Vaccines as a preventive tool for substance use disorder: A systematic review including a meta-analysis on nicotine vaccines’ immunogenicity

Figures & data

Table 1. Illicit drug use at the global level among people aged 15–64 years in 2021.

Drug problem	Number of people (in millions)	Percentage of the global population (4,396 million persons in total)
Used drugs at least once during 2021	241	5.5% of the population aged 15–64 years
“Problem drug users”	36.3	13% of all people who used drugs

Table 2. Statistical bulletin (2021) on the drug situation in Europe.

Drug	Last year use (Adults 15–64 years)	Lifetime use (Adults 15–64 years)	Last year use (Young adults 15–34 years)	National estimates of use in last year (Young adults 15–34 years)
Cannabis	22.2 million (7.7%)	78.6 million (27.3%)	15.8 million (15.5%)	Lowest 3.4% Highest 22.9%
Cocaine	3.5 million (1.2%)	14.4 million (5.0%)	2.2 million (2.2%)	Lowest 0.2% Highest 5.6%
MDMA	2.6 million (0.9%)	10.6 million (3.7%)	1.9 million (1.9%)	Lowest 0.2% Highest 7.7%
Amphetamines	2.0 million (0.7%)	8.9 million (3.1%)	1.4 million (1.4%)	Lowest 0.0% Highest 4.2%

Table 3. Statistical bulletin 2021 on the use of heroin and other opioids in Europe.

Drug	High-risk opioid users	Opioid users who received substitution treatment in 2020	Drug treatment requests	Fatal overdoses
Heroin and other opioids	1.0 million	514,000	28%	74%

Figure 1. Anti-addiction mechanism of vaccine immunotherapy.

Figure 2. PRISMA 2020 flow diagram for new systematic reviews which include searches of databases and registers only.

Table 4. Comparison of cocaine vaccine clinical trials.

The study, phase of the trial	Vaccine	Follow-up	Doses	Participants (Vaccine-Placebo)	Mean Age (Vaccine-Placebo)	Sex (Vaccine-Placebo)	Ethnicity (Vaccine-Placebo)	Abstinence rate	Antibody level
Kosten et al.^Citation6	TA-CD	12 months	3 doses (13 μg, 82 μg, 702 μg)	34 (28–6)	27 years	Male: 32 Female: 2	17 Caucasian, 12 African American, 2 Native American 3 Hispanic/other race	No data	In the vaccinated group, antibody levels were correlated with vaccine dose and the number of injections. No Ab formation in the placebo group.
Martell et al.^14	TA-CD	14 weeks	1) 4 doses of 100 μg 2) 5 doses of 400 μg	18 (18–0)	No data	No data	No data	The 2000 µg group was more likely to maintain cocaine-free urine than those in the 400 µg group.	18 subjects: antibody levels were correlated with vaccine dose and the number of injections.
Martell et al.^Citation29 Phase IIb	TA-CD	24 weeks	5 doses (360 μg)	115 (58–57)	35.6–36.2 years	Male: 35–41 Female: 22 – 16	53–46 Caucasian 2–8 African-American 2–3 Mixed	The proportion of subjects showing a 50% reduction in cocaine use was significantly greater in the high IgG than in low IgG subjects (0.53 vs. 0.23) (P < .04).	21 (38%) showed high IgG levels (≥43 µg/mL) anti-cocaine Ab 34 (62%) showed low IgG levels (<43 µg/mL) anti-cocaine Ab
Haney et al.^Citation27 Phase I	TA-CD	13 weeks	1) 4 doses of 82 μg 2) 4 doses of 360 μg	10 (10–0)	39 years	Male: 10	6 black, 3 white, 1 Hispanic	No data	5 people showed high Ab level, 5 people low Ab level
Kosten et al.^Citation19 Phase III	TA-CD	24 weeks	5 doses (400 μg)	300 (152–148)	45.76–46.40 years	Male: 114 – 114	33–33 Caucasian, 109–108 African-American, 1–2 Asian, 2–1 American Indian/Alaskan Native, 7–4 Unknown	After week 8, more vaccinated than placebo subjects attained abstinence for at least two weeks of the trial (24% vs. 18%).	Of the 152 subjects randomized to receive active vaccine, the mean peak antibody levels were 46 μg/ml at week 9 and 59 μg/ml at week 16 with a 95% confidence interval of 0 to 186 μg/ml.

Table 5. Comparison of nicotine vaccine clinical trials.

Study, phase of trial	Vaccine	Follow-up	Doses	Participants (Vaccine-Placebo)	Mean Age (Vaccine-Placebo)	Sex (Vaccine-Placebo)	Ethnicity (Vaccine-Placebo)	Abstinence rate	Antibody level
Hatsukami et al.^Citation31	NicVAX	38 weeks	1) 4 doses of 50 μg 2) 100 ug of 50 μg 3) 200 μg	68 (45–23)	43.8–46.8 years	Male 34 – 19 Female 11 – 4	White 41 –20 Other 4 – 3	The 30-day abstinence rate was significantly different across the 4 doses, with the highest rate of abstinence occurring at 200 μg.	The placebo group showed no antibody formation. The 50 mcg nicotine vaccine dose showed 10 mcg/ml Ab. The 100 mcg nicotine vaccine dose showed 40 mcg/ml Ab. The 200 mcg nicotine vaccine dose showed 70 mcg/ml Ab.
Wagena et al.^Citation34 Phase I/II	NicVAX	38 weeks	4 doses of 100 μg	30 (24–6)	46.5–45.0 years	Female 7 – 0	No data	No data	Vaccination elicited nicotine-specific antibody levels of 8 mg/ml or higher at day 49 in 18 subjects (50%).
Hatsukami et al.^Citation30 Phase II	NicVAX	6 months	1) 4 doses of 200 μg 2) 5 doses of 400 μg	301 (201–100)	48 years	Female 108 – 50 Male 93 – 50	White: 183 – 88 Other: 18–12	Prolonged abstinence rates of 6 months were higher in the high Ab group vs. the placebo group, with no significant differences between the placebo and low Ab groups.	30% showed the highest antibody level (>30 ug/ml).
Havermans et al.^Citation32	NicVAX	20 weeks	5 doses of 400 μg	48 (20–3)	33.4–28.8 years	Male: 48	No data	No data	Plasma antibody levels in the active treatment group were higher than those of the placebo group, as none of the participants in the latter group showed a detectable antibody level.
Hoogsteder et al.^Citation33 Phase IIb	NicVAX	54 weeks	6 doses of 400 μg	558 (278–280)	47.2–47.6 years	Male: 130 – 119	No data	No difference between the vaccine group and placebo. The top 30% antibody responders, compared to the placebo group, showed a non-significant tendency toward higher abstinence rates from weeks 37 to 52.	30% showed top high antibody level.
Cornuz et al.^Citation36 Phase II	NIC002	12 months	5 doses of 100 μg	377 (299–111)	42.1 years	Male: 59 – 58	No data	Point prevalence of abstinence at month 2 showed a significant difference between subjects treated with NIC002 (47.2%) and the placebo group (35.1%), but continuous abstinence between months 2 and 6 was not significantly different.	No induction of nicotine-specific IgG antibodies was observed for subjects receiving a placebo. In subjects receiving the active treatment, a 100% antibody responder rate was achieved with a single injection of NIC002.
Mukhin et al.^Citation37	NIC002	3 months	4 doses of 100 μg	52 (43–7)	43–44 years	Female: 22 – 4 Male: 23 – 3	No data	No data	No data
Tonstad et al.^Citation35	Niccine	12 months	6 doses of 40 μg	355 (178–177)	41.1 years	Male: 72 – 77	Caucasian for >96% of subjects in both groups	At 1 year, nonrelapse was 43.3% in the Niccine versus 51.1% in the placebo groups (difference = −7.9%; 95% CI = −20.6% to 4.9%). Niccine had no effect on smoking status at 6 or 9 months.	Nicotine antibody levels increased (mean = 1.34 μg/ml; SD = 2.84 μg/ml) in the Niccine group, but were not related to relapse.

Figure 3. Forest plot for random-effects meta-analysis of the effectiveness of vaccines against nicotine abuse.

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