The rationale for use of clinically defined outcomes in assessing the impact of pneumococcal conjugate vaccines against pneumonia

Figures & data

Table 1. Definition of terms

Vaccine Preventable Disease Incidence (VPDI): The difference in outcome incidences between the unvaccinated (or control) and vaccinated populations, which is mathematically equivalent to the control or unvaccinated population incidence multiplied by Vaccine Effectiveness (VE). Also known as the attributable risk, absolute risk reduction, or risk difference. We report this as per 100,000 subjects per year or per 100,000 person-years of follow-up. When available, we report values directly from cited studies. Number Needed to Vaccinate (NNV): Calculated as 100,000 divided by VPDI divided by either average length of subject follow-up) or average duration of vaccine immunity (e.g. for adult PCV13 use in Table 4, NNV was estimated for 1, 5, and 10 years duration of immunity). Unlike VPDI, NNV is not a rate and thus should not be calculated for a single year unless that is the duration of the study in question or the documented duration of immunity.

Table 2. Vaccine efficacy or effectiveness (VE), vaccine-preventable disease incidence (VPDI) (per 100,000 person-years of observation or 100,000 subjects per year), and numbers needed to vaccinate (NNV) based on duration of follow-up or age at which follow-up ended

Study	Reference	Study design	Age of follow-up	Outcome	VE	Incidence unvaccinated	VPDI	NNV *	Fold increase in VPDI (and decrease in NNV) compared to etiologically confirmed disease
Indonesia Hib	[3]	Cluster randomized	<2 years	Hib meningitis	86%	19	16	3125	Referent
				Hospitalization for meningitis or clinic assessment for seizures	22%	701	158	316	9.9
Gambia 9-valent PCV	[4]	Individually randomized	<2 years	Vaccine-serotype bacteremic pneumonia	70%	200	140	357	Referent
				X-ray confirmed lobar consolidation or pleural effusion	37%	3510	1300	38	9.3
Finland 10-valent PCV	[5]	Cluster randomized	<2 years	All serotype invasive pneumococcal disease	94%	80	75	671	Referent
				Clinically suspected invasive pneumococcal disease	50%	426	210	238	2.8
				Hospitalized pneumonia	23%	1234	271	185	3.6
The Netherlands PCV13	[6]	Individually randomized	65+ years, 5 years assumed immunity duration	PCV13 serotype community acquired pneumonia with radiologic confirmation	37.5%	67	25.1	798	Referent
				Hospitalized clinically defined community acquired pneumonia	8.1%	891	72.2	277	2.9
Finland, rotavirus	[7]	Pre/post	<1 year	Hospitalized rotavirus acute gastroenteritis	80%	490	390	256	Referent
				Hospitalized all-cause acute gastroenteritis	54%	1980	1070	93	2.7
US rotavirus (2008–9)	[8]	Cohort	8 to 20 months	Hospitalized rotavirus acute gastroenteritis	87–92%	100 - 121	87 - 111	901 - 1149	Referent
				Hospitalized all-cause acute gastroenteritis	40–56%	349 - 491	139 - 275	364 - 719	1.6 to 2.5
South Africa inactivated influenza virus in pregnant women	[9]	Individually randomized	≤175 days	Influenza confirmed acute lower respiratory infection	100%	218	218	458	Referent
				All acute lower respiratory infection	43%	7200	3100	32	14
Africa RTS,S malaria vaccine	[10]	Individually randomized (comparing R3R vs. C3C)	Enrolled at age 5–17 months, followed to 48 months	Malaria hospitalization			1000	25	Referent
				All-cause hospitalization			1475	17	1.5
			Enrolled at age 6–12 weeks, followed to 39 months	Malaria hospitalization			554	56	Referent
				All-cause hospitalization			1108	28	2.0

Table 3. Characteristics of three studies evaluating the efficacy or effectiveness of 13-valent pneumococcal conjugate vaccine (PCV13) against pneumonia in older adults

Study characteristic	United States observational study	Netherlands randomized controlled trial (RCT)	Germany observational study
Reference	19, 20	6, 18	21
Design/data source	Time survival model of Medicare data	RCT with 1:1 PCV13:placebo	Population based cohort study of health insurance data with propensity score-based 3:1 matching of controls to cases for vaccine effectiveness calculation
Population size	81,009,094 person-years of observation; PCV13 coverage at study start (9/14) was 0.8% and at study end (12/17) 41.5%	42,240 received PCV13 42,256 received placebo	11,395 persons received PCV13 34,185 controls did not receive PCV13
Population Characteristics	Age 65+ years No exclusion of immunocompromised	Age 65+ years Non-immunocompromised	Age 60+ years No exclusion of immunocompromised
Duration	3.25 years	4 years	3 years
Outcome ascertainment	Hospital	Almost entirely hospital (ref. 3) and hospital + outpatient (ref. 89)	Hospital and outpatient
Setting	United States	Netherlands	Saxony
Outcome	Community acquired pneumonia based on a primary diagnosis of pneumonia or a secondary diagnosis of pneumonia with a primary diagnosis of septicemia, meningitis, empyema, or acute respiratory failure	Community acquired pneumonia and lower respiratory tract infection based on based on at least 2 pre-specified clinical criteria independent of radiographic findings	Pneumonia based on ICD-10-GM coding*

*ICD-10-GM coding: International Classification of Diseases 10^th Revision, German Modification

Table 4. Incidences and vaccine-preventable disease incidence (VPDI) (per 100,000 person-years of observation [Netherlands] or 100,000 subjects per year [Germany and United States]) as well as numbers needed to vaccinate (NNV) based on either 5 years or 10 years of 13-valent pneumococcal conjugate vaccine (PCV13) duration of protection against pneumonia. NA = not available

Study	Reference	VE (95% confidence interval or p-value)	Incidence vaccinated	Incidence unvaccinated	Incidence overall	VPDI	NNV (5 yrs PCV13 immune duration)	NNV (10 yrs PCV13 immune duration)
United States PCV13-type etiologically confirmed hospitalized CAP	19,20	43% (12% to 63%)	NA	NA	17 to 76	7 to 33	600 to 2800*	300 to 1400*
United States hospitalized clinical CAP	19,20
Flu season/flu vaccine+		6.0% (4.3% to 7.8%)	NA	NA	1776**	107	188	94
Flu season/flu vaccine-		11.4% (9.4% to 13.4%)	NA	NA	1776**	202	99	49
Non-flu season/flu vaccine+		9.3% (7.5% to 11.5%)	NA	NA	1776**	165	121	61
Non-flu season/flu vaccine+		10.2% (6.8% to 13.5%)	NA	NA	1776**	181	110	55
Netherlands hospitalized CAP	6	8.1% (1.0% to 14.6%)^†	819	891	--	72	277	138
Netherlands 1^o and 2^o care	18
Clinical CAP 1^o care		5.5% (-2.6% to 13.0%)	1,910	2,020	--	110^‡	182	91
Clinical CAP 1^o and 2^o care		7.4% (0% to 14.4%)	3,120	3,370	--	250^‡	80	40
LRTI 1^o care		3.8% (-1.1% to 8.4%)	11,120	11,550	--	430^‡	47	24
LRTI 1^o and 2^o care		4.4% (-0.3% to 9.0%)	12,320	12,890	--	570^‡	39	20
Germany all pneumonia 1^o and 2^o care	21	11.9% (p=0.028)	1556	1767	NA	211	95^Ω	47

* The original presentation calculated NNV over just a single year; however, because this is not the recommended method for NNV calculation as it does not take into account duration of protection (Refs. 22,23), we do not present these results

** VE was presented only by the four strata of influenza season and influenza vaccine, while incidence was presented only for the population overall (calculated as 148 per 100,000 beneficiary-months for CAP multiplied by 12 months [Figure 4, ref. 20])

† Based on exact methods (ref. 6, Table 2a)

‡ The original publication did not present VPDI or NNV. These were calculated as described in the text from original data

Ω The original publication reported an NNV of 158, calculated over the 3-year study duration

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