Table 3.

Summary of active immunopharmacotherapies developed for fentanyl abuse.

Vaccine	Hapten structure	Carrier protein	Adjuvant	Route of administration	Vaccinations/overall time	Subjects	Main findings	References
1		TT	Alum and CpG	SC	3 injections (0, 2, 4 weeks)	Male Swiss-Webster mice	Single conjugate vaccine elicits high levels of antibodies with cross-reactivity for a wide panel of fentanyl analogs and protects against lethal fentanyl doses	Bremer et al. [123]
2		TT or KLH	Alum and CpG	SC	3 injections (0, 2, 4 weeks)	Female BALB/c mice	Admixture vaccines sequester opioid drugs in blood and reduce fentanyl-induced antinociception	Hwang et al. [142, 143]
3	Same structure as vaccine 1	TT	CpG and alhydrogel	IV	3 injections (0, 3, 17 weeks)	Male and female Sprague-Dawley rats	Vaccination is very effective in preventing the binding of fentanyl to μ-opioid receptors in the central nervous system and reduces fentanyl-induced antinociception and its reinforcing effects	Townsend et al. [124]
4	Same structure as vaccine 1	TT	Alhydrogel	IM	6 injections (0, 2, 4, 9, 19, 44 weeks)	Adult male rhesus monkeys	The vaccine increases plasma fentanyl levels and reduces fentanyl-induced antinociception	Tenney et al. [133]
5		KLH	Alum	SC	3 injections (0, 2, 4 weeks)	Male BALB/c mice and male Holtzman rats	The vaccine reduces fentanyl-induced antinociception in hot-plate test, respiratory depression, and bradycardia over a range of cumulative subcutaneous fentanyl doses	Raleigh et al. [122]
6		KLH	Alum and CpG ODN 1826	IP	4 injections (0, 2, 4, 7 weeks)	Female BALB/c mice	New vaccines developed from chemically contiguous haptens composed of both heroin- and fentanyl-like domains; they confer robust protection against heroin but attenuate protection against fentanyl	Natori et al. [141]
7	Same structure as vaccine 5	KLH	Alum	IP	3 injections (0, 3, 8 weeks)	Female A/J mice	Monoclonal antibodies generated in hybridomas from mice vaccinated with a fentanyl conjugate vaccine reverse fentanyl/carfentanil-induced antinociception	Smith et al. [135]
8		TT	ALF43A	IM	4 injections (0, 3, 6, 14 weeks)	Female BALB/c mice	The vaccine induces high-affinity antibodies against fentanyl and its highly potent analogs and protects mice against fentanyl-induced antinociceptive effects	Barrientos et al. [129]
9		KLH or CRM	Alum	IM	4 injections (0, 14, 28, 29 weeks)	Male BALB/c mice and male and female Sprague-Dawley rats	Prophylactic vaccination reduces fentanyl- and sufentanil-induced respiratory depression, antinociception, and bradycardia; therapeutic vaccination reduces intravenous fentanyl self-administration	Robinson et al. [131]
10		OVA	Alum	IP	3 injections (2 weeks)	α1,3GalT knockout mice	The vaccine reduces psychoactive effects of fentanyl without addition of the immunostimulant CpG oligodeoxynucleotide	Wang et al. [132]
11		CRM or TT	Alhydrogel	IV	4 injections (0, 14, 42, 70 days)	Male and female Sprague-Dawley rats	The vaccine attenuates thermal antinociceptive effects of fentanyl/heroin but has no effects on fentanyl/heroin mixture self-administration	Townsend et al. [139]
12	Same structure as vaccine 5	KLH	Alum	IP	3 injections (0, 2, 4 weeks)	Male and female BALB/c mice and male Sprague-Dawley rats	α-Fentanyl monoclonal antibodies generated from hybridomas via magnetic enrichment; passive immunization reduces fentanyl-induced antinociception, respiratory depression, and bradycardia	Baehr et al. [136]
13	Same structure as vaccine 1	CRM	δ-Inulin	SC	3 injections (2 weeks) in mice 4 injections (0, 1, 2, 4 months) in monkeys	Male BALB/c mice and cynomolgus monkeys	A novel vaccine against heroin and fentanyl developed through the optimization of adjuvants and enhancing stability via lyophilization; it produces high-affinity antibodies and reduces fentanyl/heroin-induced antinociception	Blake et al. [137]
14		CRM	Alum	IP	4 injections (0, 2, 4, 7 weeks)	Female BALB/c mice	The vaccine with an optimized dual hapten produces antibodies with nanomolar affinities and blocks the analgesic effects of fentanyl-contaminated heroin	Park et al. [138]
15	Same structure as vaccine 1	TT	Liposomal	IM	4 injections (0, 3, 6, 14 weeks)	Female BALB/c mice	Combining TT-6-AmHap and TT-para-AmFenHap yielded an effective bivalent vaccine that ablates the effects of heroin and fentanyl	Barrientos et al. [140]
16	Same structure as vaccine 7	CRM	dmLT or LTA1	IM	2 injections (0, 4 weeks)	Female BALB/c mice	dmLT or LTA1 adjuvants and mucosal delivery may be attractive strategies for improving the efficacy of vaccines against fentanyl use disorder	Stone et al. [128]
17	Same structure as vaccine 1	CRM	Alum	IM	4 injections (0, 3, 8, 15 weeks)	Rhesus monkeys	Fentanyl vaccine effectively reduces fentanyl vs food choice in rhesus monkeys	Townsend et al. [133]
18		TT	alum and CpG	IP	4 injections (0, 2, 4, 9 weeks)	Female Swiss-Webster mice	The two synthetic vaccines reduce carfentanil-induced antinociception and respiratory depression	Eubanks et al. [127]

TT, tetanus toxoid; CpG, cytosine-phosphodiester-guanine oligodeoxynucleotide 1826; KLH, keyhole limpet hemocyanin; CRM, diphtheria toxin; OVA, ovalbumin; IV, intravenous; IM, intramuscular; SC, subcutaneous; IP, intraperitoneal.