A hidden vulnerable population: Young children up-to-date on vaccine series recommendations except influenza vaccines.

Very young children (under 2 years old) have high risk for influenza-related complications. Children 6 months or older in the US are recommended to receive influenza vaccination annually, yet uptake is substantially lower than other routinely-recommended vaccines. Existing nationally-representative studies on very young child influenza vaccine uptake has several limitations: few examine provider-verified influenza vaccination (relying on parental report), few contain parental vaccine attitudes variables (known to be crucial to vaccine uptake), and none to our knowledge consider intersectionality of social disadvantage nor how influenza vaccine determinants differ from those of other recommended vaccines. This nationally-representative study examines provider-verified data on 7,246 children aged 6-23 months from the most recent (2011) National Immunization Survey to include the restricted Parental Concerns module, focusing on children up-to-date on a series of vaccines (the 4:3:1:3:3:1:4 series) but not influenza vaccines ("hidden vulnerability to influenza"). About 71% of children were up-to-date on the series yet only 33% on influenza vaccine recommendations by their second birthday; 44% had hidden vulnerability to influenza. Independent of parental history of vaccine refusal and a myriad of health services use factors, no parental history of delaying vaccination was associated with 7.5% (2.6-12.5) higher probability of hidden vulnerability to influenza despite being associated with 15.5% (10.8-20.2) lower probability of being up-to-date on neither the series nor influenza vaccines. Thus, parental compliance with broad child vaccine recommendations and lack of vaccine hesitancy may not indicate choice to vaccinate children against influenza. Examination of intersectionality suggests that maternal college education may not confer improved vaccination among non-Hispanic Black and Hispanic children despite that it does for non-Hispanic White children. Policymakers and researchers from public health, sociology, and other sectors need to collaborate to further examine how vaccine hesitancy and intersectional social disadvantage interact to affect influenza vaccine uptake in young US children.

Introduction

Children under the age of 5 years (“young”) and especially under 2 years (“very young”) are high risk for influenza complications simply because of their age, even if otherwise healthy. [1,2] They have increased risk of influenza-related hospitalizations, and doctor, urgent care, and emergency department visits, [3,4] comprising a substantial portion of total US influenza morbidity. [5] Influenza in children also affects family members and caregivers, [6] causing substantial parental work absenteeism, [7] and community epidemics. [8]

Influenza vaccination is the most effective preventive measure [9] and the US Centers for Disease Control and Prevention (CDC) routinely recommends it for all persons 6 months and older. [10] Influenza vaccines continually demonstrate a great safety profile, [11] and though their effectiveness varies annually, in children they prevent doctor visits, [12] febrile illnesses, [13] hospitalizations, [14] and randomized trials show high pooled efficacy of the live, attenuated vaccine (83% relative reduction of influenza risk) for children <8 years old. [15] Moreover, there is building evidence that vaccinating children against influenza has benefits extending to other adults in the household (for example, by preventing work loss [16-20]). Influenza vaccines have been increasingly affordable and available to children through public programs [21] and because the Affordable Care Act requires new health plans to cover all routinely-recommended preventive services without cost-sharing. [22]

Influenza vaccination uptake in young US children, however, remains sub-optimal. National annual uptake recently peaked at 73% during the 2018/2019 influenza season but has generally plateaued around 70% over the last decade of influenza seasons–as low as 43% in some states–representing millions of unvaccinated children. [23] Further, “complete uptake” as defined by the CDC–receiving the appropriate number of influenza vaccinations for the child’s age and birthdate–is generally much lower in young children. [24]

By contrast, complete uptake of other routinely-recommended vaccines is much higher. In the most recent published estimates (2017), the percent of children 19–35 months old up-to-date (UTD) on other recommendations was: 83.2% for 4+ diphtheria-tetanus-acellular pertussis vaccine doses, 92.7% for 3+ poliovirus vaccine doses, 91.5% for 1+ measles-mumps-rubella vaccine doses, 80.7% for 3+ Haemophilus influenza type B vaccine doses, 91.4% for 3+ Hepatitis B vaccine doses, 91.0% for 1+ varicella vaccine doses, and 82.4% for 4+ pneumococcal conjugate vaccine doses. [25] Moreover, the percentage UTD on all of these other recommendations (the “4:3:1:3:3:1:4” series) is 70.4%. [25]

Research on determinants of uptake for influenza vaccination in the US, however, is limited, tending to focus on adult (particularly elderly) populations, and substantially less on children. [26,27] Though an unpublished literature review [28] and published studies of other vaccines [29,30] provide theoretical and empirical foundations of determinants to consider, there are three limitations.

First, existing studies and frameworks have limited generalizable to the general pediatric population.

Second, there is no comparison of determinants of being UTD on influenza vaccines vs. other vaccines. This is an important research gap; that the 19-shot, 7-vaccine series (4:3:1:3:3:1:4) uptake rate is comparable to the recent 2018/2019 single-season peak in influenza vaccine uptake in young children indicates unique mechanisms affect parents’ decisions to vaccinate their child against influenza relative to every other routinely-recommended childhood vaccine.

Third, to our knowledge, no nationally-representative studies utilized a conceptual framework to ground their selection of covariates. As a result, the literature does not systematically consider and adjust for many important constructs, notably vaccine-related parental perceptions. Moreover, no studies consider interacting effects of disadvantaged social statuses, an important limitation potentially obscuring health differences and impairing efforts to reduce health disparities. [31] Intersectionality theory posits that social statuses like race/ethnicity, gender, and social class cannot be disaggregated as they reinforce each other in producing and maintaining health outcomes across the life span. [32-35]

This study has the goal of replicating prior studies examining determinations of influenza vaccine uptake of very young children while directly addressing the three aforementioned sets of limitations. To do so, this study uses a nationally-representative sample of very young children in the US that includes provider-verified vaccination status and constructs across all domains noted in the literature, including federally-restricted variables about parental attitudes of vaccination and accounting for intersectionality. It examines determinants of a newly-identified vulnerable population: those with “hidden vulnerability to influenza”–i.e., children UTD on a wide variety of vaccine recommendations (the 4:3:1:3:3:1:4 series) except influenza.

Methods

Data source

Data come from the 2011 National Immunization Survey (NIS), which includes the most recent Parental Concerns (PC) module, a restricted supplement containing important vaccine-related parental perception variables [36]. The NIS is a serial, cross-sectional survey that has monitored child vaccination uptake since 1994. [37] The target population is children 19–35 months in US households. [38] The PC module variables were merged with publicly-accessible NIS variables by National Center for Health Statistics (NCHS) analysts and accessed by the authors at the Penn State Federal Statistical Research Data Center, a Census Bureau facility housed at the Pennsylvania State University meeting all physical and information security requirements for federally-restricted data.

The research protocol was reviewed by both the NCHS Research Ethics Review Board and the Pennsylvania State University Institutional Review Board and deemed not human research.

The NIS uses random digit dialing methodology to identify households containing target children and interviews a knowledgeable adult. With consent, the NIS contacts the child’s health care provider(s) by mail to request vaccination information from the child’s medical records; 79.5% and 75.0% of landline and cell phone cases gave consent; 95.2% and 93.8% of their providers returned the questionnaires. The 2011 public-use file contains 26,741 children with completed interviews, and 19,144 with provider-verified data (excluding the Virgin Islands). Overall, the CASRO response rate was 61.6% (72.3% of which had adequate provider data). [38] Of the 19,144 children with adequate provider-verified data, 13,358 (69.8%) received the restricted PC module, and 12,559 (94.0%) completed it (unpublished NCHS data that the authors obtained via correspondence with NCHS analysts).

Dependent variable

Two binary NIS variables were used to construct the three dependent variables used in this study. The first is complete influenza vaccination–that is, whether the child received the full number of seasonal influenza vaccines given the number of influenza seasons they have experienced by their second birthday and when the survey was administered (children not 6–23 months of age during the span of September 1 to December 31 are “not eligible;” see Section 7.8.1 and Table 7 of the survey user’s guide [38]). The second variable captures whether the child is UTD on the 4:3:1:3:3:1:4 series. The three binary dependent variables used in this study are combinations of these two NIS variables–being UTD on: (1) “both” requirements; (2) “series but not influenza” requirements; and (3) “neither” requirement. These terms are used throughout the paper. The focus of this study is on the “series but not influenza” outcome in order to address the gap of identifying determinants that uniquely predict children UTD on a wide variety of vaccine recommendations except influenza in order to predict “hidden” vulnerability to influenza.

Determinants of influenza vaccination

Vaccination is the use of a health service, so selection of determinants can be grounded in Andersen’s model of health services use, [39] which divides determinants into three factors: (1) predisposing (e.g., child’s race/ethnicity, parental vaccine attitudes and beliefs); (2) enabling (e.g., family income, health insurance); and (3) need (e.g., functional state, need for medical care). The model also accounts intermediate-level health behaviors influencing health services use (e.g., personal health practices). Andersen’s model has been used across multiple healthcare system sectors in the context of a variety of diseases. [40] All NIS variables pertinent to this model or prior vaccine literature were included as described below (see Table 1 for more detail):

Table 1

Descriptive statistics of study population, U.S children aged 6–23 months old (N = 7,246), 2011 NIS.

Variable	Percent	N
Outcome variables
Total up-to-date on influenza vaccine(s) at 24 months old
No	66.7	4602
Yes	33.3	2644
Total up-to-date on 4:3:1:3:3:1:4 vaccine series
No	28.9	2048
Yes	71.1	5198
*Up-to-date on BOTH influenza vaccine(s) AND 4:3:1:3:3:1:4 vaccine series
No	72.5	5042
Yes	27.6	2204
**Up-to-date on ONLY 4:3:1:3:3:1:4 vaccine series; not influenza vaccine(s)
No	56.5	4252
Yes	43.5	2994
Up-to-date on ONLY influenza vaccine(s); not 4:3:1:3:3:1:4 vaccine series
No	94.3	6806
Yes	5.8	440
*Up-to-date on NEITHER influenza vaccine(s) NOR 4:3:1:3:3:1:4 vaccine series
No	76.8	5638
Yes	23.2	1608
Independent variables	Percent	N
Child’s sex
Female	48.2	3503
Male	51.8	3743
Child’s race/ethnicity
Non-Hispanic White only	50.8	4629
Non-Hispanic Black only	12.5	690
Non-Hispanic other or multiple race	9.2	757
Hispanic	27.5	1170
Child’s first-born status
First born	40.6	2399
Not first born	59.4	4847
Child ever received benefits from the Women, Infants, and Children program
No	47.8	4325
Yes	52.2	2921
Child uninsured
No	91.9	6755
Yes	8.1	491
Mother’s education
Less than a college graduate	63.8	3706
College graduate	36.2	3540
Mother’s age group
≤19 years	2.6	121
20–29 years	41.6	2144
≥30 years	55.9	4981
Mother’s marital status
Married	67.9	5506
Never married, widowed, divorced, separated, or deceased	32.1	1740
Language
English	87.0	6712
Spanish or other	13.0	534
Housing arrangement
Owned or being bought	57.1	5153
Rented	39.5	1889
Other arrangement	3.4	204
Provider facility type
Public/WIC	11.4	751
Hospital	10.5	836
Private	60.5	4464
Military/other facilities	3.9	242
Mixed	13.7	953
Child was ever breastfed or fed breast milk
No	22.4	1406
Yes	77.6	5840
Parent ever refused or decided not to have their child vaccinated
No	84.6	6052
Yes	15.4	1194
Parent ever delayed or put off having their child vaccinated
No	66.6	4852
Yes	33.4	2394
	Mean (SD)	N
Parent belief that vaccines are necessary to protect children’s health	9.4 (1.3)	7246
Parent belief that vaccines do a good job at preventing their diseases	9.1 (1.6)	7246
Parent belief that vaccines are safe	8.3 (2.1)	7246
Parent belief that vaccine-preventable diseases are serious and can hurt children	9.2 (2.1)	7246
Parent perception of strength of physician’s vaccine recommendation	9.3 (1.7)	7246

Source: 2011 National Immunization Survey (NIS) data, children represented in the Parental Concerns module with provider-verified vaccination data and eligible for the influenza vaccination up-to-date question who are not missing any covariates. Means and percentages weighted to be nationally-representative. N un-weighted to show actual number of observations in each cell. For the last 5 covariates (parent beliefs/perceptions), the scale is 0–10 where 0 is disagree and 10 is agree.

*Comparator outcome variables examined in this study

**Main outcome of interest in this study, “series but not influenza” (i.e., “hidden vulnerability to influenza”)

Seven variables represent contextual-level factors (family- or medical practice-level) predisposing, enabling, or creating need for influenza vaccination and other health services use:

mother’s education [41-43];

mother’s age [44];

mother’s marital status;

household language [44];

housing arrangement;

area of residence; and

provider facility type [43,44]

Seven variables represent parental perceptions and beliefs surrounding vaccines and vaccine-preventable diseases. The Parental Concerns module data are restricted and not contained in the public use dataset, but these variables were obtained by the authors and analyzed in a Research Data Center for his study. However, the survey instrument is publicly available online [36]. Questions 1–5 below ask parents to rate the statement on a scale of 0–10 where 0 is “strongly disagree” and 10 is “strongly agree.” Questions 6 and 7 below ask parents if they have ever refused or delayed getting their child vaccinated (binary question):

vaccines are necessary to protect child health [26,45-50];

vaccines do a good job at preventing their diseases [26,45-50];

vaccines are safe [45-47,51];

vaccine-preventable diseases are serious and can hurt children [26,46,52];

strength of physician vaccine recommendation [27,41,45-50,52-56];

history of refusing their child’s vaccines; and

history of delaying their child’s vaccines.

Five variables represent individual (child)-level factors:

sex;

race/ethnicity [24,43,44]);

first born status;

current receipt of Women, Infants, and Children (WIC) benefits; and

whether the child was uninsured at any time during the year [52].

One variable represents the child’s personal health practices–whether they were ever breast fed/fed breast milk. A variable for family income was considered but exhibited concerns of multicollinearity and thus was excluded.

Study population

Respondents were eligible for the study if they: (1) had provider-verified data (NIS-defined eligibility for the outcome variables; also addresses recall bias gap in other literature); (2) were not ineligible for the influenza UTD variable by age at survey date (NIS-defined eligibility for the outcome variables); and (3) received the Parental Concerns module (8,065 total eligible children). Complete case analysis was performed; 89.8% of the eligible sample were complete cases across all variables (N = 7,246). Complete case status was neither associated with the main outcome (“series but not influenza” UTD status), nor 15 of 20 covariates. Because complete case status was only slightly associated with 5 of the 20 covariates, missingness was not completely at random (a key assumption for ruling out multiple imputation for dealing with missingness). Moreover, the large size of the complete case sample, relatively low complete case missingness, and lack of association between complete case status and outcome of interest all suggest complete case analysis to be less biased than other methods of dealing with missingness such as multiple imputation, [57] so complete case analysis was performed.

Analysis

We performed three sets of analyses. First, we examined variation in each vaccine UTD outcome by independent variables of interest and covariates. Second, we performed regression analyses to examine the relationship between vaccine UTD outcomes and key independent variables controlling for covariates and using interaction terms to examine intersectionality. Third, we examined model-predicted outcome probabilities and graphed their patterns to interpret the intersectional results. Those three sets of analyses are described in detail below:

First, bivariate associations between the three UTD outcomes and all determinants (variables) were examined.

Second, each outcome was then regressed onto all determinants, including interaction terms for all combinations of child’s race/ethnicity, mother’s education, and mother’s marital status to incorporate intersectionality. Logistic regression is often used to examine bivariate outcomes, though we use Linear Probability Model (LPM) regression–Ordinary Least Squares regression of a binary outcome–because logistic regression does not produce straightforward interpretation of interaction terms. [58,59] Further, LPM regression is motivated by the literature [60-62] and its coefficients are easily interpreted as changes in the probability of observing the “1” binary response associated with unit changes in explanatory variables.

Third, given interaction term coefficients are not directly interpretable, [63] model-predicted marginal probabilities of UTD status among all interaction term subgroups were calculated and graphed. Analyzing double and triple interaction terms can be complicated to interpret from just the numbers, so we graphed the predicted probability to visually compare changes in the outcome of interest among all interaction term subgroups in a side-by-side manner.

All analyses were performed using Stata/SE 13.1 statistical software [64] and use Stata’s svy commands to apply NIS-provided sample weights to generate national-representative estimates adjusted for complex survey design, ratio, non-response, post-stratification adjustments, and heteroscedasticity.

Results

Table 1 contains weighted descriptive statistics of the complete case sample. By their second birthday, 33% of children were UTD on influenza vaccinations, and 71% were UTD on the 4:3:1:3:3:1:4 series. The cross-section of these variables (this study’s outcomes) reveals that 27% were UTD on both, 23% were UTD on neither, and 44% were UTD on the series but not influenza vaccines (again, the latter variable being the main interest of this study).

Table 2 provides weighted bivariate correlations (i.e., not adjusted for any other variables) between the three UTD outcomes and each covariate. There were several determinants associated with vulnerability across all of the UTD outcomes (see the shaded gray cells), but two findings were unique to “series but not influenza”–children in households speaking Spanish or another language (9 percentage points more likely than English households to have hidden vulnerability to influenza, p = 0.023), and never delaying vaccination (8 percentage points more likely than ever delaying to have hidden vulnerability to influenza, p = 0.003).

Table 2

Correlates of vaccination up-to-date variables, U.S children aged 6–23 months old (N = 7,246), 2011 NIS.

	Up-to-date status (combinations of seasonal influenza and the 4:3:1:3:3:1:4 series)
	“BOTH” Both flu and 4:3:1:3:3:1:4 series 72.5% 27.6%			“SERIES BUT NOT FLU” 4:3:1:3:3:1:4 series, not flu 56.5% 43.5%			“NEITHER” Neither flu, 4:3:1:3:3:1:4 series 76.8% 23.2%
	No %	Yes %	p	No %	Yes %	p	No%	Yes %	p
Child’s sex
Female	72.7	27.3	0.8430	57.4	42.6	0.4609	75.8	24.2	0.3583
Male	72.3	27.8		55.6	44.4		77.8	22.2
Child’s race/ethnicity
Non-Hispanic White only	68.4	31.6	0.0002	59.3	40.7	0.0220	78.6	21.4	0.0113
Non-Hispanic Black only	82.5	17.5		56.9	43.1		68.0	32.0
Non-Hispanic other/multiple race	68.9	31.1		57.9	42.2		78.8	21.3
Hispanic	76.6	23.4		50.5	49.5		77.0	23.0
Child’s first-born status
First born	70.1	29.9	0.0572	54.1	45.9	0.1026	82.1	18.0	0.0002
Not first born	74.1	25.9		58.1	41.9		73.3	26.7
Child ever received WIC benefits
No	65.9	34.1	<0.0001	59.3	40.7	0.0210	81.3	18.7	0.0001
Yes	78.4	21.6		53.9	46.1		72.8	27.2
Child uninsured
No	71.8	28.2	0.0270	56.4	43.6	0.9200	77.7	22.3	0.0099
Yes	79.6	20.4		56.9	43.1		67.4	32.6
Mother’s education
Less than a college graduate	77.3	22.7	<0.0001	54.4	45.6	0.0141	73.5	26.5	<0.0001
College graduate	63.9	36.1		60.0	40.0		82.8	17.2
Mother’s age group
≤19 years	83.2	16.8	<0.0001	44.0	56.0	0.1680	73.3	26.7	0.0010
20–29 years	77.8	22.2		55.6	44.4		72.5	27.5
≥30 years	68.0	32.0		57.7	42.3		80.3	19.8
Mother’s marital status
Married	69.0	31.0	<0.0001	58.0	42.0	0.0579	79.1	20.9	0.0019
Never married, widowed, divorced, separated, or deceased	79.8	20.2		53.2	46.8		72.1	27.9
Language
English	72.1	27.9	0.445	57.6	42.4	0.0228	76.3	23.7	0.2179
Spanish or other	75.0	25.0		48.6	51.4		80.3	19.7
Housing arrangement
Owned or being bought	69.5	30.5	0.0017	56.6	43.4	0.7133	80.0	20.0	0.0013
Rented	75.6	24.4		56.6	43.4		73.0	27.0
Other arrangement	85.3	14.7		41.4	48.6		68.6	31.4
Provider facility type
Public/WIC	82.0	18.0	0.0003	53.2	46.8	0.5188	67.1	32.9	<0.0001
Hospital	76.6	23.4		58.0	42.0		75.9	24.1
Private	69.6	30.4		57.6	42.4		78.9	21.1
Military/other facilities	85.5	14.6		58.7	41.3		57.6	42.4
Mixed	70.2	29.8		52.3	47.7		82.2	17.8
Child was ever breastfed or fed breast milk
No	79.5	20.5	<0.0001	53.3	46.7	0.1333	73.3	26.7	0.0500
Yes	70.4	29.6		57.4	42.6		77.9	22.1
Parent ever refused/decided not to have their child vaccinated
No	70.1	29.9	<0.0001	57.4	42.6	0.0340	78.5	21.5	<0.0001
Yes	85.4	14.6		51.1	48.9		67.8	32.3
Parent ever delayed or put off having their child vaccinated
No	69.3	30.7	0.0003	53.9	46.1	0.0032	82.6	17.4	<0.0001
Yes	78.7	21.3		61.6	38.4		65.4	34.6
	No mean (se)	Yes Mean (se)	p	No mean (se)	Yes Mean (se)	p	No mean (se)	Yes Mean (se)	p
Parent believes vaccines are necessary to protect children’s health	9.33 (0.03)	9.58 (0.04)	<0.0001	9.36 (0.04)	9.46 (0.04)	0.0775	9.50 (0.03	9.08 (0.08)	<0.0001
Parent believes vaccines do a good job at preventing their diseases	9.02 (0.05)	9.21 (0.07)	0.0252	9.01 (0.06)	9.15 (0.05)	0.0658	9.18 (0.04)	8.73 (0.11)	0.0001
Parent believes vaccines are safe	8.16 (0.06)	8.63 (0.07)	<0.0001	8.26 (0.06)	8.34 (0.09)	0.4618	8.43 (0.06)	7.83 (0.11)	<0.0001
Parent believes vaccine-preventable diseases are serious and can hurt children	9.13 (0.07)	9.27 (0.09)	0.2228	9.20 (0.07)	9.12 (0.08)	0.4880	9.20 (0.06)	9.07 (0.14)	0.4125
Parent perceived strength of physician vaccine recommendation	9.32 (0.04)	9.41 (0.12)	0.5055	9.33 (0.07)	9.36 (0.06)	0.7548	9.37 (0.06)	9.27 (0.07)	0.2852

Source: 2011 National Immunization Survey (NIS) data, children represented in the Parental Concerns module with provider-verified vaccination data and eligible for the influenza vaccination up-to-date question who are not missing any covariates. Means and percentages weighted to be nationally-representative. For the last 5 covariates (parent beliefs/perceptions), the scale is 0–10 where 0 is disagree and 10 is agree. Shaded cells indicate most vulnerable groups among those with statistically significant differences in each UTD outcome.

Table 3 shows weighted results from LPM regression of the “series but not influenza” outcome onto all determinants (i.e., adjusted for all variables), including interaction terms. Comparing all columns, several patterns emerge (see the shaded gray cells). Ever refusing vaccination was associated with 9.9 percentage points (95% confidence interval (CI): 4.2–15.7) higher probability of “series but not influenza” (hidden vulnerability to influenza) despite that ever delaying (not necessarily refusing) was associated with 7.5 percentage points (95% CI 2.6–12.5) lower probability of “series but not influenza.” The direction of the delay finding was unexpected from what was observed in the other two outcomes (S1 Table).

Table 3

Change in predicted probabilities of up-to-date vaccine status, multivariate linear probability model regression, U.S children aged 6–23 months old (N = 7,246), 2011 NIS.

	Up-to-date status: “SERIES BUT NOT FLU” 4:3:1:3:3:1:4 series, not flu
	ΔPr.	95% CI
Child’s race/ethnicity (ref: non-Hispanic White)
Non-Hispanic Black	-0.040	-0.145, 0.092
Non-Hispanic other or multiple race	0.001	-0.018, 0.105
Hispanic	-0.027	-0.155, 0.157
Mother is a college graduate (ref: education less than a college graduate)	*-0.083	-0.150, -0.016
Mother never married, widowed, divorced, separated, or deceased (ref: married)	0.009	-0.090, 0.108
Child’s race/ethnicity*mother’s education
(Ref: non-Hispanic White with college graduate mother)
Non-Hispanic Black with college graduate mother	0.121	-0.094, 0.336
Non-Hispanic other/multiple race with college graduate mother	0.058	-0.122, 0.238
Hispanic with college graduate mother	**0.263	0.104, 0.422
Child’s race/ethnicity*mother’s marital status
(Ref: non-Hispanic White; mother never married, widowed, divorced, separated, or deceased)
Non-Hispanic Black; mother never married, widowed, divorced, separated, or deceased	0.022	-0.157, 0.202
Non-Hispanic other/multiple race; mother never married, widowed, divorced, separated, or deceased	-0.042	-0.253, 0.169
Hispanic; mother never married, widowed, divorced, separated, or deceased	0.068	-0.082, 0.217
Mother is college graduate*never married/widowed/divorced/separated/deceased (Ref: mother is college graduate*married)	-0.080	-0.240, 0.081
Child’s race/ethnicity*mother’s education*mother’s marital status
(Ref: non-Hispanic White; mother is college graduate; never married, widowed, divorced, separated, or deceased)
Non-Hispanic Black; mother is college graduate; never married, widowed, divorced, separated, or deceased	0.086	-0.258, 0.430
Non-Hispanic other/multiple race; mother is college graduate; never married, widowed, divorced, separated, or deceased	0.076	-0.357, 0.510
Hispanic; mother is college graduate; never married, widowed, divorced, separated, or deceased	-0.115	-0.475, 0.244
Significant covariates
Parent ever refused/decided not to have their child vaccinated (ref: never)	**0.099	0.042, 0.157
Parent ever delayed or put off having their child vaccinated (ref: never)	**-0.075	-0.125, -0.026

Source: 2011 National Immunization Survey (NIS) data, children represented in the Parental Concerns module with provider-verified vaccination data and eligible for the influenza vaccination up-to-date question who are not missing any covariates. “ΔPr.” represents changes in predicted probabilities, weighted to be nationally-representative (e.g., “0.116” means an absolute increase in probability of series but not influenza outcome associated with change in the covariate; this is the same as an 11.6 percentage point absolute increase in chance of series but not influenza outcome associated with change in the covariate). Standard errors used to calculate 95% confidence intervals are adjusted for complex survey design. For brevity, this table only includes the main outcome of interest, main independent variables, and significant covariates. This model controls more many covariates not shown in the table: child sex, child first born status, child WIC recipiency, child insurance status, mother’s age group, household language, housing arrangement, provider facility type, child breastfed status, 5 different measures of parental beliefs of perceptions about vaccine and vaccine-preventable diseases, and area of residence. Shaded cells represent significant coefficients indicating vulnerability unique to the “series not influenza” outcome or in a direction different than suggested from the “both” or “neither” outcomes. See S1 Table for the unabridged version with all three outcomes and all covariates.

*p<0.05

**p<0.01 ***p<0.001.

Some interaction term coefficients in Table 3 related to combinations of mother’s education and child’s race/ethnicity were significant and the direction of the “series but not influenza” coefficients were also different than what would be expected from the other two outcomes (S1 Table). These warrant exploration of patterns among the interaction term variables and suggest that intersectionality matters for hidden vulnerability to influenza. Accordingly, to interpret interaction term coefficients, Table 4 shows weighted, predicted probabilities of each UTD outcome among all possible combinations of interaction terms. There were no significant interaction term coefficients involving mother’s marital status in the “series but not influenza” outcome from Table 3 and no significant differences in predicted probabilities of intersectional subgroups in Table 4. There were also no significant differences within predicted probabilities of each lone intersectional construct (see Fig 1).

Table 4

Predicted probabilities of up-to-date vaccine outcomes among intersectional interaction term subgroups, multivariate linear probability model regression, U.S children aged 6–23 months old (N = 7,246), 2011 NIS.

	Up-to-date status: “SERIES BUT NOT FLU” 4:3:1:3:3:1:4 series, not flu
Main coefficient subgroups	Pr.	95% CI
Child’s race/ethnicity
Non-Hispanic White only	0.419	0.386, 0.453
Non-Hispanic Black only	0.434	0.358, 0.509
Non-Hispanic other or multiple race	0.430	0.362, 0.498
Hispanic	0.506	0.448, 0.564
Mother’s education
Less than a college graduate	0.448	0.414, 0.482
College graduate	0.429	0.378, 0.479
Mother’s marital status
Married	0.427	0.395, 0.460
Never married, widowed, divorced, separated, or deceased	0.424	0.374, 0.474
Two-way interaction term subgroups
Child’s race/ethnicity*mother’s education
Non-Hispanic White child; non-college graduate mother	0.452	0.407, 0.498
Non-Hispanic White child; college graduate mother	0.344	0.291, 0.396
Non-Hispanic Black child; non-college graduate mother	0.419	0.323, 0.516
Non-Hispanic Black child; college graduate mother	0.460	0.331, 0.589
Non-Hispanic other or multiple race child; non-college graduate mother	0.439	0.335, 0.544
Non-Hispanic other or multiple race child; college graduate mother	0.413	0.284, 0.543
Hispanic child; non-college graduate mother	0.447	0.370, 0.524
Hispanic child; college graduate mother	0.565	0.447, 0.683
Child’s race/ethnicity*mother’s marital status
Non-Hispanic White child; married mother	0.419	0.375, 0.464
Non-Hispanic White child; never married, widowed, divorced, separated, or deceased mother	0.399	0.332, 0.466
Non-Hispanic Black child; married mother	0.423	0.320, 0.526
Non-Hispanic Black child; never married, widowed, divorced, separated, or deceased mother	0.457	0.360, 0.553
Non-Hispanic other or multiple race child; married mother	0.441	0.346, 0.536
Non-Hispanic other or multiple race child; never married, widowed, divorced, separated, or deceased mother	0.407	0.258, 0.555
Hispanic child; married mother	0.488	0.415, 0.561
Hispanic child; never married, widowed, divorced, separated, or deceased mother	0.494	0.377, 0.611
Mother’s education*mother’s marital status
Mother is not a college graduate; married	0.437	0.393, 0.481
Mother is not a college graduate; never married, widowed, divorced, separated, or deceased	0.463	0.411, 0.516
Mother is a college graduate; married	0.447	0.396, 0.498
Mother is a college graduate; never married, widowed, divorced, separated, or deceased	0.380	0.270, 0.490
Three-way interaction term subgroups
Child’s race/ethnicity*mother’s education*mother’s marital status
Non-Hisp. White child; mother is not college grad; married	0.449	0.391, 0.508
Non-Hisp. White child; mother is not college grad; never married/widowed/divorced/separated/deceased	0.458	0.382, 0.534
Non-Hisp. White child; mother is college grad; married	0.366	0.319, 0.413
Non-Hisp. White child; mother is college grad; never married/widowed/divorced/separated/deceased	0.295	0.166, 0.424
Non-Hisp. Black child; mother is not college grad; married	0.409	0.276, 0.543
Non-Hisp. Black child; mother is not college grad; never married/widowed/divorced/separated/deceased	0.441	0.351, 0.530
Non-Hisp. Black child; mother is college grad; married	0.448	0.286, 0.609
Non-Hisp. Black child; mother is college grad; never married/widowed/divorced/separated/deceased	0.485	0.275, 0.696
Non-Hisp. other/multiple race child; mother is not college grad; married	0.450	0.308, 0.592
Non-Hisp. other/multiple race child; mother is not college grad; never married/widowed/divorced/separated/deceased	0.417	0.292, 0.542
Non-Hisp. other/multiple race child; mother is college grad; married	0.425	0.333, 0.518
Non-Hisp. other/multiple race child; mother is college grad; never married/widowed/divorced/separated/deceased	0.388	0.040, 0.737
Hispanic child; mother is not college grad; married	0.423	0.325, 0.520
Hispanic child; mother is not college grad; never married/widowed/divorced/separated/deceased	0.499	0.411, 0.588
Hispanic child; mother is college grad; married	0.603	0.489, 0.717
Hispanic child; mother is college grad; never married/widowed/divorced/separated/deceased	0.485	0.206, 0.763

Source: 2011 National Immunization Survey (NIS) data, children represented in the Parental Concerns module with provider-verified vaccination data and eligible for the “series but not influenza” vaccination up-to-date question who are not missing any covariates from main analysis. Coefficients represent predicted linear probabilities of vaccination up-to-date outcomes among all hierarchical interaction term subgroups from multivariate linear probability regression models (Table 3; i.e., adjusting for all covariates). See S2 Table for the unabridged version with all three up-to-date status outcomes.

Fig 1

Model-predicted probability (with 95% confidence intervals) of “series but not flu” outcome among main coefficient subgroups from Table 4.

However, examination of the predicted probabilities of “series but not influenza” among child’s race/ethnicity*mother’s education subgroups elucidates why there were significant interactions terms observed in Table 3. First, Hispanic children with college-educated mothers have higher probability (0.565: 95% CI 0.447–0.683) of “series but not influenza” than non-Hispanic White children with college-educated mothers (0.344: 0.291–0.396) despite that the former had one of the lowest predicted probabilities of the “both” outcome (S2 Table); this indicates that a unique identifier of hidden vulnerability for influenza is in Hispanic children with college-educated mothers. Second, examining the graphical representation of this relationship (Fig 2) shows that mother’s education is associated with reduced “series but not influenza” probability among non-Hispanic White and non-Hispanic Other children but increased probability for non-Hispanic Black and Hispanic children.

Fig 2

Model-predicted probability (with 95% confidence intervals) of “series but not flu” outcome among two-way interaction term subgroups: Child’s race/ethnicity*mother’s education from Table 4.

Note the upward slanting slopes of “series but not flu” probability among non-Hispanic Black and Hispanic children when their mothers had a college education.

Finally, the triple-interaction term coefficients were examined to further explore the above intersectionality finding. In Table 4, Hispanic children with married, college-educated mothers were significantly more likely to be in the “series but not influenza” group (0.603: 0.489–0.717) than non-Hispanic White children with college-educated mothers regardless of whether the mother was married (0.366: 0.319–0.413) or not (0.295: 0.166–0.424). Visualizing this in Fig 3, which stratifies Fig 2 by mother’s marital status, a clear trend emerges: the patterns seen among married mothers (top panel of Fig 3) closely mimic the unstratified relationship depicted in Fig 2. Looking at the pattern among mothers never married, widowed, divorced, separated, or deceased (bottom panel of Fig 3), however, reveals a divergence in Hispanic women: attainment of a college degree is associated with hidden vulnerability to influenza among Hispanic children only with married Hispanic mothers. Hispanic mothers not in the married group appear to have the same education interaction as non-Hispanic White and non-Hispanic Other/multiple race children. The direction of the interaction term coefficient compared to its interaction term coefficient in the “both” or “neither” columns of Table 3 suggests this is unique to “series but not influenza” vulnerability.

Fig 3

Model-predicted probability (with 95% confidence intervals) of “series but not flu” outcome among three-way interaction term subgroups: Child’s race/ethnicity*mother’s education, stratified by mother’s marital status from Table 4.

Note that all trend lines in the top graph parallel trend lines in the bottom graph except those circled in red.

Discussion

A concerning main finding of this study is that nearly half of very young US children have “hidden vulnerability to influenza.” These children are UTD on a large series of vaccine recommendations (a 19-shot, 7-vaccine series)–and would otherwise seem like neither a population vulnerable to vaccine-preventable diseases nor suggest their parents would have tendencies to refuse vaccination–but yet are not UTD on influenza vaccinations. A recent study of complete influenza vaccine uptake among very young NIS children found nearly identical uptake [24] as reported here, though differences in respondents’ intent to receive other vaccines and the role that parental attitudes toward vaccination and vaccine-preventable diseases were not studied. We were able to examine this finding including comparisons to both uptake of other vaccines and adjusting for parental attitudes toward vaccination and vaccine-preventable diseases.

Parental history of vaccine refusal was unsurprisingly associated with lower UTD status of all vaccines studied (the 4:3:1:3:3:1:4 and complete influenza vaccine status). What is particularly interesting, however, is that a unique determinant of hidden vulnerability to influenza was parental history of never delaying vaccination. While vaccine hesitancy has risen recently, [65] child influenza vaccination rates have been lower than other vaccines for quite some time and our finding was independent of general vaccine hesitancy. This finding likely represents longstanding hesitancy specific to the influenza vaccine.

Perhaps many parents with children UTD on most vaccines, who thus appear to support the concept of vaccination, are uniquely hesitant or skeptical about the influenza vaccine. This supports the theory that vaccine hesitancy is highly context-dependent and functions differently comparing influenza to other vaccines. Vaccine hesitancy is complex; it is heavily grounded in myths about vaccines and their respective diseases, as well as interwoven with broader contexts such as socioeconomic circumstances, social norms, health beliefs, the media, and institutional trust. [65-69]

The second unique predictor of hidden vulnerability to influenza was maternal college education attainment (but only for non-Hispanic Black children, and Hispanic children with married mothers, suggesting that intersectionality is important to identifying hidden vulnerability to influenza). In other words, maternal college degree attainment was associated with higher uptake of all vaccines studied except among non-Hispanic Black and Hispanic children, for whom it was instead associated with “hidden vulnerability” to influenza.

Higher parental education is generally associated higher vaccine uptake in US children, [41-43] though the returns of higher education may differ by race/ethnicity, particularly with regards to health behavior. [70] Intersectionality is a fundamental concept not just as it pertains to social disadvantage but also as it pertains to health, [32-35] yet has unfortunately been largely neglected in the health literature. [31] Public health and health policy researchers have placed increasing recognition on the notion that health equity can only occur by incorporating health into upstream decision-making, such as social and economic policy (e.g., the “Health in All Policies” approach). [71] This study reinforces these points and criticisms coming from both sociologists and public health professionals, as the intersectionality of maternal education and child’s race/ethnicity revealed disparities not observed when examining them individually.

These findings should be interpreted within this study’s limitations. First, the influenza vaccine UTD variable does not capture vaccinations after December 31st or through the date of the interview (first dose), or after January 31st (second dose), [38] though influenza vaccine distribution is usually complete before these dates, [72] meaning that this limitation is minor. Further, the provider-verified nature of the NIS complete vaccination outcome improves on the typical annual self-reported measure of influenza vaccination, which is subject to recall bias and only covers one influenza season. Second, this study excludes children without provider-verified data, who may lack this type of data because they lack a usual source of care, which has been linked to lower preventive care use in adults. [73] However, because those excluded may use less preventive services, the implication is that our findings contain less vulnerable individuals and are likely thus conservative. Third, accounting for successive non-response first from households, then providers, and then the PC module, more than half of target children are lost due to NIS non-response issues, introducing concerns of non-response bias. This is a limitation of the data source itself that warrants investigation and needs to be addressed in future surveys. Nonetheless, the NIS still provides the only opportunity to examine nationally-representative, provider-verified uptake of multiple vaccines in young children that includes key constructs for vaccine-related parental perceptions. Fourth, the parental concerns variables refer to vaccination generally and not to any one specific vaccine, which could explain some of the non-findings (such as parent perception of physician recommendation for vaccination not being associated with our outcomes, contradicting other studies [27,41,45-50,52-56]). Fifth, this analysis is cross-sectional and thus cannot make causative claims; all findings are associative. That said, the main identifying strategies were to use only provider-verified vaccine outcomes and to include in one model a myriad of conceptually- and empirically-grounded covariates more comprehensive than in other literature, most notably the aforementioned constructs for vaccine-related parental perceptions which have seldom been utilized due to their limited availability and the restricted access required to obtain them. Though we cannot rule out the possibility of bi-directionality in our findings, we believe this to be less likely as the determinants studied here are thought to temporally precede the decision to use a health service. [39] For example, predisposing (child’s race/ethnicity) and enabling factors (mother’s education) precede personal health services use factors at the behavior level (history of vaccine refusal or delay), all of which precede health services utilization (vaccine uptake).

This study provides important findings and data regarding “hidden vulnerability to influenza”–a phenomenon whereby nearly half (44%) of very young US children are up-to-date on a large series of routinely-recommended vaccines yet are not UTD against influenza by their second birthday–despite high morbidity of influenza in this age group. Independent of an expansive set of confounders, the most important factor predicting vaccine vulnerability is history of vaccine refusal, though there was also an independent, unique association of hidden vulnerability to influenza with having never delayed vaccination.

Healthcare clinicians need to have conversations surrounding vaccine hesitancy even with parents of children who appear to be broadly up-to-date on their vaccines and thus appear to generally support the concept of vaccination. These parents are unlikely to give any indication of their skepticism of influenza vaccines yet this study finds that they may opt to not have their child vaccinated against influenza. Pediatricians and other healthcare clinicians who see children should consider adding questions to their history and physical protocols pertaining to parental history of refusing or delaying vaccination, as well as pertaining to vaccine hesitancy both broadly and specifically to influenza regardless of the child’s general vaccine history.

Further, this study suggests that parental college education and marriage may not translate into improved influenza vaccine uptake for children of historically-disadvantaged race/ethnicity despite that it does for non-Hispanic White children. Policymakers and researchers from public health, sociology, and other sectors need to collaborate to examine both how preventive health services use functions in the context of interacting social disadvantage, and how upstream social and economic policies lead to equitable health.

(DOCX)

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(DOCX)

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11 Mar 2020

PONE-D-19-33172

A hidden vulnerable population: young children up-to-date on vaccine series recommendations except influenza vaccines

PLOS ONE

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Reviewer #1: This manuscript presents an analysis of nationally representative survey data on influenza vaccine uptake in young children. The authors investigate cross-sectional associations with a number of predictors of vaccination, including social and demographic variables and past vaccine utilization. Importantly, the analysis also seeks to identify intersectionality, which is a novel and important approach that represents a significant contribution to the literature on vaccine hesitancy. Overall, the analysis is rigorous, the conclusions are supported by the data, and the manuscript is well-written and clear. I agree with the authors' conclusion that it is concerning that there may influenza vaccine specific hesitancy, even among parents who are regularly choosing vaccination for their children to prevent other diseases. I have some questions and comments, which I believe would strengthen the manuscript. These comments are separated by manuscript section below.

Introduction

It is important that the authors are clear about their assertions about risk of influenza and benefits of influenza vaccine. Specifically, children < 5 years old are typically considered to be at lower risk of influenza infection than school aged children (most likely due to to contact patterns), unless they attend child care outside of the home. The references cited here are reporting risk of complications due to influenza infection (e.g. pneumonia) which children <5 ARE considered to be at especially high risk for developing. I suggest a minor change to the language to indicate that these children are at higher risk of complications, rather than saying they are simply at high risk of influenza. Similarly, influenza vaccination is the most effective preventive measure for prevention of infection,

Methods:

The scale for parent belief variables should be stated, otherwise the mean and SD values reported in table 1 are difficult to interpret for someone who is not familiar with these data.

The primary outcome of interest is potentially problematic due to the annual nature of influenza vaccines. Unless I am misunderstanding this outcome, a 2 year old child who received two doses of influenza vaccine in the year of the survey (2011) but was unvaccinated in the previous year (2010) would be considered to have "hidden vulnerability" to influenza. This is true, even though, by ACIP recommendations that child would be considered fully vaccinated against influenza for the 2011 season. In addition, that child may actually have higher antibody titres to vaccine strains and be expected to have higher vaccine effectiveness (due to negative interference) for the 2011 season. At a minimum, I recommend a sensitivity analysis where children are classified as "fully vaccinated", "partially vaccinated" or "unvaccinated" against influenza using ACIP guidelines to determine this categorization.

Was there any correction for multiple testing? Why or why not?

Results:

The tables are difficult to read and interpret due to the large number of variables and interactions tested. I would recommend that the authors present interesting findings and relevant supporting information in the main tables and move everything else to supplemental tables. Another possibility is to present only the "series but not flu" outcome in the main tables and move other outcomes to a supplementary table.

I find the predicted probabilities much easier to interpret than the the beta coefficients, and suggest focusing on those results. The figures are particuarly helpful.

Discussion:

The strengths and limitations are adequately discussed.

Reviewer #2: This is a generally well written manuscript describing what appears to be a very well designed and conducted study (although I am unable to comment definitively on the appropriateness/rigour of the statistical analyses as this is not my particular area of expertise) exploring an important area where previously published research is limited, and with findings that should be of broad interest. A few suggestions to enhance the paper are provided.

Introduction

The sentence “Further, “complete uptake” – receiving the appropriate number of influenza vaccinations for the child’s age – is much lower, peaking at 45% in children 6-23 months old” is confusing. Children aged <9 years require 2 doses in their first season of vaccination so the number of doses of influenza vaccination recommended in any particular season depends on both the age and number of doses previously received. The paper cited looked at children aged 6-23 months from 2002 to 2012 and found that complete vaccination in this age group peaked at 45% in 2011/12, which is a quite different conclusion from that noted above. Complete vaccination for children aged 2-<5 years, who will often only need one dose, will be higher. Suggest reword this sentence.

Methods

It is not clear how ‘complete influenza vaccination’ has been assessed. This is described as “whether the child received the full number of influenza vaccines given the number of influenza seasons they have experienced by their second birthday”. However as noted above this depends on both age and number of doses previously received. In this age group, if assessing ‘complete influenza vaccination’ for the most recent influenza season this would require two doses to have been received unless two doses had been received in the previous season, in which case would only require one dose. Suggest reword to make clearer how assessed.

Discussion

2nd para states that the unique determinant of hidden vulnerability to flu identified (parental history of never delaying vaccination) “may reflect the rise in vaccine hesitancy”. However, influenza vaccination rates in children have always been lower than other vaccines, likely reflecting longstanding hesitancy specific to this vaccine. Suggest delete this wording – the remainder of the relevant sentence stands alone without this somewhat dubious assertion.

There is much mention of parental attitudes to vaccination however no mention of potential impact of provider attitudes to influenza vaccination. I am unaware what research has been conducted in this area in the US, but there is certainly evidence from other countries that ‘hesitancy’ amongst providers regarding influenza vaccination is higher than for other vaccines, particularly related to the comparatively low effectiveness of influenza vaccine, which may impact on recommendation/ strength of recommendation. This is important given the extensive evidence that strong provider recommendation is a key determinant of vaccine uptake. While parent perception of strength of physician’s vaccine recommendation was included as a variable in this study, with no significant associations detected, I assume that this was framed in the survey in general terms rather than specific to particular vaccines such as influenza. Suggest add brief discussion of this issue to the limitations section.

General comment – suggest a thorough proof read as there are a moderate number of typographical and grammatical errors.

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Reviewer #2: Yes: Frank Beard

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17 Apr 2020

See submitted "Response to Reviewers" document.

Submitted filename: Response to reviewers 2020 04 13.docx

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28 May 2020

A hidden vulnerable population: young children up-to-date on vaccine series recommendations except influenza vaccines

PONE-D-19-33172R1

Dear Dr. Bleser,

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Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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Reviewer #1: Yes

Reviewer #2: (No Response)

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Reviewer #2: (No Response)

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Reviewer #1: Yes

Reviewer #2: (No Response)

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Reviewer #1: Yes

Reviewer #2: (No Response)

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Reviewer #2: (No Response)

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Reviewer #1: No

Reviewer #2: Yes: Frank Beard

5 Jun 2020

PONE-D-19-33172R1

A hidden vulnerable population: young children up-to-date on vaccine series recommendations except influenza vaccines

Dear Dr. Bleser:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Kind regards,

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on behalf of

Prof. Maria Gańczak

Academic Editor

PLOS ONE