The impact of vaccination on the burden of invasive pneumococcal disease from a nationwide surveillance program in Lebanon: an unexpected increase in mortality driven by non-vaccine serotypes

Figures & data

Figure 1. A. Overall distribution of invasive S. pneumoniae serotypes (N = 549) from 2005–2020. B. Changes in vaccine and non-vaccine serotypes in the three different age groups across the three vaccine eras of the study. PCV7 refers to isolates with serotypes 4, 6B, 9 V, 14, 18C, 19 F, and 23 F. PCV13 refers to the additional serotypes not included in PCV7: 1, 3, 5, 6A, 7 F, 19A. NVT refers to all other serotypes including those that were not typeable. Multinomial logistic regression was used to compare the percentage of VT and NVT serotypes across the 3 eras. The PCV7 era was the reference category. The bars refer to statistically significant differences in the indicated eras. C. Changes in vaccine and non-vaccine serotypes among subjects ≤5 years of age by year. PCV7 refers to isolates with serotypes 4, 6B, 9 V, 14, 18C, 19 F, and 23 F. PCV13 refers to the additional serotypes not included in PCV7: 1, 3, 5, 6A, 7 F, 19A. NVT refers to all other serotypes including those that were not typeable.

Non-Vaccine Types (NVT) represent all the serotypes not covered by the conjugate vaccines available in Lebanon during the study period. This includes the additional serotypes covered by recently approved PCVs including PCV15 in light gray color (4.6%) (serotypes 22 F, and 33 F) and PCV20 in dark gray color (8.2%) (serotypes 10A, 15B, 8, 11A, and 12 F), and the remaining NVT in beige color that include the non-typeable (NT) isolates (5.8%) and others (18%).Note: Isolates not tested by either Quellung reaction or serotype-specific PCR were referred to as 6 or 18 serogroups; *6A (3.27%), 6A/6B/6C/6D (0.18%); **6B (2.55%), 6A/6B/6C/6D (0.72%); ***18 (2.7%), 18C (0.5%).

Table 1. Demographic features and clinical burden of patients with IPD from the LIPSP.

			Age groups, N (%)
Characteristics	Mean (±SD)	Total Number	< 2 years	2 years - < 6 years	6 years - < 21 years	21 years - < 60 years	≥ 60 years
Age groups#	34.3 (±32.5)	588	128 (21.8)	97 (16.5)	65 (11.1)	107 (18.2)	191 (32.5)
Gender (N = 588)
Male		336 (57.1)	69 (53.9)	55 (56.7)	35 (53.8)	61 (57.0)	116 (60.7)
Female		252 (42.9)	59 (46.1)	42 (43.3)	30 (46.2)	46 (43.0)	75 (39.3)
Clinical syndromes (N = 589)
Bacteremia		191 (32.4)	51 (39.8)	29 (30.2)	22 (33.8)	23 (21.5)	63 (33.5)
Pneumonia		280 (47.5)	37 (28.9)	48 (50.0)	26 (40.0)	52 (48.6)	115 (61.2)
Meningitis		107 (18.2)	37 (8.9)	16 (16.7)	16 (24.6)	28 (26.2)	10 (5.3)
Others		11 (1.9)	3 (2.3)	3 (3.1)	1 (1.5)	4 (3.7)	0 (0.0)
Outcome (N = 444)
Recovered		367 (82.7)	85 (87.6)	66 (91.7)	46 (92.0)	75 (87.2)	95 (68.3)
Died		77 (17.3)	12 (12.4)	6 (8.3)	4 (8.0)	11 (12.8)	44 (31.7)
Duration of hospital stay (N = 370)	8.3 (±8.6)
< 1 week		204 (55.1)	42 (50.6)	26 (51.0)	22 (57.9)	39 (57.4)	75 (57.7)
1–2 weeks		117 (31.6)	30 (36.1)	19 (37.3)	11 (28.9)	18 (26.5)	39 (30.0)
2–4 weeks		37 (10.0)	9 (10.8)	4 (7.8)	4 (10.5)	8 (11.8)	12 (9.2)
> 4 weeks		12 (3.2)	2 (2.4)	2 (3.9)	1 (2.6)	3 (4.4)	4 (3.1)
Presence of comorbidities (N = 442)
No comorbidities		185 (41.9)	77 (84.6)	43 (58.9)	26 (51.0)	23 (31.5)	16 (10.4)
At least one comorbidity		257 (58.1)	14 (15.4)	30 (41.1)	25 (49.0)	50 (68.5)	138 (89.6)
Comorbidities (N = 257)
Cardiovascular diseases		106 (24.0)	2 (2.2)	2 (2.7)	1 (2.0)	16 (21.9)	85 (55.2)
Respiratory diseases		56 (12.7)	1 (1.1)	9 (12.3)	4 (7.8)	8 (11.0)	34 (22.1)
Malignancy		80 (18.1)	2 (2.2)	5 (6.8)	11 (21.6)	17 (23.3)	45 (29.2)
Kidney diseases		33 (7.4)	2 (2.2)	3 (4.1)	1 (2.0)	7 (9.6)	20 (13.0)
Neurological disorders		31 (7.0)	1 (1.1)	2 (2.7)	3 (5.9)	6 (8.2)	19 (12.3)
Diabetes		44 (10.0)	0 (0.0)	0 (0.0)	0 (0.0)	9 (12.3)	35 (22.9)
Regions			Beirut	North	Mount Lebanon	South	Bekaa
N (%)		582	370 (63.6)	158 (27.1)	27 (4.6)	16 (2.7)	11 (1.9)

N: Number of patients reported with no missing data

#: Out of a total number of 593 patients with 5 cases excluded due to missing age information.

Table 2. Distribution of PCV7, PCV10, PCV13, PPV23, and other serotypes among invasive S. pneumoniae isolates recovered from all age groups during the PCV7, post-PCV7/pre-PCV13, and PCV13 eras.

SEROTYPES	isolates, N (%)
	PCV7 era (N = 172, 31.3%)	Post-PCV7/pre-PCV13 era (N = 202, 36.8%)	PCV13 era (N = 175, 31.9%)	P-value	Unadjusted OR [95% CI]
PCV7
4	4 (2.3)	6 (3.0)	6 (3.4)
6B*	14 (8.1)	3 (1.5)	1 (0.6)	0.011	0.071 [0.009–0.543]
9 V/9A	8 (4.7)	9 (4.5)	4 (2.3)
14	16 (9.3)	17 (8.4)	6 (3.4)	0.040	0.375 [0.147–0.958]
18C**	4 (2.3)	9 (4.5)	5 (2.9)
19 F	23 (13.4)	21 (10.4)	5 (2.9)	0.002	0.217 [0.083–0.572]
23 F	6 (3.5)	11 (5.4)	4 (2.3)
PCV7 TOTAL	75 (43.6)	76 (37.7)	31 (17.8)	<0.001	0.547 [0.432–0.691]
PCV10
1	10 (5.8)	17 (7.8)	15 (8.6)
5	5 (2.9)	9 (4.5)	3 (1.7)
7 F/7A	4 (2.3)	4 (2.0)	3 (1.7)
PCV10/non-pcv7	19 (11.0)	30 (14.3)	21 (12.0)
PCV10 TOTAL	94 (54.6)	106 (52.0)	52 (29.8)	<0.001	0.598 [0.481–0.744]
PCV13
3	14 (8.1)	15 (7.4)	19 (10.9)
6A***	3 (1.7)	9 (4.5)	7 (4.0)
19A	7 (4.1)	14 (6.9)	8 (4.6)
PCV13/non PCV10	24 (13.9)	38 (18.8)	34 (19.5)
PCV13 TOTAL	118 (68.6)	144 (70.8)	86 (49.1)	<0.001	0.652 [0.521–0.815]
PPV23
22 F/22A	8 (4.7)	3 (1.5)	6 (3.4)
33 F/33A/37	4 (2.3)	3 (1.5)	1 (0.6)
10A	4 (2.3)	0 (0.0)	2 (1.1)
15B/15C	4 (2.3)	3 (1.5)	5 (2.9)
8	3 (1.7)	1 (0.5)	2 (1.1)
11A/11D	2 (1.2)	3 (1.5)	4 (2.3)
12 F/12A	2 (1.2)	4 (2.0)	6 (3.4)
2	0 (0.0)	5 (2.5)	1 (0.6)
9 N****	5 (2.9)	3 (1.5)	4 (2.3)
17 F	0 (0.0)	1 (0.5)	1 (0.6)
20	0 (0.0)	1 (0.5)	1 (0.6)
PPV23-only	32 (18.6)	27 (13.5)	33 (18.9)
PPV23 TOTAL	147 (85.4)	162 (80.2)	112 (64.0)	<0.001	0.529 [0.406–0.689]
Other Serotypes TOTAL	22 (12.8)	31 (15.3)	56 (32.0)	<0.001	1.880 [1.420–2.490]

*In the PCV7 period, we considered the contributing serotype among the 6 serogroup (6A/6B/6C/6D) to be 6B. When it was not possible to identify the serotypes by either the Quellung reaction or PCR, we referred to them as the 6 serogroup.

The designations were 6B (5.8%, 1.5% and 0.6%) and 6A/6B/6C/6D (2.3%, 0%, 0%) for the PCV7, post-PCV7 and PCV13 eras, respectively.

**The isolates that were tested in the initial phase of the surveillance by the Quellung reaction were identified as 18C; otherwise, they were serotyped by PCR as serogroup 18; The designations were 18C (1.7%, 0%, 0%) and 18 (0.6%, 4.5% and 2.9%) for the PCV7, post-PCV7 and PCV13 eras, respectively.

***In the post-PCV7/pre-PCV13, 6A was considered as the predominant serotype 6A (1.7%, 4% and 4%); 6A/6B/6C/6D (0%, 0.5%, 0%) for the PCV7, post-PCV7 and PCV13 eras, respectively.

**** The isolates that were tested in the initial phase of the surveillance by the Quellung reaction were identified as either 9 N or 9 L; otherwise, they were serotyped by PCR as 9 N/9 L; 9 N (2.3%, 0% and 0%); 9 N/9 L (0.6%, 1.5%, 2.3%) for the PCV7, post-PCV7 and PCV13 eras, respectively.

ǂOther serotypes refer to the non-PPV23 serotypes: 28A, 39, 42 (1 isolate each (0.9% each)); 6C, 7C/7B/40 F, 10B, 21, 29, 35A/35C/42, 35B (2 isolates each (1.8% each)); 10 F/10C/33, 35 F/47, 38/25 (3 isolates each (2.8% each)); 13,15A/15 F,34 (4 isolates each (3.7% each)); 23B, 31 (5 isolates each (4.6% each)); 23A (8 isolates (7.3%)); 16 F (9 isolates (8.3%)), 24 (12 isolates (11%)), and NT (32 isolates (29.4%)). A total of 32S. pneumoniae isolates were NT of which 17 (8.2% of total) were from children ≤ 5 years, and 10 (5.7% of total) were from adults ˃ 60 years of age.

Multinomial logistic regression was used to compare the distribution of vaccine types and NVT within the 3 eras. The PCV7 era (2005–2009) was the reference category.

N: Frequency; %: Percentage; OR: Odds Ratio; CI: Confidence Interval.

Figure 2. Changes in antimicrobial resistance of S. pneumoniae over the three study eras. The percentage of penicillin, erythromycin and clindamycin non susceptible S. pneumoniae isolates are indicated in the PCV7, post-PCV7/Pre-PCV13 and PCV13 eras. Binomial logistic regression was used to compare the antimicrobial resistance within the 3 eras. The PCV7 era was the reference category. *p = 0.002, OR = 0.269, 95%CI = [0.119–0.612].

Table 3. Changes in the mortality rates in the three different age groups across the three vaccine eras of the study.

		Mortality rateN (%)
Age	VaccineSerotypes	PCV7 era	Post-PCV7/pre-PCV13 era	PCV13 era
All age groups	PCV7	6/160 (3.8)	9/146 (6.2)	6/113 (5.3)
	PCV13	6/160 (3.8)	9/146 (6.2)	7/113 (6.2)
	NVT	8/160 (5.0)	10/146 (6.8)	15/113 (13.3)
	Total	20/160 (12.5)	28/146 (19.2)	28/113 (24.8)
≤5 years old	PCV7	1/61 (1.6)	3/53 (5.7)	3/45 (6.7)
	PCV13	1/61 (1.6)	0/53 (0.0)	1/45 (2.2)
	NVT	2/61 (3.3)	3/53 (5.7)	4/45 (8.9)
	Total	4/61 (6.6)	6/53 (11.3)	8/45 (17.8)
6–60 years old	PCV7	1/46 (2.2)	4/48 (8.3)	1/37 (2.7)
	PCV13	0/46 (0.0)	3/48 (6.3)	3/37 (8.1)
	NVT	1/46 (2.2)	1/48 (2.1)	3/37 (8.1)
	Total	2/46 (4.3)	8/48 (16.7)	7/37 (18.9)
>60 years old	PCV7	4/53 (7.5)	2/45 (4.4)	2/31 (6.5)
	PCV13	5/53 (9.4)	6/45 (13.3)	3/31 (9.7)
	NVT	5/53 (9.4)	6/45 (13.3)	8/31 (25.8)
	Total	14/53 (26.4)	14/45 (31.1)	13/31 (41.9)

PCV7 refers to isolates with serotypes 4, 6B, 9 V, 14, 18C, 19 F, and 23 F. PCV13 refers to the additional serotypes not included in PCV7: 1, 3, 5, 6A, 7 F, 19A. NVT refers to all other serotypes including those that were not typeable. The contribution to mortality of PCV7 serotypes, PCV13-only serotypes, and NVT is indicated. The mortality rate was calculated as the (Number of IPD mortalities in a specific age group and PCV era/Total Number of IPD in the corresponding age group and PCV era) X 100.

Table 4. Antimicrobial resistance profiles of major S. pneumoniae serotypes, 2005–2020.

	Frequency and Percentage of resistant isolates, N (%)
	PCV7					PCV13					Non-PCV13
	6B	9 V/9A	14	19 F	23 F	1	3	5	6A	19A	11A/11D	12 F/12A	24	15B/15C	16 F	9 N/9 L	34
β-Lactam
Penicillin	5/16 (31.3)	3/21 (14.3)	10/30 (33.3)	20/41 (48.8)	3/14 (21.4)	0/33 (0.0)	0/38 (0.0)	0/16 (0.0)	3/15 (20.0)	1/17 (5.9)	3/9 (33.3)	2/9 (22.2)	1/10 (10.0)	0/8 (0.0)	1/8 (12.5)	3/10 (30.0)	0/4 (0.0)
Ceftriaxone	0/16 (0.0)	4/18 (22.2)	6/30 (20.0)	18/40 (45.0)	1/13 (7.7)	0/33 (0.0)	1/38 (2.6)	0/15 (0.0)	0/13 (0.0)	1/22 (4.5)	1/9 (11.1)	1/9 (11.1)	0/9 (0.0)	0/9 (0.0)	0/7 (0.0)	1/9 (11.1)	0/4 (0.0)
Non β-Lactam
Chloramphenicol	0/17 (0.0)	3/18 (16.7)	3/32 (9.4)	4/39 (10.3)	2/17 (11.8)	3/30 (10.0)	1/39 (2.6)	0/15 (0.0)	1/17 (5.9)	5/25 (20.0)	0/9 (0.0)	1/11 (9.1)	0/10 (0.0)	0/10 (0.0)	2/9 (22.2)	2/11 (18.2)	3/4 (75.0)
Clindamycin	0/6 (0.0)	1/9 (11.1)	11/19 (57.9)	7/18 (38.9)	2/10 (20.0)	2/26 (7.7)	3/26 (11.5)	3/9 (33.3)	3/10 (30.0)	7/15 (46.7)	0/4 (0.0)	6/8 (75.0)	7/10 (70.0)	1/6 (16.7)	0/6 (0.0)	0/4 (0.0)	2/3 (66.7)
Erythromycin	2/18 (11.1)	6/21 (28.6)	25/38 (65.8)	34/47 (72.3)	12/20 (60.0)	6/40 (15.0)	3/47 (6.4)	0/16 (0.0)	6/19 (31.6)	20/29 (69.0)	0/9 (0.0)	8/12 (66.7)	8/11 (72.7)	1/12 (8.3)	2/9 (22.2)	1/11 (9.1)	1/4 (25.0)
Levofloxacin	0/15 (0.0)	1/21 (4.8)	1/34 (2.9)	1/42 (2.4)	0/16 (0.0)	1/38 (2.6)	1/40 (2.5)	2/15 (13.3)	1/18 (5.6)	0/27 (0.0)	0/9 (0.0)	1/10 (10.0)	1/11 (9.1)	1/11 (9.1)	2/9 (22.2)	0/8 (0.0)	0/3 (0.0)
Tetracycline	4/18 (22.2)	7/21 (33.3)	20/35 (57.1)	28/45 (62.2)	11/18 (61.1)	5/39 (12.8)	4/42 (9.5)	2/15 (13.3)	4/19 (21.1)	16/28 (57.1)	1/9 (11.1)	7/12 (58.3)	6/11 (54.5)	2/12 (16.7)	1/9 (11.1)	4/11 (36.4)	2/4 (50.0)
TMP/SMX	12/17 (70.6)	18/20 (90.0)	29/37 (78.4)	35/43 (81.4)	14/17 (82.4)	25/38 (65.8)	7/43 (16.3)	13/14 (92.9)	11/19 (57.9)	14/28 (50.0)	5/6 (83.3)	8/11 (72.7)	8/11 (72.7)	7/12 (58.3)	5/7 (71.4)	9/11 (81.8)	3/4 (75.0)

TMP/SMX: trimethoprim/sulfamethoxazole.

Figure 3. Comparison of antibiotic resistance rates among different age groups over the three study eras. The percentage of Penicillin (A), Erythromycin (B) and Clindamycin (C)-non susceptible S. pneumoniae isolates are indicated in the PCV7, post-PCV7/Pre-PCV13 and PCV13 eras across three age groups. Clindamycin sensitivity was not performed for isolates from the 6-60 years age group in the PCV7 era due to technical reasons.

Figure 4. Impact of vaccination on antimicrobial resistance by serotypes across age groups. The contribution of vaccine and non-vaccine S. pneumoniae serotypes to penicillin (A), erythromycin (B), and clindamycin (C) resistance is indicated in the PCV7, post-PCV7/Pre-PCV13 and PCV13 eras across three age groups. Clindamycin sensitivity was not performed for isolates from the 6-60 years age group in the PCV7 era due to technical reasons. PCV7 refers to isolates with serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F. PCV13 refers to the additional serotypes not included in PCV7: 1, 3, 5, 6A, 7F, 19A. NVT refers to all other serotypes including those that were not typeable.