Do Pentavalent (DTwP-Hib-HBV) vaccines have sex-differential nonspecific effects? An observational study

Figures & data

Figure 1. Flowchart of study subjects.

Table 1. Background factors by sex of included Penta-vaccinated children.

	Females	Males	P-value^a
Number	6363	6390
Median age (IQR)^b	101 (66–155)	99 (64–151)	0.02
Region n (%)			0.57
Oio	1551 (24)	1573 (25)
Biombo	1226 (19)	1311 (21)
Gabu	736 (12)	705 (11)
Cacheu	673 (11)	643 (10)
Bafata	564 (9)	555 (9)
Quinara	317 (5)	323 (5)
Tombali	478 (8)	480 (8)
Bubaque	38 (1)	38 (1)
Bolama	22 (0)	34 (1)
Sao Domingos	758 (12)	728 (11)
Ethnicity n (%)			0.34
Balanta	1913 (30)	1968 (31)
Fula/Mandinga	1009 (16)	1058 (17)
Manjaco	2315 (36)	2318 (36)
Pepel	303 (5)	297 (5)
Others	818 (13)	743 (12)
Missing information	5 (0)	6 (0)
Maternal schooling n (%)			0.11
None	3826 (60)	3709 (58)
1–4 years	1414 (22)	1478 (23)
>4 years	862 (14)	919 (14)
Missing information	261 (4)	284 (4)
Type of roof n (%)			0.64
Straw	2345 (37)	2395 (37)
Hard	3669 (58)	3663 (57)
Missing information	349 (5)	332 (5)
Toilet facilities n (%)			0.92
None	1657 (26)	1648 (26)
Latrine	4322 (68)	4371 (68)
Inside	13 (0)	13 (0)
Missing information	371 (6)	358 (6)
Electricity n (%)			0.73
Yes	878 (14)	886 (14)
No	5113 (80)	5151 (81)
Missing information	372 (6)	353 (6)
Weight for age Z-score (WAZ)
Mean WAZ (SD)^c,d	−0.67 (1.15)	−0.72 (1.24)	0.01
BCG coverage n (%)			0.01
BCG prior to entry	4941 (78)	5065 (79)
BCG at entry or during follow up	731 (11)	731 (11)
Not BCG vaccinated	691 (11)	594 (9)
Median age at BCG vaccination
Median age (IQR)	24 (10–50)	23 (9–48)	0.21
MV vaccinated during follow up n (%)			0.80
MV vaccinated during FU	991 (16)	985 (15)
Not MV vaccinated during FU	5372 (84)	5405 (85)
Median age at MV during FU
Median age (IQR)	294 (275–318)	291 (276–315)	0.19

^aP-value test of no difference in background factors according to sex.

^bMedian age on first Penta vaccination by the BHP team counted in days. Counting all visits the median age was 117 for males, 116 for females and 116 for males and females collectively.

^cMean WAZ on first Penta vaccination by the BHP team. Counting all visits mean WAZ was −0.64 for males and −0.71 for females.

^dA total of 396 were missing information on weight, 200 males and 196 females.

Table 2. Female relative to male mortality after any dose of Penta and stratified by dose number.

		Observations (n)	MR per 1000 PYRS (deaths/PYRS)	F/M MRR (95% CI)	Adjusted F/M MRR (95% CI)^a
Any Penta	Females	9758	25.2 (73/2,901)	0.95 (0.77–1.17)	1.01 (0.82–1.25)
	Males	9909	26.6 (78/2,930)	ref	ref
Penta1	Females	3658	33.9 (36/1,063)	1.02 (0.69–1.51)	1.08 (0.74–1.56)
	Males	3664	33.0 (35/1,062)	ref	ref
Penta2	Females	3240	20.0 (17/848)	0.72 (0.29–1.78)	0.76 (0.31–1.86)
	Males	3319	27.5 (24/874)	ref	ref
Penta3	Females	2854	20.2 (20/988)	1.06 (0.63–1.76)	1.13 (0.71–1.81)
	Males	2919	19.1 (19/993)	ref	ref

^aAdjusted for Weight for age z-score.

MR: Mortality rate, F/M MRR: Female/Male Mortality Rate Ratio.

6 females and 7 males had missing information on dose of Penta vaccination.

Table 3. F/M MRR by dose number of Penta vaccine stratified by age (above or below median^a).

	Sex	Observations (n)	MR per 1000 PYRS (deaths/PYRS)	F/M MRR (95% CI)	Adjusted F/M MRR (95% CI)^b
Any Penta^c
Above median age	Females	4884	28.5 (49/1,719)	1.29 (0.84–1.98)	1.38 (0.90–2.13)
	Males	4794	22.2 (37/1,667)	ref	ref
Below median age	Females	4874	20.3 (24/1,182)	0.63 (0.43–0.91)	0.62 (0.41–0.93)
	Males	5115	32.4 (41/1,264)	ref	ref
Penta 1
Above median age	Females	1838	38.2 (25/655)	1.29 (1.09–1.53)	1.37 (1.20–1.57)
	Males	1731	29.5 (18/610)	ref	ref
Below median age	Females	1820	26.9 (11/408)	0.72 (0.26–2.01)	0.71 (0.25–2.02)
	Males	1933	37.7 (17/451)	ref	ref
Penta2
Above median age	Females	1622	20.6 (11/534)	1.21 (0.32–4.55)	1.32 (0.36–4.91)
	Males	1626	17.0 (9/529)	ref	ref
Below median age	Females	1618	19.1 (6/314)	0.42 (0.18–0.98)	0.38 (0.17–0.85)
	Males	1693	43.5 (15/345)	ref	ref
Penta3
Above median age	Females	1419	24.6 (13/529)	1.29 (0.74–2.24)	1.35 (0.76–2.41)
	Males	1433	19.0 (10/526)	ref	ref
Below median age	Females	1435	15.2 (7/459)	0.79 (0.29–2.13)	0.82 (0.31–2.18)
	Males	1486	19.3 (9/467)	ref	ref

^aMedian age at Penta vaccination was 70 days for Penta1, 116 days for Penta2, and 156 days for Penta3.

^bAdjusted for Weight for age z-score.

^cTest of no difference between early and late vaccinated children estimated in a combined model: p-value: 0.02.

Mortality rate, F/M MRR: Female/Male Mortality Rate Ratio. 6 females and 7 males had missing information on dose of Penta vaccination.

Table 4. F/M MRR after any dose of Penta stratified by co-administering other vaccines.

	Sex	Observations (n)	MR per 1000 PYRS (deaths/PYRS)	F/M MRR (95% CI)	Adjusted F/M MRR (95% CI)^a
Penta co-administered with any vaccine	Females	9470	25.7 (72/2,800)	0.94 (0.78–1.15)	1.01 (0.83–1.23)
	Males	9579	27.3 (77/2,818)
Penta alone	Females	288	9.9 (1/101)	1.14 (0.07–19.34)	1.23 (0.08–19.21)
	Males	330	8.9 (1/112)
Penta co-administered with BCG (± OPV)	Females	235	37.1 (2/54)	0.65 (0.26–1.65)	0.72 (0.26–1.97)
	Males	235	56.4 (3/53)
Penta co-administered with PCV (± OPV)	Females	899	14.1 (4/284)	0.90 (0.22–3.72)	0.81 (0.21–3.20)
	Males	1039	15.5 (5/322)
Penta co-administered with Rota (± OPV and	Females	913	19.2 (5/260)	0.60 (0.33–1.08)	0.69 (0.37–1.29)
PCV)	Males	962	32.6 (9/276)
Penta co-administered with IPV (± OPV and	Females	163	46.2 (3/65)	3.04 (1.20–7.70)	4.28 (2.71–6.77)
PCV)	Males	177	15.3 (1/65)
Penta co-administered with OPV only	Females	7088	26.8 (56/2,091)	0.97 (0.79–1.18)	1.03 (0.84–1.25)
	Males	6991	27.8 (57/2,053)
Other combinations^b	Females	172	42.9 (2/47)	1.04 (0.25–4.31)	1.37 (0.26–7.07)
	Males	175	41.2 (2/49)

BCG: Bacillus Calmette-Guérin vaccine, OPV: Oral Polio vaccine, PCV: Pneumococcal vaccine, Rota: Rotavirus vaccine, IPV: Inactivated Polio vaccine.

^aAdjusted for Weight for age z-score.

^bPenta co-administered with other vaccines, most of these are combinations of BCG, OPV, PCV (±) Rota.

Mortality rate, F/M MRR: Female/Male Mortality Rate Ratio.

Table 5. F/M MRR after any Penta stratified by period (2008–2011, 2012–2015, 2016–2017).

	Sex	Observations (n)	MR per 1000 PYRS (deaths/PYRS)	F/M MRR (95% CI)	Adjusted F/M MRR (95% CI)^a
Any Penta
2008–11	Females	1516	35.3 (25/707)	1.27 (0.87–1.87)	1.36 (0.92–2.02)
	Males	1546	27.7 (20/723)
2012–15	Females	6677	22.5 (38/1,690)	0.86 (0.70–1.06)	0.88 (0.71–1.10)
	Males	6684	26.4 (44/1,669)
2016–17	Females	1565	19.9 (10/503)	0.77 (0.47–1.26)	0.86 (0.52–1.43)
	Males	1679	26.0 (14/538)

^aAdjusted for Weight for age z-score.

Mortality rate, F/M MRR: Female/Male Mortality Rate Ratio.

Data availability statement

Data are available from the corresponding author on a collaborative basis.