Are we asking the right questions about vaccination and children’s health?

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Are we asking the right questions about vaccination and children’s health?

by Merinda Teller, MPH, PhD

Vaccines, considered by many as one of the top-ten public health achievements of the 20th century, are “powerful medical interventions.”1 Vaccines are thought to work by priming the immune system to recognize and defend itself against the specific diseases targeted by the vaccines.2 However, immunologists admit that they have little understanding of exactly how vaccines activate the immune system.3

Many vital aspects of vaccination have either been poorly studied or never studied at all, particularly in regards to longer-term effects of individual vaccines or of the vaccine program as a whole. The systems currently in place in the United States to monitor what happens after a vaccine is administered are primarily designed to detect acute, short-term adverse events arising from a single vaccine. These monitoring systems are ill-suited to discern chronic or subtle effects that manifest more than a few weeks post-vaccination.4

Some recent studies in lower-income countries have indicated that vaccines can have complex repercussions that are not specific to the disease in question, including cross-reactions to allergens and more severe consequences, including death.5,6 These “nonspecific” effects may plausibly arise as a result of interactions between vaccine antigens and adjuvants or other ingredients, through different combinations and sequencing of vaccines, or through cumulative effects of the vaccine schedule over time.7

In the U.S., careful consideration of the longer-term impact of vaccination on children’s health—including both disease-specific and nonspecific effects—has immense public health relevance. This is because the pediatric vaccination schedule has become significantly more crowded over the past two decades, at the same time that the prevalence of chronic illness and neurodevelopmental disorders (NDDs) in children has exploded.4,8,9 In their first six years, the U.S. vaccine schedule expects children to receive 48 doses of 10 vaccines covering 14 diseases,10 compared with just three vaccines for seven diseases in the 1970s.

The expanded vaccine schedule also has broadened its scope beyond a handful of classic infectious diseases to encompass vaccines addressing less virulent pathogens and non-infectious or chronic conditions.4 Some of the newer vaccines primarily seek to minimize societal and economic costs (e.g., missed time from school or work, physician visits) rather than prevent morbidity or premature deaths.4,11

Assessing nonspecific effects

Epidemiological studies seek to identify causes of diseases (or other health outcomes) by examining associations between the outcome of interest and various risk factors or exposures.12 Epidemiologists can use several different types of study designs to answer these types of questions. Longitudinal studies follow study subjects over time to determine whether exposure to a risk factor results in outcomes such as morbidity and mortality. A rigorous longitudinal study that followed vaccinated and unvaccinated children over a meaningful period of time could generate robust evidence about the prevalence of chronic or nonspecific vaccine-related health effects in vaccinated versus unvaccinated children. For a variety of reasons, however, researchers in the U.S. have had little appetite for conducting a longitudinal study of this type.

Cross-sectional studies compare different groups at a single point in time. Although they cannot provide definitive information about causality, well-designed cross-sectional studies can furnish important clues about possible relationships between exposures and outcomes.

The peer-reviewed open-access Journal of Translational Science has just published a carefully designed cross-sectional study—one of the first in the medical and public health literature to formally assess the longer-term health outcomes associated with the routine childhood vaccination program in the U.S.13

The paper reports the results of an anonymous survey conducted in 2012 with the mothers of homeschool children 6 to 12 years of age. Homeschool families and children are approximately representative of U.S. families and children as a whole, with the notable exception that a higher proportion of homeschool versus public school children are unvaccinated. Homeschool children, therefore, provide a logical and accessible pool from which to derive an otherwise demographically homogeneous sample that allows for comparisons of health outcomes by vaccination status.

The study’s lead author, Dr. Anthony R. Mawson, is a public health epidemiologist with an extensive and proven track record in children’s health research. Mawson and one of his co-authors (Dr. Brian D. Ray, president of the National Home Education Research Institute) contacted mothers indirectly through homeschool organizations in the states of Florida, Louisiana, Mississippi, and Oregon. Through a multipronged recruitment process that sought to elicit as many responses as possible, the researchers obtained information from 415 mothers about 666 children. Nine in ten of the mothers who completed the online questionnaire were white, Christian, and had at least some college education.

For a study of this type and size, epidemiologists typically use a statistical analysis technique called logistic regression, which produces an instructive output called an odds ratio (OR). ORs represent the odds that a given outcome will occur in the presence of a particular exposure. When an OR is greater than 1, the exposure is associated with a higher odds of the outcome.14 Because other factors associated with the exposure also may affect the risk of developing the disease or outcome, it can be important to adjust for their influence. Fortunately, logistic regression is capable of producing “adjusted ORs” to adjust for additional factors that might be influencing the relationship between exposure and outcome.12

In the survey, the exposure was vaccination status, assessed through questions about number of vaccines received as indicated on the child’s vaccination records. Health outcomes included acute and chronic health conditions (determined by mothers’ reports of a physician diagnosis of one or more of 40 acute and chronic illnesses), with a particular focus on NDDs. The investigators defined NDDs as one or more of three closely related and overlapping diagnoses: learning disabilities, attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD). The survey also asked mothers about children’s use of medications (such as fever and allergy medications and antibiotics), use of health services and procedures (including check-ups and sick visits to physicians, hospital stays, and use of ear drainage tubes), and maternal exposures to drugs and toxins during pregnancy.

Differences by vaccination status

The three vaccination subgroups each included roughly one-third of the sample, with 30% fully vaccinated, 31% partially vaccinated, and 39% unvaccinated. For most of the study’s results, the researchers grouped the fully and partially vaccinated children together and compared them with the unvaccinated children. The comparisons revealed a number of compelling findings.

  • Acute illness: Children in the vaccinated group were significantly less likely than unvaccinated children to be reported as having had chickenpox or pertussis. There were no meaningful differences between the two groups for other diseases targeted by pediatric vaccines. On the other hand, vaccinated children were significantly more likely to have been diagnosed with otitis media (middle ear infection) and pneumonia.
  • Chronic illness: Vaccinated children had a more than twofold greater odds of having been diagnosed with any chronic illness, and an almost fourfold greater odds of having been diagnosed with an NDD when compared with unvaccinated children. In all, 7.5% of the children (50/666) had an NDD.

 

Vaccinated children had a ____-fold greater odds of having been diagnosed with:

Condition

                   30.1

Allergic rhinitis

                     5.2

Learning disabilities

                     4.2

ADHD

                     4.2

ASD   

                     3.9

Other allergies        

                     3.7

NDD

                     2.9

Eczema/atopic dermatitis  

                     2.4

Any chronic condition

 

                          

  • Partial versus full vaccination: Partially vaccinated children had an intermediate position in between the other two groups for allergic rhinitis, eczema, ADHD, and learning disabilities.

Another set of results found that fully and partially vaccinated children were significantly more likely than unvaccinated children to use medications such as antibiotics as well as allergy and fever medications. Vaccinated children also were more likely to have had routine encounters with health care providers in the past 12 months (medical check-up or dental visit) as well as to have visited a doctor when sick in the past year or ever had a hospital stay.

 

Vaccinated children had a ____-fold greater odds of:

Medication

or health service used

                   21.5

Medication for allergies

                     8.0

Use of fitted ear drainage tubes*

                     4.6

Use of fever medication (1+ times)

                     2.4

Antibiotic use (past 12 months)

                     3.0

Sick visit (past year)

                     1.8

Hospital stay (1+ nights ever)

 

                  *Being fitted with ear tubes is indicative of frequent or chronic ear infections.

Neurodevelopmental disorders and preterm birth

To zero in on factors associated with NDDs, the researchers used a multi-tiered analysis strategy. Before statistically adjusting for other factors, logistic regression identified five factors significantly associated with NDDs: vaccination, male gender, adverse environment, maternal use of antibiotics during pregnancy, and preterm birth. Two other factors (vaccination during pregnancy and number of fetal ultrasounds) approached statistical significance.

Forty-nine of the 666 children in the sample were born preterm. After statistical adjustment, logistic regression produced some especially noteworthy adjusted ORs with regard to preterm birth. Specifically, while vaccination, male gender, and nonwhite race each remained significantly associated with NDD—resulting in an approximately twofold increased odds of NDD—the combination of preterm birth and vaccination was associated with a dramatic 6.6-fold increased odds of NDD.

A second paper by Dr. Mawson and coauthors reports more closely on the worrisome relationship between preterm birth, vaccination, and NDD.15 The analyses presented in the second paper found that:

  • Preterm birth without vaccination (n=12 children) was not associated with NDD. (In other words, none of the unvaccinated children who had been born prematurely had an NDD.)
  • Term birth with vaccination (n=367 children) was associated with a significant 2.7-fold increase in the odds of NDD.
  • Preterm birth plus vaccination (n=37 children) was associated with a significant 5.4-fold increase in the odds of NDD compared to term birth plus vaccination.
  • Preterm birth plus vaccination was associated with a significant 14.5-fold increased odds of NDD compared to term birth without vaccination (n=249 children).

In short, the findings from both papers13,15 are indicative of a “synergistic” increase in the odds of NDD among children who are both preterm and vaccinated, which strongly suggests that vaccination can “precipitate adverse neurodevelopmental outcomes in preterm infants.”15 These combined effects are critical to examine and heed because a substantial proportion of extremely preterm infants (28%) develop ASD symptoms. Unfortunately, the possible role of vaccination in preterm-associated NDD has never previously been a topic of investigation. The results presented by Mawson and coauthors suggest that the heretofore-accepted practice of giving preterm infants the same doses of recommended vaccines as term infants—and on the same schedule—should be questioned and reevaluated.

Findings from other studies

One of the chronic ailments found to be far more likely in vaccinated versus unvaccinated homeschool children was allergies. Questions regarding vaccines’ potential contribution to allergies are not new. A public health paper published in 2000 by researchers at the University of California at Los Angeles (UCLA) used information from a large national study of child health and nutrition (the Third National Health and Nutrition Examination Survey or NHANES III) to examine asthma and allergy risks in U.S. children according to vaccination status.16 Evidence from this nationwide study suggested that “one or more vaccine components may be responsible for a portion of the increased prevalence of asthma and allergies in U.S. children.”16 The study’s authors also issued a recommendation—not subsequently taken up—to evaluate the vaccines’ public health benefits “in light of these potential long-term risks.”16

The UCLA study’s findings emerged from assessment of only two vaccines: diphtheria-tetanus-pertussis (DTP) and tetanus. At the time that the NHANES III was conducted (1988–1994), five vaccines were administered through age 6: DTP/tetanus, polio, measles-mumps-rubella (MMR), and, starting in 1991, haemophilus influenza type B (Hib) and hepatitis B. Subsequent to the NHANES III study, the U.S. vaccine schedule more than doubled.

Another result from the study of homeschool children, namely the greater odds of middle ear infections in vaccinated children, also gains broader resonance when considered alongside other scientific findings. Mawson and coauthors invoke a fascinating study that examined the types of pathogenic (disease-causing) bacteria present in the nasopharynx (the part of the throat that connects with the nasal cavity) of children vaccinated and not vaccinated with pneumococcal conjugate vaccine-7 (PCV-7).17 They found that the average number of pathogenic bacteria types was significantly higher in PCV-7-immunized children and that this could “predispose” the immunized children to “a higher rate of antibiotic treatment failure” (if experiencing an acute middle ear infection) or to recurrent middle ear infections.17

In recent years, the importance of the microbiota (the ensemble of microorganisms that reside in different parts of the body) and its central role in human health have attracted growing attention.18 A “diverse and complex microbial community” resides in humans’ intestinal tract, for example, “coevolves with us,” and has noted importance for immune function.18 Changes in the microbiota may be an unintended and nonspecific consequence of vaccination, and the accompanying expansion of pathogenic bacterial species may have undesirable effects on health. Heightened surveillance is critical to understand the implications of changes in the microbiota that result from vaccination.

A 2012 study in Hong Kong identified unexpected outcomes associated with influenza vaccine. In the study, 115 children were randomized to either receive trivalent inactivated influenza vaccine (TIV) or a placebo.19 To the researchers’ surprise, the TIV recipients displayed a significantly increased risk of noninfluenza respiratory virus infections. In the authors’ words, “The protection against influenza virus infection conferred by TIV was offset by an increased risk of other respiratory virus infection.” This trading off of one set of viral risks for another suggests that vaccination can indeed have a wide variety of unrecognized nonspecific effects that may have important implications for children’s health.

Raising a red flag

The cross-sectional design of the study of homeschool children means that the study cannot be used to make conclusive statements about causality. At the same time, however, the authors note that “the strength and consistency of the findings, the apparent ‘dose-response’ relationship between vaccination status and several forms of chronic illness, and the significant association between vaccination and NDDs all support the conclusion that some aspect of the current vaccination program may be contributing to risks of childhood morbidity.”13 The findings pertaining to preterm birth also raise a number of red flags.15

Vaccine proponents do not often admit to the limitations of conventional vaccine safety testing. However, it is clear that the relatively narrow scope and timeline of safety testing makes it difficult to go beyond the search for short-term adverse events to draw meaningful inferences about the longer-term health picture of vaccinated children. For example:

  • Pre-licensing safety studies carried out by vaccine manufacturers typically focus on the 15-30-day period immediately following vaccination.4
  • The total number of subjects studied prior to licensing is often under 10,000.4
  • Post-licensing studies also tend to be short-term and do not necessarily focus on adverse events.4
  • After vaccines are licensed and in the marketplace, adverse events are principally monitored through passive surveillance systems (that is, systems that require physicians and those affected to have the knowledge and ability to report an event).4 These systems are characterized by vast underreporting.20 According to the U.S. government’s Vaccine Adverse Event Reporting System (VAERS), the system “receives reports for only a small fraction of actual adverse events.”21

Even so, public health experts acknowledge that the range of adverse events linked to vaccines has been increasing in recent years.4 Children and adults have been compensated for proven injuries related to every vaccine in the U.S. schedule, receiving an average of over $200 million annually from the National Vaccine Injury Compensation Program.22

Perhaps in response to the heightened complexity of the prescribed vaccine schedule and growing awareness of adverse events, undervaccination (delay or refusal of certain vaccines) and use of alternate vaccination schedules represent rapidly growing trends.23 In a large study involving over 300,000 pediatric managed care organization clients, half (49%) of children were undervaccinated for any reason at 24 months, and a sizeable proportion (at least 13%) were undervaccinated because of parental choice.23 Children in the parental choice subgroup displayed several indicators of superior health, including significantly lower emergency department utilization rates and fewer outpatient visits—both overall and for acute illness—when compared with children vaccinated according to the standard schedule.

The tantalizing evidence furnished by the study of homeschool children and echoed by the study of managed care organization pediatric clients suggests that at least some vaccinated children may have a greater odds (when compared with unvaccinated children) of being diagnosed with and using health services for certain chronic and acute illnesses, including NDDs. Many of these illnesses are at record levels in U.S. children.8 The core assumption buttressing increasingly compulsory mass immunization policies is that vaccines’ overall benefits incontrovertibly outweigh their risks, but these studies’ findings suggest that the calculation of vaccine risks and benefits is a moving target rather than a closed book.

The integrity of the scientific method rests on a willingness to scrutinize, test, and reexamine assumptions in light of emerging evidence.24 Cautioning budding researchers that scientific knowledge is sometimes imperfect, academic textbooks note that “other means of knowledge acquisition, such as faith or authority, cannot be considered science (emphasis added).”24 To respect the scientific method, we owe it to children to be inquisitive about the full array of short- and long-term effects engendered by vaccination.

References

1.     Stern AM, Markel H. The history of vaccines and immunization: familiar patterns, new challenges. Health Aff. 2005;24(3):611-621.

2.     Centers for Disease Control and Prevention. Understanding how vaccines work. Reviewed February 2013. http://www.cdc.gov/vaccines/hcp/patient-ed/conversations/downloads/vacsafe-understand-color-office.pdf.

3.     Siegrist C-A. Vaccine immunology. Chapter 2 in Vaccines (6th ed.), SA Plotkin, WA Orenstein, and PA Offitt (Eds.). New York: Elsevier, 2012, pp. 14-32.

4.     Ward BJ. Vaccine adverse events in the new millennium: is there reason for concern? Bull World Health Organ. 2000;78(2):205-215.

5.     Benn CS, Netea MG Selin LK, Aaby P. A small jab – a big effect: nonspecific immunomodulation by vaccines. Trends Immunol. 2013;34(9):431-439.

6.     Aaby P, Benn C, Nielsen J, Lisse IM, Rodrigues A, Ravn H. Testing the hypothesis that diphtheria-tetanus-pertussis vaccine has negative non-specific and sex-differential effects on child survival in high-mortality countries. BMJ Open. 2012;2(3). Pii: e000707. Doi: 10.1136/bmjopen-2011-000707.

7.     Aaby P, Nielsen J, Benn CS, Trape JF. Sex-differential and non-specific effects of routine vaccinations in a rural area with low vaccination coverage: an observational study from Senegal. Trans R Soc Trop Med Hyg. 2015;109(1):77-84.

8.     Van Cleave J, Gortmaker SL, Perrin JM. Dynamics of obesity and chronic health conditions among children and youth. JAMA. 2010;303(7):623-630.

9.     Boyle CA, Boulet S, Schieve LA, Cohen RA, Blumberg SJ, Yeargin-Allsopp M, Visser S, Kogan MD. Trends in the prevalence of developmental disabilities in US children, 1997–2008. Pediatrics. 2011;127(6).

10.  Centers for Disease Control and Prevention. 2016 recommended immunizations for children from birth through 6 years old. http://www.cdc.gov/vaccines/schedules/easy-to-read/child.html.

11.  Roush SW, Murphy TV, the Vaccine-Preventable Disease Table Working Group. Historical comparisons of morbidity and mortality for vaccine-preventable diseases in the United States. JAMA. 2007;298(18):2155-2163.

12.  Pourhoseingholi MA, Baghestani AR, Vahedi M. How to control confounding effects by statistical analysis. Gastroenterol Hepatol Bed Bench. 2012;5(2):79-83.

13.  Mawson AR, Ray BD, Bhuiyan AR, Jacob B. Pilot comparative study on the health of vaccinated and unvaccinated 6- to 12-year-old U.S. children. J Transl Sci. 2017;3: DOI: 10.15761/JTS.1000186

14.  Szumilas M. Explaining odds ratios. J Can Acad Child Adolesc Psychiatry. 2010;19(3): 227-229.

15.  Mawson AR, Bhuiyan A, Jacob B, Ray BD. Preterm birth, vaccination and neurodevelopmental disorders: a cross-sectional study of 6- to 12-year-old vaccinated and unvaccinated children. J Transl Sci. 2017;3: DOI: 10.15761/JTS.1000187

16.  Hurwitz EL, Morgenstern H. Effects of diphtheria-tetanus-pertussis or tetanus vaccination on allergies and allergy-related respiratory symptoms among children and adolescents in the United States. J Manipulative Physiol Ther. 2000;23(2):81-90.

17.  Revai K, McCormick DP, Patel J, Grady JJ, Saeed K, Chonmaitree T. Effect of pneumococcal conjugate vaccine on nasopharyngeal bacterial colonization during acute otitis media. Pediatrics. 2006;117(5):1823-1829.

18.  Guinane CM, Cotter PD. Role of the gut microbiota in health and chronic gastrointestinal disease: understanding a hidden metabolic organ. Therap Adv Gastroenterol. 2013;6(4):295-308.

19.  Cowling BJ, Fang VJ, Nishiura H, Chan K-H, Ng S, Ip DKM, Chiu SS, Leung GM, Peiris JSM. Increased risk of noninfluenza respiratory virus infections associated with receipt of inactivated influenza vaccine. Clin Infect Dis. 2012;54(12):1778-1783.

20.  Rosenthal S, Chen R. The reporting sensitivities of two passive surveillance systems for vaccine adverse events. Am J Public Health. 1995;85(12):1706-1709.

21.  Vaccine Adverse Event Reporting System (VAERS). VAERS data. https://vaers.hhs.gov/data/index.

22.  Health Resources and Services Administration (HRSA). National Vaccine Injury Compensation Program data report. Updated 11/01/2016. U.S. Department of Health and Human Services. http://www.hrsa.gov/vaccinecompensation/data.html.

23.  Glanz JM, Newcomer SR, Narwaney KJ, Hambidge SJ, Daley MF, Wagner NM et al. A population-based cohort study of undervaccination in 8 managed care organizations across the United States. JAMA Pediatr. 2013;167(3): 274-281.

24.  Bhattacherjee A. Social science research: principles, methods, and practices. Textbooks Collection. Book 3; 2012. http://scholarcommons.usf.edu/oa_textbooks/3.

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