Vaccine Hesitancy

The COVID-19 pandemic brought vaccine hesitancy back to the forefront. The first COVID-19 vaccine received Emergency Use Authorization (EUA) from the U.S. Food and Drug Administration (FDA) in December 2020. Since that time, more than 270 million Americans have received at least one COVID vaccine dose, but many younger adults and children remain unvaccinated (see CDC: COVID-19 Vaccinations in the United States). Serious adverse events associated with COVID-19 vaccination occur but are extremely rare. For example, the mRNA vaccines, BNT162b2 COVID-19 vaccine (mRNA) produced by Pfizer-BioNTech and mRNA-1273 COVID-19 vaccine (mRNA) produced by Moderna, have been associated with myocarditis and pericarditis. Although serious, these events are extremely rare compared to COVID-19 infection and its complications. Similar to other vaccine-preventable diseases, COVID-19 hospitalizations and deaths are much more common among unvaccinated people.

Some parents think that COVID-19 infection is not dangerous to children, but this is not the case. Although COVID-19 infection is typically milder in children than adults, it can cause significant morbidity and mortality. As of May 2023, more than 15 million children in the United States were reported to have tested positive for COVID-19 since the onset of the pandemic (1), resulting in 1,839 deaths. Additionally, COVID-19 can lead to multisystem inflammatory syndrome in children (MIS-C), a rare but serious condition diagnosed in nearly 10,000 children, resulting in 79 deaths as of May 31, 2023 (2). As in adults, hospitalization is more frequent in unvaccinated versus vaccinated adolescents (3). Additionally, children and adolescents are susceptible to long COVID, and research suggests that people who get a COVID-19 infection after vaccination are less likely to report long COVID, compared to people who are unvaccinated (see CDC: Long COVID or Post-COVID Conditions).

In 1998, Wakefield and colleagues published a brief report in The Lancet that postulated a link between the measles virus in the MMR vaccine and autism and received significant media attention worldwide; many parents began to doubt the safety of the MMR vaccine. This report concerned 12 children with developmental disorders and gastrointestinal (GI) problems; 9 of them also had autism. According to the report, parents claimed that 8 of the 12 children had received the combined MMR vaccine within 1 month before the development of symptoms. Wakefield postulated that the measles virus in the MMR vaccine traveled to the intestine where it caused inflammation, enabling proteins from the GI tract to enter the bloodstream, travel to the brain, and cause autism. In another study, Wakefield claimed to find the measles virus in intestinal biopsy specimens of 75 of 90 children with autism and in only 5 of 70 control patients, leading to speculation that the live measles virus in the MMR vaccine was somehow implicated in autism.

Because Wakefield's methodology could show only a temporal association rather than a cause-and-effect relationship, numerous other researchers studied the possible connection between the MMR vaccine and autism. Gerber and Offit reviewed at least 13 large epidemiologic studies, all of which failed to support an association between MMR vaccine and autism (1). Many of these studies showed that national trends of MMR vaccination were not directly associated with national trends in the diagnosis of autism. For example, in the UK between 1988 and 1999, the rate of MMR vaccination did not change, but the rate of autism increased.

Other studies compared the risk of autism in individual children who did or did not receive the MMR vaccine. In the largest and most compelling of these studies, Madsen et al assessed 537,303 Danish children born between 1991 and 1998, 82% of whom had received MMR vaccine (2). After controlling for possible confounders, they found no difference in relative risk of autism or other autism-spectrum disorders in vaccinated and unvaccinated children. Overall incidence of autism or an autistic-spectrum disorder was 608 of 440,655 (0.138%) in the vaccinated group and 130 of 96,648 (0.135%) in the unvaccinated group. A follow-up study of all children born in Denmark between 1999 and 2010, for a total of 657,461 children concluded that the MMR vaccine does not cause autism (hazard ratio 0.93 [95% CI, 0.85 to 1.02]) overall, nor does it increase the risk in children who are at high risk of autism because of their family history (3). Other population-based studies from across the world have reached similar conclusions.

In response to Wakefield's increased detection of measles virus in intestinal biopsy specimens from autistic children, Hornig et al searched for the measles virus in biopsy samples taken from 38 children who had GI symptoms and were having a colonoscopy; 25 children had autism, and 13 did not (4). The measles virus was not detected more often in the children with autism than in those without.

In 2010, The Lancet fully retracted the 1998 publication based on the findings of the British General Medical Council (5). Three months after The Lancet's retraction, Wakefield was removed from the UK medical register, with a statement regarding his intentional falsification of his research; as a result, he was barred from practicing medicine in the UK.

Despite the overwhelming evidence to support the safety of the MMR vaccines, and the discrediting of Wakefield's research, many parents remain unconvinced. As a result, the United States experienced the largest number of measles cases in 2019 since 1992. According to the Centers for Disease Control and Prevention (CDC), most infected people were not vaccinated (6).

Thimerosal is a mercury compound previously used as a preservative in many multidose vaccine vials; preservatives are not needed in single-dose vials and cannot be used in live-virus vaccines. Thimerosal is metabolized to ethylmercury, which is eliminated quickly from the body. Because environmental methylmercury (which is a different compound that is not eliminated from the body quickly) is toxic to humans, there was concern that the very small amounts of thimerosal used in vaccines might cause neurologic problems, particularly autism, in children. Because of these theoretical concerns, even though no studies had shown evidence of harm, thimerosal was removed from routine childhood vaccines in the United States, Europe, and several other countries by 2001. However, in these countries, small amounts of thimerosal continue to be used in certain influenza vaccines and in several other vaccines intended for use in adults. For information about vaccines that contain low levels of thimerosal in vaccines, see the FDA: Thimerosal and Vaccines. Thimerosal is also used in many vaccines used in resource-poor countries; the World Health Organization (WHO) has not recommended its removal because there is no clinical evidence of toxicity due to routine use.

Despite the removal of thimerosal, rates of autism have continued to increase, strongly suggesting that thimerosal in vaccines does not cause autism. Also, 2 separate Vaccine Safety Datalink (VSD) studies have concluded that there is no association between thimerosal and autism. In a cohort study of 124,170 children in 3 managed care organizations (MCOs), Verstraeten et al found no association between thimerosal and autism or other developmental conditions, although inconsistent associations (ie, seen in one MCO but not another) were seen between thimerosal and certain language disorders (1). In a case-control study of 1000 children (256 with an autism-spectrum disorder and 752 matched controls without autism), Price et al, using regression analysis, found no association between exposure to thimerosal and autism (2).

Health care professionals who work with parents who are still concerned about thimerosal in the influenza vaccine may use single-dose vials of injectable vaccine or the live-attenuated nasal spray vaccine, neither of which contains thimerosal.

A nationally representative survey done in the late 1990s revealed that nearly one fourth of all parents felt that their children receive more immunizations than they should. Since then, additional vaccines have been added to the immunization schedule so that by age 6, children are recommended to receive multiple doses of vaccines for 10 or more infections (see Child and Adolescent Immunization Schedule by Age). To minimize the number of injections and visits, clinicians give many vaccines as combination products (eg, diphtheria-tetanus-pertussis, measles-mumps-rubella). However, some parents have become concerned that children's (particularly infants') immune system cannot handle multiple simultaneously presented antigens. This concern has caused some parents to request alternative immunization schedules that delay and sometimes completely exclude certain vaccines. A 2011 nationally representative survey found that 13% of parents use such a schedule (1).

The use of alternative schedules is risky and scientifically unfounded. The official schedule is designed to protect children against diseases when they are most susceptible. Delaying vaccination increases the amount of time children are at risk of acquiring these diseases. In addition, although parents may plan to only delay vaccination, the increased number of visits needed for alternative schedules increases the difficulty of adherence and thus the risk that children will not receive a full series of vaccines. Regarding the immunologic challenges, parents should be informed that the amount and number of antigens contained in vaccines is miniscule compared with that encountered in everyday life. Even at birth, an infant's immune system is prepared to respond to the hundreds of antigens the infant is exposed to during delivery and being handled by the (unsterile) mother. Children typically encounter and respond immunologically to dozens and perhaps hundreds of antigens during an ordinary day without difficulty. A typical infection with a single organism stimulates an immune response to multiple antigens of that organism (perhaps 4 to 10 in a typical upper respiratory infection). Furthermore, because current vaccines contain fewer antigens overall (ie, because key antigens have been better identified and purified), children are exposed to fewer vaccine antigens today than they were for most of the 20th century.

In summary, alternative vaccine schedules are not evidence-based and put children at increased risk of infectious diseases. More importantly, they offer no advantage. Using data from the VSD, one study compared neurodevelopmental outcomes in a group of children who received all vaccines on time with those who did not (2). The children in the delayed group did not do better on any of the 42 outcomes tested. These results should reassure parents who are concerned that children receive too many vaccines too soon.

The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.

1. U.S. Food and Drug Administration (FDA): Thimerosal and Vaccines