic layers were washed with brine, dried over hydrous Na2SO4, filtered and concentrated under reduced pressure providing the crude compound, which was purified by flash column chromatography (0-5% methanol in dichloromethane) to obtain the desired compound 4 as a pale yellow viscous liquid (273 mg, 93%). 1H NMR (400 MHz, CDCl3): δ 7.42-7.34 (m, 3H), 7.28-7.24 (m, 2H), 7.19-7.14 (m, 3H), 7.08-7.06 (m, 2H), 4.68 (tt, J=12.3 Hz, 3.9 Hz, 1H), 3.60 (s, 3H), 3.03-3.0 (m, 2H), 2.75-2.71(m, 2H), 2.56-2.52 (m, 2H), 2.27 (t, J=7.1 Hz, 2H), 2.20-2.14 (m, 2H), 1.98-1.94 (m, 2H), 1.91-1.79 (m, 4H), 1.49-1.39 (qd, J=12.4 Hz, 3.7 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 173.6, 171.8, 140.0, 138.4, 130.3, 129.3, 128.6, 128.4, 126.0, 60.4, 53.0, 52.1, 51.4, 34.0, 33.7, 33.2, 30.4, 20.6.
To a solution of ester 4 (100 mg, 0.244 mmol) in methanol was added 0.5 mL of 1M aqueous LiOH solution. The reaction mixture was stirred for 4 h at room temperature. The progress of the reaction was monitored by TLC (5% methanol in dichloromethane). Upon completion, the reaction solution was acidified with 3N aqueous HCl to pH 5. Then it was concentrated in vacuo to remove methanol. The residue was extracted with ethylacetate and washed with a small amount of brine solution (note, product is water soluble). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (0-5% methanol in dichloromethane) to yield the target compound 5 as an off-white solid (78 mg, 81%). mp 60-63° C.1H NMR (400 MHz, CDCl3): δ 8.93 (brs, 1H), 7.42-7.34 (m, 3H), 7.30-7.16 (m, 5H), 7.06-7.04 (m, 2H), 4.78-4.70 (m, 1H), 3.51-3.48 (m, 2H), 3.02 (s, 4H), 2.77-2.72 (m, 2H), 2.17 (t, J=7.1 Hz, 2H), 1.98 (t, J=7.3 Hz, 2H), 1.93-1.75 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 176.9, 172.6, 137.6, 136.7, 129.8, 129.7, 129.0, 128.8, 128.6, 127.0, 58.1, 51.9, 50.3, 33.9, 33.7, 30.7, 27.7, 20.6. HRMS (ESI): m/z [M+H]+ calcd for C24H31N2O3: 395.2329; found 395.2330.
Fentanyl-CRM Conjugation:
To a mixture of fentanyl acid 5 (0.6 mg, 2.0 equiv, 1.44×10—3 mmol), EDC (0.3 mg, 2.0 equiv, 1.44×10−3 mmol) and NHS (0.2 mg, 2.0 equiv, 1.44×10−3 mmol) in 315 μL DMSO was added. The reaction mixture was stirred at room temperature for 2 h. Then the resulting reaction mixture was added drop wise to a solution of CRM197 (EcoCRM™, Fina Biosolutions) (2.1 mg, 1 equiv, 7.19×10−4 mmol, dissolved in 2100 μL water) and then stirred overnight. Next, a dialysis column (Thermo Scientific) was prepared by adding approximately 44.5 mL of sterile 1×PBS into the bottom reservoir. The top reservoir was then rinsed with 500 μL of 1×PBS and placed into the bottom and reaction mixture introduced. Column was then sealed and placed onto an orbital shaker (180 rpm) for 2 hours. After agitation, the mixture was removed and placed into eppindorf tubes and volume recorded. The mixture is then loaded into a 5 mL syringe and sterilized by filtering it through a 0.2 μm HT Tuffryn membrane (Acrodisk syringe filter, Pall Corporation, Ann Arbor, Mich).
FEN hapten-CRM conjugates were prepared at different FEN hapten:CRM carrier ratios, i.e. 2 or 20 mols of FEN per mol CRM exposed lysine residues with the ratio of FEN hapten to coupling reagents remaining at 1:1. Test formulations were evaluated by SDS-PAGE/Western blot in comparison with FEN-BSA control by Ponceau staining (for all proteins), binding of anti-Fentanyl antibodies (a-FEN) or stripped and re-probed for anti-CRM197 antibodies (a-CRM) with brightfield and chemiluminescence overlay images shown in
Subsequently, the 2:1 FEN-CRM formulation was dialyzed and used to vaccinate mice (Balb/c, N=5 per group, 1.5 μg/mouse) at 0 and 14 days. The formulation was intramuscularly injected in 20 μl alone in PBS buffer or with absorption 1:1 with 2% alyhydrogel (alum, 100 μg final done) or admixed with 1 μg dmLT.
An ELISA assay that detects anti-fentanyl antibodies at nanogram concentrations was developed and used to evaluate the exemplary vaccine. In brief, plates (Maxisorp, VWR) are first coated with BSA-1-EN (CalBioreagents, San Mateo, Calif.) for the capture antigen and mouse IgG (Sigma) for the standard curve in carbonate-bicarbonate buffer (Sigma) and incubated for one hour at 25° C. Following washing, plates were blocked with 2% skim milk in PBS-Tween20 (0.05%) for one hour. Then samples, positive (fentanyl monoclonal, Cal Bioreagents, San Mateo, Calif.) and negative (serum from unvaccinated animals) controls (diluted in assay buffer, 0.2% skim milk in PBS-T) were added directly to the appropriate wells and incubated for one hour. Plates were then washed and detection antibody (1:500) was added and plates were incubated for one hour. Plates underwent a final wash and 100 μL of substrate (1 mg/ml pNPP in diethanolamine, Sigma) was added to each well. Optical density (OD) for each well was obtained at 405 nm using a plate reader (Fischer Scientific). Antibody concentrations were then quantified using four parameter logistic curve fit for calculating symmetrical sigmoidal calibrators. Anti-fentanyl serum IgG antibody levels were analyzed by ELISA 7 days post-boost with raw data shown in the top of
Further, as shown in
Anti-nociceptive effects of FEN was assessed using a tail flick assay. For the tail flick test, radiant heat (25 IR) was applied to the tail 3 cm from the tip using a tail flick apparatus (Ugo Basile, Collegeville, Pa). The time from the onset of the heat to the withdrawal of the tail (latency) was recorded. To avoid tissue damage, the heat stimulus was discontinued after 10-s (cut-off latency). Baseline latencies to move the tail were determined three times (at least 1 minute inter-trial interval). Mice (Balb/c, N=5-20/group) were vaccinated at 0, 3 and 6 weeks with PBS (naïve), FEN-CRM (5 lig) alone, and FEN-CRM admixed with Alum or two different doses of dmLT. Latencies were determined at 10 minutes post-injection. Data generated from unvaccinated and vaccinated mice that received FEN-CRM admixed with adjuvants Alum and two doses of dmLT (0.1 and 1 μg) that underwent analgesic tests of fentanyl (30 and 100 ug/kg, IP) in the tail flick assay are presented in
Additional nociception tests in male and female Sprague Dawley rats that received no vaccine or vaccinated with FEN-CRM (5 μg)+dmLT (1 μg) at 0, 3 and 6 weeks were conducted. Male (N=60) and female (N=60) Sprague Dawley rats were divided into groups (N=15/group) that received IM injections of either no vaccine (saline) or FEN-CRM (5 μg) conjugate admixed with adjuvant dmLT at 0, 3 and 6 weeks. Blood samples were taken at 4, 6 and 8 weeks and serum anti-FEN antibody concentrations determined by ELISA. Data from male rats (N=57-60/per time point) is presented in
At approximately 14-15 weeks post-initial vaccination, nociception tests (tail flick and hot plate assays) were conducted following fentanyl dosing (0.05 and 0.1 mg/kg, SC). For the tail flick test, radiant heat (Ugo Basile, Collegeville, Pa.) was adjusted to produce an average tail flick latency of 2 seconds. During testing, heat was applied to the tail approximately 3 cm and the time from the onset of the heat to the withdrawal of the tail (latency) was recorded. Tail flick was assessed three times following saline (˜1 minute inter-trial interval). Rats were then administered one of two doses of fentanyl counterbalanced over days and tail flick again assessed. At least two days separated the two doses of fentanyl. For the hot plate test, rats were placed on a 53° C. hot plate (Hotplate Analgesia Meter, Columbus Instruments, Columbus, Ohio) and latency to first rear paw lick recorded. To avoid tissue damage, the cut-off time in which the animal was removed from the apparatus for this assay was 90 seconds. Baseline latencies were obtained following a SC injection of saline then one of two doses of FEN counterbalanced over days. As shown in
The complete blockade of FEN's analgesic effects in all rats was unexpected based on data obtained from studies using mice.
Tail flick assay data for female rats are presented in
In addition, and also consistent with tests in male rats, increases in latency following fentanyl dosing were significantly blocked in all female vaccinated rats. Rats (N=29-30/group) either received no vaccine or FEN-CRM conjugate vaccine (5 μg) with dmLT (1 μg) at 0, 3 and 6 weeks (IM). At approximately 14-16 weeks post-initial vaccination nociception tests (hot plate assays) were conducted following fentanyl dosing (0.05 and 0.1 mg/kg, SC). Data from the hot plate assay are presented in
An additional potential use of the present vaccines is use as a protectant whether to prevent overdose or for individuals that are unintentionally exposed to potent synthetic opioids (e.g. first responders, police). Lethality data for male rats is presented in
Results from an additional experiment are shown in
Overall, data presented herein supports the following conclusions:
6) The FEN-CRM+dmLT vaccine formulation provided 100% protection from multiple high-dose FEN administrations whereas 33% of un-vaccinated rats showed untimely demise.
7) The biochemical and behavioral effects described in this application were produced following administration of a small concentration of conjugate and adjuvant. Low doses of vaccine that elicit high antibody levels may be associated with a lack of adverse events in humans.
8) The effect of preventing fentanyl from entering the central nervous system in vaccinated rats was highly robust and enduring and a key factor in the vaccine's therapeutic potential for treating opioid use disorder and preventing fentanyl-induced overdose deaths.
This application claims priority to U.S. Provisional Patent Application No. 63/030,609, entitled “Adjuvanted Conjugate Opioid Vaccine,” filed May 27, 2020, the entire contents of which are hereby incorporated by reference.
This invention was made with government support under grant W81XWH-18-2-0044 awarded by the Department of Defense Alcohol and Substance Abuse Disorders Research Program and grant RO1A1114697 awarded by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. The government has certain rights in the invention.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US21/33961 | 5/25/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63030609 | May 2020 | US |
