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Introduction   

Individuals, especially caregivers, have many concerns regarding vaccinations, such as “What are vaccines?”, “Are they safe?” and “How are they tested?” Nurses and nurse practitioners are essential in developing vaccine confidence and uptake in vaccine-hesitant individuals. This course discusses immunologic memory, the two main types of vaccines, vaccine myths, and evidence-based communication strategies to encourage vaccine uptake.

Definitions

• Misinformation: False or inaccurate information (1)
• Nucleated: A cell with a nucleus (2)

Overview of the Immune System

This section discusses the immune system, the two subsystems within the immune system, and how the two subsystems work together, ultimately leading to immunologic memory.

The immune system is a complex system of different cells that can identify and eliminate harmful chemicals, pathogens (e.g., bacteria, viruses, fungi), and cancer cells while still recognizing cells and materials that are functioning parts of the body (3). The immune system comprises two subsystems: innate immunity and adaptive immunity.

The innate immune system is non-specific, meaning it will respond to pathogens the same way regardless of the pathogen or number of exposures. It does not remember previous encounters with the same pathogen. The innate system is the body’s first line of defense and quickly responds to a pathogen, usually within 12 hours (4). The innate immune system is divided into the first and second lines. The first line includes physical barriers, including the skin and mucous membranes.

Suppose a pathogen breaches the first line of the innate immune system; the components of the second work to inhibit the infection. The following white blood cells (WBC) are granulocytes and are part of the innate immune system: neutrophils, eosinophils, basophils, and mast cells.

This discussion focuses on neutrophils and mast cells. Neutrophils are the most abundant WBCs and the first to respond to an injury or infection. Neutrophils protect the body by a process called phagocytosis. Phagocytosis is when neutrophils engulf and digest pathogens to destroy them (5). Mast cells contain histamine, a signaling molecule that sends messages between cells. Mast cells are in the skin, mucous membranes, and blood vessels. If a pathogen reaches the second line of defense, mast cells will release histamine, signaling the body to cause inflammation.

Inflammation is a physiologic response to infection. Fever is also a physiologic response to infection. Cytokines and interleukins are endogenous pyrogens, produced within the body, that are released when inflammation occurs. Exogenous pyrogens include bacteria, and viruses, and stimulate endogenous pyrogen production (6). The pyrogens travel through the bloodstream to the hypothalamus, the control center of the autonomic nervous system, which controls body temperature. In the presence of pyrogens, the hypothalamus increases the body’s temperature, leading to fever, which helps fight infection by increasing immune cell function and inhibiting pathogen reproduction (6).

Dendritic cells and monocytes/macrophages are also phagocytic cells and are the connection between the innate and adaptive immune systems because they are antigen-presenting cells (APC). An antigen is a substance that provokes an immune response from the body, including toxins, chemicals, bacteria, viruses, and cancer cells (7). After phagocytosis occurs within dendritic cells and monocytes/macrophages, these cells take the pathogen’s protein and present it on their membrane, activating pathogen-specific lymphocytes (8).

The adaptive immune system is specific, but this requires a more extended period to generate a response, around four to seven days (4,8). The adaptive immune system contains two subsections: the humoral, which produces antibodies, and the cell-mediated, which works directly on the cell. Lymphocytes are white blood cells that are part of the adaptive immune system. In the humoral subsection, the lymphocytes are called B-cells because they mature in the bone marrow. The lymphocytes in the cell-mediated subsection are called T-cells because they mature in the thymus. The two types of T-cells are T-helper (CD4+) and T-cytotoxic (CD8+). B-cells and T-cells are called naive before activation or “priming” by a pathogen.

Major histocompatibility complex (MHC) I receptors are on nucleated cells (4). The MHC I receptors are not APC; however, they carry antigens until they reach a CD8+ cell containing a receptor that matches the specific antigen. This match primes the CD8+ cell, activating clonal expansion, which means the CD8+ can replicate into either memory CD8+ or a cytotoxic CD8+. T-helper (CD4+) cells also undergo clonal expansion through APC containing MHC II receptors, which bind to the CD4+ cells. The binding of the MHC II receptor to the CD4+ primes the cell to differentiate into CD4+ memory cells and cytokine-secreting CD4+ cells. Cytokines signal other immune system components (e.g., natural killer cells, macrophages) to help destroy the pathogen.

The CD4+ cells also signal the naive B-cells of the humoral subsection to select a B-cell with an antibody specific to the antigen. Once the B-cell is selected or “primed,” clonal expansion occurs, which involves the replication of the B-cells into memory B-cells or plasma cells, which are filled with antibodies specific to the specific antigen. The antibodies are released into the bloodstream and bind to the antigen, signaling cytotoxic T-cells and other immune system components to neutralize, opsonize (a form of phagocytosis), and destroy the pathogen (5, 9, 10).

Yes, this is a detailed explanation of the immune system. However, it describes the process of the defining feature of the adaptive immune system—immunologic memory- from the development of memory CD8+ cells, memory CD4+ cells, and memory B-cells. Immunologic memory allows the immune system to respond more efficiently when the body is exposed to the same antigen again, either by natural infection or vaccination (4).

There are two ways to gain immunity: active or passive. Active immunity is achieved when the adaptive immune system overcomes a pathogen by surviving a disease-causing infection or through vaccination. Like natural infection, vaccines contain antigens that stimulate an individual’s immune system to generate an immune response (3). Natural infection generally causes better immunity than vaccines because natural infection generates immunity typically after one infection, whereas immunity with vaccines requires several doses. Immunity from natural infection and vaccines produces long-standing immunity; however, vaccines eliminate the possibility of experiencing infection and potential disease complications (11).

Passive immunity occurs when antibodies or antitoxin produced by one human is transferred to another, offering immediate though temporary immunity. The most common form of passive immunity is antibodies transferred across the placenta to the infant during gestation (3). This transmission of antibodies across the placenta protects infants from certain diseases during the first few months after delivery. Maternal antibodies provide better protection against measles, rubella, and tetanus than they do against polio and pertussis (3).

Classification of Vaccines

The basic types of vaccines are live, attenuated, and inactivated.

Live, attenuated vaccines contain live bacteria or viruses, but the pathogens are attenuated, which means weakened, in a laboratory. The immune system does not detect a significant difference between an infection caused by an attenuated pathogen and a natural infection. The majority of recipients develop immunity with one dose; however, to ensure that a high level of immunity is achieved, a second dose is administered (i.e., a two-dose series for measles, mumps, and rubella [MMR] vaccine) (3).

There is a risk of contracting the disease that the vaccine targets because live, attenuated vaccines can replicate (3, 4). The illness is usually mild, except in immunocompromised individuals, where unchecked replication is possible. Live attenuated vaccines are not recommended in immunocompromised individuals (3).

Inactivated vaccines are not live and cannot replicate, producing an antibody response that is not as robust as the cellular immunity produced by live vaccines (3, 12). An example of this is diphtheria, tetanus, and acellular pertussis (DTaP) vaccine, which is a multidose series in childhood, administered at two months, four months, six months, and boosters at 15-18 months, and 4 – 6 years old (13). The first dose(s) prime the immune system and the following doses provide protective immunity (3). Antibody titers produced by inactivated antigens wane over time. Some inactivated vaccines require doses to increase or “boost” antibody titers, which is why starting at eleven years old, tetanus, diphtheria, and acellular pertussis (Tdap) vaccine is administered and recommended every ten years after that or with each pregnancy (3, 13). The advantages of inactivated vaccines are safer to administer to immunocompromised individuals and less reactogenic, meaning fewer side effects (3, 12).

Vaccine Myths and Facts

Numerous vaccine myths exist. This course divides the myths into the following categories: vaccines are not safe, vaccines are not effective, and the vaccine schedule is aggressive.

Myth: Vaccines are not safe

Fact: The FDA and other entities regulate and monitor vaccine development and manufacturing. Many systems are in place to ensure ongoing efficacy and detect adverse events.

This section addresses vaccine safety, includes information on vaccine development and approval, and the facts addressing specific myths concerning autism, “toxins,” and vaccines causing the disease they are designed to prevent.

In the United States, vaccines are regulated by the Food and Drug Administration’s (FDA) Center for Biologics Evaluation and Research. Because vaccines are administered to generally healthy individuals, vaccine development is held to even higher safety standards (14, 15). Vaccine development and evaluation principles are safety, efficacy, and quality (14).

The earliest stage of vaccine development is research and discovery, which often takes 10-15 years of laboratory research. The research usually happens in the private sector and in collaboration with researchers at a university (15, 16). Several vaccines started as a joint venture between academia and private industry, including a rotavirus vaccine with the Children’s Hospital of Philadelphia and a COVID-19 vaccine with several academic teams, including the National Institutes of Health (15).

During the next stage, proof of concept or preclinical testing, researchers must prove that the vaccine can cause an immune response through animal studies or in vitro testing (15, 16). This phase aims to identify approximate dose(s) and administration routes that are safe and immunogenic in humans and identify any potential toxicology (14). If a vaccine meets safety standards and immunogenicity in preclinical testing, a pre-investigational new drug (IND) meeting is held with the FDA to determine the proposed manufacturing process, the preclinical testing data, and the study design for clinical trials. Most vaccines do not pass preclinical testing for safety concerns or inability to produce a sufficient immune response (15).

If the vaccine passes the IND, it enters the development stage, also known as a clinical trial. This stage consists of three phases and possibly a fourth if the vaccine meets FDA approval. Routine safety evaluations are built into study protocols throughout all clinical trial phases (15). Phase one involves administering the trial vaccine to 20 to 100 trial participants. Researchers collect information on vaccine safety and identify side effects and the immune response. The second phase involves administering the trial vaccine to a larger number group of 100 to 300 trial participants, providing additional safety information on side effects and risks (16).

In phase three, clinical participants increase to 3,000, allowing research to identify less common adverse events and confirm the vaccine’s efficacy. A large sample size allows for a 95% chance of detecting the likelihood of more common adverse events in 1 in 1000 participants (15, 16). Studies in pediatric patients use a stepwise approach to age and dose de-escalation, starting after safety and immunogenicity are determined in adults (15).

Phase four occurs after the FDA licenses (approves) a vaccine for the general population. This phase is a continued formal study to monitor the new vaccine’s safety and effectiveness over a more extended period (16). After licensure, the FDA monitors vaccine manufacturing, including regular manufacturing facility inspections. The Vaccine Adverse Event Reporting System (VAERS) and the Vaccine Safety Datalink (VSD) are other sources used to monitor vaccine safety post licensure.

The CDC uses these two surveillance systems. VAERS is co-managed by the CDC and FDA. VAERS receives and analyzes reports of possible health issues after vaccination, commonly called adverse events. Anyone can submit a VAERS report, including healthcare professionals, vaccine manufacturers, and the general public, making VAERS the frontline national surveillance system (17). Given its national scope, VAERS and its capability to detect rare adverse events make it a sound hypothesis generation system (18). The VSD is a collaboration between the CDC, designated healthcare organizations, and networks within the United States. The VSD gathers information on the vaccine type given to each patient, the date of vaccination, and any other vaccines administered on the same day. The VSD also performs studies on vaccine safety based on any questions or concerns raised in the medical literature or reports to the VAERS (19). Both systems are essential for identifying vaccine adverse events and are of equal importance; the systems aid in determining when there is no actual relationship between a reported event and the vaccine (15).

A myth about vaccine safety developed after two studies concluded that the MMR vaccine caused autism spectrum disorder (ASD). The first study, published in 1998, describes a cascade of events started by the MMR vaccine involving intestinal inflammation and proteins harmful proteins in the brain that lead to autism (20, 21). The researchers collected data on twelve children with intestinal complaints who developed autism within one month of receiving the MMR vaccine. All twelve children had developmental delays, eight of which were diagnosed with ASD.

There were significant issues with the research methodology. It is expected that many children with ASD will receive an MMR vaccine, but the vaccine is administered at an age when many children are diagnosed with ASD. Researching the incidence of autism in both vaccinated and unvaccinated children would better support and refute the hypothesis that the MMR vaccine causes ASD (21). Also, many children developed intestinal symptoms after being diagnosed with autism. A key element in the hypothesis was that intestinal inflammation was part of the cascade causing autism (21).

In 2002, the second study examined the relationship between the measles virus and ASD. The results appear concerning because they showed 75 out of 91 children with ASD had measles virus in intestinal biopsy tissue versus only five of 70 children without ASD had measles virus on intestinal biopsy (21). However, the study design had many flaws. The measles vaccine is a live, attenuated vaccine that activates the adaptive immune system and likely encounters APCs. APCs travel throughout the body, including the intestine.

It is possible that an individual vaccinated with the measles virus would show measles virus in the intestinal tissue (21). The study also did not distinguish whether the measles virus was natural or a vaccine. Methods are available to differentiate between the two (21). More than twenty-five articles published in peer-reviewed medical journals refute the connection between vaccines, specifically MMR, and autism (20). Ultimately, the medical journal retracted the article (20,22).

None of the studies found a causal relationship between childhood vaccines and autism (23). In 2013, the CDC published a study focusing on the number of antigens given during the first two years of life. The data showed that the total amount of antigen received from vaccines was the same between children with ASD and those without (24).

There is also disinformation regarding vaccine ingredients, particularly thimerosal, which has also been studied as a cause of autism (23). Thimerosal is a mercury-based preservative used to prevent pathogens from contaminating multidose vials of vaccines. Individuals may be exposed to two types of mercury, a naturally occurring element found in air, soil, and water (23). The first type is methylmercury, found in certain kinds of fish (e.g., shark, swordfish, and bluefin tuna) (24). Methylmercury is toxic at high exposure levels. However, the United States federal guidelines aim to keep methylmercury out of the environment and food as much as possible. Over an individual’s lifetime, there is some exposure to methylmercury (24).

Thimerosal contains ethylmercury, which is eliminated from the body more quickly than methylmercury, meaning it is less likely to cause harm. Preservatives, like thimerosal, are used in vaccines to prevent contamination of multidose vials of vaccines with bacteria and fungi. The low doses of thimerosal in vaccines may cause minor reactions like redness and swelling at the injection site. Some individuals are allergic to thimerosal. Otherwise, no significant harm is evident based on data from many studies (24).

Since 2003, the Centers for Disease Control and Prevention (CDC) funded or conducted nine studies regarding the safety of thimerosal in vaccines. These studies found no link between thimerosal-containing vaccines and ASD. (23, 25). As of 2001, thimerosal is no longer added to childhood vaccines in the United States to minimize the overall exposure to mercury in children (24). Autism rates continue to rise even after thimerosal is removed from vaccines. The multidose influenza vaccine is the only vaccine that contains thimerosal (24).

Adjuvants, including aluminum salts, help vaccines work better by creating a more robust immune response. Not all vaccines contain an added adjuvant. Live, attenuated vaccines have naturally occurred adjuvants, helping them produce a robust immune response. Most vaccines produced are only portions of the bacteria or virus; these are the inactivated vaccines. An adjuvant is added to ensure a robust immune response to protect individuals from the disease they are vaccinated against (26, 27).

Myth: The effectiveness of vaccines has never been proven.

Fact: Vaccines are highly effective, proven by science and a vaccine history review.

The previous section addressed vaccine development, licensing, and manufacturing. The trial vaccine’s efficacy is measured in each of the four phases of vaccine development. A vaccine’s efficacy measures how much the vaccine lowers the risk of contracting the disease it targets. For example, a trial vaccine has an efficacy of 75%, so the trial participants who received the trial vaccine have a 75% lower risk of contracting the disease than those who received the placebo (27).

Efficacy does not mean the vaccine will only work 75% of the time; it means the risk of contracting the disease is lowered by a specific percentage. Vaccine effectiveness is a measure of how well a vaccine performs in the real world. Vaccine effectiveness is measured by comparing the frequency of health outcomes in vaccinated and unvaccinated individuals. The health outcomes include infection, symptomatic illness, hospitalization, and death (28).

A review of vaccine history highlights and proves the effectiveness of vaccines. In the early 1950s, approximately 50 million smallpox cases occurred annually worldwide. The smallpox vaccine was highly successful. The 33rd World Health Assembly announced the world was smallpox-free on May 8, 1980 (29).

In the 1940s and 1950s, poliomyelitis (polio) killed and paralyzed at least half a million people globally each year. Jonas Salk developed the formalin-inactivated poliovirus vaccine (IPV) in 1953, and Albert Sabin developed the live-attenuated oral poliovirus (OPV) in 1956. The US incidence of paralytic polio decreased from 13.9 cases per 100,000 to 0.8 cases per 100,000 from 1964 to 1961, respectively (29). Polio was eliminated from the United States in 1979 (37).

The universal childhood vaccination, which included the diphtheria toxoid program, significantly impacted diphtheria infection rates. Before the vaccine, 100,000 to 200,000 cases of diphtheria and 13,000 to 15,000 deaths were reported annually during the 1920s. Fourteen cases of diphtheria were reported from 1996 to 2018 (30).

The measles vaccine became available in 1643. Before the vaccine, nearly every child was infected with measles by age 15. Approximately 3 million to 4 million people in the United States are infected with measles annually, including an estimated 400 to 500 deaths, 48,000 hospitalizations, and 1,000 cases of encephalitis. In 2000, endemic measles was declared eliminated in the United States due to a highly effective vaccination program (31).

Another myth impacting the effectiveness of vaccines is that declining to vaccinate oneself or one’s dependent(s) only impacts oneself), not the community at large, leading to problems with herd immunity. Herd immunity is when enough people in a community, the “herd,” are vaccinated or immune from infection, and individuals who have not developed immunity will not get the disease (11). In 2002 Van de Hof et al., published a study that found that unimmunized individuals in a highly immunized community are less likely to experience measles infection than immunized individuals in a community with lower immunization rates (32).

The ability to effectively immunize a community depends on three primary considerations. The first is the contagiousness of the disease. Some diseases are highly contagious, including measles. The second is the effectiveness of the vaccine. No vaccine is 100% effective. Some vaccines require many doses before sufficient immunity develops. Some individuals may not mount an adequate immune response. The third primary consideration is the number of susceptible individuals in the herd, meaning some individuals cannot receive the specific vaccine(s) due to an allergy to the components or are immunocompromised. And other individuals choose to decline vaccination, increasing the number of susceptible individuals (11). Declining vaccines impact more than the individual choosing to not participate in herd immunity.

Myth: The vaccine schedule is too aggressive and should be spaced out.

Fact: The immunization schedule is developed based on medical evidence. Antigen exposure from vaccines is not greater than everyday exposure from a child’s environment.

Early vaccination is essential to prevent diseases, especially in more vulnerable populations such as infants, when they are at the greatest risk of getting sick or dying from the disease. Vaccines are administered in infancy to develop immunity before exposure to a vaccine-preventable disease, including measles, pertussis, rotavirus, pneumococcal, and Haemophilus influenzae, which are associated with higher morbidity and mortality in infants and young children (14). There is concern that the number of antigens in vaccines can overwhelm an infant or young child’s immune system. Even from birth, infants and children are exposed daily to numerous bacteria and viruses—the sources of exposure range from childhood food to environmental and disease exposures (14).

Each vaccine in the childhood vaccination schedule contains one to sixty-nine antigens, totaling 320 antigens administered by the age of two if a child receives all the recommended vaccines (33). When children experience an upper respiratory tract infection, they are exposed to up to ten antigens, and exposure to strep pharyngitis is between 25 and 50 antigens.

Children are exposed to thousands of antigens daily, and an infant’s immune system can manage many immunologic exposures (24,34). In everyday exposures and common childhood illnesses, a significant number of antigen exposures far outnumber the cumulative number of antigens in vaccines.

Approaching Vaccine Misinformation

Several causes or myths contribute to vaccine hesitancy, which is a state of being conflicted about or opposed to getting vaccinated (35). In 2019, the CDC National Immunization Survey found that 20% of caregivers in the United States reported they were “vaccine hesitant” about childhood vaccines (14).

Nurses and nurse practitioners play a crucial role in developing vaccine confidence and ultimately vaccine uptake in vaccine-hesitant individuals. Vaccine confidence is the belief that vaccines are safe, effective, and part of a trustworthy medical system. Vaccine uptake is the receiving the recommended vaccine (14). While it is important for healthcare providers to know and understand facts supporting vaccine safety and effectiveness, it is equally important how those facts are communicated.

The discussion on childhood vaccines should ideally take place at the prenatal visit so expectant caregivers can hear the benefits of vaccines and their safety profile. Previously, primary care providers were the sole trusted source regarding vaccines, today individuals have access to an overwhelming amount of vaccine information and are likely ill-equipped to determine the reliability of a source (35).

There is evidence that some caregivers have already formed an opinion regarding vaccines during the prenatal period, so early vaccine education is encouraged (14). Early discussion regarding vaccines allows for time to address any concerns in vaccine-hesitant individuals.

There is strong evidence of increased vaccine uptake when a healthcare provider takes the presumptive format when discussing vaccines (14). The presumptive format requires the healthcare provider to use a closed-ended statement, in which the provider assumes vaccination (14, 36). For example, “Patient A is due for MMR and influenza vaccine today” or “Today we will vaccinate against tetanus, diphtheria, pertussis, and influenza.”

The effectiveness of the presumptive approach is rooted in choice architecture, which is how a choice is presented. The presumptive approach makes the vaccination the default option, elevating it to the status quo. Most individuals generally avert making a decision that is either already seemingly made or is the status quo (14). A patient or caregiver can still decline vaccination. The presumptive approach does not supersede the right to an individual’s autonomy regarding medical decisions.

Other communication strategies can be employed if an individual or caregiver continues to express vaccine hesitancy after using the presumptive approach. Another evidence-based technique is motivational interviewing (MI). A study published by the Journal of the American Medical Association collected data on Human papillomavirus (HPV) vaccine uptake using the presumptive approach and MI if the caregiver was still vaccine hesitant. Clinicals who utilized the presumptive approach and MI, if needed, found a significant increase in HPV completion in children whose caregivers received the evidence-based communication versus the clinicians who used usual communication (control practice) (37). MI is patient-centered, goal-oriented (i.e. vaccine uptake), and collaborative decision-making.

Motivational interviewing is a skill with four main principles of MI. The first principle is asking open-ended questions or statements to help understand an individual’s or caregiver’s stance on vaccines. Examples: What questions about the DTaP vaccine do you still have after doing your own research? In your opinion, what is the harm if you choose not to vaccinate today? The second principle is to affirm efforts and strengths. This allows the healthcare provider to connect and help the patient or caregiver to feel supported and understood. Example Your concern shows how much you care about your infant’s health. The third principle is reflective listening. This is an important step in MI because it encourages provider-patient/caregiver partnership and guides patients and/or caregivers to understand and reflect on their vaccine decisions more deeply. Example: You’re worried about the presence of aluminum in vaccines.

Motivational interviewing allows the individual to process their (mis)understanding regarding vaccines. Understandably, a healthcare provider feels the need to interrupt or counter any misinformation shared about vaccines, this approach may make the patient or caregiver defensive. It is more effective to ask permission to share what you know as it can make them more receptive. Example: May I share what I know about adjuvants? (14, 36)

The final principle is autonomy support to increase a patient or caregiver’s sense of control. The healthcare provider can also use this time to assess readiness to change. Examples: “Thank you for listening to the information. That said, this is a decision only you can make.” “Thank you for listening to the information. What advantages do you see from vaccines and what worries do you still have? (14,36).

Though this content orders the MI principles, the principles are applied throughout the discussion and more than one may be used as a provider responds and encourages the patient or caregiver to share more.

Implications for Nurses

Nursing is a trusted profession that plays a crucial role in educating patients and caregivers about vaccine safety and effectiveness. Nurses need to have a strong understanding of the interplay between the human immune system and vaccines, as this is crucial in addressing many of the vaccine myths. The presumptive format is not limited to the primary care providers. Nurses should also participate to maximize its effects (14).

Conclusion

Patients and caregivers have access to innumerable resources regarding vaccines. The risk is that the information is inaccurate generating vaccine hesitancy and lack of confidence in vaccine safety and effectiveness. Addressing concerns regarding vaccines with patients and caregivers should focus on evidence-based communication strategies to improve vaccine confidence and vaccine uptake.

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