M-M-R® II: Contraindication Specificity Matters

Courts have awarded billions in damages to parents of children who have suffered grievous harm from vaccines. The CDC has admitted publicly — and dozens of studies have demonstrated — that some children have impaired immune systems that make them especially vulnerable to unintended vaccine effects.  Eric Ranger looks at which children are at risk and why isn’t public health doing anything to protect them?

 

The following are comments from Dr. Bernadine Healy, former Director of the National Institutes of Health, during a 2008 CBS News interview:

“This is the time when we do have the opportunity to understand whether or not there are susceptible children, perhaps genetically, perhaps they have a metabolic issue, mitochondrial disorder, immunological issue, that makes them more susceptible to vaccines plural, or to one particular vaccine, or to a component of vaccine….”

“The government has said in a report by the Institute of Medicine, and by the way, I’m a member of the Institute of Medicine, I love the Institute of Medicine, but a report in 2004, it basically said, do not pursue susceptibility groups, don’t look for those patients, those children who may be vulnerable.”

“The reason why they [government and certain government officials] didn’t want to look for those susceptible groups was because they’re afraid that if they found them, however big or small they were, that that would scare the public away.”[1],[2]

Introduction

Many children of vaccine-compliant parents do not receive certain vaccines.  Vaccines can be contraindicated for these children who may have had a prior serious reaction, or whose underlying disorder excluded them from pre-licensure clinical trials, or whose disorder can impair their immune system’s response, or put them at greater risk of an adverse reaction to the vaccine.  Children who are given medical exemptions to certain vaccines for their disorder(s) are typically very sick, where their contraindication is easily identifiable, or have had a documented adverse reaction to a particular vaccine.  The modern principle of herd or community immunity is to vaccinate the population to a minimum threshold that would, ostensibly, work to protect these vulnerable children from exposure to once commonly acquired childhood diseases, and also reduce the risk of large outbreaks.

According to Merck & Co., Inc.’s (Merck) M-M-R II package insert, the vaccine is contraindicated in certain individuals, including those in “Primary and acquired immunodeficiency states.”  The package insert gives other contraindications, and says in the same section: “Individuals with a family history of congenital or hereditary immunodeficiency, until the immune competence of the potential vaccine recipient is demonstrated.”[3]  These specific contraindications will be focal points of this article.

Even though vaccine manufacturers list contraindications on their package inserts, many organizations still recommend certain vaccines contraindicated for some individuals based on their own risk-reward assessments.  For example, in 2014, the Immune Defense Foundation (IDF) Medical Advisory Committee (MAC) published an article in The Journal of Allergy and Clinical Immunology called, “Recommendations for live viral and bacterial vaccines in immunodeficient patients and their close contacts,” which addressed the uncertainty regarding which vaccines can be given to patients with primary immunodeficiencies (PIDs).[4]  The IDF’s MAC determined that certain PIDs are relative and not absolute contraindications, and the M-M-R II vaccine is still recommended for children with these PIDs.  Additionally, the Advisory Committee on Immunization Practices (ACIP) has stated that “patients with leukemia in remission,” under certain circumstances, are not immunosuppressed and can receive the M-M-R II vaccine as well.[5]

Very little research though has attempted to determine, from a historical perspective, how many individuals received vaccines they were unknowingly contraindicated for, as their particular contraindication went overlooked or ignored by pediatricians, or because the contraindication had not yet been discovered or acknowledged by the vaccine manufacturer.  This number of children could be surprisingly high, and the consequences of such actions are widely unknown.  This article examines Merck’s M-M-R II vaccine, specifically, and attempts to determine the likelihood and potential consequences of this scenario, and to evaluate whether parental concern in the matter is substantiated.

Background

Immunodeficiency is a “weakness in a person’s immune system or the failure of a person’s immune system” in fighting infection.[6]  This inability to form a normal immune response can be due to a genetic predisposition (primary immunodeficiencies), or it can be acquired (secondary immunodeficiencies or SIDs) due to many factors, such as: “age; pregnancy; acquired illnesses, including infections, malignancies, metabolic disorders, trauma or surgery; pharmaceuticals; malignant disorders; and nutritional defects.[7]  Unlike with PIDs, SIDs are oftentimes reversible conditions that improve or disappear when the offending condition or agent is removed, except in cases of older age, surgical “-ectomies,” and chronic diseases.[8]  Some immunodeficiencies are more serious than others, but all will impair the immune system to some extent, by definition.

Searches on PubMed regarding immunodeficiencies show how this is a growing field of study and knowledge.  A search of “primary immunodeficiency” resulted in 275 hits in 1978 and peaked at 1,662 in 2016, with an exponential rise in between.  A search for “primary immunodeficiency diseases” resulted in 26 hits in 1978 and peaked at 1,008 in 2016, with an exponential rise in between.  A search for “acquired immunodeficiencies” resulted in 21 hits in 1978 and peaked at 6,308 in 1988, probably due to the heightened awareness at the time of human immune deficiency virus (HIV) and acquired immune deficiency syndrome (AIDs), and then tapered off to 1,006 in 2016.  A search for “secondary immunodeficiency diseases” resulted in 13 hits in 1978 and peaked at 350 hits in 2017.  A search for “secondary immunodeficiencies” resulted in 24 hits in 1978 and peaked at 452 in 2017.  Clearly, the scientific community and our regulatory agencies are still in an infancy stage of understanding PIDs and SIDs.

Diagnosing anyone, adult or otherwise, is difficult for doctors to get right.  A study at the Mayo Clinic found that 20% of patients with a serious condition were first misdiagnosed.   In more than 70% of cases, Mayo Clinic doctors were able to improve upon their first diagnosis, which means that doctors agreed upon the diagnosis in only 12% of cases.[9]  Mark Graber, senior fellow at the research institute RTI International and founder of the Society to Improve Diagnosis in Medicine, said, “Diagnosis is extremely hard.  There are 10,000 diseases and only 200 to 300 symptoms.”[10] 

Merck knows some children have a problem, but they give the vaccine anyway.

In particular, immunodeficiencies are extremely hard to diagnose.  According to Mayo Clinic, “Some forms of primary immunodeficiency are so mild they can go unnoticed for years.[11]  According to a 2007 article in the journal Science, “…some PIDs remain clinically silent for a long period and first manifest in adulthood….”[12]  The Merck Manual states: “…some primary immunodeficiency disorders (such as common variable immunodeficiency) are not recognized until adulthood.”[13]  Moreover, a 2011 study in the European Journal of Pediatrics said that, “It is not easy to timely identify potential PID patients among the many children seen in everyday practice by pediatricians; PIDs often present with very common and/or aspecific signs and symptoms.”[14] 

Diagnosing complex and rare disorders in children is especially difficult, particularly in those who cannot speak and/or are asymptomatic.  In fact, diagnostic errors in children are much more common than in adults.[15]  To make matters worse, there is growing evidence that pediatricians are not well trained to identify PIDs and SIDs.  Several studies from various countries, evaluating pediatrician level of knowledge with respect to PIDs, have shown a huge knowledge gap with respect to these disorders.[16],[17],[18]  According to a 2013 study in the Archives of Disease in Childhood: Education and Practice Edition, “Children with primary immune deficiencies (PIDs) are difficult to differentiate from normal children, especially in those less than 2 years of age.[19]  Symptoms can be mistaken for common infections, since even healthy children without PIDs can get sick frequently, which is one common screening indicator for PID.[20]

The greater diversity of secondary immunodeficiencies touches practitioners in nearly every medical specialty, from neonatologists to geriatricians, internists, immunologists, internists and surgeons, obstetricians, transplant specialists, nutritionists, and more.  Even the generalist, working mainly in the clinic, performs multiple duties that may challenge the immune system.  Developing countries are particularly overwhelmed with these disorders.  Conditions such as poverty, poor hygiene and sanitation inherently weaken the immune system, and lead to much worse morbidity and mortality of infectious diseases than more developed nations, where many people handle those infections asymptomatically.[21]

Diagnosing SIDs is an even greater challenge, especially when the person may not know they are sick.  For example, 1 in 7 people are living with HIV and are unware of their infection.[22]  Without genetic markers, the pediatrician and/or immunologist is faced with the challenge of assessing a child’s immune system state, which can be in flux based on many confounders.  For example, the gut microbiota plays an important role in the adaptive immune system.  A small study showed that the composition of the gut microbiota of volunteers, who followed a strictly vegetarian diet for five days, moving then to a strictly carnivorous diet five days later, changed within just 24 to 48 hours.[23]  Another example is vitamin D, a critical nutrient for the immune system, where depending on factors like skin tone, location, time of day, use of sunscreen, and the amount of exposed skin, the human body can produce huge amounts of vitamin D in just a little under the time it takes for the skin to burn.[24]  Theoretically, this short window of time could temporarily relieve someone from an immunodeficient state due to low vitamin D. 

Diagnoses of PIDs and SIDS are often quite delayed.  A 2013 study in the journal BioMed Research International of patients in Guanajuato, Mexico found that the mean time that had elapsed from the onset of symptoms to the reference and diagnosis of PID by a tertiary hospital was over four years.  Until diagnosis, patients had a mean of 12.5 visits to the emergency room, 16.1 doctor visits per year per patient, and 6.35 hospitalizations related to PID.[25]  According to a 2011 study in the European Journal of Pediatrics, “There is a lack of awareness of PIDs among the public and health care workers alike, resulting in diagnostic delay.”[26]  According to a 2013 study in the Archives of Disease in Childhood: Education and Practice Edition, the average delay in diagnosis for adults in young children with PIDs is 1.9 years.[27] 

The spectrum of clinical presentations of PID is now recognized to include autoinflammation, autoimmunity, and neoplasia as well as serious, recurrent, or unusual infection.[28]  At least 23.5 million U.S. citizens have autoimmune diseases, with some estimates as high as 50 million by the American Autoimmune Related Diseases Association.[29],[30]  Diagnosis of these conditions, which are clinical presentations of certain PIDs, takes many years.[31]  People, on average, see six doctors over a period of four years before they get a diagnosis of an autoimmune disease.[32] 

                              “Screening children for immunodeficiencies

                               is extremely challenging.”

Several autoimmune disorders are commonly reported as vaccine injuries from the M-M-R II vaccine.  In 2011, the Institute of Medicine (IOM) conducted a formal assessment regarding vaccine safety.  With respect to the M-M-R II vaccine, the IOM found that the scientific literature was inadequate to accept or reject a causal relationship with M-M-R II and several commonly reported vaccine injuries, such as: optic neuritis, neuromyelitis optica, fibromyalgia, multiple sclerosis, Guillain-Barré syndrome, and chronic inflammatory disseminated polyneuropathy, which all happen to be autoimmune diseases.[33]  Of the over 150 most common vaccine injuries evaluated, there was only one that the IOM favored rejection of a causal relationship with the M-M-R II vaccine—just one.  More research is needed.

Screening children for primary and secondary immunodeficiencies is extremely challenging.  A 2011 study in the Annals of the New York Academy of Sciences showed that, “except for family history, need for intravenous antibiotics and failure to thrive, the 10 warning signs are not a useful screen of primary immunodeficiency diseases (PIDs).”[34]  The 10 warning signs referenced were based largely on clinical presentation of antibody immunodeficiencies in adults and expert opinion, and were heavily promoted through World Primary Immunodeficiency Week 2011.[35]  The warning signs were made into a leaflet, which advised physicians that if two or more warning signs are present, PID should be considered.  The study evaluated 563 children attending two tertiary pediatric immunology centers in England.   Of children who actually had a PID (430 or 76%), 38% had less than two warning signs on the leaflet.  Of children who did not have a PID (133 or 24%), 48% had at least two warning signs.  Furthermore, two or more warning signs identified children with neutrophil PID, but not those with complement, B cell, or T cell PID.[36]

Neonatal screening for PIDs has been a somewhat effective public health measure and strategy for advancing clinical research.  For instance, it has been instrumental in uncovering an unbiased incidence of Severe Combined Immunodeficiency (SCID) of 1/58,000 live births, which is significantly higher than the previous estimate of 1/100,000 live births.[37]

Guthrie card Dried Blood Spots (DBS) taken from newborns is another screening tool for early diagnosis of some PIDs and other disorders that could lead to SIDs.  However, in states like Washington where it is mandated, less than 30 disorders are tested, most of which are not PIDs.  A follow-up newborn screen is recommended for all infants between 7 and 14 days of age, but is not required and is rarely performed.[38]  Sadly, the IOM acknowledged in 2011 that “Some of these predispositions [that result in vaccine adverse reactions] may be detectable prior to the administration of vaccine; others, at least with current technology and practice, are not.”  In fact, despite improved screening and diagnostic tools, “the occurrence of the adverse event is often the first sign of the underlying condition that confers susceptibility.”[39]

“Vitamin D is just one nutrient required for a

normal immune response;

one third of 1 to 5-year-old US children

do not have sufficient serum vitamin D levels.”

Undernutrition is a common cause of secondary immunodeficiency.[40],[41]  According to the Merck Manual, undernutrition is a deficiency of calories or of one or more essential nutrients.   You can be underweight, normal weight, or obese and still be undernourished.[42]  Undernutrition and malnutrition affect the U.S. population more than one might imagine.  In 2010 (the most recent year with complete figures), 2,948 people died from nutritional deficiencies.[43]  Undernutrition is a critical factor in morbidity and mortality for certain infectious diseases, like the well-documented role of vitamin A deficiency in the immune system’s response to measles infection, for example.[44],[45],[46] 

Insufficient vitamin D levels have attracted increasing interest in the media and public as a possible underlying risk factor in disorders of the immune and central nervous system, including autism.  The role of vitamin D as an essential nutrient extends well beyond that of regulating calcium and phosphorous homeostasis.  It is well established that Vitamin D is a regulatory of both adaptive and innate immune responses.[47]  In recent years, it has been demonstrated that vitamin D directly or indirectly regulates up to 1,250 genes.[48]  Vitamin D is a fat-soluble vitamin that is naturally present in some foods, and is available as a dietary supplement.  It is also produced endogenously when the sun’s ultraviolet rays (UV-B) strike the skin and trigger vitamin D synthesis.[49]  In this sense, vitamin D is somewhat unique in its relationship with the immune system, as its source is from dietary and environmental mechanisms, both of which are potential vectors for secondary immunodeficiencies.[50]

The IOM published a comprehensive report in 2010 on vitamin D and calcium.  The IOM committee’s review of data suggested that persons are at risk of vitamin D deficiency at serum 25-hydroxyvitamine D (25(OH)D) levels of < 12 ng/mL (30 nmol/L).  Some, but not all, persons are potentially at risk of inadequacy at serum 25(OH)D levels 12 to < 20 ng/mL (30 to < 50 nmol/L).  The IOM committee determined that practically all persons are sufficient at levels of 20 ng/mL (50 nmol/L) and above.[51]  The report also stated that 50 nmol/L is the serum 25(OH)D level that covers the needs of 97.5% of the population.[52] 

However, data from National Health and Nutritional Examination Surveys for U.S. children ages 1 to 5 showed that 8% were at risk of vitamin D deficiency, and 24% were at risk of vitamin D inadequacy.[53]  The two-dose M-M-R II vaccine is typically administered at ages 1 and 5, which means that nearly a third of children age-eligible for this triple live-virus vaccine in the U.S. are at risk of inadequate serum 25(OH)D levels or worse, per the IOM.[54]  In other words, a significant portion of the 1 to 5 age range, as a subset of the entire U.S. population, appears to be at risk of vitamin D inadequacy or worse, which could impair their immune system’s response, and by definition place them in a state of acquired immunodeficiency.  Of note, serum 25(OH)D levels are not normally screened in children prior to vaccination. 

A lot of science has been done with respect to vitamin D and health, as the IOM report highlighted, but even the IOM committee acknowledged a fundamental lack of knowledge with respect to this nutrient: “…its [vitamin D] role is complex and not fully understood.”[55]  The report also stated:

Because uncertainties exist in the knowledge base related to the role of vitamin D and calcium in health outcomes, it is important to acknowledge that there are uncertainties surrounding these reference values for calcium and vitamin D.  The development of any reference value should be viewed as a work in progress, which may be subject to change if there are significant changes in the science base.”[56] 

Perhaps the most limiting characteristic of the IOM’s report on vitamin D, though, is the fact that the science it used to evaluate daily reference intakes (DRIs), was science that was “not designed to see data maximally useful for DRI development….”[57]  The report admits, too, that “Most vitamin D studies were conducted using older persons or postmenopausal women,”[58] and “many data gaps remain for younger age groups….”[59]  The IOM committee recommended “investigation of causal relationships between vitamin D nutriture and potential non-skeletal health outcomes.”[60]  This hardly seems like the rebuke the media made the IOM report out to be with respect to the reported health risks of inadequate vitamin D levels in volumes of peer-reviewed scientific literature.[61],[62]   

To examine the safety profile of vitamin D, or its causative role in certain health outcomes, randomized placebo-controlled double-blind trials were considered the highest form of evidence in the IOM’s evaluation, as they tend to significantly reduce bias and are the only type of study that “can show a causal relationship between an intervention and an outcome.”[63],[64]  It goes without saying that the IOM expected these trials to use an inert placebo in the control group, such as a sugar pill or saline injection, as the “placebo-controlled trial is widely regarded as the gold standard” for testing the safety and efficacy of treatments.”[65]   The IOM also preferred large, long-term studies, as the potential benefits or risks of any proposed treatment often take a long time to clinically present, and because the larger size increases statistical significance of the findings. 

In fact, all drugs licensed by the FDA undergo randomized long-term double-blind placebo-controlled pre-licensure clinical trials.  For example, Enbrel’s pre-licensure trials followed subjects up to 80 months and controls received a saline injection.  Lipitor’s pre-licensure trials lasted a median of 4.8 years and controls received a sugar pill.  Botox’s pre-licensure trials lasted a median of 51 weeks and controls received a saline injection.  Of note, these are drugs most commonly given to adults, and licensed drugs are still often recalled despite these high licensing standards.[66]  However, according to Melinda Wharton, Acting Director of the National Vaccine Program Office of the U.S. Department of Health and Human Services (HHS), “Inert placebo controls are not required to understand the safety profile of a new vaccine, and are thus not required.  In some cases, inclusion of placebo control group is considered unethical.[67]  The FDA allows this exemption for vaccines, as vaccines are classified by the Center for Biologics Evaluation and Research as “biologics” and not “drugs,” and therefore have different licensing standards and procedures.[68] 

 

The ethical dilemma highlighted by Dr. Wharton should not go unchallenged.  Most vaccines on the CDC’s childhood vaccine schedule have a recommended window of at least one month, and sometimes several months.[69]  Dr. Wharton’s quote was based on information provided to her showing several examples of safety monitoring periods for pre-licensure trials of vaccines that lasted only a couple of days or weeks.[70]  If the monitoring period of solicited adverse reactions for most vaccines in pre-licensure trials is days or weeks (not months), this would not put the control group at risk by requiring completion of a catch-up schedule.  It would, however, put the pre-licensure trial at risk of inaccuracy, as most problems associated with primary and secondary immunodeficiencies, such as autoimmune diseases, will take much longer than this to manifest.  Dr. Stanley Plotkin, world-renowned physician and vaccinologist, who was instrumental in the development of rubella, polio, rabies, varicella, rotavirus, anthrax, and other vaccines, confirms this in a sworn deposition in January 2018 (minute markers 18:15, 30:15, and 36:00).[71],[72]  This is also confirmed in the National Vaccine Injury Compensation Program’s Vaccine Injury Table, which lists the injuries covered in the compensation program, and the time period for first symptom or manifestation of onset or of significant aggravation following vaccine administration.  Many of these time periods are beyond those used to monitor solicited adverse reactions during pre-licensure clinical trials.[73]

Furthermore, without a true placebo-control group, there is no way to determine causality with the vaccine and solicited and unsolicited adverse reactions during clinical trials or post-marketing surveillance, as confirmed by Dr. Stanley Plotkin, author of four studies referenced on the M-M-R II package insert (minute markers 25:00, 27:20. 34:00, 37:30, and 43:00).  Additionally, for pre-licensure studies that included just 147 healthy infants and children up to 10 years of age, like with the RECOMBIVAX HB (Hepatitis B) vaccine recommended on the first day of a baby’s life, this is not enough people to capture the rate of these complications seen in the general population.[74]   

The M-M-R II vaccine has a lot of controversy surrounding its pre-licensure clinical trials.  For example, “The package insert for the M-M-R II vaccine references a number of pre-licensure trials, typically with small sample sizes and often using children from orphanages, psychiatric institutions, or schools for the handicapped.  In total, it cites: one trial for the M-M-R II comparing it with other vaccines (ref. # 16), one for the measles vaccine in which the test and control group both received the measles vaccine (ref. # 7), three trials for the mumps vaccine in which controls were injected with various experimental vaccines (ref. # 8, 9, 11) and fifteen trials for the rubella vaccine comparing different types of rubella vaccine, except for one trial with 23 apparently untreated controls and one trial with 19 controls receiving a saline nasal spray where rubella vaccine was also given intranasally (ref. # 1, 2, 19-26, 28, 29, 31, 56, 57).[75],[76]   This research would likely pass as notable by IOM standards, but certainly inadequate to determine safety; yet, this is all that was required to license this vaccine.  Sadly, for objective parents who wish to read the science referenced by Merck in the M-M-R II package insert, they will not have access beyond the abstracts.  This is because most of the 62 references in the M-M-R II package insert cannot be viewed, in their entirety, without submitting a freedom of information request, accessing Merck’s research laboratories, a public library with access to the journal, subscribing to the journal, purchasing the article, or renting it. In fact, the studies that the FDA relied upon when licensing the M-M-R II vaccine were obtained just this year, and publicly published for the first time by the Informed Consent Action Network. One of the clinical trials reported to the FDA had the following shocking results: “Upper respiratory and gastrointestinal infections were reported in about 55% and 40% of vaccinees respectively.” Some of the participants suffered with these symptoms for six weeks, and perhaps longer, but the study only monitored their health status for 42 days. Other studies used by the FDA to evaluated the M-M-R II vaccine showed similarly poor health outcomes in vaccinees, yet this vaccine was approved and administered to millions of children around the globe. [77]

Additionally, there are questions surrounding the first and only study conducted by the CDC with American children looking at a link between the M-M-R II vaccine and autism.  Dr. William Thompson, a senior research scientist for the CDC and whistleblower, said that the CDC “omitted statistically significant information” with respect to this vaccine safety science involving the M-M-R II vaccine.[78],[79]  One of his more disturbing quotes from recorded conversations was, “Oh my God.  I cannot believe we did what we did.  But we did.”[80] 

Furthermore, two former Merck virologists, Stephen Krahling and Joan Wlockowski, filed a whistleblower lawsuit in 2010 alleging that Merck knowingly overstated effectiveness of its mumps vaccine (part of the M-M-R II vaccine) in order to maintain its patent.  The former Merck virologists allege this was done by skewing tests of the vaccine by adding animal antibodies to blood samples, thus falsifying the results in favor of the drug maker.  In 2012, Alabama-based Chatom Primary Care and two individual doctors, all purchasers of the vaccine, filed a proposed antitrust class action based on the allegations in the whistleblower suit.  The two suits are now being coordinated before U.S. District Judge C. Darnell Jones and Magistrate Judge Sitarski.[81] 

The lack of clear safety data on the MMR-II vaccine was summarized in an article published in the journal Vaccine in 2003 by the Cochrane Collaboration (now known as Cochrane), one of the world’s most respected mainstream research organizations.  The group examined twenty-two research studies done on the M-M-R II vaccine and concluded: “the design and reporting of safety outcomes in MMR-II vaccine studies, both pre- and postmarketing, are largely inadequate.”[82] 

Since the IOM’s report on vitamin D was published, data from newer research continues to demonstrate strong evidence of a correlation between low vitamin D levels and poor health outcomes.  For example, a 2015 study in Molecular Autism examined stored dried blood spots taken in the neonatal period for 58 Sweden-born sibling pairs, in which one child had autism and the other did not.  The children with autism had significantly lower vitamin D levels as compared with their siblings.  The differences were most likely not accounted for by difference in season of birth.[83]  Additionally, a 2016 Cochrane meta-analysis of a modest number of trials in people with predominantly mild to moderate asthma suggests that vitamin D is likely to reduce the risk of severe asthma exacerbation and healthcare use.[84]

According to a 2017 article in Reviews in Endocrine & Metabolic Disorders, it is now evident that children are, or who are destined to become autistic, have lower 25(OH)D levels at 3 months of gestation, at birth, and at age 8 compared to their unaffected siblings.  Additionally, vitamin D supplementation during pregnancy and during infancy and early childhood has been found to significantly reduce the expected incidence of autism in mothers who have one autistic child.[85]  Another 2017 study in the journal Physiological Research concluded: “Vitamin D deficiency is undoubtedly a risk factor for autism.[86]  Likewise, a 2018 study in the Italian Journal of Pediatrics found that children with autism had significantly lower serum 25(OH)D levels than healthy children, despite having no significant difference in sun exposure between the two groups.[87]

A comprehensive review, similar to the IOM’s report in 2010, was published in 2018 in the Italian Journal of Pediatrics.  This consensus evaluation of the Italian Pediatric Society and the Italian Society of Preventive and Social Pediatrics, as well as the Italian Federation of Pediatricians, was intended for hospital and primary care pediatricians making recommendations regarding the prevention and treatment of vitamin D deficiency in Italian children and adolescents, considering both the skeletal and extra-skeletal effects of vitamin D and potential risk factors in specific subgroups of children.  One of the most striking revelations from this report is the lack of consensus, globally, on ranges for vitamin D status, dietary reference intakes, as well as recommended indications for serum 25(OH)D level evaluation.[88]  The IOM is just one body and one voice, but there are many other notables and their evaluations, different as they may be from the IOM, matter too.  Using the range cutoffs for vitamin D deficiency and inadequacy from some of these medical authorities would put even more U.S. children, ages 1 to 5, in the deficient end of the spectrum.

“This issue has likely affected

tens of thousands of children in the U.S.

over the last 40 years.”

Discussion

A 2018 study summarized the number of Inborn Errors of Immunity (primary immunodeficiencies) listed in each publication of the World Health Organization (WHO) and the International Union of Immunological Societies (IUIS) Primary Immunodeficiencies Committee between 1979 (M-M-R II was licensed in 1978) and 2017.  There were less than 5 disorders listed in 1979 and over 350 listed in 2017.[89]  Therefore, children in those decades with unknown PIDs at the time of vaccination were receiving a vaccine that was contraindicated for them.  Additionally, children with known PIDs, but undiagnosed at the time of vaccination were also receiving a vaccine that was contraindicated for them.  At an average pace of discovery of about nine PIDs per year, this likely affected several thousand children in that nearly forty-year period.    

The incidence of PIDs is increasing for several reasons, but the exact rate is still hard to pinpoint.  In a 1988 article from the Archives of Disease in Childhood, it was reported that in countries where immunodeficiency registers had been established (Australia, Japan, Spain, and Sweden), there was an overall incidence of “appreciable symptomatic antibody deficiency” of 1/11,000 live births.  A 2011 study in the European Journal of Pediatrics said that PIDs “are more frequent than generally acknowledged.”[90]  This same study estimated that prevalence of PIDs differs widely, from 1/500 for IgA deficiency to 1/100,000 for more serious forms.[91]  A 2013 study in the Archives of Disease in Childhood: Education and Practice Edition estimated the incidence of all currently recognized pediatric PIDs taken together is approximately 1:2000….”[92]  Of note, this particular incidence of 1/2,000 was based on authors’ knowledge of “over 180” primary immune deficiencies; not the over 350 acknowledged by the WHO in 2017.  According to an article in the journal Science, “It is now clear that most, if not all individuals, suffer from at least one PID, the clinical expression of which depends on exposure to ad hoc environmental factors, infectious or otherwise.[93] 

According to the online professional version of the Merck Manual, “Overall incidence of symptomatic [primary immunodeficiency] disease is about 1/280 people.[94]  Using Merck’s estimate, while assuming four million live births in the U.S. each year, that would be about 14,285 “symptomatic” children each year with a PID.[95]  For decades, these children would not have been diagnosed with a PID at the time of M-M-R II vaccination, as their specific disorder had not yet been discovered, and their diagnosis even upon discovery, would have been unlikely or significantly delayed.  Also, the 14,285 number does not include the children who were age-eligible for the M-M-R II vaccine and were asymptomatic, which is likely an even larger number. 

From a PID perspective alone, this issue has likely affected tens of thousands of children in the U.S. over the last forty years.  Therefore, it is not surprising to see published statistics that show an estimated 43% of U.S children (32 million) have at least 1 of 20 chronic health conditions, and that this rate has been rising over the last forty years in-step with the CDC’s expansion of recommended childhood vaccines.[96]  Certain childhood cancers have also been increasing as well.[97]  Interestingly, data from the National Health and Nutrition Examination Surveys showed that the risk of vitamin D deficiency increased between 1988 and 1994 and 2001 to 2002 in both sexes.[98]  This would imply that something in that timeframe changed in our diets, environments, and/or lifestyle, which reduced the levels of a critical vitamin for proper immune system function.    

Acquired or secondary immunodeficiency disorders are more common than primary and are not hereditary.[99]  No source could be found that stated a specific estimate for the incidence of all secondary immunodeficiencies.  Acquired Immune Deficiency Syndrome (AIDS) is the most commonly known acquired immunodeficiency, with nearly 18,000 people diagnosed in the U.S. in 2017 alone, but there are others.[100]  At this time, we can only guess how many individuals in a state of acquired immunodeficiency have received the M-M-R II vaccine since it was licensed in 1978. 

The following is in reference to the family history part of the M-M-R II contraindications section, which states: “Individuals with a family history of congenital or hereditary immunodeficiency, until the immune competence of the potential vaccine recipient is demonstrated.”[101]  Few people know their family’s entire medical history, especially an existence of congenital or hereditary immunodeficiencies.  I would assume that most people are lucky if they know their grandparents’ cause of death, let alone are aware of genetic predispositions they might have latently harbored, but were unknown to exist by the medical community during their lifetimes.  I would argue that most people cannot define congenital or hereditary immunodeficiencies.  I would also argue that “immune competence” greatly implies subjectivity, which is understandable given that no objective measures can assess the entirety of the efficiency of the immune system, especially in real-time.  This was admitted by Garry Fathman, M.D., professor of immunology and rheumatology and associate director of the Institute for Immunology, Transplantation and Infection at Stanford University in 2011:

“For now, from the standpoint of the practicing clinician the immune system remains a black box…. If a patient were to ask me, ‘How’s my immune system doing today?’ I would have no idea how to answer that, and I’m an immunologist. None of us can answer that. Right now we’re still doing the same tests I did when I was a medical student in the late 1960s.”[102]

There is a difference between an absolute and relative contraindication.[103]  However, why should parents take a pediatrician or foundation’s assessment that these contraindications are relative in nature and that the benefits outweigh the risks when the manufacturer–over decades–has chosen to leave it open-ended?  Merck could have updated their package insert, especially once they were freed from financial liability following the National Childhood Vaccine Injury Act (NCVIA) of 1986. However, they have not done so in over forty years following M-M-R II’s release.  Even if a contraindicated vaccine is recommended for a child by a medical professional, it should not be considered taboo for the parent to exercise prudence and decline the vaccine anyway.

Merck’s package insert gives no specificity for the immunodeficiency contraindication.  When taken literally, the manufacturer is advising all people with any primary or acquired immunodeficiency, as they are currently defined, no matter how ephemeral or severe the condition, to avoid their product.  The contraindication also implies that any factor that can cause a primary or acquired immunodeficiency, no matter how transient or obvious the response, must be vetted with knowledge and technology of the time to rule out the possibility of contraindication to the individual considering vaccination.  Only in doing so, could it be proven in a lawsuit, that the child was not contraindicated at the time of vaccination.  Given the greater awareness and understanding of primary and acquired immunodeficiencies, Merck’s package insert appears to be either outdated, or purposefully unspecific for reasons unknown, but certainly advantageous to the manufacturer, nonetheless.

“Merck and the general medical industry have a problem.  A vaccine was contraindicated for thousands of children in the U.S., but given anyway.”

Before the NCVIA of 1986, Merck could always claim in a lawsuit that it was possible the child was in an immunodeficient “state” at the time of vaccination, and that the vaccine was contraindicated.  The burden would be on the parents to first prove their child was not in this state, and then prove the vaccine caused the damage they were suing Merck for—two very difficult things to prove, especially in the 1970s and 1980s.

Merck and the general medical industry promoting vaccines has a problem.  A vaccine was contraindicated for thousands of children in the U.S., but given anyway.  We have no understanding of the impact this has had over the last forty years.  However, given the current abysmal state of health in the U.S., even a small causal relationship to some of the chronic illnesses our children experience today would be a huge mainstream headline.  Even the IOM agrees that much of the science remains to be done with respect to identifying individual susceptibility to serious vaccine injuries:

Both epidemiologic and mechanistic research suggest that most individuals who experience an adverse reaction to vaccines have a preexisting susceptibility.  These predispositions can exist for a number of reasons—genetic variants (in human or microbiome DNA), environmental exposures, behaviors, intervening illness, or developmental stage, to name just a few—all of which can interact….  Some of these adverse reactions are specific to the particular vaccine, while others may not be.  Some of these predispositions may be detectable prior to the administration of vaccine….  …much work remains to be done to elucidate and to develop strategies to document the immunologic mechanisms that lead to adverse effects in individual patients.”

Vitamin D is just one essential nutrient required for a normal immune response, and a third of U.S. children ages 1 to 5 do not have sufficient serum 25(OH)D levels.  There are so many other factors that impair an immune system response, thereby allowing the affected person to acquire an immunodeficient state, by definition.  Evaluating all of these factors and assessing one’s immune efficiency in real-time would require a team of doctors and scientists, working with state-of-the-art equipment and labs, and an unlimited budget.  Even then, it may not be achievable given our limited understanding of “the most complex system [immune] that the human body has,” and the natural delay inherent to the discovery process.[104]  Even Dr. Plotkin, whose name is engraved on the Advisory Committee on Immunization Practices gavel, acknowledged that modern immunology does not fully understand the complete sequence of biological events going from vaccination to immunity (minute marker 2:30).[105],[106]  Additionally, it took until 2015 before scientists discovered the immune system’s connection to the brain by vessels previously thought to not exist, which overturned decades of textbook teaching.[107],[108]  Furthermore, a 2015 study in the journal Nature Immunology is suggesting that the appendix may not be a vestige of evolution after all, as has been taught to doctors for decades.  The appendix may actually play a crucial role in our immune systems, serving as a reservoir for maintenance of gut flora.[109]  Appendectomy is one of the most common surgical procedures in the U.S., yet is assumed to have no effect on the immune system and is currently an unlisted cause of secondary immunodeficiency.[110]  More research is needed.

There are many examples of factors that are not commonly known to impair an immune response.  Many over-the-counter drugs, which are widely accepted by the medical community as non-immunosuppressive agents, have been described to modulate the humoral and cellular immune responses in humans and animals.[111]  Aspirin is a nonsteroidal anti-inflammatory drug (NSAID)—pain reliever and fever reducer–that has been linked with Reye’s syndrome, especially during an infection of chicken-pox and influenza.  People have been taking these drugs during infections (including those from vaccinations) for decades, yet little is known about this syndrome, or the drug’s ability to induce immunodeficiency.  There is currently no medical screening tool to determine whether someone is predisposed to the syndrome, which is odd given the pervasive use of these drugs in the general population, and the heightened risk for Reye’s syndrome specific to childhood infectious diseases for which there is a vaccine.[112]

NSAIDs have been shown to inhibit antibody production in human cells, and Aspirin, specifically, has been demonstrated to impair the development of a cellular immune response.[113]  In the other words, the immune system can be negatively impacted by this drug, at least enough beyond its normal function.  More research is needed.

Systematic evaluation of the immune status of patients with mitochondrial disease, in its early stages, suggests the presence of immunodeficiency in children with mitochondrial disease.  A 2010 study in the Journal of Allergy and Clinical Immunology argues for a paradigm shift with respect to mitochondrial disease and the interpretation of immunodeficiency.  The immune’s response to infection requires vast amounts of energy in the form of adenosine triphosphate (ATP) synthase, which is a key enzyme generated by mitochondria.[114]  Children with mitochondrial disease have limited ATP production, which can impair a protective immune response due to infection.  This means children with mitochondrial dysfunction are likely immunodeficient; whether caused by genetics or environmental factors remains to be determined.[115] 

Yet, a decade later, the CDC still does not engage

in screening for this acknowledged but unlisted

mitochondrial disorder contraindication

that may result in autism-like symptoms.

In March, 2008, Dr. Julie Gerberding, CDC Director at the time, and later President of Merck Vaccines (2010-2014), told CNN’s Dr. Sanjay Gupta the following (minute marker 2:55):

Now, we all know that vaccines can occasionally cause fevers in kids.  So, if a child was immunized, got a fever, had other complications from the vaccine, then if you’re predisposed with the mitochondrial disorder, it can certainly set off some damage.  Some of the symptoms can be symptoms that have characteristics of autism.”[116]

Yet, over a decade later, the CDC still does not engage in screening for this CDC-acknowledged, unlisted mitochondrial disorder contraindication for vaccines, as their website states: “More research is needed to find out how common it is for people to have autism and a mitochondrial disorder,” and “Children are not routinely tested for mitochondrial diseases.[117]  This too, despite the fact that numerous studies highlight mitochondrial involvement in autism.[118],[119]  It appears that for these metabolically vulnerable children, receiving vaccines may be the “last straw” that leads to these children revealing their underlying genotype.  More research is needed.

Newer research is showing that vaccines using human fetal cells, such as Merck’s M-M-R II vaccine and several others, contain residual DNA fragments and endogenous retroviral contaminants.  It is possible that these contaminating fragments could be incorporated into a child’s genome and disrupt normal gene function.[120],[121]  Since PIDs are genetic in nature, and given the fact that Merck’s M-M-R II vaccine has not been evaluated for its carcinogenicity or mutagenicity, this raises concern.  A recent clinical study conducted at Duke University demonstrated evidence that autism is contracted after birth, not before.[122]  In other words, genes of the evaluated children at birth did not predispose them to become autistic.  More research is needed.

Research in the field of epigenetics is helping us to better understand the role of processes like DNA methylation, histone modifications, and chromatin remodelling in immune function.[123],[124]  Epigenetics refers to external modifications to DNA that turn genes “on” or off.”  These modifications do not change the DNA sequence, but instead, affect how cells “read” genes.  Diet, stress, sleep, exercise, aging and vaccination—essentially all environmental stimuli—can cause these chemical modifications around the genes that will turn those genes “on” or “off” over time.[125]  By their very nature, primary immunodeficiencies are immune disorders resulting from defects in genes involved in the immune regulation process and manifest as increased susceptibility to infections, autoimmunity, and cancer.  Alterations in epigenetic regulators are increasingly being described in PIDs in the scientific literature, but more research is needed.[126]  Mark Davis, Ph.D., is the Bert and Marion Avery Professor in the Department of Microbiology and Immunology and director for the Institute for Immunology, Transplantation and Infection at Stanford University. In 2011 he stated:

“It’s [the immune system] staggeringly complex, comprising at least 15 different interacting cell types that spew dozens of different molecules into the blood to communicate with one another and do battle. Within each of those cells sits tens of thousands of genes whose activity can be altered by age, exercise, infection, vaccination status, diet, stress, you name it. That’s a lot of moving parts. And we don’t really know what the vast majority of them do, or should be doing. We can’t even be sure how to tell when the immune system’s not working right, let alone why not, because we don’t have good metrics of what a healthy immune system looks like.”[127]

Consider a case description published in 2018 in the Annals of Allergy, Asthma & Immunology titled, “Secondary Immunodeficiency Due to Gaming Disorder.”  This is an actual case where gaming disorder, which is now a legitimately classified ICD-11 diagnosis, was described to lead to a secondary immunodeficiency.  The patient had a negative primary immunodeficiency workup.  Researchers in this case study did not think to test for serum 25(OH)D levels, despite the fact that the patient “spent most of the day playing video games,” which is most commonly done indoors.  Additionally, mitochondrial dysfunction was not screened, nor were sleep patterns.  “With improved nutritional status,” some of the patient’s immune-related issues resolved, but not all.  Regardless, the researchers concluded that the immunodeficiency was secondary to malnutrition alone.  This case study reveals the need for more research in the field, and provides an example of modern disturbing human behaviors, such as spending inordinate amounts of time indoors playing video games while eating junk food and drinking soda as main sources of entertainment and nutrition, respectively.  According to data from NPD, 91% of children ages 2 to 17 play video games, which is up nearly 13% from a 2008 study.  Sadly, gaming among kids ages 2 to 5 has increased the most.[128] 

One of the more shocking revelations from a 2011 IOM report on adverse effects of vaccines was the following:

The best-understood vaccine-associated adverse effect is the occurrence of invasive disease (such as meningoencephalitis and arthritis) caused by the vaccine virus itself in individuals with an acquired or genetic immunodeficiency who receive live vaccines such as VZV, MMR, and oral polio vaccine.  Although the incidence of such infections may decrease with the introduction of newborn screening for severe combined immunodeficiency, the occurrence of vaccine-related disease can be trigger that leads to the recognition of immunodeficiency (Galea et al., 2008; Ghaffar et al., 2000; Kramer et al., 2001; Levy et al., 2003).  Invasive disease may also occur by viral reactivation in individuals who previously received these vaccines while healthy, but who subsequently become immunocompromised, for example, as a result of chemotherapy should they later develop cancer or leukemia (Chan et al., 2007; Levin et al., 2003).  Not all individuals who suffer invasive disease have demonstrated recognized immune deficien-cies, even when vaccine virus is recovered from the patient (lyer et al., 2009; Levin et al., 2008).”[129]

Therefore, either immunocompetent people can acquire invasive disease from vaccine virus, or immunodeficient people are receiving vaccines that were contraindicated for them.  The sad truth is, the IOM admits that these are only hypotheses at the time.[130]  In other words, one of the greatest organizations to provide unbiased, evidence-based, authoritative information on the topic of vaccines in the world, admits that the for the “best-understood vaccine-associated adverse effect,” we still know very little of the mechanism(s) or predisposition(s) for harm from vaccines.

The term “adversomics” was first introduced in 2009 and refers to the application of immunogenomics and systems biology to understand the genetic and non-genetic drivers of vaccine adverse reactions at the molecular level.  Much attention in the scientific community has been given to science regarding vaccine immunogenicity, but significantly much less attention has been given to factors that influence immune-mediated adverse vaccine events and the mechanisms behind these events.  In fact, researchers at the forefront of this topic admitted in 2015: “The field of vaccine adversomics is in its infancy.  At this time, these technologies are not being used clinically.”[131]

Where the time of vaccination was between 1/1/1978 and 3/1/2019, the cumulative raw count of reported adverse events from measles, mumps, and rubella vaccines alone in the CDC and FDA’s Vaccine Adverse Event Reporting System (VAERS) was: 84,954 adverse events, 1,587 disabilities, 6,535 hospitalizations, and 328 deaths.[132],[133],[134],[135]  Taking these numbers and applying a correction factor resulted in 424,770 adverse events, 7,935 disabilities, 32,675 hospitalizations, and 1,640 deaths.  The correction factor assumed that only 10% of adverse reactions are reported to VAERS, and only 50% of those reported cases are the fault of, or related to a vaccine.  Both conservative estimates indeed, given that a 2007 three-year long HHS funded study by Harvard Medical School using 715,000 patients of Harvard Pilgrim Health Care found that “fewer than 1% of vaccine adverse events are reported [to VAERS].”[136]  A U.S. House Report similarly stated: “Former FDA Commissioner David A. Kessler has estimated that VAERS reports currently represent only a fraction of the serious adverse events.”[137] 

It is unknown how many adverse events reported to VAERS were specifically due to immunodeficiency, as this type of investigation is in its infancy.  In fact, the IOM admitted in 2011 that, “The list of factors that are known to confer susceptibility [to adverse events to vaccines] is by no means definitive or exhaustive.  Rather, we hypothesize that continued study of alleged vaccine-related injuries, the committee informed by epidemiologic studies that identify vulnerable populations and exploration of underlying mechanisms of susceptibility, will provide greater insight into these and other mechanisms and will identify more factors that contribute to vaccine susceptibility.”[138] 

Conclusion

Dr. Gregory Poland’s 2015 seminal article on adversomics in the journal Expert Review of Vaccines summarized the science that had been done on this topic, which was only six studies of adverse events specific to vaccination.  In one of the studies looking at DTP, IPV, and Hib vaccines, 100% of the cases had genetic or structural causes of the adverse events evaluated.  Given this and other information presented in this article, a significant portion of people who have, or are suffering from, adverse reactions to vaccines are, or were likely, immunodeficient at the time of vaccination.  Therefore, these people should not have received the vaccine at that time per the manufacturer’s instructions.

Referencing Dr. Healy’s quote from the beginning of the article–we cannot allow more vulnerable children to receive vaccines because of a collective fear in our public health officials to not identify those susceptible individuals.  After all, imagine the consequences if it were discovered that 10% of the population should not be receiving the M-M-R II vaccine because of an underlying immunodeficiency.  This would certainly make the 92% to 95% minimum threshold levels currently recommended for community immunity difficult to achieve.

I agree with the IOM: “…much work remains to be done to elucidate and to develop strategies to document the immunologic mechanisms that lead to adverse effects [from vaccines] in individual patients.”[139]  I also agree with Drs. Poland, Whitaker, and Ovsyannikova in their 2015 article that, “The precise mechanisms of adverse reactions associated with vaccines are not well understood.”  Of note, Dr. Poland is a world renowned expert on vaccines, research scientist for Mayo Clinic, and editor-in-chief of the prestigious journal Vaccine.[140]

Indeed, much research remains to be done on the subject of primary and secondary immunodeficiencies, as well as on the safety of the M-M-R II vaccine with respect to commonly reported adverse reactions.  Prudent parents, aware of the lack of quality data for the M-M-R II vaccine and these adverse events, should not be publicly shamed or prevented from refusing a preemptive medical procedure that uses a product that cannot be proven, beyond a shadow of doubt, to not be contraindicated for their child, given the vaccine manufacturer’s open-ended instructions and the lack of awareness and mechanistic knowledge of susceptibility to vaccine injury.  Parental freedom of choice in the matter should be honored and celebrated, as their curiosity for knowledge and truth—shared by scientists alike–is what fuels science and progress.

[1] https://www.cbsnews.com/news/the-open-question-on-vaccines-and-autism/

[2] https://childrenshealthdefense.org/events-news/stream/

[3] https://www.merck.com/product/usa/pi_circulars/m/mmr_ii/mmr_ii_pi.pdf

[4] https://www.jacionline.org/article/S0091-6749(14)00112-2/fulltext

[5] https://www.merck.com/product/usa/pi_circulars/m/mmr_ii/mmr_ii_pi.pdf

[6] https://www.collinsdictionary.com/us/dictionary/english/immunodeficiency

[7] https://www.sciencedirect.com/science/article/pii/B9780124055469000832

[8] https://www.sciencedirect.com/science/article/pii/B9780124055469000832

[9] https://www.sokolovelawfirm.com/blog/mayo-clinic-misdiagnosis/

[10] https://www.washingtonpost.com/national/health-science/20-percent-of-patients-with-serious-conditions-are-first-misdiagnosed-study-says/2017/04/03/e386982a-189f-11e7-9887-1a5314b56a08_story.html?utm_term=.e02b6560f9a7

[11] https://www.mayoclinic.org/diseases-conditions/primary-immunodeficiency/symptoms-causes/syc-20376905

[12] http://science.sciencemag.org/content/317/5838/617.full

[13] https://www.merckmanuals.com/home/immune-disorders/immunodeficiency-disorders/overview-of-immunodeficiency-disorders

[14] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022152/

[15] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627851/

[16] https://www.ncbi.nlm.nih.gov/pubmed/22846098

[17] https://www.ncbi.nlm.nih.gov/pubmed/24488388

[18] https://www.ncbi.nlm.nih.gov/pubmed/22427477

[19] https://www.ncbi.nlm.nih.gov/pubmed/23918706

[20] https://www.myigsource.com/living-with-primary-immunodeficiency/pi-facts

[21] https://www.sciencedirect.com/science/article/pii/B9780124055469000832

[22] https://www.hiv.gov/hiv-basics/overview/data-and-trends/statistics

[23] https://www.ncbi.nlm.nih.gov/pubmed/30704941

[24] https://www.vitamindcouncil.org/about-vitamin-d/how-do-i-get-the-vitamin-d-my-body-needs/#.XHg4dsBKhEY

[25] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3773974/

[26] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022152/

[27] https://www.ncbi.nlm.nih.gov/pubmed/23918706

[28] https://nyaspubs.onlinelibrary.wiley.com/doi/full/10.1111/j.1749-6632.2011.06206.x

[29] https://www.aarda.org/knowledge-base/many-americans-autoimmune-disease/

[30] https://www.niaid.nih.gov/diseases-conditions/autoimmune-diseases

[31] https://www.aarda.org/news-information/statistics/

[32] https://blog.uvahealth.com/2014/10/31/detective-work-autoimmune-disease/

[33] https://www.nap.edu/read/13164/chapter/2#8

[34] https://www.ncbi.nlm.nih.gov/pubmed/22129048

[35] https://nyaspubs.onlinelibrary.wiley.com/doi/full/10.1111/j.1749-6632.2011.06206.x

[36] https://nyaspubs.onlinelibrary.wiley.com/doi/full/10.1111/j.1749-6632.2011.06206.x

[37] https://www.frontiersin.org/research-topics/9556/screening-for-primary-immunodeficiency-disorders-pidds-in-neonates

[38] https://www.doh.wa.gov/YouandYourFamily/InfantsandChildren/NewbornScreening/Disorders

[39] https://www.nap.edu/read/13164/chapter/5#82

[40] https://www.aaaai.org/conditions-and-treatments/conditions-dictionary/secondary-immune-deficiency-disease

[41] https://www.merckmanuals.com/professional/immunology-allergic-disorders/immunodeficiency-disorders/overview-of-immunodeficiency-disorders#v27389451

[42] https://health.usnews.com/health-news/health-wellness/articles/2015/09/16/malnutrition-its-not-always-what-you-think

[43] https://www.cdc.gov/nchs/data/nvsr/nvsr61/nvsr61_04.pdf

[44] https://www.merckmanuals.com/professional/immunology-allergic-disorders/immunodeficiency-disorders/overview-of-immunodeficiency-disorders#v27389432

[45] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1245303/

[46] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1195969/

[47] https://www.nap.edu/read/13050/chapter/6?term=immune#167

[48] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5941617/

[49] https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/

[50] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151868/

[51] https://www.nap.edu/read/13050/chapter/10#487

[52] https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/

[53] https://pdfs.semanticscholar.org/c380/0fe75456c0fb4dc8fc6f527af9cd13bf01a3.pdf

[54] https://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html

[55] https://www.nap.edu/read/13050/chapter/6?term=immune#167

[56] https://www.nap.edu/read/13050/chapter/10#481

[57] https://www.nap.edu/read/13050/chapter/10#485

[58] https://www.nap.edu/read/13050/chapter/11#516

[59] https://www.nap.edu/read/13050/chapter/11#516

[60] https://www.nap.edu/read/13050/chapter/11#517

[61] https://www.nytimes.com/2017/04/10/health/vitamin-d-deficiency-supplements.html

[62] https://www.thestreet.com/story/12808121/1/vitamin-d-calcium-deficiencies-are-overstated.html

[63] https://www.nap.edu/read/13050/chapter/6#130

[64] https://www.nap.edu/read/13050/chapter/6#133

[65] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601706/

[66] https://icandecide.org/wp-content/uploads/whitepapers/ICAN-HHS-Notice.pdf

[67] https://icandecide.org/hhs/HHS-Response.pdf

[68] https://www.fda.gov/biologicsbloodvaccines/ucm121134.htm

[69] https://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html

[70] https://icandecide.org/wp-content/uploads/whitepapers/ICAN-HHS-Notice.pdf

[71] http://www.nfid.org/awards/plotkin.pdf

[72] https://www.youtube.com/watch?v=tiABomhZm5Q&list=PL1YEOqhXrSRdkrPjjyf4InpquMkIZ84n2&index=4

[73] https://www.hrsa.gov/vaccine-compensation/index.html

[74] https://www.fda.gov/downloads/biologicsbloodvaccines/vaccines/approvedproducts/ucm110114.pdf

[75] https://icandecide.org/hhs/ICAN-Reply.pdf

[76] https://www.merck.com/product/usa/pi_circulars/m/mmr_ii/mmr_ii_pi.pdf

[77] https://icandecide.org/government/FDA-Production-FOIA.pdf

[78] https://www.focusforhealth.org/dr-brian-hooker-statement-william-thompson/

[79] https://www.rescuepost.com/files/william-thompson-statement-27-august-2014-3.pdf

[80] Barry, Kevin Esq. Vaccine Whistleblower—Exposing Autism Research Fraud at the CDC. New York: Skyhorse Publishing, 2015. Print.

[81] https://www.reuters.com/article/health-vaccine/merck-accused-of-stonewalling-in-mumps-vaccine-antitrust-lawsuit-idUSL1N0YQ0W820150604

[82] Jefferson T., et al.  “Unintended events following immunization with MMR-II: a systematic review.”  Vaccine 2003; 21(25-26): 3954-3960.

[83] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396835/

[84] https://www.ncbi.nlm.nih.gov/pubmed/27595415

[85] https://www.ncbi.nlm.nih.gov/pubmed/28217829

[86] http://www.biomed.cas.cz/physiolres/pdf/66/66_S333.pdf

[87] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296143/

[88] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5941617/

[89] https://www.ncbi.nlm.nih.gov/pubmed/29226302

[90] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022152/

[91] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022152/

[92] https://www.ncbi.nlm.nih.gov/pubmed/23918706

[93] http://science.sciencemag.org/content/317/5838/617.full

[94] https://www.merckmanuals.com/professional/immunology-allergic-disorders/immunodeficiency-disorders/overview-of-immunodeficiency-disorders

[95] https://www.babycenter.com/0_surprising-facts-about-birth-in-the-united-states_1372273.bc

[96] https://www.academicpedsjnl.net/article/S1876-2859(10)00250-0/fulltext

[97] https://childrenshealthdefense.org/news/incidence-of-childhood-cancers-skyrocket-is-modern-life-destroying-the-health-of-our-children/

[98] https://pdfs.semanticscholar.org/c380/0fe75456c0fb4dc8fc6f527af9cd13bf01a3.pdf

[99] https://www.merckmanuals.com/professional/immunology-allergic-disorders/immunodeficiency-disorders/overview-of-immunodeficiency-disorders#v27389451

[100] https://www.hiv.gov/hiv-basics/overview/data-and-trends/statistics

[101] https://www.merck.com/product/usa/pi_circulars/m/mmr_ii/mmr_ii_pi.pdf

[102] http://sm.stanford.edu/archive/stanmed/2011summer/article7.html

[103]https://www.medicinenet.com/script/main/art.asp?articlekey=17824

[104] https://www.ncbi.nlm.nih.gov/books/NBK279364/

[105] https://www.cdc.gov/vaccines/acip/meetings/downloads/min-archive/min-2017-10-508.pdf

[106] https://www.youtube.com/watch?v=tiABomhZm5Q&list=PL1YEOqhXrSRdkrPjjyf4InpquMkIZ84n2&index=4

[107] https://www.sciencedaily.com/releases/2015/06/150601122445.htm

[108] https://www.scientificamerican.com/article/important-link-between-the-brain-and-immune-system-found/

[109] https://www.nature.com/articles/ni.3332

[110] https://www.sciencefocus.com/the-human-body/what-does-the-appendix-do-a-lot-more-than-we-thought/

[111] https://www.hindawi.com/journals/mi/2015/349176/

[112] https://www.mayoclinic.org/diseases-conditions/reyes-syndrome/symptoms-causes/syc-20377255

[113] https://www.hindawi.com/journals/mi/2015/349176/

[114] https://www.sciencedirect.com/science/article/pii/S0005272806001022

[115] https://www-sciencedirect-com.du.idm.oclc.org/science/article/pii/S0091674909018715

[116] https://www.youtube.com/watch?v=Dh-nkD5LSIg

[117] https://www.cdc.gov/ncbddd/autism/mitochondrial-faq.html

[118] https://www.sciencedirect.com/science/article/abs/pii/S0959438817300764

[119] https://www.sciencedirect.com/science/article/pii/S1071909113000624

[120] https://soundchoice.org/wp-content/uploads/2012/08/DNA_Contaminants_in_Vaccines_Can_Integrate_Into_Childrens_Genes.pdf

[121] https://academicjournals.org/article/article1411048618_Deisher%20et%20al.pdf

[122] https://autismcenter.duke.edu/research/efficacy-umbilical-cord-blood-infusion-improving-outcomes-children-autism-spectrum-disorder

[123] https://www.sciencedirect.com/science/article/pii/S1521661603002031

[124] https://www.sciencedirect.com/science/article/pii/S0264410X16310167

[125] https://www.cell.com/neuron/fulltext/S0896-6273(15)00475-4

[126] https://www.sciencedirect.com/science/article/pii/S1471490618302126

[127] http://sm.stanford.edu/archive/stanmed/2011summer/article7.html

[128]https://www.digitaltrends.com/computing/91-percent-of-kids-play-video-games-says-study/

[129] https://www.nap.edu/read/13164/chapter/5#82

[130] https://www.nap.edu/read/13164/chapter/5#83

[131] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630804/

[132] https://medalerts.org/vaersdb/findfield.php

[133] https://medalerts.org/vaersdb/findfield.php

[134] https://medalerts.org/vaersdb/findfield.php

[135] https://medalerts.org/vaersdb/findfield.php

[136] https://healthit.ahrq.gov/sites/default/files/docs/publication/r18hs017045-lazarus-final-report-2011.pdf

[137] https://www.congress.gov/106/crpt/hrpt977/CRPT-106hrpt977.pdf

[138] https://www.nap.edu/read/13164/chapter/5#84

[139] https://www.nap.edu/read/13164/chapter/5#83

[140] https://www.mayo.edu/research/faculty/poland-gregory-a-m-d/bio-00078220